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The MS Disease Info(Penyakit Pelawak Pepeng)

 

MUSEUM DUNIA MAYA DR IWAN S.

Dr IWAN ‘S CYBERMUSEUM

 THE FIRST INDONESIAN CYBERMUSEUM

  MUSEUM DUNIA MAYA PERTAMA DI INDONESIA

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     PENDIRI DAN PENEMU IDE

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    Dr IWAN SUWANDY, MHA

                     

The Driwan’s  Cybermuseum

special for Mas Pepeng.family and his friend in order to open the diesease mystery

Khusu buat Mas pepeng,family and teman-temannya serta para pengemarnya untuk mengungkap misteri penyakit yang dideritanya

Saya salut atas semangat Mas pepeng yang tetap kreatif walaupun menderita penyakit MS

Multiple sclerosis

 
 
 
Multiple sclerosis
Classification and external resources

Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100
ICD-10 G35
ICD-9 340
OMIM 126200
DiseasesDB 8412
MedlinePlus 000737
eMedicine neuro/228 oph/179 emerg/321 pmr/82 radio/461
MeSH D009103
GeneReviews Multiple Sclerosis Overview

Multiple sclerosis (abbreviated MS, known as disseminated sclerosis or encephalomyelitis disseminata) is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.[1] Disease onset usually occurs in young adults, and it is more common in women.[1] It has a prevalence that ranges between 2 and 150 per 100,000.[2] MS was first described in 1868 by Jean-Martin Charcot.[3]

MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are contained within an insulating substance called myelin. In MS, the body’s own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals.[4] The name multiple sclerosis refers to scars (scleroses—better known as plaques or lesions) particularly in the white matter of the brain and spinal cord, which is mainly composed of myelin.[3] Although much is known about the mechanisms involved in the disease process, the cause remains unknown. Theories include genetics or infections. Different environmental risk factors have also been found.[4][5]

Almost any neurological symptom can appear with the disease, and often progresses to physical and cognitive disability.[4] MS takes several forms, with new symptoms occurring either in discrete attacks (relapsing forms) or slowly accumulating over time (progressive forms).[6] Between attacks, symptoms may go away completely, but permanent neurological problems often occur, especially as the disease advances.[6]

There is no known cure for multiple sclerosis. Treatments attempt to return function after an attack, prevent new attacks, and prevent disability.[4] MS medications can have adverse effects or be poorly tolerated, and many patients pursue alternative treatments, despite the lack of supporting scientific study. The prognosis is difficult to predict; it depends on the subtype of the disease, the individual patient’s disease characteristics, the initial symptoms and the degree of disability the person experiences as time advances.[7] Life expectancy of people with MS is 5 to 10 years lower than that of the unaffected population.[1]

indonesia version

Multiple sclerosis (disingkat MS, yang dikenal sebagai disebarluaskan sclerosis atau encephalomyelitis disseminata) adalah penyakit inflamasi di mana selubung mielin di sekitar akson lemak otak dan sumsum tulang belakang yang rusak, menyebabkan demielinasi dan jaringan parut serta spektrum yang luas dari tanda-tanda dan gejala [1]. Onset penyakit biasanya terjadi pada dewasa muda, dan lebih umum pada perempuan. [1] Ia memiliki prevalensi yang berkisar antara 2 dan 150 per 100.000. [2] MS pertama kali dijelaskan pada 1868 oleh Jean-Martin Charcot [3].

MS mempengaruhi kemampuan sel-sel saraf di otak dan sumsum tulang belakang untuk berkomunikasi satu sama lain secara efektif. Sel saraf berkomunikasi dengan mengirimkan sinyal-sinyal listrik yang disebut potensial aksi turun serat panjang yang disebut akson, yang terkandung dalam zat isolator yang disebut mielin. Pada MS, serangan tubuh sendiri sistem kekebalan tubuh dan kerusakan myelin. Ketika myelin hilang, akson tidak bisa lagi efektif melakukan sinyal. [4] nama multiple sclerosis mengacu pada bekas luka (scleroses-lebih dikenal sebagai plak atau lesi) khususnya dalam masalah putih otak dan sumsum tulang belakang, yang terutama terdiri mielin [3]. Meskipun banyak yang diketahui tentang mekanisme yang terlibat dalam proses penyakit, penyebabnya masih belum diketahui. Teori termasuk genetika atau infeksi. Berbagai faktor risiko lingkungan juga telah ditemukan [4] [5].

Hampir semua gejala neurologis dapat muncul dengan penyakit ini, dan sering berkembang menjadi cacat fisik dan kognitif [4]. MS mengambil beberapa bentuk, dengan gejala baru yang terjadi baik dalam serangan diskrit (kambuh bentuk) atau perlahan-lahan terakumulasi dari waktu ke waktu (bentuk progresif). [ 6] Antara serangan, gejala bisa hilang sepenuhnya, tapi masalah neurologis permanen sering terjadi, terutama karena kemajuan penyakit. [6]

Tidak ada obat dikenal untuk multiple sclerosis. Perawatan upaya untuk kembali berfungsi setelah serangan, mencegah serangan baru, dan mencegah kecacatan [4] MS obat dapat memiliki efek samping atau buruk ditoleransi, dan banyak pasien mengejar pengobatan alternatif,. Meskipun kurangnya mendukung studi ilmiah. Prognosis sulit untuk memprediksi;. Itu tergantung pada subtipe penyakit, karakteristik penyakit pasien individu, gejala awal dan tingkat kecacatan orang mengalami seiring kemajuan zaman [7] Harapan hidup orang dengan MS adalah 5 sampai 10 tahun lebih rendah dari populasi tidak terpengaruh [1].

Contents

 

Classification

Progression of MS subtypes

Several subtypes, or patterns of progression, have been described. Subtypes use the past course of the disease in an attempt to predict the future course. They are important not only for prognosis but also for therapeutic decisions. In 1996 the United States National Multiple Sclerosis Society standardized four subtype definitions:[6]

  1. relapsing remitting,
  2. secondary progressive,
  3. primary progressive, and
  4. progressive relapsing.

The relapsing-remitting subtype is characterized by unpredictable relapses followed by periods of months to years of relative quiet (remission) with no new signs of disease activity. Deficits suffered during attacks may either resolve or leave sequelae, the latter being more common as a function of time.[1] This describes the initial course of 80% of individuals with MS.[1] When deficits always resolve between attacks, this is sometimes referred to as benign MS,[8] although patients will still accrue some degree of disability in the long term.[1] The relapsing-remitting subtype usually begins with a clinically isolated syndrome (CIS). In CIS, a patient has an attack suggestive of demyelination, but does not fulfill the criteria for multiple sclerosis.[1][9] However only 30 to 70% of persons experiencing CIS later develop MS..

indonesia version

Perkembangan subtipe MS

Beberapa subtipe, atau pola perkembangan, telah dijelaskan. Subtipe menggunakan saja masa lalu penyakit dalam upaya untuk memprediksi masa depan saja. Mereka penting tidak hanya untuk prognosis tetapi juga untuk keputusan terapeutik. Pada tahun 1996 Amerika Serikat National Multiple Sclerosis Masyarakat standar empat subtipe definisi: [6]

timbul kambuh,
sekunder progresif,
primer progresif, dan
kambuh progresif.
Subtipe hilang-timbul kambuh ditandai dengan tidak terduga diikuti oleh periode bulan untuk tahun relatif tenang (remisi) dengan tidak ada tanda-tanda aktivitas penyakit baru. Defisit menderita selama serangan baik dapat mengatasi atau meninggalkan gejala sisa, yang terakhir menjadi lebih umum sebagai fungsi waktu [1]. Ini menjelaskan program awal 80% dari individu dengan MS. [1] Ketika defisit selalu menyelesaikan antara serangan, ini kadang-kadang disebut sebagai MS jinak, [8] walaupun pasien masih akan bertambah beberapa derajat kecacatan dalam jangka panjang [1]. subtipe hilang-timbul biasanya dimulai dengan suatu sindrom klinis terisolasi (CIS). Dalam CIS, pasien memiliki serangan sugestif dari demielinasi, tetapi tidak memenuhi kriteria untuk multiple sclerosis. [1] [9] Namun hanya 30 sampai 70% dari orang mengalami CIS kemudian mengembangkan MS

 
 
 
 

Nerve axon with myelin sheath

Secondary progressive MS

Secondary progressive MS (sometimes called “galloping MS”) describes around 65% of those with an initial relapsing-remitting MS, who then begin to have progressive neurologic decline between acute attacks without any definite periods of remission.[1][6] Occasional relapses and minor remissions may appear.[6] The median time between disease onset and conversion from relapsing-remitting to secondary progressive MS is 19 years.[10] The primary progressive subtype describes the approximately 10–15% of individuals who never have remission after their initial MS symptoms.[11] It is characterized by progression of disability from onset, with no, or only occasional and minor, remissions and improvements.[6] The age of onset for the primary progressive subtype is later than for the relapsing-remitting, but similar to mean age of progression between the relapsing-remitting and the secondary progressive. In both cases it is around 40 years of age.[1]

Progressive relapsing MS describes those individuals who, from onset, have a steady neurologic decline but also suffer clear superimposed attacks. This is the least common of all subtypes.[6]

Atypical variants of MS with non-standard behavior have been described; these include Devic’s disease, Balo concentric sclerosis, Schilder’s diffuse sclerosis and Marburg multiple sclerosis. There is debate on whether they are MS variants or different diseases.[12] Multiple sclerosis also behaves differently in children, taking more time to reach the progressive stage.[1] Nevertheless they still reach it at a lower mean age than adults.[1]

indonesia version

Sekunder progresif MS

Sekunder progresif MS (kadang-kadang disebut “berderap MS”) menjelaskan sekitar 65% dari mereka dengan hilang-timbul MS awal, yang kemudian mulai memiliki penurunan neurologis progresif antara serangan akut tanpa periode tertentu remisi [1] [6]. Sesekali kambuh dan remisi kecil mungkin muncul [6] median waktu antara onset penyakit dan konversi dari hilang-timbul ke MS progresif sekunder adalah 19 tahun.. [10] subtipe progresif primer menjelaskan sekitar 10-15% individu yang tidak pernah memiliki pengampunan setelah gejala awal mereka MS [11]. Hal ini ditandai dengan perkembangan cacat dari awal, tanpa, atau hanya sesekali dan ringan, remisi dan perbaikan. [6] usia onset untuk subtipe progresif primer ini kemudian dibandingkan untuk kambuh -timbul, tetapi mirip dengan usia rata-rata perkembangan antara hilang-timbul dan progresif sekunder. Dalam kedua kasus itu adalah sekitar 40 tahun. [1]

MS kambuh Progresif menggambarkan orang-orang yang, dari awal, mengalami penurunan neurologis stabil tapi juga menderita serangan ditumpangkan jelas. Ini adalah yang paling umum dari semua subtipe. [6]

Atipikal varian dari MS dengan non-standar perilaku telah dijelaskan, ini termasuk penyakit Devic itu, Balo konsentris sclerosis, sklerosis menyebar Schilder dan sclerosis multiple Marburg. Ada perdebatan tentang apakah mereka MS varian atau penyakit yang berbeda [12] Multiple sclerosis juga berperilaku berbeda pada anak-anak, mengambil lebih banyak waktu untuk mencapai tahap progresif.. [1] Meskipun demikian mereka masih mencapainya pada usia rata-rata lebih rendah daripada orang dewasa

Signs and symptoms

Main symptoms of multiple sclerosis

A person with MS can suffer almost any neurological symptom or sign, including changes in sensation such as loss of sensitivity or tingling, pricking or numbness (hypoesthesia and paresthesia), muscle weakness, clonus, muscle spasms, or difficulty in moving; difficulties with coordination and balance (ataxia); problems in speech (dysarthria) or swallowing (dysphagia), visual problems (nystagmus, optic neuritis including phosphenes,[13][14] or diplopia), fatigue, acute or chronic pain, and bladder and bowel difficulties.[1] Cognitive impairment of varying degrees and emotional symptoms of depression or unstable mood are also common.[1] Uhthoff’s phenomenon, an exacerbation of extant symptoms due to an exposure to higher than usual ambient temperatures, and Lhermitte’s sign, an electrical sensation that runs down the back when bending the neck, are particularly characteristic of MS although not specific.[1] The main clinical measure of disability progression and symptom severity is the Expanded Disability Status Scale or EDSS.[15]

Symptoms of MS usually appear in episodic acute periods of worsening (called relapses, exacerbations, bouts, attacks, or “flare-ups”), in a gradually progressive deterioration of neurologic function, or in a combination of both.[6] Multiple sclerosis relapses are often unpredictable, occurring without warning and without obvious inciting factors with a rate rarely above one and a half per year.[1] Some attacks, however, are preceded by common triggers. Relapses occur more frequently during spring and summer.[16] Viral infections such as the common cold, influenza, or gastroenteritis increase the risk of relapse.[1] Stress may also trigger an attack.[17] Pregnancy affects the susceptibility to relapse, with a lower relapse rate at each trimester of gestation. During the first few months after delivery, however, the risk of relapse is increased.[1] Overall, pregnancy does not seem to influence long-term disability. Many potential triggers have been examined and found not to influence MS relapse rates. There is no evidence that vaccination and breast feeding,[1] physical trauma,[18] or Uhthoff’s phenomenon[16] are relapse triggers.

 Causes

Most likely MS occurs as a result of some combination of genetic, environmental and infectious factors,[1] and possibly other factors like vascular problems.[19] Epidemiological studies of MS have provided hints on possible causes for the disease. Theories try to combine the known data into plausible explanations, but none has proved definitive.

indonesian version

Gejala Utama multiple sclerosis

Seseorang dengan MS dapat mengalami gejala neurologis hampir semua atau tanda, termasuk perubahan sensasi seperti kehilangan sensitivitas atau kesemutan, menusuk atau mati rasa (hypoesthesia dan paresthesia), kelemahan otot, clonus, kejang otot, atau kesulitan dalam bergerak; kesulitan dengan koordinasi dan keseimbangan (ataksia); masalah dalam pidato (disartria) atau menelan (disfagia), masalah visual (nystagmus, neuritis optik termasuk phosphenes, [13] [14] atau diplopia), nyeri kelelahan, akut atau kronis, dan kandung kemih dan usus kesulitan [1]. gangguan kognitif dari berbagai derajat dan gejala emosional dari depresi atau mood yang tidak stabil juga umum. [1] Uhthoff itu fenomena, eksaserbasi gejala yang masih ada karena eksposur lebih tinggi dari suhu lingkungan biasa, dan menandatangani Lhermitte, sebuah sensasi listrik yang berjalan di belakang ketika menekuk leher, terutama karakteristik dari MS meskipun tidak tertentu [1]. Ukuran klinis utama dari perkembangan dan keparahan gejala kecacatan adalah Skala Cacat Status Expanded atau EDSS. [15]

Gejala biasanya muncul MS dalam periode akut episodik yang memburuk (disebut kambuh, eksaserbasi, pertarungan, serangan, atau “flare-up”), dalam penurunan secara bertahap progresif fungsi neurologis, atau kombinasi keduanya sclerosis [6]. Beberapa kambuh sering tidak terduga, terjadi tanpa peringatan dan tanpa faktor menghasut yang jelas dengan tingkat jarang di atas satu setengah per tahun [1]. Beberapa serangan, bagaimanapun, adalah didahului oleh pemicu umum. Relaps terjadi lebih sering selama musim semi dan musim panas [16]. Infeksi virus seperti pilek, influenza, atau gastroenteritis meningkatkan risiko kambuh [1] Stres juga dapat memicu serangan [17]. Kehamilan mempengaruhi kerentanan terhadap kambuh,. dengan tingkat kekambuhan lebih rendah pada setiap trimester kehamilan. Selama beberapa bulan pertama setelah melahirkan, bagaimanapun, risiko kekambuhan meningkat. [1] Secara keseluruhan, kehamilan tampaknya tidak mempengaruhi kecacatan jangka panjang. Memicu banyak potensi telah diperiksa dan ditemukan tidak mempengaruhi tingkat MS kambuh. Tidak ada bukti bahwa vaksinasi dan menyusui, [1] trauma fisik, [18] atau fenomena Uhthoff itu [16] adalah pemicu kambuh.

 Penyebab
MS paling mungkin terjadi sebagai hasil dari beberapa kombinasi dari faktor genetik, lingkungan dan menular, [1] dan mungkin faktor-faktor lain seperti masalah vaskuler [19]. Studi epidemiologis dari MS telah memberikan petunjuk tentang kemungkinan penyebab penyakit. Teori mencoba untuk menggabungkan data yang dikenal dalam penjelasan yang masuk akal, tetapi tidak ada yang terbukti definitif

Genetics

HLA region of Chromosome 6. Changes in this area increase the probability of suffering MS.

MS is not considered a hereditary disease. However, a number of genetic variations have been shown to increase the risk of developing the disease.[20]

The risk of acquiring MS is higher in relatives of a person with the disease than in the general population, especially in the case of siblings, parents, and children.[4] The disease has an overall familial recurrence rate of 20%.[1] In the case of monozygotic twins, concordance occurs only in about 35% of cases, while it goes down to around 5% in the case of siblings and even lower in half-siblings. This indicates susceptibility is partly polygenically driven.[1][4]

It seems to be more common in some ethnic groups than others.[21]

Apart from familial studies, specific genes have been linked with MS. Differences in the human leukocyte antigen (HLA) system—a group of genes in chromosome 6 that serves as the major histocompatibility complex (MHC) in humans—increase the probability of suffering MS.[1] The most consistent finding is the association between multiple sclerosis and alleles of the MHC defined as DR15 and DQ6.[1] Other loci have shown a protective effect, such as HLA-C554 and HLA-DRB1*11.[1]

Environmental factors

Different environmental factors, both of infectious and non infectious origin have been proposed as risk factors for MS. Although some are partly modifiable, only further research—especially clinical trials—will reveal whether their elimination can help prevent MS.[22]

MS is more common in people who live farther from the equator, although many exceptions exist.[1] Decreased sunlight exposure has been linked with a higher risk of MS.[22] Decreased vitamin D production and intake has been the main biological mechanism used to explain the higher risk among those less exposed to sun.[22][23][24]

Severe stress may also be a risk factor although evidence is weak.[22] Smoking has also been shown to be an independent risk factor for developing MS.[23] Association with occupational exposures and toxins—mainly solvents—has been evaluated, but no clear conclusions have been reached.[22]Vaccinations were also considered as causal factors for the disease; however, most studies show no association between MS and vaccines.[22] Several other possible risk factors, such as diet[25] and hormone intake, have been investigated; however, evidence on their relation with the disease is “sparse and unpersuasive”.[23]

Gout occurs less than would statistically be expected in people with MS, and low levels of uric acid have been found in MS patients as compared to normal individuals. This led to the theory that uric acid protects against MS, although its exact importance remains unknown.[26]

 Infections

Many microbes have been proposed as potential infectious triggers of MS, but none have been substantiated.[4]

Genetic susceptibility can explain some of the geographic and epidemiological variations in MS incidence, like the high incidence of the disease among some families or the risk decline with genetic distance, but does not account for other phenomena, such as the changes in risk that occur with migration at an early age.[5] An explanation for this epidemiological finding could be that some kind of infection, produced by a widespread microbe rather than a rare pathogen, is the origin of the disease.[5] Different hypotheses have elaborated on the mechanism by which this may occur. The hygiene hypothesis proposes that exposure to several infectious agents early in life is protective against MS, the disease being a response to a later encounter with such agents.[1] The prevalence hypothesis proposes that the disease is due to a pathogen more common in regions of high MS prevalence. This pathogen is very common, causing in most individuals an asymptomatic persistent infection. Only in a few cases, and after many years since the original infection, does it cause demyelination.[5][27] The hygiene hypothesis has received more support than the prevalence hypothesis.[5]

Evidence for viruses as a cause includes the presence of oligoclonal bands in the brain and cerebrospinal fluid of most patients, the association of several viruses with human demyelination encephalomyelitis, and induction of demyelination in animals through viral infection.[28] Human herpes viruses are a candidate group of viruses linked to MS. Individuals who have never been infected by the Epstein-Barr virus have a reduced risk of having the disease, and those infected as young adults have a greater risk than those who had it at a younger age.[1][5] Although some consider that this goes against the hygiene hypothesis, since the non-infected have probably experienced a more hygienic upbringing,[5] others believe that there is no contradiction since it is a first encounter at a later moment with the causative virus that is the trigger for the disease.[1] Other diseases that have also been related with MS are measles, mumps and rubella.[1]

Pathophysiology

 Blood-brain barrier breakdown

Demyelination in MS. On Klüver-Barrera myelin staining, decoloration in the area of the lesion can be appreciated (Original scale 1:100).

The blood–brain barrier is a capillary system that should prevent entrance of T cells into the nervous system.[4] The blood–brain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctions forming the barrier.[4] When the blood–brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain.[4]

Autoimmunology

MS is currently believed to be an immune-mediated disorder mediated by a complex interaction of the individual’s genetics and as yet unidentified environmental insults.[4] Damage is believed to be caused by the patient’s own immune system. The immune system attacks the nervous system, possibly as a result of exposure to a molecule with a similar structure to one of its own.[4]

Lesions

The name multiple sclerosis refers to the scars (scleroses – better known as plaques or lesions) that form in the nervous system. MS lesions most commonly involve white matter areas close to the ventricles of the cerebellum, brain stem, basal ganglia and spinal cord; and the optic nerve. The function of white matter cells is to carry signals between grey matter areas, where the processing is done, and the rest of the body. The peripheral nervous system is rarely involved.[4]

More specifically, MS destroys oligodendrocytes, the cells responsible for creating and maintaining a fatty layer—known as the myelin sheath—which helps the neurons carry electrical signals.[4] MS results in a thinning or complete loss of myelin and, as the disease advances, the cutting (transection) of the neuron’s extensions or axons. When the myelin is lost, a neuron can no longer effectively conduct electrical signals.[4] A repair process, called remyelination, takes place in early phases of the disease, but the oligodendrocytes cannot completely rebuild the cell’s myelin sheath.[29] Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons.[29] Different lesion patterns have been described.[30]

Inflammation

Apart from demyelination, the other pathologic hallmark of the disease is inflammation. According to a strictly immunological explanation of MS, the inflammatory process is caused by T cells, a kind of lymphocyte. Lymphocytes are cells that play an important role in the body’s defenses.[4] In MS, T cells gain entry into the brain via the previously described blood–brain barrier. Evidence from animal models also point to a role of B cells in addition to T cells in development of the disease.[31]

The T cells recognize myelin as foreign and attack it as if it were an invading virus. This triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Leaks form in the blood–brain barrier, which in turn cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other destructive proteins.[4]

Diagnosis

T1-weighted MRI scans (post-contrast) of the same brain slice at monthly intervals. Bright spots indicate active lesions.

Multiple sclerosis can be difficult to diagnose since its signs and symptoms may be similar to other medical problems.[1][32] Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process especially in the first stages of the disease.[1] Historically, the Schumacher and Poser criteria were both popular.[33]

Currently, the McDonald criteria focus on a demonstration with clinical, laboratory and radiologic data of the dissemination of MS lesions in time and space for non-invasive MS diagnosis, though some have stated that the only proved diagnosis of MS is autopsy, or occasionally biopsy, where lesions typical of MS can be detected through histopathological techniques.[1][34][35]

Clinical data alone may be sufficient for a diagnosis of MS if an individual has suffered separate episodes of neurologic symptoms characteristic of MS.[34] Since some people seek medical attention after only one attack, other testing may hasten and ease the diagnosis. The most commonly used diagnostic tools are neuroimaging, analysis of cerebrospinal fluid and evoked potentials. Magnetic resonance imaging of the brain and spine shows areas of demyelination (lesions or plaques). Gadolinium can be administered intravenously as a contrast to highlight active plaques and, by elimination, demonstrate the existence of historical lesions not associated with symptoms at the moment of the evaluation.[34][36] Testing of cerebrospinal fluid obtained from a lumbar puncture can provide evidence of chronic inflammation of the central nervous system. The cerebrospinal fluid is tested for oligoclonal bands of IgG on electrophoresis, which are inflammation markers found in 75–85% of people with MS.[34][37] The nervous system of a person with MS responds less actively to stimulation of the optic nerve and sensory nerves due to demyelination of such pathways. These brain responses can be examined using visual and sensory evoked potentials.[38]

Management

Although there is no known cure for multiple sclerosis, several therapies have proven helpful. The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS have several adverse effects. Alternative treatments are pursued by some patients, despite the shortage of supporting, comparable, replicated scientific study.

Acute attacks

During symptomatic attacks, administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the routine therapy for acute relapses.[1] Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[39] Oral and intravenous administration seem to have similar efficacy.[40] Consequences of severe attacks which do not respond to corticosteroids might be treated by plasmapheresis.[1]

Disease-modifying treatments

Disease-modifying treatments are expensive and most of these require frequent (up-to-daily) injections. Others require IV infusions at 1–3 month intervals.

Fingolimod (trade name Gilenya) was approved for MS by the FDA in 2010, and in Europe in 2011. As of 2011[update], after this approval, there are six disease-modifying treatments for MS approved by regulatory agencies of various countries, being the other five: Interferon beta-1a (trade names Avonex, CinnoVex, ReciGen and Rebif) and interferon beta-1b (U.S. trade name Betaseron, in Europe and Japan Betaferon). A third medication is glatiramer acetate (Copaxone), a non-interferon, non-steroidal immunomodulator. The fourth medication, mitoxantrone, is an immunosuppressant also used in cancer chemotherapy. The fifth is a humanized monoclonal antibody immunomodualtor, natalizumab (marketed as Tysabri).[1] The interferons and glatiramer acetate are delivered by frequent injections, varying from once-per-day for glatiramer acetate to once-per-week (but intra-muscular) for Avonex. Natalizumab and mitoxantrone are given by IV infusion at monthly intervals.

All six kinds of medications are modestly effective at decreasing the number of attacks in relapsing-remitting MS (RRMS) while the capacity of interferons and glatiramer acetate is more controversial. Studies of their long-term effects are still lacking.[1][41] Comparisons between immunomodulators (all but mitoxantrone) show that the most effective is natalizumab, both in terms of relapse rate reduction and halting disability progression.[42] Mitoxantrone may be the most effective of them all; however, it is generally not considered as a long-term therapy, as its use is limited by severe secondary effects.[1][41] The earliest clinical presentation of RRMS is the clinically isolated syndrome (CIS). Treatment with interferons during an initial attack can decrease the chance that a patient will develop clinical MS.[1]

Treatment of progressive MS is more difficult than relapsing-remitting MS. Mitoxantrone has shown positive effects in patients with secondary progressive and progressive relapsing courses. It is moderately effective in reducing the progression of the disease and the frequency of relapses in patients in short-term follow-up.[43] No treatment has been proven to modify the course of primary progressive MS.[44]

As with many medical treatments, these treatments have several adverse effects. One of the most common is irritation at the injection site for glatiramer acetate and the interferon treatments. Over time, a visible dent at the injection site, due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons produce symptoms similar to influenza;[45] some patients taking glatiramer experience a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes.[46] More dangerous but much less common are liver damage from interferons,[47] severe cardiotoxicity, infertility, and acute myeloid leukemia of mitoxantrone,[1][41] and the putative link between natalizumab and some cases of progressive multifocal leukoencephalopathy.[1]

Management of the effects of MS

Disease-modifying treatments reduce the progression rate of the disease, but do not stop it. As multiple sclerosis progresses, the symptomatology tends to increase. The disease is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and disability. Management of these deficits is therefore very important. Both drug therapy and neurorehabilitation have shown to ease the burden of some symptoms, though neither influences disease progression.[1][48] Some symptoms have a good response to medication, such as unstable bladder and spasticity, while management of many others is much more complicated.[1] As for any patient with neurologic deficits, a multidisciplinary approach is key to improving quality of life; however, there are particular difficulties in specifying a ‘core team’ because people with MS may need help from almost any health profession or service at some point.[1] Multidisciplinary rehabilitation programs increase activity and participation of patients but do not influence impairment level.[49]

Historically, individuals suffering from MS were advised against participation in physical activity due to worsening symptoms.[50] However, under the direction of a physiotherapist, participation in physical activity can be safe and has been proven beneficial for patients with MS.[51] Research has supported the rehabilitative role of physical activity in improving muscle power,[52] mobility,[52] mood,[53] bowel health,[54] general conditioning and quality of life.[52] However, it is important to be cautious about not overworking or overheating the patient during the course of exercise. Physiotherapists have the expertise needed to adequately prescribe exercise programs that are suitable for the individual. The FITT equation (frequency of exercise, intensity of exercise, type of exercise and time/duration of exercise) is typically used to prescribe exercises.[51] Depending on the patient, activities may include resistance training,[55] walking, swimming, yoga, tai chi, and others.[54] Determining an appropriate and safe exercise program is challenging and must be carefully individualized to each patient being sure to account for all contraindications and precautions.[51]

 Alternative treatments

As with most chronic diseases, alternative treatments for multiple sclerosis, which are unsupported by clinical or scientific evidence, are pursued by some patients.[56] Examples are a dietary regimen,[57] herbal medicine (including the use of medical cannabis),[58] hyperbaric oxygenation[59] and self-infection with hookworm (known generally as helminthic therapy).[60]

 Prognosis

Disability-adjusted life yearfor multiple sclerosis per 100,000 inhabitants in 2004

  no data
  less than 13
  13–16
  16–19
  19–22
  22–25
  25–28
  28–31
  31–34
  34–37
  37–40
  40–43
  more than 43

The prognosis (the expected future course of the disease) for a person with multiple sclerosis depends on the subtype of the disease; the individual’s sex, age, and initial symptoms; and the degree of disability the person experiences.[7] The disease evolves and advances over decades, 30 being the mean years to death since onset.[1]

Female sex, relapsing-remitting subtype, optic neuritis or sensory symptoms at onset, few attacks in the initial years and especially early age at onset, are associated with a better course.[7][61]

The life expectancy of people with MS is 5 to 10 years lower than that of unaffected people.[1] Almost 40% of patients reach the seventh decade of life.[61] Nevertheless, two-thirds of the deaths in people with MS are directly related to the consequences of the disease.[1] Suicide also has a higher prevalence than in the healthy population, while infections and complications are especially hazardous for the more disabled ones.[1]

Although most patients lose the ability to walk prior to death, 90% are still capable of independent walking at 10 years from onset, and 75% at 15 years.[61][62]

Epidemiology

Ethnic groups such as the Sami have a lower incidence of MS, possibly due to genetic factors.

Two main measures are used in epidemiological studies: incidence and prevalence. Incidence is the number of new cases per unit of person–time at risk (usually number of new cases per thousand person–years); while prevalence is the total number of cases of the disease in the population at a given time. Prevalence is known to depend not only on incidence, but also on survival rate and migrations of affected people. MS has a prevalence that ranges between 2 and 150 per 100,000 depending on the country or specific population.[2] Studies on populational and geographical patterns of epidemiological measures have been very common in MS,[27] and have led to the proposal of different etiological (causal) theories.[5][22][23][27]

MS usually appears in adults in their thirties but it can also appear in children.[1] The primary progressive subtype is more common in people in their fifties.[11] As with many autoimmune disorders, the disease is more common in women, and the trend may be increasing.[1][63] In children, the sex ratio difference is higher,[1] while in people over fifty, MS affects males and females almost equally.[11]

There is a north-to-south gradient in the northern hemisphere and a south-to-north gradient in the southern hemisphere, with MS being much less common in people living near the equator.[1][63] Climate, sunlight and intake of vitamin D have been investigated as possible causes of the disease that could explain this latitude gradient.[23] However, there are important exceptions to the north–south pattern and changes in prevalence rates over time;[1] in general, this trend might be disappearing.[63] This indicates that other factors such as environment or genetics have to be taken into account to explain the origin of MS.[1] MS is also more common in regions with northern Europe populations.[1] But even in regions where MS is common, some ethnic groups are at low risk of developing the disease, including the Samis, Turkmen, Amerindians, Canadian Hutterites, Africans, and New Zealand Māori.[64]

Environmental factors during childhood may play an important role in the development of MS later in life. Several studies of migrants show that if migration occurs before the age of 15, the migrant acquires the new region’s susceptibility to MS. If migration takes place after age 15, the migrant retains the susceptibility of his home country.[1][22] However, the age–geographical risk for developing multiple sclerosis may span a larger timescale.[1] A relationship between season of birth and MS has also been found which lends support to an association with sunlight and vitamin D. For example fewer people with MS are born in November as compared to May.[65]

 History

Medical discovery

Detail of drawing from Carswell book depicting MS lesions in the brain stem and spinal cord (1838)

The French neurologist Jean-Martin Charcot (1825–1893) was the first person to recognize multiple sclerosis as a distinct disease in 1868.[66] Summarizing previous reports and adding his own clinical and pathological observations, Charcot called the disease sclerose en plaques. The three signs of MS now known as Charcot’s triad 1 are nystagmus, intention tremor, and telegraphic speech, though these are not unique to MS. Charcot also observed cognition changes, describing his patients as having a “marked enfeeblement of the memory” and “conceptions that formed slowly”.[3]

Prior to Charcot, Robert Carswell (1793–1857), a British professor of pathology, and Jean Cruveilhier (1791–1873), a French professor of pathologic anatomy, had described and illustrated many of the disease’s clinical details, but did not identify it as a separate disease.[66] Specifically, Carswell described the injuries he found as “a remarkable lesion of the spinal cord accompanied with atrophy”.[1] Under the microscope, Swiss pathologist Georg Eduard Rindfleisch (1836–1908) noted in 1863 that the inflammation-associated lesions were distributed around blood vessels.[67][68]

After Charcot’s description, Eugène Devic (1858–1930), Jozsef Balo (1895–1979), Paul Ferdinand Schilder (1886–1940), and Otto Marburg (1874–1948) described special cases of the disease. During all the 20th century there was an important development on the theories about the cause and pathogenesis of MS while efficacious treatments began to appear in 1990.[1]

 Historical cases

There are several historical accounts of people who lived before or shortly after the disease was described by Charcot and probably had MS.

1.Halidora

A young woman called Halldora, who lived in iceland around 1200, suddenly lost her vision and mobility, but after praying to the saints, recovered them seven days after.

Saint Lidwina of Schiedam (1380–1433),

 a Dutch nun, may be one of the first clearly identifiable MS patients. From the age of 16 until her death at 53, she suffered intermittent pain, weakness of the legs, and vision loss—symptoms typical of MS.[69] Both cases have led to the proposal of a ‘Viking gene’ hypothesis for the dissemination of the disease.[70]

3.Augustus Frederick d’Este (1794–1848),

son of Prince Augustus Frederick, Duke of Sussex and Lady Augusta Murray and the grandson of George III of the United Kingdom, almost certainly suffered from MS. D’Este left a detailed diary describing his 22 years living with the disease. His diary began in 1822 and ended in 1846, although it remained unknown until 1948. His symptoms began at age 28 with a sudden transient visual loss (amaurosis fugax) after the funeral of a friend. During the course of his disease, he developed weakness of the legs, clumsiness of the hands, numbness, dizziness, bladder disturbances, and erectile dysfunction. In 1844, he began to use a wheelchair. Despite his illness, he kept an optimistic view of life.[71][72]

4.WNP Barbelion

Another early account of MS was kept by the British diarist W. N. P. Barbellion, nom-de-plume of Bruce Frederick Cummings (1889–1919), who maintained a detailed log of his diagnosis and struggle with MS.[72] His diary was published in 1919 as The Journal of a Disappointed Man.[73]

5.Indonesian Artist Pepeng

 

Stay in the Hospital Comforts Pepeng

- Ferrasta Soebardi alias Pepeng did not give up.
His passion to entertain, work, and science menutuntut never extinguished, although the disease Multiple gnawing Scleorosis since March 2005.
The house is located dipertemuan Pepeng two watershed, precisely at the very back corner of the Earth Heritage Complex Cinere, Depok, a lot changed. Not only that, his hobby of hanging out in pengkolan also never again dilakoninya. Now dive into the life he learned from the bed where he lay suffering from the disease. “Many consider me sick because of the location of this house. I do not believe it. I am more afraid of thieves than a ghost, “joke.
The proof, every day something came to my house Pepeng. Not to put a sense of pity, but instead draw from the life sciences Pepeng.
It has been over five years Pepeng friends with Scleorosis Multiple disease (MS). Rare disease that makes the sufferer paralyzed. Even at a specific stage of the autonomic nervous taxable, the brain can go wrong command.
However, the disease which attacked him did not make Pepeng stop ‘ngebanyol’. Although the actions that had to do with his group, Sergeant Geronimo ‘, currently only done while lying in bed. Pepeng obstinacy, in addition to fighting the disease, also encouraged a love that never faded from his beloved wife, Siti Aishah Mariam Utami. “Love it makes my life as it is now,” said Pepeng when met recently.
Not just trying to make a living, in the midst of the struggle against diseases, remains persistent Pepeng studying to reach his goal earned a Bachelor Two (S2) in Post Graduate, Faculty of Psychology, University of Indonesia. Master’s degree in the field of Social Psychology Interventions achieved with the predicate ‘cum laude’ in 2006.
Not quite just that, Pepeng also berancana continuing education to a doctorate (S3). Pepeng spirit is once again showing and proving that the conditions of her condition at this time does not become an obstacle to academic achievement. “Hopefully I can reach S3,” said Pepeng vigorously.

Got a ‘wife’ New

Pepeng first glance seemed helpless because the condition can only lie in bed and wheelchair. However, the same conditions which made him even more excited to have a ‘wife’ new. Thus, his days are never quiet from a busy work ‘wife’ a new form of a laptop which he uses to develop his new business, sell the domain.
Even according to his wife, Utami, new activities Pepeng with his laptop had become like his own wife. “Wake up he immediately held a ‘wife’ new and can take hours. If I only ‘wife’ second. His new wife, yes the laptop, “explains Utami. With the same tool Pepeng working on a book about his life that was nearly completed, he added.
Indeed Pepeng illness, can no longer make a career in the performing and entertainment presenter. However, he would still be a man who is fortunate to have a pious wife. So Pepeng remains strong and able to meet the needs of families by performing a number of activities such as Moslem received stitches in his home.
In diseased condition, Pepeng also able to send their children to college broadcast in the neighbor country, Malaysia. “Honestly, almost Mamas education is hampered due to lack of fees. However, before the tuition payment deadline, some colleagues came to see her deliver the fees and others. With the money, eventually Mamas could continue his studies again. All this because God intervened, “he said.

Want Not Lost Meaning of Life

Pepeng also revealed exposures of MS disease-fighting spirit that attacked since last five years. “I can only pray and most importantly, the spirit should not be extinguished. I maker crowd. My prayer when the first pain is not to lonely because of my behavior. I know, all diseases are created at once with the medicine. Hopefully I still miss the cure, “jokes the father of Mamas, Mio, Lalo, and Izra it.
Once convicted of MS disease, Pepeng space is very limited. His days were spent more in the bedroom. From the bedroom, too, Pepeng work. Every Tuesday from morning until evening, Pepeng shooting for the show program ‘Meet Pepeng’ from her bedroom.
In the bedroom newly renovated it, Pepeng also receive his guests. He never refused to those who want to visit. An acquaintance of the Facebook social networking account, for example, comes with 100 colleagues sekantornya invites. There was absolutely no privacy in the home space Pepeng and he only comes once limited to 30 guests still have some breathing room in a room measuring 6 x 7 meters.
Madura typical joke has always been a fresh distraction while talking with the guests. However, every speech, Pepeng bombarded true pain. Because the jokes fresh and warm greeting, the other person often forget that Pepeng was ill. Pepeng actually able to spread the spirit of life and the laptop remains the flagship for a relationship with the outside world. O ato

BIODATA Pepeng
Birth name: Ferrasta Soebardi
Date of Birth: 23 September 1954)
Place of Birth: Sumenep, Madura, Indonesia
Wife: Siti Aishah Mariam Utami
Children: Mamas, Mio, Lalo, and Izra
Occupation: Presenter, actor, writer
Years active: 1978 – present
Education: Graduate School of Psychology, University of Indonesia, majoring in Psychology of Social Intervention, passed August 4, 2006 with a very satisfactory value (A).
Which movie Starring: Rojali and Juleha (1979), Win-Delicious (1986), and his goods You (1986).
Work Experience: Employee Bank Pinaesaan (1988) and Bakrie Brothers (1989)

 
 
Ferrasta “Pepeng” Soebardi: “I’m Just Waiting for God’s Promise”
Rarely found who are grateful when wracked exam. Ferrasta Soebardi or better known as Pepeng is the one who bit it. In the middle of exams in the form of chronic pain that he could still smile and prejudice either to God.

Pepeng bersama istri tercinta

As is known, since five years ago, convicted Pepeng rare disease Multiple Sclerosis (MS), which is a disease that attacks the central nervous system and bring the process of inflammation (inflammation) of the spine. This disease will interfere with the delivery of “messages” between the brain and other body parts.
 

MS disease who suffered a former presenter of this famous cause paralysis and every moment felt incredible pain from waist to toe. How sakitkah? “As diketok mallet finger. But pain is not the time diketok, but after diketok. Carried away, carried away, carried away, “said Pepeng.

Pepeng sure there is wisdom behind a disease that God gives. He did not want depression and dissolve by this ordeal. This he proved by staying productive activity, although lived in the bed.

Pepeng admitted it when he gets sick a lot. Earned a master psychologist, for example. Even more closely interwoven friendship and wide when he was sick. Pepeng house almost every day on Earth Heritage Cinere guests visited Depok West Java, whether known or not. Not infrequently, many guests are enlightened after visiting the house Pepeng.

Middle of last month, Ahmad Damanik, Dadang Kusmayadi, Ibn Intercession, Saiful Hamiwanto, and Surya Fachrizal of Sound Hidayatullah visit to the residence Pepeng. This visit is solely for the interview, but also in the framework of friendship.

In the rooms there are many patches of paper testimonials from the guests, told the magazine Pepeng share stories of perseverance to face the disease

original info

Dalam Sakit Pepeng Tetap Menghibur

- Ferrasta Soebardi alias Pepeng tak menyerah.
Semangatnya untuk menghibur, berkarya, dan menutuntut ilmu tak pernah padam, walau penyakit Multiple Scleorosis menggerogotinya sejak Maret 2005.Rumah Pepeng yang terletak dipertemuan dua aliran sungai, persisnya di pojok paling belakang Kompleks Bumi Pusaka Cinere, Depok, banyak berubah. Tidak hanya itu, hobinya nongkrong di pengkolan juga tak pernah lagi dilakoninya. Kini dia belajar menyelami kehidupan dari atas ranjang tempatnya terbaring sejak menderita penyakit. “Banyak yang menganggap saya sakit karena lokasi rumah ini. Saya nggak percaya. Saya lebih takut maling daripada hantu,” kelakarnya.
Buktinya, setiap hari selalu ada saja yang datang ke rumah Pepeng. Bukan untuk menaruh rasa iba, tapi justru menimba ilmu hidup dari Pepeng.
Sudah lebih lima tahun Pepeng berteman akrab dengan penyakit Multiple Scleorosis (MS). Penyakit langka itu membuat penderitanya lumpuh. Bahkan pada stadium tertentu syaraf otonom kena, otak bisa salah perintah.
Namun, penyakit yang menyerangnya tak membuat Pepeng berhenti ‘ngebanyol’. Meskipun aksi-aksi yang dulu dilakukannya bersama grupnya, Sersan Prambors’, saat ini hanya dilakukannya sambil berbaring di tempat tidur. Ketegaran Pepeng, selain untuk melawan penyakitnya, juga didorong cinta kasih yang tak pupus dari istri tercintanya, Utami Mariam Siti Aisyah. “Cinta itu membuat saya hidup seperti sekarang,” kata Pepeng saat ditemui baru-baru ini. 
Tidak hanya berusaha mencari nafkah, di tengah perjuangan melawan penyakit, Pepeng tetap gigih menuntut ilmu untuk mewujudkan cita-citanya meraih gelar Strata Dua (S2) di  Pasca Sarjana, Fakultas Psikologi, Universitas Indonesia. Gelar master  dibidang Psikologi Intervensi Sosial diraihnya dengan predikat ‘cumlaude’ pada 2006 silam.
Tidak cukup hanya itu, Pepeng juga berancana melanjutkan pendidikan hingga meraih gelar doktor (S3). Semangat Pepeng ini sekaligus menunjukkan dan membuktikan bahwa kondisi yang kondisi yang dialaminya saat ini tidak menjadi kendala untuk mengukir prestasi akademik. “Mudah-mudahan saya mampu meraih S3,” ungkap Pepeng penuh semangat.Punya ‘Istri’ BaruSepintas Pepeng tampak tak berdaya karena kondisinya yang hanya bisa terbaring di tempat tidur dan kursi roda. Namun, kondisi itu pula yang membuatnya semakin bersemangat hingga memiliki ‘istri’ baru. Sehingga, hari-harinya tak pernah sepi dari kesibukan mengerjakan ‘istri’ baru berupa laptop yang digunakannya untuk mengembangkannya bisnis barunya, menjual domain.
Bahkan menurut istrinya, Utami, kegiatan baru Pepeng bersama laptopnya sudah dijadikan layaknya istri sendiri. “Bangun tidur dia langsung megang ‘istri’ barunya dan bisa berjam-jam. Kalau saya cuma ‘istri’ kedua. Istri barunya, ya laptop,” jelas Utami. Dengan alat itu pula Pepeng menggarap buku tentang kehidupannya yang sudah hampir rampung, tambahnya.
Memang penyakit yang diderita Pepeng, membuatnya tak bisa lagi tampil berkarir di dunia presenter dan entertainment. Namun, dia tetap masih menjadi seorang pria yang beruntung karena memiliki istri yang soleh. Sehingga Pepeng tetap tegar dan mampu memenuhi kebutuhan keluarga dengan melakukan sejumlah  kegiatan seperti menerima jahitan busana muslim di rumahnya.
Dalam kondisi sakit, Pepeng juga mampu menyekolahkan anaknya kuliah broadcast di negeri Jiran, Malaysia. “Jujur saja, pendidikan Mamas nyaris terhambat karena ketiadaan biaya. Namun, sebelum batas waktu pembayaran kuliah, beberapa rekan datang menjenguk sambil mengantarkan honor dan lain-lainnya. Dengan uang itu, akhirnya Mamas bisa melanjutkan kuliahnya kembali. Semua ini karena turut campur tangan Allah,” ungkapnya.Tak Mau Kehilangan Makna HidupPepeng juga mengungkapkan, ikhwal semangatnya melawan penyakit MS yang menyerangnya sejak lima tahun terakhir. “Saya hanya bisa berdoa dan yang paling penting, semangat tidak boleh padam. Saya pembuat keramaian. Doa saya ketika pertama sakit adalah jangan sampai kesepian karena perilaku saya.  Saya tahu, semua penyakit diciptakan sekaligus dengan obatnya. Mudah-mudahan saya masih kebagian obatnya,” kelakar ayah dari Mamas, Mio, Lalo, dan Izra itu.
Setelah divonis penyakit MS, ruang gerak Pepeng memang sangat terbatas. Hari-harinya lebih banyak dihabiskan di kamar tidur. Dari kamar tidur itu pula, Pepeng bekerja. Tiap Selasa sejak pagi hingga petang, Pepeng melakukan pengambilan gambar untuk program acara ‘Ketemu Pepeng’ dari ruang tidurnya.
Di kamar tidur yang baru direnovasi itu, Pepeng juga menerima tamu-tamunya. Dia tak pernah menolak orang-orang yang ingin bertandang. Seorang kenalan dari akun jejaring sosial Facebook, misalnya, datang dengan mengajak 100 rekan sekantornya. Sama sekali tak ada ruang privasi di rumah Pepeng dan dia hanya membatasi 30 tamu sekali datang agar tetap punya ruang bernapas di kamar berukuran 6 x 7 meter itu.
Guyonan khas Madura selalu menjadi selingan segar ketika berbincang dengan para tamu. Tetapi, setiap berbicara, Pepeng sejatinya dihujani rasa sakit. Karena guyonan segar dan sapaan hangatnya, lawan bicara sering lupa bahwa Pepeng sedang sakit. Pepeng justru mampu menebar semangat hidup dan laptop tetap menjadi andalannya untuk menjalin hubungan dengan dunia luar. O atoBIODATA PEPENG
Nama lahir        : Ferrasta Soebardi
Tanggal Lahir    : 23 September 1954)
Tempat Lahir    : Sumenep, Madura, Indonesia
Istri                : Utami Mariam Siti Aisyah
Anak            : Mamas, Mio, Lalo, dan Izra
Pekerjaan         : Presenter, aktor, penulis
Tahun aktif         : 1978 – sekarang
Pendidikan        : Pasca Sarjana Fakultas Psikologi Universitas Indonesia, jurusan Psikologi Intervensi Sosial, lulus 4 Agustus 2006 dengan nilai sangat memuaskan (A).
Film Yang Dibintangi: Rojali dan Juleha (1979), Sama-Sama Enak (1986), dan Anunya Kamu (1986).
Pengalaman Kerja:  Pegawai Bank Pinaesaan (1988) dan Bakrie Brothers (1989)
 
 
 

Ferrasta “Pepeng” Soebardi:“Saya Tinggal Menunggu Janji Allah” 

Jarang sekali ditemukan orang yang bersyukur ketika didera ujian. Ferrasta Soebardi atau lebih dikenal dengan Pepeng adalah orang yang sedikit itu. Di tengah ujian berupa sakit yang menahun ia masih bisa tersenyum dan berprasangka baik kepada Allah.

Pepeng bersama istri tercinta 

Seperti diketahui,  sejak lima tahun silam, Pepeng divonis penyakit langka  Multiple Sclerosis (MS-red), yakni sebuah penyakit yang menyerang sistem saraf pusat dan memunculkan terjadinya proses inflamasi(peradangan) pada tulang belakang. Penyakit ini akan mengganggu penyampaian “pesan” antara otak dan bagian-bagian tubuh lainnya.

 

Penyakit MS yang dideritanya menyebabkan mantan presenter kondang ini mengalami kelumpuhan dan setiap saat merasakan nyeri yang luar biasa dari pinggang hingga ujung kaki. Seberapa sakitkah? “Seperti jari diketok palu. Tapi nyerinya bukan saat diketok, tapi setelah diketok. Nyut, nyut,nyut,” kata Pepeng.

Pepeng yakin ada hikmah di balik penyakit yang Allah berikan. Ia tak ingin depresi dan larut oleh penderitaan yang dialaminya ini. Ini ia buktikan dengan tetap melakukan aktivitas yang produktif, meski dijalani di atas tempat tidur.

Pepeng mengaku justru saat sakit ia mendapatkan banyak hal. Memperoleh gelar master psikolog, misalnya. Jalinan pertemanannya pun semakin erat dan luas saat ia sakit. Hampir setiap harinya rumah Pepeng di Bumi Pusaka Cinere Depok Jawa Barat dikunjungi tamu, baik yang dikenal maupun yang tidak. Tak jarang banyak tamu yang tercerahkan setelah berkunjung ke rumah Pepeng.

Pertengahan bulan lalu, Ahmad Damanik, Dadang Kusmayadi, Ibnu Syafaat, Saiful Hamiwanto, dan Surya Fachrizal dari Suara Hidayatullah berkunjung ke kediaman Pepeng. Kunjungan kali ini tidak semata-mata untuk wawancara, tapi juga dalam rangka silaturahim.

Di dalam kamarnya yang terdapat banyak tempelan kertas testimoni dari para tamu itu, kepada majalah ini Pepeng berbagi kisah tentang ketabahannya menghadapi penyakit.

Research directions

 

 Therapies

Chemical structure of alemtuzumab

Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.[74] A number of treatments that may curtail attacks or improve function are under investigation. Emerging agents for RRMS that have shown promise in phase 2 trials include alemtuzumab (trade name Campath), daclizumab (trade name Zenapax), rituximab, dirucotide, BHT-3009, cladribine, dimethyl fumarate, estriol, fingolimod, laquinimod, minocycline, statins, temsirolimus and teriflunomide.[74]

In 2010, an FDA committee recommended approving fingolimod for the treatment of MS attacks,[75] and on September 22, 2010, fingolimod (trade name Gilenya) became the first oral drug approved by the Food and Drug Administration to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis.[76] Clinical trials of fingolimod have demonstrated side effects in treated patients, including cardiovascular conditions, macular edema, infections, liver toxicity and malignancies.[77][78]

Much interest has been focused on the prospect of utilizing vitamin D analogs in the prevention and management of CIS and MS, especially given its possible role in the pathogenesis of the disease. While there is anecdotal evidence of benefit for low dose naltrexone,[79] only results from a pilot study in primary progressive MS have been published.[80]

Disease biomarkers

The variable clinical presentation of MS and the lack of diagnostic laboratory tests lead to delays in diagnosis and the impossibility of predicting diagnosis. New diagnostic methods are being investigated. These include work with anti-myelin antibodies, analysis of microarray gene expression and studies with serum and cerebrospinal fluid but none of them has yielded reliable positive results.[81]

Currently there are no clinically established laboratory investigations available that can predict prognosis. However, several promising approaches have been proposed. Investigations on the prediction of evolution have centered on monitoring disease activity. Disease activation biomarkers include interleukin-6, nitric oxide and nitric oxide synthase, osteopontin, and fetuin-A.[81] On the other hand since disease progression is the result of neurodegeneration the roles of proteins indicative of neuronal, axonal, and glial loss such as neurofilaments, tau and N-acetylaspartate are under investigation.[81]

A final investigative field is work with biomarkers that distinguish between medication responders and nonresponders.[81]

Chronic cerebrospinal venous insufficiency

In 2008, Italian vascular surgeon Paolo Zamboni reported research suggesting that MS involves a vascular disease process he referred to as chronic cerebrospinal venous insufficiency (CCSVI, CCVI), in which veins from the brain are constricted. He found CCSVI in the majority of MS patients, performed a surgical procedure to correct it and claimed that 73% of patients improved.[82] Concern has been raised with Zamboni’s research as it was neither blinded nor controlled[83] and further studies have had variable results.[84] This has raised serious objections to the hypothesis of CCSVI originating multiple sclerosis.[85] The neurology community currently recommends not to use the proposed treatment until its effectiveness is confirmed by controlled studies, the need for which has been recognized by the scientific bodies engaged in MS research

the end @ copyright Dr iwan suwandy 2011

The Differentiation Between Benign and Malignant Hiperthrophy Prostate Informations

MUSEUM DUNIA MAYA DR IWAN S.

Dr IWAN ‘S CYBERMUSEUM

 THE FIRST INDONESIAN CYBERMUSEUM

  MUSEUM DUNIA MAYA PERTAMA DI INDONESIA

   DALAM PROSES UNTUK MENDAPATKAN SERTIFIKAT MURI

     PENDIRI DAN PENEMU IDE

      THE FOUNDER

    Dr IWAN SUWANDY, MHA

                     

The Driwan’s  Cybermuseum

HYPERTHROPHY P[ROSTATE

PART ONE BENIGN HIPRERPLASIA PROSTATE

Benign prostatic hyperplasia

(BPH)

 
 
Benign prostatic hyperplasia
Classification and external resources

Diagram illustrating normal prostate (left) and benign prostatic hyperplasia (right).
ICD-10 N40
ICD-9 600
DiseasesDB 10797
eMedicine med/1919
MeSH D011470

Benign prostatic hyperplasia (BPH) also known as benign prostatic hypertrophy (technically a misnomer), benign enlargement of the prostate (BEP), and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate.

Properly, BPH involves hyperplasia rather than hypertrophy, but the nomenclature is often interchangeable, even amongst urologists.[1] It involves hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. When sufficiently large, the nodules compress the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra, which interferes with the normal flow of urine. It leads to symptoms of urinary hesitancy, frequent urination, dysuria (painful urination), increased risk of urinary tract infections, and urinary retention. Although prostate specific antigen levels may be elevated in these patients because of increased organ volume and inflammation due to urinary tract infections, BPH is not considered to be a premalignant lesion.

Adenomatous prostatic growth is believed to begin at approximately age 30 years. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. In 40-50% of these patients, BPH becomes clinically significant.[2]

Contents

Signs and symptoms

Benign prostatic hyperplasia symptoms are classified as storage or voiding.

Storage symptoms include urinary frequency, urgency (compelling need to void that cannot be deferred), urgency incontinence, and voiding at night (nocturia).

Voiding symptoms include urinary stream, hesitancy (needing to wait for the stream to begin), intermittency (when the stream starts and stops intermittently), straining to void, and dribbling. Pain and dysuria are usually not present. These storage and voiding symptoms are evaluated using the International Prostate Symptom Score (IPSS) questionnaire, designed to assess the severity of BPH.[3]

BPH can be a progressive disease, especially if left untreated. Incomplete voiding results in stasis of bacteria in the bladder residue and an increased risk of urinary tract infection. Urinary bladder stones are formed from the crystallization of salts in the residual urine. Urinary retention, termed acute or chronic, is another form of progression. Acute urinary retention is the inability to void, while in chronic urinary retention the residual urinary volume gradually increases, and the bladder distends. Some patients that suffer from chronic urinary retention may eventually progress to renal failure, a condition termed obstructive uropathy.

Cause

A study published in 2008 in the journal of andrology “Andrologia”[4] reports on a newly discovered venous route by which free (active) testosterone reaches the prostate in extremely high concentrations, promoting the accelerated proliferation of prostate cells, leading to the gland’s enlargement. The study (conducted by two Israeli doctors: Dr. Yigal Gat and Dr. Menachem Goren) suggests that BPH is caused by malfunction of the valves in the internal spermatic veins manifesting as varicocele, a phenomenon which has been shown to increase rapidly with age,[5][6] roughly equal to 10-15% each decade of life. The 6- to 8-fold elevated hydrostatic pressure then leads to retrograde venous drainage, allowing free communication with the prostatic circulation. Having measured a concentration of free testosterone of some 130-fold above serum level in the internal spermatic vein (the testes being the main source and the blood being undiluted in systemic circulation), the authors conclude that the elevated venous pressure causes hypertrophy and exposure to high concentrations of free testosterone causes hyperplasia in the prostate. The study also proposes a treatment method (Gat–Goren Technique) similar to that used in treating varicocele, which restores normal pressure in the venous drainage system, effectively reducing the volume of the prostate and clinical manifestation of BPH.

Most experts consider androgens (testosterone and related hormones) to play a permissive role. This means that androgens have to be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by the fact that castrated boys do not develop BPH when they age. On the other hand, administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms.[citation needed] Dihydrotestosterone (DHT), a metabolite of testosterone, is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the enzyme 5α-reductase, type 2. This enzyme is localized principally in the stromal cells; hence, those cells are the main site for the synthesis of DHT.

DHT can act in an autocrine fashion on the stromal cells or in paracrine fashion by diffusing into nearby epithelial cells. In both of these cell types, DHT binds to nuclear androgen receptors and signals the transcription of growth factors that are mitogenic to the epithelial and stromal cells. DHT is 10 times more potent than testosterone because it dissociates from the androgen receptor more slowly. The importance of DHT in causing nodular hyperplasia is supported by clinical observations in which an inhibitor of 5α-reductase is given to men with this condition. Therapy with 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and, in many cases, BPH symptoms.[citation needed]

Testosterone promotes prostate cell proliferation,[7] but relatively low levels of serum testosterone are found in patients with BPH.[8][9] One small study has shown that medical castration lowers the serum and prostate hormone levels unevenly, having less effect on testosterone and dihydrotestosterone levels in the prostate.[10]

While there is some evidence that estrogen may play a role in the etiology of BPH, this effect appears to be mediated mainly through local conversion of estrogen to androgens in the prostate tissue rather than a direct effect of estrogen itself.[11] In canine in vivo studies castration, which significantly reduced androgen levels but left estrogen levels unchanged, caused significant atrophy of the prostate.[12] Studies looking for a correlation between prostatic hyperplasia and serum estrogen levels in humans have generally shown none.[9][13]

On a microscopic level, BPH can be seen in the vast majority of men as they age, in particular over the age of 70 years, around the world. However, rates of clinically significant, symptomatic BPH vary dramatically depending on lifestyle. Men that lead a western lifestyle have a much higher incidence of symptomatic BPH than men that lead a traditional or rural lifestyle. This is confirmed by research in China showing that men in rural areas have very low rates of clinical BPH, while men living in cities adopting a western lifestyle have a skyrocketing incidence of this condition, though it is still below rates seen in the West.

Much work remains to be done to completely clarify the causes of BPH.

 Diagnosis

Urinary bladder (black butterfly-like shape) and hyperplastic prostate (BPH) visualized by sonography

Micrograph showing nodular hyperplasia (left off center) of the prostate from a transurethral resection of the prostate (TURP). H&E stain.

Microscopic examination of different types of prostate tissues (stained with immunohistochemical techniques): A. Normal (non-neoplastic) prostatic tissue (NNT). B. Benign prostatic hyperplasia. C. High-grade prostatic intraepithelial neoplasia (PIN). D. Prostatic adenocarcinoma (PCA).

Prostate with a large median lobe bulging upwards. A metal instrument is placed in the urethra (which passes through the prostate). This specimen was almost 7 centimeters long with a volume of about 60 cubic centimetres on transrectal ultrasound and was removed during a Hryntschak procedure or transvesical prostatectomy (removal of the prostate through the bladder) for benign prostatic hyperplasia.

Rectal examination (palpation of the prostate through the rectum) may reveal a markedly enlarged prostate, usually affecting the middle lobe.

Often, blood tests are performed to rule out prostatic malignancy: Elevated prostate specific antigen (PSA) levels needs further investigations such as reinterpretation of PSA results, in terms of PSA density and PSA free percentage, rectal examination and transrectal ultrasonography. These combined measures can provide early detection.

Ultrasound examination of the testicles, prostate, and kidneys is often performed, again to rule out malignancy and hydronephrosis.

Screening and diagnostic procedures for BPH are similar to those used for prostate cancer. Some signs to look for include:[14]

  • Weak urinary stream
  • Prolonged emptying of the bladder
  • Abdominal straining
  • Hesitancy
  • Irregular need to urinate
  • Incomplete bladder emptying
  • Post-urination dribble
  • Irritation during urination
  • Frequent urination
  • Nocturia (need to urinate during the night)
  • Urgency
  • Incontinence (involuntary leakage of urine)
  • Bladder pain
  • Dysuria (painful urination)
  • Problems in ejaculation

 Management

Lifestyle

Patients should decrease fluid intake before bedtime, moderate the consumption of alcohol and caffeine-containing products, and follow timed voiding schedules.

Medications

The two main medications for management of BPH are alpha blockers and 5α-reductase inhibitors.

  • The 5α-reductase inhibitors finasteride[23] and dutasteride[24] are another treatment option. These medications inhibit 5a-reductase, which in turn inhibits production of DHT, a hormone responsible for enlarging the prostate. Effects may take longer to appear than alpha blockers, but they persist for many years.[25] When used together with alpha blockers, a reduction of BPH progression to acute urinary retention and surgery has been noted in patients with larger prostates.[26] Side effects include decreased libido and ejaculatory or erectile dysfunction.[23]

Antimuscarinics such as tolterodine may also be used, especially in combination with alpha blockers.[27] They act by decreasing acetylcholine effects on the smooth muscle of the bladder, thus helping control symptoms of an overactive bladder.[citation needed]

Sildenafil citrate shows some symptomatic relief, suggesting a possible common etiology with erectile dysfunction.[28]

 Herbal remedies

People often seek herbal remedies for BPH.[29] Several are approved in European countries, but none in the USA. Saw palmetto extract from Serenoa repens is one of the most extensively studied. It showed promise in early studies,[30] though later trials of higher methodological quality indicated no difference from placebo.[31][32][33] There are no known negative effects of saw palmetto, so if taking the supplement relieves symptoms, there is no harm in taking it. The quality of saw palmetto products varies.[34]

Other herbal medicines that have research support in systematic reviews include beta-sitosterol[35] from Hypoxis rooperi (African star grass) and pygeum (extracted from the bark of Prunus africana),[36] while there is less substantial support for the efficacy of pumpkin seed (Cucurbita pepo) and stinging nettle (Urtica dioica) root.[37] There is weak evidence that pollen extracts frp, rye grass (Secale cereale) may also correlate with modest symptomatic relief.[38]

Minimally invasive therapies

Medication is often prescribed as the first treatment option, there are many patients who do not achieve success with this line of treatment. Those patients may not achieve sustained improvement in symptoms or they may stop taking the medication because of side-effects.[39] There are options for treatment in a urologist’s office before proceeding to surgery. The two most common types of office-based therapies are transurethral microwave thermotherapy (TUMT) and transurethral needle ablation (TUNA). Both of these procedures rely on delivering enough energy to create sufficient heat to cause cell death (necrosis) in the prostate. The goal of the therapies is to cause enough necrosis so that, when the dead tissue is reabsorbed by the body, the prostate shrinks, relieving the obstruction of the urethra. These procedures are typically performed with local anesthesia, and the patient returns home the same day. Some urologists have studied and published long-term data on the outcomes of these procedures, with data out to five years. The most recent American Urological Association (AUA) Guidelines for the Treatment of BPH in 2003 lists minimally invasive therapies including TUMT and TUNA as acceptable alternatives for certain patients with BPH.[40]

Transurethral microwave therapy (TUMT) was originally approved by the FDA in 1996, with the first generation system by EDAP Technomed. Since 1996, other companies have received FDA approval for TUMT devices, including Urologix, Dornier, Thermatrix, Celsion, and Prostalund. Multiple clinical studies have been published on TUMT. The general principle underlying all the devices is that a microwave antenna that resides in a urethral catheter is placed in the intraprostatic area of the urethra. The catheter is connected to a control box outside of the patient’s body and is energized to emit microwave radiation into the prostate to heat the tissue and cause necrosis. It is a one-time treatment that takes approximately 30 minutes to 1 hour, depending on the system used. It takes approximately 4 to 6 weeks for the damaged tissue to be reabsorbed into the patient’s body. Some of the devices incorporate circulating coolant through the treatment area with the intent of preserving the urethra while the microwave energy heats the prostatic tissue surrounding the urethra.

Transurethral needle ablation (TUNA) operates with a different type of energy, radio frequency (RF) energy, but is designed along the same premise as TUMT devices, that the heat the device generates will cause necrosis of the prostatic tissue and shrink the prostate. The TUNA device is inserted into the urethra using a rigid scope much like a cystoscope. The energy is delivered into the prostate using two needles that emerge from the sides of the device, through the urethral wall and into the prostate. The needle-based ablation devices are very effective at heating a localized area to a high enough temperature to cause necrosis. The treatment is typically performed in one session, but may require multiple sticks of the needles depending on the size of the prostate.

Surgery

If medical treatment fails, and the patient elects not to try office-based therapies or the physician determines the patient is a better candidate for transurethral resection of prostate (TURP), surgery may need to be performed. In general, TURP is still considered the gold standard of prostate interventions for patients that require a procedure. This involves removing (part of) the prostate through the urethra. There are also a number of new methods for reducing the size of an enlarged prostate, some of which have not been around long enough to fully establish their safety or side-effects. These include various methods to destroy or remove part of the excess tissue while trying to avoid damaging what remains. Transurethral electrovaporization of the prostate (TVP), laser TURP, visual laser ablation (VLAP), ethanol injection, and others are studied as alternatives.

Newer techniques involving lasers in urology have emerged in the last 5–10 years, starting with the VLAP technique involving the Nd:YAG laser with contact on the prostatic tissue. A similar technology called Photoselective Vaporization of the Prostate (PVP) with the GreenLight (KTP) laser have emerged very recently. This procedure involves a high-power 80-watt KTP laser with a 550-micrometre laser fiber inserted into the prostate. This fiber has an internal reflection with a 70-degree deflecting angle. It is used to vaporize the tissue to the prostatic capsule. KTP lasers target haemoglobin as the chromophore and typically have a penetration depth of 2.0 mm (four times deeper than holmium).

Another procedure termed Holmium Laser Ablation of the Prostate (HoLAP) has also been gaining acceptance around the world. Like KTP, the delivery device for HoLAP procedures is a 550 um disposable side-firing fiber that directs the beam from a high-power 100-watt laser at a 70-degree angle from the fiber axis. The holmium wavelength is 2,140 nm, which falls within the infrared portion of the spectrum and is invisible to the naked eye. Whereas KTP relies on haemoglobin as a chromophore, water within the target tissue is the chromophore for Holmium lasers. The penetration depth of Holmium lasers is <0.5 mm, avoiding complications associated with tissue necrosis often found with the deeper penetration and lower peak powers of KTP.

HoLEP, Holmium Laser Enucleation of the Prostate, is another Holmium laser procedure reported to carry fewer risks compared with either TURP or open prostatectomy.[41] HoLEP is largely similar to the HoLAP procedure; the main difference is that this procedure is typically performed on larger prostates. Instead of ablating the tissue, the laser cuts a portion of the prostate, which is then cut into smaller pieces and flushed with irrigation fluid. As with the HoLAP procedure, there is little bleeding during or after the procedure.

Both wavelengths, KTP and Holmium, ablate approximately one to two grams of tissue per minute.

Post surgery care often involves placement of a Foley catheter or a temporary prostatic stent to permit healing and allow urine to drain from the bladder.

 Epidemiology

Disability-adjusted life year for benign prostatic hyperplasia per 100,000 inhabitants in 2004.[42]

  no data
  less than 20
  20-28
  28-36
  36-44
  44-52
  52-60
  60-68
  68-76
  76-84
  84-92
  92-100
  more than 100

The prostate gets larger in most men as they get older, and, overall, 45% of men over the age of 46 can expect to suffer from the symptoms of BPH if they survive 30 years. Incidence rates increase from 3 cases per 1000 man-years at age 45–49 years, to 38 cases per 1000 man-years by the age of 75–79 years. Whereas the prevalence rate is 2.7% for men aged 45–49, it increases to 24% by the age of 80 years.[43]

For some men, the symptoms may be severe enough to require treatment

indonesia version

BAGIAN SATU

HIPRERPLASIA PROSTAT
JINAK

Hiperplasia prostat jinak
(BPH)
 
 
Hiperplasia prostat jinak
Klasifikasi dan sumber daya eksternal

Diagram yang menggambarkan prostat normal (kiri) dan benign prostatic hyperplasia (kanan).
ICD-10 N40
ICD-9 600
DiseasesDB 10797
eMedicine med/1919
MESH D011470

Benign prostatic hyperplasia (BPH) juga dikenal sebagai benign prostatic hypertrophy (secara teknis keliru), pembesaran prostat jinak dari (BEP), dan hiperplasia adenofibromyomatous, mengacu pada peningkatan ukuran prostat.

Benar, BPH melibatkan hiperplasia daripada hipertrofi, namun nomenklatur sering dipertukarkan, bahkan di antara urolog [1]. Ini melibatkan hiperplasia sel stroma dan epitel prostat, menghasilkan pembentukan besar, nodul cukup diskrit di wilayah periuretra prostat . Jika sudah cukup besar, nodul kompres kanal uretra menyebabkan obstruksi parsial, atau kadang-kadang hampir lengkap, dari uretra, yang mengganggu aliran normal urin. Ini menyebabkan gejala keraguan kencing, sering buang air kecil, disuria (kencing terasa sakit), peningkatan risiko infeksi saluran kemih, dan retensi urin. Meskipun kadar antigen prostat spesifik dapat meningkat pada pasien ini karena volume organ meningkat dan peradangan akibat infeksi saluran kemih, BPH tidak dianggap sebagai lesi premalignant.

Pertumbuhan prostat adenomatosa diyakini akan dimulai pada sekitar usia 30 tahun. Diperkirakan 50% pria memiliki bukti histologis BPH pada usia 50 tahun dan 75% pada usia 80 tahun. Dalam 40-50% dari pasien tersebut, BPH menjadi klinis signifikan. [2]

Isi
1 Tanda dan gejala
2 Penyebab
3 Diagnosis
4 Manajemen
4.1 Gaya Hidup
4.2 Obat-obatan
4.3 obat herbal
4.4 terapi invasif minimal
4,5 Bedah
5 Epidemiologi
6 Lihat juga
7 Bacaan lebih lanjut
8 Referensi
9 Pranala luar
 

Tanda dan gejala
Gejala jinak prostatic hyperplasia diklasifikasikan sebagai penyimpanan atau berkemih.

Gejala Penyimpanan termasuk frekuensi kencing, urgensi (kebutuhan mendesak untuk kekosongan yang tidak dapat ditangguhkan), inkontinensia urgensi, dan berkemih pada malam hari (nokturia).

Gejala berkemih termasuk aliran kemih, hesitansi (perlu menunggu aliran untuk mulai), intermittency (ketika sungai mulai dan berhenti sebentar-sebentar), berusaha untuk membatalkan, dan dribbling. Nyeri dan disuria biasanya tidak hadir. Gejala-gejala penyimpanan dan berkemih dievaluasi menggunakan Prostat Internasional Skor Gejala (IPSS) kuesioner, yang dirancang untuk menilai keparahan BPH [3].

BPH dapat menjadi penyakit yang progresif, terutama jika tidak diobati. Lengkap membatalkan hasil dalam stasis bakteri dalam kandung kemih dan residu peningkatan risiko infeksi saluran kemih. Batu kandung kemih yang terbentuk dari kristalisasi garam dalam urin residual. Retensi urin, disebut akut atau kronis, adalah bentuk lain dari kemajuan. Retensi urin akut adalah ketidakmampuan untuk membatalkan, sementara di retensi urin kronis volume residu urin secara bertahap meningkat, dan kandung kemih mengalami distensi. Beberapa pasien yang menderita retensi urin kronis pada akhirnya dapat berkembang menjadi gagal ginjal, kondisi disebut uropati obstruktif.

Menyebabkan
Sebuah studi yang diterbitkan pada tahun 2008 dalam jurnal andrologi “Andrologia” [4] laporan pada rute vena yang baru ditemukan oleh yang bebas (aktif) testosteron mencapai prostat dalam konsentrasi yang sangat tinggi, mempromosikan proliferasi dipercepat sel prostat, yang menyebabkan kelenjar itu pembesaran. Penelitian (yang dilakukan oleh dua dokter-dokter Israel: Dr Yigal Gat dan Dr Menachem Goren) menunjukkan bahwa BPH disebabkan oleh kerusakan katup dalam vena spermatika internal yang mewujudkan sebagai varikokel, sebuah fenomena yang telah terbukti meningkatkan cepat dengan usia, [5] [6] kurang lebih sama dengan 10-15% setiap dekade kehidupan. The 6 – untuk tekanan hidrostatik meningkat 8 kali lipat kemudian menyebabkan drainase vena retrograde, yang memungkinkan komunikasi bebas dengan sirkulasi prostat. Setelah mengukur konsentrasi testosteron bebas dari beberapa tingkat 130 kali lipat serum di atas dalam vena spermatika internal (testis menjadi sumber utama dan darah yang murni dalam sirkulasi sistemik), penulis menyimpulkan bahwa tekanan vena meningkat menyebabkan hipertrofi dan paparan konsentrasi tinggi menyebabkan hiperplasia testosteron bebas dalam prostat. Penelitian ini juga mengusulkan metode pengobatan (Gat-Goren Teknik) mirip dengan yang digunakan dalam mengobati varikokel, yang mengembalikan tekanan normal dalam sistem drainase vena, efektif mengurangi volume prostat dan manifestasi klinis BPH.

Kebanyakan ahli menganggap androgen (testosteron dan hormon terkait) untuk memainkan peran permisif. Ini berarti bahwa androgen harus hadir untuk BPH terjadi, tetapi tidak selalu secara langsung menyebabkan kondisi tersebut. Hal ini didukung oleh fakta bahwa anak laki-laki dikebiri tidak mengembangkan BPH ketika mereka usia. Di sisi lain, pemberian testosteron eksogen tidak terkait dengan peningkatan yang signifikan pada risiko gejala BPH. [Kutipan diperlukan] dihidrotestosteron (DHT), suatu metabolit testosteron, adalah mediator kritis pertumbuhan prostat. DHT disintesis dalam prostat dari beredar testosteron oleh aksi dari enzim 5α-reduktase, tipe 2. Enzim ini lokal terutama di sel-sel stroma, maka, sel-sel adalah situs utama untuk sintesis DHT.

DHT dapat bertindak dalam mode autokrin pada sel stroma atau dalam mode parakrin dengan menyebarkan ke dalam sel epitel di dekatnya. Dalam kedua jenis sel, DHT berikatan dengan reseptor androgen sinyal nuklir dan transkripsi faktor pertumbuhan yang mitogenik ke sel epitel dan stroma. DHT adalah 10 kali lebih kuat daripada testosteron karena berdisosiasi dari reseptor androgen lebih lambat. Pentingnya DHT dalam menyebabkan hiperplasia nodular didukung oleh pengamatan klinis di mana suatu inhibitor 5α-reduktase diberikan kepada laki-laki dengan kondisi ini. Terapi dengan inhibitor 5α-reduktase nyata mengurangi isi DHT prostat dan, pada gilirannya, mengurangi volume prostat dan, dalam banyak kasus, gejala BPH. [Kutipan diperlukan]

Testosteron meningkatkan proliferasi sel prostat, [7] tetapi tingkat yang relatif rendah testosteron serum yang ditemukan pada pasien dengan BPH [8]. [9] Salah satu penelitian kecil telah menunjukkan bahwa pengebirian medis menurunkan kadar hormon serum dan prostat tidak merata, memiliki efek kurang pada tingkat testosteron dan dihidrotestosteron dalam prostat [10].

Sementara ada beberapa bukti bahwa estrogen mungkin memainkan peran dalam etiologi BPH, efek ini tampaknya dimediasi terutama melalui konversi lokal estrogen terhadap androgen dalam jaringan prostat ketimbang efek langsung dari estrogen itu sendiri [11]. Pada anjing di vivo pengebirian, yang secara signifikan mengurangi tingkat androgen tetapi tingkat estrogen tidak berubah, menyebabkan atrofi signifikan dari prostat. [12] Studi mencari korelasi antara hiperplasia prostat dan tingkat estrogen serum pada manusia umumnya menunjukkan tidak ada. [9] [13]

Pada tingkat mikroskopis, BPH dapat dilihat di sebagian besar laki-laki dengan bertambahnya usia mereka, khususnya di atas usia 70 tahun, di seluruh dunia. Namun, tingkat signifikan secara klinis, gejala BPH bervariasi secara dramatis tergantung pada gaya hidup. Pria yang menjalani gaya hidup Barat memiliki insiden yang lebih tinggi BPH gejala dibandingkan laki-laki yang menjalani gaya hidup tradisional atau pedesaan. Hal ini dikonfirmasi oleh penelitian di Cina menunjukkan bahwa laki-laki di daerah pedesaan memiliki tingkat yang sangat rendah klinis BPH, sedangkan pria yang tinggal di kota mengadopsi gaya hidup barat memiliki insiden meroket kondisi ini, meskipun masih di bawah tingkat yang terlihat di Barat.

Masih banyak pekerjaan yang harus dilakukan untuk benar-benar mengklarifikasi penyebab BPH.

 Diagnosa

Kandung kemih (hitam kupu-kupu seperti bentuk) dan hiperplastik prostat (BPH) divisualisasikan dengan sonografi

Mikrograf menunjukkan hiperplasia nodular (kiri dari pusat) dari prostat dari reseksi transurethral dari prostat (TURP). H & E noda.

Pemeriksaan mikroskopik dari berbagai jenis jaringan prostat (diwarnai dengan teknik imunohistokimia): A. Normal (non-neoplastik) jaringan prostat (NNT). B. jinak prostat hiperplasia. C. neoplasia intraepitel kelas tinggi prostat (PIN). D. adenokarsinoma prostat (PCA).

Prostat dengan lobus median besar menggembung ke atas. Sebuah instrumen logam ditempatkan di uretra (yang melewati prostat). Spesimen ini hampir 7 cm panjang dengan volume sekitar 60 sentimeter kubik pada USG transrectal dan telah dihapus selama prosedur Hryntschak atau prostatektomi transvesical (pengangkatan prostat melalui kandung kemih) untuk hiperplasia prostat jinak.

Pemeriksaan rektal (palpasi prostat melalui dubur) dapat mengungkapkan sebuah prostat yang membesar nyata, biasanya mempengaruhi lobus tengah.

Seringkali, tes darah dilakukan untuk menyingkirkan keganasan prostat: Peningkatan antigen prostat spesifik (PSA) tingkat kebutuhan penyelidikan lebih lanjut seperti reinterpretasi hasil PSA, dalam hal kepadatan PSA dan persentase PSA bebas, pemeriksaan dubur dan ultrasonografi transrectal. Langkah-langkah ini dikombinasikan dapat memberikan deteksi dini.

USG pemeriksaan testis, prostat, dan ginjal sering dilakukan, sekali lagi untuk menyingkirkan keganasan dan hidronefrosis.

Skrining dan diagnostik prosedur untuk BPH mirip dengan yang digunakan untuk kanker prostat. Beberapa tanda-tanda untuk mencari mencakup: [14]

Lemahnya aliran kemih
Berkepanjangan pengosongan kandung kemih
Abdomen tegang
Keraguan
Tidak teratur perlu buang air kecil
Mengosongkan kandung kemih tidak lengkap
Pasca-buang air kecil menggiring bola
Iritasi saat buang air kecil
Sering buang air kecil
Nokturia (perlu buang air kecil pada malam hari)
Urgensi
Inkontinensia (kebocoran urin involunter)
Nyeri kandung kemih
Disuria (nyeri buang air kecil)
Masalah ejakulasi
 Manajemen
Gaya hidup
Pasien harus mengurangi asupan cairan sebelum tidur, sedang konsumsi alkohol dan kafein mengandung produk, dan mengikuti jadwal berkemih waktunya.

Obat-obatan
Dua obat utama untuk manajemen BPH adalah alpha blockers dan 5α-reduktase inhibitor.

Alpha blocker (teknis α1-adrenergik antagonis reseptor) adalah pilihan yang paling umum untuk terapi awal di Amerika Serikat [15] [16] dan Eropa [17] Alpha blocker digunakan untuk BPH termasuk doxazosin, [18]. Terazosin, alfuzosin, [19 ] [20] tamsulosin, dan silodosin. Semua lima sama-sama efektif tetapi memiliki profil efek samping yang sedikit berbeda. [21] Obat-obatan yang lebih tua phenoxybenzamine dan prazosin tidak dianjurkan [22]. Alpha blocker rileks otot polos di prostat dan leher kandung kemih, sehingga mengurangi penyumbatan aliran urin. Efek samping yang umum dari alpha blockers termasuk hipotensi ortostatik, perubahan ejakulasi, hidung tersumbat, dan kelemahan. [Kutipan diperlukan]
Para 5α-reduktase inhibitor finasterida [23] dan dutasteride [24] adalah pilihan lain pengobatan. Obat-obat ini menghambat 5a-reduktase, yang pada gilirannya menghambat produksi DHT, hormon yang bertanggung jawab untuk memperbesar prostat. Efek mungkin memakan waktu lebih lama untuk muncul dari alpha blockers, tetapi mereka bertahan selama bertahun-tahun. [25] Ketika digunakan bersama dengan alpha blockers, penurunan perkembangan BPH untuk retensi urin akut dan pembedahan telah dicatat pada pasien dengan prostat yang lebih besar. [26] Efek samping termasuk penurunan libido dan ejakulasi atau disfungsi ereksi. [23]
Antimuscarinics seperti tolterodine juga dapat digunakan, terutama dalam kombinasi dengan alpha blockers [27]. Mereka bertindak dengan mengurangi efek asetilkolin pada otot polos kandung kemih, sehingga membantu mengendalikan gejala dari kandung kemih terlalu aktif. [Kutipan diperlukan]

Sildenafil sitrat menunjukkan beberapa bantuan gejala, menunjukkan etiologi umum mungkin dengan disfungsi ereksi. [28]

 Obat herbal
Orang sering mencari obat herbal untuk BPH [29]. Beberapa disetujui di negara-negara Eropa, tetapi tidak ada di Amerika Serikat. Saw palmetto ekstrak dari Serenoa repens adalah salah satu yang paling ekstensif dipelajari. Ini menunjukkan janji dalam studi awal, [30] meskipun percobaan kemudian kualitas metodologi yang lebih tinggi menunjukkan tidak ada perbedaan dari plasebo. [31] [32] [33] Tidak ada efek negatif diketahui saw palmetto, jadi jika mengambil suplemen mengurangi gejala, tidak ada salahnya dalam mengambil itu. Kualitas produk saw palmetto bervariasi [34].

Obat herbal lain yang memiliki dukungan penelitian di review sistematis termasuk beta-sitosterol [35] dari Hypoxis rooperi (Afrika rumput bintang) dan pygeum (diekstraksi dari kulit Prunus africana), [36] sementara ada kurang mendukung substansial untuk keberhasilan biji labu (Cucurbita pepo) dan jelatang menyengat (urtika dioica) akar. [37] Ada bukti lemah bahwa ekstrak serbuk sari FRP, rye rumput (Secale cereale) juga dapat berhubungan dengan bantuan gejala yang sederhana. [38]

Terapi minimal invasif
Obat ini sering diresepkan sebagai pilihan pengobatan pertama, ada banyak pasien yang tidak mencapai sukses dengan lini pengobatan. Pasien tidak dapat mencapai perbaikan berkelanjutan dalam gejala atau mereka mungkin berhenti minum obat karena efek samping [39]. Ada pilihan untuk pengobatan di kantor seorang urolog sebelum melanjutkan ke operasi. Dua jenis yang paling umum dari terapi kantor berbasis microwave transurethral thermotherapy (TUMT) dan ablasi jarum transurethral (TUNA). Kedua prosedur ini mengandalkan memberikan energi yang cukup untuk menciptakan panas yang cukup untuk menyebabkan kematian sel (nekrosis) dalam prostat. Tujuan dari terapi adalah untuk menyebabkan nekrosis cukup sehingga, ketika jaringan mati adalah diserap kembali oleh tubuh, menyusut prostat, menghilangkan obstruksi uretra. Prosedur ini biasanya dilakukan dengan anestesi lokal, dan pasien kembali pulang hari yang sama. Beberapa urolog telah mempelajari dan menerbitkan data jangka panjang pada hasil dari prosedur ini, dengan data keluar untuk lima tahun. Amerika paling baru Urological Association (AUA) Pedoman Pengobatan BPH pada tahun 2003 daftar terapi minimal invasif termasuk TUMT dan TUNA sebagai alternatif diterima untuk pasien tertentu dengan BPH. [40]

Terapi microwave transurethral (TUMT) awalnya disetujui oleh FDA pada tahun 1996, dengan sistem generasi pertama oleh EDAP Technomed. Sejak tahun 1996, perusahaan lain telah menerima persetujuan FDA untuk perangkat TUMT, termasuk Urologix, Dornier, Thermatrix, Celsion, dan Prostalund. Beberapa studi klinis telah dipublikasikan pada TUMT. Prinsip umum yang mendasari semua perangkat adalah bahwa antena microwave yang berada dalam sebuah kateter uretra ditempatkan di daerah intraprostatic uretra. Kateter terhubung ke kotak kontrol di luar tubuh pasien dan energi untuk memancarkan radiasi gelombang mikro ke dalam prostat untuk memanaskan jaringan dan nekrosis menyebabkan. Ini adalah pengobatan satu-waktu yang berlangsung sekitar 30 menit sampai 1 jam, tergantung pada sistem yang digunakan. Dibutuhkan sekitar 4 sampai 6 minggu untuk jaringan yang rusak diserap kembali ke dalam tubuh pasien. Beberapa perangkat menggabungkan beredar pendingin melalui area pengobatan dengan maksud melestarikan uretra sedangkan energi microwave memanaskan jaringan prostat di sekitarnya uretra.

Ablasi jarum transurethral (TUNA) beroperasi dengan berbagai jenis energi, energi frekuensi radio (RF), tetapi dirancang sepanjang premis yang sama sebagai perangkat TUMT, bahwa panas perangkat akan menyebabkan nekrosis menghasilkan dari jaringan prostat dan mengecilkan prostat. Perangkat TUNA dimasukkan ke dalam uretra menggunakan lingkup kaku seperti sebuah cystoscope. Energi diserahkan ke prostat menggunakan dua jarum yang muncul dari sisi perangkat, melalui dinding uretra dan masuk ke prostat. Jarum perangkat berbasis ablasi sangat efektif pada area lokal pemanasan dengan suhu yang cukup tinggi untuk menyebabkan nekrosis. Pengobatan ini biasanya dilakukan dalam satu sesi, tapi mungkin membutuhkan beberapa batang jarum tergantung pada ukuran prostat.

Operasi
Jika perawatan medis gagal, dan pasien memilih untuk tidak mencoba kantor berbasis terapi atau dokter menentukan pasien adalah kandidat yang lebih baik untuk reseksi transurethral dari prostat (TURP), pembedahan mungkin perlu dilakukan. Secara umum, TURP masih dianggap standar emas intervensi prostat bagi pasien yang memerlukan prosedur. Hal ini melibatkan menghapus (bagian dari) prostat melalui uretra. Ada juga sejumlah metode baru untuk mengurangi ukuran pembesaran prostat, beberapa yang belum cukup lama untuk sepenuhnya membangun keselamatan mereka atau efek samping. Ini meliputi berbagai metode untuk menghancurkan atau menghapus bagian dari jaringan yang berlebihan ketika mencoba untuk menghindari kerusakan apa yang tersisa. Electrovaporization transurethral dari prostat (TVP), laser TURP, visual ablasi laser (VLAP), injeksi etanol, dan lain-lain dipelajari sebagai alternatif.

Teknik-teknik baru melibatkan laser dalam urologi telah muncul dalam 5-10 tahun terakhir, mulai dengan teknik VLAP melibatkan Nd: YAG laser dengan kontak pada jaringan prostat. Sebuah teknologi serupa yang disebut Penguapan Photoselective dari Prostat (PVT) dengan Greenlight tersebut (KTP) laser telah muncul baru-baru ini. Prosedur ini melibatkan daya tinggi-80-watt KTP laser dengan laser serat 550-micrometre dimasukkan ke dalam prostat. Serat ini memiliki refleksi internal dengan sudut 70 derajat membelokkan. Hal ini digunakan untuk menguapkan jaringan untuk kapsul prostat. KTP laser sasaran hemoglobin sebagai kromofor dan biasanya memiliki kedalaman penetrasi 2,0 mm (empat kali lebih dalam dari holmium).

Prosedur lain disebut Laser Ablation holmium Prostat (HOLAP) juga telah mendapatkan penerimaan di seluruh dunia. Seperti KTP, perangkat pengiriman untuk HOLAP prosedur adalah 550 mm pakai sisi-menembak serat yang mengarahkan balok dari daya tinggi-100-watt laser pada sudut 70 derajat dari sumbu serat. Panjang gelombang adalah 2.140 nm holmium, yang jatuh dalam bagian inframerah dari spektrum dan tidak terlihat dengan mata telanjang. Sedangkan KTP bergantung pada hemoglobin sebagai air, kromofor dalam jaringan target adalah kromofor untuk laser holmium. Kedalaman penetrasi holmium laser adalah <0,5 mm, menghindari komplikasi yang terkait dengan nekrosis jaringan sering ditemukan dengan penetrasi lebih dalam dan kekuatan puncak yang lebih rendah dari KTP.

HoLEP, holmium enukleasi Laser Prostat, adalah suatu prosedur holmium laser yang dilaporkan membawa risiko lebih sedikit dibandingkan dengan TURP baik atau prostatektomi terbuka [41] HoLEP sebagian besar serupa dengan prosedur HOLAP;. Perbedaan utama adalah bahwa prosedur ini biasanya dilakukan pada lebih besar prostat. Alih-alih terablasi jaringan, laser memotong sebagian dari prostat, yang kemudian dipotong-potong kecil dan memerah dengan cairan irigasi. Seperti prosedur HOLAP, ada sedikit perdarahan selama atau setelah prosedur.

Kedua panjang gelombang, KTP dan holmium, mengikis sekitar satu hingga dua gram jaringan per menit.

Perawatan pasca operasi sering melibatkan penempatan kateter Foley atau stent prostat sementara untuk memungkinkan penyembuhan dan memungkinkan urin mengalir dari kandung kemih.

 Epidemiologi

Cacat-tahun hidup disesuaikan untuk benign prostatic hyperplasia per 100.000 penduduk pada tahun 2004. [42]

  tidak ada data
  kurang dari 20
  20-28
  28-36
  36-44
  44-52
  52-60
  60-68
  68-76
  76-84
  84-92
  92-100
  lebih dari 100
Prostat semakin besar pada kebanyakan pria ketika usia mereka bertambah, dan, secara keseluruhan, 45% pria di atas usia 46 dapat mengharapkan untuk menderita gejala BPH jika mereka bertahan hidup 30 tahun. Tingkat insiden meningkat dari 3 kasus per 1000 orang-tahun pada usia 45-49 tahun, menjadi 38 kasus per 1000 orang-tahun pada usia 75-79 tahun. Sedangkan angka prevalensi 2,7% untuk laki-laki berusia 45-49, itu meningkat menjadi 24% pada usia 80 tahun [43].

Bagi sebagian pria, gejala dapat cukup parah untuk memerlukan perawatan

 
 
 
 
 

PART TWO MALIGNANT HIPERTROPHY PORSTATE

 Prostatelead.jpg

 
 

Prostate cancer

 
Prostate Cancer
Classification and external resources

Micrograph of prostate adenocarcinoma, acinar type, the most common type of prostate cancer. Gleason pattern 4. Needle biopsy. H&E stain.
ICD-10 C61
ICD-9 185
OMIM 176807
DiseasesDB 10780
MedlinePlus 000380
eMedicine radio/574
MeSH D011471

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers.[1] The cancer cells may metastasize (spread) from the prostate to other parts of the body, particularly the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, problems during sexual intercourse, or erectile dysfunction. Other symptoms can potentially develop during later stages of the disease.

Rates of detection of prostate cancers vary widely across the world, with South and East Asia detecting less frequently than in Europe, and especially the United States.[2] Prostate cancer tends to develop in men over the age of fifty and although it is one of the most prevalent types of cancer in men, many never have symptoms, undergo no therapy, and eventually die of other causes. This is because cancer of the prostate is, in most cases, slow-growing, symptom-free, and since men with the condition are older they often die of causes unrelated to the prostate cancer, such as heart/circulatory disease, pneumonia, other unconnected cancers, or old age. About two-thirds of cases are slow growing, the other third more aggressive and fast developing.[3]

Many factors, including genetics and diet, have been implicated in the development of prostate cancer. The presence of prostate cancer may be indicated by symptoms, physical examination, prostate-specific antigen (PSA), or biopsy. The PSA test increases cancer detection but does not decrease mortality.[4] Moreover, prostate test screening is controversial at the moment and may lead to unnecessary, even harmful, consequences in some patients.[5] Nonetheless, suspected prostate cancer is typically confirmed by taking a biopsy of the prostate and examining it under a microscope. Further tests, such as CT scans and bone scans, may be performed to determine whether prostate cancer has spread.

Treatment options for prostate cancer with intent to cure are primarily surgery, radiation therapy, stereotactic radiosurgery, and proton therapy. Other treatments, such as hormonal therapy, chemotherapy, cryosurgery, and high intensity focused ultrasound (HIFU) also exist, although not FDA approved, depending on the clinical scenario and desired outcome.

The age and underlying health of the man, the extent of metastasis, appearance under the microscope, and response of the cancer to initial treatment are important in determining the outcome of the disease. The decision whether or not to treat localized prostate cancer (a tumor that is contained within the prostate) with curative intent is a patient trade-off between the expected beneficial and harmful effects in terms of patient survival and quality of life.

[edit] Overview

See also: Prostate
Prostatelead.jpg

The prostate is a part of the male reproductive system that helps make and store seminal fluid. In adult men, a typical prostate is about three centimeters long and weighs about twenty grams.[6] It is located in the pelvis, under the urinary bladder and in front of the rectum. The prostate surrounds part of the urethra, the tube that carries urine from the bladder during urination and semen during ejaculation.[7] Because of its location, prostate diseases often affect urination, ejaculation, and rarely defecation. The prostate contains many small glands which make about twenty percent of the fluid constituting semen.[8] In prostate cancer, the cells of these prostate glands mutate into cancer cells. The prostate glands require male hormones, known as androgens, to work properly. Androgens include testosterone, which is made in the testes; dehydroepiandrosterone, made in the adrenal glands; and dihydrotestosterone, which is converted from testosterone within the prostate itself. Androgens are also responsible for secondary sex characteristics such as facial hair and increased muscle mass.

Classification

An important part of evaluating prostate cancer is determining the stage, or how far the cancer has spread. Knowing the stage helps define prognosis and is useful when selecting therapies. The most common system is the four-stage TNM system (abbreviated from Tumor/Nodes/Metastases). Its components include the size of the tumor, the number of involved lymph nodes, and the presence of any other metastases.[9]

The most important distinction made by any staging system is whether or not the cancer is still confined to the prostate. In the TNM system, clinical T1 and T2 cancers are found only in the prostate, while T3 and T4 cancers have spread elsewhere. Several tests can be used to look for evidence of spread. These include computed tomography to evaluate spread within the pelvis, bone scans to look for spread to the bones, and endorectal coil magnetic resonance imaging to closely evaluate the prostatic capsule and the seminal vesicles. Bone scans should reveal osteoblastic appearance due to increased bone density in the areas of bone metastasis—opposite to what is found in many other cancers that metastasize.

After a prostate biopsy, a pathologist looks at the samples under a microscope. If cancer is present, the pathologist reports the grade of the tumor. The grade tells how much the tumor tissue differs from normal prostate tissue and suggests how fast the tumor is likely to grow. The Gleason system is used to grade prostate tumors from 2 to 10, where a Gleason score of 10 indicates the most abnormalities. The pathologist assigns a number from 1 to 5 for the most common pattern observed under the microscope, then does the same for the second-most-common pattern. The sum of these two numbers is the Gleason score. The Whitmore-Jewett stage is another method sometimes used.

 Signs and symptoms

Early prostate cancer usually causes no symptoms. Often it is diagnosed during the workup for an elevated PSA noticed during a routine checkup.

Sometimes, however, prostate cancer does cause symptoms, often similar to those of diseases such as benign prostatic hyperplasia. These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), and dysuria (painful urination).

Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds the prostatic urethra. Changes within the gland, therefore, directly affect urinary function. Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the prostate gland itself are included in semen content, prostate cancer may also cause problems with sexual function and performance, such as difficulty achieving erection or painful ejaculation.[10]

Advanced prostate cancer can spread to other parts of the body, possibly causing additional symptoms. The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis, or ribs. Spread of cancer into other bones such as the femur is usually to the proximal part of the bone. Prostate cancer in the spine can also compress the spinal cord, causing leg weakness and urinary and fecal incontinence.[11]

[edit] Causes

The specific causes of prostate cancer remain unknown.[12] The primary risk factors are age and family history. Prostate cancer is very uncommon in men younger than 45, but becomes more common with advancing age. The average age at the time of diagnosis is 70.[13] However, many men never know they have prostate cancer. Autopsy studies of Chinese, German, Israeli, Jamaican, Swedish, and Ugandan men who died of other causes have found prostate cancer in thirty percent of men in their 50s, and in eighty percent of men in their 70s.[14] Men who have first-degree family members with prostate cancer appear to have double the risk of getting the disease compared to men without prostate cancer in the family.[15] This risk appears to be greater for men with an affected brother than for men with an affected father. In the United States in 2005, there were an estimated 230,000 new cases of prostate cancer and 30,000 deaths due to prostate cancer.[16] Men with high blood pressure are more likely to develop prostate cancer.[17] A 2010 study found that prostate basal cells were the most common site of origin for prostate cancers.[18]

 Genetic

Genetic background may contribute to prostate cancer risk, as suggested by associations with race, family, and specific gene variants. Men who have a first-degree relative (father or brother) with prostate cancer have twice the risk of developing prostate cancer, and those with two first-degree relatives affected have a fivefold greater risk compared with men with no family history.[19] In the United States, prostate cancer more commonly affects black men than white or Hispanic men, and is also more deadly in black men.[20] [21] In contrast, the incidence and mortality rates for Hispanic men are one third lower than for non-Hispanic whites. Studies of twins in Scandinavia suggest that forty percent of prostate cancer risk can be explained by inherited factors.[22]

No single gene is responsible for prostate cancer; many different genes have been implicated. Mutations in BRCA1 and BRCA2, important risk factors for ovarian cancer and breast cancer in women, have also been implicated in prostate cancer.[23] Other linked genes include the Hereditary Prostate cancer gene 1 (HPC1), the androgen receptor, and the vitamin D receptor.[20] TMPRSS2-ETS gene family fusion, specifically TMPRSS2-ERG or TMPRSS2-ETV1/4 promotes cancer cell growth.[24]

Loss of cancer suppressor genes, early in the prostatic carcinogenesis, have been localized to chromosomes 8p, 10q, 13q,and 16q. P53 mutations in the primary prostate cancer are relatively low and are more frequently seen in metastatic settings, hence, p53 mutations are late event in pathology of prostate cancer. Other tumor suppressor genes that are thought to play a role in prostate cancer include PTEN (gene) and KAI1. “Up to 70 percent of men with prostate cancer have lost one copy of the PTEN gene at the time of diagnosis”[25] Relative frequency of loss of E-cadherin and CD44 has also been observed.

 Dietary

While a number of dietary factors have been linked to prostate cancer the evidence is still tentative.[26] Evidence supports little role for dietary fruits and vegetables in prostate cancer occurrence.[27] Red meat and processed meat also appear to have little effect.[28] Lower blood levels of vitamin D may increase the risk of developing prostate cancer.[29] This may be linked to lower exposure to ultraviolet (UV) light, since UV light exposure can increase vitamin D in the body.[30]

Green tea may be protective (due to its catechins content),[31] although the most comprehensive clinical study indicates that it has no protective effect.[32] Other holistic methods are also studied.[33]

Taking multivitamins more than seven times a week may increase the risks of contracting the disease.[34][35] This research was unable to highlight the exact vitamins responsible for this increase (almost double), although they suggest that vitamin A, vitamin E and beta-carotene may lie at its heart. It is advised that those taking multivitamins never exceed the stated daily dose on the label.

Folic acid supplements have recently been linked to an increase in risk of developing prostate cancer.[36] A ten-year research study led by University of Southern California researchers showed that men who took daily folic acid supplements of 1 mg were three times more likely to be diagnosed with prostate cancer than men who took a placebo.[36]

High alcohol intake may increase the risk of prostate cancer and interfere with folate metabolism.[37] Low folate intake and high alcohol intake may increase the risk of prostate cancer to a greater extent than the sole effect of either one by itself.[37] A case control study consisting of 137 veterans addressed this hypothesis and the results were that high folate intake was related to a 79% lower risk of developing prostate cancer and there was no association between alcohol consumption by itself and prostate cancer risk.[37] Folate’s effect however was only significant when coupled with low alcohol intake.[37] There is a significant decrease in risk of prostate cancer with increasing dietary folate intake but this association only remains in individuals with low levels of alcohol consumption.[37] There was no association found in this study between folic acid supplements and risk of prostate cancer.[37]

 Medication exposure

There are also some links between prostate cancer and medications, medical procedures, and medical conditions.[38] Use of the cholesterol-lowering drugs known as the statins may also decrease prostate cancer risk.[39]

Infection or inflammation of the prostate (prostatitis) may increase the chance for prostate cancer while another study shows infection may help prevent prostate cancer by increasing blood to the area. In particular, infection with the sexually transmitted infections chlamydia, gonorrhea, or syphilis seems to increase risk.[40] Finally, obesity[41] and elevated blood levels of testosterone[42] may increase the risk for prostate cancer. There is an association between vasectomy and prostate cancer however more research is needed to determine if this is a causative relationship.[43]

Research released in May 2007, found that US war veterans who had been exposed to Agent Orange had a 48% increased risk of prostate cancer recurrence following surgery.[44]

Viral

In 2006, researchers associated a previously unknown retrovirus, Xenotropic MuLV-related virus or XMRV, with human prostate tumors.[45] Subsequent reports on the virus have been contradictory. A group of US researchers found XMRV protein expression in human prostate tumors,[46] while German scientists failed to find XMRV-specific antibodies or XMRV-specific nucleic acid sequences in prostate cancer samples.[47]

Pathophysiology

When normal cells are damaged beyond repair, they are eliminated by apoptosis. Cancer cells avoid apoptosis and continue to multiply in an unregulated manner.

Prostate cancer is classified as an adenocarcinoma, or glandular cancer, that begins when normal semen-secreting prostate gland cells mutate into cancer cells. The region of prostate gland where the adenocarcinoma is most common is the peripheral zone. Initially, small clumps of cancer cells remain confined to otherwise normal prostate glands, a condition known as carcinoma in situ or prostatic intraepithelial neoplasia (PIN). Although there is no proof that PIN is a cancer precursor, it is closely associated with cancer. Over time, these cancer cells begin to multiply and spread to the surrounding prostate tissue (the stroma) forming a tumor. Eventually, the tumor may grow large enough to invade nearby organs such as the seminal vesicles or the rectum, or the tumor cells may develop the ability to travel in the bloodstream and lymphatic system. Prostate cancer is considered a malignant tumor because it is a mass of cells that can invade other parts of the body. This invasion of other organs is called metastasis. Prostate cancer most commonly metastasizes to the bones, lymph nodes, and may invade rectum, bladder and lower ureters after local progression. The route of metastasis to bone is thought to be venous as the prostatic venous plexus draining the prostate connects with the vertebral veins.[48]

The prostate is a zinc accumulating, citrate producing organ. The protein ZIP1 is responsible for the active transport of zinc into prostate cells. One of zinc’s important roles is to change the metabolism of the cell in order to produce citrate, an important component of semen. The process of zinc accumulation, alteration of metabolism, and citrate production is energy inefficient, and prostate cells sacrifice enormous amounts of energy (ATP) in order to accomplish this task. Prostate cancer cells are generally devoid of zinc. This allows prostate cancer cells to save energy not making citrate, and utilize the new abundance of energy to grow and spread. The absence of zinc is thought to occur via a silencing of the gene that produces the transporter protein ZIP1. ZIP1 is now called a tumor suppressor gene product for the gene SLC39A1. The cause of the epigenetic silencing is unknown. Strategies which transport zinc into transformed prostate cells effectively eliminate these cells in animals. Zinc inhibits NF-κB pathways, is anti-proliferative, and induces apoptosis in abnormal cells. Unfortunately, oral ingestion of zinc is ineffective since high concentrations of zinc into prostate cells is not possible without the active transporter, ZIP1.[49]

RUNX2 is a transcription factor that prevents cancer cells from undergoing apoptosis thereby contributing to the development of prostate cancer.[50]

The PI3k/Akt signaling cascade works with the transforming growth factor beta/SMAD signaling cascade to ensure prostate cancer cell survival and protection against apoptosis.[51] X-linked inhibitor of apoptosis (XIAP) is hypothesized to promote prostate cancer cell survival and growth and is a target of research because if this inhibitor can be shut down then the apoptosis cascade can carry on its function in preventing cancer cell proliferation.[52] Macrophage inhibitory cytokine-1 (MIC-1) stimulates the focal adhesion kinase (FAK) signaling pathway which leads to prostate cancer cell growth and survival.[53]

The androgen receptor helps prostate cancer cells to survive and is a target for many anti cancer research studies; so far, inhibiting the androgen receptor has only proven to be effective in mouse studies.[54] Prostate specific membrane antigen (PSMA) stimulates the development of prostate cancer by increasing folate levels for the cancer cells to use to survive and grow; PSMA increases available folates for use by hydrolyzing glutamated folates.[55]

 Early Detection and Diagnosis

The American Cancer Society’s position regarding early detection is “Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment. The American Cancer Society believes that men should not be tested without learning about what we know and don’t know about the risks and possible benefits of testing and treatment. Starting at age 50, (45 if African American or brother or father suffered from condition before age 65) talk to your doctor about the pros and cons of testing so you can decide if testing is the right choice for you.”[56]

The only test that can fully confirm the diagnosis of prostate cancer is a biopsy, the removal of small pieces of the prostate for microscopic examination. However, prior to a biopsy, less invasive testing can be conducted.

According to Professor Hardev Pandha, The Prostate Project Chair of Urological Oncology at the University of Surrey’s Postgraduate Medical School, a non-invasive test looking for the presence of the protein Engrailed-2 (EN2) in the urine to be more reliable and accurate than existing tests.

“In this study, we showed that the new test was twice as good at finding prostate cancer as the standard PSA test. Only rarely did we find EN2 in the urine of men who were cancer free, so if we find EN2 we can be reasonably sure that a man has prostate cancer. EN2 was not detected in men with non-cancer disorders of the prostate such as prostatitis or benign enlargement. These conditions often cause a high PSA result, causing considerable stress for the patient and sometimes also unnecessary further tests such as prostate biopsies.” [57]

There are also several other tests that can be used to gather more information about the prostate and the urinary tract. Digital rectal examination (DRE) may allow a doctor to detect prostate abnormalities. Cystoscopy shows the urinary tract from inside the bladder, using a thin, flexible camera tube inserted down the urethra. Transrectal ultrasonography creates a picture of the prostate using sound waves from a probe in the rectum.

Prostate Imaging

Ultrasound (US) and Magnetic Resonance Imaging (MRI)are the two main imaging methods used for prostate cancer detection. Urologists use transrectal ultrasound during prostate biopsy and can sometimes see a hypoechoic area. But US has poor tissue resolution and thus, is generally not clinically used. In contrast, prostate MRI has superior soft tissue resolution. MRI is a type of imaging that uses magnetic fields to locate and characterize prostate cancer. Multi-parametric prostate MRI consists of four types of MRI sequences called T2 weighted imaging, T1 weighted imaging, Diffusion Weighted Imaging, MR Spectrocopic Imaging and Dynamic-Contrast Enhanced Imaging.[58] Genitourinary radiologists use multi-parametric MRI to locate and identify prostate cancer. Currently, MRI is used to identify targets for prostate biopsy using fusion MRI with ultrasound (US) or MRI-guidance alone. In men who are candidates for active surveillance, fusion MR/US guided prostate biopsy detected 33% of cancers compared to 7% with standard ultrasound guided biopsy. [59] Prostate MRI is also used for surgical planning for men undergoing robotic prostatectomy. It has also shown to help surgeons decide whether to resect or spare the neurovascular bundle, determine return to urinary continence and help assess surgical difficulty. [60]. Some prostate advocacy groups believe prostate MRI should be used to screen for prostate cancer–“manogram”– like mammogram is for breast cancer. [61]

 Biopsy

Main article: Prostate biopsy

Micrograph showing a prostate cancer (conventional adenocarcinoma) with perineural invasion. H&E stain.

If cancer is suspected, a biopsy is offered expediently. During a biopsy a urologist or radiologist obtains tissue samples from the prostate via the rectum. A biopsy gun inserts and removes special hollow-core needles (usually three to six on each side of the prostate) in less than a second. Prostate biopsies are routinely done on an outpatient basis and rarely require hospitalization. Fifty-five percent of men report discomfort during prostate biopsy.[62]

Gleason score

Main article: Gleason score

The tissue samples are then examined under a microscope to determine whether cancer cells are present, and to evaluate the microscopic features (or Gleason score) of any cancer found. Prostate specific membrane antigen is a transmembrane carboxypeptidase and exhibits folate hydrolase activity.[36] This protein is overexpressed in prostate cancer tissues and is associated with a higher Gleason score.[36]

Tumor markers

Tissue samples can be stained for the presence of PSA and other tumor markers in order to determine the origin of malignant cells that have metastasized.[63]

Small cell carcinoma is a very rare (1%[64]) type of prostate cancer that cannot be diagnosed using the PSA.[64][65] As of 2009[update] researchers are trying to determine the best way to screen for this type of prostate cancer because it is a relatively unknown and rare type of prostate cancer but very serious and quick to spread to other parts of the body.[65] Possible methods include chromatographic separation methods by mass spectrometry, or protein capturing by immunoassays or immunized antibodies. The test method will involve quantifying the amount of the biomarker PCI, with reference to the Gleason Score. Not only is this test quick, it is also sensitive. It can detect patients in the diagnostic grey zone, particularly those with a serum free to total Prostate Specific Antigen ratio of 10-20%.[66]

The oncoprotein BCL-2, has been associated with the development of androgen-independent prostate cancer due to its high levels of expression in androgen-independent tumours in advanced stages of the pathology. The upregulation of BCL-2 after androgen ablation in prostate carcinoma cell lines and in a castrated-male rat model further established a connection between BCL-2 expression and prostate cancer progression.[67]

The expression of Ki-67 by immunohistochemistry may be a significant predictor of patient outcome for men with prostate cancer.[68]

ERK5 is a protein that may be used as a marker. ERK5 is present in abnormally high levels of prostate cancer, including invasive cancer which has spread to other parts of the body. It is also present in relapsed cancer following previous hormone therapy. Research shows that reducing the amount of ERK5 found in cancerous cells reduces their invasiveness.[69]

Screening

Prostate cancer screening is an attempt to find unsuspected cancers, and may lead to more specific follow-up tests such as a biopsy, with cell samples taken for closer study. Options include the digital rectal exam (DRE) and the prostate-specific antigen (PSA) blood test. Such screening is controversial and, in some patients, may lead to unnecessary, even harmful, consequences.[5] A 2010 analysis concluded that routine screening with either a DRE or PSA is not supported by the evidence as there is no mortality benefit from screening.[4] More recently, the United States Preventive Services Task Force (USPSTF) recommended against the PSA test for prostate cancer screening in healthy men.[70] This USPSTF recommendation, released in October 2011, is based on “review of evidence” studies concluding that “Prostate-specific antigen–based screening results in small or no reduction in prostate cancer–specific mortality and is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary.”[71]

Modern screening tests have found cancers that might never have developed into serious disease, and that “the slight reduction of risk by surgically removing the prostate or treating it with radiation may not outweigh the substantial side effects of these treatments,” an opinion also shared by the CDC.[72][73]

Prevention

There is a significant relation between lifestyle (including food consumption) and cancer prevention.[74] Exercise and diet may help prevent prostate cancer to the same extent as may medications such as alpha-blockers and 5-alpha-reductase inhibitors.

 Medications

Two medications which block the conversion of testosterone to dihydrotestosterone, finasteride[75] and dutasteride,[76] have also shown some promise. The use of these medications for primary prevention is still in the testing phase, and they are not widely used for this purpose. A 2008 study found that finasteride reduces the incidence of prostate cancer by 30%, without any increase in the risk of High-Grade prostate cancer.[77] In the original study it turns out that the smaller prostate caused by finasteride means that a doctor is more likely to hit upon cancer nests and more likely to find aggressive-looking cells.[77]

Compared to placebo treatment, taking 5-alpha-reductase inhibitors (5-ARIs) can reduce a man’s risk of being diagnosed with prostate cancer from around 5–9% to around 4-6% during up to 7 years of treatment, according to a Cochrane Review of studies.[78]

 Ejaculation frequency

More frequent ejaculation also may decrease a man’s risk of prostate cancer. One study showed that men who ejaculated 3-5 times a week at the age of 15-19 had a decreased rate of prostate cancer when they are old, though other studies have shown no benefit.[79][80] The results contradict those of previous studies, that suggested that having many sexual partners, or a high frequency of sexual activity, increases the risk of prostate cancer by up to 40 percent. A key difference may be that these earlier studies defined sexual activity as sexual intercourse, whereas this study focused on the number of ejaculations, whether or not intercourse was involved.[81] Another study completed in 2004 reported that “Most categories of ejaculation frequency were unrelated to risk of prostate cancer. However, high ejaculation frequency was related to decreased risk of total prostate cancer.” The report abstract concluded, “Our results suggest that ejaculation frequency is not related to increased risk of prostate cancer.”[82]

Diet

Consuming fish appears to lower prostate cancer deaths but not the occurrence of prostate cancer.[83] Omega-3 fatty acids are unlikely to prevent prostate cancer.[84] There is no evidence that vitamin supplements affect risk.[85] Trans fats may be associated with an increased risk of cancer but the evidence is still limited.[86] The American Dietetic Association and Dieticians of Canada report a decreased incidence of prostate cancer for those following a vegetarian diet.[87]

 Management

Treatment for prostate cancer may involve active surveillance (monitoring for tumor progress or symptoms), surgery (i.e. radical prostatectomy), radiation therapy including brachytherapy (prostate brachytherapy) and external beam radiation therapy, High-intensity focused ultrasound (HIFU), chemotherapy, oral chemotherapeutic drugs (Temozolomide/TMZ), cryosurgery, hormonal therapy, or some combination.[88][89][90] William J. Catalona, MD: regarding Active Surveillance, “Watchful Waiting or for some patients, Wishful Waiting: Can delay prompt treatment of life-threatening tumors, it would require repeated biopsies that often make subsequent nerve-sparing surgery more difficult and it causes many patients anxiety about living with untreated cancer, thus diminishing their quality of life.” These men may have already been chemically castrated and impotent.

Which option is best depends on the stage of the disease, the Gleason score, and the PSA level. Other important factors are age, general health, and patient views about potential treatments and their possible side-effects. Because all treatments can have significant side-effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations. Prostate cancer patients are strongly recommended to work closely with their physicians and use a combination of the treatment options when managing their prostate cancer.[91][92][93]

Because of PSA screening, almost 90% of patients are diagnosed when the cancer is localized to the prostate gland and its removal by surgery or radiotherapy will in most cases lead to a cure. Because of this almost 94% of U.S. patients choose treatment. However, in 50% to 75% of these patients the cancer would not have affected their survival even without treatment, and by accepting treatment they have a high chance of sexual, urinary, and bowel side effects. For instance, two-thirds of treated patients cannot get sufficient erections for intercourse, and almost a third have urinary leakage. However, some cancers will grow faster and prostate cancer is the second most common reason of cancer death in U.S. men, after lung cancer. Even the most intelligent and educated patient faces this uncertainty, and 1 in 6 men will be diagnosed with prostate cancer in their life time. The National Comprehensive Cancer Network (NCCN) offers annually updated and the most evidence-based guidelines for prostate cancer, as for all cancers, that can help newly-diagnosed and established patients to choose the best option for their specific clinical situation. For prostate cancer the NCCN guideline has been rated the most highly. However, all guidelines including the NCCN guideline need a good estimation of the patient’s long-term health-adjusted life expectancy, because this factor is the most important determinant of survival in newly diagnosed patients. Primary care physicians and urologists find it hard to make this estimate – which might be the reason why guidelines are not used even though the treatment choice is so complex. An easy and evidence-based approach (http://www.ncbi.nlm.nih.gov/pubmed/21842788)[94] to decision-making has been published in the August 15, 2011 issue of the American Family Physician, the most commonly read journal in primary care. The authors have shown how to estimate health-adjusted life expectancy and have simplified NCCN guidelines so that patients can have a roadmap to reach the decision recommended for their clinical situation from where they can use personal preferences based on side-effect profiles of different treatment options. Patients can use a newly-developed 18-item questionnaire to find if they have good knowledge and understanding about treatment options before they choose an option; over half of 184 surveyed patients who had been newly-diagnosed and had already met with their urologist after the diagnosis and had chosen a treatment option could not correctly answer over half of questions even though 90% patients had good health literacy and over 60% were college-educated. The authors have also provided a one-page patient information handout.

Although the widespread use of prostate specific antigen (PSA) screening in the USA has resulted in diagnosis at earlier age and cancer stage, the vast majority of cases are still diagnosed in men older than 65 years, and approximately 25% of cases are diagnosed in men older than 75 years.[95] Though US National Comprehensive Cancer Network guidelines[96] recommend using life expectancy greater than or less than 10 years to help make treatment decisions, in practice, many elderly patients are not offered curative treatment options such as radical prostatectomy (RP) or radiation therapy and are instead treated with hormonal therapy or watchful waiting. This pattern can be attributed to factors such as medical co-morbidity and patient preferences is regard to quality of life in addition to prostate cancer specific risk factors such as pretreatment PSA, Gleason score and clinical stage. As the average life expectancy increases due to advances in treatment of cardiovascular, pulmonary and other chronic disease, it is likely that more elderly patients will be living long enough to suffer the consequences of their prostate cancer. Therefore, there is currently much interest in the role of aggressive prostate cancer treatment modalities such as with surgery or radiation in the elderly population who have localized disease. The results of one randomized controlled trial published by the Scandinavian Prostate Cancer Group 4 [97] evaluated cancer-specific mortality in patients treated with RP compared with watchful waiting. The patients receiving radical prostatectomy had a relative risk reduction of 30.7% [95% confidence interval 2.5%-50.7%], but an absolute risk reduction of 6% [95% confidence interval 0.5%-11.5%]. The number needed to treat was calculated to be 16. This means that, over the median follow up period of approximately 10 years, 16 patients with localized prostate cancer would need to receive radical prostatectomy rather than watchful waiting in order to prevent one death due to prostate cancer. Further subset analysis revealed that this benefit did not apply to all ages equally. In men younger than 65 years, patients randomized to receive radical prostatectomy actually had a 10-18% absolute risk reduction in cancer-specific mortality compared to those randomized to watchful waiting. However, in men older than 65, there was no statistically significant risk reduction even when adjusted for PSA level, Gleason score and tumor stage. Randomized, controlled trials comparing radical prostatectomy, radiation therapy, hormonal therapy and watchful waiting would provide the best evidence for how to best treat elderly patients. Such trials are urgently needed, as the elderly population is rapidly growing and is expected to continue to do so. Study results in 2011 suggest active surveillance is the best choice for older ‘low-risk’ patients.[98]

The selection of treatment options may be a complex decision involving many factors. For example, radical prostatectomy after primary radiation failure is a very technically challenging surgery and may not be an option, while salvage radiation therapy after surgical failure may have many complications.[99] This may enter into the treatment decision.

If the cancer has spread beyond the prostate, treatment options significantly change, so most doctors that treat prostate cancer use a variety of nomograms to predict the probability of spread. Treatment by watchful waiting/active surveillance, external beam radiation therapy, brachytherapy, cryosurgery, HIFU, and surgery are, in general, offered to men whose cancer remains within the prostate. Hormonal therapy and chemotherapy are often reserved for disease that has spread beyond the prostate. However, there are exceptions: radiation therapy may be used for some advanced tumors, and hormonal therapy is used for some early stage tumors. Cryotherapy (the process of freezing the tumor), hormonal therapy, and chemotherapy may also be offered if initial treatment fails and the cancer progresses.[100]

Castration-resistant prostate cancer

Most hormone dependent cancers become refractory after one to three years and resume growth despite hormone therapy. Previously considered “hormone-refractory prostate cancer” or “androgen-independent prostate cancer”, the term castration-resistant has replaced “hormone refractory” because while they are no longer responsive to castration treatment (reduction of available androgen/testosterone/DHT by chemical or surgical means), these cancers still show reliance upon hormones for androgen receptor activation.[101] Before 2004, all treatments for castration-resistant prostate cancer (CRPC) were considered[who?] palliative and not shown to prolong survival.[citation needed] However, there are now several treatments available to treat CRPC that improve survival.

The cancer chemotherapic docetaxel has been used as treatment for (CRPC) with a median survival benefit of 2 to 3 months.[102][103] Docetaxel’s FDA approval in 2004 was significant as it was the first treatment proven to prolong survival in CRPC. In 2010, the FDA approved a second-line chemotherapy treatment known as cabazitaxel.[104]

Off-label use of the oral drug ketoconazole is sometimes used as a way to further manipulate hormones with a therapeutic effect in CRPC. However, many side effects are possible with this drug and abiraterone is likely to supplant usage since it has a similar mechanism of action with less toxic side effects.

A combination of bevacizumab (Avastin), docetaxel, thalidomide and prednisone appears effective in the treatment of CRPC.[105]

The immunotherapy treatment with sipuleucel-T is also effective in the treatment of CRPC with a median survival benefit of 4.1 months.[106]

The second line hormonal therapy abiraterone (Zytiga) completed a phase 3 trial for CRPC patients who have failed chemotherapy in 2010. Results were positive with overall survival increased by 4.6 months when compared to placebo. On April 28, 2011, the U.S. Food and Drug Administration approved abiraterone acetate in combination with prednisone to treat patients with late-stage (metastatic) castration-resistant prostate cancer who have received prior docetaxel (chemotherapy).[107]

Alpharadin completed a phase 3 trial for CRPC patients with bone metastasis. A pre-planned interim analysis showed improved survival and quality of life. The study was stopped for ethical reasons to give the placebo group the same treatment. Apharadin uses bone targeted Radium-223 isotopes to kill cancer cells by alpha radiation. Alpharadin is an investigational agent and is not approved for marketing by the European Medicines Agency (EMA), the U.S. Food and Drug Administration (FDA), or any other health authorities.[108]

There are also several treatments currently in clinical trials to treat CRPC. These include the 2nd generation hormonal therapies MDV3100 and orteronel (TAK-700), the immunotherapy PROSTVAC, and the bone metastasis-targeting cabozantinib (XL-184).

 Prognosis

Prostate cancer rates are higher and prognosis poorer in developed countries than the rest of the world. Many of the risk factors for prostate cancer are more prevalent in the developed world, including longer life expectancy and diets high in red meat. (People who consume larger amounts of meat and dairy also tend to consume fewer portions of fruits and vegetables. It is not currently clear whether both of these factors, or just one of them, contribute to the occurrence of prostate cancer.[109]) Also, where there is more access to screening programs, there is a higher detection rate. Prostate cancer is the ninth-most-common cancer in the world, but is the number-one non-skin cancer in men from the United States. Prostate cancer affected eighteen percent of American men and caused death in three percent in 2005.[110] In Japan, death from prostate cancer was one-fifth to one-half the rates in the United States and Europe in the 1990s.[111] In India in the 1990s, half of the people with prostate cancer confined to the prostate died within ten years.[112] African-American men have 50–60 times more prostate cancer and prostate cancer deaths than men in Shanghai, China.[113] In Nigeria, two percent of men develop prostate cancer, and 64% of them are dead after two years.[114]

In patients who undergo treatment, the most important clinical prognostic indicators of disease outcome are stage, pre-therapy PSA level, and Gleason score. In general, the higher the grade and the stage, the poorer the prognosis. Nomograms can be used to calculate the estimated risk of the individual patient. The predictions are based on the experience of large groups of patients suffering from cancers at various stages.[115]

In 1941, Charles Huggins reported that androgen ablation therapy causes regression of primary and metastatic androgen-dependent prostate cancer.[116] He was awarded the 1966 Nobel Prize for Physiology or Medicine for this discovery. Androgen ablation therapy causes remission in 80-90% of patients undergoing therapy, resulting in a median progression-free survival of 12 to 33 months. After remission, an androgen-independent phenotype typically emerges, wherein the median overall survival is 23–37 months from the time of initiation of androgen ablation therapy.[117] The actual mechanism contributes to the progression of prostate cancer is not clear and may vary between individual patient. A few possible mechanisms have been proposed.[118]

Classification systems

Many prostate cancers are not destined to be lethal, and most men will ultimately die from causes other than of the disease. Decisions about treatment type and timing may, therefore, be informed by an estimation of the risk that the tumor will ultimately recur after treatment and/or progress to metastases and mortality. Several tools are available to help predict outcomes, such as pathologic stage and recurrence after surgery or radiation therapy. Most combine stage, grade, and PSA level, and some also add the number or percent of biopsy cores positive, age, and/or other information.

  • The D’Amico classification stratifies men by low, intermediate, or high risk based on stage, grade, and PSA. It is used widely in clinical practice and research settings. The major downside to the 3-level system is that it does not account for multiple adverse parameters (e.g., high Gleason score and high PSA) in stratifying patients.
  • The Partin tables predict pathologic outcomes (margin status, extraprostatic extension, and seminal vesicle invasion) based on the same three variables and are published as lookup tables.
  • The Kattan nomograms predict recurrence after surgery and/or radiation therapy, based on data available either at time of diagnosis or after surgery. The nomograms can be calculated using paper graphs or software available on a website or for handheld computers. The Kattan score represents the likelihood of remaining free of disease at a given time interval following treatment.
  • The UCSF Cancer of the Prostate Risk Assessment (CAPRA) score predicts both pathologic status and recurrence after surgery. It offers comparable accuracy as the Kattan preoperative nomogram, and can be calculated without paper tables or a calculator. Points are assigned based on PSA, Grade, stage, age, and percent of cores positive; the sum yields a 0–10 score, with every 2 points representing roughly a doubling of risk of recurrence. The CAPRA score was derived from community-based data in the CaPSURE database. It has been validated among over 10,000 prostatectomy patients, including patients from CaPSURE;[119] the SEARCH registry, representing data from several Veterans Administration and active military medical centers;[120] a multi-institutional cohort in Germany;[121] and the prostatectomy cohort at Johns Hopkins University.[122] More recently, it has been shown to predict metastasis and mortality following prostatectomy, radiation therapy, watchful waiting, or androgen deprivation therapy.[123]

Epidemiology

Age-standardized death from prostate cancer per 100,000 inhabitants in 2004.[124]

  no data
  less than 4
  4-8
  8-12
  12-16
  16-20
  20-24
  24-28
  28-32
  32-36
  36-40
  40-44
  more than 44

Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States.[2] According to the American Cancer Society, prostate cancer is least common among Asian men and most common among black men, with figures for white men in between.[125][126] The average annual incidence rate of prostate cancer between 1988 and 1992 among Chinese men in the United States was 15 times higher than that of their counterparts living in Shanghai and Tianjin.[125][126][127] However, these high rates may be affected by increasing rates of detection.[128] Many suggest that prostate cancer may be under reported, yet BPH incidence in China and Japan is similar to rates in Western countries.,[129][130]

Prostate cancer develops primarily in men over fifty. It is the most common type of cancer in men in the United States, with 186,000 new cases in 2008 and 28,600 deaths.[131] It is the second leading cause of cancer death in U.S. men after lung cancer. In the United Kingdom it is also the second most common cause of cancer death after lung cancer, where around 35,000 cases are diagnosed every year and of which around 10,000 die of it. Many factors, including genetics and diet, have been implicated in the development of prostate cancer. The Prostate Cancer Prevention Trial found that finasteride reduces the incidence of prostate cancer by 30%. There had been a controversy about this also increasing the risk of more aggressive cancers, but more recent research showed this may not be the case.[77][132]

More than 80% of men will develop prostate cancer by the age of 80.[133] However, in the majority of cases, it will be slow-growing and harmless. In such men, diagnosing prostate cancer is overdiagnosis—the needless identification of a technically aberrant condition that will never harm the patient—and treatment in such men exposes them to all of the adverse effects, with no possibility of extending their lives.[134]

History

Although the prostate was first described by Venetian anatomist Niccolò Massa in 1536, and illustrated by Flemish anatomist Andreas Vesalius in 1538, prostate cancer was not identified until 1853.[135] Prostate cancer was initially considered a rare disease, probably because of shorter life expectancies and poorer detection methods in the 19th century. The first treatments of prostate cancer were surgeries to relieve urinary obstruction.[136] Removal of the entire gland (radical perineal prostatectomy) was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital.[137] Surgical removal of the testes (orchiectomy) to treat prostate cancer was first performed in the 1890s, but with limited success. Transurethral resection of the prostate (TURP) replaced radical prostatectomy for symptomatic relief of obstruction in the middle of the 20th century because it could better preserve penile erectile function. Radical retropubic prostatectomy was developed in 1983 by Patrick Walsh.[138] This surgical approach allowed for removal of the prostate and lymph nodes with maintenance of penile function.

In 1941, Charles B. Huggins published studies in which he used estrogen to oppose testosterone production in men with metastatic prostate cancer. This discovery of “chemical castration” won Huggins the 1966 Nobel Prize in Physiology or Medicine.[139] The role of the hormone GnRH in reproduction was determined by Andrzej W. Schally and Roger Guillemin, who both won the 1977 Nobel Prize in Physiology or Medicine for this work.

Receptor agonists, such as leuprolide and goserelin, were subsequently developed and used to treat prostate cancer.[140][141]

Radiation therapy for prostate cancer was first developed in the early 20th century and initially consisted of intraprostatic radium implants. External beam radiation became more popular as stronger radiation sources became available in the middle of the 20th century. Brachytherapy with implanted seeds was first described in 1983.[142]

Systemic chemotherapy for prostate cancer was first studied in the 1970s. The initial regimen of cyclophosphamide and 5-fluorouracil was quickly joined by multiple regimens using a host of other systemic chemotherapy drugs.[143]

On 30 July 2010 Owen Witte M.D. et al. of UCLA published a series of studies in Science during which they had introduced viruses known to cause cancerous mutation in prostate cells: AKT, ERG, and AR into isolated samples of basal and luminal cells and grafted the treated tissue into mice. After 16 weeks, none of the luminal samples had undergone malignant mutation, while the basal samples had mutated into prostate-like tubules which had then developed malignancy and formed cancerous tumors, which appeared identical to human samples under magnification. This led to the conclusion that the prostate basal cell may be the most likely “site of origin” of prostate cancer.[144]

Society and culture

Discrimination

People with prostate cancer generally encounter significant disparities in awareness, funding, media coverage, and research—and therefore, inferior treatment and poorer outcomes—compared to other cancers of equal prevalence.[145] In 2001 The Guardian noted that Britain had 3,000 nurses specializing in breast cancer, compared to only one for prostate cancer. It also discovered that the waiting time between referral and diagnosis was two weeks for breast cancer but three months for prostate cancer.[146] A 2007 report by The National Prostate Cancer Coalition stated that for every prostate cancer drug on the market, there were seven used to treat breast cancer. The Times also noted an “anti-male bias in cancer funding” with a four to one discrepancy in the United Kingdom by both the government and by cancer charities such as Cancer Research UK.[145][147] Equality campaigners such as author Warren Farrell cite such stark spending inequalities as a clear example of governments unfairly favouring women’s health over men’s health.[148]

Disparities also extend into areas such as detection, with governments failing to fund or mandate prostate cancer screening while fully supporting breast cancer programs. For example, a 2007 report found 49 U.S. states mandate insurance coverage for routine breast cancer screening, compared to 28 for prostate cancer.[145][149] Prostate cancer also experiences significantly less media coverage than other, equally prevalent cancers, with a study by Prostate Coalition showing 2.6 breast cancer stories for each one covering cancer of the prostate.[145]

Prostate cancer awareness month

Prostate cancer awareness month takes place in September in a number of countries. A blue ribbon is used to promote the cause.[150][151]

 Research

Androgen at a concentration of 10-fold higher than the physiological concentration has also been shown to cause growth suppression and reversion of androgen-independent prostate cancer xenografts or androgen-independent prostate tumors derived in vivo model to an androgen-stimulated phenotype in athymic mice.[152][153] These observation suggest the possibility to use androgen to treat the development of relapsed androgen-independent prostate tumors in patients.

Oral infusion of green tea catechins, a potential alternative therapy for prostate cancer by natural compounds, has been shown to inhibit the development, progression, and metastasis as well in autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which spontaneously develops prostate cancer.[154]

The insulin-like growth factor signaling axis is thought to play a key role in the progression of prostate carcinoma. It consists of two ligands (IGF-1 and IGF-2), two receptors (IGF-IR and IGF-IIR) and six related high-affinity IGF-binding proteins (IGFBP 1-6).[155] Altered expression of IGF axis members has been implicated in the development of many different types of cancers, including prostate.[156][157]

A genistein derivative KBU2046 is under investigation for prostate cancer.[158] MDV3100 is in phase III trials for HRPC (chemo-naive and post-chemo patient populations).[159]

 Prostate cancer models

Scientists have established a few prostate cancer cell lines to investigate the mechanism involved in the progression of prostate cancer. LNCaP, PC-3 (PC3), and DU-145 (DU145) are commonly used prostate cancer cell lines. The LNCaP cancer cell line was established from a human lymph node metastatic lesion of prostatic adenocarcinoma. PC-3 and DU-145 cells were established from human prostatic adenocarcinoma metastatic to bone and to brain, respectively. LNCaP cells express androgen receptor (AR); however, PC-3 and DU-145 cells express very little or no AR. AR, an androgen-activated transcription factor, belongs to the steroid nuclear receptor family. Development of the prostate is dependent on androgen signaling mediated through AR, and AR is also important during the development of prostate cancer. The proliferation of LNCaP cells is androgen-dependent but the proliferation of PC-3 and DU-145 cells is androgen-insensitive. Elevation of AR expression is often observed in advanced prostate tumors in patients.[160][161] Some androgen-independent LNCaP sublines have been developed from the ATCC androgen-dependent LNCaP cells after androgen deprivation for study of prostate cancer progression. These androgen-independent LNCaP cells have elevated AR expression and express prostate specific antigen upon androgen treatment. The paradox is that androgens inhibit the proliferation of these androgen-independent prostate cancer cells.[162][163][164]

 Diagnosis

At present, an active area of research and non-clinically applied investigations involve non-invasive methods of prostate tumor detection. Adenoviruses modified to transfect tumor cells with harmless yet distinct genes (such as luciferase) have proven capable of early detection. So far, however, this area of research has been tested only in animal and LNCaP cell models.[165]

EN2

Presence of the EN2 (gene) in urine has been correlated to a high probability of prostate cancer.[166] Co-researchers Hardev Pandha, and Richard Morgan published their findings in the 1 March 2011 issue of the journal Clinical Cancer Research.[167] A laboratory test currently identifies EN2 in urine, and a home test kit is envisioned similar to a home pregnancy test strip. According to Morgan, “We are preparing several large studies in the UK and in the US and although the EN2 test is not yet available, several companies have expressed interest in taking it forward.” [168]

PCA3

Another potential non-invasive method of early prostate tumor detection is through a molecular test that detects the presence of cell-associated PCA3 mRNA in fluid massaged from the prostate by the doctor and first-void urinated out within a limited amount of urine into the specimen container. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. The test result is currently reported as a specimen ratio of PCA3 mRNA to PSA mRNA. Although not a replacement for serum PSA level, the PCA3 test is an additional tool to help decide whether, in men suspected of having prostate cancer (especially if an initial biopsy fails to explain the elevated serum PSA), a biopsy/rebiopsy is really needed. The higher the expression of PCA3 in the sample, the greater the likelihood of a positive biopsy; i.e., the presence of cancer cells in the prostate.

Early prostate cancer antigen-2

It was reported in April 2007 that research is being conducted on a new blood test for early prostate cancer antigen-2 (EPCA-2) that may alert men if they have prostate cancer and how aggressive it will be.[169][170]

Thrombophlebitis is associated with an increased risk of prostate cancer and may be a good way for physicians to remind themselves to screen patients with thrombophlebitis for prostate cancer as well since these two are closely linked.[171]

Prostasomes

Epithelial cells of the prostate secrete prostasomes as well as PSA. Prostasomes are membrane–surrounded, prostate-derived organelles that appear extracellularly, and one of their physiological functions is to protect the sperm from attacks by the female immune system. Cancerous prostate cells continue to synthesize and secrete prostasomes, and may be shielded against immunological attacks by these prostasomes. Research of several aspects of prostasomal involvement in prostate cancer has been performed

Indonesia version

Kanker Prostat
Klasifikasi dan sumber daya eksternal

Mikrograf adenokarsinoma prostat, asinar jenis, jenis yang paling umum dari kanker prostat. Gleason pola 4. Biopsi jarum. H & E noda.
ICD-10 C61
ICD-9 185
OMIM 176807
DiseasesDB 10780
MedlinePlus 000380
eMedicine radio/574
MESH D011471

Kanker prostat adalah bentuk kanker yang berkembang di prostat, sebuah kelenjar dalam sistem reproduksi laki-laki. Kanker prostat paling lambat tumbuh, namun, ada kasus-kasus kanker prostat agresif [1] Sel-sel kanker dapat bermetastasis (menyebar) dari prostat ke bagian lain dari tubuh, khususnya tulang dan kelenjar getah bening.. Kanker prostat dapat menyebabkan rasa sakit, kesulitan dalam buang air kecil, masalah selama hubungan seksual, atau disfungsi ereksi. Gejala lain yang berpotensi dapat mengembangkan selama tahap-tahap akhir dari penyakit.

Tingkat deteksi kanker prostat sangat bervariasi di seluruh dunia, dengan Asia Selatan dan Timur mendeteksi lebih jarang daripada di Eropa, dan terutama Amerika Serikat [2] Kanker prostat cenderung untuk mengembangkan pada pria di atas usia lima puluh dan meskipun. Ini adalah salah satu jenis yang paling umum dari kanker pada pria, banyak yang tidak pernah memiliki gejala, menjalani terapi tidak ada, dan akhirnya meninggal karena penyebab lain. Hal ini karena kanker prostat adalah, dalam banyak kasus, lambat tumbuh, gejala-bebas, dan karena laki-laki dengan kondisi lebih tua mereka sering meninggal karena penyebab yang tidak terkait dengan kanker prostat, seperti jantung / penyakit peredaran darah, radang paru-paru, lainnya tidak berhubungan kanker, atau usia tua. Sekitar dua-pertiga kasus lambat tumbuh, ketiga lainnya lebih agresif dan cepat berkembang [3].

Banyak faktor, termasuk genetika dan diet, telah terlibat dalam perkembangan kanker prostat. Kehadiran kanker prostat dapat diindikasikan dengan gejala-gejala, pemeriksaan fisik, antigen spesifik prostat-(PSA), atau biopsi. Tes PSA meningkatkan deteksi kanker tetapi tidak menurunkan angka kematian [4]. Selain itu, tes skrining prostat adalah kontroversial saat ini dan dapat menyebabkan tidak perlu, bahkan berbahaya, konsekuensi pada beberapa pasien. [5] Meskipun demikian, diduga kanker prostat biasanya dikonfirmasi dengan mengambil biopsi prostat dan memeriksanya di bawah mikroskop. Tes lebih lanjut, seperti CT scan dan scan tulang, dapat dilakukan untuk menentukan apakah kanker prostat telah menyebar.

Pilihan pengobatan untuk kanker prostat dengan maksud untuk menyembuhkan terutama pembedahan, terapi radiasi, radiosurgery stereotactic, dan terapi proton. Pengobatan lain, seperti terapi hormonal, kemoterapi, cryosurgery, dan intensitas tinggi terfokus USG (HIFU) juga ada, meskipun tidak disetujui FDA, tergantung pada skenario klinis dan hasil yang diinginkan.

Usia dan kesehatan mendasar dari manusia, sejauh mana metastasis, penampilan di bawah mikroskop, dan respon kanker terhadap pengobatan awal adalah penting dalam menentukan hasil dari penyakit. Keputusan apakah atau tidak untuk mengobati kanker prostat lokal (suatu tumor yang terkandung dalam prostat) dengan maksud penyembuhan adalah trade off-pasien antara efek menguntungkan dan merugikan yang diharapkan dalam hal kelangsungan hidup pasien dan kualitas hidup.

Ikhtisar

Prostat adalah bagian dari sistem reproduksi laki-laki yang membantu membuat dan menyimpan cairan seminal. Pada pria dewasa, prostat tipikal adalah sekitar tiga sentimeter panjang dan berat sekitar dua puluh gram [6]. Hal ini terletak di panggul, di bawah kandung kemih dan di depan rektum. Prostat mengelilingi bagian dari urethra, tabung yang membawa urin dari kandung kemih saat buang air kecil dan air mani saat ejakulasi [7] Karena lokasinya, prostat sering mempengaruhi penyakit kencing, ejakulasi, dan jarang buang air besar.. Berisi kelenjar prostat kecil yang membuat sekitar dua puluh persen dari cairan mani yang merupakan [8] Pada kanker prostat, sel-sel kelenjar prostat ini bermutasi menjadi sel kanker.. Kelenjar prostat memerlukan hormon laki-laki, yang dikenal sebagai androgen, untuk bekerja dengan baik. Androgen termasuk testosteron, yang dibuat di testis, dehydroepiandrosterone, yang dibuat di kelenjar adrenal, dan dihidrotestosteron, yang dikonversi dari testosteron dalam prostat itu sendiri. Androgen juga bertanggung jawab untuk karakteristik seks sekunder seperti rambut wajah dan massa otot meningkat.

Manajemen
Artikel utama: Manajemen kanker prostat
Pengobatan untuk kanker prostat mungkin melibatkan surveilans aktif (pemantauan untuk kemajuan tumor atau gejala), operasi (yaitu prostatektomi radikal), terapi radiasi termasuk brachytherapy (brachytherapy prostat) dan terapi radiasi sinar eksternal, intensitas tinggi terfokus USG (HIFU), kemoterapi, lisan obat-obat kemoterapi (Temozolomide / TMZ), cryosurgery, terapi hormonal, atau beberapa kombinasi [88] [89] [90] William J. Catalona, ​​MD:. tentang Pengawasan aktif, “Menunggu Waspada atau untuk beberapa pasien, Menunggu Wishful: Dapatkah keterlambatan perawatan segera dari kehidupan-mengancam tumor, itu akan memerlukan biopsi berulang yang sering membuat selanjutnya saraf-sparing lebih sulit dan hal itu menyebabkan kecemasan banyak pasien tentang hidup dengan kanker tidak diobati, sehingga mengurangi kualitas hidup mereka. ” Orang-orang ini mungkin telah dikebiri dan tidak berdaya kimia.

Pilihan mana yang terbaik tergantung pada tahap penyakit, skor Gleason, dan tingkat PSA. Faktor penting lainnya adalah usia, kesehatan umum, dan pandangan pasien tentang perawatan potensial dan kemungkinan efek samping. Karena semua perawatan dapat memiliki efek samping yang signifikan, seperti disfungsi ereksi dan inkontinensia urin, diskusi pengobatan sering fokus pada menyeimbangkan tujuan terapi dengan risiko perubahan gaya hidup. Kanker prostat pasien sangat dianjurkan untuk bekerja sama dengan dokter mereka dan menggunakan kombinasi pilihan pengobatan kanker prostat ketika mengelola mereka [91] [92] [93].

Karena skrining PSA, hampir 90% dari pasien yang didiagnosis ketika kanker terlokalisasi kelenjar prostat dan penghapusan dengan pembedahan atau radioterapi di kebanyakan kasus akan mengarah untuk menyembuhkan. Karena ini hampir 94% dari pasien AS memilih pengobatan. Namun, dalam 50% sampai 75% dari pasien kanker tidak akan terpengaruh kelangsungan hidup mereka bahkan tanpa pengobatan, dan dengan menerima perlakuan mereka memiliki kesempatan tinggi seksual, urin, dan efek samping usus. Sebagai contoh, dua pertiga dari pasien yang diobati tidak bisa mendapatkan ereksi yang cukup untuk melakukan hubungan, dan hampir sepertiga memiliki kebocoran kemih. Namun, beberapa kanker akan tumbuh lebih cepat dan kanker prostat adalah alasan kedua yang paling umum kematian kanker pada pria AS, setelah kanker paru-paru. Bahkan pasien yang paling cerdas dan berpendidikan wajah ketidakpastian ini, dan 1 di 6 orang akan didiagnosis dengan kanker prostat dalam waktu kehidupan mereka. Jaringan Kanker Komprehensif Nasional (NCCN) menawarkan setiap tahun diperbaharui dan pedoman berbasis bukti paling untuk kanker prostat, seperti untuk semua kanker, yang dapat membantu yang baru didiagnosis dan mendirikan pasien untuk memilih pilihan terbaik untuk situasi yang spesifik klinis mereka. Untuk kanker prostat pedoman NCCN telah dinilai yang paling tinggi. Namun, semua pedoman termasuk pedoman NCCN membutuhkan estimasi yang baik jangka panjang kesehatan disesuaikan Harapan hidup pasien, karena faktor ini adalah determinan paling penting dari kelangsungan hidup pada pasien yang baru didiagnosis. Dokter perawatan primer dan urolog merasa sulit untuk membuat perkiraan ini – yang mungkin menjadi alasan mengapa pedoman tidak digunakan meskipun pilihan pengobatan sangat kompleks. Sebuah pendekatan yang mudah dan berbasis bukti (http://www.ncbi.nlm.nih.gov/pubmed/21842788) [94] untuk pengambilan keputusan telah diterbitkan dalam edisi 15 Agustus 2011 dari Dokter Keluarga Amerika, paling sering membaca jurnal dalam perawatan primer. Para penulis telah menunjukkan bagaimana untuk memperkirakan kesehatan disesuaikan harapan hidup dan telah menyederhanakan NCCN pedoman sehingga pasien dapat memiliki peta jalan untuk mencapai keputusan yang direkomendasikan untuk situasi klinis mereka dari mana mereka dapat menggunakan preferensi pribadi berdasarkan profil efek samping pilihan pengobatan yang berbeda . Pasien dapat menggunakan baru dikembangkan 18-item kuesioner untuk menemukan jika mereka memiliki pengetahuan dan pemahaman yang baik tentang pilihan pengobatan sebelum mereka memilih pilihan; lebih dari setengah dari 184 pasien yang disurvei yang telah baru didiagnosis dan telah bertemu dengan urolog mereka setelah diagnosis dan memilih pilihan pengobatan tidak bisa menjawab secara benar lebih dari setengah pertanyaan meskipun 90% pasien memiliki melek kesehatan yang baik dan lebih dari 60% adalah berpendidikan tinggi. Para penulis juga memberikan selebaran satu halaman informasi pasien.

Meskipun meluasnya penggunaan skrining prostat spesifik (PSA) antigen di Amerika Serikat telah mengakibatkan diagnosis pada usia awal dan tahap kanker, sebagian besar kasus masih didiagnosis pada pria lebih tua dari 65 tahun, dan sekitar 25% dari kasus yang didiagnosis di pria yang lebih tua dari 75 tahun [95] Meskipun. US National Comprehensive Cancer pedoman Jaringan [96] pilihan pengobatan merekomendasikan menggunakan harapan hidup lebih besar dari atau kurang dari 10 tahun untuk membantu membuat keputusan pengobatan, dalam praktek, pasien usia lanjut banyak yang tidak ditawarkan kuratif seperti prostatektomi radikal (RP) atau terapi radiasi dan malah diobati dengan terapi hormon atau menunggu waspada. Pola ini dapat dikaitkan dengan faktor-faktor seperti medis co-morbiditas dan pasien preferensi yang berkaitan dengan kualitas hidup di samping faktor risiko kanker prostat tertentu seperti pretreatment PSA, skor Gleason dan stadium klinis. Sebagai harapan hidup rata-rata meningkat karena kemajuan dalam pengobatan kardiovaskular, penyakit kronis paru dan lainnya, kemungkinan bahwa lebih banyak pasien lansia akan tinggal cukup lama menderita akibat kanker prostat mereka. Oleh karena itu, saat ini ada minat banyak peran agresif modalitas pengobatan kanker prostat seperti dengan operasi atau radiasi pada populasi lanjut usia yang memiliki penyakit lokal. Hasil dari salah satu uji coba terkontrol secara acak yang diterbitkan oleh Kelompok Kanker Prostat Skandinavia 4 [97] dievaluasi spesifik kanker kematian pada pasien yang diobati dengan RP dibandingkan dengan menunggu waspada. Pasien yang menerima prostatektomi radikal mengalami penurunan risiko relatif dari 30,7% [95% confidence interval 2,5% -50,7%], tetapi pengurangan risiko absolut dari 6% [95% confidence interval 0,5% -11,5%]. Jumlah yang diperlukan untuk mengobati dihitung menjadi 16. Ini berarti bahwa, selama median masa tindak lanjut sekitar 10 tahun, 16 pasien dengan kanker prostat lokal akan perlu untuk menerima prostatektomi radikal daripada menunggu waspada untuk mencegah satu kematian akibat kanker prostat. Analisis subset lebih lanjut mengungkapkan bahwa manfaat ini tidak berlaku untuk semua usia sama. Pada pria yang lebih muda dari 65 tahun, pasien diacak untuk menerima prostatektomi radikal benar-benar memiliki 10-18% pengurangan risiko absolut kanker kematian spesifik dibandingkan dengan mereka secara acak menunggu waspada. Namun, pada pria lebih tua dari 65, tidak ada pengurangan risiko statistik signifikan bahkan ketika disesuaikan dengan PSA, skor Gleason dan stadium tumor. Acak, percobaan dikontrol membandingkan prostatektomi radikal, terapi radiasi, terapi hormonal dan menunggu waspada akan memberikan bukti terbaik untuk cara terbaik untuk mengobati pasien usia lanjut. Percobaan tersebut sangat dibutuhkan, karena populasi lansia berkembang pesat dan diperkirakan akan terus melakukannya. Hasil penelitian pada 2011 menunjukkan surveilans aktif adalah pilihan terbaik untuk ‘risiko rendah’ ​​tua pasien. [98]

Pemilihan pilihan pengobatan mungkin keputusan yang kompleks yang melibatkan banyak faktor. Sebagai contoh, prostatektomi radikal setelah kegagalan radiasi utama adalah operasi yang sangat teknis menantang dan tidak mungkin menjadi pilihan, sementara menyelamatkan terapi radiasi setelah kegagalan bedah mungkin memiliki banyak komplikasi [99]. Hal ini dapat masuk ke dalam keputusan pengobatan.

Jika kanker telah menyebar keluar prostat, pilihan pengobatan secara signifikan berubah, sehingga kebanyakan dokter yang mengobati kanker prostat menggunakan berbagai nomogram untuk memprediksi kemungkinan menyebar. Pengobatan dengan menunggu waspada / surveilans aktif, terapi sinar radiasi eksternal, brakiterapi, cryosurgery, HIFU, dan operasi, secara umum, ditawarkan kepada laki-laki yang kanker masih dalam prostat. Terapi hormonal dan kemoterapi yang sering disediakan untuk penyakit yang telah menyebar ke luar prostat. Namun, ada pengecualian: terapi radiasi dapat digunakan untuk beberapa tumor maju, dan terapi hormonal digunakan untuk beberapa tumor tahap awal. Cryotherapy (proses pembekuan tumor), terapi hormonal, dan kemoterapi juga dapat ditawarkan jika pengobatan awal gagal dan kanker berkembang. [100]

Pengebirian-tahan kanker prostat
Kebanyakan kanker tergantung hormon menjadi refrakter setelah satu sampai tiga tahun dan melanjutkan pertumbuhan meskipun terapi hormon. Sebelumnya dianggap “hormon-refraktori kanker prostat” atau “androgen-independen kanker prostat”, istilah pengebirian-tahan telah menggantikan “hormon refraktori” karena sementara mereka tidak lagi responsif terhadap pengobatan pengebirian (pengurangan androgen tersedia / testosteron / DHT oleh kimia atau cara bedah), kanker ini masih menunjukkan ketergantungan pada hormon untuk aktivasi reseptor androgen [101] Sebelum 2004, semua pengobatan untuk pengebirian-tahan kanker prostat (CRPC) dianggap. [siapa?] paliatif dan tidak ditampilkan untuk memperpanjang kelangsungan hidup. [kutipan diperlukan] Namun, sekarang ada beberapa perawatan yang tersedia untuk mengobati CRPC yang meningkatkan kelangsungan hidup.

Kanker chemotherapic docetaxel telah digunakan sebagai pengobatan untuk (CRPC) dengan manfaat kelangsungan hidup rata-rata 2 sampai 3 bulan [102]. [103] docetaxel yang disetujui FDA pada 2004 sangat signifikan itu adalah pengobatan pertama terbukti memperpanjang kelangsungan hidup di CRPC. Pada tahun 2010, FDA menyetujui pengobatan kemoterapi lini kedua dikenal sebagai cabazitaxel. [104]

Off-label penggunaan obat oral ketoconazole kadang-kadang digunakan sebagai cara untuk lebih memanipulasi hormon dengan efek terapeutik pada CRPC. Namun, banyak efek samping yang mungkin dengan obat ini dan abiraterone kemungkinan untuk menggantikan penggunaan karena memiliki mekanisme serupa tindakan dengan efek samping yang kurang beracun.

Sebuah kombinasi bevacizumab (Avastin), docetaxel, thalidomide dan prednison muncul efektif dalam pengobatan CRPC [105].

Perlakuan imunoterapi dengan sipuleucel-T juga efektif dalam pengobatan CRPC dengan manfaat kelangsungan hidup rata-rata 4,1 bulan. [106]

Baris kedua terapi hormon abiraterone (Zytiga) menyelesaikan fase 3 percobaan untuk pasien CRPC yang telah gagal kemoterapi pada 2010. Hasilnya positif dengan kelangsungan hidup secara keseluruhan meningkat sebesar 4,6 bulan bila dibandingkan dengan plasebo. Pada tanggal 28 April 2011, US Food and Drug Administration disetujui asetat abiraterone dalam kombinasi dengan prednisone untuk mengobati pasien dengan stadium akhir (metastasis) pengebirian-tahan kanker prostat yang telah menerima docetaxel sebelumnya (kemoterapi) [107].

Alpharadin menyelesaikan fase 3 percobaan untuk pasien dengan metastasis tulang CRPC. Sebuah analisis pra-direncanakan sementara menunjukkan peningkatan kelangsungan hidup dan kualitas hidup. Penelitian ini dihentikan karena alasan etis untuk memberikan kelompok plasebo perlakuan yang sama. Apharadin menggunakan tulang ditargetkan Radium-223 isotop untuk membunuh sel kanker dengan radiasi alpha. Alpharadin adalah agen diteliti dan tidak disetujui untuk pemasaran oleh European Medicines Agency (EMA), US Food and Drug Administration (FDA), atau otoritas kesehatan lainnya. [108]

Ada juga beberapa perawatan saat ini dalam uji klinis untuk mengobati CRPC. Ini termasuk generasi 2 hormon terapi MDV3100 dan orteronel (TAK-700), yang PROSTVAC imunoterapi, dan tulang metastasis-penargetan cabozantinib (XL-184).

 Prognosa
Kanker prostat tingkat lebih tinggi dan prognosis yang lebih buruk di negara maju daripada seluruh dunia. Banyak faktor risiko untuk kanker prostat lebih umum di negara maju, termasuk harapan hidup lebih lama dan diet tinggi daging merah. (Orang yang mengkonsumsi sejumlah besar daging dan susu juga cenderung mengkonsumsi lebih sedikit porsi buah-buahan dan sayuran Hal ini tidak jelas apakah kedua faktor ini, atau hanya salah satu dari mereka, berkontribusi terhadap terjadinya kanker prostat.. [109]) Juga, di mana ada lebih banyak akses ke program skrining, ada tingkat deteksi lebih tinggi. Kanker prostat adalah kanker kesembilan yang paling umum di dunia, tetapi nomor-satu non-kanker kulit pada pria dari Amerika Serikat. Terkena kanker prostat delapan belas persen pria Amerika dan menyebabkan kematian dalam tiga persen pada tahun 2005 [110] Di Jepang, kematian akibat kanker prostat seperlima satu setengah tingkat di Amerika Serikat dan Eropa pada 1990-an. [111]. Di India pada 1990-an, setengah dari orang dengan kanker prostat terbatas pada prostat meninggal dalam sepuluh tahun [112] Afrika-Amerika laki-laki memiliki kanker prostat 50-60 kali lebih dan kematian akibat kanker prostat daripada laki-laki di Shanghai, Cina.. [113 ] Di Nigeria, dua persen pria menderita kanker prostat, dan 64% dari mereka yang tewas setelah dua tahun [114].

Pada pasien yang menjalani pengobatan, prognosis indikator paling penting dari hasil klinis penyakit tahap, pra-terapi tingkat PSA, dan skor Gleason. Secara umum, semakin tinggi kelas dan panggung, miskin prognosis. Nomogram dapat digunakan untuk menghitung risiko yang diperkirakan dari masing-masing pasien. Prediksi didasarkan pada pengalaman kelompok besar pasien yang menderita kanker pada berbagai tahap. [115]

Pada tahun 1941, Charles Huggins melaporkan bahwa terapi ablasi androgen menyebabkan regresi primer dan metastasis androgen tergantung kanker prostat [116]. Dia dianugerahi Hadiah Nobel 1966 untuk Fisiologi atau Kedokteran untuk penemuan ini. Terapi ablasi androgen menyebabkan remisi pada 80-90% dari pasien yang menjalani terapi, sehingga kelangsungan hidup bebas perkembangan penyakit rata-rata 12 sampai 33 bulan. Setelah remisi, fenotip androgen-independen biasanya muncul, dimana kelangsungan hidup secara keseluruhan median 23-37 bulan dari saat inisiasi terapi ablasi androgen [117]. Mekanisme yang sebenarnya memberikan kontribusi terhadap perkembangan kanker prostat tidak jelas dan dapat bervariasi antara pasien individu. Sebuah mekanisme beberapa kemungkinan telah diusulkan

Klasifikasi
Artikel utama: Prostat stadium kanker
Suatu bagian penting dari mengevaluasi kanker prostat adalah menentukan panggung, atau seberapa jauh kanker telah menyebar. Mengetahui panggung membantu menentukan prognosis dan berguna ketika memilih terapi. Sistem yang paling umum adalah empat tahap sistem TNM (disingkat dari Tumor / Nodes / Metastasis). Komponen-komponennya termasuk ukuran tumor, jumlah kelenjar getah bening yang terlibat, dan kehadiran dari setiap metastasis lainnya. [9]

Perbedaan yang paling penting yang dibuat oleh sistem staging adalah apakah atau tidak kanker masih terbatas pada prostat. Dalam sistem TNM, T1 T2 klinis dan kanker hanya ditemukan di prostat, sementara kanker T3 dan T4 telah menyebar di tempat lain. Beberapa tes dapat digunakan untuk mencari bukti penyebaran. Ini termasuk computed tomography untuk mengevaluasi menyebar di dalam panggul, tulang scan untuk mencari menyebar ke tulang, dan kumparan pencitraan resonansi magnetik untuk endorectal erat mengevaluasi kapsul prostat dan vesikula seminalis. Scan tulang harus mengungkapkan penampilan osteoblastik karena kepadatan tulang meningkat di daerah tulang metastasis-berlawanan dengan apa yang ditemukan pada kanker lain yang bermetastasis.

Setelah biopsi prostat, ahli patologi melihat sampel di bawah mikroskop. Jika kanker hadir, ahli patologi laporan grade dari tumor. Kelas memberitahu berapa banyak jaringan tumor berbeda dari jaringan prostat normal dan menunjukkan seberapa cepat tumor cenderung tumbuh. Sistem Gleason digunakan untuk tumor prostat kelas 2 sampai 10, di mana skor Gleason dari 10 menunjukkan kelainan yang paling. Ahli patologi memberikan nomor dari 1 sampai 5 untuk pola yang paling umum diamati di bawah mikroskop, kemudian melakukan hal yang sama untuk pola kedua-paling-umum. Jumlah dari kedua angka ini adalah skor Gleason. Tahap Whitmore-Jewett adalah metode lain kadang-kadang digunakan.

 Klasifikasi sistem
Kanker prostat Banyak yang tidak ditakdirkan untuk menjadi mematikan, dan kebanyakan pria pada akhirnya akan mati dari penyebab lain dari penyakit. Keputusan tentang jenis pengobatan dan waktu mungkin, karena itu, akan diinformasikan oleh perkiraan resiko bahwa tumor akhirnya akan kambuh setelah pengobatan dan / atau kemajuan untuk metastasis dan kematian. Beberapa alat yang tersedia untuk membantu memprediksi hasil, seperti tahap patologis dan kekambuhan setelah operasi atau terapi radiasi. Kebanyakan tahap menggabungkan, kelas, dan tingkat PSA, dan beberapa juga menambahkan jumlah atau persen dari core biopsi positif, usia, dan / atau informasi lainnya.D’Amico klasifikasi stratifies pria dengan risiko rendah, menengah, atau tinggi berdasarkan tahap, kelas, dan PSA. Hal ini digunakan secara luas dalam praktek klinis dan pengaturan penelitian. Kelemahan utama sistem 3-tingkat adalah bahwa hal itu tidak memperhitungkan parameter yang merugikan (misal, tinggi skor Gleason dan PSA tinggi) pada pasien stratifikasi.
Tabel Partin memprediksi hasil patologis (margin status, ekstensi extraprostatic, dan invasi vesikula seminalis) berdasarkan tiga variabel yang sama dan diterbitkan sebagai tabel lookup.
Para nomogram Kattan memprediksi kekambuhan setelah operasi dan / atau terapi radiasi, berdasarkan data yang tersedia baik pada saat diagnosis atau setelah operasi. Para nomogram dapat dihitung menggunakan grafik kertas atau perangkat lunak yang tersedia di situs Web atau untuk komputer genggam. Skor Kattan mewakili kemungkinan tetap bebas dari penyakit pada interval waktu tertentu setelah pengobatan.
Kanker UCSF skor Penilaian Risiko Prostat (Capra) memprediksi baik status yang patologis dan kekambuhan setelah operasi. Ia menawarkan akurasi yang sebanding sebagai nomogram Kattan praoperasi, dan dapat dihitung tanpa tabel kertas atau kalkulator. Poin ditetapkan berdasarkan PSA, Kelas, panggung, usia, dan persen dari core positif; jumlah tersebut menghasilkan nilai 0-10, dengan setiap 2 poin mewakili sekitar dua kali lipat risiko kekambuhan. Capra skor berasal dari data berbasis masyarakat dalam database CaPSURE. Ini telah divalidasi di antara lebih dari 10.000 pasien prostatektomi, termasuk pasien dari CaPSURE; [119] registri SEARCH, yang mewakili data dari Administrasi Veteran dan aktif beberapa pusat medis militer; [120] kohort multi-institusi di Jerman; [121] dan prostatektomi kohort di Johns Hopkins University [122]. Baru-baru ini, telah ditunjukkan untuk memprediksi metastasis dan kematian setelah prostatektomi, terapi radiasi, menunggu waspada, atau terapi androgen kekurangan. [123]
Epidemiologi

Umur-standar kematian dari kanker prostat per 100.000 penduduk pada tahun 2004 [124].

  tidak ada data
  kurang dari 4
  4-8
  8-12
  12-16
  16-20
  20-24
  24-28
  28-32
  32-36
  36-40
  40-44
  lebih dari 44
Tingkat kanker prostat sangat bervariasi di seluruh dunia. Meskipun tarif sangat bervariasi antar negara, itu paling umum di Asia Selatan dan Timur, lebih umum di Eropa, dan yang paling umum di Amerika Serikat. [2] Menurut American Cancer Society, kanker prostat paling umum di antara pria Asia dan paling umum di kalangan laki-laki hitam, dengan angka untuk orang kulit putih di antara [125] [126]. Tingkat kejadian tahunan rata-rata kanker prostat antara 1988 dan 1992 di kalangan pria Cina di Amerika Serikat adalah 15 kali lebih tinggi daripada rekan-rekan mereka yang tinggal di Shanghai dan Tianjin [125]. [126] [127] Namun, harga ini tinggi mungkin dipengaruhi oleh tingkat peningkatan deteksi. [128] Banyak menunjukkan bahwa kanker prostat mungkin kurang dilaporkan, namun kejadian BPH di Cina dan Jepang mirip dengan tarif di negara-negara Barat., [129] [130]

Kanker prostat berkembang terutama pada pria di atas lima puluh. Ini adalah jenis yang paling umum dari kanker pada pria di Amerika Serikat, dengan 186.000 kasus baru pada 2008 dan 28.600 kematian [131]. Ini adalah penyebab kedua kematian kanker pada pria Amerika Serikat setelah kanker paru-paru. Di Inggris juga merupakan penyebab paling umum kedua kematian kanker setelah kanker paru-paru, di mana sekitar 35.000 kasus didiagnosis setiap tahun dan yang sekitar 10.000 mati itu. Banyak faktor, termasuk genetika dan diet, telah terlibat dalam perkembangan kanker prostat. Kanker Prostat Pencegahan Trial menemukan bahwa finasterida mengurangi insiden kanker prostat sebesar 30%. Ada telah menjadi kontroversi tentang ini juga meningkatkan risiko kanker yang lebih agresif, tetapi penelitian yang lebih baru menunjukkan bahwa hal ini tidak mungkin terjadi. [77] [132]

Lebih dari 80% pria akan mengembangkan kanker prostat pada usia 80 [133] Namun, pada kebanyakan kasus, akan tumbuh lambat dan tidak berbahaya.. Pada pria tersebut, mendiagnosis kanker prostat adalah overdiagnosis-identifikasi perlu dari suatu kondisi teknis menyimpang yang tidak akan pernah merugikan pasien dan pengobatan pada pria tersebut menghadapkan mereka ke semua efek samping, tanpa kemungkinan memperpanjang hidup mereka. [134]

Sejarah
Meskipun prostat pertama kali dijelaskan oleh ahli anatomi Venesia NiccoMassa di 1536, dan diilustrasikan oleh Flemish anatomi Andreas Vesalius pada tahun 1538, kanker prostat tidak teridentifikasi sampai 1853. [135] Kanker prostat awalnya dianggap sebagai penyakit langka, mungkin karena harapan hidup lebih pendek dan metode deteksi miskin di abad ke-19. Perlakuan pertama kanker prostat operasi untuk menghilangkan obstruksi kemih. [136] Penghapusan dari seluruh kelenjar (prostatektomi radikal perineum) pertama kali dilakukan pada tahun 1904 oleh Hugh H. Young di Johns Hopkins Hospital. [137] Operasi pengangkatan testis ( orchiectomy) untuk mengobati kanker prostat pertama kali dilakukan di tahun 1890, tetapi dengan keberhasilan yang terbatas. Reseksi transurethral dari prostat (TURP) diganti prostatektomi radikal untuk mengurangi gejala-gejala obstruksi pada pertengahan abad ke-20 karena lebih bisa memelihara fungsi ereksi penis. Prostatektomi radikal retropubik dikembangkan pada tahun 1983 oleh Patrick Walsh. [138] Hal ini memungkinkan untuk pendekatan bedah pengangkatan prostat dan kelenjar getah bening dengan pemeliharaan fungsi penis.

Pada tahun 1941, Charles B. Huggins menerbitkan studi di mana ia digunakan estrogen untuk menentang produksi testosteron pada pria dengan kanker prostat metastasis. Ini penemuan “pengebirian kimiawi” memenangkan Huggins tahun 1966 Penghargaan Nobel dalam Fisiologi atau Kedokteran. [139] Peran GnRH hormon dalam reproduksi ditentukan oleh Andrzej W. Schally dan Roger Guillemin, yang keduanya memenangkan Hadiah Nobel 1977 dalam Fisiologi atau Kedokteran untuk pekerjaan ini.

Reseptor agonis, seperti leuprolid dan goserelin, yang kemudian dikembangkan dan digunakan untuk mengobati kanker prostat [140]. [141]

Terapi radiasi untuk kanker prostat pertama kali dikembangkan pada awal abad 20 dan pada awalnya terdiri dari implan intraprostatic radium. Radiasi sinar eksternal menjadi lebih populer sebagai sumber radiasi kuat menjadi tersedia pada pertengahan abad ke-20. Brachytherapy dengan biji ditanamkan pertama kali dijelaskan pada tahun 1983. [142]

Kemoterapi sistemik untuk kanker prostat pertama kali dipelajari tahun 1970-an. Regimen awal siklofosfamid dan 5-fluorouracil segera bergabung dengan beberapa rejimen menggunakan sejumlah obat kemoterapi sistemik lainnya. [143]

Pada 30 Juli 2010 Owen Witte M.D. et al. dari UCLA menerbitkan serangkaian studi di Science di mana mereka telah memperkenalkan virus diketahui menyebabkan kanker mutasi dalam sel prostat: Akt, ERG, dan AR ke dalam sampel diisolasi dari sel-sel basal dan luminal dan dicangkokkan jaringan diperlakukan ke tikus. Setelah 16 minggu, tidak ada sampel telah mengalami mutasi luminal ganas, sementara sampel basal telah bermutasi menjadi prostat seperti tubulus yang kemudian berkembang dan membentuk tumor keganasan kanker, yang tampaknya identik dengan sampel manusia di bawah pembesaran. Hal ini membawa pada kesimpulan bahwa sel prostat basal mungkin “tempat asal” yang paling mungkin dari kanker prostat [144].

Masyarakat dan budaya
Diskriminasi
Orang dengan kanker prostat umumnya menemukan perbedaan yang signifikan dalam kesadaran, dana, liputan media, dan penelitian-dan karena itu, pengobatan lebih rendah dan lebih miskin dibandingkan dengan hasil-kanker lain dari prevalensi yang sama [145] Pada tahun 2001. The Guardian mencatat bahwa Inggris memiliki 3.000 perawat yang mengkhususkan diri pada kanker payudara, dibandingkan dengan hanya satu untuk kanker prostat. Hal ini juga menemukan bahwa waktu tunggu antara rujukan dan diagnosis adalah dua minggu untuk kanker payudara namun tiga bulan untuk kanker prostat. [146] Sebuah laporan tahun 2007 oleh Koalisi Kanker Prostat Nasional menyatakan bahwa untuk setiap obat kanker prostat di pasar, ada tujuh digunakan untuk mengobati kanker payudara. Times juga mencatat sebuah “anti-laki-laki bias dalam pendanaan kanker” dengan perbedaan 4-1 di Inggris oleh pemerintah maupun oleh badan amal kanker seperti Cancer Research Inggris [145]. [147] Kesetaraan juru kampanye seperti penulis Warren Farrell mengutip kesenjangan pengeluaran tersebut sebenarnya sebagai contoh yang jelas dari pemerintah tidak adil mendukung kesehatan perempuan atas kesehatan pria [148].

Disparitas juga memperluas ke daerah-daerah seperti deteksi, dengan pemerintah gagal untuk mendanai atau mandat skrining kanker prostat sementara sepenuhnya mendukung program kanker payudara. Misalnya, laporan tahun 2007 menemukan 49 negara bagian AS mandat cakupan asuransi untuk skrining kanker payudara rutin, dibandingkan dengan 28 untuk kanker prostat [145]. [149] Kanker prostat juga mengalami liputan media yang secara signifikan lebih sedikit daripada yang lain, kanker juga lazim, dengan studi oleh Koalisi Prostat menampilkan cerita payudara kanker 2,6 untuk setiap satu meliputi kanker prostat. [145]

Kanker prostat kesadaran bulan
Kanker prostat bulan kesadaran berlangsung pada bulan September di sejumlah negara. Sebuah pita biru digunakan untuk mempromosikan menyebabkan [150]. [151]

 Penelitian
Androgen pada konsentrasi 10-kali lipat lebih tinggi daripada konsentrasi fisiologis juga telah terbukti menyebabkan penekanan pertumbuhan dan pengembalian androgen-independen kanker prostat atau androgen xenografts-independen tumor prostat diturunkan dalam model vivo untuk fenotip androgen pada tikus athymic dirangsang. [152] [153] Observasi ini menunjukkan kemungkinan untuk menggunakan androgen untuk mengobati pengembangan kambuh androgen-independen tumor prostat pada pasien.

Infus oral katekin teh hijau, terapi alternatif yang potensial untuk kanker prostat oleh senyawa-senyawa alami, telah terbukti dapat menghambat pembangunan, kemajuan, dan metastasis juga dalam adenocarcinoma transgenik asli dari prostat mouse (gelandangan) model, yang secara spontan mengembangkan kanker prostat [154].

Insulin-seperti faktor pertumbuhan signaling sumbu berpikir untuk memainkan peran kunci dalam perkembangan kanker prostat. Ini terdiri dari dua ligan (IGF-1 dan IGF-2), dua reseptor (IGF-IR dan IGF-IIR) dan enam protein tinggi afinitas pengikatan IGF-terkait (IGFBP 1-6) [155] ekspresi. Perubahan IGF sumbu anggota telah terlibat dalam pengembangan berbagai jenis kanker, termasuk prostat [156]. [157]

Sebuah turunan genistein KBU2046 sedang diselidiki untuk kanker prostat. [158] MDV3100 dalam uji fase III untuk HRPC (kemo-naif dan pasca-populasi pasien kemo). [159]

 Kanker prostat model
Para ilmuwan telah membentuk garis sel kanker prostat beberapa untuk menyelidiki mekanisme yang terlibat dalam perkembangan kanker prostat. LNCaP, PC-3 (PC3), dan DU-145 (DU145) yang umumnya digunakan garis sel kanker prostat. Kanker LNCaP garis sel didirikan dari lesi metastasis kelenjar getah bening manusia adenokarsinoma prostat. PC-3 dan DU-145 sel didirikan dari adenokarsinoma prostat manusia metastasis ke tulang dan ke otak, masing-masing. LNCaP sel mengekspresikan reseptor androgen (AR), namun, PC-3 dan DU-145 sel mengekspresikan AR sangat sedikit atau tidak ada. AR, faktor transkripsi androgen diaktifkan, milik keluarga reseptor steroid nuklir. Pengembangan prostat tergantung pada sinyal androgen dimediasi melalui AR, dan AR juga penting selama perkembangan kanker prostat. Proliferasi sel LNCaP adalah androgen tergantung tetapi proliferasi PC-3 dan DU-145 sel adalah androgen sensitif. Ketinggian ekspresi AR sering diamati pada tumor prostat pada pasien [160]. [161] Beberapa androgen-independen sublines LNCaP telah dikembangkan dari sel tergantung androgen ATCC LNCaP setelah kekurangan androgen untuk studi perkembangan kanker prostat. Ini androgen-independen sel LNCaP telah mengangkat AR ekspresi dan mengekspresikan antigen spesifik prostat pada pengobatan androgen. Paradoksnya adalah bahwa androgen menghambat proliferasi dari androgen-independen sel kanker prostat. [162] [163] [164]

 Diagnosa
Saat ini, area aktif penelitian dan investigasi non-klinis diterapkan melibatkan non-invasif metode deteksi tumor prostat. Adenovirus dimodifikasi untuk transfect sel tumor dengan gen tidak berbahaya namun berbeda (seperti luciferase) telah terbukti mampu deteksi dini. Sejauh ini, bagaimanapun, ini daerah penelitian telah diuji hanya pada model sel hewan dan LNCaP. [165]

EN2
Kehadiran EN2 (gen) dalam urin telah berkorelasi dengan probabilitas tinggi kanker prostat [166]. Co-peneliti Hardev Pandha, dan Richard Morgan menerbitkan temuan mereka pada edisi 1 2011 Maret jurnal Clinical Cancer Research. [167 ] Sebuah tes laboratorium saat ini mengidentifikasi EN2 dalam urin, dan test kit rumah dibayangkan mirip dengan strip tes kehamilan di rumah. Menurut Morgan, “Kami sedang mempersiapkan beberapa penelitian besar di Inggris dan di Amerika Serikat dan meskipun tes EN2 belum tersedia, beberapa perusahaan telah menyatakan minatnya dalam mengambil ke depan.” [168]

PCA3
Metode lain non-invasif potensi deteksi tumor prostat dini adalah melalui tes molekuler yang mendeteksi adanya sel-terkait PCA3 mRNA dalam cairan memijat dari prostat oleh dokter dan pertama-kekosongan kencing keluar dalam jumlah terbatas ke dalam spesimen urin kontainer. PCA3 mRNA dinyatakan hampir secara eksklusif oleh sel prostat dan telah terbukti sangat lebih-disajikan dalam sel-sel kanker prostat. Hasil tes saat ini dilaporkan sebagai rasio spesimen PCA3 mRNA untuk mRNA PSA. Meskipun tidak pengganti untuk tingkat serum PSA, tes PCA3 adalah alat tambahan untuk membantu memutuskan apakah, pada pria diduga menderita kanker prostat (terutama jika biopsi awal gagal untuk menjelaskan serum PSA tinggi), sebuah rebiopsy biopsi / adalah benar-benar dibutuhkan . Semakin tinggi ekspresi PCA3 dalam sampel, semakin besar kemungkinan biopsi yang positif, yaitu, adanya sel-sel kanker dalam prostat.

Awal kanker prostat antigen-2
Hal itu dilaporkan pada April 2007 bahwa penelitian sedang dilakukan pada tes darah baru untuk kanker prostat dini antigen-2 (EPCA-2) yang dapat mengingatkan pria jika mereka memiliki kanker prostat dan seberapa agresif itu akan [169] [170].

Tromboflebitis dikaitkan dengan peningkatan risiko kanker prostat dan mungkin cara yang baik bagi dokter untuk mengingatkan diri untuk pasien layar dengan tromboflebitis untuk kanker prostat juga karena kedua terkait erat [171].

Prostasomes
Sel epitel dari prostat mensekresi prostasomes serta PSA. Prostasomes yang dikelilingi membran-, prostat yang diturunkan dari organel yang muncul ekstrasel, dan salah satu fungsi fisiologis mereka adalah untuk melindungi sperma dari serangan oleh sistem kekebalan tubuh wanita. Sel-sel kanker prostat terus mensintesis dan mensekresi prostasomes, dan mungkin dilindungi terhadap serangan imunologi oleh prostasomes. Penelitian beberapa aspek keterlibatan prostasomal pada kanker prostat telah dilakukan

 
 
 
 

 

 
 
 
 

 

 

the end @ copyright dr iwan suwandy 2011

The Health Info Of Steven Johnson Syndrome

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Stevens–Johnson syndrome

 
Stevens–Johnson syndrome
Classification and external resources

Man with Stevens–Johnson syndrome
ICD-10 L51.1
ICD-9 695.13
OMIM 608579
DiseasesDB 4450
MedlinePlus 000851
eMedicine emerg/555 derm/405
MeSH D013262

Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)[1] are two forms of a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis. The syndrome is thought to be a hypersensitivity complex that affects the skin and the mucous membranes. Although the majority of cases are idiopathic (without a known cause), the main class of known causes is medication, followed by infections and, rarely, cancers.

 Classification

There is agreement in the medical literature that Stevens–Johnson syndrome (SJS) can be considered a milder form of toxic epidermal necrolysis (TEN). These conditions were first recognised in 1922.[2]

Both diseases can be mistaken for erythema multiforme. Erythema multiforme is sometimes caused by a reaction to a medication but is more often a type III hypersensitivity reaction to an infection (caused most often by Herpes simplex) and is relatively benign. Although both SJS and TEN can also be caused by infections, they are most often adverse effects of medications. Their consequences are potentially more dangerous than those of erythema multiforme.

 Signs and symptoms

Mucosal desquamation in a person with Stevens-Johnson syndrome

Conjunctivitis (inflammation of eye and eyelid) in SJS

SJS usually begins with fever, sore throat, and fatigue, which is misdiagnosed and usually treated with antibiotics. Ulcers and other lesions begin to appear in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient’s ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children who develop SJS. A rash of round lesions about an inch across arises on the face, trunk, arms and legs, and soles of the feet, but usually not the scalp.[3]

 Pathology

Micrograph showing full thickness epidermal necrosis with a basket weave-like stratum corneum and separation of the dermis and epidermis. Skin biopsy. H&E stain.

SJS, like toxic epidermal necrolysis and erythema multiforme, are characterized by confluent epidermal necrosis with minimal associated inflammation. The acuity is apparent from the (normal) basket weave-like pattern of the stratum corneum.

 Causes

SJS is thought to arise from a disorder of the immune system.[3] The immune reaction can be triggered by infections, drugs, or medications. In some groups, drug reaction may be aggravated by genetic factors.

Infections

SJS can be caused by infections. It usually follows common infections such as herpes simplex virus, influenza, mumps, cat-scratch fever, histoplasmosis, Epstein-Barr virus, mycoplasma pneumoniae, or similar.

Medication/drugs

Although Stevens–Johnson Syndrome can be caused by viral infections, malignancies, or severe allergic reactions to medication, the leading cause appears to be the use of antibiotics and sulfa drugs.

SJS can be caused by adverse effects of drugs allopurinol (a.k.a. Aloprim), Zyloprim, Dilantin, Depakote, Levaquin, diclofenac, etravirine, isotretinoin (a.k.a. Accutane), fluconazole,[4] valdecoxib, sitagliptin, oseltamivir, penicillins, barbiturates, sulfonamides, phenytoin, azithromycin, oxcarbazepine, zonisamide, modafinil,[5] lamotrigine, nevirapine, pyrimethamine, ibuprofen,[6] ethosuximide, carbamazepine, nystatin, and gout medications.[7][8]

Medications that have traditionally been known to lead to SJS, erythema multiforme and toxic epidermal necrolysis include sulfonamides (antibiotics), penicillins (antibiotics), barbiturates (sedatives), lamotrigine, and phenytoin (e.g. Dilantin) (anticonvulsants). Combining lamotrigine with sodium valproate increases the risk of SJS.

Non-steroidal anti-inflammatory drugs are a rare cause of SJS in adults; the risk is higher for older patients, women and those initiating treatment.[2] Typically, the symptoms of drug-induced SJS arise within a week of starting the medication. People with systemic lupus erythematosus or HIV infections are more susceptible to drug-induced SJS.[3]

SJS may also be caused by cocaine use.[9]

Genetics

In some East Asian populations studied (Han Chinese and Thai), carbamazepine- and phenytoin-induced SJS is strongly associated with HLA-B*1502 (HLA-B75), an HLA-B serotype of the broader serotype HLA-B15.[10][11][12] A study in Europe suggested that the gene marker is only relevant for East Asians.[13][14]

Based on the Asian findings, similar studies in Europe showed 61% of allopurinol-induced SJS/TEN patients carried the HLA-B58 (phenotype frequency of the B*5801 allele in Europeans is typically 3%). One study concluded: “Even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease.”[15]

Treatment

SJS constitutes a dermatological emergency. All medications should be discontinued, particularly those known to cause SJS reactions. Patients with documented mycoplasma infections can be treated with oral macrolide or oral doxycycline.[3]

Initially, treatment is similar to that for patients with thermal burns, and continued care can only be supportive (e.g. intravenous fluids and nasogastric or parenteral feeding) and symptomatic (e.g., analgesic mouth rinse for mouth ulcer). Dermatologists and surgeons tend to disagree about whether the skin should be debrided.[3]

Beyond this kind of supportive care, there is no accepted treatment for SJS. Treatment with corticosteroids is controversial. Early retrospective studies suggested that corticosteroids increased hospital stays and complication rates. There are no randomized trials of corticosteroids for SJS, and it can be managed successfully without them.[3]

Other agents have been used, including cyclophosphamide and cyclosporine, but none has exhibited much therapeutic success. Intravenous immunoglobulin (IVIG) treatment has shown some promise in reducing the length of the reaction and improving symptoms. Other common supportive measures include the use of topical pain anesthetics and antiseptics, maintaining a warm environment, and intravenous analgesics. An ophthalmologist should be consulted immediately, as SJS frequently causes the formation of scar tissue inside the eyelids, leading to corneal vascularization, impaired vision and a host of other ocular problems.

 Prognosis

SJS proper (with less than 10% of body surface area involved) has a mortality rate of around 5%. The risk for death can be estimated using the SCORTEN scale, which takes a number of prognostic indicators into account.[9] Other outcomes include organ damage/failure, cornea scratching, and blindness.

 Epidemiology

Stevens–Johnson syndrome is a rare condition, with a reported incidence of around 2.6[3] to 6.1[2] cases per million people per year. In the United States, there are about 300 new diagnoses per year. The condition is more common in adults than in children. Women are affected more often than men, with cases occurring at a two to one (2:1) ratio.[2]

 History

Stevens-Johnson Syndrome is named for Albert Mason Stevens and Frank Chambliss Johnson, American pediatricians who in 1922 jointly published a description of the disorder in the American Journal of Diseases of Children.[16][17][18][19]

 Notable cases

  • Padma Lakshmi, actress, model, television personality, and cookbook writer;[20]
  • Tessa Keller of MTV show Laguna Beach;[21]
  • Sabrina Brierton Johnson, whose family unsuccessfully sued the manufacturer of Children’s Motrin, Johnson & Johnson, after a case of SJS blinded her.[22]
  • Manute Bol, former professional basketball player and member of NBA’s Washington Bullets, Golden State Warriors, Philadelphia 76ers, and Miami Heat, who died from complications.
  • OTHER INFO
  • Stevens-Johnson Syndrome is an immune complex hypersensitivity reaction that can be caused from an infection or immune response to drugs. The symptoms of SJS are life altering.It is a severe expression of a simple rash known as erythema multiforme. SJS is also known as erythema multiforme major. It affects all ages and genders including pediatric populations. The most severe form of SJS is toxic epidermal necrolysis (TENS). SJS occurs twice as often in men as in women. Most cases of SJS appear in children and young adults under age 30.

    Females with SJS are twice as likely as males to develop TENS, and have an even higher chance if taking a category of drugs known as NSAIDs, non-steroidal anti-inflammatory drugs.

    If you or a loved one has been diagnosed by a doctor with the condition know as Stevens-Johnson Syndrome call our Law Firm at 1-800-862-1260. Stevens-Johnson Syndrome can be a potentially deadly skin disease that usually results from a drug reaction. Another form of this disease is called Toxic Epidermal Necrolysis. This condition can also be the result of a negative drug-related reaction. These conditions have been linked to adverse drug reactions. Some of the drugs are “over the counter” some are prescription. The results and consequences of this condition can be extremely painful and potentially deadly. Our Law Firm can help you determine if your condition was caused by the negligence of one of the drug manufactures. Call us today at 1-800-862-1260.

    Common Symptoms of Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis:

    Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can start with non-specific symptoms such as cough, aching, headaches, and feverishness. This may be followed by a red rash across the face and the trunk of the body, which can continue to spread to other parts of the body. The rash can form into blisters, and these blisters can form in areas such as the eyes, mouth and vaginal area. The mucous membranes can become inflamed, and with Toxic Epidermal Necrolysis layers of the skin can also come away with ease and often the skin peels away in sheets. The hair and nails can also come away in some cases, and sufferers can become cold and feverish.

    With Toxic Epidermal Necrolysis the most common cause of death is infection, which can enter through the exposed areas. This disease can leave the skin looking as though it has been burned, and areas where skin has flayed away can seep copiously and quickly become infected.

    Both Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can start with non-specific symptoms such as:

    • Coughing
    • Aching
    • Headaches
    • Feverishness
    • Vomiting
    • Diarrhoea

    This is usually followed by a red rash across the face and the trunk of the body, which can continue to spread to other parts of the body. Blisters then form across the body in places such as the nose, mouth, eyes, and genital areas, and the mucous membrane becomes inflamed. With some people the nails and hair begin to come out as well. In the case of Toxic Epidermal Necrolysis patients, the skin can start to come away in sheets leaving exposed flesh that could be likened to serious burning and is very susceptible to infection. Both of these disease variations are potentially deadly. In drug related cases, the symptoms for both diseases can take one or two weeks to manifest from the first time the patient takes the drug.

    Drugs that have been linked to Stevens-Johnson Syndrome include:

    • NSAIDS (non-steroid anti-inflammatory drugs),
    • Allopurinol,
    • Phenytoin,
    • Carbamazepine,
    • Barbiturates,
    • Anticonvulsants,
    • Sulfa Antibiotics,
    • Children’s Motrin,
    • Advil,
    • Children’s Advil,
    • Cox-2 Inhibitor

    In some cases, the condition is caused by a bacterial infection. However, in many cases there is no known cause for the onset of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. These skin diseases can cause massive pain, suffering and anxiety. People that have taken or are taking medications such as the ones mentioned above are urged to familiarize themselves with the symptoms of SJS (Stevens-Johnson Syndrome) and Toxic Epidermal Necrolysis (TEN). This will enable you to seek immediate medical attention should the need arise, and early initiation of treatment can make a big difference to the seriousness of the disease as this can stop any secondary infections. The aim of this website page is to help educate and informed the public about the symptoms, causes and treatment of SJS and TEN, and also to offer advice with regards to possible legal options of those affected by these diseases.

    As stated above Stevens-Johnson Syndrome is a potentially deadly skin disease that usually results from a negative drug reaction. Another form of the disease is called Toxic Epidermal Necrolysis, and again this usually results from a drug-related reaction. Both forms of the disease can be deadly as well as very painful and distressing. In most cases, these disorders are caused by a reaction to a drug, and one drug that has come under fire lately is the cox-2 inhibitor Bextra, which is already linked to these disorders.

    There are other drugs that have been linked to Stevens-Johnson Syndrome, and these include some other NSAIDS (non-steroid anti-inflammatory drugs), Allopurinol, Phenytoin, Carbamazepine, barbiturates, anticonvulsants, and sulfa antibiotics. The condition can sometimes – although not very often – be attributed to a bacterial infection, and in some cases there is no known cause for the onset of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. However, the most common cause is through drug related reaction.

    Stevens-Johnson Syndrome can affect any age group. However, it occurs most commonly in older people, and this could be because older people tend to use more of the drugs associated with the disease and are therefore collectively more at risk from the disease. People that have AIDS are also at an increased risk of contracting Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis. Those in the higher risk groups are urged to remain vigilant for any signs of these skin diseases, and are also advised to remain well informed about the symptoms that could indicate the presence or onset of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis.

    Most Common Treatments for this Condition:

    Those individuals suffering from SJS or TEN are treated in hospital, and if the cause of the problem is drug related then the drugs are stopped with immediate effect. Surviving patients are treated intravenously to replace any lost fluids, and the skin is left to re-grow on its own. However, the chances of survival can be hit and miss depending on the level of damage and the degree of infection incurred by the patient.

    It is vital that those taking drugs that could result in these skin diseases are vigilant and can identify the danger signs associated with these problems. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis can be deadly, and the earlier the symptoms are recognized the faster treatment can be initiated. Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis are very serious, potentially deadly conditions and have to be treated accordingly. Firstly, the cause of the condition has to be identified if possible. So, if the cause if drug related, doctors can stop the drug immediately. In the case of a new infection on top of the condition or a bacterial infection, doctors may use a suitable antibiotic. In severe cases, the patient is treated in a burns unit. Patients have to be treated in meticulously hygienic environments to alleviate the risk of further infection, which could result in death. In cases where the patients has lost a lot of fluid through seeping areas where the skin has come away, intravenous fluid replacement may be required. The hos

  • The only way to get rid of this disease is to eliminate the source of the problem. Anything, the atmosphere, the drugs or the medicines that are causing this disease have to be changed so that it may not aggravate the problem. The immunity of the system suffers a great setback. Anyone who does not have a strong immunity is bound to suffer from more severe complexities than those who do. Treatment process is similar to the burn therapy process as the condition of the skin almost becomes the same. There is fluid loss, the nerves in the location do not respond and the skin starts to peel causing great trauma.

    Treatment involves providing the patient with high levels of fluids and electrolytic correction till the time restoration is not achieved. There is no specific treatment for this disease which is a cause of worry and because these are due to consumption of medicines, many pharmaceuticals are facing legal ca

INDONESIA VERSION

Sindrom Stevens-Johnson


Sindrom Stevens-Johnson
Klasifikasi dan sumber daya eksternal

Manusia dengan sindrom Stevens-Johnson
ICD-10 L51.1
ICD-9 695,13
OMIM 608579
DiseasesDB 4450
MedlinePlus 000851
eMedicine emerg/555 derm/405
MESH D013262

Sindrom Stevens-Johnson (SJS) dan toksik epidermal nekrolisis (SEPULUH) [1] adalah dua bentuk kondisi kulit mengancam jiwa, di mana kematian sel menyebabkan epidermis untuk terpisah dari dermis. Sindrom ini dianggap kompleks hipersensitivitas yang mempengaruhi kulit dan selaput lendir. Meskipun mayoritas kasus idiopatik (tanpa diketahui penyebabnya), kelas utama dari penyebab yang diketahui adalah obat, diikuti oleh infeksi dan, jarang, kanker.

Isi
1 Klasifikasi
2 Tanda dan gejala
2.1 Patologi
3 Penyebab
3.1 Infeksi
3.2 Obat / obat
3.3 Genetika
4 Pengobatan
5 Prognosis
6 Epidemiologi
7 Sejarah
8 Terkemuka kasus
9 Referensi
10 Pranala luar
 

 Klasifikasi
Ada kesepakatan dalam literatur medis yang sindrom Stevens-Johnson (SJS) dapat dianggap sebagai bentuk ringan dari nekrolisis epidermal toksik (TEN). Kondisi ini pertama kali diakui pada tahun 1922. [2]

Kedua penyakit dapat keliru untuk eritema multiforme. Eritema multiforme kadang-kadang disebabkan oleh reaksi terhadap obat, tetapi lebih sering tipe III reaksi hipersensitivitas terhadap infeksi (yang disebabkan paling sering oleh Herpes simpleks) dan relatif jinak. Meskipun kedua SJS dan TEN juga bisa disebabkan oleh infeksi, mereka yang paling sering efek samping dari obat. Konsekuensi mereka berpotensi lebih berbahaya daripada orang-orang dari eritema multiforme.

 Tanda dan gejala

Deskuamasi mukosa pada orang dengan sindrom Stevens-Johnson

Konjungtivitis (radang mata dan kelopak mata) di SJS
SJS biasanya dimulai dengan demam, sakit tenggorokan, dan kelelahan, yang salah didiagnosis dan biasanya diobati dengan antibiotik. Ulkus dan lesi lainnya mulai muncul di selaput lendir, hampir selalu di mulut dan bibir tapi juga di daerah genital dan anal. Mereka di mulut biasanya sangat menyakitkan dan mengurangi kemampuan pasien untuk makan atau minum. Konjungtivitis mata terjadi pada sekitar 30% anak-anak yang mengembangkan SJS. Ruam lesi putaran sekitar satu inci di seluruh timbul pada, wajah batang, lengan dan kaki, dan telapak kaki, tetapi biasanya tidak kulit kepala [3].

 Patologi

Mikrograf menunjukkan nekrosis epidermal ketebalan penuh dengan keranjang menenun seperti stratum korneum dan pemisahan dermis dan epidermis. Biopsi kulit. H & E noda.
SJS, seperti nekrolisis epidermal toksik dan eritema multiforme, yang ditandai dengan nekrosis epidermis konfluen dengan peradangan yang terkait minimal. Ketajaman ini terlihat dari keranjang (normal) menenun seperti pola stratum korneum.

 Penyebab
SJS diduga timbul dari gangguan sistem kekebalan tubuh. [3] Reaksi kekebalan dapat dipicu oleh infeksi, obat-obatan, atau obat. Pada beberapa kelompok, reaksi obat dapat diperburuk oleh faktor genetik.

Infeksi
SJS dapat disebabkan oleh infeksi. Ini biasanya mengikuti infeksi biasa seperti virus herpes simpleks, influenza, gondok, kucing-awal demam, histoplasmosis, virus Epstein-Barr, Mycoplasma pneumoniae, atau mirip.

Obat / obat
Lihat juga: Daftar zat merangsang SJS
Meskipun Stevens-Johnson Syndrome dapat disebabkan oleh infeksi virus, keganasan, atau reaksi alergi yang parah terhadap pengobatan, penyebab utama tampaknya penggunaan antibiotik dan obat sulfa.

SJS dapat disebabkan oleh efek samping obat allopurinol (alias Aloprim), Zyloprim, Dilantin, Depakote, Levaquin, diklofenak, etravirine, isotretinoin (Accutane alias), flukonazol, [4] valdecoxib, sitagliptin, oseltamivir, penisilin, barbiturat, sulfonamida, fenitoin, azitromisin, oxcarbazepine, zonisamide, modafinil, [5] lamotrigin, nevirapine, pirimetamin, ibuprofen, [6] ethosuximide, carbamazepine, nistatin, dan obat asam urat [7]. [8]

Obat-obat yang secara tradisional telah dikenal untuk menyebabkan SJS, eritema multiforme dan nekrolisis epidermal toksik termasuk sulfonamide (antibiotik), penisilin (antibiotik), barbiturat (obat penenang), lamotrigin, dan fenitoin (Dilantin misalnya) (antikonvulsan). Menggabungkan lamotrigin dengan valproate natrium meningkatkan risiko SJS.

Non-steroid anti-inflamasi obat adalah penyebab langka SJS pada orang dewasa;. Risiko lebih tinggi untuk pasien yang lebih tua, perempuan dan orang-orang memulai pengobatan [2] Biasanya, gejala obat-induced SJS muncul dalam waktu seminggu dari mulai obat . Orang dengan lupus eritematosus sistemik atau infeksi HIV lebih rentan terhadap obat-induced SJS. [3]

SJS juga bisa disebabkan oleh penggunaan kokain. [9]

Genetika
Dalam beberapa populasi Asia Timur dipelajari (Han China dan Thailand), karbamazepin dan fenitoin-diinduksi SJS sangat terkait dengan HLA-B * 1502 (HLA-B75), sebuah serotipe HLA-B dari serotipe HLA-B15 yang lebih luas [10. ] [11] [12] Sebuah penelitian di Eropa menunjukkan bahwa penanda gen hanya relevan untuk Asia Timur. [13] [14]

Berdasarkan temuan di Asia, penelitian serupa di Eropa menunjukkan 61% dari allopurinol-induced SJS / TEN pasien membawa HLA-B58 (fenotip frekuensi alel B * 5801 di Eropa biasanya 3%). Satu studi menyimpulkan: “Bahkan ketika alel HLA-B berperilaku sebagai faktor resiko yang kuat, seperti untuk allopurinol, mereka tidak cukup dan tidak perlu untuk menjelaskan penyakit.” [15]

Pengobatan
SJS merupakan darurat dermatologis. Semua obat harus dihentikan, terutama yang diketahui menyebabkan reaksi SJS. Pasien dengan infeksi Mycoplasma didokumentasikan dapat diobati dengan doksisiklin oral atau makrolida lisan. [3]

Awalnya, pengobatan mirip dengan yang untuk pasien dengan luka bakar termal, dan perawatan lanjutan hanya dapat mendukung (misalnya cairan intravena dan pemberian makan nasogastrik atau parenteral) dan gejala (misalnya, analgesik mulut berkumur selama sariawan). Dermatologists dan ahli bedah cenderung tidak setuju tentang apakah kulit harus debridement. [3]

Selain jenis perawatan suportif, tidak ada pengobatan diterima untuk SJS. Pengobatan dengan kortikosteroid masih kontroversial. Studi retrospektif awal menyarankan bahwa kortikosteroid peningkatan rawat inap dan tingkat komplikasi. Tidak ada uji coba acak dari kortikosteroid untuk SJS, dan dapat dikelola berhasil tanpa mereka. [3]

Agen lainnya telah digunakan, termasuk cyclophosphamide dan cyclosporine, tetapi tidak ada yang menunjukkan banyak keberhasilan terapi. Imunoglobulin pengobatan (IVIG) intravena telah menunjukkan beberapa janji dalam mengurangi panjang dari reaksi dan meningkatkan gejala. Lain langkah-langkah dukungan umum termasuk penggunaan anestesi nyeri topikal dan antiseptik, menjaga lingkungan yang hangat, dan analgesik intravena. Dokter mata harus berkonsultasi langsung, karena SJS sering menyebabkan pembentukan jaringan parut di dalam kelopak mata, menyebabkan vaskularisasi kornea, gangguan penglihatan dan sejumlah masalah mata lainnya.

 Prognosa
SJS yang tepat (dengan kurang dari 10% dari luas permukaan tubuh terlibat) memiliki angka kematian sekitar 5%. Risiko kematian dapat diperkirakan dengan menggunakan skala SCORTEN, yang membutuhkan sejumlah indikator prognostik ke account [9]. Hasil lainnya termasuk kerusakan organ / kegagalan, kornea menggaruk, dan kebutaan.

 Epidemiologi
Sindrom Stevens-Johnson adalah suatu kondisi yang jarang, dengan insiden dilaporkan sekitar 2,6 [3] untuk 6,1 [2] kasus per juta orang per tahun. Di Amerika Serikat, ada sekitar 300 diagnosa baru per tahun. Kondisi ini lebih umum pada orang dewasa dibandingkan pada anak-anak. Wanita lebih sering terkena daripada pria, dengan kasus yang terjadi pada rasio 0:58 (2:1). [2]

 Sejarah
Sindrom Stevens-Johnson adalah nama untuk Albert Mason Stevens dan Frank Chambliss Johnson, dokter anak Amerika yang pada tahun 1922 bersama-sama menerbitkan deskripsi gangguan dalam American Journal of Penyakit Anak [16] [17] [18] [19].

 kasus Terkemuka
Padma Lakshmi, aktris, model, kepribadian televisi, dan penulis buku resep; [20]
Tessa Keller dari MTV menunjukkan Laguna Beach; [21]
Sabrina Brierton Johnson, yang keluarganya tidak berhasil menggugat produsen, Motrin Anak Johnson & Johnson, setelah kasus SJS membutakannya [22].
Manute Bol, mantan pemain basket profesional dan anggota NBA Washington Bullets, Golden State Warriors, Philadelphia 76ers, dan Miami Heat, yang meninggal dari komplikasi.

 
 
 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

the end @ copyright dr Iwan suwandy 2011

The Parkinson Disease Informations

 

MUSEUM DUNIA MAYA DR IWAN S.

Dr IWAN ‘S CYBERMUSEUM

 THE FIRST INDONESIAN CYBERMUSEUM

  MUSEUM DUNIA MAYA PERTAMA DI INDONESIA

   DALAM PROSES UNTUK MENDAPATKAN SERTIFIKAT MURI

     PENDIRI DAN PENEMU IDE

      THE FOUNDER

    Dr IWAN SUWANDY, MHA

                     

The Driwan’s  Cybermuseum

Parkinson’s disease

 
Parkinson’s disease
Classification and external resources
Two sketches (one from the front and one from the right side) of a man, with an expressionless face. He is stooped forward and is presumably having difficulty walking.
Illustration of Parkinson’s disease by William Richard Gowers, which was first published in A Manual of Diseases of the Nervous System (1886)
ICD-10 G20, F02.3
ICD-9 332
OMIM 168600 556500
DiseasesDB 9651
MedlinePlus 000755
eMedicine neuro/304 neuro/635 in young
pmr/99 rehab
GeneReviews Parkinson Disease Overview

Parkinson’s disease (also known as Parkinson disease, Parkinson’s, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans) is a degenerative disorder of the central nervous system. It results from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of cell-death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related, including shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, cognitive and behavioural problems may arise, with dementia commonly occurring in the advanced stages of the disease. Other symptoms include sensory, sleep and emotional problems. PD is more common in the elderly with most cases occurring after the age of 50.

The main motor symptoms are collectively called parkinsonism, or a “parkinsonian syndrome”. Parkinson’s disease is often defined as a parkinsonian syndrome that is idiopathic (having no known cause), although some atypical cases have a genetic origin. Many risk and protective factors have been investigated: the clearest evidence is for an increased risk of PD in people exposed to certain pesticides and a reduced risk in tobacco smokers. The pathology of the disease is characterized by the accumulation of a protein called alpha-synuclein into inclusions called Lewy bodies in neurons, and from insufficient formation and activity of dopamine produced in certain neurons within parts of the midbrain. Diagnosis of typical cases is mainly based on symptoms, with tests such as neuroimaging being used for confirmation.

Modern treatments are effective at managing the early motor symptoms of the disease, mainly through the use of levodopa and dopamine agonists. As the disease progresses and dopamine neurons continue to be lost, a point eventually arrives at which these drugs become ineffective at treating the symptoms and at the same time produce a complication called dyskinesia, marked by involuntary writhing movements. Diet and some forms of rehabilitation have shown some effectiveness at alleviating symptoms. Surgery and deep brain stimulation have been used to reduce motor symptoms as a last resort in severe cases where drugs are ineffective. Research directions include a search of new animal models of the disease and investigations of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents. Medications to treat non-movement-related symptoms of PD, such as sleep disturbances and emotional problems, also exist.

The disease is named after the English doctor James Parkinson, who published the first detailed description in An Essay on the Shaking Palsy in 1817. Several major organizations promote research and improvement of quality of life of those with the disease and their families. Public awareness campaigns include Parkinson’s disease day on the birthday of James Parkinson, April 11, and the use of a red tulip as the symbol of the disease. People with parkinsonism who have enhanced the public’s awareness include Michael J. Fox and Muhammad Ali.

Contents

 Classification

The term parkinsonism is used for a motor syndrome whose main symptoms are tremor at rest, stiffness, slowing of movement and postural instability. Parkinsonian syndromes can be divided into four subtypes according to their origin: primary or idiopathic, secondary or acquired, hereditary parkinsonism, and parkinson plus syndromes or multiple system degeneration.[1] Parkinson’s disease is the most common form of parkinsonism and is usually defined as “primary” parkinsonism, meaning parkinsonism with no external identifiable cause.[2][3] In recent years several genes that are directly related to some cases of Parkinson’s disease have been discovered. As much as this can go against the definition of Parkinson’s disease as an idiopathic illness, genetic parkinsonism disorders with a similar clinical course to PD are generally included under the Parkinson’s disease label. The terms “familial Parkinson’s disease” and “sporadic Parkinson’s disease” can be used to differentiate genetic from truly idiopathic forms of the disease.[4]

PD is usually classified as a movement disorder, although it also gives rise to several non-motor types of symptoms such as sensory deficits,[5] cognitive difficulties or sleep problems. Parkinson plus diseases are primary parkinsonisms which present additional features.[2] They include multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies.[2]

In terms of pathophysiology, PD is considered a synucleinopathy due to an abnormal accumulation of alpha-synuclein protein in the brain in the form of Lewy bodies, as opposed to other diseases such as Alzheimer’s disease where the brain accumulates tau protein in the form of neurofibrillary tangles.[6] Nevertheless, there is clinical and pathological overlap between tauopathies and synucleinopathies. The most typical symptom of Alzheimer’s disease, dementia, occurs in advanced stages of PD, while it is common to find neurofibrillary tangles in brains affected by PD.[6]

Dementia with Lewy bodies (DLB) is another synucleinopathy that has similarities with PD, and especially with the subset of PD cases with dementia. However the relationship between PD and DLB is complex and still has to be clarified.[7] They may represent parts of a continuum or they may be separate diseases.[7]

Signs and symptoms

First line of text is "Catherine Metzger" Second line of text is "13 Octobre 1869" (October 13th of 1869; in French).

Handwriting of a person affected by PD in Lectures on the diseases of the nervous system by Charcot (1879). The original description of the text states “The strokes forming the letters are very irregular and sinuous, whilst the irregularities and sinuosities are of a very limited width. (…) the down-strokes are all, with the exception of the first letter, made with comparative firmness and are, in fact, nearly normal — the finer up-strokes, on the contrary, are all tremulous in appearance (…).”

Parkinson’s disease affects movement, producing motor symptoms.[1] Non-motor symptoms, which include autonomic dysfunction, neuropsychiatric problems (mood, cognition, behavior or thought alterations), and sensory and sleep difficulties, are also common.[1]

Motor

Black and white picture of male with PD stooping forward as he walks. He is viewed from the left side and there is a chair behind him.

A man with Parkinson’s disease displaying a flexed walking posture pictured in 1892. Photo appeared in Nouvelle Iconographie de la Salpètrière, vol. 5.

Further information: Parkinsonian gait

Four motor symptoms are considered cardinal in PD: tremor, rigidity, slowness of movement, and postural instability.[1]

Tremor is the most apparent and well-known symptom.[1] It is the most common; though around 30% of individuals with PD do not have tremor at disease onset, most develop it as the disease progresses.[1] It is usually a rest tremor: maximal when the limb is at rest and disappearing with voluntary movement and sleep.[1] It affects to a greater extent the most distal part of the limb and at onset typically appears in only a single arm or leg, becoming bilateral later.[1] Frequency of PD tremor is between 4 and 6 hertz (cycles per second). A feature of tremor is “pill-rolling”, a term used to describe the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement.[1][8] The term derives from the similarity between the movement in PD patients and the earlier pharmaceutical technique of manually making pills.[8]

Bradykinesia (slowness of movement) is another characteristic feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement.[1] Performance of sequential and simultaneous movement is hindered.[1] Bradykinesia is the most disabling symptom in the early stages of the disease.[2] Initial manifestations are problems when performing daily tasks which require fine motor control such as writing, sewing or getting dressed.[1] Clinical evaluation is based in similar tasks such as alternating movements between both hands or both feet.[2] Bradykinesia is not equal for all movements or times. It is modified by the activity or emotional state of the subject, to the point that some patients are barely able to walk yet can still ride a bicycle.[1] Generally patients have less difficulty when some sort of external cue is provided.[1][9]

Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles.[1] In parkinsonism the rigidity can be uniform (lead-pipe rigidity) or ratchety (cogwheel rigidity).[1][2][10][11] The combination of tremor and increased tone is considered to be at the origin of cogwheel rigidity.[12] Rigidity may be associated with joint pain; such pain being a frequent initial manifestation of the disease.[1] In early stages of Parkinson’s disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities.[13] With the progression of the disease, rigidity typically affects the whole body and reduces the ability to move.

Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls, and secondarily to bone fractures.[1] Instability is often absent in the initial stages, especially in younger people.[2] Up to 40% of the patients may experience falls and around 10% may have falls weekly, with number of falls being related to the severity of PD.[1]

Other recognized motor signs and symptoms include gait and posture disturbances such as festination (rapid shuffling steps and a forward-flexed posture when walking),[1] speech and swallowing disturbances including voice disorders,[14] mask-like face expression or small handwriting, although the range of possible motor problems that can appear is large.[1]

Neuropsychiatric

Parkinson’s disease can cause neuropsychiatric disturbances which can range from mild to severe. This includes disorders of speech, cognition, mood, behaviour, and thought.[1]

Cognitive disturbances can occur in the initial stages of the disease and sometimes prior to diagnosis, and increase in prevalence with duration of the disease.[1][15] The most common cognitive deficit in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information. Fluctuations in attention and slowed cognitive speed are among other cognitive difficulties. Memory is affected, specifically in recalling learned information. Nevertheless, improvement appears when recall is aided by cues. Visuospatial difficulties are also part of the disease, seen for example when the individual is asked to perform tests of facial recognition and perception of the orientation of drawn lines.[15]

A person with PD has two to six times the risk of suffering dementia compared to the general population.[1][15] The prevalence of dementia increases with duration of the disease.[15] Dementia is associated with a reduced quality of life in people with PD and their caregivers, increased mortality, and a higher probability of needing nursing home care.[15]

Behavior and mood alterations are more common in PD without cognitive impairment than in the general population, and are usually present in PD with dementia. The most frequent mood difficulties are depression, apathy and anxiety.[1] Impulse control behaviors such as medication overuse and craving, binge eating, hypersexuality, or pathological gambling can appear in PD and have been related to the medications used to manage the disease.[1][16] Psychotic symptoms—hallucinations or delusions—occur in 4% of patients, and it is assumed that the main precipitant of psychotic phenomena in Parkinson’s disease is dopaminergic excess secondary to treatment; it therefore becomes more common with increasing age and levodopa intake.[17][18]

Other

In addition to cognitive and motor symptoms, PD can impair other body functions. Sleep problems are a feature of the disease and can be worsened by medications.[1] Symptoms can manifest in daytime drowsiness, disturbances in REM sleep, or insomnia.[1] Alterations in the autonomic nervous system can lead to orthostatic hypotension (low blood pressure upon standing), oily skin and excessive sweating, urinary incontinence and altered sexual function.[1] Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health.[19] PD is related to several eye and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision.[1][20] Changes in perception may include an impaired sense of smell, sensation of pain and paresthesia (skin tingling and numbness).[1] All of these symptoms can occur years before diagnosis of the disease.[1]

Causes

PDB rendering of Parkin (ligase)

Most people with Parkinson’s disease have idiopathic Parkinson’s disease (having no specific known cause). A small proportion of cases, however, can be attributed to known genetic factors. Other factors have been associated with the risk of developing PD, but no causal relationship has been proven.

PD traditionally has been considered a non-genetic disorder; however, around 15% of individuals with PD have a first-degree relative who has the disease.[2] At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes.[21]

Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.[4][21] In most cases, people with these mutations will develop PD. With the exception of LRRK2, however, they account for only a small minority of cases of PD.[4] The most extensively studied PD-related genes are SNCA and LRRK2. Mutations in genes including SNCA, LRRK2 and glucocerebrosidase (GBA) have been found to be risk factors for sporadic PD. Mutations in GBA are known to cause Gaucher’s disease.[21] Genome-wide association studies, which search for mutated alleles with low penetrance in sporadic cases, have now yielded many positive results.[22]

The role of the SNCA gene is important in PD because the alpha-synuclein protein is the main component of Lewy bodies.[21] Missense mutations of the gene (in which a single nucleotide is changed), and duplications and triplications of the locus containing it have been found in different groups with familial PD.[21] Missense mutations are rare.[21] On the other hand, multiplications of the SNCA locus account for around 2% of familial cases.[21] Multiplications have been found in asymptomatic carriers, which indicate that penetrance is incomplete or age-dependent.[21]

The LRRK2 gene (PARK8) encodes for a protein called dardarin. The name dardarin was taken from a Basque word for tremor, because this gene was first identified in families from England and the north of Spain.[4] Mutations in LRRK2 are the most common known cause of familial and sporadic PD, accounting for approximately 5% of individuals with a family history of the disease and 3% of sporadic cases.[4][21] There are many different mutations described in LRRK2, however unequivocal proof of causation only exists for a small number.[21]

Pathology

Several brain cells stained in blue. The largest one, a neurone, with an approximately circular form, has a brown circular body inside it. The brown body is about 40% the diameter of the cell in which it appears.

A Lewy body (stained brown) in a brain cell of the substantia nigra in Parkinson’s disease. The brown colour is positive immunohistochemistry staining for alpha-synuclein.

Anatomical pathology

The basal ganglia, a group of “brain structures” innervated by the dopaminergic system, are the most seriously affected brain areas in PD.[23] The main pathological characteristic of PD is cell death in the substantia nigra and, more specifically, the ventral (front) part of the pars compacta, affecting up to 70% of the cells by the time death occurs.[4]

Macroscopic alterations can be noticed on cut surfaces of the brainstem, where neuronal loss can be inferred from a reduction of melanin pigmentation in the substantia nigra and locus coeruleus.[24] The histopathology (microscopic anatomy) of the substantia nigra and several other brain regions shows neuronal loss and Lewy bodies in many of the remaining nerve cells. Neuronal loss is accompanied by death of astrocytes (star-shaped glial cells) and activation of the microglia (another type of glial cell). Lewy bodies are a key pathological feature of PD.[24]

 Pathophysiology

Composite of three images, one in top row (described in caption as A), two in second row (described in caption as B). Top shows a mid-line sagittal plane of the brainstem and cerebellum. There are three circles superimposed along the brainstem and an arrow linking them from bottom to top and continuing upward and forward towards the frontal lobes of the brain. A line of text accompanies each circle: lower is "1. Dorsal Motor X Nucleus", middle is "2. Gain Setting Nuclei" and upper is "3. Substantia Nigra/Amygdala". A fourth line of text above the others says "4. ...". The two images at the bottom of the composite are magnetic resonance imaging (MRI) scans, one saggital and the other transverse, centred at the same brain coordinates (x=-1, y=-36, z=-49). A colored blob marking volume reduction covers most of the brainstem.

A. Schematic initial progression of Lewy body deposits in the first stages of Parkinson’s disease, as proposed by Braak and colleagues
B. Localization of the area of significant brain volume reduction in initial PD compared with a group of participants without the disease in a neuroimaging study, which concluded that brain stem damage may be the first identifiable stage of PD neuropathology[25]

The primary symptoms of Parkinson’s disease result from greatly reduced activity of dopamine-secreting cells caused by cell death in the pars compacta region of the substantia nigra.[23]

There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the motor, oculo-motor, associative, limbic and orbitofrontal circuits, with names indicating the main projection area of each circuit.[23] All of them are affected in PD, and their disruption explains many of the symptoms of the disease since these circuits are involved in a wide variety of functions including movement, attention and learning.[23] Scientifically, the motor circuit has been examined the most intensively.[23]

A particular conceptual model of the motor circuit and its alteration with PD has been of great influence since 1980, although some limitations have been pointed out which have led to modifications.[23] In this model, the basal ganglia normally exert a constant inhibitory influence on a wide range of motor systems, preventing them from becoming active at inappropriate times. When a decision is made to perform a particular action, inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine acts to facilitate this release of inhibition, so high levels of dopamine function tend to promote motor activity, while low levels of dopamine function, such as occur in PD, demand greater exertions of effort for any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, an overall reduction in motor output.[23] Drugs that are used to treat PD, conversely, may produce excessive dopamine activity, allowing motor systems to be activated at inappropriate times and thereby producing dyskinesias.[23]

 Brain cell death

There is speculation of several mechanisms by which the brain cells could be lost.[26] One mechanism consists of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. This insoluble protein accumulates inside neurones forming inclusions called Lewy bodies.[4][27] According to the Braak staging, a classification of the disease based on pathological findings, Lewy bodies first appear in the olfactory bulb, medulla oblongata and pontine tegmentum, with individuals at this stage being asymptomatic. As the disease progresses, Lewy bodies later develop in the substantia nigra, areas of the midbrain and basal forebrain, and in a last step the neocortex.[4] These brain sites are the main places of neuronal degeneration in PD; however, Lewy bodies may not cause cell death and they may be protective.[26][27] In patients with dementia, a generalized presence of Lewy bodies is common in cortical areas. Neurofibrillary tangles and senile plaques, characteristic of Alzheimer’s disease, are not common unless the person is demented.[24]

Other cell-death mechanisms include proteosomal and lysosomal system dysfunction and reduced mitochondrial activity.[26] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation and neuronal death, but the mechanisms are not fully understood.[28]

 Diagnosis

Sagittal PET scan at the level of the striatum. Hottest areas are the cortical grey matter and the striatum.

Fludeoxyglucose (18F) (FDG)] PET scan of a healthy brain. Hotter areas reflect higher glucose uptake. A decreased activity in the basal ganglia can aid in diagnosing Parkinson’s disease.

A physician will diagnose Parkinson’s disease from the medical history and a neurological examination.[1] There is no lab test that will clearly identify the disease, but brain scans are sometimes used to rule out disorders that could give rise to similar symptoms. Patients may be given levodopa and resulting relief of motor impairment tends to confirm diagnosis. The finding of Lewy bodies in the midbrain on autopsy is usually considered proof that the patient suffered from Parkinson’s disease. The progress of the illness over time may reveal it is not Parkinson’s disease, and some authorities recommend that the diagnosis be periodically reviewed.[1][29]

Other causes that can secondarily produce a parkinsonian syndrome are Alzheimer’s disease, multiple cerebral infarction and drug-induced parkinsonism.[29] Parkinson plus syndromes such as progressive supranuclear palsy and multiple system atrophy must be ruled out.[1] Anti-Parkinson’s medications are typically less effective at controlling symptoms in Parkinson plus syndromes.[1] Faster progression rates, early cognitive dysfunction or postural instability, minimal tremor or symmetry at onset may indicate a Parkinson plus disease rather than PD itself.[30] Genetic forms are usually classified as PD, although the terms familial Parkinson’s disease and familial parkinsonism are used for disease entities with an autosomal dominant or recessive pattern of inheritance.[2]

Medical organizations have created diagnostic criteria to ease and standardize the diagnostic process, especially in the early stages of the disease. The most widely known criteria come from the UK Parkinson’s Disease Society Brain Bank and the US National Institute of Neurological Disorders and Stroke.[1] The PD Society Brain Bank criteria require slowness of movement (bradykinesia) plus either rigidity, resting tremor, or postural instability. Other possible causes for these symptoms need to be ruled out. Finally, three or more of the following features are required during onset or evolution: unilateral onset, tremor at rest, progression in time, asymmetry of motor symptoms, response to levodopa for at least five years, clinical course of at least ten years and appearance of dyskinesias induced by the intake of excessive levodopa.[1] Accuracy of diagnostic criteria evaluated at autopsy is 75–90%, with specialists such as neurologists having the highest rates.[1]

Computed tomography (CT) and magnetic resonance imaging (MRI) brain scans of people with PD usually appear normal.[31] These techniques are nevertheless useful to rule out other diseases that can be secondary causes of parkinsonism, such as basal ganglia tumors, vascular pathology and hydrocephalus.[31] A specific technique of MRI, diffusion MRI, has been reported to be useful at discriminating between typical and atypical parkinsonism, although its exact diagnostic value is still under investigation.[31] Dopaminergic function in the basal ganglia can be measured with different PET and SPECT radiotracers. Examples are ioflupane (123I) (trade name DaTSCAN) and iometopane (Dopascan) for SPECT or fludeoxyglucose (18F) for PET.[31] A pattern of reduced dopaminergic activity in the basal ganglia can aid in diagnosing PD.[31]

 Management

 

There is no cure for Parkinson’s disease, but medications, surgery and multidisciplinary management can provide relief from the symptoms. The main families of drugs useful for treating motor symptoms are levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonists and MAO-B inhibitors.[32] The stage of the disease determines which group is most useful. Two stages are usually distinguished: an initial stage in which the individual with PD has already developed some disability for which he needs pharmacological treatment, then a second stage in which an individual develops motor complications related to levodopa usage.[32] Treatment in the initial stage aims for an optimal tradeoff between good symptom control and side-effects resulting from enhancement of dopaminergic function. The start of levodopa (or L-DOPA) treatment may be delayed by using other medications such as MAO-B inhibitors and dopamine agonists, in the hope of delaying the onset of dyskinesias.[32] In the second stage the aim is to reduce symptoms while controlling fluctuations of the response to medication. Sudden withdrawals from medication or overuse have to be managed.[32] When medications are not enough to control symptoms, surgery and deep brain stimulation can be of use.[33] In the final stages of the disease, palliative care is provided to enhance quality of life.[34]

 Levodopa

Levodopa has been the most widely used treatment for over 30 years.[32] L-DOPA is converted into dopamine in the dopaminergic neurons by dopa decarboxylase.[32] Since motor symptoms are produced by a lack of dopamine in the substantia nigra, the administration of L-DOPA temporarily diminishes the motor symptoms.[32]

Only 5–10% of L-DOPA crosses the blood-brain barrier. The remainder is often metabolized to dopamine elsewhere, causing a variety of side effects including nausea, dyskinesias and joint stiffness.[32] Carbidopa and benserazide are peripheral dopa decarboxylase inhibitors,[32] which help to prevent the metabolism of L-DOPA before it reaches the dopaminergic neurons, therefore reducing side effects and increasing bioavailability. They are generally given as combination preparations with levodopa.[32] Existing preparations are carbidopa/levodopa (co-careldopa) and benserazide/levodopa (co-beneldopa). Levodopa has been related to dopamine dysregulation syndrome, which is a compulsive overuse of the medication, and punding.[16] There are controlled release versions of levodopa in the form intravenous and intestinal infusions that spread out the effect of the medication. These slow-release levodopa preparations have not shown an increased control of motor symptoms or motor complications when compared to immediate release preparations.[32][35]

Tolcapone inhibits the COMT enzyme, which degrades dopamine, thereby prolonging the effects of levodopa.[32] It has been used to complement levodopa; however, its usefulness is limited by possible side effects such as liver damage.[32] A similarly effective drug, entacapone, has not been shown to cause significant alterations of liver function.[32] Licensed preparations of entacapone contain entacapone alone or in combination with carbidopa and levodopa.[32]

Levodopa preparations lead in the long term to the development of motor complications characterized by involuntary movements called dyskinesias and fluctuations in the response to medication.[32] When this occurs a person with PD can change from phases with good response to medication and few symptoms (“on” state), to phases with no response to medication and significant motor symptoms (“off” state).[32] For this reason, levodopa doses are kept as low as possible while maintaining functionality.[32] Delaying the initiation of therapy with levodopa by using alternatives (dopamine agonists and MAO-B inhibitors) is common practice.[32] A former strategy to reduce motor complications was to withdraw L-DOPA medication for some time. This is discouraged now, since it can bring dangerous side effects such as neuroleptic malignant syndrome.[32] Most people with PD will eventually need levodopa and later develop motor side effects.[32]

 Dopamine agonists

Several dopamine agonists that bind to dopaminergic post-synaptic receptors in the brain have similar effects to levodopa.[32] These were initially used for individuals experiencing on-off fluctuations and dyskinesias as a complementary therapy to levodopa; they are now mainly used on their own as an initial therapy for motor symptoms with the aim of delaying motor complications.[32][36] When used in late PD they are useful at reducing the off periods.[32] Dopamine agonists include bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride.

Dopamine agonists produce significant, although usually mild, side effects including drowsiness, hallucinations, insomnia, nausea and constipation.[32] Sometimes side effects appear even at a minimal clinically effective dose, leading the physician to search for a different drug.[32] Compared with levodopa, dopamine agonists may delay motor complications of medication use but are less effective at controlling symptoms.[32] Nevertheless, they are usually effective enough to manage symptoms in the initial years.[2] They tend to be more expensive than levodopa.[2] Dyskinesias due to dopamine agonists are rare in younger people who have PD, but along with other side effects, become more common with age at onset.[2] Thus dopamine agonists are the preferred initial treatment for earlier onset, as opposed to levodopa in later onset.[2] Agonists have been related to a impulse control disorders (such as compulsive sexual activity and eating, and pathological gambling and shopping) even more strongly than levodopa.[16]

Apomorphine, a non-orally administered dopamine agonist, may be used to reduce off periods and dyskinesia in late PD.[32] It is administered by intermittent injections or continuous subcutaneous infusions.[32] Since secondary effects such as confusion and hallucinations are common, individuals receiving apomorphine treatment should be closely monitored.[32] Two dopamine agonists that are administered through skin patches (lisuride and rotigotine) have been recently found to be useful for patients in initial stages and preliminary positive results has been published on the control of off states in patients in the advanced state.[35]

 MAO-B inhibitors

MAO-B inhibitors (selegiline and rasagiline) increase the level of dopamine in the basal ganglia by blocking its metabolism. They inhibit monoamine oxidase-B (MAO-B) which breaks down dopamine secreted by the dopaminergic neurons. The reduction in MAO-B activity results in increased L-DOPA in the striatum.[32] Like dopamine agonists, MAO-B inhibitors used as monotherapy improve motor symptoms and delay the need for levodopa in early disease, but produce more adverse effects and are less effective than levodopa. There are few studies of their effectiveness in the advanced stage, although results suggest that they are useful to reduce fluctuations between on and off periods.[32] An initial study indicated that selegiline in combination with levodopa increased the risk of death, but this was later disproven.[32]

 Other drugs

Other drugs such as amantadine and anticholinergics may be useful as treatment of motor symptoms. However, the evidence supporting them lacks quality, so they are not first choice treatments.[32] In addition to motor symptoms, PD is accompanied by a diverse range of symptoms. A number of drugs have been used to treat some of these problems.[37] Examples are the use of clozapine for psychosis, cholinesterase inhibitors for dementia, and modafinil for daytime sleepiness.[37][38] A 2010 meta-analysis found that non-steroidal anti-inflammatory drugs (apart from acetaminophen and aspirin), have been associated with at least a 15 percent (higher in long-term and regular users) reduction of incidence of the development of Parkinson’s disease.[39]

Surgery and deep brain stimulation

Placement of an electrode into the brain. The head is stabilised in a frame for stereotactic surgery.

Treating motor symptoms with surgery was once a common practice, but since the discovery of levodopa, the number of operations declined.[40] Studies in the past few decades have led to great improvements in surgical techniques, so that surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient.[40] Surgery for PD can be divided in two main groups: lesional and deep brain stimulation (DBS). Target areas for DBS or lesions include the thalamus, the globus pallidus or the subthalamic nucleus.[40] Deep brain stimulation (DBS) is the most commonly used surgical treatment. It involves the implantation of a medical device called a brain pacemaker, which sends electrical impulses to specific parts of the brain. DBS is recommended for people who have PD who suffer from motor fluctuations and tremor inadequately controlled by medication, or to those who are intolerant to medication, as long as they do not have severe neuropsychiatric problems.[33] Other, less common, surgical therapies involve the formation of lesions in specific subcortical areas (a technique known as pallidotomy in the case of the lesion being produced in the globus pallidus).[40]

 Rehabilitation

There is some evidence that speech or mobility problems can improve with rehabilitation, although studies are scarce and of low quality.[41][42] Regular physical exercise with or without physiotherapy can be beneficial to maintain and improve mobility, flexibility, strength, gait speed, and quality of life.[42] However, when an exercise program is performed under the supervision of a physiotherapist, there are more improvements in motor symptoms, mental and emotional functions, daily living activities, and quality of life compared to a self-supervised exercise program at home.[43] In terms of improving flexibility and range of motion for patients experiencing rigidity, generalized relaxation techniques such as gentle rocking have been found to decrease excessive muscle tension. Other effective techniques to promote relaxation include slow rotational movements of the extremities and trunk, rhythmic initiation, diaphragmatic breathing, and meditation techniques.[44] As for gait and addressing the challenges associated with the disease such as hypokinesia (slowness of movement), shuffling and decreased arm swing; physiotherapists have a variety of strategies to improve functional mobility and safety. Areas of interest with respect to gait during rehabilitation programs focus on but are not limited to improving gait speed, base of support, stride length, trunk and arm swing movement. Strategies include utilizing assistive equipment (pole walking and treadmill walking), verbal cueing (manual, visual and auditory), exercises (marching and PNF patterns) and altering environments (surfaces, inputs, open vs. closed).[45] Strengthening exercises have shown improvements in strength and motor function for patients with primary muscular weakness and weakness related to inactivity with mild to moderate Parkinson’s disease. However, reports show a significant interaction between strength and the time the medications was taken. Therefore, it is recommended that patients should perform exercises 45 minutes to one hour after medications, when the patient is at their best.[46] Also, due to the forward flexed posture, and respiratory dysfunctions in advanced Parkinson’s disease, deep diaphragmatic breathing exercises are beneficial in improving chest wall mobility and vital capacity.[47] Exercise may improve constipation.[19]

One of the most widely practiced treatments for speech disorders associated with Parkinson’s disease is the Lee Silverman voice treatment (LSVT).[41][48] Speech therapy and specifically LSVT may improve speech.[41] Occupational therapy (OT) aims to promote health and quality of life by helping people with the disease to participate in as many of their daily living activities as possible.[41] There have been few studies on the effectiveness of OT and their quality is poor, although there is some indication that it may improve motor skills and quality of life for the duration of the therapy.[41][49]

 Diet

Muscles and nerves that control the digestive process may be affected by PD, resulting in constipation and gastroparesis (food remaining in the stomach for a longer period of time than normal).[19] A balanced diet, based on periodical nutritional assessments, is recommended and should be designed to avoid weight loss or gain and minimize consequences of gastrointestinal dysfunction.[19] As the disease advances, swallowing difficulties (dysphagia) may appear. In such cases it may be helpful to use thickening agents for liquid intake and an upright posture when eating, both measures reducing the risk of choking. Gastrostomy to deliver food directly into the stomach is possible in severe cases.[19]

Levodopa and proteins use the same transportation system in the intestine and the blood-brain barrier, thereby competing for access.[19] When they are taken together, this results in a reduced effectiveness of the drug.[19] Therefore, when levodopa is introduced, excessive protein consumption is discouraged and well balanced Mediterranean diet is recommended. In advanced stages, additional intake of low-protein products such as bread or pasta is recommended for similar reasons.[19] To minimize interaction with proteins, levodopa should be taken 30 minutes before meals.[19] At the same time, regimens for PD restrict proteins during breakfast and lunch, allowing protein intake in the evening.[19]

Palliative care

Palliative care is often required in the final stages of the disease when all other treatment strategies have become ineffective. The aim of palliative care is to maximize the quality of life for the person with the disease and those surrounding him or her. Some central issues of palliative care are: care in the community while adequate care can be given there, reducing or withdrawing drug intake to reduce drug side effects, preventing pressure ulcers by management of pressure areas of inactive patients, and facilitating end-of-life decisions for the patient as well as involved friends and relatives.[34]

 Other treatments

Repetitive transcranial magnetic stimulation temporarily improves levodopa-induced dyskinesias.[50] Its usefulness in PD is an open research topic,[51] although recent studies have shown no effect by rTMS.[52] Several nutrients have been proposed as possible treatments; however there is no evidence that vitamins or food additives improve symptoms.[53] There is no evidence to substantiate that acupuncture and practice of Qigong, or T’ai chi, have any effect on the course of the disease or symptoms. Further research on the viability of Tai chi for balance or motor skills are necessary.[54][55][56] Fava beans and velvet beans are natural sources of levodopa and are eaten by many people with PD. While they have shown some effectiveness in clinical trials,[57] their intake is not free of risks. Life-threatening adverse reactions have been described, such as the neuroleptic malignant syndrome.[58][59]

 Prognosis

 

Global burden of Parkinson’s disease, measured in disability-adjusted life yearsper 100,000 inhabitants in 2004

  no data
  < 5
  5–12.5
  12.5–20
  20–27.5
  27.5–35
  35–42.5
  42.5–50
  50–57.5
  57.5–65
  65–72.5
  72.5–80
  > 80

PD invariably progresses with time. The Hoehn and Yahr scale, which defines five stages of progression, is commonly used to estimate the progress of the disease.

Motor symptoms, if not treated, advance aggressively in the early stages of the disease and more slowly later. Untreated, individuals are expected to lose independent ambulation after an average of eight years and be bedridden after ten years.[60] However, it is uncommon to find untreated people nowadays. Medication has improved the prognosis of motor symptoms, while at the same time it is a new source of disability because of the undesired effects of levodopa after years of use.[60] In people taking levodopa, the progression time of symptoms to a stage of high dependency from caregivers may be over 15 years.[60] However, it is hard to predict what course the disease will take for a given individual.[60] Age is the best predictor of disease progression.[26] The rate of motor decline is greater in those with less impairment at the time of diagnosis, while cognitive impairment is more frequent in those who are over 70 years of age at symptom onset.[26]

Since current therapies improve motor symptoms, disability at present is mainly related to non-motor features of the disease.[26] Nevertheless, the relationship between disease progression and disability is not linear. Disability is initially related to motor symptoms.[60] As the disease advances, disability is more related to motor symptoms that do not respond adequately to medication, such as swallowing/speech difficulties, and gait/balance problems; and also to motor complications, which appear in up to 50% of individuals after 5 years of levodopa usage.[60] Finally, after ten years most people with the disease have autonomic disturbances, sleep problems, mood alterations and cognitive decline.[60] All of these symptoms, especially cognitive decline, greatly increase disability.[26][60]

The life expectancy of people with PD is reduced.[60] Mortality ratios are around twice those of unaffected people.[60] Cognitive decline and dementia, old age at onset, a more advanced disease state and presence of swallowing problems are all mortality risk factors. On the other hand a disease pattern mainly characterized by tremor as opposed to rigidity predicts an improved survival.[60] Death from aspiration pneumonia is twice as common in individuals with PD as in the healthy population.[60]

 Epidemiology

PD is the second most common neurodegenerative disorder after Alzheimer’s disease.[61] The prevalence (proportion in a population at a given time) of PD is about 0.3% of the whole population in industrialized countries. PD is more common in the elderly and prevalence rises from 1% in those over 60 years of age to 4% of the population over 80.[61] The mean age of onset is around 60 years, although 5–10% of cases, classified as young onset, begin between the ages of 20 and 50.[2] PD may be less prevalent in those of African and Asian ancestry, although this finding is disputed.[61] Some studies have proposed that it is more common in men than women, but others failed to detect any differences between the two sexes.[61] The incidence of PD is between 8 and 18 per 100,000 person–years.[61]

Many risk factors and protective factors have been proposed, sometimes in relation to theories concerning possible mechanisms of the disease, however none have been conclusively related to PD by empirical evidence. When epidemiological studies have been carried out in order to test the relationship between a given factor and PD, they have often been flawed and their results have in some cases been contradictory.[61] The most frequently replicated relationships are an increased risk of PD in those exposed to pesticides, and a reduced risk in smokers.[61]

 Risk factors

U.S. Army helicopter spraying Agent Orange over Vietnamese agricultural land during the Vietnam war. Agent Orange has been associated with PD.

Injections of the synthetic neurotoxin MPTP produce a range of symptoms similar to those of PD as well as selective damage to the dopaminergic neurons in the substantia nigra. This observation has led to theorizing that exposure to some environmental toxins may increase the risk of having PD.[61] Exposure to toxins that have been consistently related to the disease can double the risk of PD, and include certain pesticides, such as rotenone or paraquat, and herbicides, such as Agent Orange.[61][62][63] Indirect measures of exposure, such as living in rural environments, have been found to increase the risk of PD.[63] Heavy metals exposure has been proposed to be a risk factor, through possible accumulation in the substantia nigra; however, studies on the issue have been inconclusive.[61]

Protective factors

Smoking has been related to a reduced risk of having PD. Smokers’ risk of having PD may be reduced down to a third when compared to non-smokers.[61] The basis for this effect is not known, but possibilities include an effect of nicotine as a dopamine stimulant.[61] Tobacco smoke contains compounds that act as MAO inhibitors that also might contribute to this effect.[64] Caffeine consumption also protects against PD.[65] Antioxidants, such as vitamins C and D, have been proposed to protect against the disease but results of studies have been contradictory and no positive effect has been proven.[61] The results regarding fat and fatty acids have been contradictory, with various studies reporting protective effects, risk-enhancing effects or no effects.[61] Finally there have been preliminary indications of a possible protective role of estrogens and anti-inflammatory drugs.[61]

History

 

A 1893 photograph of Jean-Martin Charcot, who made important contributions to the understanding of the disease and proposed its current name honoring James Parkinson

Several early sources, including an Egyptian papyrus, an Ayurvedic medical treatise, the Bible, or Galen‘s writings, describe symptoms resembling those of PD.[66] After Galen there are no references unambiguously related to PD until the 17th century.[66] In the 17th and 18th centuries, several authors wrote about elements of the disease, including Sylvius, Gaubius, Hunter and Chomel.[66][67][68]

In 1817 an English doctor, James Parkinson, published his essay reporting six cases of paralysis agitans.[69] An Essay on the Shaking Palsy described the characteristic resting tremor, abnormal posture and gait, paralysis and diminished muscle strength, and the way that the disease progresses over time.[69][70] Early neurologists who made further additions to the knowledge of the disease include Trousseau, Gowers, Kinnier Wilson and Erb, and most notably Jean-Martin Charcot, whose studies between 1868 and 1881 were a landmark in the understanding of the disease.[69] Among other advances, he made the distinction between rigidity, weakness and bradykinesia.[69] He also championed the renaming of the disease in honor of James Parkinson.[69]

In 1912 Frederic Lewy described microscopic particles in affected brains, later named “Lewy bodies“.[69] In 1919 Konstantin Tretiakoff reported that the substantia nigra was the main cerebral structure affected, but this finding was not widely accepted until it was confirmed by further studies published by Rolf Hassler in 1938.[69] The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Arvid Carlsson on the neurotransmitter dopamine and its role on PD.[71] In 1997, alpha-synuclein was found to be the main component of Lewy bodies.[27]

Anticholinergics and surgery (lesioning of the corticospinal pathway or some of the basal ganglia structures) were the only treatments until the arrival of levodopa, which reduced their use dramatically.[67][72] Levodopa was first synthesized in 1911 by Casimir Funk, but it received little attention until the mid 20th century.[71] It entered clinical practice in 1967 and brought about a revolution in the management of PD.[71][73] By the late 1980s deep brain stimulation emerged as a possible treatment.[74]

Research directions

 

There is little prospect of dramatic new PD treatments expected in a short time frame.[75] Currently active research directions include the search for new animal models of the disease and studies of the potential usefulness of gene therapy, stem cell transplants and neuroprotective agents.[26]

Animal models

PD is not known to occur naturally in any species other than humans, although animal models which show some features of the disease are used in research. The appearance of parkinsonian symptoms in a group of drug addicts in the early 1980s who consumed a contaminated batch of the synthetic opiate MPPP led to the discovery of the chemical MPTP as an agent that causes a parkinsonian syndrome in non-human primates as well as in humans.[76] Other predominant toxin-based models employ the insecticide rotenone, the herbicide paraquat and the fungicide maneb.[77] Models based on toxins are most commonly used in primates. Transgenic rodent models that replicate various aspects of PD have been developed.[78]

 Gene therapy

Gene therapy involves the use of a non-infectious virus to shuttle a gene into a part of the brain. The gene used leads to the production of an enzyme that helps to manage PD symptoms or protects the brain from further damage.[26][79] In 2010 there were four clinical trials using gene therapy in PD.[26] There have not been important adverse effects in these trials although the clinical usefulness of gene therapy is still unknown.[26] One of these reported positive results in 2011.[80]

Neuroprotective treatments

While several chemical compounds such as GDNF (chemical structure pictured) have been proposed as neuroprotectors in PD, none have proven efficacy.

Investigations on neuroprotection are at the forefront of PD research. Several molecules have been proposed as potential treatments.[26] However, none of them have been conclusively demonstrated to reduce degeneration.[26] Agents currently under investigation include anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, monoamine oxidase inhibitors (selegiline, rasagiline), promitochondrials (coenzyme Q10, creatine), calcium channel blockers (isradipine) and growth factors (GDNF).[26] Preclinical research also targets alpha-synuclein.[75]

 Neural transplantation

Since early in the 1980s, fetal, porcine, carotid or retinal tissues have been used in cell transplants, in which dissociated cells are injected into the substantia nigra in the hope that they will incorporate themselves into the brain in a way that replaces the dopamine-producing cells that have been lost.[26] Although there was initial evidence of mesencephalic dopamine-producing cell transplants being beneficial, double-blind trials to date indicate that cell transplants produce no long-term benefit.[26] An additional significant problem was the excess release of dopamine by the transplanted tissue, leading to dystonias.[81] Stem cell transplants are a recent research target, because stem cells are easy to manipulate and stem cells transplanted into the brains of rodents and monkeys have been found to survive and reduce behavioral abnormalities.[26][82] Nevertheless, use of fetal stem cells is controversial.[26] It has been proposed that effective treatments may be developed in a less controversial way by use of induced pluripotent stem cells taken from adults.[26]

Society and culture

Muhammad Ali at the age of 64 in 2006. He has shown signs of parkinsonism since the age of 38.

Cost

The costs of PD to society are high, but difficult to calculate exactly due to methodological difficulties in research and differences between countries.[83] The annual cost in the UK is estimated to be between 449 million and 3.3 billion pounds, while the cost per patient per year in the US is probably around $10,000 and the total burden around 23 billion dollars.[83] The largest share of direct cost comes from inpatient care and nursing homes, while the share coming from medications is substantially lower.[83] Indirect costs are high, due to reduced productivity and the burden on caregivers.[83] In addition to economic costs, PD reduces quality of life of those with the disease and their caregivers.[83]

 Advocacy

April 11, the birthday of James Parkinson, has been designated as the world’s Parkinson’s disease day.[69][84] A red tulip was chosen by several international organizations as the symbol of the disease in 2005: it represents the James Parkinson Tulip cultivar, registered in 1981 by a Dutch horticulturalist.[84] Advocacy organizations on the disease include the National Parkinson Foundation, which has provided more than $155 million in care, research and support services since 1982,[85] Parkinson’s Disease Foundation, which has provided more than $90 million for research and $37 million for education and advocacy programs since its founding in 1957 by William Black;[86][87] the American Parkinson Disease Association, founded in 1961;[88] and the European Parkinson’s Disease Association, founded in 1992.[89]

Notable cases

Among the many famous people with PD, one who has greatly increased the public awareness of the disease is the actor Michael J. Fox. Fox was diagnosed in 1991 when he was 30, but kept his condition secret from the public for seven years.[90] He has written two autobiographic books in which his fight against the disease plays a major role,[91] and appeared before the United States Congress without medication to illustrate the effects of the disease.[91] The Michael J. Fox Foundation aims to develop a cure for Parkinson’s disease. In recent years it has been the major Parkinson’s fundraiser in the US, providing 140 million dollars in research funding between 2001 and 2008.[91] Fox’s work led him to be named one of the 100 people “whose power, talent or moral example is transforming the world” in 2007 by Time magazine,[90] and he received an honorary doctorate in medicine from Karolinska Institutet for his contributions to research in Parkinson’s disease.[92] Another foundation that supports Parkinson’s research was established by professional cyclist Davis Phinney.[93] The Davis Phinney Foundation strives to improve the lives of those living with Parkinson’s disease by providing them with information and tools.[94] Muhammad Ali has been called the “world’s most famous Parkinson’s patient”.[95] He was 42 at diagnosis although he already showed signs of Parkinson’s when he was 38.[96] Nevertheless, whether he has PD or a parkinsonian syndrome caused by boxing is still an open question.

INDONESIA VERSION

Penyakit Parkinson

Penyakit Parkinson
Klasifikasi dan sumber daya eksternal

Two sketches (one from the front and one from the right side) of a man, with an expressionless face. He is stooped forward and is presumably having difficulty walking.

Ilustrasi penyakit Parkinson oleh William Richard Gowers, yang pertama kali diterbitkan dalam A Manual Penyakit pada Sistem Saraf (1886)
ICD-10 G20, F02.3
ICD-9 332
OMIM 168600 556500
DiseasesDB 9651
MedlinePlus 000755
eMedicine neuro/304 neuro/635 di muda
pmr/99 rehabilitasi
Penyakit Parkinson GeneReviews Ikhtisar

Penyakit Parkinson (juga dikenal sebagai penyakit Parkinson, Parkinson, parkinson idiopatik, parkinson primer, PD, atau agitans kelumpuhan) adalah gangguan degeneratif sistem saraf pusat. Ini hasil dari kematian dopamin-menghasilkan sel-sel di substansia nigra, sebuah wilayah otak tengah, penyebab kematian sel tidak diketahui. Di awal perjalanan penyakit, gejala yang paling jelas adalah gerakan-terkait, termasuk gemetar, kekakuan, lambatnya gerakan dan kesulitan dengan berjalan dan kiprah. Kemudian, kognitif dan masalah perilaku mungkin timbul, dengan demensia sering terjadi pada tahap lanjut dari penyakit. Gejala lain termasuk sensorik, tidur dan masalah emosional. PD adalah lebih umum pada orang tua dengan sebagian besar kasus terjadi setelah usia 50.

Gejala motor utama secara kolektif disebut parkinson, atau “sindrom parkinsonian”. Penyakit Parkinson sering didefinisikan sebagai sindrom parkinsonian yang idiopatik (tidak memiliki diketahui penyebabnya), meskipun beberapa kasus atipikal memiliki asal-usul genetik. Banyak risiko dan faktor pelindung telah diselidiki: bukti yang paling jelas adalah untuk peningkatan risiko PD pada orang terpapar pestisida tertentu dan mengurangi risiko pada perokok tembakau. Patologi penyakit ini ditandai oleh akumulasi protein yang disebut alpha-synuclein menjadi inklusi disebut badan Lewy di neuron, dan dari pembentukan cukup dan aktivitas dopamin diproduksi di neuron tertentu dalam bagian otak tengah. Diagnosis kasus khas adalah terutama didasarkan pada gejala, dengan tes seperti neuroimaging digunakan untuk konfirmasi.

Pengobatan modern efektif mengelola gejala motor awal penyakit, terutama melalui penggunaan levodopa dan dopamin agonis. Sebagai penyakit berlangsung dan neuron dopamin terus hilang, titik akhirnya tiba di mana obat ini menjadi tidak efektif untuk mengobati gejala dan pada saat yang sama menghasilkan komplikasi yang disebut tardive, ditandai oleh gerakan menggeliat disengaja. Diet dan beberapa bentuk rehabilitasi telah menunjukkan efektivitas beberapa di mengurangi gejala. Bedah dan stimulasi otak dalam telah digunakan untuk mengurangi gejala motor sebagai pilihan terakhir pada kasus yang berat di mana obat tidak efektif. Arah penelitian memasukan sebuah pencarian dari model hewan baru dari penyakit dan penyelidikan dari kegunaan potensi terapi gen, transplantasi stem sel dan agen saraf. Obat untuk mengobati non-gerakan-gejala terkait dari PD, seperti gangguan tidur dan masalah emosional, juga ada.

Penyakit ini dinamai setelah doctor dari Inggris James Parkinson, yang menerbitkan deskripsi rinci pertama di Sebuah Esai tentang Cerebral Gemetar pada tahun 1817. Beberapa organisasi besar mempromosikan penelitian dan peningkatan kualitas hidup dari orang-orang dengan penyakit dan keluarga mereka. Kampanye kesadaran publik termasuk hari penyakit Parkinson pada ulang tahun James Parkinson, 11 April, dan penggunaan tulip merah sebagai simbol dari penyakit. Orang dengan parkinson yang telah meningkatkan kesadaran masyarakat termasuk Michael J. Fox dan Muhammad Ali.

Isi
1 Klasifikasi
2 Tanda dan gejala
2.1 motor
Neuropsikiatrik 2.2
Lainnya 2,3
3 Penyebab
4 Patologi
4.1 Anatomi Patologi
4.2 Patofisiologi
4.3 Otak kematian sel
5 Diagnosis
6 Manajemen
6.1 Levodopa
6.2 Dopamin agonis
6.3 MAO-B inhibitor
6.4 Obat lain
6,5 Bedah dan stimulasi otak dalam
6.6 Rehabilitasi
6,7 Diet
6.8 Perawatan paliatif
6.9 Lain perawatan
7 Prognosis
8 Epidemiologi
8.1 Faktor risiko
8.2 Perlindungan faktor
9 Sejarah
10 Penelitian arah
10.1 Hewan Model
10.2 Terapi gen
10,3 neuroprotektif perawatan
10,4 Neural transplantasi
11 Masyarakat dan budaya
11.1 Biaya
11.2 Advokasi
11.3 Terkemuka kasus
12 Referensi
13 Pranala luar
 

Klasifikasi
Para parkinsonisme Istilah digunakan untuk sindrom bermotor yang utama gejala tremor saat istirahat, kekakuan, memperlambat gerak dan instabilitas postural. Sindrom parkinsonian dapat dibagi menjadi empat subtipe menurut asal mereka: primer atau idiopatik, sekunder atau diperoleh, parkinson turun-temurun, dan ditambah parkinson sindrom atau degenerasi sistem multi [1] penyakit Parkinson adalah bentuk paling umum dari parkinson dan biasanya didefinisikan sebagai. “primer” parkinson, parkinsonism berarti tanpa penyebab yang dapat diidentifikasikan eksternal [2] [3]. Dalam beberapa tahun terakhir beberapa gen yang secara langsung berkaitan dengan beberapa kasus penyakit Parkinson telah ditemukan. Sebanyak ini bisa menentang definisi penyakit Parkinson sebagai penyakit idiopatik, gangguan parkinson genetik dengan perjalanan klinis yang sama dengan PD umumnya termasuk dalam label penyakit Parkinson. Istilah “penyakit Parkinson kekeluargaan” dan “penyakit Parkinson sporadis yang” dapat digunakan untuk membedakan genetik dari bentuk yang benar-benar idiopatik penyakit. [4]

PD biasanya diklasifikasikan sebagai gangguan gerakan, meskipun juga menimbulkan beberapa non-motor jenis gejala seperti defisit sensorik, [5] kognitif kesulitan atau masalah tidur. Ditambah penyakit Parkinson parkinsonisms primer yang hadir fitur tambahan. [2] Mereka termasuk atrofi sistem multi, palsy supranuclear progresif, degenerasi corticobasal dan demensia dengan badan Lewy. [2]

Dalam hal patofisiologi, PD dianggap sebagai synucleinopathy karena adanya akumulasi abnormal dari alfa-synuclein protein dalam otak dalam bentuk badan Lewy, sebagai lawan dari penyakit lain seperti penyakit Alzheimer mana otak terakumulasi protein tau dalam bentuk neurofibrillary kusut [6]. Namun demikian, ada tumpang tindih klinis dan patologis antara tauopathies dan synucleinopathies. Gejala yang paling khas, demensia penyakit Alzheimer, terjadi pada tahap lanjut dari PD, sementara itu adalah umum untuk menemukan kusut neurofibrillary di otak terpengaruh oleh PD. [6]

Demensia dengan badan Lewy (DLB) synucleinopathy lain yang memiliki kesamaan dengan PD, dan terutama dengan subset kasus PD dengan demensia. Namun hubungan antara PD dan DLB adalah kompleks dan masih harus diklarifikasi. [7] Mereka mungkin merupakan bagian dari kontinum atau mereka mungkin penyakit yang terpisah. [7]

Tanda dan gejala

Tulisan tangan seseorang yang dipengaruhi oleh PD dalam Ceramah pada penyakit pada sistem saraf oleh Charcot (1879). Deskripsi asli dari teks menyatakan “Para stroke membentuk huruf sangat tidak teratur dan berliku-liku, sedangkan penyimpangan dan sinuosities adalah dengan lebar sangat terbatas. (…) Down-stroke semua, dengan pengecualian huruf pertama , dibuat dengan ketegasan komparatif dan, pada kenyataannya, hampir normal – lebih halus up-stroke, sebaliknya, semua gemetar dalam penampilan (…).”
Artikel utama: Tanda dan gejala penyakit Parkinson
Penyakit Parkinson mempengaruhi gerakan, menghasilkan gejala motor [1] Non-motor gejala, yang termasuk disfungsi otonom, masalah neuropsikiatri (suasana hati, kognisi, perilaku atau pikiran perubahan), dan kesulitan sensorik dan tidur, juga umum. [1].

 Bermotor

Seorang pria dengan penyakit Parkinson menampilkan menekuk postur berjalan digambarkan pada tahun 1892. Foto muncul di Nouvelle Iconographie de la Salpetriere, vol. 5.
Informasi lebih lanjut: Parkinsonian kiprah
Empat gejala motor dianggap kardinal di PD:. Tremor, kekakuan, lambatnya gerakan, dan instabilitas postural [1]

Tremor adalah gejala yang paling jelas dan terkenal [1] Ini adalah yang paling umum;. Meskipun sekitar 30% dari individu dengan PD tidak memiliki tremor saat onset penyakit, yang paling berkembang sebagai penyakit berlangsung [1] Hal ini biasanya. getaran istirahat: maksimal saat ekstremitas berada pada istirahat dan menghilang dengan gerakan sukarela dan tidur [1] Ini mempengaruhi untuk sebagian besar bagian paling distal ekstremitas dan saat onset biasanya hanya muncul di lengan tunggal atau kaki, menjadi bilateral. kemudian [1]. Frekuensi getaran PD adalah antara 4 dan 6 hertz (siklus per detik). Sebuah fitur getaran adalah “pil-rolling”, sebuah istilah yang digunakan untuk menggambarkan kecenderungan jari telunjuk dari tangan untuk mendapatkan ke dalam kontak dengan ibu jari dan melakukan bersama-sama gerakan melingkar [1] [8]. Istilah ini berasal dari kesamaan antara gerakan pada pasien PD dan teknik sebelumnya farmasi secara manual membuat pil. [8]

Bradykinesia (lambatnya gerakan) adalah fitur lain karakteristik dari PD, dan berhubungan dengan kesulitan sepanjang perjalanan seluruh proses gerakan, mulai dari perencanaan sampai inisiasi dan akhirnya pelaksanaan gerakan [1] Kinerja gerakan sekuensial dan simultan terhalang.. [1] bradykinesia adalah gejala yang paling melumpuhkan pada tahap awal penyakit ini. [2] manifestasi awal masalah ketika melakukan tugas sehari-hari yang memerlukan kontrol motorik halus seperti menulis, menjahit atau berpakaian [1] evaluasi klinis. yang berbasis di tugas-tugas serupa seperti bergantian gerakan antara kedua tangan atau kedua kaki [2] bradykinesia tidak sama untuk semua gerakan atau kali.. Hal ini dimodifikasi oleh aktivitas atau keadaan emosi subjek, ke titik bahwa beberapa pasien yang hampir tidak bisa berjalan namun masih bisa naik sepeda [1]. Umumnya pasien mengalami sedikit kesulitan ketika beberapa jenis isyarat eksternal disediakan. [1 ] [9]

Kekakuan adalah kekakuan dan ketahanan terhadap gerakan anggota tubuh yang disebabkan oleh nada otot meningkat, kontraksi berlebihan dan terus menerus otot [1] Dalam parkinsonisme kekakuan dapat seragam (timbal-pipa kekakuan) atau ratchety (kekakuan cogwheel).. [1] [2 ] [10] [11] Kombinasi tremor dan peningkatan nada dianggap di asal kekakuan cogwheel [12] Kekakuan mungkin berhubungan dengan nyeri sendi;. sakit seperti menjadi manifestasi awal dari penyakit yang sering [1]. Pada tahap awal penyakit Parkinson, kekakuan seringkali asimetris dan cenderung mempengaruhi otot leher dan bahu sebelum otot-otot wajah dan ekstremitas [13] Dengan perkembangan penyakit, kekakuan biasanya mempengaruhi seluruh tubuh dan mengurangi. kemampuan untuk bergerak.

Instabilitas postural adalah khas dalam tahap akhir dari penyakit, yang menyebabkan gangguan keseimbangan dan jatuh sering, dan sekunder untuk patah tulang [1]. Ketidakstabilan ini sering absen pada tahap awal, terutama pada orang muda. [2] Sampai dengan 40% dari pasien mungkin mengalami jatuh dan sekitar 10% mungkin telah jatuh mingguan, dengan jumlah yang jatuh berhubungan dengan keparahan dari PD [1].

Tanda-tanda motor lain diakui dan gejala termasuk gangguan gaya berjalan dan postur seperti festination (langkah mengocok cepat dan postur tubuh ke depan tertekuk ketika berjalan), [1] berbicara dan gangguan menelan termasuk gangguan suara, [14] seperti topeng ekspresi wajah atau tulisan tangan kecil , meskipun berbagai masalah motorik yang mungkin yang dapat muncul adalah besar [1].

 Neuropsikiatrik
Penyakit Parkinson dapat menyebabkan gangguan neuropsikiatri yang bisa berkisar dari ringan sampai parah. Ini termasuk gangguan berbicara, kognisi, mood, perilaku, dan pikiran [1].

Gangguan kognitif dapat terjadi pada tahap awal penyakit dan kadang-kadang sebelum diagnosis, dan peningkatan prevalensi dengan durasi penyakit [1] [15]. Defisit kognitif yang paling umum pada individu yang terkena adalah disfungsi eksekutif, yang dapat mencakup masalah dengan perencanaan, fleksibilitas kognitif, berpikir abstrak, akuisisi aturan, memulai tindakan yang tepat dan tindakan tidak pantas menghambat, dan memilih informasi sensorik relevan. Fluktuasi perhatian dan memperlambat kecepatan kognitif antara kesulitan kognitif lainnya. Memori dipengaruhi, khususnya dalam mengingat informasi yang dipelajari. Namun demikian, perbaikan muncul ketika mengingat dibantu oleh isyarat. Kesulitan visuospatial juga merupakan bagian dari penyakit, dilihat misalnya ketika individu diminta untuk melakukan tes pengenalan wajah dan persepsi orientasi garis yang ditarik [15].

Seseorang dengan PD memiliki dua sampai enam kali risiko menderita demensia dibandingkan dengan populasi umum [1] [15]. Prevalensi demensia meningkat dengan durasi penyakit. [15] Demensia dikaitkan dengan berkurangnya kualitas hidup di orang dengan PD dan pengasuh mereka, meningkatnya kematian, dan probabilitas yang lebih tinggi membutuhkan perawatan di rumah. [15]

Perubahan perilaku dan suasana hati lebih sering terjadi pada PD tanpa gangguan kognitif dibandingkan pada populasi umum, dan biasanya hadir dalam PD dengan demensia. Kesulitan suasana hati yang paling sering adalah depresi, apatis dan kecemasan. [1] perilaku kontrol impuls seperti obat-obatan dan keinginan berlebihan, makan pesta, hypersexuality, atau judi patologis dapat muncul di PD dan telah terkait dengan obat yang digunakan untuk mengelola penyakit ini. [1] [16] psikotik gejala-halusinasi atau delusi-terjadi pada 4% pasien, dan diasumsikan bahwa tergesa-gesa utama fenomena psikotik pada penyakit Parkinson adalah kelebihan dopaminergik sekunder untuk pengobatan; karena itu menjadi lebih umum dengan bertambahnya usia dan asupan levodopa [17]. [18]

Lain-lain
Selain gejala kognitif dan motor, PD dapat merusak fungsi tubuh lainnya. Masalah tidur adalah fitur dari penyakit dan dapat diperburuk oleh obat [1] Gejala. Dapat terwujud dalam rasa kantuk di siang hari, gangguan dalam tidur REM, atau insomnia. [1] Perubahan dalam sistem saraf otonom dapat menyebabkan hipotensi ortostatik (darah rendah tekanan terhadap berdiri), kulit berminyak dan berkeringat berlebihan, inkontinensia urin dan fungsi seksual diubah [1]. Sembelit dan dismotilitas lambung dapat cukup parah untuk menyebabkan ketidaknyamanan dan bahkan membahayakan kesehatan [19]. PD adalah terkait dengan beberapa mata dan kelainan visi seperti sebagai penurunan tingkat berkedip, mata kering, mata mengejar kekurangan (pelacakan mata) dan gerakan saccadic (gerakan otomatis cepat dari kedua mata di arah yang sama), kesulitan dalam mengarahkan pandangannya ke atas, dan penglihatan kabur atau ganda [1]. [20] Perubahan dalam persepsi mungkin termasuk rasa gangguan penciuman, sensasi rasa sakit dan paresthesia (kesemutan dan mati rasa kulit) [1]. Semua gejala ini dapat terjadi tahun sebelum diagnosis penyakit. [1]

 Penyebab

PDB rendering Parkin (ligase)
Kebanyakan orang dengan penyakit Parkinson memiliki penyakit Parkinson idiopatik (tidak memiliki diketahui penyebabnya yang spesifik). Sebagian kecil kasus, bagaimanapun, dapat dikaitkan dengan faktor genetik dikenal. Faktor lain telah dikaitkan dengan risiko pengembangan PD, tetapi tidak ada hubungan kausal telah terbukti.

PD tradisional telah dianggap sebagai gangguan non-genetik;. Namun, sekitar 15% dari individu dengan PD memiliki kerabat tingkat pertama yang memiliki penyakit [2] Setidaknya 5% dari orang kini diketahui memiliki bentuk penyakit yang terjadi karena mutasi dari salah satu gen yang spesifik. [21]

Mutasi pada gen-gen tertentu telah meyakinkan terbukti menyebabkan PD. Ini kode gen untuk alfa-synuclein (SPMB), Parkin (PRKN), leusin kaya kinase mengulang 2 (LRRK2 atau dardarin), PTEN-diinduksi kinase putatif 1 (PINK1), DJ-1 dan ATP13A2. [4] [21] Dalam kebanyakan kasus, orang dengan mutasi ini akan mengembangkan PD. Dengan pengecualian LRRK2, bagaimanapun, mereka account hanya minoritas kecil dari kasus PD [4] PD-terkait paling ekstensif dipelajari gen SPMB dan LRRK2.. Mutasi pada gen termasuk SPMB, LRRK2 dan glucocerebrosidase (GBA) telah ditemukan menjadi faktor risiko untuk PD sporadis. Mutasi di GBA diketahui menyebabkan penyakit Gaucher. [21] Genome-wide studi hubungan, yang mencari alel bermutasi dengan penetrasi yang rendah dalam kasus-kasus sporadis, kini telah menghasilkan banyak hasil positif. [22]

Peran dari gen SPMB adalah penting dalam PD karena protein alpha-synuclein adalah komponen utama dari badan Lewy. [21] mutasi missense gen (di mana nukleotida tunggal berubah), dan duplikasi dan triplications dari lokus yang berisi itu telah ditemukan dalam kelompok-kelompok yang berbeda dengan PD keluarga [21] missense mutasi jarang terjadi.. [21] Di sisi lain, perkalian dari account lokus SPMB untuk sekitar 2% dari kasus keluarga. [21] perkalian telah ditemukan di asimtomatik operator, yang menunjukkan bahwa penetrasi tidak lengkap atau usia tergantung. [21]

Gen LRRK2 (PARK8) mengkode untuk protein yang disebut dardarin. Nama dardarin diambil dari kata Basque untuk tremor, karena gen ini pertama kali diidentifikasi pada keluarga dari Inggris dan bagian utara Spanyol [4]. Mutasi di LRRK2 adalah penyebab paling umum dikenal PD keluarga dan sporadis, akuntansi untuk sekitar 5 % dari individu dengan riwayat keluarga penyakit dan 3% dari kasus sporadis. [4] [21] Ada banyak mutasi yang berbeda dijelaskan dalam LRRK2, namun bukti tegas dari sebab-akibat hanya ada untuk sejumlah kecil. [21]

 Patologi

Sebuah tubuh Lewy (coklat patri) dalam sel otak substantia nigra dalam penyakit Parkinson. Warna coklat adalah pewarnaan imunohistokimia positif untuk alfa-synuclein.

patologi anatomi
Ganglia basal, sebuah kelompok “struktur otak” diinervasi oleh sistem dopaminergik, adalah yang paling serius terkena dampak area otak di PD [23]. Karakteristik patologis utama dari PD adalah kematian sel dalam substantia nigra dan, lebih khusus, ventral (depan) bagian dari pars compacta, yang mempengaruhi hingga 70% dari kematian sel dengan waktu terjadi. [4]

Perubahan makroskopik dapat melihat pada permukaan dipotong dari batang otak, di mana hilangnya neuron dapat disimpulkan dari pengurangan pigmentasi melanin dalam substantia nigra dan lokus coeruleus [24]. Para histopatologi (anatomi mikroskopik) dari substantia nigra dan beberapa daerah otak lainnya menunjukkan hilangnya neuron dan badan Lewy dalam banyak sel-sel saraf yang tersisa. Hilangnya neuron disertai dengan kematian astrosit (berbentuk bintang sel-sel glial) dan aktivasi dari mikroglia (jenis lain dari sel glial). Badan Lewy adalah fitur kunci dari PD patologis. [24]

Patofisiologi

A. Skema awal perkembangan deposito tubuh Lewy pada tahap pertama penyakit Parkinson, seperti yang diusulkan oleh Braak dan rekan
B. Lokalisasi wilayah volume otak penurunan yang signifikan di PD awal dibandingkan dengan kelompok peserta tanpa penyakit dalam studi neuroimaging, yang menyimpulkan bahwa kerusakan batang otak mungkin tahap pertama diidentifikasi PD neuropatologi [25]
Gejala utama hasil penyakit Parkinson dari kegiatan sangat mengurangi sel mensekresi dopamin yang disebabkan oleh kematian sel di daerah pars compacta dari substantia nigra. [23]

Ada lima jalur utama di otak yang menghubungkan daerah otak lainnya dengan ganglia basal. Ini dikenal sebagai motor, oculo-motor, sirkuit asosiatif, limbik dan orbitofrontal, dengan nama yang menunjukkan area proyeksi utama dari setiap sirkuit [23]. Semua dari mereka yang terkena di PD, dan gangguan mereka menjelaskan banyak gejala penyakit sejak sirkuit ini terlibat dalam berbagai fungsi termasuk gerakan, perhatian dan belajar. [23] Secara ilmiah, sirkuit motor telah diperiksa paling intensif [23].

Sebuah model konseptual tertentu dari sirkuit motor dan perubahan dengan PD telah pengaruh besar sejak tahun 1980, meskipun beberapa keterbatasan telah menunjukkan yang telah menyebabkan modifikasi. [23] Dalam model ini, ganglia basal biasanya memberikan pengaruh penghambatan konstan pada berbagai sistem motor, mencegah mereka dari menjadi aktif pada waktu yang tidak tepat. Ketika keputusan dibuat untuk melakukan suatu tindakan tertentu, penghambatan berkurang untuk sistem motor yang diperlukan, sehingga melepaskannya untuk aktivasi. Dopamin bertindak untuk memfasilitasi pelepasan inhibisi, tingkat begitu tinggi fungsi dopamin cenderung mempromosikan aktivitas motorik, sementara tingkat rendah fungsi dopamin, seperti yang terjadi pada PD, permintaan pengerahan tenaga lebih besar dari upaya untuk setiap gerakan yang diberikan. Jadi efek bersih dari deplesi dopamin adalah untuk menghasilkan hypokinesia, pengurangan secara keseluruhan dalam output bermotor [23]. Obat yang digunakan untuk mengobati PD, sebaliknya, bisa menghasilkan aktivitas dopamin berlebihan, yang memungkinkan sistem motor yang akan diaktifkan pada saat yang tidak tepat dan dengan demikian menghasilkan dyskinesias [23].

 Kematian otak sel
Ada spekulasi beberapa mekanisme dimana sel-sel otak bisa hilang [26]. Salah satu mekanisme terdiri dari akumulasi abnormal dari protein alfa-synuclein terikat ubiquitin dalam sel yang rusak. Protein ini tidak larut terakumulasi di dalam neuron membentuk inklusi disebut Lewy tubuh [4]. [27] Menurut pementasan Braak, klasifikasi penyakit berdasarkan temuan patologis, badan Lewy pertama kali muncul di olfactory bulb, medulla oblongata dan pons tegmentum, dengan individu pada tahap ini menjadi asimtomatik. Sebagai penyakit berlangsung, badan Lewy kemudian berkembang di substantia nigra, area otak tengah dan otak depan basal, dan langkah terakhir neokorteks [4] Situs-situs otak adalah tempat utama degenerasi saraf di PD,. Namun, badan Lewy mungkin tidak menyebabkan kematian sel dan mereka mungkin menjadi pelindung [26]. [27] Pada pasien dengan demensia, kehadiran umum dari badan Lewy yang umum di daerah kortikal. Kusut neurofibrillary dan plak pikun, karakteristik penyakit Alzheimer, yang tidak umum kecuali orang itu gila. [24]

Lain-sel mati Mekanisme ini termasuk disfungsi sistem proteosomal dan lisosomal dan aktivitas mitokondria berkurang [26]. Besi akumulasi dalam substantia nigra biasanya diamati dalam hubungannya dengan inklusi protein. Ini mungkin berhubungan dengan stres oksidatif, agregasi protein dan kematian neuronal, tetapi mekanisme tidak sepenuhnya dipahami [28].

Diagnosis

Fludeoxyglucose (18F) (FDG)] PET scan otak yang sehat. Daerah panas mencerminkan penyerapan glukosa yang lebih tinggi. Sebuah penurunan aktivitas di ganglia basal dapat membantu dalam mendiagnosa penyakit Parkinson.
Seorang dokter akan mendiagnosa penyakit Parkinson dari riwayat medis dan pemeriksaan neurologis [1]. Tidak ada tes laboratorium yang jelas akan mengidentifikasi penyakit, tetapi pemindaian otak kadang-kadang digunakan untuk mengesampingkan gangguan yang dapat menimbulkan gejala yang sama. Pasien dapat diberikan levodopa dan lega yang dihasilkan dari gangguan motorik cenderung untuk mengkonfirmasikan diagnosis. Temuan badan Lewy di otak tengah pada otopsi biasanya dianggap bukti bahwa pasien menderita penyakit Parkinson. Kemajuan dari penyakit dari waktu ke waktu dapat mengungkapkan itu bukan penyakit Parkinson, dan beberapa pihak berwenang merekomendasikan bahwa diagnosis secara periodik terakhir [1] [29].

Penyebab lain yang secara sekunder dapat menghasilkan sindrom parkinsonian adalah penyakit Alzheimer, infark serebral ganda dan obat-induced parkinson. [29] Parkinson ditambah sindrom seperti palsy supranuclear progresif dan atrofi sistem multi harus dikesampingkan [1] obat anti-Parkinson. biasanya kurang efektif mengendalikan gejala di Parkinson ditambah sindrom [1]. angka kemajuan lebih cepat, disfungsi kognitif awal atau instabilitas postural, tremor minimal atau simetri saat onset mungkin mengindikasikan penyakit Parkinson ditambah ketimbang PD itu sendiri. [30] bentuk genetik biasanya diklasifikasikan sebagai PD, meskipun istilah penyakit Parkinson keluarga dan parkinson kekeluargaan yang digunakan untuk entitas penyakit dengan pola dominan atau resesif autosomal dari warisan. [2]

Organisasi medis telah menciptakan kriteria diagnostik untuk kemudahan dan standarisasi proses diagnostik, terutama pada tahap awal penyakit ini. Kriteria yang paling banyak dikenal berasal dari Otak Masyarakat Bank Parkinson Inggris Penyakit dan US National Institute of Neurological Gangguan dan Stroke [1]. Kriteria PD Otak Bank Masyarakat membutuhkan lambatnya gerakan (bradykinesia) plus kekakuan, tremor istirahat, atau postural ketidakstabilan. Kemungkinan penyebab lain untuk gejala ini harus dikesampingkan. Akhirnya, tiga atau lebih dari fitur berikut diperlukan saat onset atau evolusi: onset sepihak, tremor saat istirahat, kemajuan dalam waktu, asimetri gejala motorik, respon terhadap levodopa setidaknya selama lima tahun, perjalanan klinis setidaknya sepuluh tahun dan penampilan dari dyskinesias diinduksi oleh asupan levodopa berlebihan [1] Akurasi kriteria diagnostik dievaluasi pada otopsi adalah 75-90%, dengan spesialis seperti ahli saraf memiliki tingkat tertinggi.. [1]

Computed tomography (CT) dan magnetic resonance imaging scan otak (MRI) dari orang-orang dengan PD biasanya tampak normal. [31] Teknik-teknik ini tetap berguna untuk menyingkirkan penyakit lain yang dapat menyebabkan parkinson sekunder, seperti tumor basal ganglia, vaskular patologi dan hidrosefalus [31]. Sebuah teknik khusus dari MRI, difusi MRI, telah dilaporkan berguna untuk membedakan antara parkinson khas dan atipikal, meskipun nilai yang tepat diagnostik masih dalam penyelidikan. [31] fungsi dopaminergik di ganglia basal dapat diukur dengan PET dan SPECT radiotracers yang berbeda. Contohnya adalah ioflupane (123I) (nama dagang DaTSCAN) dan iometopane (Dopascan) untuk SPECT atau fludeoxyglucose (18F) untuk PET. [31] Sebuah pola aktivitas dopaminergik berkurang di ganglia basal dapat membantu dalam mendiagnosa PD. [31]

 Manajemen
Artikel utama: Pengobatan penyakit Parkinson
Tidak ada obat untuk penyakit Parkinson, tetapi obat-obatan, operasi dan manajemen multidisiplin dapat memberikan bantuan dari gejala. Keluarga utama dari obat yang berguna untuk mengobati gejala motor levodopa (biasanya dikombinasikan dengan inhibitor dekarboksilase dopa atau inhibitor COMT), agonis dopamin dan MAO-B inhibitor [32]. Tahap penyakit menentukan kelompok mana yang paling berguna. Dua tahap biasanya dibedakan:. Tahap awal di mana individu dengan PD telah mengembangkan beberapa cacat yang dia butuhkan pengobatan farmakologis, maka tahap kedua di mana seorang individu mengembangkan komplikasi motorik yang berhubungan dengan penggunaan levodopa [32] Pengobatan di awal tahap bertujuan untuk tradeoff yang optimal antara kontrol gejala yang baik dan efek samping yang dihasilkan dari peningkatan fungsi dopaminergik. Awal levodopa (atau L-dopa) pengobatan mungkin tertunda dengan menggunakan obat lain seperti MAO-B inhibitor dan agonis dopamin, dengan harapan menunda timbulnya dyskinesias [32] Pada tahap kedua. Tujuannya adalah untuk mengurangi gejala sambil mengontrol fluktuasi dari respon terhadap pengobatan. Penarikan mendadak dari obat atau berlebihan harus dikelola [32]. Bila obat tidak cukup untuk mengontrol gejala, operasi dan stimulasi otak dalam dapat berguna. [33] Pada tahap akhir dari penyakit, perawatan paliatif diberikan untuk meningkatkan kualitas hidup [34].

Levodopa
Levodopa telah menjadi pengobatan yang paling banyak digunakan untuk lebih dari 30 tahun [32]. L-dopa diubah menjadi dopamin di neuron dopaminergik oleh dopa dekarboksilase. [32] Karena gejala motor yang diproduksi oleh kurangnya dopamin dalam substansia nigra, yang administrasi L-dopa sementara mengurangi gejala motor. [32]

Hanya 5-10% L-dopa melintasi penghalang darah-otak. Sisanya sering dimetabolisme untuk dopamin di tempat lain, menyebabkan berbagai efek samping termasuk mual, diskinesia dan kekakuan sendi [32]. Carbidopa dan benserazide adalah inhibitor dekarboksilase dopa perifer, [32] yang membantu mencegah metabolisme L-dopa sebelum mencapai neuron dopaminergik, sehingga mengurangi efek samping dan meningkatkan bioavailabilitas. Mereka umumnya diberikan sebagai persiapan kombinasi dengan levodopa [32] persiapan yang ada. Yang carbidopa / levodopa (co-careldopa) dan benserazide / levodopa (co-beneldopa). Levodopa telah terkait dengan sindrom disregulasi dopamin, yang merupakan berlebihan kompulsif obat, dan punding [16]. Ada versi rilis dikendalikan dari levodopa dalam bentuk infus intravena dan usus yang menyebar efek obat. Ini lambat-release persiapan levodopa belum menunjukkan peningkatan kontrol gejala motor atau komplikasi motor ketika dibandingkan dengan persiapan segera dibebaskan. [32] [35]

Tolcapone menghambat enzim COMT, yang menurunkan dopamin, sehingga memperpanjang efek levodopa [32] ini telah digunakan untuk melengkapi levodopa;.. Namun, kegunaannya dibatasi oleh efek samping yang mungkin seperti kerusakan hati [32] Sebuah obat sama efektif , entacapone, belum terbukti menyebabkan perubahan yang signifikan dari fungsi hati [32] persiapan Berlisensi dari entacapone mengandung entacapone sendiri atau dalam kombinasi dengan carbidopa dan levodopa.. [32]

Persiapan levodopa memimpin dalam jangka panjang untuk pengembangan komplikasi motorik ditandai dengan gerakan tak terkendali yang disebut dyskinesias dan fluktuasi dalam respon terhadap pengobatan [32]. Ketika ini terjadi orang dengan PD dapat berubah dari fase dengan respon yang baik terhadap obat dan beberapa gejala ( “pada” negara), untuk fase dengan tidak ada respon terhadap pengobatan dan gejala motor yang signifikan (“off” negara) [32] Untuk alasan ini,. dosis levodopa yang dijaga serendah mungkin dengan tetap menjaga fungsi [32] Menunda inisiasi. terapi dengan levodopa dengan menggunakan alternatif (agonis dopamin dan MAO-B inhibitor) adalah praktek yang umum. [32] Sebuah strategi mantan untuk mengurangi komplikasi motor untuk menarik L-dopa obat untuk beberapa waktu. Ini tidak disarankan sekarang, karena dapat membawa efek samping yang berbahaya seperti sindrom neuroleptik ganas. [32] Kebanyakan orang dengan PD akhirnya akan membutuhkan levodopa dan kemudian mengembangkan efek samping motorik. [32]

 agonis Dopamin
Beberapa agonis dopamin yang mengikat pasca-sinaptik dopaminergik reseptor di otak memiliki efek yang sama terhadap levodopa [32] ini pada awalnya digunakan untuk individu mengalami on-off fluktuasi dan diskinesia sebagai terapi komplementer untuk levodopa,. Mereka sekarang terutama digunakan pada mereka sendiri sebagai terapi awal untuk gejala motor dengan tujuan menunda komplikasi bermotor [32]. [36] Ketika digunakan di PD an mereka berguna untuk mengurangi periode off. [32] agonis Dopamin termasuk bromokriptin, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine dan lisuride.

Agonis dopamin menghasilkan signifikan, meskipun biasanya ringan, efek samping termasuk rasa kantuk, halusinasi, mual insomnia, dan sembelit. [32] Kadang-kadang efek samping muncul bahkan pada dosis klinis efektif minim, menyebabkan dokter untuk mencari obat yang berbeda. [32] Dibandingkan dengan levodopa, agonis dopamin dapat menunda komplikasi motor menggunakan obat tetapi kurang efektif mengendalikan gejala [32] Meskipun demikian, mereka biasanya cukup efektif untuk mengelola gejala pada tahun-tahun awal.. [2] Mereka cenderung lebih mahal daripada levodopa [2]. dyskinesias akibat agonis dopamin jarang pada orang muda yang memiliki PD, namun seiring dengan efek samping lainnya, menjadi lebih umum dengan usia saat onset [2] Jadi. agonis dopamin adalah pengobatan awal yang lebih disukai untuk onset awal, sebagai lawan terhadap levodopa dalam onset kemudian [2]. Agonis telah terkait dengan gangguan impuls kontrol (seperti aktivitas seksual kompulsif dan makan, dan judi patologis dan belanja) bahkan lebih kuat dari levodopa. [16]

Apomorphine, suatu agonis dopamin non-oral, dapat digunakan untuk mengurangi off periode dan tardive di PD-an [32]. Hal ini dikelola oleh suntikan subkutan intermiten atau kontinu infus [32]. Karena efek sekunder seperti kebingungan dan halusinasi yang umum , individu-individu yang menerima pengobatan apomorphine harus diawasi secara ketat. [32] Dua agonis dopamin yang diberikan melalui patch kulit (lisuride dan rotigotine) telah baru-baru ini ditemukan bermanfaat bagi pasien dalam tahap awal dan hasil positif awal telah dipublikasikan pada kontrol mematikan negara pada pasien di negara maju [35].

MAO-B inhibitor
MAO-B inhibitor (selegiline dan rasagiline) meningkatkan tingkat dopamin di ganglia basal dengan menghalangi metabolisme. Mereka menghambat monoamin oksidase-B (MAO-B) yang memecah dopamin disekresikan oleh neuron dopaminergik. Pengurangan MAO-B hasil kegiatan dalam peningkatan L-dopa di striatum [32] Seperti agonis dopamin, MAO-B inhibitor yang digunakan sebagai monoterapi memperbaiki gejala motorik dan menunda kebutuhan untuk levodopa pada penyakit awal, tetapi menghasilkan efek yang lebih merugikan dan. kurang efektif daripada levodopa. Ada beberapa studi efektivitas mereka dalam stadium lanjut, meskipun hasil menunjukkan bahwa mereka berguna untuk mengurangi fluktuasi antara on dan off periode [32]. Sebuah studi awal mengindikasikan bahwa selegiline dalam kombinasi dengan levodopa meningkatkan risiko kematian, tapi ini kemudian disproven. [32]

 Obat lain
Obat lain seperti amantadine dan antikolinergik mungkin berguna sebagai pengobatan gejala motor. Namun, bukti mendukung mereka tidak memiliki kualitas, sehingga mereka tidak pengobatan pilihan pertama. [32] Selain gejala motor, PD disertai dengan beragam gejala. Sejumlah obat telah digunakan untuk mengobati beberapa masalah [37]. Contohnya adalah penggunaan clozapine untuk psikosis, cholinesterase inhibitor untuk demensia, dan modafinil untuk kantuk di siang hari. [37] [38] Sebuah meta-analisis 2010 menemukan bahwa non-steroid anti-inflammatory drugs (selain asetaminofen dan aspirin), telah dihubungkan dengan setidaknya 15 persen (lebih tinggi dalam jangka panjang dan pengguna biasa) pengurangan kejadian perkembangan penyakit Parkinson. [39]

  Epidemiologi
PD adalah gangguan neurodegeneratif kedua yang paling umum setelah penyakit Alzheimer [61]. Prevalensi (proporsi dalam populasi pada suatu waktu tertentu) dari PD adalah sekitar 0,3% dari seluruh penduduk di negara-negara industri. PD lebih umum pada lansia dan prevalensi meningkat dari 1% pada mereka yang 60 tahun lebih dari usia sampai 4% dari populasi lebih dari 80 [61]. Rata-rata usia onset adalah sekitar 60 tahun, meskipun 5-10% dari kasus, diklasifikasikan sebagai onset muda, mulai antara usia 20 dan 50 [2]. PD mungkin kurang lazim dalam orang-orang keturunan Afrika dan Asia, meskipun temuan ini diperdebatkan. [61] Beberapa penelitian telah mengusulkan bahwa itu adalah lebih umum pada laki-laki daripada perempuan, tetapi yang lain gagal untuk mendeteksi perbedaan antara kedua jenis kelamin. [61] Insiden PD adalah antara 8 dan 18 per 100.000 orang-tahun [61].

Banyak faktor risiko dan faktor pelindung telah diusulkan, kadang-kadang dalam kaitannya dengan teori-teori tentang kemungkinan mekanisme penyakit ini, namun belum ada yang meyakinkan terkait dengan PD oleh bukti empiris. Ketika studi epidemiologis telah dilakukan dalam rangka untuk menguji hubungan antara faktor yang diberikan dan PD, mereka sering telah cacat dan hasil mereka dalam beberapa kasus telah bertentangan [61]. Hubungan yang paling sering ditiru adalah peningkatan risiko PD di mereka yang terpapar pestisida, dan mengurangi risiko pada perokok [61].

 Faktor risiko

US Army helikopter penyemprotan Agen Oranye atas tanah pertanian Vietnam selama perang Vietnam. Agen Oranye telah dikaitkan dengan PD.

Suntikan dari MPTP neurotoksin sintetik menghasilkan berbagai gejala mirip dengan PD serta kerusakan selektif ke neuron dopaminergik di substansia nigra. Pengamatan ini telah menyebabkan teori bahwa paparan terhadap beberapa racun lingkungan dapat meningkatkan risiko memiliki PD. [61] Paparan racun yang telah secara konsisten terkait dengan penyakit ini dapat melipatgandakan risiko PD, dan termasuk pestisida tertentu, seperti rotenone atau parakuat, dan herbisida, seperti Agent Orange [61]. [62] [63] langkah-langkah tidak langsung paparan, seperti tinggal di lingkungan pedesaan, telah ditemukan untuk meningkatkan risiko PD. [63] logam berat telah diusulkan paparan menjadi faktor risiko, melalui akumulasi mungkin dalam substantia nigra;. Namun, studi tentang masalah ini telah meyakinkan [61]

Faktor pelindung
Merokok telah dikaitkan dengan penurunan risiko memiliki PD. Risiko perokok memiliki PD dapat dikurangi turun ke ketiga ketika dibandingkan non-perokok [61]. Dasar untuk efek ini tidak diketahui, tetapi kemungkinan mencakup efek dari nikotin sebagai stimulan dopamin. [61] Asap tembakau mengandung senyawa yang bertindak sebagai inhibitor MAO yang mungkin juga berkontribusi terhadap efek ini [64] konsumsi Kafein juga melindungi terhadap PD. [65] Antioksidan, seperti vitamin C dan D, telah diusulkan untuk melindungi terhadap penyakit, tetapi hasil penelitian telah. bertentangan dan tidak ada efek positif telah terbukti. [61] Hasil mengenai asam lemak dan lemak telah bertentangan, dengan berbagai penelitian melaporkan efek protektif, risiko-meningkatkan efek atau tanpa efek. [61] Akhirnya ada indikasi awal dari suatu kemungkinan peran protektif estrogen dan anti-inflamasi [61].

Sejarah

Sebuah foto dari 1893 Jean-Martin Charcot, yang membuat kontribusi penting untuk memahami penyakit dan diusulkan namanya sekarang menghormati James Parkinson

Sumber-sumber awal Beberapa, termasuk papirus Mesir, sebuah risalah medis Ayurvedic, Alkitab, atau tulisan Galen, menggambarkan gejala menyerupai orang-orang PD [66]. Setelah Galen tidak ada referensi jelas terkait dengan PD sampai abad ke-17. [66] Dalam abad 17 dan 18, beberapa penulis menulis tentang unsur-unsur dari penyakit, termasuk Sylvius, Gaubius, Hunter dan Chomel. [66] [67] [68]

Pada 1817 seorang dokter Inggris, James Parkinson, menerbitkan esainya melaporkan enam kasus agitans kelumpuhan. [69] Sebuah Esai tentang Cerebral Sambil menggambarkan karakteristik tremor istirahat, postur abnormal dan kiprah, kelumpuhan dan kekuatan otot berkurang, dan cara yang Penyakit berlangsung dari waktu ke waktu. [69] [70] ahli saraf Awal yang membuat penambahan lebih lanjut untuk pengetahuan tentang penyakit ini termasuk Trousseau, Gowers, Kinnier Wilson dan Erb, dan terutama Jean-Martin Charcot, yang penelitiannya antara 1868 dan 1881 adalah tengara dalam pemahaman penyakit ini [69] Di antara kemajuan lain., dia membuat perbedaan antara kekakuan, kelemahan dan bradykinesia. [69] Ia juga memperjuangkan penggantian nama penyakit untuk menghormati James Parkinson. [69]

Pada tahun 1912 Frederic Lewy dijelaskan partikel mikroskopis dalam otak yang terkena, kemudian dinamai “badan Lewy” [69] Pada tahun 1919 melaporkan bahwa Konstantin Tretiakoff substantia nigra adalah struktur otak utama yang terkena dampak, namun temuan ini tidak diterima secara luas sampai dikonfirmasi oleh lebih lanjut. studi yang diterbitkan oleh Rolf Hassler tahun 1938 [69]. Perubahan biokimia yang mendasari di otak diidentifikasi pada tahun 1950, terutama disebabkan oleh Arvid Carlsson pekerjaan pada neurotransmitter dopamin dan perannya di PD. [71] Pada tahun 1997, alfa- synuclein ditemukan menjadi komponen utama dari badan Lewy. [27]

Antikolinergik dan pembedahan (lesioning dari jalur kortikospinalis atau beberapa struktur basal ganglia) adalah pengobatan hanya sampai kedatangan levodopa, yang mengurangi penggunaan mereka secara dramatis [67] [72]. Levodopa pertama kali disintesis pada tahun 1911 oleh Casimir Funk, namun itu mendapat sedikit perhatian sampai pertengahan abad ke-20 [71] Ini masuk praktek klinis pada tahun 1967 dan membawa sebuah revolusi dalam manajemen PD [71] [73]. Dengan stimulasi otak 1980-an yang mendalam muncul sebagai pengobatan mungkin.. [ 74]

Penelitian arah

Ada sedikit prospek dramatis perawatan PD baru yang diharapkan dalam jangka waktu yang singkat [75] arah penelitian Saat ini aktif meliputi mencari model hewan baru dari penyakit dan studi tentang manfaat potensi terapi gen, transplantasi stem sel dan agen saraf.. [26]

Hewan model
PD tidak diketahui terjadi secara alami dalam spesies selain manusia, meskipun model hewan yang menunjukkan beberapa fitur penyakit yang digunakan dalam penelitian. Munculnya gejala parkinsonian dalam kelompok pecandu narkoba di awal 1980-an yang mengkonsumsi terkontaminasi batch dari candu sintetis MPPP menyebabkan penemuan MPTP kimia sebagai agen yang menyebabkan sindrom parkinsonian dalam primata non-manusia serta manusia [76]. Lain dominan racun model berbasis mempekerjakan rotenone insektisida, herbisida paraquat dan fungisida maneb [77]. Model didasarkan pada racun yang paling sering digunakan pada primata. Hewan model transgenik yang meniru berbagai aspek dari PD telah dikembangkan. [78]

 Terapi gen
Terapi gen melibatkan penggunaan virus tidak menular untuk antar-jemput gen menjadi bagian dari otak. Gen yang digunakan menyebabkan produksi enzim yang membantu untuk mengelola gejala PD atau melindungi otak dari kerusakan lebih lanjut [26]. [79] Pada tahun 2010 ada empat uji klinis menggunakan terapi gen pada PD. [26] belum ada efek samping penting dalam ujicoba tersebut meskipun kegunaan klinis terapi gen masih belum diketahui [26] Salah satu hasil positif yang dilaporkan pada tahun 2011.. [80]

Perawatan saraf

Sementara beberapa senyawa kimia seperti GDNF (struktur kimia digambarkan) telah diusulkan sebagai neuroprotectors di PD, belum terbukti kemanjurannya.

Investigasi pada pelindung saraf berada di garis depan PD penelitian. Beberapa molekul telah diusulkan sebagai perawatan potensial. [26] Namun, tidak satupun dari mereka telah meyakinkan menunjukkan untuk mengurangi degenerasi [26]. Agen saat ini sedang diselidiki termasuk anti-apoptotics (omigapil, CEP-1347), antiglutamatergics, inhibitor monoamine oxidase ( selegiline, rasagiline), promitochondrials (koenzim Q10, creatine), calcium channel blockers (isradipine) dan faktor pertumbuhan (GDNF) [26] Penelitian praklinis juga menargetkan alpha-synuclein.. [75]

 Neural transplantasi
Sejak awal 1980-an, janin, babi, jaringan karotis atau retina telah digunakan dalam transplantasi sel, di mana sel terdisosiasi yang disuntikkan ke dalam substantia nigra dengan harapan bahwa mereka akan menggabungkan diri ke otak dengan cara yang menggantikan dopamin- memproduksi sel-sel yang telah hilang [26]. Meskipun ada bukti awal yang memproduksi dopamin mesensefalik transplantasi sel yang menguntungkan, double-blind uji coba sampai saat ini menunjukkan bahwa transplantasi sel tidak menghasilkan manfaat jangka panjang. [26] Sebuah masalah yang signifikan tambahan pelepasan dopamin kelebihan oleh jaringan transplantasi, menyebabkan distonia [81]. Transplantasi sel induk adalah target penelitian terbaru, karena sel-sel induk yang mudah untuk memanipulasi dan sel induk yang ditransplantasikan ke dalam otak tikus dan monyet telah ditemukan untuk bertahan hidup dan mengurangi kelainan perilaku [26] [82]. Namun demikian, penggunaan sel induk janin kontroversial. [26] Telah diusulkan bahwa perawatan yang efektif dapat dikembangkan dalam cara yang kurang kontroversial oleh penggunaan sel induk pluripotent yang diambil dari orang dewasa. [ 26]

Masyarakat dan budaya

Muhammad Ali pada usia 64 pada tahun 2006. Dia telah menunjukkan tanda-tanda parkinson sejak usia 38.

Biaya
Biaya PD untuk masyarakat yang tinggi, tetapi sulit untuk menghitung persis karena kesulitan metodologis dalam penelitian dan perbedaan antara negara-negara [83]. Biaya tahunan di Inggris diperkirakan antara 449 juta dan 3.3 miliar pounds, sedangkan biaya per pasien per tahun di AS mungkin sekitar $ 10.000 dan total beban sekitar 23 miliar dolar [83]. Bagian terbesar dari biaya langsung berasal dari rawat inap dan panti jompo, sedangkan pangsa datang dari obat secara substansial lebih rendah. [83] Tidak Langsung biaya tinggi, karena produktivitas berkurang dan beban pada pengasuh [83] Di samping biaya ekonomi, PD mengurangi kualitas hidup dari orang-orang dengan penyakit dan pengasuh mereka.. [83]

 Pembelaan
April 11, ulang tahun James Parkinson, telah ditunjuk sebagai hari penyakit dunia Parkinson [69] [84] Sebuah bunga tulip merah dipilih oleh beberapa organisasi internasional sebagai simbol penyakit pada tahun 2005:. Itu merupakan kultivar James Tulip Parkinson , terdaftar pada tahun 1981 oleh seorang holtikultura Belanda [84] organisasi Advokasi pada penyakit termasuk National Parkinson Foundation, yang telah memberikan lebih dari $ 155,000,000 dalam pelayanan perawatan, penelitian dan dukungan sejak 1982., [85] Penyakit Yayasan Parkinson, yang telah memberikan lebih dari $ 90 juta untuk penelitian dan $ 37.000.000 untuk program pendidikan dan advokasi sejak didirikan pada tahun 1957 oleh William Hitam; [86] [87] American Parkinson Penyakit Asosiasi, didirikan pada tahun 1961; [88] dan Parkinson Eropa Penyakit Asosiasi, didirikan pada tahun 1992 [89].

Terkemuka kasus
Artikel utama: Daftar orang didiagnosis dengan penyakit Parkinson
Di antara banyak orang terkenal dengan PD, orang yang telah sangat meningkatkan kesadaran masyarakat dari penyakit adalah aktor Michael J. Fox. Fox didiagnosis pada tahun 1991 ketika ia berumur 30, tapi kondisinya dirahasiakan dari publik selama tujuh tahun [90] Ia telah menulis dua buku yg berhubungan dgn riwayat hidup sendiri di mana perjuangannya melawan penyakit tersebut memainkan peran utama, [91]. Dan muncul sebelum Kongres Amerika Serikat tanpa obat untuk menggambarkan efek dari penyakit [91]. Michael J. Fox Foundation bertujuan untuk mengembangkan obat untuk penyakit Parkinson. Dalam beberapa tahun terakhir ini telah menjadi penggalang dana utama Parkinson di Amerika Serikat, menyediakan 140 juta dolar dalam pendanaan penelitian antara 2001 dan 2008 [91]. Kerja Fox membuatnya menjadi nama salah satu dari 100 orang “yang kekuasaannya, bakat atau contoh moral mengubah dunia “pada tahun 2007 oleh majalah Time, [90] dan ia menerima gelar doktor kehormatan dalam kedokteran dari Karolinska Institutet atas kontribusi untuk penelitian dalam penyakit Parkinson [92]. lain yayasan yang mendukung riset Parkinson didirikan oleh pengendara sepeda profesional Davis Phinney. [93] Para Davis Phinney Yayasan berusaha untuk memperbaiki kehidupan mereka yang hidup dengan penyakit Parkinson dengan menyediakan mereka dengan informasi dan alat-alat [94]. Muhammad Ali telah disebut “pasien yang paling terkenal di dunia Parkinson” itu. [95] Dia adalah 42 pada Diagnosis meskipun dia sudah menunjukkan tanda-tanda Parkinson ketika ia 38. [96] Namun demikian, apakah ia telah PD atau sindrom parkinsonian disebabkan oleh tinju masih merupakan pertanyaan terbuka
  
  
  
  
  
  
  
  
  
  

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The end @ copyright Dr Iwan suwandy 2011

The Mysterious Black Death(Plague Pes or Anthrax Disease)

 

MUSEUM DUNIA MAYA DR IWAN S.

Dr IWAN ‘S CYBERMUSEUM

 THE FIRST INDONESIAN CYBERMUSEUM

  MUSEUM DUNIA MAYA PERTAMA DI INDONESIA

   DALAM PROSES UNTUK MENDAPATKAN SERTIFIKAT MURI

     PENDIRI DAN PENEMU IDE

      THE FOUNDER

    Dr IWAN SUWANDY, MHA

                     

The Driwan’s  Cybermuseum

 The Mysterious Black Death

SEJARAH MISTERI  KEMATIAN HITAM

Ilustrasi dari Black Death dari Alkitab Toggenburg (1411)
The Black Death adalah salah satu pandemi yang paling menghancurkan dalam sejarah manusia, memuncak di Eropa antara 1348 dan 1350. Dari beberapa teori yang bersaing, penjelasan yang dominan untuk Black Death adalah teori wabah, yang atribut wabah ke Yersinia pestis bakteri. Pemikiran telah dimulai di Cina, perjalanan sepanjang Jalan Sutra dan mencapai Krimea oleh 1346. Dari sana, mungkin dibawa oleh kutu tikus Oriental hidup di tikus hitam yang penumpang reguler pada kapal dagang, menyebar di seluruh Mediterania dan Eropa.

The Black Death diperkirakan telah membunuh 30-60 persen dari populasi Eropa, [1] mengurangi populasi dunia diperkirakan dari 450 juta untuk antara 350 dan 375 juta di abad ke-14. Setelah wabah menciptakan serangkaian pergolakan agama, sosial dan ekonomi, yang memiliki efek mendalam pada sejarah Eropa. Butuh waktu 150 tahun bagi penduduk Eropa untuk memulihkan. Wabah kembali pada berbagai waktu, membunuh lebih banyak orang, sampai meninggalkan Eropa di abad 19.

Isi
1 Ikhtisar
1.1 Penamaan
2 Migrasi
2.1 Populasi dalam krisis
2.2 Infeksi dan migrasi
2.3 Eropa wabah
2,4 wabah Timur Tengah
3 Gejala
4 Penyebab
4.1 Wabah
4.2 Alternatif penjelasan
4,3 bukti DNA
5 Konsekuensi
5.1 Kambuh
5.2 Dalam budaya
6 Lihat juga
7 Referensi
8 Bacaan lebih lanjut
9 Pranala luar
 

Ikhtisar


Terinspirasi oleh Black Death, The Dance of Death, sebuah alegori tentang universalitas kematian, merupakan motif lukisan umum dalam periode akhir abad pertengahan.
Ada tiga wabah utama dari wabah. Wabah dari Justinian pada abad 6 dan 7 adalah serangan pertama yang diketahui pada catatan, dan menandai pola tegas tercatat pertama wabah pes. Dari uraian sejarah, sebanyak 40 persen dari penduduk Konstantinopel meninggal karena wabah. Perkiraan modern menunjukkan setengah dari penduduk Eropa dihapuskan sebelum wabah menghilang di 700s [2] Setelah 750, penyakit epidemi besar tidak muncul lagi di Eropa sampai Black Death abad 14.. [3] Ketiga Pandemi melanda China di tahun 1890-an dan hancur India tetapi itu terbatas pada wabah yang terbatas di barat. [4]

The Black Death berasal di atau dekat Cina dan menyebar dengan cara Jalan Sutera atau dengan kapal. [4] Ini mungkin telah mengurangi populasi dunia diperkirakan dari 450 juta untuk antara 350 dan 375 juta pada 1400. [5]

Wabah diperkirakan telah kembali pada interval dengan virulensi yang bervariasi dan mortalitas sampai abad ke-18 [6] Setelah kembali di 1603, misalnya, wabah membunuh 38.000 London. [7]. Penting lain abad ke-17 wabah adalah Wabah Italia (1629-1631), Wabah Besar Seville (1647-1652), Wabah Besar London (1665-1666), [8] dan Wabah Besar Wina (1679). Ada beberapa kontroversi mengenai identitas dari penyakit, tetapi dalam bentuk virulen, setelah Wabah Besar Marseille pada 1720-1722, [9] Wabah Besar 1738 (yang menghantam Eropa Timur), dan wabah Rusia 1770 – 1772, tampaknya secara bertahap menghilang dari Eropa. Dengan awal abad ke 19, ancaman wabah telah berkurang, tapi itu cepat digantikan oleh penyakit baru. Kolera Asiatik adalah yang pertama dari pandemi kolera beberapa menyapu Asia dan Eropa selama abad 19 dan 20 [10].

Letusan abad ke-14 dari Black Death memiliki efek drastis terhadap populasi Eropa, tidak dapat ditarik kembali mengubah struktur sosial. Itu, boleh dibilang, sebuah pukulan serius terhadap Gereja Katolik, dan mengakibatkan penganiayaan luas minoritas seperti Yahudi, orang asing, pengemis, dan penderita kusta. Ketidakpastian kelangsungan hidup sehari-hari telah dilihat sebagai menciptakan suasana umum morbiditas, mempengaruhi orang untuk “hidup untuk saat ini”, seperti yang digambarkan oleh Giovanni Boccaccio dalam The Decameron (1353) [11].

Penamaan
Abad Pertengahan orang yang disebut bencana abad ke-14 baik “Sampar Agung” ‘atau “Wabah Besar” [12] Penulis kontemporer wabah disebut acara sebagai “Mortalitas Besar”.. Sejarah Swedia dan Denmark abad ke-16 menggambarkan peristiwa sebagai “hitam” untuk pertama kalinya, tidak menggambarkan tanda tahap akhir dari penyakit, di mana kulit penderita akan menghitamkan karena perdarahan subepidermal dan ekstremitas akan gelap dengan gangren , tetapi lebih cenderung untuk merujuk pada hitam dalam arti murung atau yang mengerikan dan untuk menunjukkan terribleness dan kesuraman dari peristiwa [13] Para dokter Jerman dan medis penulis Justus Hecker. menyarankan bahwa kesalahan penerjemahan dari mors atra Latin (yang mengerikan, atau hitam, kematian) telah terjadi di Skandinavia ketika ia menggambarkan bencana di 1832 [12] dalam bukunya “Der Tod im Schwarze vierzehnten Jahrhundert”. Pekerjaan itu diterjemahkan ke dalam bahasa Inggris pada tahun berikutnya, dan dengan epidemi kolera yang terjadi pada waktu itu, “The Black Death di abad 14″ mendapat perhatian luas dan istilah Schwarzer Tod dan Kematian Hitam menjadi lebih banyak digunakan dalam berbahasa Jerman dan Inggris dunia, masing-masing.

Migrasi
Artikel utama: migrasi Black Death
Populasi dalam krisis
Di Eropa, Warm Period Abad Pertengahan berakhir kadang menjelang akhir abad ke-13, membawa “Little Ice Age” [14] dan musim dingin yang lebih keras dengan hasil panen berkurang. Di Eropa Utara, inovasi teknologi baru seperti bajak berat dan sistem tiga-lapangan tidak efektif dalam membersihkan ladang baru untuk panen karena mereka di Mediterania karena utara telah miskin, seperti tanah liat tanah [12]. Kekurangan Makanan dan cepat menggembungkan harga adalah kenyataan hidup sebanyak satu abad sebelum wabah. Gandum, gandum, rumput kering dan akibatnya ternak, semua dalam pasokan pendek. Kelangkaan mereka mengakibatkan malnutrisi, yang meningkatkan kerentanan terhadap infeksi karena sistem kekebalan yang melemah. Tingkat kesuburan tinggi secara konsisten, pada 5 anak / wanita atau lebih di seluruh Eropa, mengakibatkan tingkat pertumbuhan penduduk yang tinggi dan memberikan kontribusi kepada kekurangan pangan. Pada musim gugur 1314, hujan lebat mulai turun, yang merupakan awal dari beberapa tahun musim dingin dan basah [12] panen sudah lemah dari utara menderita dan kelaparan yang terjadi tujuh tahun.. Pada tahun-tahun 1315-1317 sebuah bencana kelaparan, yang dikenal sebagai Kelaparan Besar, melanda sebagian besar Eropa Barat Utara. Itu bisa dibilang yang terburuk dalam sejarah Eropa, mungkin mengurangi populasi lebih dari 10 persen. [12]

Infeksi dan migrasi

 

Penyebaran kematian hitam di Eropa (1346-1353)
Wabah penyakit, umumnya diduga disebabkan oleh Yersinia pestis, yang enzootic (biasa hadir) dalam populasi kutu dibawa oleh hewan pengerat tanah, termasuk marmut, di berbagai daerah termasuk Asia Tengah, Kurdistan, Asia Barat, India Utara dan Uganda. [15 ] Nestorian kuburan dating ke 1338-9 dekat Danau Issyk Kul di Kyrgizstan harus mengacu pada prasasti dan investigasi wabah terbaru oleh arkeolog Rusia yang Chwolson menunjukkan angka kejadian yang tinggi dan diperkirakan oleh banyak ahli epidemiologi untuk menandai wabah epidemi, dari mana mereka bisa mudah telah menyebar ke China dan India [16] Pada bulan Oktober 2010, genetika medis menegaskan bahwa wabah berasal dari Cina. [4] Di Cina, Mongol abad ke-13 penaklukan menyebabkan penurunan dalam pertanian dan perdagangan.. Namun, pemulihan ekonomi telah diamati pada awal abad ke-14. Pada frekuensi tinggi 1330-an bencana alam dan wabah penyakit menyebabkan kelaparan luas yang dimulai pada 1331 dengan wabah mematikan tiba segera setelah [17]. Populasi menurun dari sekitar 120-60000000. [18] abad ke-14 wabah menewaskan sekitar 25 juta China memperkirakan dan Asia lainnya selama 15 tahun sebelum memasuki Konstantinopel pada tahun 1347. [19]

Penyakit ini mungkin memiliki perjalanan sepanjang Jalan Sutra dengan tentara Mongol dan pedagang atau bisa datang melalui kapal [20] Pada akhir 1346 laporan wabah telah mencapai pelabuhan Eropa:. “India depopulasi, Tartar, Mesopotamia, Suriah , Armenia ditutupi dengan mayat “. [21]

Wabah dilaporkan pertama kali diperkenalkan ke Eropa di kota perdagangan Caffa di Krimea pada tahun 1347. Setelah pengepungan yang berlarut-larut, di mana pasukan Mongol di bawah Jani Beg adalah menderita penyakit ini, mereka terlempar mayat-mayat yang terinfeksi selama tembok kota untuk menginfeksi penduduk. Para pedagang Genoa melarikan diri, mengambil wabah dengan kapal ke Sisilia dan selatan Eropa, dari mana ia menyebar utara [22] Apakah atau tidak hipotesis ini adalah akurat, jelas bahwa beberapa kondisi yang ada seperti perang, kelaparan, dan cuaca berkontribusi. dengan tingkat keparahan dari Black Death.

Eropa wabah
Ada tampaknya telah beberapa perkenalan ke Eropa. It mencapai Sisilia pada Oktober 1347 yang dibawa oleh dua belas kapal Genoa, [23] di mana ia dengan cepat tersebar di seluruh pulau. Kapal dari Caffa mencapai Genoa dan Venesia di Januari 1348 tetapi wabah itu di Pisa beberapa minggu kemudian bahwa adalah titik masuk ke bagian utara Italia. Menjelang akhir Januari salah satu kapal diusir dari Italia tiba di Marseilles. [24]

Dari Italia penyakit menyebar di seluruh Eropa barat laut, mencolok Perancis, Spanyol, Portugal dan Inggris pada bulan Juni 1348, lalu berbalik dan menyebar ke timur melalui Jerman dan Skandinavia 1348-1350. Saat itu diperkenalkan di Norwegia pada 1349 ketika sebuah kapal mendarat di Askøy, kemudian mulai menyebar ke Bjørgvin (modern Bergen) tetapi tidak pernah mencapai Islandia [25]. Akhirnya menyebar ke utara-barat Rusia di 1351. Wabah terhindar dari beberapa bagian Eropa, termasuk Kerajaan Polandia dan bagian terisolasi dari Belgia dan Belanda [kutipan diperlukan].

Timur Tengah wabah
Wabah melanda berbagai negara di Timur Tengah selama pandemi, yang menyebabkan depopulasi serius dan perubahan permanen dalam struktur ekonomi dan sosial. Seperti menyebar ke Eropa Barat, penyakit ini juga memasuki wilayah tersebut dari Rusia selatan. Dengan musim gugur 1347, wabah mencapai Alexandria di Mesir, mungkin melalui perdagangan pelabuhan dengan Konstantinopel, dan pelabuhan di Laut Hitam. Selama 1347, penyakit yang ditempuh ke arah timur ke Gaza, dan utara di sepanjang pantai timur ke kota-kota di Lebanon, Suriah dan Palestina, termasuk Ashkelon, Acre, Yerusalem, Sidon, Damaskus, Homs, dan Aleppo. Pada 1348-49, penyakit mencapai Antiokhia. Penduduk kota melarikan diri ke utara, sebagian besar dari mereka meninggal selama perjalanan, tetapi infeksi telah menyebar ke orang-orang di Asia Kecil.

Mekkah menjadi terinfeksi pada 1349. Pada tahun yang sama, catatan menunjukkan kota Mawsil (Mosul) mengalami epidemi besar, dan kota Baghdad mengalami putaran kedua penyakit. Pada 1351, Yaman mengalami pecahnya wabah. Hal ini bertepatan dengan kembalinya Raja Mujahid Yaman dari penjara di Kairo. Partainya telah membawa penyakit dengan mereka dari Mesir.

Gejala

Buboes dalam korban wabah

Sebuah adegan menunjukkan bhikkhu, rusak oleh wabah penyakit, yang diberkati oleh seorang imam. Inggris, 1360-1375
Rekening kontemporer dari wabah sering bervariasi atau tidak tepat. Gejala yang paling sering dicatat adalah munculnya buboes (atau gavocciolos) di selangkangan, leher dan ketiak, yang mengalir nanah dan berdarah ketika dibuka [26] deskripsi Boccaccio adalah grafis.:

“Pada laki-laki dan perempuan sama-sama pertama kali dikhianati sendiri oleh munculnya tumor tertentu di paha atau ketiak, beberapa di antaranya tumbuh sebagai besar sebagai apel umum, orang lain sebagai telur … Dari dua kata bagian dari tubuh ini mematikan gavocciolo segera mulai menyebarkan dan menyebarkan dirinya sendiri ke segala arah acuh tak acuh, setelah mana bentuk penyakit mulai berubah, bintik hitam atau marah membuat penampilan mereka dalam banyak kasus di lengan atau paha atau di tempat lain, sekarang sedikit dan besar, sekarang menit dan banyak. Sebagai gavocciolo telah dan masih merupakan tanda kematian mendekati sempurna, seperti juga yang bintik-bintik pada siapapun mereka menunjukkan diri mereka sendiri “[27].

Ziegler komentar bahwa detail-satunya medis yang dipertanyakan adalah kemaksuman mendekati kematian, seolah-olah pembuangan bubo, pemulihan adalah mungkin. [28]

Ini diikuti dengan demam akut dan muntah darah. Kebanyakan korban meninggal dalam waktu dua sampai tujuh hari setelah infeksi. David Herlihy mengidentifikasi tanda lain potensi wabah: bintik-bintik dan ruam [29] yang dapat menjadi hasil dari gigitan kutu.

Beberapa account, seperti Louis Heyligen, seorang musisi di Avignon yang meninggal wabah di 1348, mencatat bentuk yang berbeda dari penyakit yang menginfeksi paru-paru dan menyebabkan masalah pernapasan [26] dan yang diidentifikasi dengan wabah pneumonia.

“Dikatakan bahwa wabah itu mengambil tiga bentuk Pada orang pertama menderita infeksi paru-paru, yang menyebabkan kesulitan bernapas.. Siapapun yang ini korupsi atau kontaminasi sampai batas tertentu tidak dapat melarikan diri tetapi akan mati dalam waktu dua hari. Bentuk lain .. di mana bisul meletus di bawah ketiak, … bentuk ketiga di mana orang dari kedua jenis kelamin diserang di selangkangan “[30]..

Penyebab
Artikel utama: Teori Black Death
Pengetahuan medis telah mengalami stagnasi selama Abad Pertengahan dan akun paling otoritatif pada saat itu berasal dari Fakultas Kedokteran di Paris dalam sebuah laporan kepada Raja Prancis, yang menyalahkan langit-konjungsi planet-planet di tiga 1345, yang menyebabkan “besar wabah penyakit di udara “[31]. Laporan ini menjadi yang pertama dan paling luas beredar dari serangkaian” traktat wabah “yang berusaha untuk memberikan nasihat kepada penderita. Bahwa wabah itu disebabkan oleh udara yang buruk menjadi teori yang paling diterima secara luas. Adalah penting untuk menyadari bahwa wabah kata tidak memiliki makna khusus saat ini. Namun terulangnya wabah selama Abad Pertengahan memberinya reputasi yang unik dan nama telah menjadi istilah medis.

Pentingnya kebersihan hanya diakui dalam abad kesembilan belas dan sampai saat itu adalah umum bahwa jalan-jalan kotor, dengan binatang hidup dari segala macam sekitar dan kutu kutu manusia dan berlimpah. Setiap penyakit menular akan menyebar dengan mudah dalam kondisi seperti itu. Salah satu perkembangan sebagai hasil dari Black Death adalah pembentukan ide karantina di Dubrovnik di 1377 setelah wabah terus [kutipan diperlukan].

Wabah

 

Yersinia pestis dilihat di 200x pembesaran. Bakteri ini, dibawa dan disebarkan oleh kutu, umumnya dianggap telah menjadi penyebab jutaan kematian. [32]
Penjelasan yang dominan untuk Black Death adalah teori wabah, yang atribut wabah untuk Yersinia pestis, juga bertanggung jawab untuk epidemi yang dimulai di China selatan pada tahun 1865, akhirnya menyebar ke India. Penyelidikan patogen yang menyebabkan wabah abad ke-19 dimulai oleh tim ilmuwan yang mengunjungi Hong Kong pada tahun 1894, di antaranya adalah Alexandre Yersin, setelah yang patogen itu bernama Yersinia pestis. [33] Mekanisme dimana Y. pestis biasanya ditularkan didirikan pada tahun 1898 oleh Paul-Louis Simond dan ditemukan untuk melibatkan gigitan kutu yang telah menjadi terhalang midguts dengan mereplikasi Y. pestis beberapa hari setelah makan pada sebuah host yang terinfeksi. Penyumbatan ini menyebabkan kelaparan dan perilaku makan agresif oleh kutu, yang berulang kali mencoba untuk menghapus penyumbatan mereka dengan regurgitasi, mengakibatkan ribuan wabah bakteri yang memerah ke situs makan, menginfeksi host. Mekanisme penyakit pes itu juga tergantung pada dua populasi tikus – satu resisten terhadap penyakit, yang bertindak sebagai tuan rumah, menjaga penyakit endemik, dan yang kedua yang kurang perlawanan. Ketika populasi kedua meninggal, kutu pindah ke host lain, termasuk orang-orang, sehingga menciptakan suatu epidemi manusia. [33]

Sejarawan Francis Aidan Gasquet, yang telah menulis tentang ‘Sampar Agung’ pada tahun 1893 [34] dan menyarankan bahwa “akan muncul menjadi beberapa bentuk dari wabah pes Timur atau biasa” mampu mengadopsi epidemiologi penyakit pes untuk Black Death untuk edisi kedua tahun 1908, melibatkan tikus dan kutu dalam proses, dan penafsirannya secara luas diterima untuk epidemi kuno dan abad pertengahan lainnya, seperti wabah Justinian yang lazim di Kekaisaran Romawi Timur 541-700 AD. [33]

Wabah pes modern memiliki tingkat kematian 30 sampai 75 persen dan gejala termasuk demam 38-41 ° C (101-105 ° F), sakit kepala, nyeri sendi sakit, mual dan muntah, dan perasaan umum malaise. Jika tidak diobati, dari mereka yang kontrak penyakit pes, 80 persen meninggal dalam waktu delapan hari [35] wabah pneumonia. Memiliki tingkat kematian 90 sampai 95 persen. Gejalanya meliputi demam, batuk, dan darah-biruan dahak. Sebagai penyakit berlangsung, dahak menjadi merah dan terang mengalir bebas. Wabah septicemia adalah yang paling umum dari tiga bentuk, dengan tingkat mortalitas mendekati 100 persen. Gejala demam tinggi dan bercak kulit ungu (purpura akibat koagulasi intravaskular diseminata). Dalam kasus wabah pneumonia dan khususnya septicemia kemajuan penyakit ini begitu cepat sehingga sering ada akan ada waktu untuk pengembangan pembesaran kelenjar getah bening yang tercatat sebagai buboes [36].

“Banyak sarjana modern menerima bahwa mematikan dari Black Death berasal dari kombinasi wabah pes dan pneumonia dengan penyakit lain dan memperingatkan bahwa setiap menyebutkan sejarah ‘hama’ bukan wabah pes tentu … Dalam studi nya wabah 15thC, Ann Carmichael menyatakan bahwa cacing, cacar, demam dan disentri jelas disertai penyakit pes “[37].

Alternatif penjelasan
Penafsiran ini pertama kali secara signifikan ditantang oleh karya bakteriologi Inggris JFD Shrewsbury pada tahun 1970, yang mencatat bahwa tingkat kematian dilaporkan di daerah pedesaan selama pandemi abad ke-14 tidak konsisten dengan penyakit pes modern, memimpin dia untuk menyimpulkan bahwa rekening kontemporer berlebihan . [33] Pada tahun 1984 ahli zoologi Graham Twigg menghasilkan karya besar pertama untuk langsung menantang teori penyakit pes, dan keraguan tentang identitas Black Death telah diambil oleh sejumlah penulis, termasuk Samuel K. Cohn, Jr (2002), David Herlihy (1997), dan Susan Scott dan Christopher Duncan (2001) [33].

Hal ini diakui bahwa account epidemiologi wabah adalah sebagai penting sebagai identifikasi gejala, namun para peneliti terhambat oleh kurangnya statistik yang dapat diandalkan dari periode ini. Pekerjaan yang paling telah dilakukan pada penyebaran wabah di Inggris, dan bahkan perkiraan populasi keseluruhan di awal bervariasi oleh lebih dari 100% karena tidak ada sensus dilakukan antara Kitab Domesday dan 1377. [38] Perkiraan korban wabah biasanya diekstrapolasi dari angka untuk para ulama.

Selain berdebat bahwa populasi tikus tidak cukup untuk account untuk pandemi penyakit pes, skeptis dari titik wabah pes teori bahwa gejala Black Death tidak unik (dan bisa dibilang dalam beberapa rekening mungkin berbeda dari wabah pes); yang transferensi melalui kutu barang itu mungkin penting marjinal dan bahwa tes DNA mungkin cacat dan belum pernah diulang di tempat lain, meskipun sampel yang luas dari kuburan massal lainnya [33] argumen lainnya termasuk:. kurangnya rekening kematian tikus sebelum wabah wabah antara abad 14 dan 17, suhu yang terlalu dingin di Eropa Utara untuk kelangsungan hidup kutu, bahwa, meskipun sistem transportasi primitif, penyebaran Black Death jauh lebih cepat daripada Bubonic plague modern, yang tingkat mortalitas dari Black Death tampaknya sangat tinggi, bahwa, selama wabah pes modern sebagian besar endemik sebagai penyakit pedesaan, Black Death melanda tanpa pandang bulu daerah perkotaan dan pedesaan; bahwa pola Black Death, dengan wabah besar di daerah yang sama yang dipisahkan oleh antara 5 dan 15 tahun, berbeda dari wabah pes yang modern, yang sering menjadi endemik selama beberapa dekade, melebar sampai pada dasar tahunan. [33]

Walløe mengeluh bahwa semua penulis “menerima begitu saja bahwa infeksi Model Simond itu, tikus hitam → kutu tikus → manusia, yang dikembangkan untuk menjelaskan penyebaran wabah di India, adalah satu-satunya cara epidemi infeksi pestis Yersinia dapat menyebar” , sementara menunjuk ke kemungkinan lainnya. [39]

Anthrax kulit lesi
Berbagai alternatif ke Y. pestis telah diajukan. Twigg menyarankan bahwa penyebabnya adalah bentuk antraks dan NF penyanyi (2001) berpikir itu mungkin telah menjadi kombinasi anthrax dan pandemi lainnya. Scott dan Duncan berpendapat bahwa pandemi adalah bentuk penyakit menular yang mencirikan sebagai wabah hemoragik mirip dengan Ebola. Barney arkeolog Sloane berpendapat bahwa ada bukti yang cukup dari kepunahan sejumlah besar tikus dalam catatan arkeologi abad pertengahan di tepi laut London dan bahwa wabah itu menyebar terlalu cepat untuk mendukung tesis bahwa Y. pestis adalah menyebar dari kutu pada tikus dan berpendapat transmisi yang pasti orang ke orang [40] [41]. Namun, ada solusi alternatif tunggal telah mencapai penerimaan luas. [33] Banyak sarjana berdebat untuk Y. pestis sebagai agen utama dari pandemi, menunjukkan bahwa perusahaan luas dan gejala dapat dijelaskan oleh kombinasi dari wabah pes dengan penyakit lain, termasuk infeksi tifus, cacar dan pernapasan. Selain infeksi pes, orang lain titik untuk septicemia tambahan (tipe “keracunan darah”) dan pneumonia (sebuah wabah udara yang menyerang paru-paru sebelum seluruh tubuh) bentuk wabah, yang memperpanjang durasi wabah seluruh musim dan membantu menjelaskan tingkat kematian yang tinggi dan gejala dicatat tambahan [26].

Bukti DNA
Pada bulan Oktober 2010 akses terbuka jurnal ilmiah PLoS Pathogens menerbitkan sebuah makalah oleh tim multinasional yang melakukan penyelidikan baru ke dalam peran Yersinia pestis di Black Death berikut identifikasi diperdebatkan oleh Drancourt & Raoult pada tahun 1998 [42]. Survei mereka diuji untuk tanda tangan DNA dan protein spesifik untuk Y. pestis dalam kerangka manusia dari kuburan massal secara luas didistribusikan di utara, tengah dan selatan Eropa yang dikaitkan arkeologis dengan Black Death dan resurgences berikutnya. Para penulis menyimpulkan bahwa penelitian baru ini, bersama dengan analisis terlebih dahulu dari bagian selatan Perancis dan Jerman

Pembakaran Yahudi selama wabah Black Death, 1349
“… Mengakhiri perdebatan mengenai etiologi dari Black Death, dan jelas menunjukkan bahwa Y. pestis adalah agen penyebab wabah epidemi yang menghancurkan Eropa selama Abad Pertengahan.” [43]
Studi ini juga menemukan bahwa ada dua clades sebelumnya tidak diketahui namun terkait (cabang genetik) dari Y. pestis genom dikaitkan dengan kuburan massal abad pertengahan. Ini clades (yang dianggap punah) ditemukan merupakan nenek moyang isolat modern dari yang modern Y. pestis strain orientalis dan medievalis, menunjukkan bahwa wabah mungkin telah masuk ke Eropa dalam dua gelombang. Survei dari pit wabah tetap di Prancis dan Inggris menunjukkan bahwa varian pertama kali memasuki Eropa melalui pelabuhan Marseille sekitar November 1347 dan menyebar melalui Prancis selama dua tahun ke depan, akhirnya mencapai Inggris pada musim semi 1349, di mana ia menyebar melalui negara dalam tiga epidemi. Survei dari pit wabah tetap dari kota Belanda Bergen op Zoom menunjukkan bahwa genotipe Y. pestis bertanggung jawab atas pandemi yang menyebar melalui Negara Rendah dari 1350 berbeda dari yang ditemukan di Inggris dan Perancis, yang menyiratkan bahwa Bergen op Zoom (dan mungkin lainnya bagian selatan Belanda) tidak secara langsung terinfeksi dari Inggris atau Perancis pada 1349 dan menyarankan bahwa gelombang kedua wabah, yang berbeda dari mereka di Inggris dan Perancis, mungkin telah dibawa ke Low Countries dari Norwegia, kota-kota Hanseatic atau situs lain . [43]

Hasil studi Haensch telah sejak dikonfirmasi dan diubah. Berdasarkan bukti genetik yang berasal dari korban Black Death di situs pemakaman Smithfield Timur di Inggris, Schuenemann et al. pada 2011 lebih lanjut menyimpulkan “bahwa Black Death di Eropa abad pertengahan disebabkan oleh Y. pestis varian yang mungkin tidak ada lagi.” [44] Sebuah studi yang dipublikasikan di Nature pada bulan Oktober 2011 sequencing genom Y. pestis dari para korban wabah penyakit dan menunjukkan bahwa strain yang menyebabkan Black Death adalah nenek moyang strain paling modern penyakit. [45]

Konsekuensi
Artikel utama: Konsekuensi dari Black Death
Angka korban tewas bervariasi menurut daerah dan dari sumber ke sumber sebagai penelitian baru dan penemuan datang ke cahaya. Ini diperkirakan menewaskan sekitar 75 juta-200 juta orang di abad ke-14 [46] [47] [48] Menurut sejarawan abad pertengahan Philip Daileader pada tahun 2007.:

Sebuah adegan menunjukkan Yahudi dibakar hidup-hidup selama periode Black Death, Liber Chronicarum.
Kecenderungan dari penelitian baru-baru ini menunjuk ke angka yang lebih seperti 45 persen menjadi 50 persen dari penduduk Eropa meninggal selama periode empat tahun. Ada cukup banyak variasi geografis. Di Mediterania Eropa, bidang-bidang seperti Italia, selatan Perancis dan Spanyol, di mana wabah berlari selama sekitar empat tahun berturut-turut, itu mungkin lebih dekat ke 75 persen menjadi 80 persen dari populasi. Di Jerman dan Inggris … itu mungkin lebih dekat ke 20 persen. [49]

Perkiraan yang paling banyak diterima untuk Timur Tengah, termasuk Irak, Iran dan Suriah, selama waktu ini, adalah untuk tingkat kematian sekitar sepertiga. [50] The Black Death membunuh sekitar 40% dari populasi Mesir. [51] Setengah dari penduduk Paris dari 100.000 orang meninggal. Di Italia, populasi Florence berkurang dari 110.000 atau 120.000 penduduk tahun 1338 menjadi 50.000 pada 1351. Setidaknya 60 persen dari Hamburg dan populasi Bremen tewas. [52] Sebelum 1350, ada sekitar 170.000 pemukiman di Jerman, dan ini berkurang hampir 40.000 dengan 1450 [53] Pada 1348, wabah menyebar begitu cepat. Bahwa sebelum dokter atau otoritas pemerintah punya waktu untuk merenungkan asal-usulnya, sekitar sepertiga dari penduduk Eropa yang sudah tewas. Di kota-kota padat, tidak jarang sebanyak 50 persen dari populasi untuk mati. Eropa yang tinggal di daerah terpencil mengalami kurang, sedangkan rahib dan pendeta yang terutama terpukul karena mereka peduli untuk korban Black Death. [54]

Flagellants dipraktekkan pembekuan daging sebagai penitensi
Karena penyembuh abad ke-14 berada di kerugian untuk menjelaskan penyebab, Eropa berpaling ke kekuatan astrologi, gempa bumi, dan keracunan sumur oleh orang Yahudi sebagai alasan mungkin untuk munculnya wabah tersebut. [12] Pemerintah Eropa telah ada respon yang jelas terhadap krisis karena tidak ada yang tahu penyebabnya atau bagaimana itu menyebar. Mekanisme infeksi dan penularan penyakit sedikit dipahami dalam abad ke-14, banyak orang percaya hanya murka Allah bisa memproduksi layar mengerikan tersebut. Ada banyak serangan terhadap komunitas Yahudi [55] Pada Agustus 1349, komunitas Yahudi dari Mainz dan Cologne dibasmi.. Pada bulan Februari tahun yang sama, warga Strasbourg 2.000 orang Yahudi dibunuh [55] Pada 1351, 60 besar dan 150 komunitas Yahudi yang lebih kecil hancur.. [56] Ikhwanul dari Flagellants, gerakan kata ke nomor sampai dengan 800.000, mencapai puncaknya popularitas [57].

Kambuh
Sebuah epidemik wabah meninggal setelah beberapa bulan karena tidak memiliki tuan rumah di mana bakteri dapat bertahan hidup. Namun itu tidak berarti bahwa tidak ada suatu tempat beberapa infeksi yang masih hidup, di tempat tikus atau kutu atau hangat, yang bertindak sebagai reservoir sehingga cepat atau lambat pecah lagi. [58]

Wabah berulang kali kembali menghantui Eropa dan Mediterania sepanjang 14 sampai 17 abad [59]. Menurut Biraben, wabah itu ada di suatu tempat di Eropa setiap tahun antara 1346 dan 1671. [60] Para Pandemi Kedua terutama luas di berikut tahun: 1360-1363, 1374, 1400, 1438-1439, 1456-1457, 1464-1466, 1481-1485, 1500-1503, 1518-1531, 1544-1548, 1563-1566, 1573-1588, 1596-1599; 1602-1611, 1623-1640, 1644-1654;. dan 1664-1667 [61] Menurut Geoffrey Parker, “Perancis saja kehilangan hampir satu juta orang untuk wabah epidemi di 1628-31.” [62]

Di Inggris, dalam ketiadaan angka sensus, sejarawan mengusulkan berbagai pra-insiden jumlah penduduk dari setinggi 7 juta untuk serendah 4 juta pada 1300, [63] dan pasca-insiden populasi angka serendah 2 juta [64] Pada akhir 1350. Black Death mereda, tapi tidak pernah benar-benar mati di Inggris. Selama beberapa ratus tahun berikutnya, ada wabah lebih lanjut dalam 1361-62, 1369, 1379-83, 1389-93, dan sepanjang paruh pertama abad ke-15 [65]. Sebuah wabah di 1471 mengambil sebanyak 10-15 persen dari populasi, sementara tingkat kematian wabah 1479-1480 bisa setinggi 20 persen [66]. Wabah yang paling umum di Tudor dan Stuart Inggris tampaknya telah dimulai pada tahun 1498, 1535, 1543, 1563, 1589, 1603, 1625, dan 1636, dan berakhir dengan Wabah Besar London pada tahun 1665. [67]

Wabah Kerusuhan di Moskow pada 1771. Selama wabah kota, antara 50.000 dan 100.000 meninggal (1 / 6 sampai 1 / 3 dari populasi nya).
Pada 1466, mungkin 40.000 orang meninggal dari wabah di Paris [68] Selama abad 16 dan 17, wabah mengunjungi Paris selama hampir satu tahun dari tiga.. [69] The Black Death melanda Eropa selama tiga tahun sebelum melanjutkan ke Rusia , dimana penyakit hit di suatu tempat sekali setiap lima atau enam tahun 1350-1490 [70] Wabah epidemi melanda London pada 1563, 1593, 1603, 1625, 1636, dan 1665, [71] mengurangi populasi 10 hingga 30%. selama tahun-tahun [72] Lebih dari 10% penduduk Amsterdam meninggal. di 1623-1625, dan sekali lagi pada 1635-1636, 1655 dan 1664. [73] Ada dua puluh dua wabah wabah di Venesia antara 1361 dan 1528. [74 ] Tulah dari 1576-1577 menewaskan 50.000 di Venice, hampir sepertiga dari penduduk [75] Akhir wabah di pusat Eropa termasuk Italia Wabah 1629-1631, yang berhubungan dengan gerakan pasukan selama Perang Tiga Puluh Tahun ‘,. dan Wabah Besar Wina pada tahun 1679. Lebih dari 60 persen penduduk Norwegia meninggal 1348-1350. [76] Wabah terakhir dilanda wabah Oslo pada 1654 [77].

Pada paruh pertama abad ke-17 mengklaim beberapa wabah 1.730.000 korban di Italia, atau sekitar 14% dari populasi [78] Pada 1656. Wabah membunuh sekitar setengah dari 300.000 Naples ‘penduduk. [79] Lebih dari 1.250.000 kematian akibat kejadian ekstrim wabah di Spanyol abad ke-17. [80] Para wabah 1649 mungkin mengurangi populasi Sevilla dengan setengah [81] Pada 1709-1713., epidemi wabah yang mengikuti Perang Besar Utara (1700-1721, Swedia v Rusia dan sekutu). [82] menewaskan sekitar 100.000 di Swedia, [83] dan 300.000 di Prusia [81]. Tulah membunuh dua-pertiga dari penduduk Helsinki, [84] dan mengklaim sepertiga dari populasi Stockholm. [85 epidemi besar terakhir] Eropa terjadi pada tahun 1720 di Marseilles. [76]

Distribusi di seluruh dunia terinfeksi wabah hewan 1998
The Black Death melanda sebagian besar dunia Islam [86]. Wabah hadir dalam setidaknya satu lokasi di dunia Islam hampir setiap tahun antara tahun 1500 dan 1850. [87] Wabah berulang kali melanda kota-kota Afrika Utara. Aljazair kehilangan 30,000-50,000 untuk wabah di 1620-21, dan sekali lagi pada 1654-57,, 1665 1691, dan 1740-42 [88]. Wabah tetap menjadi peristiwa besar dalam masyarakat Utsmani sampai kuartal kedua abad ke-19. Antara 1701 dan 1750, 37 epidemi wabah yang lebih besar dan lebih kecil tercatat di Konstantinopel, dan 31 antara 1751 dan 1800 [89]. Baghdad telah menderita parah dari kunjungan wabah, dan kadang-kadang dua-pertiga dari penduduknya telah musnah. [ 90]

Para Pandemi Ketiga (1855-1959) dimulai di Cina pada pertengahan abad ke-19, wabah menyebar ke semua benua yang dihuni dan membunuh 10 juta orang di India saja. [91]

Dari 1944 hingga 1993, 362 kasus wabah manusia yang dilaporkan di Amerika Serikat, sekitar 90 persen dari terjadi di empat negara bagian barat;. Arizona, California, Colorado, dan New Mexico [92] Wabah dikonfirmasi di Amerika Serikat dari sembilan negara Barat selama 1995 [93].

Bakteri wabah dapat mengembangkan resistensi obat dan sekali lagi menjadi ancaman kesehatan utama. Kemampuan untuk melawan banyak antibiotik digunakan untuk melawan wabah telah ditemukan sejauh ini hanya dalam satu kasus penyakit di Madagaskar, pada tahun 1995. [94]

Dalam budaya
Artikel utama: Black Death dalam budaya Abad Pertengahan

Pieter Bruegel The Triumph of Death (c. 1562) mencerminkan pergolakan sosial dan teror yang diikuti wabah yang menghancurkan Eropa Abad Pertengahan
The Black Death memiliki dampak yang mendalam pada seni dan sastra di seluruh generasi yang mengalaminya. Sebagian besar manifestasi yang paling berguna dari Black Death dalam literatur, para ahli sejarah, berasal dari rekening sejarah nya. Beberapa penulis sejarah adalah penulis terkenal, filsuf dan penguasa seperti Boccaccio dan Petrarch. Tulisan-tulisan mereka, bagaimanapun, tidak mencapai mayoritas penduduk Eropa. Petrarch pekerjaan itu dibaca terutama oleh bangsawan kaya dan pedagang negara-kota Italia. Dia menulis ratusan surat dan puisi vernakular, dan diteruskan kepada generasi berikutnya interpretasi direvisi cinta santun [95]. Ada satu penyanyi, menulis dalam gaya lirik panjang keluar dari fashion, yang aktif dalam 1348.

ORIGINAL INFO

 

 
 

THE HISTORY OF BLACK DEATH

 
 

Illustration of the Black Death from the Toggenburg Bible (1411)

The Black Death was one of the most devastating pandemics in human history, peaking in Europe between 1348 and 1350. Of several competing theories, the dominant explanation for the Black Death is the plague theory, which attributes the outbreak to the bacterium Yersinia pestis. Thought to have started in China, it travelled along the Silk Road and reached the Crimea by 1346. From there, probably carried by Oriental rat fleas living on the black rats that were regular passengers on merchant ships, it spread throughout the Mediterranean and Europe.

The Black Death is estimated to have killed 30–60 percent of Europe’s population,[1] reducing the world’s population from an estimated 450 million to between 350 and 375 million in the 14th century. The aftermath of the plague created a series of religious, social and economic upheavals, which had profound effects on the course of European history. It took 150 years for Europe’s population to recover. The plague returned at various times, killing more people, until it left Europe in the 19th century.

Contents

Overview

Inspired by the Black Death, The Dance of Death, an allegory on the universality of death, is a common painting motif in the late medieval period.

There have been three major outbreaks of plague. The Plague of Justinian in the 6th and 7th centuries is the first known attack on record, and marks the first firmly recorded pattern of bubonic plague. From historical descriptions, as much as 40 percent of the population of Constantinople died from the plague. Modern estimates suggest half of Europe’s population was wiped out before the plague disappeared in the 700s.[2] After 750, major epidemic diseases did not appear again in Europe until the Black Death of the 14th century.[3] The Third Pandemic hit China in the 1890s and devastated India but was confined to limited outbreaks in the west.[4]

The Black Death originated in or near China and spread by way of the Silk Road or by ship.[4] It may have reduced the world’s population from an estimated 450 million to between 350 and 375 million in 1400.[5]

The plague is thought to have returned at intervals with varying virulence and mortality until the 18th century.[6] On its return in 1603, for example, the plague killed 38,000 Londoners.[7] Other notable 17th-century outbreaks were the Italian Plague (1629–1631), the Great Plague of Seville (1647–1652), the Great Plague of London (1665–1666),[8] and the Great Plague of Vienna (1679). There is some controversy over the identity of the disease, but in its virulent form, after the Great Plague of Marseille in 1720–1722,[9] the Great Plague of 1738 (which hit Eastern Europe), and the Russian plague of 1770-1772, it seems to have gradually disappeared from Europe. By the early 19th century, the threat of plague had diminished, but it was quickly replaced by a new disease. The Asiatic cholera was the first of several cholera pandemics to sweep through Asia and Europe during the 19th and 20th centuries.[10]

The 14th century eruption of the Black Death had a drastic effect on Europe’s population, irrevocably changing the social structure. It was, arguably, a serious blow to the Catholic Church, and resulted in widespread persecution of minorities such as Jews, foreigners, beggars, and lepers. The uncertainty of daily survival has been seen as creating a general mood of morbidity, influencing people to “live for the moment”, as illustrated by Giovanni Boccaccio in The Decameron (1353).[11]

Naming

Medieval people called the catastrophe of the 14th century either the “Great Pestilence”‘ or the “Great Plague”.[12] Writers contemporary to the plague referred to the event as the “Great Mortality”. Swedish and Danish chronicles of the 16th century described the events as “black” for the first time, not to describe the late-stage sign of the disease, in which the sufferer’s skin would blacken due to subepidermal hemorrhages and the extremities would darken with gangrene, but more likely to refer to black in the sense of glum or dreadful and to denote the terribleness and gloom of the events.[13] The German physician and medical writer Justus Hecker suggested that a mistranslation of the Latin atra mors (terrible, or black, death) had occurred in Scandinavia when he described the catastrophe in 1832[12] in his publication “Der schwarze Tod im vierzehnten Jahrhundert”. The work was translated into English the following year, and with the cholera epidemic happening at that time, “The Black Death in the 14th century” gained widespread attention and the terms Schwarzer Tod and Black Death became more widely used in the German and English speaking worlds, respectively.

Migration

Main article: Black Death migration

Populations in crisis

In Europe, the Medieval Warm Period ended sometime towards the end of the 13th century, bringing the “Little Ice Age[14] and harsher winters with reduced harvests. In Northern Europe, new technological innovations such as the heavy plough and the three-field system were not as effective in clearing new fields for harvest as they were in the Mediterranean because the north had poor, clay-like soil.[12] Food shortages and rapidly inflating prices were a fact of life for as much as a century before the plague. Wheat, oats, hay and consequently livestock, were all in short supply. Their scarcity resulted in malnutrition, which increases susceptibility to infections due to weakened immunity. Consistently high fertility rates, at 5 children/woman or more throughout Europe, resulted in high population growth rates and contributed to food shortages. In the autumn of 1314, heavy rains began to fall, which were the start of several years of cold and wet winters.[12] The already weak harvests of the north suffered and the seven-year famine ensued. In the years 1315 to 1317 a catastrophic famine, known as the Great Famine, struck much of North West Europe. It was arguably the worst in European history, perhaps reducing the population by more than 10 percent.[12]

Infection and migration

Spread of the black death in Europe (1346–53)

The plague disease, generally thought to be caused by Yersinia pestis, is enzootic (commonly present) in populations of fleas carried by ground rodents, including marmots, in various areas including Central Asia, Kurdistan, Western Asia, Northern India and Uganda.[15] Nestorian graves dating to 1338-9 near Lake Issyk Kul in Kyrgizstan have inscriptions referring to plague and recent investigations by the Russian archeologist Chwolson show a high incidence rate and are thought by many epidemiologists to mark the outbreak of the epidemic, from which they could easily have spread to China and India.[16] In October 2010, medical geneticists confirmed that the plague came from China.[4] In China, the 13th century Mongol conquest caused a decline in farming and trading. However, economic recovery had been observed in the beginning of the 14th century. In 1330s high frequency of natural disaster and plague led to widespread famine starting in 1331 with deadly plague arriving soon after.[17] The population dropped from approximately 120 to 60 million.[18] The 14th-century plague killed an estimated 25 million Chinese and other Asians during the 15 years before it entered Constantinople in 1347.[19]

The disease may have travelled along the Silk Road with Mongol armies and traders or it could have come via ship.[20] By the end of 1346 reports of plague had reached the seaports of Europe: “India was depopulated, Tartary, Mesopotamia, Syria, Armenia were covered with dead bodies”.[21]

Plague was reportedly first introduced to Europe at the trading city of Caffa in the Crimea in 1347. After a protracted siege, during which the Mongol army under Jani Beg was suffering the disease, they catapulted the infected corpses over the city walls to infect the inhabitants. The Genoese traders fled, taking the plague by ship into Sicily and the south of Europe, whence it spread north.[22] Whether or not this hypothesis is accurate, it is clear that several existing conditions such as war, famine, and weather contributed to the severity of the Black Death.

European outbreak

There appear to have been several introductions into Europe. It reached Sicily in October 1347 carried by twelve Genoese galleys,[23] where it rapidly spread all over the island. Galleys from Caffa reached Genoa and Venice in January 1348 but it was the outbreak in Pisa a few weeks later that was the entry point to northern Italy. Towards the end of January one of the galleys expelled from Italy arrived in Marseilles.[24]

From Italy the disease spread northwest across Europe, striking France, Spain, Portugal and England by June 1348, then turned and spread east through Germany and Scandinavia from 1348 to 1350. It was introduced in Norway in 1349 when a ship landed at Askøy, then proceeded to spread to Bjørgvin (modern Bergen) but never reached Iceland.[25] Finally it spread to north-western Russia in 1351. The plague spared some parts of Europe, including the Kingdom of Poland and isolated parts of Belgium and the Netherlands.[citation needed]

Middle Eastern outbreak

The plague struck various countries in the Middle East during the pandemic, leading to serious depopulation and permanent change in both economic and social structures. As it spread to western Europe, the disease also entered the region from southern Russia. By autumn 1347, the plague reached Alexandria in Egypt, probably through the port’s trade with Constantinople, and ports on the Black Sea. During 1347, the disease travelled eastward to Gaza, and north along the eastern coast to cities in Lebanon, Syria and Palestine, including Ashkelon, Acre, Jerusalem, Sidon, Damascus, Homs, and Aleppo. In 1348–49, the disease reached Antioch. The city’s residents fled to the north, most of them dying during the journey, but the infection had been spread to the people of Asia Minor.

Mecca became infected in 1349. During the same year, records show the city of Mawsil (Mosul) suffered a massive epidemic, and the city of Baghdad experienced a second round of the disease. In 1351, Yemen experienced an outbreak of the plague. This coincided with the return of King Mujahid of Yemen from imprisonment in Cairo. His party may have brought the disease with them from Egypt.

Symptoms

Buboes in a victim of plague

A scene showing monks, disfigured by the plague, being blessed by a priest. England, 1360–75

Contemporary accounts of the plague are often varied or imprecise. The most commonly noted symptom was the appearance of buboes (or gavocciolos) in the groin, the neck and armpits, which oozed pus and bled when opened.[26] Boccaccio’s description is graphic:

“In men and women alike it first betrayed itself by the emergence of certain tumours in the groin or armpits, some of which grew as large as a common apple, others as an egg…From the two said parts of the body this deadly gavocciolo soon began to propagate and spread itself in all directions indifferently; after which the form of the malady began to change, black spots or livid making their appearance in many cases on the arm or the thigh or elsewhere, now few and large, now minute and numerous. As the gavocciolo had been and still was an infallible token of approaching death, such also were these spots on whomsoever they showed themselves.”[27]

Ziegler comments that the only medical detail that is questionable is the infallibility of approaching death, as if the bubo discharges, recovery is possible.[28]

This was followed by acute fever and vomiting of blood. Most victims died within two to seven days after infection. David Herlihy identifies another potential sign of the plague: freckle-like spots and rashes[29] which could be the result of flea-bites.

Some accounts, like that of Louis Heyligen, a musician in Avignon who died of the plague in 1348, noted a distinct form of the disease which infected the lungs and led to respiratory problems[26] and which is identified with pneumonic plague.

“It is said that the plague takes three forms. In the first people suffer an infection of the lungs, which leads to breathing difficulties. Whoever has this corruption or contamination to any extent cannot escape but will die within two days. Another form…in which boils erupt under the armpits,…a third form in which people of both sexes are attacked in the groin.”[30]

Causes

Medical knowledge had stagnated during the Middle Ages and the most authoritative account at the time came from the Medical Faculty in Paris in a report to the King of France, which blamed the heavens—a conjunction of three planets in 1345, which caused a “great pestilence in the air”.[31] This report became the first and most widely circulated of a series of “plague tracts” which sought to give advice to sufferers. That the plague was caused by bad air became the most widely accepted theory. It is important to realise that the word plague had no special significance at this time. But the recurrence of outbreaks during the Middle Ages gave it a unique reputation and the name has become the medical term.

The importance of hygiene was only recognised in the nineteenth century and until then it was common that the streets were filthy, with live animals of all sorts around and human fleas and ticks abounding. Any transmissible disease will spread easily in such conditions. One development as a result of the Black Death was the establishment of the idea of quarantine in Dubrovnik in 1377 after continuing outbreaks.[citation needed]

Plague

Yersinia pestis seen at 200x magnification. This bacterium, carried and spread by fleas, is generally thought to have been the cause of millions of deaths.[32]

The dominant explanation for the Black Death is the plague theory, which attributes the outbreak to Yersinia pestis, also responsible for an epidemic that began in southern China in 1865, eventually spreading to India. The investigation of the pathogen that caused the 19th-century plague was begun by teams of scientists who visited Hong Kong in 1894, among whom was Alexandre Yersin, after whom the pathogen was named Yersinia pestis.[33] The mechanism by which Y. pestis was usually transmitted was established in 1898 by Paul-Louis Simond and was found to involve the bites of fleas whose midguts had become obstructed by replicating Y. pestis several days after feeding on an infected host. This blockage results in starvation and aggressive feeding behaviour by the fleas, which repeatedly attempt to clear their blockage by regurgitation, resulting in thousands of plague bacteria being flushed into the feeding site, infecting the host. The bubonic plague mechanism was also dependent on two populations of rodents — one resistant to the disease, who act as hosts, keeping the disease endemic, and a second who lack resistance. When the second population dies, the fleas move on to other hosts, including people, thus creating a human epidemic.[33]

The historian Francis Aidan Gasquet, who had written about the ‘Great Pestilence’ in 1893[34] and suggested that “it would appear to be some form of the ordinary Eastern or bubonic plague” was able to adopt the epidemiology of the bubonic plague for the Black Death for the second edition in 1908, implicating rats and fleas in the process, and his interpretation was widely accepted for other ancient and medieval epidemics, such as the Justinian plague that was prevalent in the Eastern Roman Empire from 541 to 700 AD.[33]

The modern bubonic plague has a mortality rate of 30 to 75 percent and symptoms including fever of 38–41 °C (101–105 °F), headaches, painful aching joints, nausea and vomiting, and a general feeling of malaise. If untreated, of those that contract the bubonic plague, 80 percent die within eight days.[35] Pneumonic plague has mortality rate of 90 to 95 percent. Symptoms include fever, cough, and blood-tinged sputum. As the disease progresses, sputum becomes free flowing and bright red. Septicemic plague is the least common of the three forms, with a mortality rate close to 100 percent. Symptoms are high fevers and purple skin patches (purpura due to disseminated intravascular coagulation). In cases of pneumonic and particularly septicemic plague the progress of the disease is so rapid that there would often be no time for the development of the enlarged lymph nodes that were noted as buboes.[36]

“Many modern scholars accept that the lethality of the Black Death stemmed from the combination of bubonic and pneumonic plague with other diseases and warn that every historical mention of ‘pest’ was not necessarily bubonic plague…In her study of 15thC outbreaks, Ann Carmichael states that worms, the pox, fevers and dysentery clearly accompanied bubonic plague.”[37]

Alternative explanations

This interpretation was first significantly challenged by the work of British bacteriologist J. F. D. Shrewsbury in 1970, who noted that the reported rates of mortality in rural areas during the 14th century pandemic were inconsistent with the modern bubonic plague, leading him to conclude that contemporary accounts were exaggerations.[33] In 1984 zoologist Graham Twigg produced the first major work to directly challenge the bubonic plague theory, and his doubts about the identity of the Black Death have been taken up by a number of authors, including Samuel K. Cohn, Jr. (2002), David Herlihy (1997), and Susan Scott and Christopher Duncan (2001).[33]

It is recognised that an epidemiological account of the plague is as important as an identification of symptoms, but researchers are hampered by the lack of reliable statistics from this period. Most work has been done on the spread of the plague in England, and even estimates of overall population at the start vary by over 100% as no census was undertaken between the Domesday Book and 1377.[38] Estimates of plague victims are usually extrapolated from figures for the clergy.

In addition to arguing that the rat population was insufficient to account for a bubonic plague pandemic, sceptics of the bubonic plague theory point out that the symptoms of the Black Death are not unique (and arguably in some accounts may differ from bubonic plague); that transference via fleas in goods was likely to be of marginal significance and that the DNA testing may be flawed and have not been repeated elsewhere, despite extensive samples from other mass graves.[33] Other arguments include: the lack of accounts of the death of rats before outbreaks of plague between the 14th and 17th centuries; temperatures that are too cold in Northern Europe for the survival of fleas; that, despite primitive transport systems, the spread of the Black Death was much faster than modern Bubonic plague; that mortality rates of the Black Death appear to be very high; that, while modern bubonic plague is largely endemic as a rural disease, the Black Death indiscriminately struck urban and rural areas; that the pattern of the Black Death, with major outbreaks in the same areas separated by between 5 and 15 years, differs from modern Bubonic plague, which often becomes endemic for decades, flaring up on an annual basis.[33]

Walløe complains that all of these authors “take it for granted that Simond’s infection model, black rat → rat flea → human, which was developed to explain the spread of plague in India, is the only way an epidemic of Yersinia pestis infection could spread”, whilst pointing to several other possibilities.[39]

Anthrax skin lesion

A variety of alternatives to the Y. pestis have been put forward. Twigg suggested that the cause was a form of anthrax and N. F. Cantor (2001) thought it may have been a combination of anthrax and other pandemics. Scott and Duncan have argued that the pandemic was a form of infectious disease that characterise as hemorrhagic plague similar to Ebola. Archaeologist Barney Sloane has argued that there are insufficient evidence of the extinction of large number of rats in the archaeological record of the medieval waterfront in London and that the plague spread too quickly to support the thesis that the Y. pestis was spread from fleas on rats and argues that transmission must have been person to person.[40][41] However, no single alternative solution has achieved widespread acceptance.[33] Many scholars arguing for the Y. pestis as the major agent of the pandemic, suggest that its extent and symptoms can be explained by a combination of bubonic plague with other diseases, including typhus, smallpox and respiratory infections. In addition to the bubonic infection, others point to additional septicemic (a type of “blood poisoning”) and pneumonic (an airborne plague that attacks the lungs before the rest of the body) forms of the plague, which lengthen the duration of outbreaks throughout the seasons and help account for its high mortality rate and additional recorded symptoms.[26]

DNA evidence

In October 2010 the open-access scientific journal PLoS Pathogens published a paper by a multinational team who undertook a new investigation into the role of Yersinia pestis in the Black Death following the disputed identification by Drancourt & Raoult in 1998.[42] Their surveys tested for DNA and protein signatures specific for Y. pestis in human skeletons from widely distributed mass graves in northern, central and southern Europe that were associated archaeologically with the Black Death and subsequent resurgences. The authors concluded that this new research, together with prior analyses from the south of France and Germany

Burning of Jews during the Black Death epidemic, 1349

“…ends the debate about the etiology of the Black Death, and unambiguously demonstrates that Y. pestis was the causative agent of the epidemic plague that devastated Europe during the Middle Ages.”[43]

The study also found that there were two previously unknown but related clades (genetic branches) of the Y. pestis genome associated with medieval mass graves. These clades (which are thought to be extinct) were found to be ancestral to modern isolates of the modern Y. pestis strains Orientalis and Medievalis, suggesting that the plague may have entered Europe in two waves. Surveys of plague pit remains in France and England indicate that the first variant entered Europe through the port of Marseille around November 1347 and spread through France over the next two years, eventually reaching England in the spring of 1349, where it spread through the country in three epidemics. Surveys of plague pit remains from the Dutch town of Bergen op Zoom showed that the Y. pestis genotype responsible for the pandemic that spread through the Low Countries from 1350 differed from that found in Britain and France, implying that Bergen op Zoom (and possibly other parts of the southern Netherlands) was not directly infected from England or France in 1349 and suggesting that a second wave of plague, different from those in Britain and France, may have been carried to the Low Countries from Norway, the Hanseatic cities or another site.[43]

The results of the Haensch study have since been confirmed and amended. Based on genetic evidence derived from Black Death victims in the East Smithfield burial site in England, Schuenemann et al. in 2011 further conclude “that the Black Death in medieval Europe was caused by a variant of Y. pestis that may no longer exist.”[44] A study published in Nature in October 2011 sequenced the genome of Y. pestis from plague victims and indicated that the strain which caused the Black Death is ancestral to most modern strains of the disease.[45]

Consequences

Figures for the death toll vary widely by area and from source to source as new research and discoveries come to light. It killed an estimated 75 million–200 million people in the 14th century.[46][47][48] According to medieval historian Philip Daileader in 2007:

A scene showing Jews being burned alive during the period of Black Death, Liber Chronicarum.

The trend of recent research is pointing to a figure more like 45 percent to 50 percent of the European population dying during a four-year period. There is a fair amount of geographic variation. In Mediterranean Europe, areas such as Italy, the south of France and Spain, where plague ran for about four years consecutively, it was probably closer to 75 percent to 80 percent of the population. In Germany and England … it was probably closer to 20 percent.[49]

The most widely accepted estimate for the Middle East, including Iraq, Iran and Syria, during this time, is for a death rate of about a third.[50] The Black Death killed about 40% of Egypt’s population.[51] Half of Paris’s population of 100,000 people died. In Italy, Florence‘s population was reduced from 110,000 or 120,000 inhabitants in 1338 to 50,000 in 1351. At least 60 percent of Hamburg‘s and Bremen‘s population perished.[52] Before 1350, there were about 170,000 settlements in Germany, and this was reduced by nearly 40,000 by 1450.[53] In 1348, the plague spread so rapidly that before any physicians or government authorities had time to reflect upon its origins, about a third of the European population already perished. In crowded cities, it was not uncommon for as much as 50 percent of the population to die. Europeans living in isolated areas suffered less, whereas monks and priests were especially hard hit since they cared for the Black Death’s victims.[54]

Flagellants practised mortification of the flesh as a penance

Because 14th century healers were at a loss to explain the cause, Europeans turned to astrological forces, earthquakes, and the poisoning of wells by Jews as possible reasons for the plague’s emergence.[12] The governments of Europe had no apparent response to the crisis because no one knew its cause or how it spread. The mechanism of infection and transmission of diseases was little understood in the 14th century; many people believed only God’s anger could produce such horrific displays. There were many attacks against Jewish communities.[55] In August 1349, the Jewish communities of Mainz and Cologne were exterminated. In February of that same year, the citizens of Strasbourg murdered 2,000 Jews.[55] By 1351, 60 major and 150 smaller Jewish communities were destroyed.[56] The Brotherhood of the Flagellants, a movement said to number up to 800,000, reached its peak of popularity.[57]

Recurrence

An epidemic of plague dies out after a few months because it has no host in which the bacteria can survive. However that does not mean that there is not somewhere some surviving infection, in a rodent or flea or warm place, that acts as a reservoir so that sooner or later it breaks out again.[58]

The plague repeatedly returned to haunt Europe and the Mediterranean throughout the 14th to 17th centuries.[59] According to Biraben, plague was present somewhere in Europe in every year between 1346 and 1671.[60] The Second Pandemic was particularly widespread in the following years: 1360–1363; 1374; 1400; 1438–1439; 1456–1457; 1464–1466; 1481–1485; 1500–1503; 1518–1531; 1544–1548; 1563–1566; 1573–1588; 1596–1599; 1602–1611; 1623–1640; 1644–1654; and 1664–1667.[61] According to Geoffrey Parker, “France alone lost almost a million people to plague in the epidemic of 1628–31.”[62]

In England, in the absence of census figures, historians propose a range of pre-incident population figures from as high as 7 million to as low as 4 million in 1300,[63] and a post-incident population figure as low as 2 million.[64] By the end of 1350 the Black Death subsided, but it never really died out in England. Over the next few hundred years, there were further outbreaks in 1361–62, 1369, 1379–83, 1389–93, and throughout the first half of the 15th century.[65] An outbreak in 1471 took as much as 10-15 percent of the population, while the death rate of the plague of 1479-80 could have been as high as 20 percent.[66] The most general outbreaks in Tudor and Stuart England seem to have begun in 1498, 1535, 1543, 1563, 1589, 1603, 1625, and 1636, and ended with the Great Plague of London in 1665.[67]

Plague Riot in Moscow in 1771. During the course of the city’s plague, between 50,000 and 100,000 died (1/6 to 1/3 of its population).

In 1466, perhaps 40,000 people died of plague in Paris.[68] During the 16th and 17th centuries, plague visited Paris for almost one year out of three.[69] The Black Death ravaged Europe for three years before it continued on into Russia, where the disease hit somewhere once every five or six years from 1350 to 1490.[70] Plague epidemics ravaged London in 1563, 1593, 1603, 1625, 1636, and 1665,[71] reducing its population by 10 to 30% during those years.[72] Over 10% of Amsterdam‘s population died in 1623–1625, and again in 1635–1636, 1655, and 1664.[73] There were twenty-two outbreaks of plague in Venice between 1361 and 1528.[74] The plague of 1576-1577 killed 50,000 in Venice, almost a third of the population.[75] Late outbreaks in central Europe included the Italian Plague of 1629–1631, which is associated with troop movements during the Thirty Years’ War, and the Great Plague of Vienna in 1679. Over 60 percent of Norway’s population died from 1348 to 1350.[76] The last plague outbreak ravaged Oslo in 1654.[77]

In the first half of the 17th century a plague claimed some 1,730,000 victims in Italy, or about 14% of the population.[78] In 1656 the plague killed about half of Naples‘ 300,000 inhabitants.[79] More than 1,250,000 deaths resulted from the extreme incidence of plague in 17th century Spain.[80] The plague of 1649 probably reduced the population of Seville by half.[81] In 1709–1713, a plague epidemic that followed the Great Northern War (1700–1721, Sweden v. Russia and allies)[82] killed about 100,000 in Sweden,[83] and 300,000 in Prussia.[81] The plague killed two-thirds of the inhabitants of Helsinki,[84] and claimed a third of Stockholm‘s population.[85] Europe’s last major epidemic occurred in 1720 in Marseilles.[76]

Worldwide distribution of plague-infected animals 1998

The Black Death ravaged much of the Islamic world.[86] Plague was present in at least one location in the Islamic world virtually every year between 1500 and 1850.[87] Plague repeatedly struck the cities of North Africa. Algiers lost 30,000–50,000 to plague in 1620–21, and again in 1654–57, 1665, 1691, and 1740–42.[88] Plague remained a major event in Ottoman society until the second quarter of the 19th century. Between 1701 and 1750, 37 larger and smaller plague epidemics were recorded in Constantinople, and 31 between 1751 and 1800.[89] Baghdad has suffered severely from visitations of the plague, and sometimes two-thirds of its population has been wiped out.[90]

The Third Pandemic (1855–1959) started in China in the middle of the 19th century, spreading plague to all inhabited continents and killing 10 million people in India alone.[91]

From 1944 through 1993, 362 cases of human plague were reported in the United States; approximately 90 percent of these occurred in four western states; Arizona, California, Colorado, and New Mexico.[92] Plague was confirmed in the United States from nine western states during 1995.[93]

The plague bacterium could develop drug-resistance and again become a major health threat. The ability to resist many of the antibiotics used against plague has been found so far in only a single case of the disease in Madagascar, in 1995.[94]

In culture

Pieter Bruegel‘s The Triumph of Death (c. 1562) reflects the social upheaval and terror that followed the plague which devastated medieval Europe

The Black Death had a profound impact on art and literature throughout the generation that experienced it. Much of the most useful manifestations of the Black Death in literature, to historians, comes from the accounts of its chroniclers. Some of these chroniclers were famous writers, philosophers and rulers such as Boccaccio and Petrarch. Their writings, however, did not reach the majority of the European population. Petrarch’s work was read mainly by wealthy nobles and merchants of Italian city-states. He wrote hundreds of letters and vernacular poetry, and passed on to later generations a revised interpretation of courtly love.[95] There was one troubadour, writing in the lyric style long out of fashion, who was active in 1348. Peire Lunel de Montech composed the sorrowful sirventes “Meravilhar no·s devo pas las gens” during the height of the plague in Toulouse.

They died by the hundreds, both day and night, and all were thrown in … ditches and covered with earth. And as soon as those ditches were filled, more were dug. And I, Agnolo di Tura … buried my five children with my own hands … And so many died that all believed it was the end of the world.
—The Plague in Siena: An Italian Chronicle[96]
How many valiant men, how many fair ladies, breakfast with their kinfolk and the same night supped with their ancestors in the next world! The condition of the people was pitiable to behold. They sickened by the thousands daily, and died unattended and without help. Many died in the open street, others dying in their houses, made it known by the stench of their rotting bodies. Consecrated churchyards did not suffice for the burial of the vast multitude of bodies, which were heaped by the hundreds in vast trenches, like goods in a ships hold and covered with a little earth.
—Giovanni Boccaccio[97]
 
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Thromboangitis Obliterans(Buerger Disease) Informations

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TROMBO-ANGİTİS OBLİTERANS

(BUERGER Disease)

 

Leo Buerger (1879-1943)

In 1908, Mount Sinai Hospital, Dr. Leo Buerger’s disease, while studies on Buerger’s disease has managed to define the clinical entity, and histological features.

The disease is mainly young and male smokers, the lower extremity arteries is defined as a failure. Often associated tromboflebitle.
Histological appearance of a clearly tanımlanamasa; karekteritiktir segmental involvement. Occlusive lesions, recanalization mediada inward capillary growth and absence of elastic tissue is divided into aterosklerozisten.
Buerger’s disease, acute venous thrombophlebitis was noted that most attacks.

BIOGRAPHY


Leo Buerger was born in Vienna, his family emigrated to America.
Built in 1901 and based surgical training Colombiya graduated from the University. Lennox Hill hastenesinde Stajerliğini completed surgical section. Breslow surgery clinic in Germany in 1905 after working for a while and returned to NewYorka served as a professor of urology at Mount Sinai hastenesinde.
Buerger of the interest, as well as radiology and radium therapy on hematological tumors gelişimiylede concerned. Tilder F. Brown worked on the development in conjunction with cystoscopy and partly recognized as Brown-Buerger cystoscope later became known as Buerger cystoscope. Listen to the music, Dr. Leo is a good piano sniffer. Task used to do it again when they had married in 1929 in Los Angeles, chair of urology. California is seen as people who were offended and very negative in 1934 and again in New York Mt.Sinai Dr.Buerger in appointed.

.

ETYOLOJİ

Buerger’s disease (thromboangiitis obliterans) 75 years, although a pathology known for a long time, despite improvements in surgical or medical treatments, 2-in 4% of patients with chronic limb amputations, which are inevitable in a progressive inflammatory disease of non-atheromatous arterial (1.2) . Creates a group of small arteries in Buerger’s disease of unknown cause. Age, sex, race, hereditary factors (HLA antigen), and non-autoimmune mechanism is known as secondary etiologic factors. Smoking, the most important etiological factor is considered to be secondary. Recurrence of the disease, and the progress of agrevasyonu very tight link between smoking and there.

Amount of medium-sized vessels in the lower and upper extremity. The disease with an average around 28 years, male smokers are 95% (3). Due to the characteristics of the disease due to involvement of the distal vessel, a large group of patients, surgical revascularization is not a chance, conservative treatment techniques. The risk of peripheral gangrene in diabetic patients 70 years of age on the other hand, non-diabetic patients seen by more than 70 times. Microangiopathic dominated in this patient group, the microcirculation of functional disorders develop due to the non-glukolitik metabolism. The third clinical scenario is not applicable in the distal peripheral bypass surgery is the patient group as a result of atherosclerosis. These three clinical cases, limb amputation appears to be the last treatment option, but to be accepted by both patients and surgeons faced with extremely difficult as a result of which We remain a morbidity.

Modification of risk factors for peripheral vascular disease (smoking cessation, such as the regulation of hyperlipidemia and diabetes) can help slow the progression of the disease. Medical treatment antiagreganlar (4) (acetyl salicylic acid, klopidegrol), anticoagulants (warfarin), drugs that increase red blood cell fleksibilitesini (4), hyperlipidemia regulation (exercise, statins, fibrates), regulation of diabetes (or insulin with oral anticoagulants), α-receptor blockers, prostaglandin anaologları (5) (iloprost), Osijek hyperbaric therapy (6) options used to date. Not be performed when curative treatment is surgical sympathectomy, sympathetic blockade, debridement of infected tissue was used until the present day as the surgical approaches used with palliative intent (7). 12-in 15% of patients with ischemic foot ulcers of all kinds of medical treatment, limb amputation within 3-5 years required (8).

CLINICAL RESULTS

The disease most often begins with 20-35 years of age. Thromboangiitis obliterans, thrombophlebitis in 40% of patients seen roaming. Most of the patients seen in the lower extremity findings. The disease begins with a small artery. (Posterior tibial, anterior tibial, radial, ulnar, plantar, or palmar digital arteries). Medium and large arteries (popliteal, femoral, or brachial arteries) also affected by late season. Mayor arteries (aorta and iliac) disease involvement have been reported very rarely. Segmental lesions and episodic dağılımlıdır cruise tracks. In the acute stage, all the layers of the vessel wall is an acute inflammatory changes (panarteritis). Central thrombi and their purulent center and periphery of the foci of giant cells found. During the recovery period, (intermediate term), this characteristic is lost views. Is organized and recanalized thrombus. Recently, the lumen, which is the end product of the specified histological changes in tissue with konjektif is occluded by connective tissue.

Symptoms of the disease, pathological changes in the arterial occlusion Be cause, ie, inflammatory lesions and the destruction of the tissue after ischemia depends. Early symptoms appear as the bottom of the feet or fingers, pain and more pain is at rest. He’s mostly small-diameter arteries of the disease, intermittent claudication ASO’da (arteriosklerosis obliterans) is seen less often than seen. During periods of mild or the beginning of the disease, trophic changes, color changes, and may be changes in the form of coldness. Later periods, or standing on your toes gagren occurs. Inflammatory changes, causing ischemic pain at rest and thrombophlebitis can cause neuritis.

METHODS OF DIAGNOSIS

Ultrasound:
Doppler ultrasound method is determined with the flow and segmental pressure values ​​decreased.

Angiography:
Artery occlusion proximal to the smooth-looking, and usually the normal diameter. Anjiografideki most characteristic finding of occlusion of the vessel in view of increasingly finds ways to thinning and tree roots. Obstructions can also be seen around the short kolleteral network.

The diagnosis is taken into consideration the following criteria:
Coldness of the extremity ends of the asymmetric
Peripheral artery pulzasyonlarının (tibial and dorsalis pedis arteries) or the absence of relief
Tapering gradually, showing a sudden occlusion of blood vessels, and the corkscrew shaped structure showing kolleteral anjiogram
The absence of atheroma plaques
These findings are evaluated together with symptoms of the disease is decisive for diagnosis.

CLINICAL COURSE AND PROGNOSIS

At the end of a long-term observations, in terms of the natural course of disease is divided into 3 groups.

Group I: In this group, the initial period of transient ischemic attack, followed by a period without incident. Patients in this group, comprises 50% of all cases.

Group II: After the initial period, show a moderate periods of recurrence of symptoms occurs. Generates 42% of the patients in this group.

Group III: This group of patients, again during the acute attack, amputation, and often have serious clinical symptoms occur. This group covers 8% of cases.

TREATMENT

Constitute the mainstay of treatment, smoking cessation and supportive medical treatment. Foot hygiene is important to protect. Show multifocal lesions of the disease, the benefits of transactions prevents rekonsrüktif. Applicable to the method of surgical treatment of lumbar sympathectomy. In this method, the lumbar sympathetic ganglia outside the retroperitoneal ganglia removed first. The goal is to increase the blood supply by removing the vasomotor activity. Ticlopidine antiplatelet agent used in medical treatment, increases in erythrocytes fleksibiliteyi Pentoxifylline (Trental) and defibrinated Batroxobin’in agent shown to be effective as chronic arterial lesions. If no cases of wound healing and spread finger or foot amputation may be required.

TROMBO-ANGİTİS obliterans
(Buerger Disease)
 
 
Leo Buerger (1879-1943)
Pada tahun 1908, Rumah Sakit Mount Sinai, penyakit Buerger Dr Leo, sedangkan penelitian pada penyakit Buerger telah berhasil mendefinisikan entitas klinis, dan fitur histologis.
Penyakit ini terutama muda dan perokok laki-laki, arteri ekstremitas bawah didefinisikan sebagai kegagalan. Sering dikaitkan tromboflebitle.
Histologis munculnya jelas tanımlanamasa; karekteritiktir keterlibatan segmental. Lesi oklusif, rekanalisasi mediada pertumbuhan kapiler ke dalam dan tidak adanya jaringan elastis dibagi menjadi aterosklerozisten.
Penyakit Buerger, tromboflebitis vena akut dicatat bahwa sebagian besar serangan.
BIOGRAFI
 
Leo Buerger lahir di Wina, keluarganya beremigrasi ke Amerika.
Dibangun pada tahun 1901 dan pelatihan berbasis Colombiya bedah lulus dari Universitas. Lennox Hill Stajerliğini hastenesinde menyelesaikan bagian bedah. Breslow operasi klinik di Jerman pada tahun 1905 setelah bekerja untuk sementara waktu dan kembali ke NewYorka menjabat sebagai profesor urologi di Gunung Sinai hastenesinde.
Buerger dari bunga, seperti radiologi dan terapi radium pada tumor hematologi gelişimiylede bersangkutan. Tilder F. Brown bekerja pada pengembangan bersama dengan sistoskopi dan sebagian diakui sebagai Brown-Buerger cystoscope kemudian menjadi dikenal sebagai cystoscope Buerger. Mendengarkan musik, Dr Leo adalah sniffer piano yang baik. Tugas yang digunakan untuk melakukannya lagi ketika mereka telah menikah pada tahun 1929 di Los Angeles, ketua urologi. California dipandang sebagai orang-orang yang tersinggung dan sangat negatif pada tahun 1934 dan lagi di New York Mt.Sinai Dr.Buerger dalam ditunjuk.
.
ETYOLOJİ
Buerger penyakit (thromboangiitis obliterans) 75 tahun, meskipun patologi dikenal untuk waktu yang lama, meskipun peningkatan dalam perawatan bedah atau medis, 2-in 4% dari pasien dengan amputasi tungkai kronis, yang tak terelakkan dalam suatu penyakit peradangan yang progresif non-ateromatosa arteri (1,2). Menciptakan sekelompok arteri kecil pada penyakit Buerger penyebabnya tidak diketahui. Usia, jenis kelamin, ras, faktor keturunan (HLA antigen), dan non-mekanisme autoimun dikenal sebagai faktor etiologi sekunder. Merokok, faktor etiologi yang paling penting adalah dianggap sekunder. Kambuhnya penyakit, dan kemajuan agrevasyonu sangat ketat hubungan antara merokok dan ada.
Jumlah menengah pembuluh darah di ekstremitas bawah dan atas. Penyakit dengan rata-rata sekitar 28 tahun, perokok laki-laki adalah 95% (3). Karena karakteristik dari penyakit akibat keterlibatan kapal distal, sekelompok besar pasien, revaskularisasi bedah bukanlah kebetulan, teknik pengobatan konservatif. Risiko gangren perifer pada pasien diabetes berusia 70 tahun di sisi lain, pasien non-diabetes dilihat oleh lebih dari 70 kali. Mikroangiopati mendominasi pada kelompok pasien ini, gangguan mikrosirkulasi fungsional berkembang karena metabolisme non-glukolitik. Skenario klinis ketiga tidak berlaku dalam operasi bypass distal perifer adalah kelompok pasien sebagai akibat dari aterosklerosis. Ketiga kasus klinis, amputasi tungkai tampaknya menjadi pilihan pengobatan terakhir, tetapi untuk dapat diterima oleh kedua pasien dan ahli bedah dihadapkan dengan sangat sulit sebagai akibat dari yang Kami tetap morbiditas sebuah.
Modifikasi faktor risiko untuk penyakit vaskular perifer (berhenti merokok, seperti regulasi hiperlipidemia dan diabetes) dapat membantu memperlambat perkembangan penyakit. Perawatan medis antiagreganlar (4) (asetil asam salisilat, klopidegrol), antikoagulan (warfarin), obat yang meningkatkan sel darah merah fleksibilitesini (4), hiperlipidemia regulasi (olahraga, statin, fibrat), regulasi diabetes (atau insulin dengan antikoagulan oral) , α-reseptor blocker, prostaglandin anaologları (5) (iloprost), terapi hiperbarik Osijek (6) opsi yang digunakan untuk tanggal. Tidak dilakukan ketika pengobatan kuratif simpatektomi bedah, blokade simpatik, debridemen jaringan yang terinfeksi digunakan sampai hari ini sebagai pendekatan bedah yang digunakan dengan maksud paliatif (7). 12-dalam 15% dari pasien dengan ulkus kaki iskemik dari semua jenis perawatan medis, amputasi tungkai dalam waktu 3-5 tahun diperlukan (8).
HASIL KLINIS
Penyakit ini paling sering dimulai dengan usia 20-35 tahun. Thromboangiitis obliterans, tromboflebitis dalam 40% dari pasien terlihat berkeliaran. Sebagian besar pasien terlihat dalam temuan ekstremitas bawah. Penyakit ini dimulai dengan arteri kecil. (Posterior tibialis, tibialis anterior, radial, ulnaris, plantaris, arteri palmaris atau digital). Arteri menengah dan besar (poplitea, arteri femoralis, atau brakialis) juga dipengaruhi oleh musim terlambat. Arteri Walikota (aorta dan iliaka) keterlibatan penyakit telah dilaporkan sangat jarang. Lesi segmental dan trek dağılımlıdır episodik pesiar. Pada tahap akut, semua lapisan dinding pembuluh darah adalah suatu perubahan inflamasi akut (panarteritis). Trombi Tengah dan pusat purulen mereka dan pinggiran fokus sel raksasa ditemukan. Selama periode pemulihan, (jangka menengah), karakteristik ini hilang pandangan. Apakah trombus terorganisir dan recanalized. Baru-baru ini, lumen, yang merupakan produk akhir dari perubahan histologis yang ditentukan dalam jaringan dengan konjektif yang tersumbat oleh jaringan ikat.
Gejala dari penyakit, perubahan patologis pada oklusi arteri Jadilah penyebab, yaitu, lesi inflamasi dan kerusakan jaringan setelah iskemia tergantung. Gejala awal muncul sebagai bagian bawah kaki atau jari, rasa sakit dan nyeri lebih banyak beristirahat. Dia kebanyakan berdiameter kecil arteri dari penyakit, klaudikasio intermiten ASO’da (arteriosklerosis obliterans) terlihat kurang sering daripada terlihat. Selama periode ringan atau awal dari penyakit, perubahan trofik, perubahan warna, dan mungkin perubahan dalam bentuk dingin. Kemudian periode, atau berdiri di atas jari kaki gagren terjadi. Perubahan inflamasi, menyebabkan nyeri iskemik saat istirahat dan tromboflebitis dapat menyebabkan neuritis.
 
METODE Diagnosis
USG:
Metode Doppler USG ditentukan dengan aliran dan nilai tekanan segmental menurun.
Angiografi:
Arteri proksimal halus yang tampak, dan diameter biasanya oklusi normal. Menemukan Anjiografideki paling karakteristik oklusi kapal dalam tampilan yang semakin menemukan cara untuk penipisan dan akar pohon. Penghalang juga dapat dilihat di jaringan kolleteral pendek.
Diagnosis dipertimbangkan kriteria sebagai berikut:
Dinginnya ekstremitas ujung asimetris
Peripheral pulzasyonlarının arteri (arteri dorsalis pedis dan tibialis) atau tidak adanya bantuan
Lonjong secara bertahap, menunjukkan oklusi mendadak pembuluh darah, dan struktur pembuka botol berbentuk menampilkan anjiogram kolleteral
Tidak adanya plak ateroma
Temuan ini dievaluasi bersama-sama dengan gejala penyakit ini yang menentukan untuk diagnosis.
KLINIS KURSUS dan prognosis
Pada akhir jangka panjang pengamatan, dalam hal perjalanan alami penyakit ini dibagi menjadi 3 kelompok.
Kelompok I: Dalam kelompok ini, periode awal serangan iskemik transien, diikuti dengan periode tanpa insiden. Pasien dalam kelompok ini, terdiri dari 50% dari semua kasus.
Kelompok II: Setelah periode awal, menunjukkan periode moderat kambuhnya gejala terjadi. Menghasilkan 42% dari pasien dalam kelompok ini.
Kelompok III: Kelompok ini pasien, lagi selama serangan akut, amputasi, dan sering memiliki gejala klinis yang serius terjadi. Kelompok ini mencakup 8% dari kasus.
PENGOBATAN
Merupakan andalan pengobatan, berhenti merokok dan pengobatan suportif. Kebersihan kaki adalah penting untuk melindungi. Tampilkan lesi multifokal dari penyakit, manfaat dari transaksi mencegah rekonsrüktif. Berlaku untuk metode pengobatan bedah simpatektomi lumbalis. Dalam metode ini, ganglia simpatis lumbalis luar ganglia retroperitoneal dihapus terlebih dahulu. Tujuannya adalah untuk meningkatkan suplai darah dengan menghapus aktivitas vasomotor. Tiklopidin agen antiplatelet digunakan dalam pengobatan medis, peningkatan eritrosit fleksibiliteyi pentoxifylline (Trental) dan agen Batroxobin’in defibrinated terbukti efektif sebagai lesi arteri kronis. Jika tidak ada kasus penyembuhan luka dan jari kaki menyebar atau amputasi mungkin diperlukan

the end @ copyright Dr Iwan suwandy 2011

Anomali Medis Neurofibromatosis(Kelainan Tumor Jinak Yang Dapat Bersifat Ganas Pada Jaringan Saraf Yang Merusak Postur Manusia)

MUSEUM DUNIA MAYA DR IWAN S.

Dr IWAN ‘S CYBERMUSEUM

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     PENDIRI DAN PENEMU IDE

      THE FOUNDER

    Dr IWAN SUWANDY, MHA

                     

     WELCOME TO THE MAIN HALL OF FREEDOM               

  SELAMAT DATANG DI GEDUNG UTAMA “MERDEKA

The Driwan’s  Cybermuseum

                    

(Museum Duniamaya Dr Iwan)

Showroom : 

 

Dr Iwan Health Cybermuseum

Buku Karangan Dr Iwan Suwandy:

 Anomaly Medis Neurofibromatosis(Kelainan Tumor Jinak yang bersifat ganas Jaringan Saraf Dengan Keruskan postur Manusia)

KATA PENGANTAR(Preface)

Neurofibromatosis adalah suatu kelainan(anomali atau Osis) Medis akibat pertumbuhan jaringan(fibro) saraf(neuro) baru (neoplasma atau tumor) yang abnormal ,walaupun bersifat jinak,tetapi kerusakan yang ditimbulkannya bersifat ganas karena  merusak postur tubuh dan wajah penderita.

Tanpa melihat pasien secara langsung , pasti anda tidak akan dapat membayangkan bagaimana penampilan penderita , bagi yang ringan saya sudah pernah lihat seperti tubuh dengan pembengkakan  jaringan kulit yang sangat banyak ibarat seperti pohon dengan buah yang bergantungan, tetapi pada kasus yang ekstrim terlihat seperti seorang manusia monster, kasus ini baru saja dilaporkan oleh para dokter ahli tumor(Onkologi) dari Rumah Sakit(Hospital) di Amerika Serikat, ada dua kasus yang dilaporkan.

Apabila ada yang melihat kasus seperti ini di lingkungan kediamannya ,harap dapat membantu saya dengan mengirimkan foto pasien tersebut dengan riwayat singaktnya.

Saya harap tulisan ini, yang merupakan bagian dari buku karangan saya yang berjudul” MENGENAL DAN MENGATASI ANOMALI MEDIS”

SEHARUSNYA ,KASUS SEPERTI INI TIDAK PERLU TERJADI,APABILA  MASYARAKAT MENGETAHUI PERKEMBANGAN PENYAKIT(PATOGENESIS) DAN UPAYA MEDIS YANG DAPAT DILAKSANAKAN.

Saya harap tulisan ini dapat menambaH wawasan pembaca,sekaligus mencegah kelainan menjadi anomali yang sangat parah seperti yang dilaporkan oleh sejawat dari Amerika Serikat.

Jakarta .Juni 2011

Dr Iwan suwandy,MHA

ENGLISH VERSION:

Neurofibromatosis is a disorder (anomaly or Osis) Medical from the growing  tissue (fibro) nerve (neuro) new (neoplasms or tumors) are abnormal, though it may be benign, but malignant demaged caused the  body and face posture ‘s demage .Without view the patients directly, you definitely will not be imaging  how the appearance of the patient, for a light I’ve ever seen as the body with swelling of skin tissue that is very much like a like a tree with hanging fruit, but in extreme cases look like a human monster, the case This new  reported by the physician experts tumor (Oncology) from the Hospital (Hospital) in the United States, there are two reported cases.

If anyone sees a case like this in his home environment, I hope to help by submitting photos of patients with a short history

I hope this paper, which is part of my essay book entitled “KNOW AND OVERCOMING MEDICAL ANOMALY”

SHOULD, LIKE THIS CASE DOES NOT NEED TO HAPPEN, IF PEOPLE KNOW PERKEMABNAGN DISEASE (PAOGENESIS) MEDICAL AND EFFORT THAT CAN BE EXECUTED.

I hope this article can menambas insightful readers, and prevent the disorder becomes severe anomalies as reported by colleagues from the United States.

Jakarta. June 2011

Dr Iwan suwandy, MHA

CHAPTER ONE:

 STUDI KASUS(CASE STUDY) 1. JENIS KELAINAN(ANOMALIES TYPE)

(1)KASUS SATU(CASE ONE)

 (2).CASE TWO(KASUS DUA)

 2.PERKEMBANGAN KELAINAN(ANOMALIES DEVELOPMENT) A.CASE ONE

(1) ANAK(CHILDREN)

 

2. REMAJA(TEANS)

 3.DEWASA (ADULT)

B.CASE TWO

(1) ANAK(CHILDREN)

2. REMAJA(TEANS)

 3.DEWASA (ADULT)

3.MEDICAL OPERATION(TINDAKAN OPERASI) 

CHAPTER TWO:

THE NEUROFRIBOMATOSIS INFORMATIONS

Neurofibromatosis

 
Neurofibromatosis
Classification and external resources

Back of an elderly woman with neurofibromatosis
ICD-10 Q85.0
ICD-9 237.7
ICD-O: 9540/0
eMedicine derm/287
MeSH D017253

Neurofibromatosis (commonly abbreviated NF; neurofibromatosis type 1 is also known as von Recklinghausen disease) is a genetically-inherited disorder in which the nerve tissue grows tumors (i.e., neurofibromas) that may be benign or may cause serious damage by compressing nerves and other tissues.

The disorder affects all neural crest cells (Schwann cells, melanocytes and endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body, forming tumors; melanocytes also function abnormally in this disease, resulting in disordered skin pigmentation and “cafe-au-lait” spots. The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.[1][2]

Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop. Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals can vary, this may be due to variable expressivity. Approximately half of cases are due to de novo mutations and no other affected family members are seen. It affects males and females equally.

 Classification

Neurofibromatosis type 1 (NF 1)

Plexiform neurofibroma on the neck of a patient; plexiform neurofibromas are a cause of morbidity in the affected individuals.

Patient with multiple small cutaneous neurofibromas and a ‘café au lait spot’ (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions.

Neurofibromatosis type 1 (also known as “von Recklinghausen disease”[1]) is the most common form of NF, accounting for up to 90% of the cases. NF 1 has a disorder frequency of 1 in 4,000, making it more common than neurofibromatosis type 2, with a frequency of 1 in 45,000 people.[3] It occurs following the mutation of neurofibromin on chromosome 17q11.2. 100,000 Americans have neurofibromatosis. Neurofibromin is a tumor suppressor gene whose function is to inhibit the p21 ras oncoprotein.[3] In absence of this tumor suppressor’s inhibitory control on the ras oncoprotein, cellular proliferation is erratic and uncontrolled, resulting in unbalanced cellular proliferation and tumor development. The diagnosis of NF1 is made if any two of the following seven criteria are met:

  • Two or more neurofibromas on or under the skin, or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves); neurofibromas are the subcutaneous bumps characteristic of the disease, and increase in number with age.
  • Freckling of the groin or the axilla (arm pit).
  • Café au lait spots (pigmented, light brown macules located on nerves, with a smooth edges(“coast of California”)[4] birthmarks). Six or more measuring 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals.

 

NF 1 also increases the risk of tumor development, particularly, meningiomas, gliomas and pheochromocytomas.

Neurofibromatosis type 2 (NF 2)

Neurofibromatosis type 2 (also called “central neurofibromatosis”[1]) is the result of mutation of the merlin (also known as “schwannomin”[1]) in chromosome 22q12. It accounts for only 10% of all cases of NF, and its frequency is lower than NF1. It is also caused by a mutation in a tumor suppressor gene (NF2 or merlin). The normal function of merlin is not well understood.[3] The disorder manifests in the following fashion:

NF 2 increases the risk of meningiomas and ependymomas.[3]

Schwannomatosis

 

Main article: Schwannomatosis

Schwannomatosis – mutation in both chromosomes 17 and 22

  1. Multiple schwannomas occur.
  2. The schwannomas develop on cranial, spinal and peripheral nerves.
  3. Chronic pain, and sometimes numbness, tingling and weakness
  4. About 1/3 of patients have segmental schwannomatosis, which means the schwannomas are limited to a single part of the body, such as an arm, a leg or the spine.
  5. Unlike the other forms of NF, the schwannomas do not develop on vestibular nerves, and as a result, no loss of hearing is associated with schwannomatosis.
  6. Patients with schwannomatosis do not have learning disabilities related to the disorder.

One must keep in mind, however, that neurofibromatosis can occur in or affect any of the organ systems, whether that entails simply compressing them (from tumor growth) or in fact altering the organs in some fundamental way. This disparity in the disorder is one of many factors that makes it difficult to diagnose, and eventually find a prognosis for.

 Signs and symptoms

Patients with neurofibromatosis can be affected in many different ways. Morbidity is often a result of plexiform neuromas, optic gliomas, or acoustic neuromas, but mortality can also be associated with malignant transformation of the neuromas, such as neurofibrosarcomas[1] (often there is a malignant transformation in less than 3% of the cases of NF1[3]). There is a high incidence of learning disabilities or cognitive deficit[1][5] in patients with NF, particularly NF-1, however severe retardation is not part of the syndrome. Because of the tumor generating nature of the disorder and its involvement of the nervous system and also because of early onset macrocephaly in the pediatric population, there is often an increased chance of development of epilepsy in those affected. Neurofibromatosis also increases the risk of leukemia particularly in children; Children with NF-1 have 200 to 500 times the normal risk of developing leukemia compared to the general population.[1] Since the tumors grow where there are nerves, they can also grow in areas that are visible, causing considerable social suffering for those affected. The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient’s safety.[6] Affected individuals may need multiple surgeries (such as reduction surgery, or Gamma knife surgery), depending on where the tumors are located. For instance, those affected with NF 2 might benefit from a surgical decompression of the vestibular tumors to prevent deafness.[2]

Diagnosis

 Prenatal testing

 Embryo

For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis (PGD) to screen for NF-1.[7]

“PGD has about 95-98% accuracy but requires that the partner with NF2 have a recognizeable genetic mutation, which is only the case for about 60% of people with a clinical diagnosis of NF2. Having the initial genetic testing to determine if the mutation is recognizeable takes approximately 6 months, and then preparing the probes for the PDG testing takes approximately another 6 months.” [8]

PGD can not be used to detect Schwannomatosis‎, because the gene for it has not yet been identified.[9]

 Fetus

Chorionic villus sampling or amniocentesis can be used:[10]

 Related disorders

Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses).[2] In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.

 Genetics

NF-1 and NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation.

Neurofibromatosis type 1 is caused by mutation on chromosome 17q11.2 , the gene product being neurofibromin (a GTPase activating enzyme (GAP)).[1][11] Neurofibromatosis type 2 is due to mutation on chromosome 22q, the gene product is merlin, a cytoskeletal protein.[1]

Both NF-1 and NF-2 are autosomal dominant disorders, meaning only one copy of the mutated gene need be inherited to pass the disorder. A child of a parent with NF-1 or NF-2 and an unaffected parent will have a 50%-100% chance of inheriting the disorder, depending on whether the affected parent is heterozygous (Aa) or homozygous (AA) for the trait (“A” depicts the affected dominant allele, while “a” depics the recessive allele).

Complicating the question of heritability is the distinction between genotype and phenotype, that is, between the genetics and the actual manifestation of the disorder. In the case of NF1, no clear links between genotype and phenotype have been found, and the severity and the specific nature of the symptoms may vary widely among family members with the disorder. This is a good example of the phenomenon of variable expressivity: the differing severities of disease in different individuals with the same genotype.[12] In the case of NF-2, however, manifestations are similar among family members; a strong genotype-phenotype correlation is believed to exist.[12] Both NF-1 and NF-2 can also appear to be spontaneous de novo mutations, with no family history. These cases account for about one half of neurofibromatosis cases.[12]

Similar to polydactyly, NF is also a autosomally dominant mutation, that is not prevalent in the society. Neurofibromatosis-1 is found in approximately 1 in 2,500-3,000[3] live births (carrier incidence 0.0004, gene frequency 0.0002) and is more common than NF-2.

 Pathophysiology

The gene affected in NF-1, is located on the long arm of the chromosome 17 (q11.2). It encodes for a protein called neurofibromin, otherwise known as “the tumor suppressor” protein. This protein is a negative regulator of the Ras kinase pathway (p21 oncoprotein).[13] Neurofibromatosis alters or weakens this protein (due to deletion, missense mutation, or nonsense mutations,[1]) allowing rapid, radical growth of cells all over the body, especially around the nervous system. The essential problem is the inability to inactivate GTP due to a defective GTP-ase (neurofibromin). This leads to the common symptoms for neurofibromatosis – clumpings of the tumors, called neurofibromas and schwannomas. Less is known about the NF-2 linked gene and its product, merlin. However, it is on the long arm of the chromosome 22q(11.1-13.1[1]) and codes for the protein.

 Treatment

Because there is no cure for the condition itself, the only therapy for patients with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 10% of people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful.[14]

Although there is no cure for NF, the Neurofibromatosis Association is optimistic there will be an effective treatment within the next five to ten years. For families with NF, genetic screening and counselling is available.[15]

The St. Louis Children’s Hospital Neurofibromatosis Center maintains a comprehensive list of current NF research studies.

 History

Neurofibromatosis (or von Recklinghausen disease[2]) was first described in 1882 by the German pathologist, Friedrich Daniel von Recklinghausen (December 2, 1833-August 26, 1910). As a young scientist, Recklinghausen was the student of the then renowned Rudolf Virchow in Berlin. Recklinghausen was successful in generating some of the most descriptive medical observations of his time, making him the first person to describe and coin the term “hemachromatosis” (Hämochromatose, Tageblatt der Naturforschenden Versammlung). Recklinghausen is now known for his contributions to staining methods, and most importantly for his important paper on neurofibromatosis published in 1881, to honor Rudolf Virchow’s 25 year jubilee, in which he describes neurofibromatosis. Recognized as a distinguished histopathologist, and a great scientist to this date, he lends his name to the syndrome, which he himself elucidated.[16]

 Notable cases

In May 2011, a case was reported in the United Kingdom in which a 15-month-old child who turned out to have Neurofibromatosis type I was misdiagnosed as being abused under the assumption that the mother had Münchausen syndrome, because the child gained weight while in hospital and lost weight while at home.[17] The child was placed in foster care for 6 months and then returned to his parents after he was correctly diagnosed.

In January 2008, 32-year-old Huang Chuncai of China underwent a second operation to remove another 4.5 kg (9.9 lb) of tumor from his face. A previous operation removed 15 kg (33 lb) from what was originally a 23 kg (55.7 lb) tumor.[18][19]

In March 2007, the treatment of 30-year-old neurofibromatosis patient Pascal Coler of France ended after he had received what his doctors call the world’s first successful full face transplant.[20][21]

In November 2006, there was an hour-long documentary on the British television network Channel 4 about Facing the World, an organization that helps children with severe facial disfigurements in developing countries. One of the children featured on the documentary was Arianto, an Indonesian boy who suffered from a severe form of neurofibroma resulting in hemifacial giganticism.

Also in that year, another documentary on BBC2 (edge of life) featured a neurofibromatosis case. On that documentary was a young teenager, Amit Ghose, who had decided for himself to have corrective surgery at the age of 14. In this case, the neurofibroma occurred on the face, resulting in the loss of sight in one eye and having to have it removed. This was a case of NF-2, resulting in the disfigurement of the one side of the face, while leaving the other side completely normal.

Joseph Merrick, the Elephant Man, was once considered to have been affected with neurofibromatosis type I. However, it is possible Merrick suffered from the very rare Proteus syndrome. This, however, has given rise to the common misconception that neurofibromatosis and “Elephant Man disease” are one and the same.

Research Organizations

[edit] Foundations

Several national organizations provide support for those challenged by neurofibromatosis. Some include:

 Academic Research and Clinical Centers

The following research and clinical centers specialize in neurofibromatosis in the United States:

Drug Companies

The following drug companies are supporters of the Children’s Tumor Foundation and are actively developing NF-related drugs:

 Versi Indonesia:

 Neurofibromatosis (biasa disingkat NF; neurofibromatosis tipe 1 juga dikenal sebagai penyakit von Recklinghausen) adalah kelainan genetik-mewarisi di mana jaringan saraf tumbuh tumor (yaitu, Neurofibroma) yang mungkin jinak atau dapat menyebabkan kerusakan serius oleh mengompresi saraf dan jaringan lain . Kelainan ini mempengaruhi semua sel pial neural (Schwann sel, melanosit dan fibroblast endoneurial). Cellular elemen dari jenis sel berkembang biak secara berlebihan di seluruh tubuh, membentuk tumor; melanosit juga berfungsi normal pada penyakit ini, mengakibatkan gangguan pigmentasi kulit dan “cafe-au-lait” spot. Tumor dapat menyebabkan benjolan di bawah kulit, bintik-bintik berwarna, masalah tulang, tekanan pada akar saraf tulang belakang, dan masalah-masalah neurologis lainnya. [1] [2]

Neurofibromatosis merupakan gangguan dominan autosomal, yang berarti hanya satu salinan gen yang terkena diperlukan untuk gangguan untuk dikembangkan. Oleh karena itu, jika hanya satu orangtua memiliki neurofibromatosis, nya atau anak-anaknya memiliki kesempatan 50% mengembangkan kondisi juga. Tingkat keparahan pada individu yang terkena dapat bervariasi, hal ini mungkin karena expressivity variabel. Sekitar setengah dari kasus disebabkan oleh mutasi de novo dan tidak ada anggota keluarga lain yang terkena dampak terlihat. Ini mempengaruhi laki-laki dan perempuan sama.

Isi
1 Klasifikasi
1.1 Neurofibromatosis tipe 1 (NF 1)
1.2 Neurofibromatosis tipe 2 (NF 2)
1.3 Schwannomatosis
2 Tanda dan gejala
3 Diagnosis
3.1 Prenatal pengujian
3.1.1 Embrio
3.1.2 Janin
3.2 Terkait gangguan
4 Genetika
5 Patofisiologi
6 Pengobatan
7 Sejarah
8 Terkemuka kasus
9 Penelitian Organisasi
9.1 Yayasan
9.2 Akademik dan Pusat Penelitian Klinis
9.3 Obat Perusahaan
10 Referensi
 

 Klasifikasi
Neurofibromatosis tipe 1 (NF 1)

Plexiform neurofibroma pada leher pasien; Neurofibroma plexiform adalah penyebab kematian pada individu yang terkena.

Pasien dengan beberapa Neurofibroma kulit kecil dan ‘café au lait spot’ (bawah foto, di sebelah kanan pusat). Biopsi telah diambil dari salah satu lesi.

Artikel utama: Neurofibromatosis tipe I
Neurofibromatosis tipe 1 (juga dikenal sebagai “penyakit von Recklinghausen” [1]) adalah bentuk paling umum dari NF, akuntansi hingga 90% dari kasus. NF 1 memiliki frekuensi gangguan dari 1 di 4.000, sehingga lebih umum daripada neurofibromatosis tipe 2, dengan frekuensi 1 dalam 45.000 orang. [3] Ini terjadi setelah mutasi pada kromosom neurofibromin 17q11.2. 100.000 Amerika telah neurofibromatosis. Neurofibromin adalah tumor supresor gen yang berfungsi untuk menghambat onkoprotein p21 ras [3] Dalam tidak adanya kontrol penghambatan ini supresor tumor pada onkoprotein ras,. Proliferasi seluler tidak menentu dan tidak terkendali, yang mengakibatkan proliferasi seluler tidak seimbang dan perkembangan tumor. Diagnosis NF1 dilakukan jika ada dua dari tujuh kriteria berikut ini terpenuhi:

Dua atau lebih Neurofibroma pada atau di bawah kulit, atau satu neurofibroma plexiform (sekelompok besar tumor yang melibatkan beberapa saraf); Neurofibroma adalah benjolan subkutan karakteristik penyakit, dan peningkatan jumlah dengan usia.
Freckling dari pangkal paha atau ketiak (arm pit).
Café au lait spot (pigmen, makula coklat muda terletak pada saraf, dengan tepi halus (“pantai California”) [4] tanda lahir). Enam atau lebih ukuran 5 mm diameter terbesar dalam individu prepubertal dan lebih dari 15 mm dengan diameter terbesar dalam individu postpubertal.
Kelainan rangka, seperti displasia sphenoid atau penipisan korteks tulang panjang tubuh (tulang yaitu kaki, berpotensi menghasilkan membungkuk kaki) [1]
Lisch nodul (hamartomas iris), freckling di iris
Tumor pada saraf optik, juga dikenal sebagai glioma optik
Macrocephaly dalam 30-50% dari populasi anak tanpa [5] hidrosefalus
Epilepsi (kejang)
opacity Juvenile lenticular posterior [1]
NF 1 juga meningkatkan resiko perkembangan tumor, khususnya, meningioma, glioma dan pheochromocytomas.

Neurofibromatosis tipe 2 (NF 2)
Artikel utama: Neurofibromatosis tipe II
Neurofibromatosis tipe 2 (juga disebut “neurofibromatosis pusat” [1]) adalah hasil mutasi dari merlin (juga dikenal sebagai “schwannomin” [1]) di 22q12 kromosom. Ini account hanya 10% dari semua kasus NF, dan frekuensi lebih rendah daripada NF1. Hal ini juga disebabkan oleh mutasi pada gen supresor tumor (NF2 atau merlin). Fungsi normal merlin tidak dipahami [3] memanifestasikan Gangguan dengan cara berikut.:

neuromas akustik bilateral (tumor dari saraf vestibulocochlear atau saraf kranial 8 (CN VIII) juga dikenal sebagai schwannoma), yang sering menimbulkan gangguan pendengaran. Bahkan, ciri khas NF 2 adalah gangguan pendengaran akibat neuromas akustik sekitar usia dua puluh.
Tumor dapat menyebabkan:
sakit kepala
keseimbangan masalah, dan vertigo perifer sering karena schwannoma dan keterlibatan dari telinga bagian dalam
wajah kelemahan / kelumpuhan akibat keterlibatan atau kompresi pada saraf wajah (saraf kranial 7 atau CN VII)
pasien dengan NF2 juga dapat mengembangkan tumor otak lainnya, serta tumor tulang belakang.
tuli dan tinnitus
NF 2 meningkatkan risiko meningioma dan ependymomas. [3]

Schwannomatosis
Artikel utama: Schwannomatosis
Schwannomatosis – mutasi di kedua kromosom 17 dan 22

Beberapa schwannomas terjadi.
The schwannomas mengembangkan pada saraf kranial, tulang belakang dan perifer.
Sakit kronis, dan kadang-kadang mati rasa, kesemutan dan kelemahan
Sekitar 1 / 3 dari pasien memiliki schwannomatosis segmental, yang berarti schwannomas terbatas pada satu bagian dari tubuh, seperti tangan, kaki atau tulang belakang.
Berbeda dengan bentuk lain dari NF, yang schwannomas tidak berkembang pada saraf vestibular, dan sebagai akibatnya, tidak ada kehilangan pendengaran dikaitkan dengan schwannomatosis.
Pasien dengan schwannomatosis tidak memiliki ketidakmampuan belajar yang terkait dengan gangguan tersebut.
Salah satu harus diingat, bagaimanapun, bahwa neurofibromatosis dapat terjadi pada atau mempengaruhi salah satu sistem organ, apakah yang memerlukan hanya memadatkan mereka (dari pertumbuhan tumor) atau bahkan mengubah organ dalam beberapa cara fundamental. Perbedaan dalam gangguan ini merupakan salah satu faktor yang membuat sulit untuk mendiagnosa, dan akhirnya menemukan prognosis untuk.

 Tanda dan gejala
Pasien dengan neurofibromatosis dapat dipengaruhi dalam berbagai cara. Morbiditas sering merupakan akibat dari neuromas plexiform, glioma optik, atau neuromas akustik, namun kematian juga dapat dikaitkan dengan transformasi ganas dari neuromas, seperti neurofibrosarcomas [1] (sering ada transformasi ganas kurang dari 3% dari kasus dari NF1 [3]). Ada insiden tinggi ketidakmampuan belajar atau defisit kognitif [1] [5] pada pasien dengan NF, khususnya NF-1, namun keterbelakangan yang parah bukan merupakan bagian dari sindrom tersebut. Karena sifat tumor menghasilkan kekacauan dan keterlibatan terhadap sistem saraf dan juga karena onset awal macrocephaly pada populasi anak, sering terjadi peluang peningkatan pengembangan epilepsi pada mereka yang terkena dampak. Neurofibromatosis juga meningkatkan risiko leukemia terutama pada anak-anak, Anak-anak dengan NF-1 memiliki 200 sampai 500 kali risiko leukemia normal berkembang dibandingkan dengan populasi umum [1] Sejak tumor tumbuh di mana terdapat saraf, mereka juga bisa tumbuh dalam. daerah yang terlihat, menyebabkan penderitaan sosial yang cukup untuk mereka yang terkena dampak. Tumor juga bisa tumbuh di tempat-tempat yang dapat menyebabkan masalah kesehatan lain yang mungkin mengharuskan mereka harus dikeluarkan untuk keselamatan pasien. [6] individu yang terkena mungkin perlu operasi beberapa (seperti operasi pengurangan, atau operasi Gamma pisau), tergantung di mana tumor berada. Misalnya, mereka yang terkena dampak dengan NF 2 mungkin mendapat manfaat dari dekompresi bedah dari tumor vestibular untuk mencegah tuli. [2]

Diagnosa
 Prenatal testing
 Embrio
Untuk embrio yang dihasilkan melalui fertilisasi in vitro, adalah mungkin melalui praimplantasi genetik diagnosis (PGD) ke layar untuk NF-1. [7]

“PGD memiliki ketepatan sekitar 95-98% tetapi mengharuskan bermitra dengan NF2 memiliki mutasi genetik recognizeable, yang hanya berlaku untuk sekitar 60% orang dengan diagnosis klinis NF2 Setelah pengujian genetik awal untuk menentukan. Apakah mutasi adalah recognizeable diperlukan sekitar 6 bulan, dan kemudian mempersiapkan probe untuk pengujian PDG berlangsung sekitar 6 bulan lagi. ” [8]

PGD ​​tidak dapat digunakan untuk mendeteksi Schwannomatosis, karena gen untuk itu belum teridentifikasi. [9]

 Janin
Chorionic villus sampling atau amniosentesis dapat digunakan: [10]

Untuk mendeteksi jenis Neurofibromatosis saya.
Untuk mendeteksi Neurofibromatosis tipe II dengan akurasi 95%.
Tidak bisa digunakan untuk mendeteksi Schwannomatosis, karena gen untuk itu belum teridentifikasi.
 Terkait gangguan
Neurofibromatosis dianggap sebagai anggota sindrom neurocutaneous (phakomatoses). [2] Di samping jenis neurofibromatosis, yang phakomatoses juga termasuk tuberous sclerosis, sindrom Sturge-Weber dan von penyakit Hippel-Lindau. Pengelompokan ini adalah artefak dari waktu sebelumnya dalam kedokteran, sebelum dasar genetik yang berbeda dari masing-masing penyakit dipahami.

 Genetika

NF-1 dan NF-2 dapat diwariskan dengan cara dominan autosomal, serta melalui mutasi acak.

Neurofibromatosis tipe 1 disebabkan oleh mutasi pada kromosom 17q11.2, produk gen neurofibromin menjadi (a enzim GTPase mengaktifkan (GAP)). [1] [11] Neurofibromatosis tipe 2 adalah karena mutasi pada kromosom 22q, produk gen yang merlin , sebuah protein cytoskeletal. [1]

Kedua-NF 1 dan NF-2 adalah gangguan dominan autosomal, yang berarti hanya satu salinan mutasi gen perlu diwariskan untuk lulus gangguan tersebut. Seorang anak dari orang tua dengan NF-1 atau NF-2 dan orang tua yang tidak terpengaruh akan memiliki kemungkinan 50% -100% dari mewarisi gangguan, tergantung pada apakah orang tua yang terkena heterozigot (Aa) atau homozigot (AA) untuk trait (“A” melukiskan alel dominan yang mempengaruhi, sementara “sebuah” depics alel resesif).

Rumit pertanyaan tentang heritabilitas adalah perbedaan antara genotipe dan fenotipe, yaitu, antara genetika dan manifestasi aktual dari kekacauan. Dalam kasus NF1, tidak ada hubungan yang jelas antara genotip dan fenotip telah ditemukan, dan tingkat keparahan dan sifat khusus dari gejala dapat bervariasi secara luas di antara anggota keluarga dengan gangguan tersebut. Ini adalah contoh yang baik dari fenomena expressivity variabel: severities berbeda dengan penyakit pada individu yang berbeda dengan genotipe yang sama [12] Dalam kasus NF-2, bagaimanapun, manifestasi yang serupa di antara anggota keluarga, sebuah fenotipe genotipe-kuat. korelasi diyakini ada [12] Kedua NF-1 dan. NF-2 juga dapat tampak spontan de novo mutasi, dengan tidak ada riwayat keluarga. Kasus-kasus ini mencapai sekitar satu setengah dari kasus neurofibromatosis. [12]

Serupa dengan polydactyly, NF juga merupakan mutasi autosomally dominan, yang tidak lazim di masyarakat. Neurofibromatosis-1 ditemukan pada sekitar 1 dari 2,500-3,000 [3] kelahiran hidup (pembawa kejadian 0,0004, frekuensi gen 0,0002) dan lebih umum daripada NF-2.

 Patofisiologi
Gen terpengaruh di NF-1, terletak pada lengan panjang kromosom 17 (q11.2). Ia mengkodekan untuk protein yang disebut neurofibromin, atau dikenal sebagai “penekan tumor” protein. Protein ini adalah pengatur negatif dari jalur kinase Ras (p21 onkoprotein) [13] Neurofibromatosis mengubah atau. melemahkan protein ini (karena penghapusan, mutasi missense, atau mutasi omong kosong, [1]) memungkinkan cepat, pertumbuhan radikal dari sel-sel di seluruh tubuh, terutama di sekitar sistem saraf. Masalah penting adalah ketidakmampuan untuk menonaktifkan GTP karena ase-cacat GTP (neurofibromin). Hal ini mengakibatkan gejala yang umum untuk neurofibromatosis – clumpings dari tumor, Neurofibroma menelepon dan schwannomas. Sedikit yang diketahui tentang gen-2 NF terkait dan produk, merlin. Namun, di lengan panjang kromosom 22q (11,1-13,1 [1]) dan kode untuk protein.

 Pengobatan
Karena tidak ada obat untuk kondisi itu sendiri, satu-satunya terapi untuk pasien dengan neurofibromatosis adalah sebuah program pengobatan oleh tim spesialis untuk mengelola gejala atau komplikasi. Pembedahan mungkin diperlukan ketika tumor kompres organ atau struktur lainnya. Kurang dari 10% orang dengan neurofibromatosis mengembangkan pertumbuhan kanker;. Dalam kasus-kasus, kemoterapi mungkin bisa berhasil [14]

Meskipun tidak ada obat untuk NF, Asosiasi Neurofibromatosis optimis akan ada pengobatan yang efektif dalam lima sampai sepuluh tahun. Untuk keluarga dengan NF, skrining genetik dan konseling tersedia. [15]

St Louis Children’s Hospital Neurofibromatosis Center maintain daftar komprehensif studi penelitian NF saat ini.

 Sejarah
Neurofibromatosis (penyakit von Recklinghausen atau [2]) pertama kali dijelaskan pada tahun 1882 oleh ahli patologi Jerman, Friedrich Daniel von Recklinghausen (2 Desember 1833-Agustus 26, 1910). Sebagai seorang ilmuwan muda, Recklinghausen adalah murid dari Rudolf Virchow kemudian terkenal di Berlin. Recklinghausen berhasil dalam menghasilkan beberapa pengamatan medis yang paling deskriptif waktunya, membuatnya orang pertama yang menggambarkan dan koin “hemachromatosis” istilah (Hämochromatose, Tageblatt der Naturforschenden Versammlung). Recklinghausen sekarang dikenal karena kontribusinya untuk metode pewarnaan, dan yang paling penting untuk kertas penting tentang neurofibromatosis diterbitkan pada 1881, untuk menghormati 25 tahun Rudolf Virchow’s Yobel, di mana ia menjelaskan neurofibromatosis. Diakui sebagai histopatologis dibedakan, dan seorang ilmuwan besar untuk tanggal ini, dia meminjamkan namanya sindrom, yang dia sendiri dijelaskan. [16]

 Terkemuka kasus
Pada bulan Mei 2011, kasus dilaporkan di Inggris di mana anak 15-bulan-tua yang ternyata memiliki tipe Neurofibromatosis aku misdiagnosed sebagai disalahgunakan dengan asumsi bahwa ibu telah Munchausen syndrome, karena anak yang diperoleh berat badan sementara di rumah sakit dan kehilangan berat badan sementara di rumah [17] Anak itu ditempatkan dalam anak asuh selama 6 bulan dan kemudian kembali kepada orang tuanya setelah dia benar didiagnosis..

Pada bulan Januari 2008, 32 tahun Huang Chuncai Cina menjalani operasi kedua untuk menghapus lain 4,5 kg (9,9 lb) tumor dari wajahnya. Sebuah operasi sebelumnya dihapus 15 kg (33 lb) dari apa yang awalnya 23 kg (£ 55,7) tumor. [18] [19]

Pada bulan Maret 2007, pengobatan pasien neurofibromatosis 30 tahun Pascal Coler Perancis berakhir setelah ia telah menerima apa yang dokter sebut transplantasi wajah pertama yang sukses di dunia penuh. [20] [21]

Pada bulan November 2006, ada dokumenter selama satu jam di jaringan televisi Inggris Channel 4 tentang Menghadapi Dunia, sebuah organisasi yang membantu anak-anak dengan wajah disfigurements parah di negara-negara berkembang. Salah satu dari anak-anak ditampilkan di film dokumenter itu Arianto, seorang anak Indonesia yang menderita bentuk parah neurofibroma mengakibatkan giganticism hemifacial.

Juga pada tahun itu, lain dokumenter BBC2 (pinggir hidup) menampilkan kasus neurofibromatosis. Di dokumenter itu adalah remaja muda, Amit Ghose, yang telah memutuskan untuk dirinya sendiri untuk menjalani operasi perbaikan pada usia 14. Dalam hal ini, neurofibroma terjadi pada wajah, yang mengakibatkan kehilangan penglihatan pada satu mata dan harus menghapusnya. Ini merupakan kasus NF-2, yang mengakibatkan cacat dari sisi yang satu wajah, sementara meninggalkan sisi lain normal.

Joseph Merrick, Manusia Gajah, pernah dianggap telah terpengaruh dengan neurofibromatosis tipe I. Namun, Merrick mungkin menderita sindrom Proteus sangat jarang. Ini, bagaimanapun, telah menimbulkan kesalahpahaman umum bahwa neurofibromatosis, dan “penyakit Elephant Man” adalah satu dan sama.

Penelitian Organisasi
[Sunting] Yayasan
Beberapa organisasi nasional memberikan dukungan bagi mereka ditantang oleh neurofibromatosis. Yang meliputi:

Australia: Little Frog Foundation (sebuah organisasi nirlaba yang bekerja menyediakan informasi dan sumber daya untuk keluarga berurusan dengan NF1, NF2, dan neurofibromatosis tumor-terkait di Australia)
Belgia: NF KONTAKT.be (sebuah organisasi nirlaba yang menyediakan informasi dan sumber daya untuk keluarga, Sekolah dan Perawatan kesehatan pekerja berurusan dengan NF1, NF2, dan neurofibromatosis tumor terkait di Belgia dan memberikan kesadaran dan dukungan dari Neurofibromatosis di Eropa)
Kanada: Asosiasi Neurofibromatosis Quebec
Perancis:
Asosiasi Neurofibromatosis dan Recklinghausen
Centre de Referensi labellisé NEUROFIBROMATOSES
United Kingdom: Yayasan Neuro
Amerika Serikat:
Children’s Tumor Foundation (KKP) (sebuah organisasi nirlaba yang bergerak menuju obat untuk neurofibromatosis)
Neurofibromatosis Inc (sebuah organisasi nirlaba yang bekerja untuk mendukung neurofibromatosis pasien)
Neurofibromatosis Cafe (sebuah organisasi nirlaba yang bekerja memberikan pendidikan kesadaran, pasien dan dukungan dari Neurofibromatosis)
 Akademik Penelitian dan Pusat Klinis
Penelitian lanjutan dan pusat klinis mengkhususkan diri pada neurofibromatosis di Amerika Serikat:

California:
House Ear Institute di Los Angeles adalah NFPC KKP fokus pada schwannoma NF2 dan meningioma.
NF / Ras Pathway Clinic di UCSF Medical Center di San Francisco. Ini adalah NFPC KKP berfokus pada NF1 leukemia myeloid.
Florida:
The Wallace Lab dan Muir Lab di University of Florida di Gainesville, Florida fokus pada studi molekuler tumor jinak sel Schwann dan pengembangan terapi baru untuk NF1.
Pusat Neurofibromatosis di Rumah Sakit Anak Miami.
Illinois: Neurofibromatosis Program di Universitas Chicago Medical Center.
Indiana: Klinik Neurofibromatosis di Universitas Indiana. Klinik ini telah mempelopori penggunaan Imatinib untuk mengobati Neurofibroma. [22]
Maryland: The Johns Hopkins Center Neurofibromatosis menyeluruh di Rumah Sakit Johns Hopkins
Massachusetts:
Pusat Neurofibromatosis dan Sekutu Gangguan di Sekolah Kedokteran Harvard dan Massachusetts Rumah Sakit Umum. Ini adalah KKP NFPC fokus pada schwannoma NF2 dan meningioma.
Brigham dan Women’s Hospital di Harvard Medical School adalah NFPC KKP NF1 berfokus pada saraf tepi tumor ganas selubung.
Pusat Genetika Manusia di Boston University School of Medicine menyediakan layanan uji laboratorium genetik untuk jenis Neurofibromatosis I dan sindrom Legius. Pengujian meliputi sekuensing DNA dan amplifikasi probe Multiplex ligasi-dependen.
Missouri: Pusat Neurofibromatosis di Rumah Sakit St Louis Children’s [23] Ini adalah NFPC KKP fokus pada jalur NF1 glioma optik.. Mereka mempertahankan daftar lengkap studi penelitian NF saat ini.
New Jersey: Pusat Neurofibromatosis dari New Jersey dan Institute of Medicine Genomic di Rumah Sakit Universitas (Newark, New Jersey)
New York:
Pusat Sistem Kesehatan Neurofibromatosis di North Shore-LIJ
The Neurofibromatosis Center di NYU Langone Medical Center (lihat juga Departemen THT).
Klinik Comprehensive Neurofibromatosis di Rumah Sakit NewYork-Presbyterian.
Ohio: Neurofibromatosis Pusat Rumah Sakit Anak Cincinnati di Cincinnati Medical Center. Ini adalah NFPC KKP berfokus pada NF1 Neurofibroma plexiform. Lab Ratner memfokuskan pada interaksi antara sel glial dan akson dalam pengembangan sistem saraf dan bagaimana interaksi pergi miring mengarah ke NF1 dan kondisi NF2.
Pennsylvania: Program Neurofibromatosis di Rumah Sakit Anak Philadelphia
Texas:
Klinik Comprehensive Neurofibromatosis pada University of Texas Southwestern Medical Center.
Klinik Neurofibromatosis di Children’s Medical Center (Dallas)
Obat Perusahaan
Perusahaan-perusahaan obat berikut pendukung dari Children’s Tumor Foundation dan secara aktif mengembangkan obat NF-terkait:

Avila Terapi
Genentech
Merck
Novartis
Pfizer

 
 

References

   
  1. ^ a b c d e f g h i j k l m Raphael Rubin, David S. Strayer (2008 Baltimore). Rubin’s Pathology: Clinicopathologic Foundation of Medicine (5 ed.). Wolters Kluwer Health: Lippincot Williams & Wilkins. pp. 201–3. ISBN 9780781795166
  2. ^ a b c d Conrad Fischer, Farshad Bagheri, Rajpal Manchandani, Richard Pinsker, Sudheer Chauhan, Parenkumar Patel, Mohammad Maruf, Dhaval Satani, Kaushik Doshi, Ayaz Alwani, Naveen Pathak, Craigh Thurm, Mohammad Babury, Mahendra C. Patel, Arthur Shalanov, Samir Sarkar, Sabiha Raouf, Jebun Nahar, Prakashkumar Patel (2010). Master the Board USMLE Step 2 CK. KAPLAN Medical. p. 287. ISBN 9781607146537
  3. ^ a b c d e f John Barone (2008). USMLE Step 1 Lecture Notes: Pathology. KAPLAN Inc. pp. 57. 
  4. ^ William D James, Raj D Sheth, Nazanin Saedi (Jul 20, 2009). Cafe Au Lait Spots. eMedicine from WebMD. http://emedicine.medscape.com/article/911900-overview. Retrieved 13 December 2010. 
  5. ^ a b Steen RG, Taylor JS, Langston JW, Glass JO, Brewer VR, Reddick WE, Mages R, Pivnick EK. (2001, May). Prospective evaluation of the brain in asymptomatic children with neurofibromatosis type 1: relationship of macrocephaly to T1 relaxation changes and structural brain abnormalities.. 22. American Journal of Neuroradiology. pp. 810–7. PMID 11337320
  6. ^ Hayashi M, Chernov M, Tamura N, Yomo S, Ochiai T, Nagai M, Tamura M, Izawa M, Muragaki Y, Iseki H, Okada Y, Takakura K. (December 2010). Gamma Knife surgery for abducent nerve schwannoma. Report of 4 cases. 113. Journal of Neurosurgery. pp. 136–43. PMID 21121795
  7. ^ “British couple successfully screens out genetic disorder using NHS-funded PGD” by Antony Blackburn-Starza, June 9, 2008, BioNews 461
  8. ^ NF2 Planned Parenthood: Current prenatal testing options
  9. ^ Schwannomatosis, by Susan Toomey MS, page 4
  10. ^ “Are there any prenatal tests for the neurofibromatoses?”
  11. ^ Fauci, et al. Harrison’s Principles of Internal Medicine (Small textbook) (16 ed.). pp. 2453. 
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