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BLOOD BRAIN BARRIER

(Sawar Darah Otak)


PENDAHULUAN
Blood Brain Barrier (BBB=Sawar Darah Otak) adalah struktur membran yang secara primer
berfungsi untuk melindungi otak dari bahan-bahan kimia dalam darah, dimana fungsi metabolik masih
dapat dilakukan. Sawar darah otak ini terdiri dari sel-sel endotelial, yang tersusun sangat rapat di
kapiler otak. BBB berbeda dengan blood-cerebrospinal fluid barrier yang menyerupainya, suatu sel-sel
koroid pada pleksus koroideus, dan dari blood-retinal barrier, yang dapat dimasukkan sebagai bagian dari
BBB.(1)

FISIOLOGI
Diseluruh tubuh selain otak, dinding-dinding kapiler (pembuluh darah terkecil) dibuat dari sel-sel
endotel yang fenestrata, berarti mereka memiliki celah kecil yang disebut fenestrasi. Bahan kimia yang
larut dapat melewati celah ini, dari darah ke jaringan atau dari jaringan ke darah. Selanjutnya di otak, selsel endotel ini tersusun lebih rapat disebut dengan tight junction. Ini membuat BBB menghambat gerakan
seluruh molekul kecuali yang mampu melewati membran sel dengan kalarutan dalam lemak (mis :
oksigen, karbondioksida, etanol, dan hormon-hormon steroid) dan yang dapat melewati sistem
transpor spesifik (mis : gula dan asam amino). Substansi dengan berat molekul lebih dari 500 dalton
(500 u) biasanya tidak dapat melewati BBB, dimana molekul yang lebih kecil dapat melewatinya. Sebagai
tambahan, sel-sel endotel memetabolisme molekul-molekul tertentu untuk mencegah mereka masuk ke
SSP. Contohnya : L-DOPA, prekursor dopamin, dapat menembus BBB, dimana dopamin sendiri tidak
dapat menembusnya. (hasilnya, L-DOPA diberikan untuk defisiensi dopamin (mis : penyakit parkinson)
dibandingkan dopamin).
Dalam kimia, berat dihitung tidak dalam kg tetapi dalam Dalton. Faktanya, terungkap bahwa hanya
molekul yang berat molekulnya kurang dari 500 dalton yang dapat menembus BBB. Sekaran berat
molekul 500 dalton tidak sangat besar. Air memiliki berat molekul 18 dalton, insulin juga tidak begitu besar.
Virus-virus (dengan berat molekul dalam hitungan juta) jauh lebih besar daripada ini, dan bakteri sangat
jauh lebih besar lagi. Jadi jarang untuk bahan kimia, virus, dan bakteri untuk dapat menembus BBB dan
masuk ke otak.(2)
Sebagai tambahan dari tight junction yang berfungsi mencegah transpor anatara sel-sel endotel,
ada 2 mekanisme untuk mencegah difusi pasif melalui membran sel. Sel-sel glia yang mengelilingi kapiler
otak menyediakan rintangan kedua untuk molekul-molekul yang hidrofilik, dan konsentrasi yang rendah
dari protein interstitial di otak mencegah akses molekul hidrofilik.
BBB melindungi otak dari aliran bahan-bahan kimia dalam darah. Banyak fungsi tubuh dikendalikan
oleh hormon dalam dalam darah, dan ketika sekresi hormon-hormon tersebut dikendalikan oleh otak,
hormon-hormon ini umumnya tidak memasuki otak dari darah. Ini akan mencegah otak untuk langsung
memonitor tingkat hormon. Dalam tujuan untuk mengendalikan sekresi hormon secara efektif, ada tempat
khusus dimana neuron dapat mencontohkan komposisi sirkulasi darah. Di tempat ini, BBB lemah; tempat
ini termasuk tiga organ sirkumventrikular, yaitu organ subfornikal, area postrema, dan organum
vasculosum dari lamina terminalis (OVLT).
BBB berfungsi sangat efektif untuk melindungi otak dari infeksi. Karena ini, infeksi pada otak sangat
jarang. Antibodi terlalu besar untuk menembus BBB, infeksi otak sering sangat serius dan sulit diobati. (1)
FUNGSI BBB
Blood Brain Barrier mempunyai beberapa fungsi penting :
1. Melindungi otak dari substansi asing dari darah yang dapat melukai otak.

2. Melindungi otak dari hormon-hormon dan neurotransmitter di seluruh tubuh.


3. Mempertahankan lingkungan yang konstan pada otak.(3)
ANATOMI BBB
BBB adalah semi permeabel, yang membolehkan beberapa material untuk menembusnya, tetapi
menghalangi material lainnya. Jaringan endotelial memiliki ruangan kecil di antara tiap sel individu
sehingga substansi dapat lewat di antara bagian luar dan dalam pembuluh darah. Meskipun, pada otak,
sel-sel endotel saling berhubungan dan substansi-substansi tidak dapat melewati aliran darah. (beberapa
molekul, seperti glukosa, ditranspor oleh darah dengan cara khusus).
Sel-sel glia (astrosit) membentuk lapisan disekitar pembuluh darah otak dan dapat penting dalam
perkembangan BBB. Astrosit juga dapat bertanggung jawab dalam transpor ion dari otak ke darah. (3)
BARRIER PELINDUNG
BBB disusun oleh sel-sel yang mengikuti pembuluh darah kecil (kapiler) otak, disebut sel endotelial.
Sel-sel ini membentuk hubungan yang rapat satu sama lain yang tidak dihadirkan secara umum dalam
banyak organ dan menghentikan pertukaran substansi yang bebas terjadi antara otak dan darah. Barrier ini
melindungi otak menciptakan lingkungan yang unik.
Otak memerlukan transport khusus untuk nutrisi yang dibutuhkannya, seperti glukosa, untuk
menembus barrier dari darah ke otak.
Adanya BBB menyebabkan banyak obat yang ditujukan untuk penyakit syaraf pusat sulit mencapai
otak dalam jumlah yang penting untuk dapat efektif. Hal ini terjadi pada kondisi-kondisi seperti tumor-tumor
otak, penyakit parkinson, penyakit alzheimer, epilepsi, malaria, HIV, meningitis dan tentu saja penyakit
penyimpanan lisosomal neuropatik.(4)
KERUSAKAN BBB
Bukti masih berkembang bahwa BBB sendiri dapat rusak dalam beberapa penyakit penyimpanan
lisosom yang berperan pada gejala-gejala neurologis, masalah secara langsung disebabkan oleh
terkumpulnya produk-produk yang tersimpan dalam sel-sel otak. Karena adanya BBB, terapi penggantian
enzim sekarang digunakan untuk mengobati beberapa penyakit penyimpanan lisosom yang tidak dapat
mencapai sel otak.
Seiring dengan meningkatnya angka bertahan hidup sebagai akibat pengobatan sekarang ini,
insidensi beberapa masalah neuronopatik dapat menjadi bukti lebih. Perkembangan strategi yang efektif
secara jelas mengarahkan agar terapi dan enzim melewati BBB dengan tujuan untuk mencapat dan
mengobati otak adalah penting.(4)
BBB dapat dirusak oleh :
1. Hipertensi (tekanan darah tinggi) : tekanan darah tinggi membuka BBB.
2. Perkembangan : BBB tidak terbentuk utuh saat kelahiran.
3. HIperosmolitas: Konsentrasi yang tinggi dari substansi di darah dapat membukan BBB.
4. Gelombang mikro : Pemaparan terhadap gelombang mikro dapat membuka BBB.
5. Radiasi : Pemaparan terhadap radiasi dapat membuka BBB.
6. Infeksi : Pemaparan pada bahan-bahan infeksius dapat membuka BBB.
7. Trauma, iskemia, inflamasi, tekanan : Luka pada otak dapat membuka BBB. (3)
ORGAN SIRKUMVENTRIKULAR
Ada beberapa area di otak dimana BBB lemah. Hal ini menyebabkan substansi dapat menembus
otak dengan bebas. Area ini disebut organ sirkumventrikular. Melalui organ sirkumventrikular ini otak
dapat memantau bentuk darah. Organ sirkumventrikular ini termasuk :
1. Badan Pineal : Mensekresikan melatonin dan peptida neuroaktif. Berhubungan dengan irama
sirkadian.

2. Neurohipofise (pituitari posterior) : Melepaskan neurohormon seperti oksitosin dan vasopresin ke


dalam darah.
3. Area Postrema : Pusat muntah : Ketika bahan beracun memasuki aliran darah, dan menuju ke
area postrema.
4. Organ Subfornikal : Penting untuk regulasi cairan tubuh.
5. Organ vaskular dari Lamina terminalis : Area kemosensoris yang mendeteksi peptida dan molekul
lain.
6. Median eminence : Regulasi pituitari anterior melalui pelepasan neurohormon. (3)

1.

2.

3.

4.

5.

PERUBAHAN PADA BBB


Gangguan Metabolik
Terjadi kompetisi tempat pembawa oleh asam amino yang ditranspor. Ketika konsentrasi plasma untuk
kompetisi asam amino meningkat, gerakan untuk menyebrang meningkat. Kompetisi ini terutama
berkembang pada kegagalan hati. Selama puasa, transpor lactat. 3 hidroksihidrat dan asetoasetat
meningkat.
Epilepsi
Peningkatan tekanan darah yang akut, dan aliran darah yang mengikuti kejang berhubungan dengan
meningkatnya jumlah dan volume piknosis vesikel di kapiler otak dengan mengubah susunan hubungan
sel yang rapat yang meningkatkan gerakan substansi yang secara normal tidak masuk ke BBB.
Penyakit Serebrovaskuler.
Sebagai aturan umumnya, ada kehancuran BBB dengan kelebihan serum protein dan berkembangnya
odek otak vasogenik. Kelonggaran dan kelemahan hubungan yang rapat dan perkembangan piknosis
vesikel selama hipertensi akut diperkirakan sebagai penyebabnya. Pada iskemia, pembukaan yang
pertama terjadi segera setelah resirkulasi dan akibat vasodilatasi yang berhubungan dengan hiperemia
reaktif. Yang kedua adalah penundaan dan berhubungan dengan perubahan patologis di jaringan otak.
Tumor Otak
Pada tumor otak primer, kapiler-kapiler abnormal ditemukan pada banyak tumor ganas dan memiliki
fenestrasi selular, h
ubungan yang lebar, piknosis vesikel dan terlipatnya permukaan lamina.Metastase tumor memiliki properti
kapiler yang sama dengan jaringan derivatif. Perubahan ini pada dasarnya dari uptake isotop dan media
kontras yang lebih tinggi. Efek samping odem otak vasogenik yang sering mengiringi, pada metabolisme
dan fungsi otak akibat perubahan primer lingkungan neuronal, kolapsnya pembuluh darah mikro oleh
edema cairan, hipoksia jaringan dan efek selular dari serum protein yang berlebihan. Radioterapi juga
dapat mengubah BBB, perubahan dapat terlihat beberapa tahun setelah ekspos.
Infeksi SSP
Ada kehancuran BBB yang selektif sama dengan yang terjadi pada tumor otak. Leukosit melewati BBB dan
ada perubahan susunan dalam transpor glukosa. Ketika pengobatan efektif, antibiotik sangat sulit untuk
memasuki BBB karena BBB kembali normal.

Bloodbrain barrier

Part of a network of capillaries supplying brain cells

The astrocytes type 1 surrounding capillaries in the brain

A cortical microvessel stained for bloodbrain barrier protein ZO-1 Image: Nathan S. Ivey, PhD and Andrew G.
MacLean, PhD

The bloodbrain barrier (BBB) is a separation of circulating blood from the brain extracellular
fluid (BECF) in the central nervous system (CNS). It occurs along all capillaries and consists of tight
junctions around the capillaries that do not exist in normal circulation.Endothelial cells restrict the diffusion
of microscopic objects (e.g., bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF),
while allowing the diffusion of small hydrophobic molecules (O2, CO2, hormones). Cells of the barrier
actively transportmetabolic products such as glucose across the barrier with specific proteins. This barrier
also

Physiology

Schematic sketch showing constitution of blood vessels inside the brain

This "barrier" results from the selectivity of the tight junctions between endothelial cells in CNS vessels that
restricts the passage of solutes. At the interface between blood and the brain, endothelial cells are stitched
together by these tight junctions, which are composed of smaller subunits, frequently biochemical dimers,
that are transmembrane proteins such as occludin, claudins, junctional adhesion molecule (JAM), or
ESAM, for example. Each of these transmembrane proteins is anchored into the endothelial cells by
another protein complex that includes zo-1 and associated proteins.
The bloodbrain barrier is composed of high-density cells restricting passage of substances from the
bloodstream much more than endothelial cells in capillaries elsewhere in the body. Astrocyte cell
projections called astrocytic feet (also known as "glia limitans") surround the endothelial cells of the BBB,
providing biochemical support to those cells. The BBB is distinct from the quite similar bloodcerebrospinalfluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the bloodretinal
barrier, which can be considered a part of the whole realm of such barriers. [2]
Several areas of the human brain are not on the brain side of the BBB. These include the circumventricular
organs. Example of this include: the roof of the third and fourth ventricles; capillaries in the pineal gland on
the roof of the diencephalon and the pineal gland. The pineal gland secretes the
hormone melatonin "directly into the systemic circulation"[3], thus melatonin is not affected by the blood
brain barrier.[4]

[edit]Development
Originally, experiments in the 1920s showed that the bloodbrain barrier (BBB) was still immature in
newborns. The reason for this fallacy was a mistake in methodology (the osmotic pressure was too high
and the delicate embryonal capillary vessels were partially damaged). It was later shown in experiments
with a reduced volume of the injected liquids that the markers under investigation could not pass the BBB.
It was reported that those natural substances such as albumin, -1-fetoprotein or transferrin with elevated
plasma concentration in the newborn could not be detected outside of cells in the brain. The transporter Pglycoprotein exists already in the embryonal endothelium.[citation needed]

The measurement of brain uptake of acetamide, antipyrine, benzyl


alcohol, butanol, caffeine, cytosine, diphenyl hydantoin, ethanol, ethylene
glycol, heroin, mannitol, methanol,phenobarbital, propylene glycol, thiourea, and urea in ether-anesthetized
newborns vs. adult rabbits shows that newborn rabbit and adult rat brain endothelia are functionally similar
with respect to lipid-mediated permeability.[citation needed] These data confirmed no differences in permeability
could be detected between newborn and adult BBB capillaries. No difference in brain uptake of
glucose, amino acids, organic acids, purines, nucleosides, or choline was observed between adult and
newborn rabbits.[citation needed] These experiments indicate that the newborn BBB has restrictive properties
similar to that of the adult. In contrast to suggestions of an immature barrier in young animals, these studies
indicate that a sophisticated, selective BBB is operative at birth.

[edit]Pathophysiology
The bloodbrain barrier acts very effectively to protect the brain from many common bacterial infections.
Thus, infections of the brain are very rare. Infections of the brain that do occur are often very serious and
difficult to treat. Antibodies are too large to cross the bloodbrain barrier, and only certain antibiotics are
able to pass.[5] In some cases the pharmacon has to be administered directly into the Cerebrospinal fluid.
[citation needed]

However, drugs delivered directly to the CSF do not effectively penetrate into the brain tissue

itself, possibly due to the tortuous nature of the interstitial space in the brain. [5] The bloodbrain barrier
becomes more permeable during inflammation. This allows some antibiotics and phagocytes to move
across the BBB. However, this also allows bacteria and viruses to infiltrate the BBB. [5][6] An exception to the
bacterial exclusion is the diseases caused by spirochetes, such asBorrelia, which causes Lyme disease,
and Treponema pallidum, which causes syphilis. These harmful bacteria seem to breach the bloodbrain
barrier by physically tunneling through the blood vessel walls [citation needed].
There are also some biochemical poisons that are made up of large molecules that are too big to pass
through the bloodbrain barrier. This was especially important in primitive or medieval times when people
often ate contaminated food. Neurotoxins such as Botulinum in the food might affect peripheral nerves, but
the bloodbrain barrier can often prevent such toxins from reaching the central nervous system, where they
could cause serious or fatal damage.[7]

[edit]Drugs

targeting the brain

Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major
challenge to treatment of most brain disorders. In its neuroprotective role, the bloodbrain barrier functions
to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain.
Therapeutic molecules and antibodies that might otherwise be effective in diagnosis and therapy do not
cross the BBB in adequate amounts.
Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Modalities
for drug delivery/Dosage form through the BBB entail its disruption by osmoticmeans; biochemically by the
use of vasoactive substances such as bradykinin; or even by localized exposure to high-intensity focused

ultrasound (HIFU).[8] Other methods used to get through the BBB may entail the use of endogenous
transport systems, including carrier-mediated transporters such as glucose and amino acid carriers;
receptor-mediated transcytosisfor insulin or transferrin; and the blocking of active efflux transporters such
as p-glycoprotein. Methods for drug delivery behind the BBB include intracerebral implantation (such as
with needles) and convection-enhanced distribution. Mannitol can be used in bypassing the BBB.

[edit]Nanoparticles
Nanotechnology may also help in the transfer of drugs across the BBB.[9] Recently, researchers have been
trying to build liposomes loaded with nanoparticles to gain access through the BBB. More research is
needed to determine which strategies will be most effective and how they can be improved for patients
with brain tumors. The potential for using BBB opening to target specific agents to brain tumors has just
begun to be explored.
Delivering drugs across the bloodbrain barrier is one of the most promising applications of
nanotechnology in clinical neuroscience. Nanoparticles could potentially carry out multiple tasks in a
predefined sequence, which is very important in the delivery of drugs across the bloodbrain barrier.
A significant amount of research in this area has been spent exploring methods of nanoparticle-mediated
delivery of antineoplastic drugs to tumors in the central nervous system. For example,
radiolabeled polyethylene glycol coated hexadecylcyanoacrylate nanospheres targeted and accumulated in
a rat gliosarcoma.[10] However, this method is not yet ready for clinical trials, due to the accumulation of the
nanospheres in surrounding healthy tissue.
It should be noted that vascular endothelial cells and associated pericytes are often abnormal in tumors
and that the bloodbrain barrier may not always be intact in brain tumors. Also, the basement membrane is
sometimes incomplete. Other factors, such as astrocytes, may contribute to the resistance of brain tumors
to therapy.[11][12]

[edit]Peptides
Peptides are able to cross the blood-brain barrier (BBB) through various mechanisms, opening new
diagnostic and therapeutic avenues.[13]

[edit]Diseases

involving the bloodbrain barrier

[edit]Meningitis
Meningitis is an inflammation of the membranes that surround the brain and spinal cord (these membranes
are known as meninges). Meningitis is most commonly caused by infections with various pathogens,
examples of which are Streptococcus pneumoniae and Haemophilus influenzae. When the meninges are
inflamed, the bloodbrain barrier may be disrupted. [5]This disruption may increase the penetration of
various substances (including either toxins or antibiotics) into the brain. Antibiotics used to treat meningitis
may aggravate the inflammatory response of the central nervous system by releasing neurotoxins from the
cell walls of bacteria-like lipopolysaccharide (LPS).[14] Depending on the causative pathogen, whether it is

bacterial, fungal, or protozoan, treatment with third-generation or fourth-generation


cephalosporin or amphotericin B is usually prescribed.[15]

[edit]Brain

abscess

A brain or cerebral abscess, like other abscesses is caused by inflammation and collection of lymphatic
cells and infected material originating from a local or remote infection. Brain abscess is a rare, lifethreatening condition. Local sources may include infections of the ear, the oral cavity and teeth, the
paranasal sinuses, or epidural abscess. Remote sources may include infections in the lung, heart or
kidney. A brain abscess may also be caused by head trauma or as a complication of surgery. In children
cerebral abscesses are usually linked to congenital heart disease. [16] In most cases, 8-12 weeks of
antibacterial therapy is required.[5]

[edit]Epilepsy
Epilepsy is a common neurological disease that is characterized by recurrent and sometimes untreatable
seizures. Several clinical and experimental data have implicated the failure of bloodbrain barrier function
in triggering chronic or acute seizures. [17][18] Some studies implicate the interactions between a common
blood protein (albumin) and astrocytes.[19] These findings suggest that acute seizures are a predictable
consequence of disruption of the BBB by either artificial or inflammatory mechanisms. In addition,
expression of drug resistance molecules and transporters at the BBB are a significant mechanism of
resistance to commonly used anti-epileptic drugs.[20]

[edit]Multiple

sclerosis

Multiple sclerosis (MS) is considered to be an auto-immune and neurodegenerative disorder in which


the immune system attacks the myelin that protects and electrically insulates the neurons of the central
and peripheral nervous systems. Normally, a person's nervous system would be inaccessible to the white
blood cells due to the bloodbrain barrier. However,magnetic resonance imaging has shown that when a
person is undergoing an MS "attack," the bloodbrain barrier has broken down in a section of the brain or
spinal cord, allowingwhite blood cells called T lymphocytes to cross over and attack the myelin. It has
sometimes been suggested that, rather than being a disease of the immune system, MS is a disease of the
bloodbrain barrier.[21] A recent study suggests that the weakening of the bloodbrain barrier is a result of a
disturbance in the endothelial cells on the inside of the blood vessel, due to which the production of the
protein P-glycoprotein is not working well.[citation needed]
There are currently active investigations into treatments for a compromised bloodbrain barrier. It is
believed that oxidative stress plays an important role into the breakdown of the barrier. Anti-oxidants such
as lipoic acid may be able to stabilize a weakening bloodbrain barrier.[22]

[edit]Neuromyelitis

optica

Neuromyelitis optica, also known as Devic's disease, is similar to and is often confused with multiple
sclerosis. Among other differences from MS, a different target of the autoimmune response has been

identified. Patients with neuromyelitis optica have high levels of antibodies against
a protein called aquaporin 4 (a component of the astrocytic foot processes in the bloodbrain barrier). [23]

[edit]Late-stage

neurological trypanosomiasis (Sleeping sickness)

Late-stage neurological trypanosomiasis, or sleeping sickness, is a condition in which


trypanosoma protozoa are found in brain tissue. It is not yet known how the parasites infect the brain from
the blood, but it is suspected that they cross through the choroid plexus, a circumventricular organ.

[edit]Progressive

multifocal leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous


system that is caused by reactivation of a latent papovavirus (the JC polyomavirus) infection, that can cross
the BBB. It affects immune-compromised patients and it is usually seen with patients suffering from AIDS.

[edit]De

Vivo disease

De Vivo disease (also known as GLUT1 deficiency syndrome) is a rare condition caused by inadequate
transportation of the sugar, glucose, across the bloodbrain barrier, resulting in developmental delays and
other neurological problems. Genetic defects in glucose transporter type 1 (GLUT1) appears to be the
primary cause of De Vivo disease.[24][25]

[edit]Alzheimer's

Disease

Some new evidence indicates[26] that disruption of the bloodbrain barrier in Alzheimer's Disease patients
allows blood plasma containing amyloid beta (A) to enter the brain where the A adheres preferentially to
the surface of astrocytes. These findings have led to the hypotheses that (1) breakdown of the bloodbrain
barrier allows access of neuron-binding autoantibodies and soluble exogenous A42 to brain neurons and
(2) binding of these auto-antibodies to neurons triggers and/or facilitates the internalization and
accumulation of cell surface-bound A42 in vulnerable neurons through their natural tendency to clear
surface-bound autoantibodies via endocytosis. Eventually the astrocyte is overwhelmed, dies, ruptures,
and disintegrates, leaving behind the insoluble A42 plaque. Thus, in some patients, Alzheimer's disease
may be caused (or more likely, aggravated) by a breakdown in the bloodbrain barrier.[27]

[edit]HIV

encephalitis

It is believed[28] that latent HIV can cross the bloodbrain barrier inside circulating monocytes in the
bloodstream ("Trojan horse theory") within the first 14 days of infection. Once inside, these monocytes
become activated and are transformed into macrophages. Activated macrophages release virions into the
brain tissue proximate to brain microvessels. These viral particles likely attract the attention of sentinel
brain microglia and perivascular macrophages initiating an inflammatory cascade that may cause a series
of intracellular signaling in brain microvascular endothelial cells and damage the functional and structural
integrity of the BBB.[29] This inflammation is HIV encephalitis (HIVE). Instances of HIVE probably occur
throughout the course of AIDS and are a precursor for HIV-associated dementia (HAD). The premier model
for studying HIV and HIVE is the simian model.

[edit]Rabies
During lethal rabies infection of mice, the bloodbrain barrier (BBB) does not allow anti-viral immune cells
to enter the brain, the primary site of rabies virus replication. This aspect contributes to the pathogenicity of
the virus and artificially increasing BBB permeability promotes viral clearance. Opening the BBB during
rabies infection has been suggested as a possible novel approach to treating the disease, even though no
attempts have yet been made to determine whether or not this treatment could be successful.

Meningitis
Meningitis adalah radang selaput pelindung sistem saraf pusat. Penyakit ini dapat disebabkan oleh
mikroorganisme, luka fisik, kanker, atau obat-obatan tertentu. Meningitis adalah penyakit serius karena
letaknya dekat otak dan tulang belakang, sehingga dapat menyebabkan kerusakan kendali gerak, pikiran,
bahkan kematian.
Kebanyakan kasus meningitis disebabkan oleh mikroorganisme, seperti virus, bakteri, jamur,
atau pasilan yang menyebar dalam darah ke cairan otak. Daerah "sabuk penyakit meningitis"
di Afrika terbentang dari Senegal di barat ke Ethiopia di timur. Daerah ini ditinggali kurang lebih 300 juta
manusia. Pada 1996 terjadi wabah penyakit meningitis di mana 250.000 orang menderita penyakit ini
dengan 25.000 korban jiwa.

[sunting]MENINGITIS

PURULEN AKUT

Merupakan penyakit yang disebabkan oleh infeksi bakteri. Bakteri mendapatkan akses ke ruang ventriculosubarachnoid melalui berbagai jalur. Infeksi bisa berasal dari darah darah, dalam perjalanan septikemia
sistemik ataupun sebagai metastasis dari infeksi pada jantung,paru-paru, atau organ viscera lainnya.
Meningen juga dapat diserang melalui penyebaran langsung dari lesi septik pada tengkorak, tulang
belakang, atau parenkim dari sistem saraf (misalnya, sinusitis, otitis, osteomielitis, dan abses otak).
Organisme mungkin mendapatkan pintu masuk ke ruang subarachnoid melalui patah tulang gabungan dari
tulang tengkorak ataupun patah tulang sinus hidung atau mastoid, bisa juga setelah prosedur bedah saraf.
Akan tetapi infeksi pada meningen akibat lumbal pungsi jarang terjadi. Walaupun patomekanisme, gejala,
dan perjalanan klinis kebanyakan pasien dengan meningitis purulen akut adalah sama, akan tetapi
diagnosis dan terapi tetap perlu disesuaikan dengan hasil isolasi dan identifikasi organisme sumber infeksi.
[1]

Meningitis purulen akut dapat merupakan hasil dari infeksi dengan hampir semua bakteri patogen. Di

Amerika Serikat, Saat ini Streptococcus pneumonia menjadi penyumbang terbesar dengan sekitar satusetengah dari kasus keseluruhan MPA, sedangkan Neisseria meningitidis menyumbang sekitar
seperempat dari kasus.[1]

[sunting]Epidemiologi

MPA

Dalam beberapa tahun terakhir, telah terjadi peningkatan insiden kasus dimana tidak ada organisme dapat
diisolasi. Pasien-pasien ini sekarang membentuk tiga kategori besar dari meningitis purulen. Dalam
periode neonatal, kelompok streptokokus B dan Escherichia coli adalah agen penyebab paling umum.

Sedangkan pada meningitis bakteri anak-anak postneonatal sebanyak 60% disebabkan oleh Hemophilus
influenzae. Dampak penggunaan vaksin H. influenzae B telah secara dramatis merubah keadaan ini.
Dalam dekade terakhir telah terjadi penurunan 100 kali lipat dalam insiden MPA pada anak. Pada tahun
1997 ada kurang lebih 300 kasus yang dilaporkan. Saat ini secara keseluruhan tingkat kematian akibat
meningitis bakteri adalah sekarang 10% atau kurang. [

Meningitis
From Wikipedia, the free encyclopedia

Meningitis
Classification and external resources

Meninges of the central nervous system: dura mater, arachnoid, and pia
mater.

ICD-10

G00G03

ICD-9

320322

DiseasesDB

22543

MedlinePlus

000680

eMedicine

med/2613 emerg/309emerg/390

MeSH

D008581

Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known
collectively as the meninges.[1] The inflammation may be caused by infection with viruses, bacteria, or
other microorganisms, and less commonly by certain drugs.[2]Meningitis can be life-threatening because of
the inflammation's proximity to the brain and spinal cord; therefore the condition is classified as a medical
emergency.[1][3]

The most common symptoms of meningitis are headache and neck stiffness associated
with fever, confusion or altered consciousness, vomiting, and an inability to tolerate light (photophobia) or
loud noises (phonophobia). Sometimes, especially in small children, onlynonspecific symptoms may be
present, such as irritability and drowsiness. If a rash is present, it may indicate a particular cause of
meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied by a
characteristic rash.[1][4]
A lumbar puncture may be used to diagnose or exclude meningitis. This involves inserting a needle into
the spinal canal to extract a sample of cerebrospinal fluid (CSF), the fluid that envelops the brain and spinal
cord. The CSF is then examined in a medical laboratory.[3]The usual treatment for meningitis is the prompt
administration of antibiotics and sometimes antiviral drugs. In some situations,corticosteroid drugs can also
be used to prevent complications from excessive inflammation.[3][4] Meningitis can lead to serious long-term
consequences such as deafness, epilepsy, hydrocephalus and cognitive deficits, especially if not treated
quickly.[1][4] Some forms of meningitis (such as those associated with meningococci, Haemophilus
influenzae type B, pneumococci or mumps virus infections) may be prevented by immunization.[1]
Contents
[hide]

1 Signs and symptoms


o

1.1 Clinical features

1.2 Early complications


2 Causes

2.1 Bacterial

2.2 Viral

2.3 Fungal

2.4 Parasitic

2.5 Non-infectious
3 Mechanism
4 Diagnosis

4.1 Blood tests and imaging

4.2 Lumbar puncture

4.3 Postmortem
5 Prevention

5.1 Behavioral

5.2 Vaccination

5.3 Antibiotics
6 Treatment

6.1 Bacterial meningitis

6.2 Viral meningitis

6.3 Fungal meningitis


7 Prognosis
8 Epidemiology
9 History
10 References
11 External links

[edit]Signs

and symptoms

[edit]Clinical

features

Neck stiffness, Texas meningitis epidemic of 191112.

In adults, a severe headache is the most common symptom of meningitis occurring in almost 90% of
cases of bacterial meningitis, followed by nuchal rigidity (inability to flex the neck forward passively due to
increased neck muscle tone and stiffness).[5] The classic triad of diagnostic signs consists of nuchal rigidity,
sudden high fever, and altered mental status; however, all three features are present in only 4446% of all
cases of bacterial meningitis.[5][6] If none of the three signs is present, meningitis is extremely unlikely.
[6]

Other signs commonly associated with meningitis include photophobia (intolerance to bright light)

and phonophobia (intolerance to loud noises). Small children often do not exhibit the aforementioned
symptoms, and may only be irritable and look unwell.[1] In infants up to 6 months of age, bulging of
thefontanelle (the soft spot on top of a baby's head) may be present. Other features that might distinguish
meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin
color.[7][8]
Nuchal rigidity occurs in 70% of adult cases of bacterial meningitis. [6] Other signs of meningism include the
presence of positive Kernig's signor Brudzinski's sign. Kernig's sign is assessed with the person
lying supine, with the hip and knee flexed to 90 degrees. In a person with a positive Kernig's sign, pain
limits passive extension of the knee. A positive Brudzinski's sign occurs when flexion of the neck causes
involuntary flexion of the knee and hip. Although Kernig's sign and Brudzinski's sign are both commonly
used to screen for meningitis, thesensitivity of these tests is limited.[6][9] They do, however, have very
good specificity for meningitis: the signs rarely occur in other diseases. [6] Another test, known as the "jolt
accentuation maneuver" helps determine whether meningitis is present in those reporting fever and
headache. A person is asked to rapidly rotate his or her head horizontally; if this does not make the
headache worse, meningitis is unlikely.[6]
Meningitis caused by the bacterium Neisseria meningitidis (known as "meningococcal meningitis") can be
differentiated from meningitis with other causes by a rapidly spreadingpetechial rash which may precede
other symptoms.[7] The rash consists of numerous small, irregular purple or red spots ("petechiae") on the
trunk, lower extremities, mucous membranes, conjuctiva, and (occasionally) the palms of the hands or
soles of the feet. The rash is typically non-blanching: the redness does not disappear when pressed with a
finger or a glass tumbler. Although this rash is not necessarily present in meningococcal meningitis, it is
relatively specific for the disease; it does, however, occasionally occur in meningitis due to other bacteria.
[1]

Other clues as to the nature of the cause of meningitis may be the skin signs of hand, foot and mouth

disease and genital herpes, both of which are associated with various forms of viral meningitis. [10]

[edit]Early

complications

A severe case of meningococcal meningitis in which the petechial rash progressed to gangrene and
requiredamputation of all limbs. The person,Charlotte Cleverley-Bisman, survived the disease and became a poster
child for a meningitis vaccination campaign in New Zealand.

People with meningitis may develop additional problems in the early stages of their illness. These may
require specific treatment, and sometimes indicate severe illness or worse prognosis. The infection may
trigger sepsis, a systemic inflammatory response syndrome of fallingblood pressure, fast heart rate, high or
abnormally low temperature and rapid breathing. Very low blood pressure may occur early, especially but
not exclusively in meningococcal illness; this may lead to insufficient blood supply to other organs.
[1]

Disseminated intravascular coagulation, the excessive activation of blood clotting, may cause both the

obstruction of blood flow to organs and a paradoxical increase of bleeding risk. In meningococcal
disease, gangrene of limbs can occur.[1] Severe meningococcal and pneumococcal infections may result in
hemorrhaging of theadrenal glands, leading to Waterhouse-Friderichsen syndrome, which is often lethal.[11]
The brain tissue may swell, with increasing pressure inside the skull and a risk of swollen brain tissue
causing herniation. This may be noticed by a decreasing level of consciousness, loss of the pupillary light
reflex, and abnormal posturing.[4] Inflammation of the brain tissue may also obstruct the normal flow of CSF
around the brain (hydrocephalus).[4] Seizures may occur for various reasons; in children, seizures are
common in the early stages of meningitis (30% of cases) and do not necessarily indicate an underlying
cause.[3] Seizures may result from increased pressure and from areas of inflammation in the brain tissue.
[4]

Focal seizures (seizures that involve one limb or part of the body), persistent seizures, late-onset

seizures and those that are difficult to control with medication are indicators of a poorer long-term outcome.
[1]

The inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves
arising from the brain stem that supply the head and neck area and which control eye movement, facial
muscles and hearing, among other functions.[1][6] Visual symptoms and hearing loss may persist after an
episode of meningitis.[1] Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as
well as the formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness,
loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area in
the brain.[1][4]

[edit]Causes
Meningitis is usually caused by an infection by microorganisms. Most infections are due to viruses,
[6]

with bacteria, fungi, and protozoa being the next most common causes.[2] It may also result from various

non-infectious causes.[2] The term aseptic meningitis refers loosely to all cases of meningitis in which no
bacterial infection can be demonstrated. This is usually due to viruses, but it may be due to bacterial
infection that has already been partially treated, with disappearance of the bacteria from the meninges, or
by infection in a space adjacent to the meninges (e.g. sinusitis). Endocarditis (infection of the heart

valves with spread of small clusters of bacteria through the bloodstream) may cause aseptic meningitis.
Aseptic meningitis may also result from infection with spirochetes, a type of bacteria that
includes Treponema pallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme
disease). Meningitis may be encountered in cerebral malaria (malaria infecting the brain) or amoebic
meningitis, meningitis due to infection with amoebae such as Naegleria fowleri, as contracted from
freshwater sources.[2]

[edit]Bacterial
The types of bacteria that cause bacterial meningitis vary by age group. In premature
babies and newborns up to three months old, common causes are group B streptococci (subtypes III which
normally inhabit the vagina and are mainly a cause during the first week of life) and those that normally
inhabit the digestive tract such as Escherichia coli (carrying K1 antigen).Listeria monocytogenes (serotype
IVb) may affect the newborn and occurs in epidemics. Older children are more commonly affected
by Neisseria meningitidis (meningococcus),Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and
those under five by Haemophilus influenzae type B (in countries that do not offer vaccination).[1][3] In
adults, N. meningitidis and S. pneumoniae together cause 80% of all cases of bacterial meningitis, with
increased risk of L. monocytogenes in those over 50 years old.[3][4] Since the pneumococcal vaccine was
introduced, however, rates of pneumococcal meningitis have declined in both children and adults. [12]
Recent trauma to the skull gives bacteria in the nasal cavity the potential to enter the meningeal space.
Similarly, individuals with a cerebral shunt or related device (such as anextraventricular drain or Ommaya
reservoir) are at increased risk of infection through those devices. In these cases, infections
with staphylococci are more likely, as well as infections by pseudomonas and other Gram-negative bacilli.
[3]

The same pathogens are also more common in those with an impaired immune system.[1] In a small

proportion of people, an infection in the head and neck area, such as otitis media or mastoiditis, can lead to
meningitis.[3] Recipients of cochlear implants for hearing loss are at an increased risk of pneumococcal
meningitis.[13]
Tuberculous meningitis, meningitis due to infection with Mycobacterium tuberculosis, is more common in
those from countries where tuberculosis is common, but is also encountered in those with immune
problems, such as AIDS.[14]
Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or
acquired, or by disorders of the immune system.[15] Anatomical defects allow continuity between the
external environment and the nervous system. The most common cause of recurrent meningitis is a skull
fracture,[15] particularly fractures that affect the base of the skull or extend towards the sinuses and petrous
pyramids.[15] Approximately 59% of cases are due to such anatomical abnormalities, 36% due to immune
deficiencies (such ascomplement deficiency, which predisposes especially to recurrent meningococcal
meningitis), and 5% due to ongoing infections in areas adjacent to the meninges. [15]

[edit]Viral

Viruses that can cause meningitis include enteroviruses, herpes simplex virus type 2 (and less commonly
type 1), varicella zoster virus (known for causing chickenpox and shingles),mumps virus, HIV, and LCMV.
[10]

[edit]Fungal
There are a number of risk factors for fungal meningitis including the use of immunosuppressants (such as
after organ transplantation), HIV/AIDS,[16] and the loss of immunity associated with aging.[17] It is uncommon
in those with a normal immune system.[18] Symptom onset is typically more gradual with headaches and
fever being present for at least a couple of weeks before diagnosis. [17] The most common fungal meningitis
is cryptococcal meningitis due to Cryptococcus neoformans.[19] In Africa, cryptococcal meningitis is
estimated to be the most common cause of meningitis overall[20] where it accounts for 20-25% of AIDSrelated deaths in Africa.[21] Other common fungal agents include Histoplasma capsulatum, Coccidioides
immitis, Blastomyces dermatitidis, and Candida species.[17]

[edit]Parasitic
A parasitic cause is often assumed when there is a predominance of eosinophils (a type of white blood cell)
in the CSF. The most common parasites implicated are Angiostrongylus cantonensis, Gnathostoma
spinigerum, Schistosoma, as well as the
conditions cysticercosis, toxocariasis, baylisascariasis, paragonimiasis, and a number of rarer infections
and noninfective conditions.[22]

[edit]Non-infectious
Meningitis may occur as the result of several non-infectious causes: spread of cancer to the meninges
(malignant or neoplastic meningitis)[23] and certain drugs (mainly non-steroidal anti-inflammatory
drugs, antibiotics and intravenous immunoglobulins).[24] It may also be caused by several inflammatory
conditions such as sarcoidosis (which is then calledneurosarcoidosis), connective tissue disorders such
as systemic lupus erythematosus, and certain forms of vasculitis (inflammatory conditions of the blood
vessel wall) such asBehet's disease.[2] Epidermoid cysts and dermoid cysts may cause meningitis by
releasing irritant matter into the subarachnoid space.[2][15] Mollaret's meningitis is a syndrome of recurring
episodes of aseptic meningitis; it is thought to be caused by herpes simplex virus type 2.
Rarely, migraine may cause meningitis, but this diagnosis is usually only made when other causes have
been eliminated.[2]

[edit]Mechanism
The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect
the brain and spinal cord (the central nervous system). The pia mater is a very delicate impermeable
membrane that firmly adheres to the surface of the brain, following all the minor contours. The arachnoid
mater (so named because of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater.
The subarachnoid space separates the arachnoid and pia mater membranes, and is filled with

cerebrospinal fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is
attached to both the arachnoid membrane and the skull.
In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream or
through direct contact between the meninges and either the nasal cavity or the skin. In most cases,
meningitis follows invasion of the bloodstream by organisms that live upon mucous surfaces such as
the nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier
provided by the mucous surfaces. Once bacteria have entered the bloodstream, they enter
the subarachnoid space in places where thebloodbrain barrier is vulnerablesuch as the choroid plexus.
Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci; this
phenomenon is less common in adults.[1] Direct contamination of the cerebrospinal fluid may arise from
indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed a
tract with the subarachnoid space (see above); occasionally, congenital defects of the dura mater can be
identified.[1]
The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result
of bacterial infection but can rather largely be attributed to the response of theimmune system to the
entrance of bacteria into the central nervous system. When components of the bacterial cell membrane are
identified by the immune cells of the brain (astrocytesand microglia), they respond by releasing large
amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues to
participate in an immune response. The bloodbrain barrier becomes more permeable, leading
to "vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels). Large
numbers ofwhite blood cells enter the CSF, causing inflammation of the meninges, and leading
to "interstitial" edema (swelling due to fluid between the cells). In addition, the walls of the blood vessels
themselves become inflamed (cerebral vasculitis), which leads to a decreased blood flow and a third type
of edema, "cytotoxic" edema. The three forms of cerebral edema all lead to an increased intracranial
pressure; together with the lowered blood pressure often encountered in acute infection, this means that it
is harder for blood to enter the brain, andbrain cells are deprived of oxygen and
undergo apoptosis (automated cell death).[1]
It is recognized that administration of antibiotics may initially worsen the process outlined above, by
increasing the amount of bacterial cell membrane products released through the destruction of bacteria.
Particular treatments, such as the use of corticosteroids, are aimed at dampening the immune system's
response to this phenomenon.[1][4]

[edit]Diagnosis
CSF findings in different forms of meningitis[25]

Type of meningitis

Glucose

Protein

Cells

Acute bacterial

low

high

PMNs,
often > 300/mm

Acute viral

normal

normal or high

mononuclear,
< 300/mm

Tuberculous

low

high

mononuclear and
PMNs, < 300/mm

Fungal

low

high

< 300/mm

Malignant

low

high

usually
mononuclear

[edit]Blood

tests and imaging

In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. Creactive protein,complete blood count), as well as blood cultures.[3][26]
The most important test in identifying or ruling out meningitis is analysis of the cerebrospinal fluid
through lumbar puncture(LP, spinal tap).[27] However, lumbar puncture is contraindicated if there is a mass
in the brain (tumor or abscess) or theintracranial pressure (ICP) is elevated, as it may lead to brain
herniation. If someone is at risk for either a mass or raised ICP (recent head injury, a known immune
system problem, localizing neurological signs, or evidence on examination of a raised ICP),
a CT or MRI scan is recommended prior to the lumbar puncture. [3][26][28] This applies in 45% of all adult
cases.[4] If a CT or MRI is required before LP, or if LP proves difficult, professional guidelines suggest that
antibiotics should be administered first to prevent delay in treatment, [3] especially if this may be longer than
30 minutes.[26][28] Often, CT or MRI scans are performed at a later stage to assess for complications of
meningitis.[1]
In severe forms of meningitis, monitoring of blood electrolytes may be important; for
example, hyponatremia is common in bacterial meningitis, due to a combination of factors including
dehydration, the inappropriate excretion of the antidiuretic hormone (SIADH), or overly
aggressive intravenous fluid administration.[4][29]

[edit]Lumbar

puncture

Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs

A lumbar puncture is done by positioning the patient, usually lying on the side, applying local anesthetic,
and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF).
When this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The
pressure is normally between 6 and 18 cm water (cmH2O);[27] in bacterial meningitis the pressure is usually
elevated.[3][26] In cryptococcal meningitis, intracranial pressure is markedly elevated.[30] The initial
appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher
levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis.
[3]

The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content
and glucose level.[3] Gram stainingof the sample may demonstrate bacteria in bacterial meningitis, but
absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure
is reduced by a further 20% if antibiotics were administered before the sample was taken, and Gram
staining is also less reliable in particular infections such as listeriosis. Microbiological culture of the sample
is more sensitive (it identifies the organism in 7085% of cases) but results can take up to 48 hours to
become available.[3] The type of white blood cell predominantly present (see table) indicates whether
meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant),
[3]

although in the beginning of the disease this is not always a reliable indicator. Less

commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others. [22]
The concentration of glucose in CSF is normally above 40% of that in blood. In bacterial meningitis it is
typically lower; the CSF glucose level is therefore divided by the blood glucose(CSF glucose to serum
glucose ratio). A ratio 0.4 is indicative of bacterial meningitis;[27] in the newborn, glucose levels in CSF are
normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal. [3] High levels of lactate in
CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count. [27] If lactate
levels are less than 35 mg/dl and the person has not previously received antibiotics than this may rule out
bacterial meningitis.[31]
Various more specialized tests may be used to distinguish between various types of meningitis. A latex
agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria
meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not
encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic.
Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of
limited use unless other tests have been unhelpful. [3] Polymerase chain reaction (PCR) is a technique used
to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in
cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's
DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various
causes of viral meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for this).

[10]

Serology (identification of antibodies to viruses) may be useful in viral meningitis. [10] If tuberculous

meningitis is suspected, the sample is processed for Ziehl-Neelsen stain, which has a low sensitivity, and
tuberculosis culture, which takes a long time to process; PCR is being used increasingly.[14] Diagnosis of
cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for
cryptococcal antigen in blood or CSF is more sensitive, particularly in persons with AIDS. [32][33]
A diagnostic and therapeutic difficulty is the "partially treated meningitis", where there are meningitis
symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings
may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is
definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR). [10]

[edit]Postmortem

Histopathology of bacterial meningitis: autopsy case of a person with pneumococcal meningitis showing inflammatory
infiltrates of the pia materconsisting of neutrophil granulocytes (inset, higher magnification).

Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a
widespread inflammation of the pia mater and arachnoid layers of the meninges. Neutrophil
granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial
nerves and the spinal cord, may be surrounded with pus as may the meningeal vessels.[34]

[edit]Prevention
For some causes of meningitis, protection can be provided in the long term through vaccination, or in the
short term with antibiotics. Some behavioral measure may also be effective.

[edit]Behavioral
Bacterial and viral meningitis are contagious; however, neither are as contagious as the common
cold or flu.[35] Both can be transmitted through droplets of respiratory secretions during close contact such
as kissing, sneezing or coughing on someone, but cannot be spread by only breathing the air where a
person with meningitis has been.[35] Viral meningitis is typically caused by Enteroviruses, and is most
commonly spread through fecal contamination.[35] The risk of infection can be decreased by changing the
behavior that lead to transmission.

[edit]Vaccination

Since the 1980s, many countries have included immunization against Haemophilus influenzae type B in
their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of
meningitis in young children in those countries. In the countries where the disease burden is highest,
however, the vaccine is still too expensive.[36][37] Similarly, immunization against mumps has led to a sharp
fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of
mumps.[10]
Meningococcus vaccines exist against groups A, C, W135 and Y.[38] In countries where the vaccine for
meningococcus group C was introduced, cases caused by this pathogen have decreased substantially.[36] A
quadrivalent vaccine now exists, which combines all four vaccines. Immunization with the ACW135Y
vaccine against four strains is now a visa requirement for taking part in the Hajj.[39] Development of a
vaccine against group B meningococci has proved much more difficult, as its surface proteins (which would
normally be used to make a vaccine) only elicit a weak response from the immune system, or cross-react
with normal human proteins.[36][38] Still, some countries (New Zealand, Cuba, Norway andChile) have
developed vaccines against local strains of group B meningococci; some have shown good results and are
used in local immunization schedules.[38] In Africa, until recently, the approach for prevention and control of
meningococcal epidemics was based on early detection of the disease and emergency reactive mass
vaccination of the at-risk population with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines,
[40]

though the introduction of MenAfriVac (meningiococcus group A vaccine) has demonstrated

effectiveness in young people and has been described as a model for product development partnerships in
resource-limited settings.[41][42]
Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV),
which is active against seven common serotypes of this pathogen, significantly reduces the incidence of
pneumococcal meningitis.[36][43] The pneumococcal polysaccharide vaccine, which covers 23 strains, is only
administered in certain groups (e.g. those who have had a splenectomy, the surgical removal of the
spleen); it does not elicit a significant immune response in all recipients, e.g. small children. [43] Childhood
vaccination with Bacillus Calmette-Gurin has been reported to significantly reduce the rate of tuberculous
meningitis, but its waning effectiveness in adulthood has prompted a search for a better vaccine. [36]

[edit]Antibiotics
Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis.
In cases of meningococcal meningitis, prophylactic treatment of close contacts with antibiotics
(e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of contracting the condition, but does not
protect against future infections.[26][44] Resistance to rifampicin has been noted to increase after its use
which has caused some to recommend considering other agents. [44] While antibiotics are frequently used in
an attempt to prevent meningitis in those with a basilar skull fracture there is insufficient evidence to
determine if this is either a beneficial or harmful. [45] This applies in both those with and without a CSF leak.
[45]

[edit]Treatment

Meningitis is potentially life-threatening and has a high mortality rate if untreated; [3] delay in treatment has
been associated with a poorer outcome.[4] Thus treatment with wide-spectrum antibiotics should not be
delayed while confirmatory tests are being conducted. [28] If meningococcal disease is suspected in primary
care, guidelines recommend that benzylpenicillinbe administered before transfer to hospital.
[7]

Intravenous fluids should be administered if hypotension (low blood pressure) or shock are present.

[28]

Given that meningitis can cause a number of early severe complications, regular medical review is

recommended to identify these complications early,[28] as well as admission to an intensive care unit if
deemed necessary.[4]
Mechanical ventilation may be needed if the level of consciousness is very low, or if there is evidence
of respiratory failure. If there are signs of raised intracranial pressure, measures to monitor the pressure
may be taken; this would allow the optimization of the cerebral perfusion pressure and various treatments
to decrease the intracranial pressure with medication (e.g. mannitol).[4] Seizures are treated
with anticonvulsants.[4] Hydrocephalus (obstructed flow of CSF) may require insertion of a temporary or
long-term drainage device, such as acerebral shunt.[4]

[edit]Bacterial

meningitis

[edit]Antibiotics

Structural formula of ceftriaxone, one of the third-generation cefalosporin antibiotics recommended for the initial
treatment of bacterial meningitis.

Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the
results of the lumbar puncture and CSF analysis are known. The choice of initial treatment depends largely
on the kind of bacteria that cause meningitis in a particular place and population. For instance, in the
United Kingdom empirical treatment consists of a third-generation cefalosporin such
as cefotaxime orceftriaxone.[26][28] In the USA, where resistance to cefalosporins is increasingly found in
streptococci, addition of vancomycin to the initial treatment is recommended.[3][4][26] Chloramphenicol either
alone or in combination with ampicillin however appears to work equally well.[46]
Empirical therapy may be chosen on the basis of the person's age, whether the infection was preceded by
a head injury, whether the person has undergone recent neurosurgery and whether or not a cerebral shunt
is present.[3] In young children and those over 50 years of age, as well as those who are
immunocompromised, addition of ampicillin is recommended to cover Listeria monocytogenes.[3][26] Once
the Gram stain results become available, and the broad type of bacterial cause is known, it may be
possible to change the antibiotics to those likely to deal with the presumed group of pathogens. [3] The

results of the CSF culture generally take longer to become available (2448 hours). Once they do, empiric
therapy may be switched to specific antibiotic therapy targeted to the specific causative organism and its
sensitivities to antibiotics.[3] For an antibiotic to be effective in meningitis, it must not only be active against
the pathogenic bacterium, but also reach the meninges in adequate quantities; some antibiotics have
inadequate penetrance and therefore have little use in meningitis. Most of the antibiotics used in meningitis
have not been tested directly on people with meningitis inclinical trials. Rather, the relevant knowledge has
mostly derived from laboratory studies in rabbits.[3] Tuberculous meningitis requires prolonged treatment
with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous
meningitis are typically treated for a year or longer.[14]

[edit]Steroids
Adjuvant treatment with corticosteroids (usually dexamethasone) has shown some benefits such as a
reduction of hearing loss,[47] and better short term neurological outcomes[48] in adolescents and adults from
high income countries with low rates of HIV.[49] Some have research has found reduced rates of
death[49] while others have not.[48] They also appear to be beneficial in those with tuberculosis meningitis, at
least in those who are HIV negative.[50]
Professional guidelines therefore recommend the commencement of dexamethasone or a similar
corticosteroid just before the first dose of antibiotics is given, and continued for four days.[26][28] Given that
most of the benefit of the treatment is confined to those with pneumococcal meningitis, some guidelines
suggest that dexamethasone be discontinued if another cause for meningitis is identified. [3][26] The likely
mechanism is suppression of overactive inflammation.[51]
Adjuvant corticosteroids have a different role in children than in adults. Though the benefit of corticosteroids
has been demonstrated in adults as well as in children from high-income countries, their use in children
from low-income countries is not supported by the evidence; the reason for this discrepancy is not clear.
[48]

Even in high-income countries, the benefit of corticosteroids is only seen when they are given prior to

the first dose of antibiotics, and is greatest in cases of H. influenzae meningitis,[3][52] the incidence of which
has decreased dramatically since the introduction of the Hib vaccine. Thus, corticosteroids are
recommended in the treatment of pediatric meningitis if the cause is H. influenzae and only if given prior to
the first dose of antibiotics, whereas other uses are controversial. [3]

[edit]Viral

meningitis

Viral meningitis typically only requires supportive therapy; with most viruses responsible for causing
meningitis not amenable to specific treatment. Viral meningitis tends to run a more benign course than
bacterial meningitis. Herpes simplex virus and varicella zoster virus may respond to treatment with antiviral
drugs such as aciclovir, but there are no clinical trials that have specifically addressed whether this
treatment is effective.[10] Mild cases of viral meningitis can be treated at home with conservative measures
such as fluid, bedrest, and analgesics.[53]

[edit]Fungal

meningitis

Fungal meningitis, such as cryptococcal meningitis, is treated with long courses of highly
dosed antifungals, such as amphotericin B and flucytosine.[32][54] Raised intracranial pressure is common in
fungal meningitis, and frequent (ideally daily) lumbar punctures to relieve the pressure are recommended,
[32]

or alternatively a lumbar drain.[30]

[edit]Prognosis

Disability-adjusted life year for meningitis per 100,000 inhabitants in 2004.[55]


no data
<10
10-25
25-50
50-75
75-100
100-200

200-300
300-400
400-500
500-750
750-1000
>1000

Untreated, bacterial meningitis is almost always fatal. Viral meningitis, in contrast, tends to resolve
spontaneously and is rarely fatal. With treatment, mortality (risk of death) from bacterial meningitis depends
on the age of the patient and the underlying cause. Of newborns, 2030% may die from an episode of
bacterial meningitis. This risk is much lower in older children, whose mortality is about 2%, but rises again
to about 1937% in adults.[1][4] Risk of death is predicted by various factors apart from age, such as the
pathogen and the time it takes for the pathogen to be cleared from the cerebrospinal fluid, [1] the severity of
the generalized illness, decreased level of consciousness or abnormally low count of white blood cells in
the CSF.[4] Meningitis caused by H. influenzae and meningococci has a better prognosis compared to cases
caused by group B streptococci, coliforms and S. pneumonia.[1] In adults, too, meningococcal meningitis
has a lower mortality (37%) than pneumococcal disease. [4]
In children there are several potential disabilities which may result from damage to the nervous system
including: sensorineural hearing loss,epilepsy, learning and behavioral difficulties, as well as decreased
intelligence.[1] These occur in about 15% of survivors. [1] Some of the hearing loss may be reversible. [56] In
adults, 66% of all cases emerge without disability. The main problems are deafness (in 14%) andcognitive
impairment (in 10%).[4]

[edit]Epidemiology

Demography of meningococcalmeningitis.
meningitis belt
epidemic zones
sporadic cases only

Although meningitis is a notifiable disease in many countries, the exact incidence rate is unknown.
[10]

Bacterial meningitis occurs in about 3 people per 100,000 annually in Western countries. Population-

wide studies have shown that viral meningitis is more common, at 10.9 per 100,000, and occurs more often
in the summer. In Brazil, the rate of bacterial meningitis is higher, at 45.8 per 100,000 annually.[6] SubSaharan Africa has been plagued by large epidemics of meningococcal meningitis for over a century,
[57]

leading to it being labeled the "meningitis belt". Epidemics typically occur in the dry season (December

to June), and an epidemic wave can last two to three years, dying out during the intervening rainy seasons.
[58]

Attack rates of 100800 cases per 100,000 are encountered in this area, [59] which is poorly served

by medical care. These cases are predominantly caused by meningococci. [6] The largest epidemic ever
recorded in history swept across the entire region in 19961997, causing over 250,000 cases and 25,000
deaths.[60]
Meningococcal disease occurs in epidemics in areas where many people live together for the first time,
such as army barracks during mobilization, college campuses [1] and the annual Hajj pilgrimage.[39] Although
the pattern of epidemic cycles in Africa is not well understood, several factors have been associated with
the development of epidemics in the meningitis belt. They include: medical conditions (immunological
susceptibility of the population), demographic conditions (travel and large population displacements),
socioeconomic conditions (overcrowding and poor living conditions), climatic conditions (drought and dust
storms), and concurrent infections (acute respiratory infections). [59]
There are significant differences in the local distribution of causes for bacterial meningitis. For instance,
while N. meningitides groups B and C cause most disease episodes in Europe, group A is found in Asia
and continues to predominate in Africa, where it causes most of the major epidemics in the meningitis belt,
accounting for about 80% to 85% of documented meningococcal meningitis cases. [59]

Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known
as meningoencephalitis. Symptoms includeheadache, fever, confusion, drowsiness, and fatigue. More
advanced and serious symptoms include seizures or convulsions, tremors,hallucinations, and memory
problems.

Cause
Viral
Main article: Viral encephalitis

Viral encephalitis can occur either as a direct effect of an acute infection, or as one of the sequelae of a
latent infection. The most common causes of acute viral encephalitis are rabies virus, Herpes
simplex, poliovirus, measles virus, and JC virus.[1] Other causes include infection by flaviviruses such
as Japanese encephalitis virus, St. Louis encephalitis virus or West Nile virus, or by Togaviridae such
as Eastern equine encephalitis virus (EEE virus), Western equine encephalitis virus (WEE virus)
or Venezuelan equine encephalitis virus (VEE virus). Henipaviruses; Hendra (HeV) and Nipah (NiV), are
also known to cause viral encephalitis.

Bacterial and other


It can be caused by a bacterial infection, such as bacterial meningitis, spreading directly to the brain
(primary encephalitis), or may be a complication of a current infectious diseasesyphilis (secondary
encephalitis). Certain parasitic or protozoal infestations, such as toxoplasmosis, malaria, or primary
amoebic meningoencephalitis, can also cause encephalitis in people with compromised immune
systems. Lyme disease and/or Bartonella henselae may also cause encephalitis. Cryptococcus
neoformans is notorious for causing fungal encephalitis in the
immunocompromised. Streptococci, staphylococci and certain Gram-negative bacilli cause cerebritis prior
to the formation of a brain abscess.
Autoimmune disease may also cause encephalitis.[2]

Diagnosis
Adult patients with encephalitis present with acute onset of fever, headache, confusion, and sometimes
seizures. Younger children or infants may present irritability, poor appetite and fever.
Neurological examinations usually reveal a drowsy or confused patient. Stiff neck, due to the irritation of the
meninges covering the brain, indicates that the patient has either meningitis or meningoencephalitis.
Examination of the cerebrospinal fluid obtained by a lumbar puncture procedure usually reveals increased
amounts of protein and white blood cells with normal glucose, though in a significant percentage of
patients, the cerebrospinal fluid may be normal. CT scan often is not helpful, as cerebral abscess is
uncommon. Cerebral abscess is more common in patients with meningitis than encephalitis. Bleeding is
also uncommon except in patients with herpes simplex type 1 encephalitis. Magnetic resonance
imaging offers better resolution. In patients with herpes simplex encephalitis, electroencephalograph may
show sharp waves in one or both of the temporal lobes. Lumbar puncture procedure is performed only after
the possibility of prominent brain swelling is excluded by a CT scan examination. Diagnosis is often made
with detection of antibodies in the cerebrospinal fluid against a specific viral agent (such as herpes simplex
virus) or by polymerase chain reaction that amplifies the RNA or DNA of the virus responsible (such
as varicella zoster virus). Serological tests may show high antibody titre against the causative antigen.

Treatment

Treatment is usually symptomatic. Reliably tested specific antiviral agents are few in number
(e.g. acyclovir for herpes simplex virus) and are used with limited success in treatment of viral infection,
with the exception of herpes simplex encephalitis. In patients who are very sick, supportive treatment, such
as mechanical ventilation, is equally important. Corticosteroids (e.g., methylprednisolone) are used to
reduce brain swelling and inflammation. Sedatives may be needed for irritability or restlessness.
For Mycoplasma infection,parenteral tetracycline is given. Encephalitis due to Toxoplasma is treated by
giving a combination of pyrimethamine and sulphadimidine.

Prevention
Post-infectious encephalomyelitis complicating small pox vaccination is totally avoidable now as small pox
is now eradicated. Contraindication to Pertussis immunisation should be observed in patients with
encephalitis. An immunodeficient patient who has had contact with chicken pox virus should be
given prophylaxis with hyperimmune zoster immunoglobulin.

Encephalitis lethargica
Encephalitis lethargica is an atypical form of encephalitis which caused an epidemic from 1918 to 1930.
Those who survived sank into a semi-conscious state that lasted for decades. Neurologist Oliver
Sacks used the Parkinson's drug L-DOPA to revive those still alive in the late 1960s.
There have been only a small number of isolated cases in the years since, though in recent years a few
patients have shown very similar symptoms. The cause is now thought to be either a bacterial agent or an
autoimmune response following infection.

Limbic system encephalitis


In a large number of cases, called limbic encephalitis, the pathogens responsible for encephalitis attack
primarily the limbic system (a collection of structures at the base of the brain responsible for emotions and
many other basic functions).

Epidemiology
The incidence of acute encephalitis in Western countries is 7.4 cases per 100,000 population per year. In
tropical countries, the incidence is 6.34 per 100,000 per year.[3]

Herpes simplex encephalitis has an incidence of 24 per million population per year.[4]

Meningitis
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version
Meningitis is a bacterial infection of the membranes covering the brain and spinal cord (meninges).
See also:

Aseptic meningitis

Meningitis - Gram-negative

Meningitis - H. influenzae

Meningitis - meningococcal

Meningitis - pneumococcal

Meningitis - staphylococcal

Meningitis - tuberculous

Causes
The most common causes of meningitis are viral infections that usually get better without treatment.
However, bacterial meningitis infections are extremely serious, and may result in death or brain
damage, even if treated.
Meningitis may also be caused by:

Chemical irritation

Drug allergies

Fungi

Tumors

Types include:

Aseptic meningitis

Cryptococcal meningitis

Gram negative meningitis

H. influenza meningitis

Meningitis due to cancer (carcinomatous meningitis)

Meningococcal meningitis

Pneumococcal meningitis

Staphylococcal meningitis

Syphilitic aseptic meningitis

Tuberculous meningitis

Acute bacterial meningitis is a medical emergency, and requires immediate treatment in a hospital.
Viral meningitis is milder and occurs more often than bacterial meningitis. It usually develops in the
late summer and early fall, and often affects children and adults under age 30. Most infections occur
in children under age 5. Most viral meningitis is due to enteroviruses, which are viruses that also can
cause intestinal illness.
Many other types of viruses can cause meningitis. For example, viral meningitis can be caused by
herpes viruses, the same virus that can cause cold sores and genital herpes (although people with
cold sores or genital herpes are not at a greater risk of developing herpes meningitis).
Recently, West Nile virus, spread by mosquito bites, has become a cause of viral meningitis in most of
the United States.
Symptoms
Symptoms usually come on quickly, and may include:

Fever and chills

Mental status changes

Nausea and vomiting

Sensitivity to light (photophobia)

Severe headache

Stiff neck (meningismus)

Other symptoms that can occur with this disease:

Agitation

Bulging fontanelles

Decreased consciousness

Poor feeding or irritability in children

Rapid breathing

Unusual posture, with the head and neck arched backwards (opisthotonos)

Meningitis is an important cause of fever in children and newborns.

People cannot tell if they have bacterial or viral meningitis by how they feel, so they should seek
prompt medical attention.
Exams and Tests
Physical examination will usually show:

Fast heart rate

Fever

Mental status changes

Stiff neck

For any patient who is suspected of having meningitis, it is important to perform a lumbar puncture
("spinal tap"), in which spinal fluid (known as cerebrospinal fluid, or CSF) is collected for testing.
Tests that may be done include:

Blood culture

Chest x-ray

CSF examination for cell count, glucose, and protein

CT scan of the head

Gram stain, other special stains, and culture of CSF

Treatment
Doctors prescribe antibiotics for bacterial meningitis. The type will vary depending on the bacteria
causing the infection. Antibiotics are not effective in viral meningitis.
Other medications and intravenous fluids will be used to treat symptoms such as brain
swelling, shock, andseizures. Some people may need to stay in the hospital, depending on the
severity of the illness and the treatment needed.
Outlook (Prognosis)
Early diagnosis and treatment of bacterial meningitis is essential to prevent permanent neurological
damage. Viral meningitis is usually not serious, and symptoms should disappear within 2 weeks with
no lasting complications.
Possible Complications

Brain damage

Buildup of fluid between the skull and brain (subdural effusion)

Hearing loss

Hydrocephalus

Seizures

When to Contact a Medical Professional


If you think that you or your child has symptoms of meningitis, get emergency medical help
immediately. Early treatment is key to a good outcome.
Prevention

Haemophilus vaccine (HiB vaccine) in children will help prevent one type of meningitis.

The pneumococcal conjugate vaccine is now a routine childhood immunization and is very
effective at preventing pneumococcal meningitis.

Household members and others in close contact with people who have meningococcal
meningitis should receive preventive antibiotics to avoid becoming infected themselves.

The meningococcal vaccination is recommended for:

Adolescents ages 11 - 12 and adolescents entering high school (about age 15) who have not
already received the vaccination.

All college freshmen who have not been vaccinated and are living in dorms.

Children age 2 and older who do not have their spleen or who have other problems with their
immune system.

Those traveling to countries where diseases caused by meningococcus are very common
(ask your doctor).

Rabies
Rabies adalah penyakit infeksi tingkat akut pada susunan saraf pusat yang disebabkan
oleh virus rabies. [1] Penyakit ini bersifat zoonotik, yaitu dapat ditularkan dari hewan ke manusia. [1] Virus
rabies ditularkan ke manusia melalu gigitan hewan misalnya olehanjing, kucing, kera, rakun,
dan kelelawar. [1] Rabies disebut juga penyakit anjing gila.

[2]

[sunting]Etimologi
Kata rabies berasal dari bahasa Sanskerta kuno rabhas yang artinya melakukan kekerasan/kejahatan.
[3]

Dalam bahasa Yunani, rabies disebut Lyssa atau Lytaa yang artinya kegilaan.[3] Dalam bahasa Jerman,

rabies disebut tollwut yang berasal dari bahasa Indojerman Dhvar yang artinya merusak dan wut yang
artinya marah. [3] Dalam bahasa Prancis, rabies disebutrage berasal dari kata benda robere yang artinya
menjadi gila.[3]

[sunting]Sejarah
Rabies bukanlah penyakit baru dalam sejarah perabadan manusia.

[4]

Catatan tertulis mengenai perilaku

anjing yang tiba-tiba menjadi buas ditemukan pada Kode Mesopotamia yang ditulis 4000 tahun lalu serta
pada Kode Babilonia Eshunna yang ditulis pada 2300 SM.[4] Democritus pada 500 SM juga menuliskan
karakteristik gejala penyakit yang menyerupai rabies.[2]
Aristotle, pada 400 SM, menulis di Natural History of Animals edisi 8, bab 22 [5]

.... anjing itu menjadi gila. Hal ini menyebabkan mereka menjadi agresif dan
semua binatang yang digigitnya juga mengalami sakit yang sama.

Hippocrates, Plutarch, Xenophon, Epimarcus, Virgil, Horace, dan Ovid adalah orang-orang yang pernah
menyinggung karakteristik rabies dalam tulisan-tulisannya.

[5]

Celsius, seorangdokter di zaman Romawi,

mengasosiasikan hidrofobia (ketakutan terhadap air) dengan gigitan anjing, pada tahun 100
Masehi. [4] Cardanus, seorang penulis zaman Romawimenjelaskan sifat infeksi yang ada di air liur anjing
yang terkena rabies.[5] Pada penulis Romawi zaman itu mendeskripsikan rabies sebagai racun, yang mana
adalah kata Latin bagi virus. [5] Pliny dan Ovid adalah orang yang pertama menjelaskan penyebab lain dari
rabies, yang saat itu disebut cacing lidah anjing (dog tongue worm).[5] Untuk mencegah rabies di masa itu,
permukaan lidah yang diduga mengandung "cacing" dipotong. [5] Anggapan tersebut bertahan sampai abad
19, ketika akhirnya Louis Pasteur berhasil mendemonstrasikan penyebaran rabies dengan menumbuhkan
jaringan otak yang terinfeksi pada tahun 1885 [5] Goldwasser dan Kissling menemukan cara diagnosis
rabies secara modern pada tahun1958, yaitu dengan teknik antibodi imunofluoresens untuk
menemukan antigen rabies pada jaringan.[4]

[sunting]Penyebab
Rabies disebabkan oleh virus rabies yang masuk ke
keluarga Rhabdoviridae dan genus Lysavirus. [6] Karakteristik utama virus keluarga Rhabdoviridae adalah
hanya memiliki satu utas negatif RNA yang tidak bersegmen. [6] Virus ini hidup pada beberapa jenis hewan
yang berperan sebagai perantara penularan.

[7]

Spesies hewan perantara bervariasi pada berbagai

letak geografis. [7] Hewan-hewan yang diketahui dapat menjadi perantara rabies antara lain rakun (Procyon
lotor) dan sigung (Memphitis memphitis) di Amerika Utara, rubah merah (Vulpes vulpes) di Eropa, dan
anjing di Afrika, Asia, dan Amerika Latin. Afrika, Asia, dan Amerika Latin memiliki tingkat rabies yang masih
tinggi [7] Hewan perantara menginfeksi inang yang bisa berupa hewan lain atau manusia melalui gigitan.
[1]

[2]

Infeksi juga dapat terjadi melalui jilatan hewan perantara pada kulit yang terluka. [2][1] Setelah infeksi, virus

akan masuk melalui saraf-saraf menuju ke sumsum tulang belakang dan otak dan bereplikasi di
sana. [2] Selanjutnya virus akan berpindah lagi melalui saraf ke jaringan non saraf, misalnya kelenjar liur
dan masuk ke dalam air liur. [2] Hewan yang terinfeksi bisa mengalami rabies buas/ ganas ataupun rabies
jinak/ tenang. [8] [9] Pada rabies buas/ ganas, hewan yang terinfeksi tampak galak, agresif, menggigit dan

menelan segala macam barang, air liur terus menetes, meraung-raung gelisah kemudian
menjadi lumpuh dan mati. [8][9] Pada rabies jinak/tenang, hewan yang terinfeksi mengalami kelumpuhan
lokal atau kelumpuhan total, suka bersembunyi di tempat gelap, mengalami kejang dan sulit bernapas,
serta menunjukkan kegalakan[8][9]
Meskipun sangat jarang terjadi, rabies bisa ditularkan melalui penghirupan udara yang
tercemar virus rabies. [10] Dua pekerja laboratorium telah mengkonfirmasi hal ini setelah mereka terekspos
udara yang mengandung virus rabies.

[10]

Pada tahun 1950, dilaporkan dua kasus rabies terjadi pada

penjelajah gua di Frio Cave, Texas yang menghirup udara di mana ada jutaan kelelawar hidup di tempat
tersebut. [10] Mereka diduga tertular lewat udara karena tidak ditemukan sama sekali adanya tanda-tanda
bekas gigitan kelelawar. [10]

]Manifestasi

Klinis

Gejala rabies biasanya mulai timbul dalam waktu 30-50 hari setelah terinfeksi.

[11]

Masa inkubasi virus

hingga munculnya penyakit adalah 10-14 hari pada anjing tetapi bisa mencapai 9 bulan pada
manusia [1] Bila disebabkan oleh gigitan anjing, luka yang memiliki risiko tinggi meliputi infeksi
pada mukosa, luka di atas daerah bahu (kepala, muka, leher), luka pada jari tangan atau kaki, luka
padakelamin, luka yang lebar atau dalam, dan luka yang banyak.

[9]

Sedangkan luka dengan risiko rendah

meliputi jilatan pada kulit yang luka, garukan atau lecet, serta luka kecil di sekitar tangan, badan,
dan kaki. [9]
Gejala sakit yang akan dialami seseorang yang terinfeksi rabies meliputi 4 stadium:

[sunting]Stadium

[9]

prodromal

Dalam stadium prodomal sakit yang timbul pada penderita tidak khas, menyerupai infeksi virus pada
umumnya yang meliputi demam, sulit makan yang menuju taraf anoreksia, pusing dan pening (nausea),
dan lain sebagainya. [9]

[sunting]Stadium

sensoris

Dalam stadium sensori penderita umumnya akan mengalami rasa nyeri pada daerah luka gigitan, panas,
gugup, kebingungan, keluar banyak air liur (hipersalivasi), dilatasi pupil,hiperhidrosis, hiperlakrimasi.[9]

[sunting]Stadium

eksitasi

Pada stadium eksitasi penderita menjadi gelisah, mudah kaget, kejang-kejang setiap ada rangsangan dari
luar sehingga terjadi ketakutan pada udara (aerofobia), ketakutan padacahaya (fotofobia), dan ketakutan
air (hidrofobia).[9] Kejang-kejang terjadi akibat adanya gangguan daerah otak yang mengatur proses
menelan dan pernapasan. [8] Hidrofobia yang terjadi pada penderita rabies terutama karena adanya
rasa sakit yang luar biasa di kala berusaha menelan air

[sunting]Stadium

paralitik

[8]

Pada stadium paralitik setelah melalui ketiga stadium sebelumnya, penderita memasuki stadium paralitik
ini menunjukkan tanda kelumpuhan dari bagian atas tubuh ke bawah yang progresif.

[9]

Karena durasi penyebaran penyakit yang cukup cepat maka umumnya keempat stadium di atas tidak
dapat dibedakan dengan jelas. [9] Gejala-gejala yang tampak jelas pada penderita di antaranya adanya
nyeri pada luka bekas gigitan dan ketakutan pada air, udara, dan cahaya, serta suara yang
keras. [9] Sedangkan pada hewan yang terinfeksi, gelaja yang tampak adalah dari jinak menjadi ganas,
hewan-hewan peliharaan menjadi liar dan lupa jalan pulang, serta ekor dilengkungkan di bawah perut. [9]

[sunting]Diagnosis
Jika seseorang digigit hewan, maka hewan yang menggigit harus diawasi.

[12]

Satu-satunya uji yang

menghasilkan keakuratan 100% terhadap adanya virus rabies adalah dengan uji antibodi fluoresensi
langsung (direct fluorescent antibody test/ dFAT) pada jaringan otak hewan yang terinfeksi.
digunakan lebih dari 40 tahun dan dijadikan standar dalam diagnosis rabies.

[12][13]

[12]

Uji ini telah

Prinsipnya adalah ikatan

antara antigen rabies dan antibodi spesifik yang telah dilabel dengan senyawa fluoresens yang akan
berpendar sehingga memudahkan deteksi [12] Namun, kelemahannya adalah subjek uji harus disuntik
mati terlebih dahulu (eutanasia) sehingga tidak dapat digunakan terhadap manusia. [12] Akan tetapi, uji
serupa tetap dapat dilakukan menggunakan serum, cairan sumsum tulang belakang, atau air liur penderita
walaupun tidak memberikan keakuratan 100%.

[12]

Selain itu, diagnosis dapat juga dilakukan

dengan biopsi kulit leher atau sel epitel kornea mata walaupun hasilnya tidak terlalu tepat sehingga
nantinya akan dilakukan kembali diagnosis post mortemsetelah hewan atau manusia yang terinfeksi
meninggal. [13]

[sunting]Penanganan
Bila terinfeksi rabies, segera cari pertolongan medis.

[14]

Rabies dapat diobati, namun harus dilakukan

sedini mungkin sebelum menginfeksi otak dan menimbulkan gejala. [14][11] Bila gejala mulai terlihat, tidak ada
pengobatan untuk menyembuhkan penyakit ini.

[14]

Kematian biasanya terjadi beberapa hari setelah

terjadinya gejala pertama.[14]


Jika terjadi kasus gigitan oleh hewan yang diduga terinfeksi rabies atau berpotensi rabies
(anjing, sigung, rakun, rubah, kelelawar) segera cuci luka dengan sabun atau pelarut lemaklain di
bawah air mengalir selama 10-15 menit lalu beri antiseptik alkohol 70% atau betadin. [9] Orang-orang yang
belum diimunisasi selama 10 tahun terakhir akan diberikan suntikantetanus. [15] Orang-orang yang belum
pernah mendapat vaksin rabies akan diberikan suntikan globulin imun rabies yang dikombinasikan dengan
vaksin. [15] Separuh dari dosisnya disuntikkan di tempat gigitan dan separuhnya disuntikan ke otot,
biasanya di daerah pinggang. [11] Dalam periode 28 hari diberikan 5 kali suntikan.

[11]

Suntikan pertama

untuk menentukan risiko adanya virus rabies akibat bekas gigitan. [11] Sisa suntikan diberikan pada hari ke
3, 7, 14, dan 28.[11] Kadang-kadang terjadi rasa sakit, kemerahan, bengkak, atau gatal pada tempat
penyuntikan vaksin. [15]

[sunting]Pencegahan

Pencegahan rabies pada manusia harus dilakukan sesegera mungkin setelah terjadi gigitan
oleh hewan yang berpotensi rabies, karena bila tidak dapat mematikan (letal)

[1]

Langkah-langkah untuk mencegah rabies bisa diambil sebelum terjangkit virus atau segera setelah terkena
gigitan [7] Sebagai contoh, vaksinasi bisa diberikan kapada orang-orang yang berisiko tinggi terhadap
terjangkitnya virus, yaitu: [16]

Dokter hewan. [16]

Petugas laboratorium yang menangani hewan-hewan yang terinfeksi.

Orang-orang yang menetap atau tinggal lebih dari 30 hari di daerah yang rabies pada anjing

[16]

banyak ditemukan [7]

Para penjelajah gua kelelawar. [10]

Vaksinasi idealnya dapat memberikan perlindungan seumur hidup.

[17]

Tetapi seiring berjalannya waktu

kadar antibodi akan menurun, sehingga orang yang berisiko tinggi terhadap rabies harus mendapatkan
dosis booster vaksinasi setiap 3 tahun. [1] Pentingnya vaksinasi rabies terhadap hewan peliharaan seperti
anjing juga merupakan salah satu cara pencegahan yang harus diperhatikan.

[11]

Prognosis
Treatment after exposure (receiving the vaccines), PEP, is highly successful in preventing the disease
if administered promptly, in general within 10 days of infection. Begun with little or no delay, PEP is
100% effective against rabies.[11] In the case of significant delay in administering PEP, the treatment
still has a chance of success.[27]
In unvaccinated humans, rabies is usually fatal after neurological symptoms have developed, but
prompt postexposure vaccination may prevent the virus from progressing. Rabies kills around 55,000
people a year, mostly in Asia and Africa.[3]
Survival data using the Milwaukee protocol are available from the rabies registry.[37]
[edit]Epidemiology

Transmission
Main article: Rabies transmission
Any warm-blooded animal, including humans, may become infected with the rabies virus and develop
symptoms, although birds have only been known to be infected in experiments. [38] The virus has even
been adapted to grow in cells of poikilothermic ("cold-blooded") vertebrates.[39][40] Most animals can be
infected by the virus and can transmit the disease to humans. Infected bats,[41]
[42]
monkeys,raccoons, foxes, skunks, cattle, wolves, coyotes, dogs, mongooses (normally yellow
mongoose)[43]or cats present the greatest risk to humans.
Rabies may also spread through exposure to infected domestic farm
animals, groundhogs, weasels,bears, and other wild carnivores. Small rodents, such as squirrels,
hamsters, guinea pigs, gerbils, chipmunks, rats, and mice, and lagomorphs, such as rabbits and

hares, are almost never found to be infected with rabies and are not known to transmit rabies to
humans.[44] The Virginia opossum is resistant but not immune to rabies.[45]
The virus is usually present in the nerves and saliva of a symptomatic rabid animal.[46][47] The route
of infection is usually, but not always, by a bite. In many cases, the infected animal is exceptionally
aggressive, may attack without provocation, and exhibits otherwise uncharacteristic behavior.[48]
Transmission between humans is extremely rare. A few cases have been recorded through transplant
surgery.[49]
After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels
along the nerves toward the central nervous system.[50] During this phase, the virus cannot be easily
detected within the host, and vaccination may still confer cell-mediated immunity to prevent
symptomatic rabies. When the virus reaches the brain, it rapidly causesencephalitis, the prodromal
phase, and is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is
almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord, producing
transverse myelitis.[51][52]
[edit]Prevalence
Main article: Prevalence of rabies
The rabies virus survives in widespread, varied, rural fauna reservoirs. It is present in the animal
populations of almost every country in the world, except in Australia and New Zealand. [53]Australian
bat lyssavirus (ABLV) discovered in 1996 is similar to rabies, and is believed to be prevalent in native
bat populations. In some countries, such as those in western Europe and Oceania, rabies is
considered to be prevalent among bat populations only.[citation needed]
In Asia, parts of the Americas, and large parts of Africa, dogs remain the principal host. Mandatory
vaccination of animals is less effective in rural areas. Especially in developing countries, pets may not
be privately kept and their destruction may be unacceptable. Oral vaccines can be safely distributed in
baits, a practice that has successfully reduced rabies in rural areas of Canada, France, and the United
States. In Montral, Canada, baits are successfully used on raccoons in the Mont-Royal Park area.
Vaccination campaigns may be expensive, and cost-benefit analysis suggests baits may be a costeffective method of control.[54]
An estimated 55,000 human deaths occur annually from rabies worldwide, with about 31,000 in Asia
and 24,000 in Africa.[3] India has the highest rate of human rabies in the world, primarily because of
stray dogs,[55] whose number has greatly increased since a 2001 law forbade the killing of dogs.
[56]
20,000 people are estimated to die every year from rabies in India more than a third of the
global toll.[56] As of 2007, Vietnam had the second-highest rate, followed by Thailand; in these
countries, the virus is primarily transmitted through canines (feral dogs and other wild canine species).
[57]
Another source of rabies in Asia is the pet boom. In 2006 China introduced the "one-dog policy"
in Beijing to control the problem.[58]
Rabies is common among wild animals in the US. Bats, raccoons, skunks and foxes account for
almost all reported cases (98% in 2009). Rabid bats are found in all 48 contiguous states. Other
reservoirs are more limited geographically; for example, the raccoon rabies virus variant is only found
in a relatively narrow band along the East Coast. Due to a high public awareness of the virus, efforts
at vaccination of domestic animals and curtailment of feral populations, and availability
of postexposure prophylaxis, incidents of rabies in humans are very rare. A total of 49 cases of the

disease were reported in the country in 1995-2011; of these, 11 are thought to have been acquired
abroad. Almost all domestically acquired cases are attributed to bat bites. [59]

Virology
The rabies virus is the type species of the Lyssavirus genus, in the family Rhabdoviridae,
order Mononegavirales. Lyssaviruses have helical symmetry, with a length of about 180 nm and a
cross-section of about 75 nm.[1] These viruses are enveloped and have a singlestranded RNAgenome with negative sense. The genetic information is packed as
a ribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. The RNA
genome of the virus encodes five genes whose order is highly conserved: nucleoprotein (N),
phosphoprotein (P), matrix protein (M), glycoprotein (G), and the viral RNA polymerase (L). [60]
Once within a muscle or nerve cell, the virus undergoes replication. The trimeric spikes on the exterior
of the membrane of the virus interact with a specific cell receptor, the most likely one being the
acetylcholine receptor. The cellular membrane pinches in a procession known aspinocytosis and
allows entry of the virus into the cell by way of an endosome. The virus then uses the acidic
environment of that endosome and binds to its membrane simultaneously, releasing its five proteins
and single strand RNA into the cytoplasm.[27]
The L protein then transcribes five mRNA strands and a positive strand of RNA all from the original
negative strand RNA using free nucleotides in the cytoplasm. These five mRNA strands are then
translated into their corresponding proteins (P, L, N, G and M proteins) at free ribosomes in the
cytoplasm. Some proteins require post-translative modifications. For example, the G protein travels
through the roughendoplasmic reticulum, where it undergoes further folding, and is then transported
to the Golgi apparatus, where a sugar group is added to it (glycosylation).[27]
Where there are enough proteins, the viral polymerase will begin to synthesize new negative strands
of RNA from the template of the positive strand RNA. These negative strands will then form
complexes with the N, P, L and M proteins and then travel to the inner membrane of the cell, where a
G protein has embedded itself in the membrane. The G protein then coils around the N-P-L-M
complex of proteins taking some of the host cell membrane with it, which will form the new outer
envelope of the virus particle. The virus then buds from the cell. [27]
From the point of entry, the virus is neurotropic, traveling quickly along the neural pathways into
the central nervous system, and then to other organs.[2] The salivary glands receive high
concentrations of the virus, thus allowing further transmission.