Handbook of Clinical Neurology, Vol. 123 (3rd series) Neurovirology A.C. Tselis and J. Booss, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 29

Rabies ALAN C. JACKSON* Departments of Internal Medicine (Neurology) and of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada

INTRODUCTION Human and animal rabies have been a problem since antiquity. Worldwide, rabies occurs mainly in developing countries, particularly in Asia and Africa, where canine rabies is endemic. Rabies in wildlife is the main threat to humans in many geographic regions such as the United States and Canada, especially from bats. Unrecognized exposures are a problem with bats. Rabies can be very effectively prevented after recognized exposures, but remains almost universally fatal after the onset of disease. Rabies has fairly typical clinical features, but the diagnosis is often not suspected until late in the clinical course or not at all by physicians in developed countries because cases are infrequent and a history of an animal bite is often absent.

HISTORY OF RABIES Rabies is an important disease today in both humans and animals and it also has a rich history that goes back to antiquity. The Latin word “rabies” is derived from the Sanskrit word rabhas that means “to do violence” (Steele and Fernandez, 1991). The myths of ancient Mesopotamia date back to the third millennium BC, and, according to the Babylonian Creation Epic, Tiamat, the goddess of chaos, was guarded by 11 monsters, including a rabid dog (Carter, 1996). The earliest known Mesopotamian legal code, which was issued in Eshnunna in about 2300 BC, specified a fine of two-thirds of a mina of silver to an owner who failed to confine his mad dog that bit and caused the death of another man (Rosner, 1974). This represents the first of many important historic landmarks in studies on rabies (Table 29.1). Ancient Chinese writings also indicate that rabid dogs were recognized centuries before the birth of Christ (Wilkinson, 1988).

The Greeks coined the word lyssa for rabies in dogs, apparently from the root lud, meaning “violent.” The writings of Democritus, Aristotle, Hippocrates, and Celsus described the clinical features of rabies (Fleming, 1872). Aristotle wrote: “the disease is fatal to the dog itself and to any animal that it may bite, man excepted,” but it is unclear whether or not he thought humans were susceptible to rabies (Wilkinson, 1977). Fracastoro (1930) suggested that he was merely emphasizing that humans may not develop disease after a bite. Hippocrates probably refers to rabies when he says that persons in a frenzy drink very little, are disturbed and frightened, tremble at the least noise, or are seized with convulsions (Fleming, 1872). In 100 AD, Celsus described human rabies and used the term hydrophobia, which is derived from Greek words meaning fear of water. He recognized that the saliva of the biting animal contained the poisonous agent, and he recommended the practice of using caustics, burning, cupping, and also sucking the wounds of those bitten by rabid dogs (Fleming, 1872). Galen also extensively wrote about rabies during the third century (Fleming, 1872). Hence, rabies was prevalent and reasonably well understood in these early times. Thomsen and Blaisdell (1994) postulated that these early ideas about rabies may have come from writings about Cerberus, the multiheaded dog of Hades. A variety of literary sources in the period 800–700 BC, including Homer’s Iliad, contained passages describing this creature, whose task it was to guard the underworld. The myth likely originated in oral folklore. Cerberus manifested mad behavior and emitted poisonous substances from his jaws. This myth resembles the features of rabies and may have influenced classic beliefs about rabies (Thomsen and Blaisdell, 1994). In early times there was the belief that rabies in dogs was caused by the presence of a worm under the tongue.

*Correspondence to: Dr. Alan C. Jackson, Health Sciences Centre, GF-543, 820 Sherbrook Street, Winnipeg, Manitoba R3A 1R9, Canada. Tel: þ1-204-787-1578, Fax: þ1-204-787-1486, E-mail: [email protected]

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A.C. JACKSON

Table 29.1 Historic landmarks in clinical, pathologic, and experimental studies on rabies Date

Event

Reference

2300 BC

Earliest known reference to rabies in Mesopotamia Description of animal rabies by Democritus Pliny writes on prevention and treatment

Rosner (1974)

400 BC 50 AD

100 1546 1769 1804 1885 1889

1892 1903 1951

Celsus recommends local prophylactic measures Description of human rabies by Fracastoro Morgagni speculates that the virus spreads in nerves Experimental transmission of infection with saliva Pasteur immunizes Joseph Meister Prevention of experimental rabies demonstrated by sectioning the sciatic nerve Babes describes microglial nodules Negri bodies are described Electron microscopic studies

1958

Fluorescent antibody staining of antigen in tissues

1965

Experimental studies in mice using antigen detection

Wilkinson (1977) Pliny the Elder and Jones (1963) Fleming (1872) Fracastoro (1930) Morgagni (1960) Zinke (1804) Pasteur (1885) DiVestea and Zagari (1889) Babes (1892) Negri (1903a) Hottle et al. (1951) Goldwasser and Kissling (1958) Johnson (1965)

An early preventive therapy for rabies in dogs that was introduced in Roman times by Pliny the Elder involved cutting the frenulum of the tongue, which is connected to the floor of the mouth, in order to remove the tongue worm (Pliny the Elder and Jones, 1963). Worming dogs was thought to produce somnolence and enlargement of the tongue, which would hinder the teeth from being closed together (Daniel, 1813). In the early 1800 s it was recognized that wormed dogs could die of rabies, but it was thought that they did not have the furious features of the disease (Daniel, 1813). An additional benefit of worming included an impression that it resulted in a dog with a glossier coat. The practice of worming dogs was continued until the 19th century. For many centuries people with rabies exposures traveled to the shrine of St. Hubert in Belgium for the cure of hydrophobia (Fleming, 1872). St. Hubert’s fame came from his miraculous cure of a man with rabies who

launched himself like a mad beast into his congregation, which St. Hubert accomplished by simply asking Jesus to heal the victim (Baer et al., 1996). St. Hubert died in 727 AD. It was felt that the stole of St. Hubert, which works the miracle, was brought from heaven by an angel (Fleming, 1872). He also had a golden key that granted him a special power over evil spirits. The “keys” of St. Hubert consist of an iron ring that was heated red-hot and applied to bite wounds of animals that were bitten by mad dogs. Pilgrimages to the shrine were made until 1919 (Vaultier, 1949; Baer et al., 1996). In 1769 the pathologist Giovanni Battista Morgagni speculated that rabies “virus does not seem to be carried through the veins, but by the nerves, up to their origins” (Morgagni, 1960). In 1804 Zinke (1804) published a volume in German that was designed to prove that the infective agent of rabies was transmitted in infected saliva. This work contained the first recorded planned transmission experiments of a viral disease. He took saliva from a rabid dog and painted it into incisions he had made in healthy animals, and the animals subsequently developed rabies. A few years earlier, in 1793, John Hunter suggested evaluating the transmissibility of rabies between species and indicated that transmission by incision and transfer of infected saliva on the point of a lancet should be feasible. However, it is unclear if Zinke had read this article and if it was the inspiration for his experiments (Wilkinson, 1977). In 1879 Galtier, who was a professor at a veterinary school in Lyon, France, used rabbits in his rabies experiments and noted the paralytic and convulsive features of disease in this species, which was technically much less difficult and dangerous than experiments using dogs and cats (Wilkinson, 1977). Shortly afterwards, the experimental rabbit model was taken up by Louis Pasteur (1822–1895). Pasteur experimentally transmitted rabies virus by inoculating central nervous system (CNS) material of rabid animals into the brains of other animals. He noted progressive shortening of the incubation period to a limit of 6–7 days, in which the virus and the incubation period became “fixed” (Pasteur, 1885). The fixed virus was found to be more neurovirulent than the street (wild-type) virus and it had a shorter and more reproducible incubation period. Pasteur also observed that sequential passage in the CNS led to attenuation for peripheral inoculation (Pasteur et al., 1884). In 1885 Pasteur successfully immunized a 9-year-old boy, Joseph Meister, who had been severely bitten by a rabid dog, with 13 inoculations of infected rabbit spinal cord material. He used spinal cord tissue because this tissue was associated with a higher viral titer than brain tissue. The spinal cord tissue contained previously passaged virus that had been partially inactivated with progressively shorter periods of desiccation, which ranged from

RABIES 15 days (first dose) to 1 day (last dose) (Pasteur, 1885). Joseph Meister never developed rabies. Over the next few decades hundreds of thousands of people with potential rabies exposures were immunized with nervous system vaccinations at the Pasteur Institute in Paris and in other locations throughout the world. Later in life Meister became a caretaker of the Pasteur Institute in Paris. He committed suicide in 1940, apparently because he preferred to die rather than open the tomb of Pasteur to the invading Nazi forces (Haas, 1998). In 1889 DiVestea and Zagari showed that inoculation of rabies virus into the sciatic nerve of a rabbit and a dog caused rabies, and that death could be prevented by sectioning and cauterizing the nerve after injection. They also noted that the clinical signs depended on the location of the inoculated nerve and the site that it entered the CNS. Definitive pathologic diagnosis of rabies became possible in 1903, when Adelchi Negri described the pathognomonic eosinophilic cytoplasmic inclusions in infected neurons using newly developed histologic techniques (Negri, 1903a). Negri thought that inclusions represented protozoan organisms and the putative parasitic organism was named Neurocytes hydrophobiae, probably a result of the similarity with Golgi’s studies on malaria with the demonstration of Plasmodium in red blood cells (Negri, 1909; Kristensson et al., 1996). Electron microscopic studies of Negri bodies were reported in 1951 (Hottle et al., 1951). In 1958 Goldwasser and Kissling used indirect fluorescent antibody staining in order to demonstrate rabies virus antigens in tissues, and this technique subsequently became important for rabies diagnosis. This technique also played an important role in the relatively modern experimental pathogenesis

603

studies of rabies in mice by Richard Johnson (1965), and later in suckling hamsters by Frederick Murphy and coworkers (Murphy et al., 1973a, b).

RABIES VIRUS Rabies virus (genotype 1) is in the virus family Rhabdoviridae and genus Lyssavirus, which includes six other genotypes of lyssaviruses. Five of these six genotypes and Irkut virus (genotype pending) have been recognized to very rarely cause human disease indistinguishable from rabies (Table 29.2). Rabies virus is a single-strand RNA virus with a non-segmented, negative-sense (antisense) genome that consists of 11 932 nucleotides and encodes five proteins: nucleocapsid protein (N), matrix protein (M), phosphoprotein (P), glycoprotein (G), and an RNA-dependent RNA polymerase or large polymerase protein (L). Virus particles are bullet-shaped (Fig. 29.1). At the center of the viral particle is encapsidated RNA forming a ribonucleoprotein (RNP) core consisting of helical genomic RNA associated with the N, P, and L proteins. The RNP is a functional template for transcription and replication (Schnell et al., 2010). The G and M proteins are associated with the lipid bilayer envelope that surrounds the RNP core. The M protein lines the viral envelope and forms an inner leaflet between the envelope and RNP core and the G protein produces spike-like projections on the surface of the viral envelope (Wunner and Conzelmann, 2013). The M protein is critical for viral assembly and budding and it also modulates viral genome replication and transcription (Okumura and Harty, 2011). The G protein plays an important role in viral entry and membrane fusion and also in viral release (Mebatsion et al., 1999;

Table 29.2 Reported human rabies cases due to other Lyssavirus genotypes Virus (genotype)

Year

Location

Age of patient

Reference

Mokola (3)* Mokola (3) Duvenhage (4) Duvenhage (4) Duvenhage (4) European bat Lyssavirus 1 (5) European bat Lyssavirus 1 (5) European bat Lyssavirus 2 (6) European bat Lyssavirus 2 (6) Australian bat Lyssavirus (7) Australian bat Lyssavirus (7) Australian bat Lyssavirus (7) Irkut (pending)

1968 1971 1970 2006 2007 1985 2002 1985 2002 1996 1998 2013 2007

Nigeria Nigeria South Africa South Africa Kenya Russia Ukraine Finland Scotland Australia Australia Australia Russia

3.5 6 31 77 34 11 34 30 55 39 37 8 20

Familusi and Moore (1972) Familusi et al. (1972) Meredith et al. (1971) Paweska et al. (2006) van Thiel et al. (2009) Selimov et al. (1989) Botvinkin et al. (2005) Roine et al. (1988) Nathwani et al. (2003) Samaratunga et al. (1998) Hanna et al. (2000) Francis et al. (2014) Leonova et al. (2009)

*It is doubtful that this patient’s clinical picture was actually caused by Mokola virus infection. Adapted from Jackson (2013a); copyright Elsevier.

604

A.C. JACKSON Glycoprotein (G) 505 a.a.

Lipid membrane

Phosphoprotein (P) 297 a.a.

RNA-dependent RNA-polymerase (L) 2130 a.a.

(-) viral RNA 12 kb

Nucleoprotein (N) 450 a.a.

Matrix protein (M) 202 a.a.

Fig. 29.1. Schematic representation of the rabies virus particle. Viral proteins: N for nucleoprotein, P for phosphoprotein, M for matrix protein, G for glycoprotein, and L for large protein; their length in amino acids is indicated. The viral membrane is covered by the glycoprotein G, whereas M is located beneath the membrane. N is bound to the genomic RNA and together with P and L forms the ribonucleoprotein, which constitutes the active viral replication unit. (Reproduced with permission from Albertini et al., 2011; copyright Elsevier.)

Schnell et al., 2010), and it is the major surface antigen of the virus and induces and binds virus-neutralizing antibodies and is important for immunity.

PATHOGENESIS The sequential pathogenetic steps that occur after an animal bite are outlined in Figure 29.2. Rabies virus is almost always transmitted by an animal bite. Exposure of mucosal membranes or contamination of skin lesions with infectious rabies virus may much less frequently lead to transmission. Rarely, transmission has been documented by aerosol transmission in a laboratory (Winkler et al., 1973; Tillotson et al., 1977b), in caves containing millions of bats (Constantine, 1962), or iatrogenically by transplantation of tissues (cornea or vascular conduit) or solid organs (e.g., kidney and liver) (Srinivasan et al., 2005; Maier et al., 2010; Jackson, 2013a; Vora et al., 2013) (Table 29.3). There have also been three reported cases with corneal transplantation from donors with rabies in which the recipients did not develop rabies (Sureau et al., 1981; Vetter et al., 2011). Studies in experimental animals have indicated that the rabies virus remains close to the site of entry for the vast majority of the long incubation period (typically lasting weeks or months) in rabies (Charlton et al., 1997). With bites involving muscles, the virus binds to the nicotinic acetylcholine receptor, which is present on the postsynaptic side of the neuromuscular junction and serves to localize and concentrate the virus and facilitates its subsequent uptake and transfer to peripheral motor neurons (Lentz et al., 1982). The virus spreads within axons of peripheral nerves by retrograde fast axonal transport,

which was shown using colchicine, a microtubuledisrupting agent, that was applied locally to the sciatic nerve of rats using elastomer cuffs (Tsiang, 1979). The earliest neurologic symptoms are likely related to infection and inflammation in local dorsal root ganglia, which results in paresthesias, pain, or pruritus. Rabies virus also disseminates throughout the CNS in axons by fast axonal transport along neuroanatomic connections. There is centrifugal spread of the virus to multiple organs in the body along autonomic and/or sensory nerves. In rabies vectors there is spread of the virus to the salivary glands with secretion of high-titer virus in the saliva. Rabies virus also spreads to the eyes, heart, gastrointestinal tract, adrenal gland, skin, and other organs. The virus may infect cardiac ganglia and the myocardium (Jackson et al., 1999), with an associated myocarditis causing cardiac complications (Ross and Armentrout, 1962; Cheetham et al., 1970; Raman et al., 1988; Metze and Feiden, 1991).

EPIDEMIOLOGY Worldwide, there are at least 55 000 human cases of rabies each year, and the vast majority of cases are related to endemic dog rabies in developing countries, especially in Asia and Africa, where there is dog-todog transmission of rabies virus and many human exposures are due to dog bites (World Health Organization, 2013). For a variety of economic and cultural reasons, effective methods of controlling dog rabies have not been employed in these locations. In contrast, in North America most human cases of rabies are caused by bat rabies variants. In 61% of human rabies cases due

RABIES

605

Fig. 29.2. Schematic diagram showing the sequential steps in the pathogenesis of rabies after an animal bite/peripheral inoculation of rabies virus. (Reproduced from Jackson and Fu, 2013; copyright Elsevier.)

606

A.C. JACKSON

Table 29.3 Cases of human rabies associated with organ transplantation in the United States (Burton et al., 2005; Srinivasan et al., 2005; Vora et al., 2013) and Germany (Maier et al., 2010)

Donor in United States Recipient 1 Recipient 2 Recipient 3 Recipient 4 Donor in Germany Recipient 1 Recipient 2 Recipient 3 Donor in United States Recipient

Sex/age

Onset of clinical Organ rabies transplanted posttransplantation

Male/20

–

Male/53 Female/50 Male/18 Female/55

Liver Kidney Kidney Iliac artery segment –

Female/26 Female/46 Male/72 Male/47

–

21 days 27 days 27 days 27 days –

Male/20

Lung 6 weeks Kidney 5 weeks Kidney and 5 weeks pancreas – –

Male/49

Kidney

18 months

Adapted from Jackson (2013a); copyright Elsevier.

to bat rabies virus variants there is no history of a bat bite or scratch and in 34% of cases there is no known history of any “contact” with bats at all (De Serres et al., 2008). Many insectivorous bats, such as silver-haired bats (Lasionycteris noctivagans), are small and their bites may not be recognized (Fig. 29.3) and, hence, effective prophylactic therapy may not be initiated after an exposure. The rabies virus variant found in silver-haired and tricolored bats (previously called eastern pipistrelle bats) is presently responsible for most human cases of rabies in the United States (Noah et al., 1998) and Canada. Brazilian (also called Mexican) free-tail bats (Tadarida brasiliensis) are medium-sized bats and frequently have endemic rabies and occasionally transmit rabies virus to humans in the United States. Vampire bats also transmit rabies virus to humans and cattle in Latin America. Some bat species, including big brown bats (Eptesicus fuscus) and little brown bats (Myotis lucifugus), are often present in houses and are frequently infected by rabies virus variants, but uncommonly transmit the infection to humans. Terrestrial rabies in the United States is associated with rabies virus variants that cause rabies in a variety of carnivore species in particular geographic regions (Fig. 29.4). Raccoons have endemic rabies throughout the eastern United States with over 1953 laboratory

Fig. 29.3. (A) Small puncture wound (arrowhead) involving the right ring finger of a bat biologist caused by a defensive bite from a canine tooth of a silver-haired bat (Lasionycteris noctivagans) (bar ¼ 10 mm). (B) Skull of a silver-haired bat (length 17.1 mm) is resting on a distal phalanx, which demonstrates the small size of the bat and its teeth. (Reproduced from Jackson and Fenton, 2001, copyright Elsevier.)

diagnosed cases per year in 2012 with passive surveillance (Dyer et al., 2013). Raccoon rabies has spread slowly north from Florida, beginning at least in the 1940s, and currently involves all states in the eastern United States. Incursions have occurred across the Canadian border into Ontario, Quebec, and New Brunswick. Raccoon rabies has been controlled in Canadian provinces with active rabies control programs. However, transmission of the raccoon rabies virus variant resulting in human rabies is very rare, with only two documented cases to date (Silverstein et al., 2003; Vora et al., 2013). In part, this is likely because raccoon bites/exposures are usually well recognized and appropriate postexposure rabies prophylactic therapy is initiated promptly. Endemic skunk rabies is present in the midwestern United States and California (Dyer et al., 2013) and also in the prairie provinces of Canada. Endemic rabies in red and gray foxes is now uncommon in the United States and rabies in red foxes has been well controlled in Canada (Ontario) and in Europe with the use of oral immunization programs (Rosatte, 2013). Worldwide, a variety of other animals may be vectors

RABIES

607

Fig. 29.4. Distribution of the major rabies virus variants among wild terrestrial reservoirs in the United States, including Alaska (left inset) and Puerto Rico (right inset), 2010. (Reproduced from Blanton et al., 2011.)

of rabies, including mongooses, jackals, coyotes, and wolves, but most human rabies exposures are actually associated with domestic animals, particularly companion animals such as dogs and cats. All mammals are considered potentially susceptible to rabies. However, opossums are considered relatively resistant to rabies (Baer et al., 1990). Rodents are not reservoirs of rabies virus. Small rodents, including mice, rats, chipmunks, squirrels, gerbils, hamsters, and guinea pigs, and lagomorphs (e.g., rabbits and hares) are rarely infected with rabies virus and have not been known to transmit rabies to humans (Manning et al., 2008). Woodchucks account for the majority of rabies in rodents that is reported to the US Centers for Disease Control and Prevention (Childs et al., 1997). Rabies virus variants can be identified using reverse transcription-polymerase chain reaction (RT-PCR) amplification and sequencing or by characterization using monoclonal antibodies. This is especially helpful in human cases in situations in which there is no history of an animal exposure.

PATHOLOGY Pathologic changes in rabies most prominently involve the central and peripheral nervous systems. There are predominantly mononuclear inflammatory changes involving the leptomeninges and perivascular regions, and within the parenchyma of the brain and spinal cord. Leptomeningeal and perivascular infiltrates are mainly composed of lymphocytes and monocytes. Perivascular cuffing is usually found in the gray matter. Microglial nodules are frequently present in the brain parenchyma

and consist of activated microglia/monocytes. In 1892 these nodules were described by Babes and they are called Babes’ nodules and have also been observed in other viral encephalitides and other infectious disorders. Rabies virus is a highly neuronotropic virus that infects many neuronal cell types in the nervous system. In the early 1900s the Italian pathologist and microbiologist Adelchi Negri first described Negri bodies, which are characteristic intracytoplasmic inclusions found in neurons in rabies (Negri, 1903a, b), and are found in 50–90% of human cases (Herzog, 1945; Dupont and Earle, 1965; Jogai et al., 2000). Negri bodies appear as round or oval eosinophilic inclusions, typically 2–10 mL in diameter, on hematoxylin and eosin-stained sections (Fig. 29.5). They are most prominent (larger and numerous) in large neurons such as Purkinje cells (Tangchai et al., 1970). Pathologists have observed that Negri bodies are more likely to be observed in areas with little inflammation (Dupont and Earle, 1965; Iwasaki and Tobita, 2002). Ultrastructurally, Negri bodies are composed of large aggregates of granulofilamentous matrix material and variable numbers of viral particles (Rossiter and Jackson, 2013). Less frequently, rabies virus infects other neural cell types, including astrocytes (Jackson et al., 2000), but this not usually very prominent. Extraneurally, there may be infection of nerve plexuses involving many organs and also in the myocardium and adrenal medulla (Jackson et al., 1999). In rabies vectors, there is usually infection of acinar cells of salivary glands. In human rabies major salivary gland infection is not usually observed, although infection may be present in the minor salivary glands

608

A.C. JACKSON

Fig. 29.5. Three large Negri bodies in the cytoplasm of a cerebellar Purkinje cell from an 8-year-old boy who died of rabies after being bitten by a rabid dog in Mexico. (Reproduced with permission from Jackson and Lopez-Corella, 1996; copyright Massachusetts Medical Society.)

of the tongue (Jackson et al., 1999). Infection of nerve fibers around hair follicles is the basis for antemortem diagnosis using skin biopsies with analysis by antigen and RNA detection techniques (Bryceson et al., 1975; Dacheux et al., 2008).

CLINICAL DISEASE Clinical rabies develops after an incubation period after an exposure, which usually lasts 20–90 days, but may be as short as only a few days (Anderson et al., 1984) or last over a year (Smith et al., 1991; McColl et al., 1993; Gautret et al., 2014) in rare cases. It is likely that the rabies virus remains close to the site of entry (e.g., the bite site) during the majority of the incubation period. There are a variety of non-specific prodromal symptoms, including malaise, headache, fever, anxiety, and agitation, that are typically the earliest symptoms of rabies. The earliest neurologic symptoms are usually paresthesias, pain, and pruritus, which normally occur close to the site of viral entry and likely represent infection and inflammation in local sensory (dorsal root or cranial) ganglia. By this time a wound from a bite may have completely healed.

During the next neurologic phase of rabies, there are two clinical forms of disease: encephalitic (furious) rabies in about 80% of cases and paralytic (dumb) rabies in about 20% of cases. The precise pathophysiologic bases of the two forms of disease are not well understood, but paralytic rabies likely reflects a greater burden of neuronal injury in the spinal cord, nerve roots, and peripheral nerves, whereas the injury in encephalitic rabies more prominently involves the brain parenchyma. In encephalitic rabies there are often episodes of generalized arousal or hyperexcitability separated by lucid intervals (Warrell, 1976). Autonomic dysfunction is very common and includes hypersalivation, piloerection (gooseflesh), cardiac arrhythmias, and priapism. The most characteristic and specific feature of rabies is hydrophobia, which means fear of water. Hydrophobia involves spasms of the diaphragm and other inspiratory muscles, typically lasting 5–15 seconds, on attempts to swallow. This is reinforced by conditioning, and even the sight of liquids may precipitate the spasms. Similarly, a draft of air can produce spasms, which is called aerophobia. Hydrophobia is likely due to selective infection of brainstem neurons near nucleus ambiguus, and there is exaggeration of defensive reflexes that protect the respiratory tract (Warrell, 1976; Warrell et al., 1976). In encephalitic rabies there is usually early brainstem involvement with preservation of consciousness, which is uncommon in other viral encephalitides. As the disease progresses there is progressive impairment of consciousness to stupor and coma and quadriparesis may develop. Cardiac, respiratory, and other organ failure often occurs (Hattwick, 1974) and, if patients are managed aggressively, then they will require endotracheal intubation and mechanical ventilation with medical management in a critical care setting. Paralytic rabies was first described in 1887 (Gamaleia, 1887). In paralytic rabies the paresis usually initially develops in the bitten extremity with subsequent spread to quadriparesis with associated bilateral facial weakness. There is usually minimal sensory involvement and sphincters are often affected. Hydrophobia does not usually develop during the course of paralytic rabies, and the clinical course may last longer with similar progression to coma. Despite aggressive approaches to the therapy of rabies, the disease is almost invariably fatal. Most exceptions have been related to cases in which rabies vaccine was administered prior to the onset of clinical disease (Jackson, 2013b) (Table 29.4). Another case did not receive vaccine and had neutralizing antirabies virus antibodies on clinical presentation (Willoughby et al., 2005), and the favorable outcome was likely related to good supportive care and probably was unrelated to any of the specific elements of the therapy administered.

RABIES

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Table 29.4 Cases of human rabies with recovery

Location

Year

Age of patient

Transmission

United States Argentina

1970 1972

6 45

Bat bite Dog bites

United States

1977

32

Mexico

1992

9

Laboratory (vaccine strain) Dog bites

India

2000

6

Dog bites

United States

2004

15

Brazil

2008

Turkey

Immunization prior to onset

Outcome

Reference

Duck embryo vaccine Suckling mouse brain vaccine Pre-exposure vaccination

Complete recovery Mild sequelae

Hattwick et al. (1972) Porras et al. (1976)

Severe sequelae Severe sequelae*

Bat bite

Postexposure vaccination (combination) Postexposure vaccination (combination) None

Tillotson et al., 1977a, b) Alvarez et al. (1994)

15

Vampire bat bite

Postexposure vaccination

Severe sequelae

2008

17

Dog bites

Complete recovery

India

2011

17

Dog bite

Post-exposure vaccination (one dose) Post-exposure vaccination (four doses)

Chile

2013

25

Dog bite(s)

Post-exposure vaccination (one dose)

Moderate sequelae

Severe sequelae{ Mild sequelae

Severe sequelae

Madhusudana et al. (2002) Willoughby et al. (2005); Hu et al. (2007) Ministerio da Saude in Brazil (2008) Karahocagil et al. (2013) de Souza and Madhusudana (2014) Galvez et al. (2013)

*Patient died less than 4 years after developing rabies with marked neurologic sequelae (Dr. L. Alvarez, personal communication). { Patient died about 2 years after developing rabies with marked neurologic sequelae (Dr. S. Mahusudana, personal communication). Adapted from Jackson (2013a); copyright Elsevier.

The therapeutic approach, which includes therapeutic coma, has been relentlessly promoted and dubbed the “Milwaukee protocol.” However, at least 28 subsequent similar approaches have not been successful (Jackson, 2009, 2010, 2013b) (Table 29.5). A recent 17-year-old patient survived rabies virus infection, but lacked the typical clinical features of rabies and did not require intensive care (Holzmann-Pazgal et al., 2010). She had fever, headache, nuchal rigidity, disorientation, and limb weakness, and had a cerebrospinal fluid (CSF) pleocytosis and enlarged lateral ventricles on magnetic resonance imaging. She developed only a low titer of rabies virus neutralizing antibodies in sera (up to 1:14) after receiving human rabies immune globulin and one dose of rabies vaccine and no detectable neutralizing antibodies in CSF (Holzmann-Pazgal et al., 2010). Other diagnostic tests for rabies (detection of rabies virus antigen and RNA) were negative. Similarly, another case is that of an 8-year-old female from California (Wiedeman et al., 2012). She experienced sore throat and vomiting and later over a few days she developed swallowing difficulties. A few days later she developed abdominal pain and neck and back pain, and then on the next day she had sore throat and abdominal pain and was noted to be confused. She deteriorated

rapidly and required endotracheal intubation. CSF showed 6 leukocytes/mL with a protein of 62 mg/dL. Over the next few days she developed ascending flaccid paralysis, decreased level of consciousness, and fever. Magnetic resonance imaging of brain showed multiple T2 and fluid-attenuated inversion recovery (FLAIR) signal abnormalities in cortical and subcortical regions and in the periventricular white matter. Electrophysiologic studies were consistent with a demyelinating and predominantly motor polyneuropathy. She had rabies virusspecific immunoglobulin G (IgG) and IgM in her serum and CSF, but she did not develop rabies virus neutralizing antibodies. All other diagnostic tests for rabies were also negative. She showed progressive improvement after just over 2 weeks in hospital and was discharged home after another 5 weeks in rehabilitation. The atypical clinical features plus the lack or minimal development of rabies virus neutralizing antibodies suggest that it is unlikely that these two patients developed rabies and recovered. However, the exact etiology and pathogenetic mechanisms involved in the illnesses of these two patients remain elusive. Healthy infants have been born to mothers with rabies (Iehle´ et al., 2008), although a single case report has documented transplacental transmission (Sipahioglu and Alpaut, 1985). Transplacental transmission of rabies

610

A.C. JACKSON

Table 29.5 Cases of human rabies with treatment failures that used the main components of the “Milwaukee Protocol” Year of death

Age and sex of patient

1

2005

47 male

2

2005

46 female

3

2005

72 male

4 5 6

2005 2005 2005

7 8

2006 2006

Unknown 7 male 20–30 female 33 male 16 male

Dog Bat

9

2006

10 female

Bat

10

2006

11 male

Dog (Philippines)

11 12 13 14 15

2007 2007 2007 2008 2008

73 male 55 male 34 female 5 male 55 male

Bat Dog (Morocco) Bat (Kenya) Dog Bat

16 17 18 19 20 21 22 23 24 25

2008 2008 2009 2009 2010 2011 2011 2012 2012 2012

8 female 15 male 37 female 42 male 11 female 41 female 25 male 63 male 9 male 41 male

Colombia Colombia Northern Ireland United States (Virginia) Romania Portugal United States (New York) United States (Massachusetts) Brazil Canada (Ontario)

26

2012

29 male

Cat Vampire bat Dog (South Africa) Dog (India) Cat Dog (Guinea-Bissau) Dog (Afghanistan) Brown bat Marmoset Dog (Dominican Republic) Dog (Mozambique)

27 28

2012 2013

58 female 28 male

Dog (India) Dog variant with no known exposure (Guatemala)

United Kingdom United States (Texas)

Case no.

Virus source

Country

Reference

Kidney and pancreas transplant (dog) Lung transplant (dog) Kidney transplant (dog) Dog Vampire bat Vampire bat

Germany

Maier et al. (2010)

Germany

Maier et al. (2010)

Germany

Maier et al. (2010)

India Brazil Brazil

Bagchi (2005) * *

Thailand United States (Texas) United States (Indiana) United States (California) Canada (Alberta) Germany The Netherlands Equatorial Guinea United States (Missouri)

Hemachudha et al. (2006) Houston Chronicle (2006)

South Africa

Christenson et al. (2007) Christenson et al. (2007) Aramburo et al. (2011) McDermid et al. (2008) Drosten (2007) van Thiel et al. (2009) Rubin et al. (2009) Pue et al. (2009); Turabelidze et al. (2009) Juncosa (2008) Badillo et al. (2009) Hunter et al. (2010) Troell et al. (2010) Luminos et al. (2011) Santos et al. (2012) Javaid et al. (2012) Greer et al. (2013) NE 10 (2012) Branswell (2012) IAfrica.com (2012); Times Live (2012) Pathak et al. (2014) Wallace et al. (2014)

*Personal communication from Dr. Rita Medeiros, University of Para, Belem, Brazil. Updated from Jackson (2011) copyright Elsevier.

virus has also been reported in animals both naturally and experimentally (Afshar, 1979). Human rabies may rarely be due to Lyssavirus genotypes other than rabies virus (Table 29.4). These cases have exhibited clinical features indistinguishable from rabies due to rabies virus, with the exception of one case of a 3.5-year-old girl who had a febrile convulsion reported to be due to Mokola virus infection (Familusi and

Moore, 1972), which was probably not the cause of the convulsion. Cross-contamination in the laboratory is a possible explanation for the viral isolation (Jackson, 2013a).

LABORATORY INVESTIGATIONS Routine blood work is not helpful for rabies diagnosis. CSF analysis frequently shows a mild mononuclear

RABIES pleocytosis (less than 100 leukocytes per mL), which develops in 87% of patients and is present during the first week of illness in 59% (Anderson et al., 1984). Electroencephalography does not show specific changes, although there may be epileptiform activity and seizures may occur during the course of the disease. Computed tomography imaging is only useful to exclude other diseases. Magnetic resonance imaging of the brain may be normal, but may show lesions that are usually located in gray-matter areas of the brain parenchyma, including the brainstem (Hantson et al., 1993; Pleasure and Fischbein, 2000; Awasthi et al., 2001; Laothamatas et al., 2011). Lesions involving spinal nerve roots have also been observed (Laothamatas et al., 1997). More specific laboratory tests for rabies include the detection of neutralizing antirabies virus antibodies in the serum of a previously unvaccinated individual. However, serum antibodies are frequently not present until the second week of illness and patients may die without developing a detectable serum antibody level. Neutralizing antirabies virus antibodies found in CSF are considered strong evidence of rabies encephalomyelitis. A skin biopsy obtained containing hair follicles (minimum of 10) by using a full-thickness punch biopsy (5–6 mm in diameter), which is typically taken from the posterior region of the neck at the hairline, is a valuable diagnostic specimen for rabies. Many sections of the biopsy specimen, which should include several hair follicles, are examined with fluorescent antibody staining for rabies virus antigen that is found in adjacent small sensory nerves (Bryceson et al., 1975; Warrell et al., 1988). Also, rabies virus RNA can be detected in skin biopsies using RT-PCR (Dacheux et al., 2008). Detection of rabies virus RNA in saliva, which can be collected with a sterile eyedropper pipette, by using RT-PCR is also an important diagnostic test. RT-PCR for rabies virus RNA can also be performed on CSF, but the sensitivity is lower than for saliva specimens. It should be emphasized that negative tests for the detection of antigens or RNA never completely exclude a diagnosis of rabies, and, if clinical suspicion is high, then these tests should be repeated.

DIFFERENTIAL DIAGNOSIS The diagnosis of rabies may be difficult if there is no history of an exposure. Patients and their relatives and friends may not be able to recall an animal exposure. There may be a history of recent travel in a rabies-endemic area. Rabies may present with bizarre neuropsychiatric symptoms, and it is most commonly misdiagnosed as a psychiatric or laryngopharyngeal disorder. Rabies hysteria may occur as a psychologic response to the fear of rabies (Wilson et al., 1975). It is often characterized by a shorter incubation period than rabies, aggressive behavior (not common in humans), inability

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of the patient to communicate, and a long clinical course with recovery. Other viral encephalitides may show behavioral disturbances with fluctuations in the level of consciousness. However, hydrophobic spasms are not observed, and it is unusual for a conscious patient to have brainstem signs in other encephalitides. Herpesvirus simiae (B virus) encephalomyelitis, in which there is transmission by monkey bites, is often associated with a shorter incubation period than in rabies and recovery may occur (Whitley, 2004). Rabies may also be misdiagnosed as Creutzfeldt– Jakob disease (Geyer et al., 1997) and, especially in Africa, as cerebral malaria (Mallewa et al., 2007). Tetanus has a shorter incubation period (usually 3–21 days) than rabies, and unlike rabies, it is characterized by sustained muscle rigidity involving paraspinal, abdominal, masseter (trismus), laryngeal, and respiratory muscles with superimposed brief recurrent muscle spasms (Bleck and Brauner, 2004). In tetanus consciousness is preserved, there is no CSF pleocytosis, and the prognosis is much better than in rabies. Anti-N-methyl-D-aspartate receptor (anti-NMDA) encephalitis occurs in young patients (especially females) and is characterized by behavioral changes, autonomic instability, hypoventilation, and seizures, and it has recently been recognized that this autoimmune disease rivals viral etiologies as a cause of encephalitis (Gable et al., 2012). Postvaccinial encephalomyelitis is the most important differential diagnosis in patients immunized with a vaccine derived from neural tissues (e.g., Semple vaccine), which is currently used in only a few resource-poor countries. Local symptoms at the site of the bite, hydrophobic spasms, and alternating intervals of agitation and lucidity are not seen in postvaccinial reactions (Hemachudha, 1989). The clinical features of paralytic rabies resemble the Guillain–Barre´ syndrome, and pathologically the conditions may also be similar (Sheikh et al., 2005). Local symptoms at the site of the bite, piloerection, early or persistent bladder dysfunction, and fever are more suggestive of paralytic rabies. Guillain–Barre´ syndrome may occasionally occur as a postvaccinial complication from rabies vaccines derived from neural tissues, especially with the suckling mouse brain vaccine (Toro et al., 1977).

PREVENTION The best method of reducing human rabies is to eliminate rabies in animal vectors. Worldwide, endemic dog rabies in many countries, particularly in Asia and Africa, remains an important public health problem and the elimination of canine rabies using mass vaccination needs greater attention. Oral vaccination of wildlife vectors such as foxes, raccoons, and coyotes has been very useful in controlling wildlife rabies in a variety of

612 A.C. JACKSON geographic regions (Rosatte, 2013). There is no effective possibility of transmission, healthcare workers should method of controlling rabies in insectivorous bats. initiate body substance precautions as soon as a diagnoRabies can be very effectively prevented after sis of rabies is seriously considered and wear gowns, recognized rabies exposures if current guidelines are gloves, masks, and eye protection, and they may also observed (Centers for Disease Control and Prevention require postexposure prophylaxis after high-risk contact (Manning et al., 2008) and World Health Organization with a patient with rabies. Oral secretions are of partic(2013), which are available on the Morbidity and Mortalular concern because of the possibility that they may conity Weekly Report (http://www.cdc.gov/mmwr/) and tain infectious rabies virus. Failure to consider a World Health Organization (http://www.who.int/en/) diagnosis of rabies and initiate appropriate precautions websites, respectively. Assessment of the risk of an may lead to recommendations for postexposure rabies exposure is based on the nature of the exposure, the speprophylaxis to be given to a large number of healthcare cies, and the clinical status of an animal and whether the workers at a very high cost. For example, 440 individuals animal is available for an observation period of 10 days required postexposure rabies prophylaxis after postmor(limited to dogs, cats, and ferrets) or laboratory testing tem diagnosis of a case of rabies in British Columbia (on brain tissues). If a dog, cat, or ferret remains healthy (Parker et al., 2003). for a period of 10 days after an exposure, then one can Although rabies may be effectively prevented, medconfidently conclude that transmission of rabies virus ical management once the clinical disease develops has did not occur during that exposure. Effective rabies proalmost universally proved to be ineffective, resulting phylaxis includes wound cleansing, rabies immunization in fatal outcomes. In 2003 a group of physicians with with a modern cell culture rabies vaccine (previously five expertise in rabies and rabies researchers published an doses, but recently reduced to four doses at appropriate article with recommendations on therapies that could intervals), and injection of human rabies immune globube considered for an aggressive approach for a patient lin (dose depends on body weight) into and around the with rabies (Jackson et al., 2003). Young and previously wound, with the residual quantity given intramuscularly healthy patients with an early clinical diagnosis of rabies at a distant site from where the vaccine was administered (prior to laboratory confirmation) were felt to be the best (Manning et al., 2008; Rupprecht et al., 2010). potential candidates for aggressive therapy (Jackson Pre-exposure rabies vaccination is available to peret al., 2003). Therapies suggested for consideration sons at risk of having rabies exposures, which simplifies include rabies vaccine, human rabies immune globulin, postexposure therapy. Booster doses of rabies vaccine monoclonal antibodies (for the future), ribavirin, can be given at periodic intervals based on serum antirainterferon-a, and ketamine. The recommendation for bies virus neutralizing antibody titers. Normally, three therapy with ketamine was based on experimental anidoses of rabies vaccine (intramuscularly or intradermal work that was performed at the Pasteur Institute mally) are given at intervals for pre-exposure vaccinain Paris in the early 1990s (Lockhart et al., 1991). Like curtion and two doses of rabies vaccine are given (on rent therapies for a variety of infectious and nondays 0 and 3) after an exposure and no human rabies infectious other diseases, it was felt that a combination immune globulin should be given. Intradermal vaccinaof therapies might be effective in situations in which spetion reduces the volume of vaccine needed and, hence, cific therapies used individually had failed in the past. reduces costs if multiple individuals can be vaccinated In 2004 a patient survived rabies who had not received from a vial of rabies vaccine. rabies vaccine prior to the onset of clinical disease (Willoughby et al., 2005). This 15-year-old female was bitten by a bat on a finger and did not receive postexpoMANAGEMENT OF RABIES sure prophylaxis therapy for rabies. About a month after Apart from the situation with transplantation of tissues the bite she developed clinical features of rabies encephor organs, there is only a single report from Ethiopia alitis and had a CSF pleocytosis. The history of the bat indicating probable human-to-human transmission of bite was not obtained until this late time. Five days after rabies virus in two cases (Fekadu et al., 1996). In this the onset of neurologic symptoms the patient was report, a 41-year-old female died of rabies 33 days after transferred to a tertiary care hospital in Milwaukee, her 5-year-old son died of rabies. He had bitten his Wisconsin. Neutralizing antirabies virus antibodies were mother on her little finger. Additionally, a 5-year-old detected in sera and CSF (initially at titers of 1:102 and boy presented with rabies 36 days after his mother died 1:47, respectively). Nuchal skin biopsies were negative of rabies. He had repeatedly received kisses on his mouth for rabies virus antigen, rabies virus RNA was not from his mother during her illness. There are no reports detected in the skin biopsies or in saliva by RT-PCR, of transmission to healthcare workers, but this remains and viral isolation on saliva was negative. The patient an important theoretic concern. As a result of the was intubated, and put into a drug-induced coma, which

RABIES included the non-competitive NMDA antagonist ketamine at 48 mg/kg/day as a continuous infusion and intravenous midazolam for 7 days. A burst suppression pattern on her electroencephalogram was deliberately maintained and supplemental phenobarbital was given as needed. She also received antiviral therapy, including intravenous ribavirin and amantadine 200 mg/day administered enterally. She improved and was discharged from hospital with neurologic deficits and she subsequently demonstrated further progressive neurologic improvement (Hu et al., 2007). This is the first documented survivor who did not receive any rabies vaccine prior to the onset of clinical rabies. It remains unknown if therapy with one or more specific agents played a significant role in her favorable outcome (Jackson, 2005). Since that time there have been at least 28 cases in which the main components of this approach (the “Milwaukee protocol”) have been used and fatal outcomes have resulted (Table 29.5). The induction of coma per se has no established benefit for the management of infectious diseases of the nervous system, and to date there is no evidence supporting this approach in rabies or other viral encephalitides. Hence, there is little justification for therapeutic coma becoming a routine therapy for the management of rabies. Experimental evidence does not support excitotoxicity in rabies, recent evidence in an animal model argues against this hypothesis, and there was lack of efficacy of ketamine therapy both in vitro and in vivo in a mouse model (Weli et al., 2006). In situations in which there has been strong experimental evidence of excitotoxicity in animal models, multiple clinical trials in humans to date have shown a lack of efficacy of neuroprotective agents in stroke (Ginsberg, 2009). Hence, a neuroprotective effect of a therapy given to a single patient without a credible scientific rationale is highly doubtful and it is much more likely that this patient would also have recovered with only supportive therapy. Neutralizing antirabies virus antibodies are an important marker of an adaptive immune response that is essential for viral clearance (Lafon, 2013). The presence of serum neutralizing antirabies virus antibodies early in a patient’s clinical course, probably occurring in less than 20% of all patients with rabies, is likely an important factor contributing to a favorable outcome. There have been nine survivors of rabies who received rabies vaccine prior to the onset of their disease (and only one without vaccine) (Table 29.4). This indicates that an early immune response is associated with a positive outcome. It should be noted that therapy of encephalitic (furious) rabies with massive doses of human rabies immune globulin resulted in the rapid development of quadriplegia and bilateral facial paralysis (Hemachudha et al., 2003), suggesting an immunopathologic mechanism of

613

neuronal injury. Bat rabies viruses may be less neurovirulent than canine or other variants that are responsible for most human cases of rabies (Lafon, 2005), and rabies due to canine rabies virus variants likely has a less favorable outcome than cases caused by bat rabies variants. One previous survivor of rabies, who was also infected with a bat rabies virus, received rabies vaccine prior to the onset of disease and made a good neurologic recovery (Hattwick et al., 1972). It is unknown if the causative bat rabies virus variant in the Milwaukee case was attenuated and had different biologic properties than previously isolated strains because there was no viral isolation from the case. Finally, most survivors of rabies to date have shown neutralizing antirabies virus antibodies in sera and CSF, but other diagnostic laboratory tests are usually negative for rabies virus antigen and RNA in fluids and tissues (brain tissues not tested). This may be because viral clearance was so effective that centrifugal spread of the infection to peripheral organ sites was reduced or there was very rapid clearance through immune-mediated mechanisms. A Canadian case of rabies was treated with the Milwaukee protocol and, after therapy with therapeutic coma, remained in a brain death-like state for about 4 weeks. At autopsy there was complete loss of neurons in the cerebral cortex and positive staining for rabies virus antigen was observed in both brainstem and cerebellar neurons, indicating a failure of clearance of the viral infection from the brain and also failure of protection against neuronal injury and loss (McDermid et al., 2008). In Germany lung and kidney/pancreas recipients from a rabies virus-infected donor developed rabies and were treated with major components of the Milwaukee protocol, including intravenous midazolam, ketamine, and phenobarbital (in one) (Maier et al., 2010). One patient died within 2 days whereas the other survived 64 days after the onset of clinical rabies. At autopsy the two patients had 1.2–2.3  109 RNA copies/mg of CNS tissue, which indicates ineffective viral clearance by the therapy. The long-surviving patient did show viral clearance from systemic organs and peripheral nerve. Viral clearance had also not occurred at the time of autopsy in a case from Belfast who was exposed in South Africa (Hunter et al., 2010). Hence, Milwaukee protocol therapy has proved ineffective in promoting viral clearance from the CNS in rabies. It remains highly doubtful that the Milwaukee protocol will prove to be useful in the management of human rabies. Unfortunately, promotion and repetition of this therapy may impede progress in developing new effective therapies for rabies. We need a better understanding of basic mechanisms underlying rabies pathogenesis in humans and animals, which may be helpful in the development of novel therapeutic approaches for the management of this disease.

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