Clinical manifestations and diagnosis of rabies

Authors: Catherine M Brown, DVM, MSc, MPH, Alfred DeMaria, Jr, MD

Section Editor: Martin S Hirsch, MD
Deputy Editor: Keri K Hall, MD, MS

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2024. | This topic last updated: Jun 14, 2024.

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. Whole genome sequencing, or
sequencing of at least the gene that codes for the inner nucleoprotein virus, is used
to identify the specific lyssavirus [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 appear
to produce neuronal dysfunction rather than neuronal death. Oxidative stress caused
by mitochondrial dysfunction in infected neurons and other cells of the CNS may also
lead 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 [2]. 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 nicotinic acetylcholine receptors, other unidentified receptors may exist to
allow nerve 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 but are not
considered diagnostic for rabies.
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 in 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. Classical rabies virus in bats is
found only in the New World [13], but related lyssaviruses (primarily found in bats)
circulate across the globe and have caused rabies-like illness in humans in Europe,
Africa, and Australia. There are at least 18 other rabies-like lyssaviruses that have
been identified across the world, 16 of them in bats. Rabies is found throughout the
United States, except in Hawaii, in bats and several different terrestrial animal
reservoirs [14].

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-limited countries in
Asia and Africa because of inadequate control of rabies in domesticated animals.

In the United States, there were 95 human cases of rabies reported from 1980
through 2021, with an average of two to three reported per year [15-18]. Among
these cases, almost all those acquired by exposure in the United States were caused
by bat strain rabies virus, 27 (28 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 may result 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-limited countries, rabid dogs account for up to 99

percent of rabies transmitted to humans [26]. 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 [27,28].

Rabies surveillance in the United States has identified four major animal reservoirs:
bats, raccoons, skunks, and foxes ( figure 1) [18,29-32]. Bats have been the leading
source for human cases based upon genetic characterization of the infecting rabies
virus variant. From 1980 through 2021, bat variants of rabies virus accounted for 53 of
61 (87 percent) of indigenously acquired human rabies cases that were not due to
tissue or organ transplant [15,16,33,34]. 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 [35]; 37
percent had an unknown exposure type, but these patients were unable to be
interviewed due to their clinical condition (since transmission of rabies virus requires
direct contact with infectious saliva, unknown is equivalent to unreported).

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 [30,36,37]. 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 [22,38-42]. 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
[38]. Immunohistochemical and direct fluorescence antibody staining of brain tissue
demonstrated rabies virus and intracytoplasmic viral inclusions ( picture 1).
Antibodies against rabies virus were present in three of the four recipients and in the
donor, who was ultimately determined to have had 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 2013, a kidney transplant recipient died from rabies virus 18 months after
transplantation [39]. Three other organ transplant recipients were asymptomatic
 at the time and received post-exposure prophylaxis; all three survived.
● In 2015, two patients who received kidneys transplanted from a donor who died
of a rabies-like illness developed signs and symptoms of rabies 42 and 48 days
after transplant [43]. In contrast, two cornea recipients who received post-
exposure prophylaxis remained well for at least eight months.

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 [12,15,44-46]. 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 to a rabid dog in Brazil eight years earlier; latent infection and/or slow
replication were hypothesized [45,47].

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 [38]. In another case, in which rabies
was transmitted from a donor to a transplant recipient, the recipient died from rabies
18 months after transplantation [39].

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 with
infection actually due to an unidentified, more recent exposure [48].

CLINICAL MANIFESTATIONS

Once the patient has exhibited clinical signs of disease, rabies usually leads to
progressive encephalopathy and death, with rare exception [47,49,50]. (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 one week [8].

Paresthesia radiating proximally from the site of a known wound is suggestive of

rabies infection [51]. The patient may describe a variety of dysesthesia, including pain,
tenderness, tingling, itching, burning, localized abnormal temperature sensation, or
numbness at the site [52]. In addition, percussion myoedema (mounding of the
muscle upon percussion) may be present during the prodrome and throughout the
illness [53].

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 follow the prodromal symptoms described above. In
humans, encephalitic rabies is more common (80 percent of cases) [54].

Occasionally, atypical cases have been described, particularly in association with bat
rabies [8]. The 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 [8,50].

Encephalitic rabies — The classic presentation of encephalitic rabies includes fever,

hydrophobia, pharyngeal spasms, and hyperactivity subsiding to paralysis, coma and
death [54]. The following symptoms and signs are classic for this form of rabies
[52,54]:
● Hydrophobia is the most characteristic clinical feature of rabies, occurring in 33 to
50 percent of patients [52,54,55]. After some preliminary feeling of discomfort in
the throat or dysphagia, the patient 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 involuntary
spasms.
● Aerophobia is also pathognomonic of rabies although it occurs less often than
hydrophobia (approximately 9 percent in one series) [56]. Pharyngeal spasms are
triggered by 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,
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 [55].
Signs of autonomic overactivity 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 [57].
● 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 [55].
● Agitation and combativeness are also common (approximately 50 percent of
patients) [55]. 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 [58].

Supraventricular arrhythmias, atrioventricular block, sinus bradycardia and sinus

arrest with non-specific ST segment and T-wave changes, including ST elevation
myocardial infarction [59], 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 often demonstrates a
lymphocytic pleocytosis (mean 60 cells/microL) [55]. 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 [60].

DIAGNOSIS
The diagnosis of rabies requires a thorough patient history and a high index of
suspicion [61]. 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) [44]. (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 [62]. Among 52 cases of human rabies
reported in the United States between 1990 and 2006, approximately 50 percent were
diagnosed postmortem [30].

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 [63]. 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)
ensures that each state has a designated expert; information is available at CDC
contacts for rabies testing. 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 in their 2018 Expert
Consultation on Rabies [13] (starting on p. 23) on their website.

The following samples and tests should be obtained for testing in the United States:
● Saliva – Saliva specimens should be collected and placed in small sterile
containers, 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 which contain 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 [51].

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) [44]. 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 [55].
(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 after 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".)

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SUMMARY AND RECOMMENDATIONS

● Epidemiology – Despite the development of an effective rabies vaccine in 1885,
the World Health Organization estimates that approximately 59,000 people die of
rabies worldwide each year. (See 'Introduction' above.)
● Pathogenesis – Rabies viruses 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.)
● Transmission – Almost all cases of rabies are transmitted from rabid animals
through a bite. In resource-poor countries, dogs account for 99 percent 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, aerosol) or
via transplantation of tissue or organs from a donor with unrecognized rabies.
(See 'Transmission' above.)
● Host factors – 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.)
● Incubation period – The average incubation period is one to three months, but
can be much longer. (See 'Incubation period' above.)
● Prodrome – The prodrome consists of nonspecific 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.)
● Neurologic symptoms – 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 infection – 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.)
● Clinical diagnosis – The clinical diagnosis of rabies is straightforward in most
cases 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.)
● Laboratory diagnosis – Before death, the diagnosis of rabies can be made by
isolation of virus or detection of viral RNA by polymerase chain reaction (PCR)
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.)
● Sample collection – 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.