Blood Brain Barrier

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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, sel-sel 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

description

BBB

Transcript of Blood Brain Barrier

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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, sel-sel 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.

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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.

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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)

 

PERUBAHAN PADA BBB1.      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.

2.      EpilepsiPeningkatan 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.

3.      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.

4.      Tumor OtakPada tumor otak primer, kapiler-kapiler abnormal ditemukan pada banyak tumor ganas dan memiliki fenestrasi selular, hubungan 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.

5.      Infeksi SSPAda 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.

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Blood–brain barrier

Part of a network of capillaries supplying brain cells

The astrocytes type 1 surrounding capillaries in the brain

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

MacLean, PhD

The blood–brain 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

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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 blood–brain 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 blood–cerebrospinal-

fluid barrier, which is a function of the choroidal cells of the choroid plexus, and from the blood–retinal

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 blood–brain 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, α-1-fetoprotein or transferrin with elevated

plasma concentration in the newborn could not be detected outside of cells in the brain. The transporter P-

glycoprotein exists already in the embryonal endothelium.[citation needed]

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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 blood–brain 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 blood–brain 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 blood–brain 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 blood–brain

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 blood–brain 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 blood–brain 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 blood–brain 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

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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 blood–brain 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 blood–brain 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 blood–brain 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 blood–brain 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 blood–brain 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

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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, life-

threatening 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 blood–brain 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 blood–brain barrier. However,magnetic resonance imaging has shown that when a

person is undergoing an MS "attack," the blood–brain 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

blood–brain barrier.[21] A recent study suggests that the weakening of the blood–brain 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 blood–brain 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 blood–brain 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

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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 blood–brain 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 blood–brain 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 blood–brain barrier in Alzheimer's Disease patients

allows blood plasma containing amyloid beta (Aβ) to enter the brain where the Aβ adheres preferentially to

the surface of astrocytes. These findings have led to the hypotheses that (1) breakdown of the blood–brain

barrier allows access of neuron-binding autoantibodies and soluble exogenous Aβ42 to brain neurons and

(2) binding of these auto-antibodies to neurons triggers and/or facilitates the internalization and

accumulation of cell surface-bound Aβ42 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 Aβ42 plaque. Thus, in some patients, Alzheimer's disease

may be caused (or more likely, aggravated) by a breakdown in the blood–brain barrier. [27]

[edit]HIV encephalitis

It is believed[28] that latent HIV can cross the blood–brain 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.

Page 10: Blood Brain Barrier

[edit]Rabies

During lethal rabies infection of mice, the blood–brain 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.

MeningitisMeningitis 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 ventriculo-

subarachnoid 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 satu-

setengah 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.

Page 11: Blood Brain Barrier

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.[

MeningitisFrom Wikipedia, the free encyclopedia

Meningitis

Classification and external resources

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

mater.

ICD-10 G 00 –G 03

ICD-9 320–322

DiseasesDB 22543

MedlinePlus 000680

eMedicine med/2613 emerg/309 emerg/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]

Page 12: Blood Brain Barrier

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

o 1.2 Early complications

2 Causes

o 2.1 Bacterial

o 2.2 Viral

o 2.3 Fungal

o 2.4 Parasitic

o 2.5 Non-infectious

3 Mechanism

4 Diagnosis

o 4.1 Blood tests and imaging

o 4.2 Lumbar puncture

o 4.3 Postmortem

5 Prevention

o 5.1 Behavioral

o 5.2 Vaccination

o 5.3 Antibiotics

6 Treatment

Page 13: Blood Brain Barrier

o 6.1 Bacterial meningitis

o 6.2 Viral meningitis

o 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 1911–12.

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 44–46% 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

Page 14: Blood Brain Barrier

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

Page 15: Blood Brain Barrier

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]

Page 16: Blood Brain Barrier

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 AIDS-

related 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

Page 17: Blood Brain Barrier

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 asBehçet'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 theblood–brain barrier is vulnerable—such 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

Page 18: Blood Brain Barrier

amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues to

participate in an immune response. The blood–brain 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/mm³

Acute viral normal normal or high

mononuclear,< 300/mm³

Tuberculous low high mononuclear andPMNs, < 300/mm³

Fungal low high < 300/mm³

Malignant low high usuallymononuclear

[edit]Blood tests and imaging

In someone suspected of having meningitis, blood tests are performed for markers of inflammation (e.g. C-

reactive protein,complete blood count), as well as blood cultures.[3][26]

Page 19: Blood Brain Barrier

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 70–85% of cases) but results can take up to 48 hours to

Page 20: Blood Brain Barrier

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

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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

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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-Guérin 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

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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 (24–48 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

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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

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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, 20–30% 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 19–37% 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 (3–7%) 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] Sub-

Saharan 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

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to June), and an epidemic wave can last two to three years, dying out during the intervening rainy seasons.[58] Attack rates of 100–800 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 1996–1997, 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]

EncephalitisEncephalitis 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

ViralMain 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

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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.

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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 2–4 per million population per year. [4]

MeningitisEmail this page to a friend Share on facebook Share on twitter Bookmark & Share Printer-friendly versionMeningitis 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

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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

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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

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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).

RabiesRabies 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]

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“ .... 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. [2]

[1] 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

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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: [9]

[sunting]Stadium 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 [8]

[sunting]Stadium paralitik

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

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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. [12] Uji ini telah

digunakan lebih dari 40 tahun dan dijadikan standar dalam diagnosis rabies. [12][13] 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. [16]

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

TransmissionMain 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

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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]PrevalenceMain 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 Montréal, 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 cost-effective 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 single-stranded 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

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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.