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Clinical manifestations and diagnosis of rabies

Clinical manifestations and diagnosis of rabies
Literature review current through: Jan 2024.
This topic last updated: Jul 01, 2022.

INTRODUCTION — Rabies has the highest case fatality rate of any human infectious disease. The epidemiology, clinical manifestations, and diagnosis of rabies will be reviewed here. Management of patients with active rabies and prevention of infection are discussed separately. (See "Rabies immune globulin and vaccine" and "Indications for post-exposure rabies prophylaxis" and "Treatment of rabies".)

VIROLOGY — Rabies and rabies-like illnesses are caused by different variants and species of neurotropic viruses in the Rhabdoviridae family, genus Lyssavirus [1,2]. Antigenic and molecular genetic techniques have demonstrated that several viruses within this genus cause diseases clinically similar to rabies. The bullet-shaped lyssavirus contains a single-stranded RNA genome encoding five structural proteins. One of these genes encodes an outer glycoprotein, which is recognized by cell surface receptors and is the target for virus-neutralizing antibodies. Sequencing of the gene that codes for the inner nucleoprotein virus can help to identify the specific lyssavirus and probable vector of transmission [3]. Most human rabies cases are due to the classical rabies virus, which has multiple virus variants named for their primary animal reservoir species.

PATHOGENESIS

Viral tropism and dissemination — Lyssaviruses have a predilection for neural tissue and spread via peripheral nerves to the central nervous system (CNS). The mechanism by which rabies causes severe CNS disease is unclear. Lyssaviruses may produce neuronal dysfunction rather than neuronal death. Oxidative stress caused by dysfunction of mitochondria in infected neurons and other cells of the CNS may also be a pathway leading to the abnormalities observed [4].

Viruses amplify near the site of inoculation in muscle cells and subsequently enter local motor and sensory nerves [5]. Each virion is surrounded by a lipoprotein envelope studded with glycoprotein spikes [1]. After inoculation, these glycoprotein projections attach to the nicotinic acetylcholine receptors of the plasma membrane of muscle cells [6]. The viruses then enter nerve cells. However, since neurons do not express acetylcholine receptors, other unidentified receptors may exist to allow cell entry.

Viruses then migrate centrally in a retrograde direction within the axoplasm of peripheral nerves at approximately 50 to 100 mm per day until reaching the dorsal root ganglia of the spinal cord [7]. Rabies viruses then ascend rapidly up the spinal cord to the brain, initially infecting the diencephalon, hippocampus, and brainstem [8].

Centrifugal spread of viruses along somatic and autonomic nerves results in widespread dissemination [9]. Productive viral replication and shedding occurs in highly innervated areas, such as the salivary glands [7,10].

Although many neurons are infected by virus, the neuropathological findings are quite mild compared with those caused by other infectious etiologies of encephalitis, such as herpes simplex virus [11]. On autopsy, findings include mild cerebral edema and vascular congestion. Microscopic changes associated with infection include perivascular cuffing with mononuclear cell infiltration and microglial activation; occasional neuronophagia (destruction of nerve cells by phagocytes) may be seen. Dense, ovoid, intracytoplasmic inclusions, (ie, "Negri bodies"), may be observed within neurons of the CNS in areas devoid of inflammation or degeneration.

Host susceptibility to infection — As is true with other infectious diseases, exposure does not always result in infection and disease. Susceptibility to rabies infection after an exposure is related to several factors, including the type and anatomical location of the exposure [10,12]. As an example, a bite that injects infectious saliva into a body part is more likely to result in a productive infection than a bite through clothing where saliva may be absorbed, or a lick on broken or abraded skin. In addition, exposures involving the head or neck of a patient are more likely to result in a productive infection than an exposure to a more distal part of the body.

Other factors that may affect host susceptibility to infection and the likelihood of developing disease include:

The virus variant

The size of the viral inoculum

The degree of innervation at the site of the bite

Host immunity and genetics

All mammals are believed to be susceptible to rabies virus infection, although species differ in relative susceptibility. As an example, foxes, coyotes, wolves, and jackals are quite susceptible, whereas opossums are relatively resistant [10].

EPIDEMIOLOGY

Geographic distribution — Rabies virus has a worldwide distribution in terrestrial animals (primarily dogs) with few exceptions, including Antarctica, New Zealand, Japan, parts of Europe, and some Caribbean Islands. Rabies virus in bats is found only in the New World [13]. Rabies is found throughout the United States, in bats and several different terrestrial animal reservoirs, except in Hawaii [14]. There are at least 17 other rabies-like lyssaviruses that have been identified from bats in Africa, Asia, Australasia, Europe, and Eurasia [13].

Despite the development of the first rabies vaccine in 1885 by Louis Pasteur, the World Health Organization estimates that about 59,000 people die of canine rabies worldwide each year [13]. Most of these deaths occur in resource-poor countries because of inadequate control of rabies in domesticated animals.

In the United States, there were 90 human cases of rabies reported from 1980 through 2019, with an average of two to three reported per year [15-18]. Among these cases, 26 (31 percent) were related to imported rabies in people who were exposed to rabid animals in endemic areas (eg, El Salvador, Haiti, the Philippines, Afghanistan, India), and five cases were in tissue or organ transplant recipients.

Transmission — Most rabies is acquired through exposure to saliva from an animal bite. In rare cases, rabies results from a non-bite exposure (eg, saliva contact with open skin or mucous membranes) or transplantation of tissue or organs from a donor with unrecognized rabies [19-22]. Although aerosol transmission of rabies has been documented in laboratory studies [21], in humans, exposure via aerosolized virus has only been documented in four cases (two spelunkers from a single cave and two laboratorians working with live virus) [19,20,23,24].

No transmission of rabies has been documented from infected patients to health care personnel or household contacts or by fomites or environmental surfaces [13,14,25]. (See "Treatment of rabies", section on 'Infection prevention'.)

Animal reservoirs — In resource-poor countries, rabid dogs account for 90 percent or more of reported cases of rabies transmitted to humans. In the United States, the canine variant of the rabies virus, transmitted by domestic dogs, was responsible for most human deaths prior to the 1950s, but was largely eliminated as an endemic source by the 1970s [10]. By the late 1960s, wild animals emerged as the most likely source of human exposure in the United States. However, rabid dogs and cats are sporadically reported from areas with enzootic wildlife rabies. In addition, domestic animals that are incubating rabies have been imported from regions of the world where canine rabies is still enzootic [26,27].

Rabies surveillance in the United States has identified four major animal reservoirs: bats, raccoons, skunks, and foxes (figure 1) [28-31]. The leading source for human cases has been bats, based upon genetic characterization of the infecting rabies virus variant. From 1980 through 2019, bat variants of rabies virus accounted for 49 of 57 (86 percent) of indigenously acquired human rabies cases that were not due to tissue or organ transplant [15,16,18,32]. In a retrospective review of 41 cases of human rabies in the United States involving bat virus variants, 17 percent had a known bat bite, 41 percent had unprotected (or likely unprotected) physical contact with a bat, and 5 percent had bats in the residence but no known contact [33]; 37 percent had an unknown exposure type, but these patients were unable to be interviewed due to their clinical condition. In general, exposures classified as unknown should be considered unreported, since transmission of rabies virus requires direct contact with infectious saliva.

Although small rodents, such as gerbils, chipmunks, guinea pigs, squirrels, rats, mice, and rabbits are susceptible to infection, rabies is extremely uncommon in these animals [29,34,35]. An additional discussion of the epidemiology of animal rabies is found elsewhere. (See "Indications for post-exposure rabies prophylaxis".)

Tissue or organ transplantation — Rabies virus transmission can occur through transplantation of tissues or organs from donors with undiagnosed rabies at the time of tissue procurement [22,36-40]. As an example, encephalitis developed in four patients who received a kidney, an arterial segment, and a liver from a common organ donor who died of encephalitis, the etiology of which was unknown at the time [36]. Immunohistochemical and direct fluorescence antibody staining demonstrated rabies virus in multiple tissues from all recipients. Histopathological findings in brain tissue from the transplant recipients demonstrated intracytoplasmic viral inclusions, suggestive of Negri bodies (picture 1). Antibodies against rabies virus were present in three of the four recipients and in the donor, who was ultimately determined to have a history of a bat bite.

Pre- and post-exposure prophylaxis appear to reduce the risk of developing infection, as illustrated in the following cases:

In a series of rabies cases related to solid organ transplantations from an infected donor, all the recipients died except one who had a history of rabies immunization in the past [22]. During the course of the investigation, two additional patients who received corneal transplants were immunized against rabies and remained healthy.

In 2015, two patients who received a kidney transplant from a donor who died of a rabies-like illness developed signs and symptoms of rabies 42 and 48 days after transplant [41]. In contrast, two cornea recipients who received post-exposure prophylaxis remained well for at least eight months.

In 2013, a kidney transplant recipient died from rabies virus 18 months after transplantation [37]. Three other organ transplant recipients were asymptomatic at the time and were administered post-exposure prophylaxis; all three survived.

More detailed information on the use of rabies prophylaxis is found elsewhere. (See "Rabies immune globulin and vaccine".)

INCUBATION PERIOD — The average incubation period of rabies is one to three months, but can range from several days to many years after an exposure [12,15,42-44]. In a series of 32 patients with rabies after a definite animal bite, the median incubation period was 85 days (range, 53 to 150 days) [15]. In another case, human rabies was attributed to an exposure from a dog in Brazil eight years earlier; latent infection and/or slow replication were hypothesized [43,45].

In transplant patients, the duration of time between transplant of infected organs and symptoms in the recipient can vary. In one report, encephalitis developed in four recipients within 30 days after transplantation [36]. In another case, in which rabies was transmitted from a donor to a transplant recipient, the recipient died from rabies 18 months after transplantation [37].

The incubation period is shorter in patients with an exposure that occurs in richly innervated areas (eg, the face versus the extremities). Longer incubation periods may also be related to inadequate rabies prophylaxis, or may be incorrectly attributed to an unidentified, more recent exposure [46].

CLINICAL MANIFESTATIONS — Once the patient has exhibited clinical signs of disease, rabies usually leads to progressive encephalopathy and death, with rare exception [45,47,48]. (See "Treatment of rabies".)

Prodromal symptoms — Rabies is usually unsuspected during the prodromal phase, which starts with non-specific symptoms, such as low-grade fever, chills, malaise, myalgias, weakness, fatigue, anorexia, sore throat, nausea, vomiting, headache, and occasionally photophobia. This stage lasts from a few days to approximately one week [8].

Paresthesia radiating proximally from the site of a known wound is suggestive of rabies infection [49]. The patient may describe a variety of symptoms, including pain, tenderness, tingling, itching, burning, localized abnormal temperature sensation, or numbness at the site [50]. In addition, percussion myoedema (mounding of the muscle upon percussion) may be present during the prodrome and throughout the illness [51].

Clinical rabies — Infection may evolve into two major forms of disease, including encephalitic (referred to as "furious" in animals) rabies or paralytic (referred to as "dumb" in animals) rabies, both starting with the nonspecific prodromal symptoms as described above [3]. In humans, encephalitic rabies is more common (80 percent of cases).

Occasionally, atypical cases have been described, particularly in association with bat rabies [8]. Atypical features include sensory or motor deficits, choreiform movements of the bitten limb during the prodromal phase, focal brainstem signs, cranial nerve palsies, myoclonus, and seizures [8,48].

Encephalitic rabies — The classic presentation of encephalitic rabies includes fever, hydrophobia, pharyngeal spasms, and hyperactivity subsiding to paralysis, coma and death [3]. The following symptoms and signs are classic for this form of rabies [3,50]:

Hydrophobia is the most characteristic clinical feature of rabies, occurring in 33 to 50 percent of patients [3,50,52]. After some preliminary feeling of discomfort in the throat or dysphagia, the patient suddenly develops an overwhelming terror of water based on involuntary pharyngeal muscle spasms during attempts to drink. Later in the disease, even the sight or mention of water may trigger these involuntary spasms.

Aerophobia is also pathognomonic of rabies although it occurs less often than hydrophobia (approximately 9 percent in one series) [53]. Pharyngeal spasms are triggered upon feeling a draft of air and can last approximately 5 to 15 seconds. Painful inspiratory spasms of the diaphragm and accessory inspiratory muscles can lead to aspiration, coughing, choking, vomiting and hiccups; when severe, these spasms can lead to asphyxiation and respiratory arrest [8,12].

The facial muscles may contract leading to a grimace, and the neck and back can become hyperextended with muscle spasticity (referred to as opisthotonos).

Autonomic instability is observed in approximately 25 percent of patients [52]. Signs of overactivity of the autonomic nervous system include hypersalivation, lacrimation, sweating, "goose flesh" and dilatation of the pupils. Hyperpyrexia alternating with hypothermia has been described. Tachycardia and cardiac arrhythmias are common and may be related to myocarditis from direct viral injury [54].

Patients may exhibit dysarthria, dysphagia or may complain of diplopia or vertigo. Dysphagia was reported in approximately half of all cases in one retrospective series [52].

Agitation and combativeness are also commonly seen (approximately 50 percent of patients) [52]. Intermittently, the patient may display symptoms of generalized arousal or hyperexcitability associated with disorientation, fluctuating consciousness, restlessness, agitation, and visual or auditory hallucinations. Patients may become aggressive and maniacal followed by periods of calm.

The physical examination is notable for mental status changes, increased muscular tone and tendon reflexes with extensor plantar responses and fasciculations. Nuchal rigidity may be present. Once the patient develops coma, flaccid paralysis with generalized areflexia is usually noted. Patients usually die as a result of respiratory failure and vascular collapse.

Paralytic rabies — Fewer than 20 percent of rabies patients present with an ascending paralysis, which can mimic Guillain-Barré syndrome. These patients have little evidence of cerebral involvement until late in their course of disease. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

After the prodromal symptoms described above, the patient develops a flaccid paralysis. Paralysis is usually most prominent in the bitten limb, and then spreads symmetrically or asymmetrically. The physical examination is notable for fasciculations; deep tendon and plantar reflexes are lost.

The patient may complain of headache and pain in the affected muscles with mild sensory disturbance. Nuchal rigidity and cranial nerve palsies are occasionally seen, while hydrophobia is unusual.

As the paralysis ascends, there is onset of dense paraplegia with loss of sphincter tone and subsequent paralysis of the muscles of deglutition and respiration, leading to death.

Complications — Most patients with rabies die within two weeks after the onset of coma, although longer courses have been described in the context of intensive care support [22]. In addition, a few cases of survival after clinical rabies have been reported since 2004. (See "Treatment of rabies".)

Patients often die of complications, such as asphyxiation and respiratory arrest secondary to muscular spasms or uncontrolled generalized seizures in encephalitic rabies or respiratory paralysis in paralytic rabies [55].

Supraventricular arrhythmias, atrioventricular block, sinus bradycardia and sinus arrest with non-specific ST segment and T-wave changes have all been reported. Myocarditis has been found at necropsy with evidence of viral invasion and lymphocytic infiltration.

The management of rabies is discussed elsewhere. (See "Treatment of rabies".)

Laboratory findings — Routine laboratory tests are non-specific. A peripheral leukocytosis is often noted. When a constellation of clinical features suggestive of meningitis or encephalitis is present, a lumbar puncture may demonstrate a lymphocytic pleocytosis (mean 60 cells/microL) [52]. CSF protein is characteristically elevated, but typically less than 100 mg/dL, with a normal glucose concentration. A hemorrhagic CSF is not characteristically seen with rabies.

Imaging — CT scans are usually normal in the early phase of the illness. In later stages, cerebral edema may be seen. MR imaging may show areas of increased T2 signaling in the hippocampus, hypothalamus and brainstem [56].

DIAGNOSIS — The diagnosis of rabies requires a thorough patient history and a high index of suspicion [57]. Paresthesia surrounding an animal bite site is suggestive of rabies. Before death, the diagnosis can be made by virus-specific immunofluorescent staining of skin biopsy specimens from the nape of the neck, isolation of virus from the saliva, or detection of anti-rabies antibodies in serum or cerebrospinal fluid (CSF). The clinical evaluation also centers on ruling out other more common and often more treatable illnesses (eg, herpes simplex virus encephalitis) (algorithm 1) [42]. (See 'Differential diagnosis' below.)

Additional information regarding the diagnosis of rabies can be accessed on the Centers for Disease Control and Prevention's website and through consultation with state or local health departments.

Clinical diagnosis — Rabies should be considered in the differential diagnosis of a patient who presents with acute progressive encephalitis, regardless of a history of an animal bite or known exposure. Encephalitic rabies should be suspected based upon hydrophobia and aerophobia. (See 'Clinical manifestations' above and 'Differential diagnosis' below.)

When considering the diagnosis of rabies in a patient who presents with encephalitis, clinicians should take into account the likelihood of infection. As an example, in resource-poor countries, the clinical diagnosis of rabies can be straightforward when a nonimmunized patient presents after a bite by a potentially or known rabid animal.

In contrast, clinical cases of rabies are very rare in the United States, and in the absence of a likely rabies exposure, diagnostic considerations should include pursuit of more common etiologies (see 'Differential diagnosis' below). However, it is important to consider rabies when the cause of encephalitis is not clearly established in order to prevent delays in diagnosis since some patients may have an unrecognized exposure (eg, to a bat) or were unaware of the risks of an exposure and did not receive post-exposure prophylaxis [58]. Among 52 cases of human rabies reported in the United States between 1990 and 2006, approximately 50 percent were diagnosed postmortem [29].

Laboratory diagnosis

General approach — Antemortem diagnosis of rabies requires several specimens (eg, saliva, skin, serum, CSF) and multiple testing modalities, since the sensitivity of any single test is limited. As an example, serum antibody titers may not be present until several days after the onset of clinical signs and may appear even later in the CSF [15]. However, the sensitivity of a combination of tests using all four specimen types approaches 100 percent depending upon specimen quality, timing of collection, and diagnostic expertise.

The accuracy of testing various biologic specimens in the diagnosis of rabies was assessed in a prospective longitudinal study of 51 patients with encephalitis from Madagascar, Cambodia, and France [59]. A total of 425 samples (including saliva, urine, serum, and skin biopsies) were obtained during the acute hospitalization or postmortem. Polymerase chain reaction (PCR) testing of nape of the neck skin biopsies was associated with high sensitivity and specificity (98 and 98.3 percent, respectively), followed by PCR testing of saliva (63.2 and 70.2 percent, respectively). The sensitivity for saliva specimens was improved to 100 percent when at least three samples were tested. The overall sensitivity of urine and serum samples was poor.

Consideration for antibody testing – The interpretation of antibody titers to rabies will depend on the specific specimen and the history of immunization.

In most cases, if no vaccine or rabies immune globulin has been given, the presence of antibody to rabies virus in serum is suggestive of infection. However, a patient who has been previously immunized or has recently received immune globulin may have rabies antibodies in serum. In the immunized patient, a second specimen can be obtained a few days later to see if antibody titers are rising, although serologic testing alone is not recommended as a diagnostic tool [7].

Antibody to virus in a CSF specimen, regardless of immunization history, suggests infection.

Sample collection — Collection of samples for the diagnosis of rabies in the United States should be performed only after consultation with the state or local health department. The United States Centers for Disease Control and Prevention (CDC) maintains a list of state and local contacts for this purpose; information is available at www.cdc.gov. If, after the consultation, it is deemed necessary to collect samples, they should be collected, frozen, and stored at -80°C. Shipping specimens to the Rabies Laboratory at the CDC must be coordinated with, and may be handled by, the state health department. Specimens must be sent on dry ice by an overnight courier.

Collection of specimens outside of the United States should be done consistent with local requirements. Guidance from WHO is that biological fluids such as saliva, CSF, tears and serum, and tissue samples should be stored at -20°C [13]. Brain tissue, for post-mortem testing, should be kept refrigerated or frozen until testing, but samples can be preserved in a 50 percent glycerin-saline solution instead if needed. Samples preserved in this way must be washed to remove the glycerin prior to testing .

All samples should be considered potentially infectious and handled and packaged for shipment with appropriate care. Specific details can be found on the CDC website for locations in the United States. Outside of the United States, specimens should be shipped according to national and international regulations. The WHO has information on packaging and transporting infectious substances on their website.

The following samples and tests should be obtained for testing in the United States:

Saliva – All saliva specimens should be collected and placed in a small sterile container and sealed securely. Laboratory tests include PCR for the detection of viral RNA and viral culture for the isolation of virus.

Skin biopsy – A section of full thickness skin (ie, five to six mm in diameter) should be taken from the posterior region of the neck at the hairline. The sample should contain a minimum of 10 hair follicles that include the cutaneous nerves at the base of the follicles. The specimen should be placed on a piece of sterile gauze moistened with sterile water (without immersion in diluent or transport media) and put in a sealed container. Laboratory tests include PCR and immunofluorescence staining for viral antigen.

Serum and cerebrospinal fluid – A minimum of 0.5 mL of serum and CSF should be obtained for testing. If the patient has been immunized, a second serum specimen should be obtained a few days later to see if antibody titers are rising [7]. Laboratory tests for rabies antibody include indirect immunofluorescence and virus neutralization assays.

Information about samples recommended by the WHO can be found on their website [13].

Postmortem testing — Postmortem testing involves examining brainstem and other neural tissues directly, utilizing immunofluorescence staining for viral antigens. Mononuclear inflammation with abundant rabies virus antigens may be seen distributed diffusely [49]. Negri bodies, eosinophilic neuronal cytoplasmic inclusions (picture 2), are pathognomonic for rabies, but are not present in all cases.

DIFFERENTIAL DIAGNOSIS — The nonspecific prodromal phase may be confused with a multitude of disorders, such as a nonspecific viral illness, mononucleosis, bacteremia, or meningitis. The diagnosis depends on whether the patient evolves a clinical picture suggesting encephalitic or paralytic rabies and is facilitated with a history of possible exposure. (See 'Epidemiology' above.)

In patients with a constellation of symptoms and signs of encephalitis, other more common infections (eg, herpes simplex virus, West Nile virus) and other noninfectious disorders (eg, central nervous system vasculitis, toxic or metabolic encephalopathy, autoimmune encephalitis) should be ruled out (algorithm 1) [42]. One series that compared patients with confirmed rabies with patients having other forms of encephalitis found that rabies cases were distinguished by the presence of hydrophobia, aerophobia, dysphagia, localized pain, weakness, or paresthesia [52]. (See "Herpes simplex virus type 1 encephalitis", section on 'Clinical features' and "Clinical manifestations and diagnosis of West Nile virus infection".)

Other causes of the muscular rigidity that can be seen with rabies include tetanus, phenothiazine dystonia, and strychnine poisoning. Although patients with delirium tremens can demonstrate agitation, experience hallucinations and have tremors, they do not exhibit hydrophobia or aerophobia.

Paralytic rabies may be confused with Guillain-Barré syndrome, poliomyelitis, West Nile virus infection and acute transverse myelitis. Patients with poliomyelitis do not have sensory disturbances and fever does not usually persist with the onset of paralysis. Other acute polyneuropathies, neuromuscular junction disorders, and processes affecting the spinal cord should also be considered. (See "Poliomyelitis and post-polio syndrome" and "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis".)

TREATMENT AND PREVENTION — In general, rabies cannot be effectively treated, so most efforts need to be focused on prevention. Topics addressing prevention and treatment of rabies are found elsewhere. (See "Treatment of rabies" and "Indications for post-exposure rabies prophylaxis" and "Rabies immune globulin and vaccine".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis" and "Society guideline links: Rabies".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Rabies (The Basics)")

Beyond the Basics topic (see "Patient education: Rabies (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Despite the development of the first rabies vaccine in 1885, the World Health Organization estimates that approximately 59,000 people die of rabies worldwide each year. (See 'Introduction' above.)

Rabies and rabies-like illnesses are caused by species of neurotropic viruses in the Rhabdoviridae family, genus Lyssavirus. (See 'Virology' above.)

Lyssaviruses are first amplified near the site of inoculation and subsequently enter local motor and sensory nerves. Viruses then migrate centrally in a retrograde direction within the axoplasm of peripheral nerves until reaching the spinal cord and brain. (See 'Pathogenesis' above.)

Almost all cases of rabies are transmitted from rabid animals through a bite. In resource-poor countries, dogs account for 90 percent or more of reported cases transmitted to humans, whereas bats account for most rabies cases in the United States. In rare cases, rabies may result from a non-bite exposure (eg, saliva contact with open skin or mucous membranes) or via transplantation of tissue or organs from a donor with unrecognized rabies. (See 'Transmission' above.)

Factors that may affect development of disease in the host include the virus variant, the size of the inoculum, the proximity of the bite to the central nervous system, the innervation of the exposed body part, and host genetic variation. (See 'Host susceptibility to infection' above.)

The average incubation period is one to three months, but can be much longer. (See 'Incubation period' above.)

The prodrome consists of nonspecific flu-like symptoms, including malaise, anorexia, irritability, low grade fever, sore throat, headache, nausea, and vomiting. There may also be specific neurologic signs and symptoms at the site of virus entry that are suggestive of rabies, including paresthesia, pain and pruritus. (See 'Prodromal symptoms' above.)

An acute neurologic syndrome of either encephalitic or paralytic rabies follows the prodrome and typically lasts for two to seven days without supportive care. Manifestations may include hyperactivity, persistent fever, fluctuating consciousness, painful pharyngeal or inspiratory spasms, autonomic stimulation (hypersalivation), hydrophobia and seizures. Paralytic rabies is characterized by quadriparesis and sphincter involvement. (See 'Clinical manifestations' above.)

Atypical rabies has been most often described in patients with bat-associated rabies. Atypical features include neuropathic pain, choreiform movements of the bitten limb during the prodromal phase, focal brainstem signs, cranial nerve palsies, myoclonus, and seizures. (See 'Clinical rabies' above.)

The clinical diagnosis of rabies is straightforward in resource-poor countries when a nonimmunized patient presents after a bite by a known or potentially rabid animal. In resource-rich countries, patients may have an unrecognized or unreported exposure (eg, to a bat), and diagnosis is often delayed. (See 'Clinical diagnosis' above.)

Before death, the diagnosis of rabies can be made by isolation of virus or detection of viral RNA by polymerase chain reaction (PCR) testing from the saliva, virus-specific immunofluorescent staining of skin biopsy specimens, or detection of anti-rabies antibodies in serum or cerebrospinal fluid. (See 'Diagnosis' above.)

Since the sensitivity of any single diagnostic test for rabies is limited, antemortem diagnosis of rabies often requires several specimens of saliva, skin, serum, and cerebrospinal fluid and multiple testing modalities, depending on the specimen type. (See 'Sample collection' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Charles Rupprecht, VMD, PhD, who contributed to an earlier version of this topic review.

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Topic 8322 Version 21.0

References

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