Rabies is aviral disease that causesencephalitis in humans and othermammals.[1] It was historically referred to ashydrophobia ("fear of water") because its victims panic when offered liquids to drink. Early symptoms can include fever and abnormal sensations at the site of exposure.[1] These symptoms are followed by one or more of the following symptoms: nausea, vomiting, violent movements, uncontrolled excitement, fear of water, an inability to move parts of the body, confusion, andloss of consciousness.[1][7][8][9] Once symptoms appear, the result is virtually always death.[1] The time period between contracting the disease and the start of symptoms is usually one to three months but can vary from less than one week to more than one year.[1] The time depends on the distance the virus must travel alongperipheral nerves to reach thecentral nervous system.[10]
Rabies is caused bylyssaviruses, including therabies virus andAustralian bat lyssavirus.[4] It is spread when an infected animal bites or scratches a human or other animals.[1] Saliva from an infected animal can also transmit rabies if the saliva comes into contact with the eyes, mouth, or nose.[1] Globally, dogs are the most common animal involved.[1] In countries where dogs commonly have the disease, more than 99% of rabies cases in humans are the direct result ofdog bites.[11] In theAmericas,bat bites are the most common source of rabies infections in humans, and less than 5% of cases are from dogs.[1][11]Rodents are very rarely infected with rabies.[11] The disease can be diagnosed only after the start of symptoms.[1]
Animal control and vaccination programs have decreased the risk of rabies from dogs in a number of regions of the world.[1] Immunizing people before they are exposed is recommended for those at high risk, including those who work with bats or who spend prolonged periods in areas of the world where rabies is common.[1] In people who have been exposed to rabies, therabies vaccine and sometimesrabies immunoglobulin are effective in preventing the disease if the person receives the treatment before the start of rabies symptoms.[1] Washing bites and scratches for 15 minutes with soap and water,povidone-iodine, or detergent may reduce the number of viral particles and may be somewhat effective at preventing transmission.[1][12] As of 2016[update], only fourteen people were documented to have survived a rabies infection after showing symptoms.[13][14] However, research conducted in 2010 among a population of people inPeru with a self-reported history of one or more bites fromvampire bats (commonly infected with rabies), found that out of 73 individuals reporting previous bat bites, seven people had rabies virus-neutralizingantibodies (rVNA).[15] Since only one member of this group reported prior vaccination for rabies, the findings of the research suggest previously undocumented cases of infection and viral replication followed by an abortive infection. This could indicate that people may have an exposure to the virus without treatment and develop natural antibodies as a result.
Rabies causes about 59,000 deaths worldwide per year,[6] about 40% of which are in children under the age of 15.[16] More than 95% of human deaths from rabies occur in Africa and Asia.[1] Rabies is present in more than 150 countries and on all continents but Antarctica.[1] More than 3 billion people live in regions of the world where rabies occurs.[1] A number of countries, including Australia and Japan, as well as much of Western Europe, do not have rabies among dogs.[17][18] Many Pacific islands do not have rabies at all.[18] It is classified as aneglected tropical disease.[19]
The global cost of rabies is estimated to be around US$8.6 billion per year including lost lives and livelihoods, medical care and associated costs, as well as uncalculatedpsychological trauma.[20]
Etymology
The name rabies is derived from theLatinrabies, meaning "madness".[21] The Greeks derived the wordlyssa, fromlud or "violent"; this root is used in the genus name of the rabies virus,Lyssavirus.[22]
Signs and symptoms
Animals with "dumb" rabies appear depressed, lethargic, and uncoordinated
Theperiod between infection and the firstsymptoms (incubation period) is typically one to three months in humans.[23] This period may be as short as four days or longer than six years, depending on the location and severity of the wound and the amount of virus introduced.[23] Initial symptoms of rabies are often nonspecific, such as fever and headache.[23] As rabies progresses and causesinflammation of the brain and meninges, symptoms can include slight or partialparalysis,anxiety,insomnia,confusion,agitation, abnormal behavior,paranoia,terror, andhallucinations.[10][23] The person may also have fear of water.[1]
The symptoms eventually progress todelirium andcoma.[10][23]Death usually occurs two to ten days after first symptoms. Survival is almost unknown once symptoms have presented, even with intensive care.[23][24]
Man with rabies displaying hydrophobia
Rabies has also occasionally been referred to as hydrophobia ("fear of water") throughout its history.[25] It refers to a set of symptoms in the later stages of an infection in which the person has difficulty swallowing, shows panic when presented with liquids to drink, and cannot quench their thirst. Saliva production is greatly increased, and attempts to drink, or even the intention or suggestion of drinking, may cause excruciatingly painful spasms of the muscles in the throat andlarynx. Since the infected individual cannot swallow saliva and water, the virus has a much higher chance of being transmitted, because it multiplies and accumulates in thesalivary glands and is transmitted through biting.[26]
Hydrophobia is commonly associated with furious rabies, which affects 80% of rabies-infected people. This form of rabies causes irrational aggression in the host, which aids in the spreading of the virus through animal bites;[27][28] a "foaming at the mouth" effect, caused by the accumulation of saliva, is also commonly associated with rabies in the public perception and in popular culture.[29][30][31] The remaining 20% may experience a paralytic form of rabies that is marked by muscleweakness, loss of sensation, andparalysis; this form of rabies does not usually cause fear of water.[32]
The rabies virus is thetype species of theLyssavirusgenus, in the familyRhabdoviridae, orderMononegavirales. Lyssavirions have helical symmetry, with a length of about 180 nm and a cross-section of about 75 nm.[34] These virions areenveloped and have a single-strandedRNA genome withnegative sense. The genetic information is packed as aribonucleoprotein complex in which RNA is tightly bound by the viral nucleoprotein. TheRNA 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).[35]
To enter cells, trimeric spikes on the exterior of the membrane of the virus interact with a specific cell receptor, the most likely one being theacetylcholine receptor. The cellular membrane pinches in a procession known aspinocytosis and allows entry of the virus into the cell by way of anendosome. The virus then uses the acidic environment, which is necessary, of that endosome and binds to its membrane simultaneously, releasing its five proteins and single-strand RNA into the cytoplasm.[36]
Once within a muscle or nerve cell, the virus undergoes replication. 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-translational modifications. For example, the G protein travels through the roughendoplasmic reticulum, where it undergoes further folding, and is then transported to theGolgi apparatus, where a sugar group is added to it (glycosylation).[36]
When there are enough viral 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.[36]
From the point of entry, the virus isneurotropic, traveling along the neural pathways into thecentral nervous system. The virus usually first infects muscle cells close to the site of infection, where they are able to replicate without being 'noticed' by the host's immune system. Once enough virus has been replicated, they begin to bind toacetylcholine receptors at the neuromuscular junction.[37] The virus then travels through the nerve cell axon viaretrograde transport, as itsP protein interacts withdynein, a protein present in the cytoplasm of nerve cells. Once the virus reaches the cell body it travels rapidly to thecentral nervous system (CNS), replicating in motor neurons and eventually reaching the brain.[10] After the brain is infected, the virus travels centrifugally to the peripheral and autonomic nervous systems, eventually migrating to the salivary glands, where it is ready to be transmitted to the next host.[38]: 317
Transmission
Rabies prevention poster
Allwarm-blooded species, including humans, may become infected with the rabies virus and develop symptoms.Birds were first artificially infected with rabies in 1884; however, infected birds are largely, if not wholly, asymptomatic, and recover.[39] Other bird species have been known to develop rabiesantibodies, a sign of infection, after feeding on rabies-infected mammals.[40][41]
The virus has also adapted to grow in cells ofcold-blooded vertebrates.[42][43] Most animals can be infected by the virus and can transmit the disease to humans. Worldwide, about 99% of human rabies cases come fromdogs.[44] Other sources of rabies in humans includebats,[45][46]monkeys,raccoons,foxes,skunks,cattle,wolves,coyotes,cats, andmongooses (normally either the small Asian mongoose or the yellow mongoose).[47]
The virus is usually present in the nerves andsaliva of a symptomatic rabid animal.[54][55] The route ofinfection 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.[56] This is an example of a viral pathogenmodifying the behavior of its host to facilitate its transmission to other hosts. After a typical human infection by bite, the virus enters theperipheral nervous system. It then travels retrograde along theefferent nerves toward thecentral nervous system.[57] 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 thebrain, it rapidly causesencephalitis, the prodromal phase, which 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 thespinal cord, producingtransverse myelitis.[58][59]
Although it is theoretically possible for rabies-infected humans to transmit it to others by biting or otherwise, no such cases have ever been documented, because infected humans are usually hospitalized and necessary precautions taken. Casual contact, such as touching a person with rabies or contact with non-infectious fluid or tissue (urine, blood, feces), does not constitute an exposure and does not require post-exposure prophylaxis. But as the virus is present in sperm and vaginal secretions, it might be possible for rabies to spread through sex.[60] There are only a small number of recorded cases of human-to-human transmission of rabies, and all occurred throughorgan transplants, most frequently withcorneal transplantation, from infected donors.[61][62]
Diagnosis
Rabies can be difficult to diagnose because, in the early stages, it is easily confused with other diseases or even with a simple aggressive temperament.[63] Thereference method for diagnosing rabies is the fluorescent antibody test (FAT), animmunohistochemistry procedure, which is recommended by theWorld Health Organization (WHO).[64] The FAT relies on the ability of a detector molecule (usually fluorescein isothiocyanate) coupled with a rabies-specific antibody, forming a conjugate, to bind to and allow the visualisation of rabies antigen using fluorescent microscopy techniques. Microscopic analysis of samples is the only direct method that allows for the identification of rabies virus-specific antigen in a short time and at a reduced cost, irrespective of geographical origin and status of the host. It has to be regarded as the first step in diagnostic procedures for all laboratories. Autolysed samples can, however, reduce the sensitivity and specificity of the FAT.[65] TheRT PCR assays proved to be a sensitive and specific tool for routine diagnostic purposes,[66] particularly in decomposed samples[67] or archival specimens.[68] The diagnosis can be reliably made from brain samples taken after death. The diagnosis can also be made from saliva, urine, and cerebrospinal fluid samples, but this is not assensitive or reliable as brain samples.[65] Cerebral inclusion bodies calledNegri bodies are 100% diagnostic for rabies infection but are found in only about 80% of cases.[34] If possible, the animal from which the bite was received should also be examined for rabies.[69]
Somelight microscopy techniques may also be used to diagnose rabies at a tenth of the cost of traditional fluorescence microscopy techniques, allowing identification of the disease in less-developed countries.[70] A test for rabies, known as LN34, is easier to run on a dead animal's brain and might help determine who does and does not need post-exposure prevention.[71] The test was developed by theCenters for Disease Control and Prevention (CDC) in 2018.[71]
New causes of viral encephalitis are also possible, as was evidenced by the 1999 outbreak in Malaysia of 300 cases of encephalitis with a mortality rate of 40% caused byNipah virus, a newly recognizedparamyxovirus.[73] Likewise, well-known viruses may be introduced into new locales, as is illustrated by the outbreak of encephalitis due to West Nile virus in the eastern United States.[74]
Almost all human exposure to rabies was fatal until a vaccine was developed in 1885 byLouis Pasteur andÉmile 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.[75] Similar nerve tissue-derived vaccines are still used in some countries, as they are much cheaper than modern cell culture vaccines.[76]
The human diploid cell rabies vaccine was started in 1967. Less expensive purified chicken embryo cell vaccine and purifiedvero cell rabies vaccine are now available.[69] Arecombinant vaccine called V-RG has been used in Belgium, France, Germany, and the United States to prevent outbreaks of rabies in undomesticated animals.[77] Immunization before exposure has been used in both human and nonhuman populations, where, as in many jurisdictions, domesticated animals are required to be vaccinated.[78]
A young girl about to receive PEP after being bitten by an animal thought to be rabid
The Missouri Department of Health and Senior Services Communicable Disease Surveillance 2007 Annual Report states the following can help reduce the risk of contracting rabies:[79]
Vaccinating dogs, cats, and ferrets against rabies
Keeping pets under supervision
Not handling wild animals or strays
Contacting an animal control officer upon observing a wild animal or a stray, especially if the animal is acting strangely
If bitten by an animal, washing the wound with soap and water for 10 to 15 minutes and contacting a healthcare provider to determine if post-exposure prophylaxis is required
28 September isWorld Rabies Day, which promotes the information, prevention, and elimination of the disease.[80]
In Asia and in parts of the Americas and 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 ofCanada,France, and theUnited States. InMontreal, Quebec, Canada, baits are successfully used on raccoons in the Mount-Royal Park area. Vaccination campaigns may be expensive, but cost-benefit analysis suggests baits may be a cost-effective method of control.[81] InOntario, a dramatic drop in rabies was recorded when an aerial bait-vaccination campaign was launched.[82]
The number of recorded human deaths from rabies in the United States has dropped from 100 or more annually in the early 20th century to one or two per year because of widespread vaccination of domestic dogs and cats and the development of human vaccines and immunoglobulin treatments. Most deaths now result from bat bites, which may go unnoticed by the victim and hence untreated.[83]
Treatment
After exposure
Treatment after exposure can prevent the disease if given within 10 days. The rabies vaccine is 100% effective if given before symptoms of rabies appear.[34][36][84] Every year, more than 15 million people get vaccinated after potential exposure. While this works well, the cost is significant.[85] In the US it is recommended people receive one dose of human rabiesimmunoglobulin (HRIG) and four doses of rabies vaccine over a 14-day period.[86] HRIG is expensive and makes up most of the cost of post-exposure treatment, ranging as high as several thousand dollars.[87] In the UK, one dose of HRIG costs the National Health Service £1,000,[88] although this is not flagged as a "high-cost medication".[89] A full course of vaccine costs £120–180.[90] As much as possible of HRIG should be injected around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site.[36]
People who have previously been vaccinated against rabies do not need to receive the immunoglobulin—only the postexposure vaccinations on days 0 and 3.[91] The side effects of moderncell-based vaccines are similar to the side effects of flu shots. The old nerve-tissue-based vaccination required multiple injections into the abdomen with a large needle but is inexpensive.[92] It is being phased out and replaced by affordable World Health Organization intradermal-vaccination regimens.[69] In children less than a year old, the lateral thigh is recommended.[93]
Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is effective in reducing the number of viral particles.[94]Povidone-iodine or alcohol is then recommended to reduce the virus further.[95]
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 an indication forpost-exposure prophylaxis (PEP). The recommendation for the precautionary use of PEP in bat encounters where no contact is recognized has been questioned in the medical literature, based on acost–benefit analysis.[96] However, a 2002 study has supported the protocol of precautionary administration of PEP where a child or mentally compromised individual has been alone with a bat, especially in sleep areas, where a bite or exposure may occur with the victim being unaware.[97]
After onset
Once rabies develops, death almost certainly follows.Palliative care in a hospital setting is recommended with administration of large doses of pain medication, and sedatives in preference to physical restraint. Ice fragments can be given by mouth for thirst, but there is no good evidence intravenous hydration is of benefit.[98]
A treatment known as the Milwaukee protocol, which involves putting people with rabies symptoms into achemically induced coma and usingantiviral medications in an attempt to protect their brain until their body has had time to produce rabies antibodies, has been occasionally used.[99] It was initially attempted in 2004 on Jeanna Giese, a teenage girl fromWisconsin, who subsequently became the first human known to have survived rabies without receiving post-exposure prophylaxis before symptom onset.[100][101] Giese did require extensive rehabilitation afterward, and her balance and neural function remained impaired.[102] The protocol has been enacted on many rabies victims since, but has been adjudged a failure; some survivors of the acute initial phase later died of rabies. Concerns have also been raised about its monetary costs and its ethics.[99][103]
Antiviral therapy to combat the effects of rabies has also been researched;favipiravir, for example, has shown potential at inhibiting the development of encephalitis. It has been suggested that such therapy in combination withimmunotherapy andneuroprotective measures could be beneficial.[104]
Prognosis
Vaccination after exposure, PEP, is highly successful in preventing rabies.[84] In unvaccinated humans, rabies is almost certainly fatal afterneurological symptoms have developed.[105]
In 2010, an estimated 26,000 people died from rabies, down from 54,000 in 1990.[106] The majority of the deaths occurred in Asia and Africa.[105] As of 2015[update], India (approximately 20,847), followed by China (approximately 6,000) and the Democratic Republic of the Congo (5,600), had the most cases.[107] A 2015 collaboration between the World Health Organization, World Organization of Animal Health (OIE), Food and Agriculture Organization of the United Nation (FAO), andGlobal Alliance for Rabies Control has a goal of eliminating deaths from rabies by 2030.[108]
India
India has the highest rate of human rabies in the world, primarily because of stray dogs,[109] whose number has greatly increased since a 2001 law forbade the killing of dogs.[110] Effective control and treatment of rabies in India is hindered by a form ofmass hysteria known aspuppy pregnancy syndrome (PPS). Dog bite victims with PPS, male as well as female, become convinced that puppies are growing inside them, and often seek help fromfaith healers rather than medical services.[111] An estimated 20,000 people die every year from rabies in India, more than a third of the global total.[110]
Australia
Australia has an official rabies-free status,[112] althoughAustralian bat lyssavirus (ABLV), discovered in 1996, is a rabies-causing virus related to therabies virus prevalent in Australian native bat populations.
United States
Rabies cases in humans and domestic animals – United States, 1938–2018
Canine-specific rabies has been eradicated in the United States, but rabies is common among wild animals, and an average of 100 dogs become infected from other wildlife each year.[113][114]
High public awareness of the virus, efforts at vaccination of domestic animals and curtailment of feral populations, and availability ofpostexposure prophylaxis have made rabies very rare in humans in the United States. From 1960 to 2018, a total of 125 such cases were reported in the United States; of them, 36 (28%) were attributed to dog bites suffered during international travel.[115] Among the 89 infections acquired in the United States, 62 (70%) were attributed to bats.[115] The most recent rabies death in the United States was in November 2021, where a Texas child was bitten by a bat in late August 2021 but his parents failed to get him treatment. He died less than three months later.[116]
Europe
Either no or very few cases of rabies are reported each year in Europe; cases are contracted both during travel and in Europe.[117]
In Switzerland the disease was virtually eliminated after scientists placed chicken heads laced with liveattenuated vaccine in theSwiss Alps.[82] Foxes, proven to be the main source of rabies in the country, ate the chicken heads and became immunized.[82][118]
Italy, after being declared rabies-free from 1997 to 2008, has witnessed a reemergence of the disease in wild animals in theTriveneto regions (Trentino-Alto Adige/Südtirol,Veneto andFriuli-Venezia Giulia) due to the spreading of an epidemic in theBalkans that also affected Austria. An extensive wild animal vaccination campaign eliminated the virus from Italy again, and it regained the rabies-free country status in 2013, the last reported case of rabies being reported in a red fox in early 2011.[119][120]
The United Kingdom has been free of rabies since the early 20th century except for arabies-like virus (EBLV-2) in a fewDaubenton's bats. There has been one fatal case of EBLV-2 transmission to a human.[121] There have been four deaths from rabies, transmitted abroad by dog bites, since 2000. The last infection in the UK occurred in 1922, and the last death from indigenous rabies was in 1902.[122][123]
Sweden and mainland Norway have been free of rabies since 1886.[124] Bat rabies antibodies (but not the virus) have been found in bats.[125] On Svalbard, animals can cross the arctic ice from Greenland or Russia.
Mexico
Mexico was certified by theWorld Health Organization as being free of dog-transmitted rabies in 2019 because no case of dog-human transmission had been recorded in two years.[126]
Asian countries
Despite rabies being preventable and the many successes of the years from countries such as North America, South Korea and Western Europe, Rabies remains endemic in many Southeast Asian countries includingCambodia,Bangladesh,Bhutan,North Korea,India,Indonesia,Myanmar,Nepal,Sri Lanka, andThailand.[127] Half the global rabies deaths occur in southeast Asia - approx. 26,000 per year.[128]
Much of what prevents Asia from implementing the same measures as other countries iscost.[129] Treating wild canines is the primary means of preventing rabies, however it costs 10 times more than treating individuals as they come with bites, and research also increases cost. As a result, India and other surrounding countries are unable to apply many preventative measures because of financial restrictions.[130]
Thailand
In 2013 human rabies was nearly eradicated in the state of Thailand after new measures were put into place requiring the vaccination of all domestic dogs as well as programs seeking to vaccinate wild dogs and large animals.[131] However, neighboring countries unable to afford rabies control measures – Cambodia, Laos, andMyanmar – allowed infected animals to continue to pass the border and infect the Thai population, leading to ~100 cases a year.[132] These areas around the border are called Rabies Red areas and are where Thailand continuously struggles with eradication and will do so until the surrounding countries eliminate the virus.[131]
Thailand has the resources and medicine necessary to tackle rabies such as implementing regulations that require all children to receive a rabies vaccination before attending schools and having clinics available for those bit or scratched by a possible rabid animal. However, individual choice is still a factor, and 10 people per year die out of refusal to seek treatment.[133]
Cambodia
Cambodia has approximately 800 cases of human rabies per year, making it one of the top countries in human rabies incidences.[134] Much of this falls on their lack of animal care; Cambodia has hundreds of thousands of animals infected with rabies, another global high, yet little surveillance of said animals and few laws requiring pets and other household animals to be vaccinated.[134] In recent yearsCambodia has improved significantly in their human rabies medical practices, with clinics all over the countries being made with treatments and vaccination on hand as well as rabies-related education in school classes.[135] However, it is still lacking in terms of animal surveillance and treatment which leads to bleeding into surrounding countries.[128]
In ancient Greece, rabies was supposed to be caused byLyssa, the spirit of mad rage.[138]
Ineffective folk remedies abounded in the medical literature of the ancient world. The physicianScribonius Largus prescribed a poultice of cloth and hyena skin;Antaeus recommended a preparation made from the skull of a hanged man.[139]
Rabies appears to have originated in the Old World, the firstepizootic in the New World occurring in Boston in 1768.[140]
Rabies was considered a scourge for its prevalence in the 19th century. In France and Belgium, whereSaint Hubert was venerated, the "St Hubert's Key" was heated and applied to cauterize the wound. By an application ofmagical thinking, dogs were branded with the key in hopes of protecting them from rabies.
It was not uncommon for a person bitten by a dog merely suspected of being rabid to commit suicide or to be killed by others.[22]
In ancient times the attachment of the tongue (thelingual frenulum, a mucous membrane) was cut and removed, as this was where rabies was thought to originate. This practice ceased with the discovery of the actual cause of rabies.[38] Louis Pasteur's 1885 nerve tissue vaccine was successful, and was progressively improved to reduce often severe side-effects.[23]
In modern times, the fear of rabies has not diminished, and the disease and its symptoms, particularly agitation, have served as aninspiration for several works ofzombie or similarly themed fiction, often portraying rabies as having mutated into a stronger virus which fills humans with murderous rage or incurable illness, bringing about a devastating, widespread pandemic.[141]
Miniature of theCantiga #275 depicting twomonks hospitaller with rabies being carried before St. Mary of Terena[142]
Two dogs with the paralytic, or dumb, form of rabies
Rabies is infectious tomammals; three stages of central nervous system infection are recognized. The clinical course is often shorter in animals than in humans, but result in similar symptoms and almost always death. The first stage is a one- to three-day period characterized by behavioral changes and is known as theprodromal stage. The second is the excitative stage, which lasts three to four days. This stage is often known as "furious rabies" for the tendency of the affected animal to be hyper-reactive to external stimuli and bite or attack anything near. In some cases, animals skip the excitative stage and develop paralysis, as in the third phase; the paralytic phase. This stage develops by damage tomotor neurons. Incoordination is seen, owing to rear limbparalysis, and drooling and difficulty swallowing is caused by paralysis of facial and throat muscles. Death is usually caused byrespiratory arrest.[143]
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^Chowdhury FR, Basher A, Amin MR, Hassan N, Patwary MI (2015). "Rabies in South Asia: fighting for elimination".Recent Pat Anti-Infect Drug Discov.10 (1):30–34.doi:10.2174/1574891x10666150410130024.PMID25858305.
^CDC (2024)."Thailand".Travelers' health. Center for Disease Control and Prevention.Rabid dogs are commonly found, rabies treatment is often available.&text=Since children are more likely, for children traveling to Thailand
^CDC (2024)."Thailand".Travelers' health. Center for Disease Control and Prevention.Dogs infected with rabies are sometimes found in Thailand. If rabies exposures occur while in Thailand, rabies vaccines are typically available throughout most of the country.
^CDC (2024)."Cambodia".Travelers' Health. Center for Disease Control.Dogs infected with rabies are commonly found in Cambodia. If rabies exposures occur while in Cambodia, rabies vaccines are typically available throughout most of the country.
^Adamson PB (1977). "The spread of rabies into Europe and the probable origin of this disease in antiquity".Journal of the Royal Asiatic Society of Great Britain & Ireland. Royal Asiatic Society of Great Britain and Ireland.109 (2):140–44.doi:10.1017/S0035869X00133829.JSTOR25210880.PMID11632333.S2CID27354751.
^Dunlop RH, Williams DJ (1996).Veterinary Medicine: An Illustrated History. Mosby.ISBN978-0-8016-3209-9.
^Baer GM (1991).The Natural History of Rabies (2nd ed.). CRC Press.ISBN978-0-8493-6760-1.The first major epizootic in North America was reported in 1768, continuing until 1771 when foxes and dogs carried the disease to swine and domestic animals. The malady was so unusual that it was reported as a new disease
![Miniature of the Cantiga #275 depicting two monks hospitaller with rabies being carried before St. Mary of Terena[142]](/mt/?noimg=&dark=on&url=https%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aCantigas_de_Santa_Maria-275-5.jpg)
