Perspective

Rabies in humans remains rare in the United States. Only 36 cases were reported in the United States in the 20 years from 1980 to 2000,^1,2 but rabies exposures in the United States require that approximately 40,000 people receive postexposure prophylaxis annually.³ Human rabies cases in the United States continue to occur, with 2 cases detected in 2008, 4 in 2009, and 1 in 2010.⁴ International travelers are at increased risk of exposure to rabies and may return to the United States to receive postexposure prophylaxis or rabies treatment. Rabies is a fatal disease.^1,2,5,6 Only 6 people are known to have survived the disease.^7–13 The low rate of occurrence of the disease challenges physicians to consider this in the differential diagnosis of encephalitides.

Postexposure prophylaxis, if started before clinical signs of rabies develop, is highly effective. With strict adherence to protocol, including wound care, passive immunization, and vaccination with a cell culture vaccine, postexposure prophylaxis prevents rabies.^2,14–16 Emergency physicians (EPs) should know when to begin rabies postexposure prophylaxis, when to delay it, and when postexposure prophylaxis is not indicated, and they should also know state and local resources for rabies information.

Anatomy

Rabies is transmitted when saliva or neural tissue from an infected host contacts open wounds or mucous membranes of a recipient. This transmission can occur through bites, aerosolized tissue, or tissue transplantation. Rabies virus is not transmitted by blood, feces, or urine. Rabies is not transmitted across intact skin.²

Once the virus is in a new host, it performs one of two actions. Some virus replicates at the site of the bite in non-nerve tissue. The virus then enters peripheral nerves and travels to the central nervous system (CNS). Some virus does not replicate at the site, but rather immediately enters the peripheral motor and sensory nerves for transport to the CNS. During this time, the virus is in an eclipse phase, and it is difficult to detect with diagnostic tests.¹⁷ The virus travels at speeds of 15 to 100 mm/day by retrograde axoplasmic flow.⁶ When the virus enters the CNS, the incubation time ends. Incubation times range from 2 weeks to several years, and the average is 2 to 3 months.^6,17 Once in the CNS, the virus replicates and spreads by cell-to-cell transfer. The virus then travels by anterograde axoplasmic flow to nervous and non-nervous tissue. At the onset of clinical symptoms, the virus is disseminated throughout the body.

Pathophysiology

Rabies is caused by a negative-stranded RNA virus that belongs to the Lyssavirus family. The virus envelope fuses to the host cell membrane, and the virion penetrates the cell, where it replicates and buds new virus.

The virus causes inflammation in the CNS, both encephalitis and myelitis. Perivascular lymphocytic infiltration occurs with lymphocytes, polymorphonuclear leukocytes, and plasma cells. Cytoplasmic eosinophilic inclusion regions (Negri bodies) in neuronal cells are associated with rabies, but they are not sensitive or specific for the diagnosis of rabies.¹⁷ Viral replication in dorsal root ganglia causes ganglionitis, and it is responsible for the first clinical symptoms of the disease.⁵

Clinical Presentation

The first clinical symptoms of rabies are neuropathic pain, paresthesias, or pruritus at the inoculation site. These symptoms were present in 61% of cases in the United States.^5,18 A prodromal, flulike illness may mark the onset of clinical rabies. Brain involvement causes encephalitis, manifesting as delirium with periods of lucidity. Two major clinical forms of the disease exist: furious and paralytic.

Furious rabies is a manifestation of brainstem encephalitis. Hyperexcitability, autonomic dysfunction, and hydrophobia mark furious rabies. Spasms are induced with olfactory, visual, auditory, and tactile stimuli, causing aerophobia and hydrophobia. These spasms are painful, and the patient remains aware of the pain. Spasms are more prominent in the furious form of the disease. Focal neurologic signs are usually absent in furious rabies. The spasms are differentiated from tetanus by a lack of rigidity or trismus between spastic episodes. Involvement of the autonomic nervous system causes hypersalivation, profuse sweating, tachycardia, and hypertension.

Paralytic rabies results in quadriplegia.¹⁹ It is more common after the bite of a vampire bat in South America. Peripheral neuropathy is responsible for the paralysis in paralytic rabies. Because peripheral nerves are involved, patients lose deep tendon reflexes. The paralysis occurs in an ascending pattern and is associated with pain and fasciculations. The anal sphincter is involved in the quadriplegia.⁶ Death results from paralysis of bulbar and respiratory muscles.

At some point in the course of the disease, spontaneous inspiratory spasms occur in all patients with rabies. These painful inspiratory spasms can escalate to opisthotonos, generalized clonus, and respiratory arrest. Inspiratory spasms persist until death. Without treatment, clinical rabies is uniformly fatal in 2 to 10 days.

Differential Diagnosis

The furious form of rabies is rapidly progressive and is fatal in 1 to 5 days (Table 179.1). The paralytic form of rabies is more slowly progressive, and patients live for up to a month. However, clinical rabies is considered a fatal disease regardless of the clinical manifestation.

Table 179.1 Differential Diagnosis of Rabies

Diagnostic Testing

In the early stage of the disease, tests may show negative results.⁶ The “gold standard” for the diagnosis of rabies is direct fluorescent antibody testing of the brain. Brain biopsy exclusively for the diagnosis of rabies is discouraged.^21,22

Multiple testing techniques exist for the diagnosis of rabies during life. Discuss with the pathologist the preferred sample at your institution. Serum, saliva, and skin samples are commonly used, whereas cerebrospinal fluid, urine, and lacrimal fluid are occasionally tested.^6,23 Do not withhold empiric antirabies therapy to obtain diagnostic studies.

Perform a lumbar puncture for analysis of cerebrospinal fluid for meningitis and encephalitis. Sedate the patient, if necessary, to control spasms. Send cerebrospinal fluid for diagnostic studies according to the patient’s geographic exposure. Perform a toxicologic screen to evaluate for intoxication, but remember that intoxicants may be incidental findings.

Rabies Transmission

Rabies is transmitted only by mammals, both domestic and wild. Common wild animals known to contract and transmit rabies include foxes, skunks, raccoons, coyotes, and bats. Dogs, cats, cattle, and other domestic animals can also contract and transmit rabies.

Patients commonly present after bites and scratches from small rodents, both wild and domestic. In these circumstances, wound care and reassurance are all that is required. Rats, mice, squirrels, chipmunks, hamsters, and guinea pigs do not transmit rabies. Rabbits and other lagomorphs have not been found to have rabies and have never been known to cause rabies.

Postexposure prophylaxis is virtually never indicated after a bite from or exposure to any rodent, so the health department should be consulted before initiating postexposure prophylaxis if the animal’s behavior was suspicious and prophylaxis appears clinically indicated.

To assess the likelihood of rabies exposure, it is helpful to know the distribution of rabid animals in the area. The local or state health department can provide information about rabies prevalence and animal vectors. A list of state health department contact numbers is available through the Centers for Disease Control and Prevention (CDC) at http://www.cdc.gov/ncidod/dvrd/rabies/Links/Links.htm