Disease that causes acute encephalitis



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Rabies (pronounced /ˈreɪbiːz/. From Latin: rabies) is a viral disease that causes acute encephalitis (inflammation of the brain) in warm-blooded animals.[1] It is zoonotic (i.e., transmitted by animals), most commonly by a bite from an infected animal but occasionally by other forms of contact. Rabies is almost invariably fatal if post-exposure prophylaxis is not administered prior to the onset of severe symptoms. The rabies virus infects the central nervous system, ultimately causing disease in the brain and death. The early symptoms of rabies in people are similar to that of many other illnesses, including fever, headache, and general weakness or discomfort. As the disease progresses, more specific symptoms appear and may include insomnia, anxiety, confusion, slight or partial paralysis, excitation, hallucinations, agitation, hypersalivation (increase in saliva), difficulty swallowing, and hydrophobia (fear of water). Death usually occurs within days of the onset of these symptoms.

The rabies virus travels to the brain by following the peripheral nerves. The incubation period of the disease is usually a few months in humans, depending on the distance the virus must travel to reach the central nervous system.[2] Once the rabies virus reaches the central nervous system and symptoms begin to show, the infection is effectively untreatable and usually fatal within days.

Early-stage symptoms of rabies are malaise, headache and fever, progressing to acute pain, violent movements, uncontrolled excitement, depression, and hydrophobia.[1] Finally, the patient may experience periods of mania and lethargy, eventually leading to coma. The primary cause of death is usually respiratory insufficiency.[2] Worldwide, the vast majority of human rabies cases (approximately 97%) come from dog bites.[3] In the United States, however, animal control and vaccination programs have effectively eliminated domestic dogs as reservoirs of rabies.[4] In several countries, including the United Kingdom, Estonia and Japan, rabies carried by animals that live on the ground has been eradicated entirely. Concerns exist about airborne and mixed-habitat animals including bats. Bats in the U.K. and in some other countries carry European Bat Lyssavirus 1 and European Bat Lyssavirus 2. The symptoms of these viruses are similar to those of rabies and so the viruses are both known as bat rabies. An unvaccinated Scottish bat handler died from an EBLV infection in 2002[2].

The economic impact is also substantial, as rabies is a significant cause of death of livestock in some countries.



Signs and symptoms

The period between infection and the first flu-like symptoms is normally two to twelve weeks, but can be as long as two years. Soon after, the symptoms expand to slight or partial paralysis, cerebral dysfunction, anxiety, insomnia, confusion, agitation, abnormal behavior, paranoia, terror, hallucinations, progressing to delirium.[2][5] The production of large quantities of saliva and tears coupled with an inability to speak or swallow are typical during the later stages of the disease; this can result in hydrophobia, in which the patient has difficulty swallowing because the throat and jaw become slowly paralyzed, shows panic when presented with liquids to drink, and cannot quench his or her thirst.

Death almost invariably results two to ten days after first symptoms; the few humans who are known to have survived the disease were all left with severe brain damage.[6] In 2005, the first patient was treated with the Milwaukee protocol,[7] and an intention to treat analysis has since found that this protocol has a survival rate of about 8%.[8]

Virology

TEM micrograph with numerous rabies virions (small, dark grey, rodlike particles) and Negri bodies (the larger pathognomonic cellular inclusions of rabies infection).

The rabies virus is the type species of the Lyssavirus genus, which encompasses other similar viruses. Lyssaviruses have helical symmetry, with a length of about 180 nm and a cross-sectional diameter of about 75 nm.[1] These viruses are enveloped and have a single stranded RNA genome with negative-sense. The genetic information is packaged 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).[9]

From the point of entry, the virus is neurotropic, traveling quickly along the neural pathways into the central nervous system (CNS), and then further into other organs.[2] The salivary glands receive high concentrations of the virus thus allowing further transmission.

Diagnosis

The reference method for diagnosing rabies is by performing PCR or viral culture on brain samples taken after death. The diagnosis can also be reliably made from skin samples taken before death.[10] It is also possible to make the diagnosis from saliva, urine and cerebrospinal fluid samples, but this is not as sensitive. Inclusion bodies called Negri bodies are 100% diagnostic for rabies infection, but are found in only about 80% of cases.[1] If possible, the animal from which the bite was received should also be examined for rabies.[11]

The differential diagnosis in a case of suspected human rabies may initially include any cause of encephalitis, particularly infection with viruses such as herpesviruses, enteroviruses, and arboviruses (e.g., West Nile virus). The most important viruses to rule out are herpes simplex virus type 1, varicella-zoster virus, and (less commonly) enteroviruses, including coxsackieviruses, echoviruses, polioviruses, and human enteroviruses 68 to 71.[12] In addition, consideration should be given to the local epidemiology of encephalitis caused by arboviruses belonging to several taxonomic groups, including eastern and western equine encephalitis viruses, St. Louis encephalitis virus, Powassan virus, the California encephalitis virus serogroup, and La Crosse virus.[citation needed]

New causes of viral encephalitis are also possible, as was evidenced by the recent outbreak in Malaysia of some 300 cases of encephalitis (mortality rate, 40%) caused by Nipah virus, a newly recognized paramyxovirus.[13] Similarly, well-known viruses may be introduced into new locations, as is illustrated by the recent outbreak of encephalitis due to West Nile virus in the eastern United States.[14] Epidemiologic factors (e.g., season, geographic location, and the patient’s age, travel history, and possible exposure to animal bites, rodents, and ticks) may help direct the diagnostic workup.

Cheaper rabies diagnosis will be possible for low-income settings: accurate rabies diagnosis can be done at a tenth of the cost of traditional testing using basic light microscopy techniques.[15]

Prevention

Eliminating rabies in dogs


Rabies is a vaccine-preventable disease. The most cost-effective strategy for preventing rabies in people is by eliminating rabies in dogs through vaccination. Vaccination of animals (mostly dogs) has reduced the number of human (and animal) rabies cases in several countries, particularly in Latin America. However, recent increases in human rabies deaths in parts of Africa, Asia and Latin America suggest that rabies is re-emerging as a serious public health issue.

Preventing human rabies through control of domestic dog rabies is a realistic goal for large parts of Africa and Asia, and is justified financially by the future savings of discontinuing post-exposure prophylaxis for people.


Preventive immunization in people


Safe, effective vaccines also exist for human use. Pre-exposure immunization in people is recommended for travellers to high-risk areas in rabies-affected countries, and for people in certain high-risk occupations such as laboratory workers dealing with live rabies virus and other lyssaviruses, and veterinarians and animal handlers in rabies-affected areas. As children are at particular risk, their immunization could be considered if living in or visiting high risk areas.

All human cases of rabies were fatal until a vaccine was developed in 1885 by Louis Pasteur and Émile Roux. Their original vaccine was harvested from infected rabbits, from which the virus in the nerve tissue was weakened by allowing it to dry for five to ten days.[16] Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines.[17] The human diploid cell rabies vaccine was started in 1967; however, a new and less expensive purified chicken embryo cell vaccine and purified vero cell rabies vaccine are now available.[11] A recombinant vaccine called V-RG has been successfully used in Belgium, France, Germany and the United States to prevent outbreaks of rabies in wildlife.[18] Currently pre-exposure immunization has been used in both human and non-human populations, whereas in many jurisdictions domesticated animals are required to be vaccinated.[19]

In the U.S., since the widespread vaccination of domestic dogs and cats and the development of effective human vaccines and immunoglobulin treatments, the number of recorded deaths from rabies has dropped from one hundred or more annually in the early twentieth century, to 1–2 per year, mostly caused by bat bites, which may go unnoticed by the victim and hence untreated.[4]

September 28 is World Rabies Day, which promotes information on, and prevention and elimination of the disease.[20]



Management

Post-exposure prophylaxis

Treatment after exposure, known as post-exposure prophylaxis (PEP), is highly successful in preventing the disease if administered promptly, generally within ten days of infection.[1] Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective at reducing the number of viral particles. “If available, a virucidal antiseptic such as povidone-iodine, iodine tincture, aqueous iodine solution, or alcohol (ethanol) should be applied after washing. Exposed mucous membranes such as eyes, nose or mouth should be flushed well with water.”[21]

In the United States, the Centers for Disease Control and Prevention (CDC) recommend patients receive one dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a fourteen day period. The immunoglobulin dose should not exceed 20 units per kilogram body weight. HRIG is very expensive and constitutes the vast majority of the cost of post-exposure treatment, ranging as high as several thousand dollars. As much as possible of this dose should be infiltrated around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site.[22] The first dose of rabies vaccine is given as soon as possible after exposure, with additional doses on days three, seven and fourteen after the first. Patients who have previously received pre-exposure vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on day 0 and 2.

Modern cell-based vaccines are similar to flu shots in terms of pain and side effects. The old nerve-tissue-based vaccinations that require multiple painful injections into the abdomen with a large needle are cheap, but are being phased out and replaced by affordable WHO ID (intradermal) vaccination regimens.[11]

Intramuscular vaccination should be given into the deltoid, not gluteal area which has been associated with vaccination failure due to injection into fat rather than muscle. In infants the lateral thigh is used as for routine childhood vaccinations.

An individual awakening to find a bat in the room, or finding a bat in the room of a previously unattended child or mentally disabled or intoxicated person is regarded as an indication for post-exposure prophylaxis. The recommendation for the precautionary use of post-exposure prophylaxis in occult bat encounters where there is no recognized contact has been questioned in the medical literature based on a cost-benefit analysis.[23] However, recent studies have further confirmed the wisdom of maintaining the current protocol of precautionary administering of PEP. In cases where a child or mentally compromised individual has been left alone with a bat, especially in sleep areas (where a bite/or exposure may occur while the victim is asleep and unaware or awake and unaware that a bite occurred). This is illustrated by the September 2000 case of a nine-year old boy from Quebec who died an agonizing death (over a 14 day period) from rabies 3 weeks after being in the presence of a sick bat, even though there was no apparent report of a bite; as shown in the following conclusion made by the doctors involved in the case:

Despite recent criticism (45), the dramatic circumstances surrounding our patient's history, as well as increasingly frequent reports of human rabies contracted in North America, support the current Canadian guidelines which state that RPEP [PEP] is appropriate in cases where a significant contact with a bat cannot be excluded (45). The notion that a bite or an overt break in the skin needs to be seen or felt for rabies to be transmitted by a bat is a myth in many cases.[24]

It is highly recommended that PEP be administered as soon as possible. Begun with little or no delay, PEP is 100% effective against rabies.[7] In the case in which there has been a significant delay in administering PEP, the treatment should be administered regardless of that delay, as it may still be effective.[22] If there has been a delay between exposure and attempts at treatment, such that the possibility exists that the virus has already penetrated the nervous system, the possibility exists that amputation of the affected limb might thwart rabies, if the bite or exposure was on an arm or leg. This treatment should be combined with an intensive PEP regimen.



Blood-brain barrier

Some recent work has shown that during lethal rabies infection, the blood-brain barrier (BBB) does not allow anti-viral immune cells to enter the brain, the primary site of rabies virus replication.[25] This aspect contributes to the pathogenicity of the virus and artificially increasing BBB permeability promotes viral clearance.[26] 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.[citation needed]



Induced coma

In 2005, American teenager Jeanna Giese survived an infection of rabies unvaccinated. She was placed into an induced coma upon onset of symptoms and given ketamine, midazolam, ribavirin, and amantadine. Her doctors administered treatment based on the hypothesis that detrimental effects of rabies were caused by temporary dysfunctions in the brain and could be avoided by inducing a temporary partial halt in brain function that would protect the brain from damage while giving the immune system time to defeat the virus. After thirty-one days of isolation and seventy-six days of hospitalization, Giese was released from the hospital.[27] She survived with almost no permanent sequelae and as of 2009 was starting her third year of university studies.[28]

Giese's treatment regimen became known as the "Milwaukee protocol", which has since undergone revision (the second version omits the use of ribavirin). There were 2 survivors out of 25 patients treated under the first protocol. A further 10 patients have been treated under the revised protocol and there have been a further 2 survivors.[29] The anesthetic drug ketamine has shown the potential for rabies virus inhibition in rats,[30] and is used as part of the Milwaukee protocol.

On April 10, 2008 in Cali, Colombia, an eleven year-old boy was reported to survive rabies and the induced coma without noticeable brain damage.[31]



Prognosis

In unvaccinated humans, rabies is almost always fatal after neurological symptoms have developed, but prompt post-exposure vaccination may prevent the virus from progressing. Rabies kills around 55,000 people a year, mostly in Asia and Africa.[32] There are only six known cases of a person surviving symptomatic rabies, and only one known case of survival in which the patient received no rabies-specific treatment either before or after illness onset.[33][34][35]

The most current survival data using the Milwaukee protocol is available from the rabies registry.

Transmission

Any warm-blooded animal (including humans) may become infected with the rabies virus and develop symptoms (though birds have only been known to be experimentally infected[37]). Indeed the virus has even been adapted to grow in cells of poikilothermic vertebrates[38][39] though natural transmission has only been documented among mammals.[citation needed] Most animals can be infected by the virus and can transmit the disease to humans. Infected bats, monkeys, raccoons, foxes, skunks, cattle, wolves, coyotes, dogs, mongoose (normally yellow mongoose)[40] 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. Rodents (mice, squirrels etc) are seldom infected.[41]

The virus is usually present in the nerves and saliva of a symptomatic rabid animal.[42][43] 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.[44]

Transmission between humans is extremely rare. A few cases have been recorded through transplant surgery.[45]



After a typical human infection by bite, the virus enters the peripheral nervous system. It then travels along the nerves towards the central nervous system.[46] 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 causes encephalitis. This is called the prodromal phase, and is the beginning of the symptoms. Once the patient becomes symptomatic, treatment is almost never effective and mortality is over 99%. Rabies may also inflame the spinal cord producing transverse myelitis.[47][48]

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