CHAPTER 9 Tropical Neurology, edited by U. K. Misra, J. Kalita and R. A. Shakir. ©2003 Landes Bioscience. Human Rabies: Pathogenesis, Clinical Aspects and Current Recommendations for Prophylaxis Te r apong Tantawichien and Visith Sitprija Rabies infection in man is one of the most common causes of encephalitis in developing countries. It is still an important health problem in many countries and almost inevitably results in death. Rabies affects terrestrial and airborne mammals, including the following families of animals: Canidae (dogs, wolves, foxes and coyotes), Procyonidae (raccoons), Viverridae (mongooses), Mustelidae (skunks, weasels and martens) and Chiroptera (bats) as reservoirs. All mammalian species are, however, believed to be susceptible. Rabies spreads amongst mammals by bites, contamina- tion of intact and abraded mucosal membranes with virus-laden saliva, inhalation of aerosol, ingestion of infected prey and transplacentally. In man, rabies is nearly al- ways secondary to bites, although exposure through the inhalation of the virus or through the transplant of an infected cornea also occurs. Rabies is essentially a zoonosis. The major reservoirs for human rabies are do- mestic dogs, stray dogs and cats. Rabies is a major public health problem in most parts of Asia, South and Central America, Africa and some Pacific Islands where unvaccinated dogs roam freely. Wild animals are less important vectors in rabies endemic areas, but they continue to pose a hazard in North America and in Western Europe. In these areas, most human rabies is due to bites by rabid wild animals, including bats. The World Health Organization (WHO) reports at least 40,000 human deaths annually from rabies, worldwide. Almost all of these deaths have resulted from dog bites. Contrary to the public perception of the disease, almost all fatal cases of rabies in developing countries did not receive post-exposure rabies treatment. These potentially preventable deaths occur primarily in Asia, Africa and Latin America, where animal control, vaccination programs and effective human post-exposure prophylaxis are not widely available. Rabies Virus The rabies virus belongs to the family Rhabdoviridae (genus Lyssavirus). It con- sists of genetically related enveloped viruses with a single, nonsegmented, negative-stranded ribonucleic acid (RNA). The average size of the bullet-shape ra- bies virions is 180 x 75 nm. The negative strand of nonsegmented RNA is closely associated with a nucleoprotein (N) and forms a helical coil. Two proteins are incor- porated into a coil: a nucleocapsid phosphoprotein (NS) and a large RNA-dependent RNA polymerase (L) molecule. A lipoprotein envelope consisting of the matrix (M) protein surrounds the nucleocapsid complex, and the surface projection of the gly- coprotein (G) extends to the exterior of the virus. Rabies virus G protein is the major antigen responsible for inducing and reacting with virus-neutralizing antibodies 155 Human Rabies 9 (VNAs) and thereby conferring immunity against rabies virus. Rabies virus N pro- tein has been shown to be a major target antigen for T-helper cells that cross-react with Lyssavirus. Rabies virus has been seen to make contact with the host cell in tissue cultures at any point on the virion. The glycoprotein probably interacts with cell membrane receptors including carbohydrates, phosphatidylserine and sialylated gangliosides, which may combine to form one or more complex receptor sites. The virus enters the cell either by fusion of its coat with the host-cell membrane or by phagocytosis to form a cytoplasmic vesicle and subsequently fuses with the vesicle membrane. The infectious ribonucleoprotein complex is released into the cytoplasm and replications can commence. 1,2 Continuous cell lines, particularly BHK-21, are most commonly used for isolation and propagation of the rabies virus due to their excellent ability to fix the rabies virus and yield a high virus load. The human dip- loid cell line WI-38 and the Vero cell line are used for human rabies vaccine produc- tion. Street rabies virus isolates (field strains) cannot be consistently recovered from these cells. Primary cell culture and a mouse neuroblastoma cell line give the most reproducible results and are, therefore, frequently used for isolation of the street virus. In animals, many species can be infected with the rabies virus, but there is a hierarchy for susceptibility. The most susceptible species are foxes, coyotes, jackals, voles, kangaroo, rats and wolves. Dogs, which are the most frequent vector for trans- mission to humans, as well as cats, have been shown to be moderately susceptible to rabies virus infection. The rabies virus is inactivated by heat at 56 o C, ultraviolet light, β-propiolactone and detergents. The lipid coat of the virion renders it vulner- able to disruption by detergents and 1% soap solution. Hypochloride and glutaral- dehyde solutions are suitable for laboratory use with the normal precautions, but phenol is not an effective virucidal. Rabies-Related Virus Lyssavirus contains seven viruses: Type 1 is the rabies virus. Rabies-related vi- ruses are classified as type 2, the Lagos bat virus; type 3 is the Mokola virus; type 4 is the Duvenhage virus; type 5 is the European bat Lyssavirus biotype 1; type 6 is the European bat lyssavirus biotype 2; and type 7 is a new isolate from Australian bats. Human rabies has not been found to be related to either type 2 or type 7 Lyssavirus. 1,2 Although rabies-related viruses are pathogenic to mammals, including humans, and infection with these viruses can result in rabies-like encephalitis, the public health significance of rabies-related viruses is still undetermined. Pathogenesis Human infections usually result from inoculation of virus-laden saliva through the skin by the bite of a rabid animal. Intact skin is an adequate barrier to infection, but intact mucosa and broken skin are not. Human infections caused by nonbite exposures include scratches, licks, inhalation of aerosols and the transplantation of an infected cornea. Human to human transmission other than corneal transplanta- tion has not been documented. Thousands of people dying of rabies have been nursed in their poverty stricken homes, yet their relatives, even though in intimate contact with saliva and tears, have not developed rabies. Transplacental infection, recognized in cattle, has been rarely reported in humans. In rabies endemic areas, babies born to mothers with rabies encephalitis were found to be healthy. Several cases of human rabies with no bite exposure have been reported. 3,4. 156 Tropical Neurology 9 The chance of developing rabies after exposure to a rabid animal depends on the location and severity of the bite, the species of animal responsible for the exposure and the virus strain. Bites on the face are more strongly associated with the disease than those on the extremities. The risk of rabies after a bite (5-80%) is about 50 times the risk after scratches (0.1-1%). The risk of rabies is very low from superficial wounds (with no or only minute bleeding), even in areas with abundant nerve sup- ply. Even when the rabies virus has been inoculated in wounds, it may take days or weeks to reach the central nervous system (CNS). This is why post-exposure pro- phylaxis is possible. There is some evidence that the rabies virus can replicate in muscle cells around the wound after the virus glycoprotein has bound to nicotinic acetylcholine receptors on the cell membrane. After multiplication, the virus spreads to the peripheral and central nervous system via neuromuscular connections. Repli- cation of the virus at a low level in myocytes followed by subsequent infection of nerve cells explains the long incubation period of rabies. Some studies have demon- strated that the rabies virus can enter the nervous system directly without prior local replication, resulting in an extremely short incubation period. The importance of replication in non-nerve cells, e.g., macrophages, in the pathogenesis of rabies re- mains controversial. The rabies virus may persist in macrophages, which may later emerge from its persistent state to produce disease. This may explain the long incu- bation period occasionally reported between exposure and death. At the neuromus- cular junction, on the post-synaptic nicotinic acetylcholine receptor, the rabies virus binds in competition with cholinergic ligands. 5 After entry into the peripheral nerve, the rabies virus moves centripetally within the axon to the cell body at an estimated rate of 8-20 mm/day. The progress of the disease may be interrupted by surgical excision or chemical destruction of nerves proximal to the site of inoculation. After reaching the dorsal root ganglion, the rabies virus is able to multiply again. The spread can be either anterograde or retrograde (to or from the cell body) and this virus movement is not affected by the presence of extracellular neutralizing antibod- ies. After reaching the spinal cord, the virus spreads throughout the central nervous system (CNS). Once CNS infection is established, the virus spreads out to the rest of the body via peripheral nerves. Centrifugal spread from the CNS along the auto- nomic nerves to peripheral organs is an important part of the rabies cycle. Although many tissues become infected, a viremia has very rarely been detected in animal models and it is unlikely to be involved in the pathogenesis or spread of rabies. At this stage, the rabies virus is shed from human salivary and lacrimal glands, the respiratory tract, is rarely in urine and is possibly in breast milk. 4 The pathogenesis of the fatal outcome of rabies is not completely understood. Although it is generally believed that human rabies infection is fatal, documented recovery and even chronic persistent infection have been reported in dogs. In CNS, the inflammatory lesions are most commonly noted in the spinal cord and brainstem in both animals and humans. The intensity of these inflammatory lesions depends on the host species, the virus strain, and course of the disease. The most characteris- tic change in the CNS during rabies infection is the formation of cytoplasmic inclu- sion bodies of neurons, ‘Negri bodies’, which consist predominately of viral nucleocapsids. The area of maximum inflammatory change in the human brain and the clinical findings, however, do not correlate with the distribution of rabies virus antigen or Negri bodies in brain tissue. Rabies encephalitis is widespread, but neu- ronal destruction is not. Impairment of neurological function rather than histo- pathological changes is responsible for the development of clinical signs. A regional 157 Human Rabies 9 imbalance in neurotransmitters, including cholinergic and endogenous opioid sys- tems, leads to neurophysiological abnormalities. The remote effects from the actual sites of virus replication, particularly in the brain stem, have been postulated. 6 Death probably results from the involvement of brain centers controlling the cardiopul- monary system. Immune Response to Rabies In human rabies, once the signs of disease develop, a fatal outcome is virtually certain. Defects in immune recognition or the activation process, or both, may be the underlying mechanisms. Although both humoral and cellular mechanisms are important in successfully clearing the rabies virus, multiple defects of immune re- sponses or “immune paralysis” have been observed in human rabies. Viral replica- tion at an immunologically “privileged” site, especially in the early stage of disease, may also impair immune activation. Antibodies, particularly those with virus-neutralizing activity, play a prominent role in immune defense against infec- tion with rabies, at least on peripheral challenges, presumably by preventing the virus from entering into the CNS. The glycoprotein (G protein) is the antigen that induces viral neutralizing antibodies and is also able to confer immunity against lethal challenge infection. The possible mechanisms whereby antibodies exert their effects include neutralization of the extracellular virus, complement-mediated lysis of virus-infected cells and antibody-dependent cytotoxicity. The rabies virus may be capable of leading to immune suppression. It appears that only a minority (25%) of nonvaccinated rabies patients with both clinical manifestations (encephalitic and paralytic types) develop a measurable antibody response. In rabies patients without a history of vaccination, serum antibodies are first detected on about the tenth day of illness and rise rapidly to higher levels thereafter. Antibodies are also present in cerebrospinal fluid late in the clinical course of the disease. Neutralizing antibodies have a key role in protecting against rabies, but recent studies have demonstrated the complexity of the immune response. The rabies virus induces a variety of T-lymphocyte-mediated responses such as helper T cells which can process virus antigens for lytic attacks by antibody-dependent cytotoxicity or complement lysis, cytotoxic T cell activity, lymphokine production and activation of macrophages. Infection with the rabies virus results in the generation of virus-specific CD8+ and CD4+ T cells. Interestingly, patients who develop a cellular immune response to the virus tend to have the encephalitic (furious) form of the disease rather than the paralytic form, and they die faster (an average of five days) than those who do not mount such a response, as determined by a lymphocyte proliferation assay. In addi- tion, the “early death” phenomenon, in which exposed animals or humans devel- oped earlier onset of rabies, depends on the presence of T cells, indicating that it is mediated by an immunopathologic cellular response. The induction of CD4+ T cells is an integral part of the protective immune response against rabies. The rabies nucleoprotein (N) is the major antigen that induces CD4+ T cells. Elimination of CD4+T cells abrogates the production of IgG neutralizing antibody in response to the rabies virus infection. The G protein appears to be the major antigen that medi- ates a cytotoxic T lymphocyte (CTL) response and is also its major target. The role of CD8+ T cells in the immune defense against rabies is not clear. Some investiga- tors report clearance of the rabies virus after transfer of virus-specific T cells and protection of mice against rabies by a CTL clone. Cytokines, produced either by activated circulating immune cells or by CNS cytokine-secreting cells in the brain 158 Tropical Neurology 9 stem where the virus resides, may cause neuropathophysiologic effects in brain. Re- cent studies confirm defects in natural killer (NK) cell response as well as in T cell activation and in the development of antibodies. NK cells of rabies patients are not fully stimulated, although their numbers are normal. Moreover, the process of acti- vation of NK cells may not occur in rabies patients and may reflect a naive condi- tion. Systemic immune dysfunctions may be affected by manipulation of the neuroendocrine control at the level of the hypothalamo-pituitary-adrenal (HPA) axis during the course of the rabies infection. 6 A recent study has shown that serum cortisol levels are elevated during the early stage in rabies patients, reflecting that the HPA axis is intensely stimulated in the beginning. Clinical Features Not all persons bitten by rabid animals develop the rabies infection. Rabies mor- tality after rabid animal bites varies from 35-57%, depending on the site and sever- ity of the wound. Human rabies is most common in children below 15 years of age, but all age groups are susceptible. Males are more commonly affected than females. There is no seasonal predilection for rabies and the incidence does not differ be- tween urban and rural areas in canine rabies endemic countries. The incubation period is usually one to two months, but may range from less than seven days to six years. Seventy-five percent of patients become ill in the first 90 days after exposure. The incubation period tends to be shortest with severe bites on the face, head and neck, especially in children and in experimental animals injected with large doses of rabies virus. The incubation period appears to be shorter in patients who have re- ceived post-exposure treatment than in those who have not. The incubation period is reported to be more than one year in only 1-7% patients. In rabies-endemic areas where frequent exposure is common, most patients with a reported incubation pe- riod exceeding one year may have been due to unrecognized or trivial exposure to bats or other animals. There may be no history of bite in human rabies. This may be due to an insufficient exposure which may have occurred long before the onset of symptoms that might have been forgotten. The clinical feature of rabies differs in many aspects from other forms of encephalitis. There are two separate types; en- cephalitic (furious) and paralytic (dumb) rabies. The clinical course of rabies can be divided into three general phases: a prodomal phase, an acute neurological phase and coma. In the prodomal period, which lasts 2 to 10 days, the symptoms are usually vague, insidious and nonspecific. The neurological complaints during this period include subtle changes in personality and cognition. Patients become anx- ious, agitated, apprehensive, restless and may have nightmares, insomnia, loss of concentration and depression. A vague feverish illness associated with change of mood may precede, by a week, the appearance of definite signs of rabies encephali- tis. Other symptoms include vague malaise, anorexia, headache, myalgia and symp- toms suggestive of upper respiratory tract infection (sore throat, cough) or gastroenteritis (nausea, vomiting, abdominal pain and diarrhea). Because of the nonspecific nature of these complaints, rabies is seldom considered early in the dif- ferential diagnosis. Only the local symptoms at a bite site, reflecting ganglioneuritis, can be reliable pointers. There can be paresthesae, tingling, itching or burning sen- sations at the bite wound. These symptoms occur at the bite site and may gradually spread to involve the whole limb in a nonradicular pattern or the ipsilateral side of face. The local symptoms may occur distant to the bite site. 7 Such local symptoms must be interpreted with caution. Only an intense progressive local reaction that 159 Human Rabies 9 involves the whole limb is a reliable indicator of rabies. Local symptoms are equally common in patients with encephalitic and paralytic rabies and may be seen in as many as 16-80% of patients. Within hours or a few days, these patients progress to an acute neurological phase and develop signs of nervous system dysfunction. Dur- ing the acute neurological phase, patients may exhibit signs such as anxiety, agita- tion, paralysis and episodes of delirium. The patients in whom hyperactivity is predominant are classified as encephalitic or furious rabies, and when paralysis domi- nates it is called paralytic or dumb rabies. The pathological distinction between the two types of rabies is unclear and does not appear to be based on virologic and antigenic differences. No host factor accounting for the different clinical forms has been found. Two-thirds of rabies patients develop an encephalitic form, and the remaining develop the paralytic form or a condition resembling acute inflammatory polyneuropathy, namely Guillain-Barre syndrome (GBS). Encephalitic Rabies Encephalitic rabies is more familiar and probably a more common presentation in humans, except in those infected by vampire bats. The earliest manifestations are fever and an intense anxiety reaction or nervousness that can be triggered by variety of stimuli. In encephalitic rabies, the main features are agitation, hyperactivity, fluc- tuating consciousness, bizarre behavior, and even nuchal rigidity. The cardinal signs of encephalitic rabies are fluctuating consciousness, phobic spasms (aero- and hy- drophobia), spontaneous inspiratory spasm and signs of autonomic dysfunction. 7,8 Alternating phases of extreme arousal and calm, and lucid intervals are typical of encephalitic rabies. The legendary, but all too real, pathognomonic sign is hydro- phobia. It occurs in all patients with encephalitic rabies; however, phobic spasms may not be present throughout all stages of the disease, especially once drowsiness and coma supervene. Encouraging the patient to swallow or offering a cup of water results in a startled reaction due to spasms of the accessory respiratory muscles of the neck and diaphragm followed by neck flexors or extensors. Aerophobia is frequently present, in which spasm occurs when a current of air is fanned across the face. Res- piratory tract instant reflexes are exaggerated, leading to intermittent inspiratory spasm. Spasms occur spontaneously every few minutes without any stimulus and the phobic spasms continue till the patient lapses into coma. Evidence of autonomic stimulation includes lacrimation, excessive sweating and hypersalivation. Hypersali- vation is a unique feature which persists till the preterminal phase. Other signs of autonomic dysfunction such as fixed dilated or constricted pupils, localized or gen- eralized piloerection, neurogenic pulmonary edema, excessive sweating, priapism and spontaneous ejaculation are occasionally observed during the confusion-agitation stage. Seizures are rare but may occasionally be seen in the preterminal stage. 4,7,8 Patients with the encephalitic presentation generally die within seven days (average five days) after the clinical onset. Paralytic Rabies This form of rabies is less easily diagnosed than the encephalitic form because of lack of aggression and relative sparing of consciousness. A uniform paralytic picture is seen in human victims with vampire bat-transmitted rabies. It is also seen in patients with post-vaccination rabies. The course of disease is usually less progressive and the average length of survival is 13 days in paralytic cases. Fever is a constant finding. Burning, tingling, numbness, cramping or weakness usually start in the 160 Tropical Neurology 9 bitten extremity and then progressively involve all the limbs, followed by a gradually ascending paralysis and hypoesthesia eventually affecting the respiratory muscles. Per- cussion myoedema and piloerection are useful signs in the early phase. In contrast to encephalitic rabies, the sensations are spared and paralysis progresses to quadriplegia with predominant involvement of proximal muscles, loss of deep tendon reflexes and urinary incontinence. Bifacial paresis is as common as in sporadic GBS. At this stage, paralytic rabies may be easily confused with GBS. Hemachuda and colleagues emphasize that fever, intact sensations, urinary incontinence and percussion myo- edema may be used to differentiate paralytic rabies from sporadic case of GBS. 4,7 On rare occasions, presentation as an ascending myelitis with fasciculations, loss of joint position sense and pinprick sensation to the thoracic level has been observed. Inter- estingly, the cardinal signs in encephalitis rabies appear late and may be only mild in paralytic cases. Phobic spasms occur in only half the patients, however, inspiratory spasms occur in all cases during the preterminal stage. As the disease progresses, the patient with paralytic rabies becomes confused and consciousness progressively de- clines to coma. In both encephalitic and paralytic rabies, patients progress with varying rapidity to either coma or recovery, although a fatal outcome is virtually certain. Coma can develop immediately after the onset of clinical symptoms, or can occur up to 14 days after the onset of clinical disease particularly in paralytic patients. It is ex- tremely difficult to diagnose rabies at this stage, however, inspiratory spasms ob- served by special attention are the only helpful signs. The two forms of rabies also are indistinguishable once the patient becomes comatose. In encephalitic rabies, tachypnea and then apnoeustic respiration replace regular breathing, which is inter- spersed with inspiratory spasms and in the terminal phase with ataxic breathing. This pattern is not observed in paralytic rabies. Alveolar hypoventilation and venti- latory failure usually develop before patients with paralytic rabies become obtunded. Death due to rabies occurs because of cardiac or respiratory complications. Fre- quently, during the preterminal stage, cardiac arrhythmia, e.g., supraventricular ta- chycardia and paroxysmal atrial tachycardia, with circulatory collapse are common. On autopsy, the virus may be recovered from the heart, which shows evidence of myocarditis. Numerous complications of the rabies infection contribute to mortal- ity which include cerebral edema, inappropriate antidiuretic hormone secretion, diabetes insipidus, hypoventilation or hyperventilation, alteration in temperature, inability to control blood pressure, myocarditis, renal failure and hematemesis. With the exception of some reports, patients with coma die within one to two weeks despite maximum supportive care. There are two patients with rabies in whom re- covery has been documented. There have been some other claims of human recov- ery but the diagnosis was never proved virologically. Diagnosis The diagnosis of rabies poses little difficulty in a nonimmunized patient present- ing with hydrophobia after a bite by a known rabid animal. When there is doubt, further laboratory confirmation must be attempted. Doubtful circumstances in- clude the absence of an exposure history, atypical manifestations, presence of local symptoms such as itching or paresthesia without other classic neurological manifes- tations and a history of post-exposure vaccination with sheep or mouse brain de- rived vaccine. Human rabies can now be diagnosed before death, however, there is no consistently reliable and sensitive technique for antemortem diagnosis of human 161 Human Rabies 9 rabies. The standard laboratory tests do not help to distinguish rabies from other encephalitis, e.g., the cerebrospinal fluid (CSF) is abnormal in a minority of pa- tients and may reveal a lymphocyte pleocytosis, glucose is normal and there is a modest protein elevation (<100 mg/dl). Laboratory diagnosis of human rabies can be achieved in three ways: antigen detection, isolation of the virus and serology. One of the most important older diagnostic tests is immunofluorescent staining of a skin biopsy from the nape of the neck above the hairline, because the rabies virus tends to localize in hair follicles. 9 The corneal impression test is no longer used because of its low sensitivity. Fluorescent antibody detection, regarded as the most sensitive test, but may have a false-negative result in one-third of patients, particularly during the early stage of the disease. A single negative result, therefore, does not rule out the possibility of rabies. Positive results from this test tend to increase as the disease progresses. Brain biopsy with Negri body detection by Seller’s stain is of no value in antemortem diagnosis due to its poor sensitivity. Polymerase chain reaction (PCR) for diagnosis of human rabies has been tried but only in a small group of patients. An alternative approach for diagnostic purpose includes virus isolation from brain tissue, saliva and CSF. It may be inoculated into suckling mice or, preferably, in cell cultures (mouse neuroblastoma cells). Isolation of the virus by this method is sensi- tive and specific, however, all samples tested must be maintained frozen after collec- tion without any preservative. Serologic approaches to the diagnosis of rabies infection have been employed in both the serum and the CSF. The rapid fluorescent focus inhibition test (RFFIT) is a serological test for rabies neutralizing antibodies. In patients who have not been vaccinated or given rabies immune globulin, rabies antibodies in serum, and espe- cially in the CSF, are diagnostic of rabies encephalitis. Seroconversion usually occurs in the second week of the illness. High antibody levels in the CSF are found after 7-10 days of illness. This is why serological testing is of limited value. Moreover, patients with allergic encephalomyelitis from a nerve tissue rabies vaccine have high rabies antibody titers during the first 14 days of the injection when they may de- velop neurologic complications. Postmortem diagnosis of rabies can be confirmed by the presence of pathogno- monic cytoplasmic inclusions (Negri bodies) in brain tissue, but these are present in less than 80% of cases. Rabies antigen may be detected by fluorescent antibody examination with a higher frequency in brain tissues of dying patients. Postmortem brain and other tissues will still yield the rabies virus. All patients with undiagnosed fatal encephalitis, therefore, should be studied for rabies, and tissue from such pa- tients should not be used for transplantation. Treatment Rabies remains an untreatable infection with near uniform fatality. At present there is no established, specific treatment for human rabies once symptoms have appeared. Antirabies antibodies (rabies polyclonal or monoclonal antibodies), inter- feron and its inducers, immunosuppressive agents (corticosteroid, cytosine arabino- side) and various antiviral drugs (ribavarin, vidarabine, tribavarin) have been used without success. Following rabies, survival has rarely been reported. The fact that all survivors have had a vaccine administered before or after the bite suggests that vac- cination modifies the course of rabies. Intensive care offers the only hope of pro- longing life and perhaps a rare chance of survival in a patient with paralytic rabies. Heavy sedation and analgesia should be given for symptomatic relief. Despite 162 Tropical Neurology 9 excellent intensive care, almost all patients succumb to the disease or its complica- tions within a few weeks of onset. However, intensive life support should be offered when there is uncertainty of the diagnosis, particularly when the history of exposure is absent and clinical signs are considered atypical. 7 Prevention Because of the high mortality rate associated with rabies and absence of an effec- tive antiviral therapy, prevention is essential. Ideally, human rabies should be pre- vented by the elimination of the rabies virus in the animal community. The control of rabies in the animal population will significantly diminish the number of cases of rabies in the community. Animal vaccination programs in developed countries have helped to control rabies in domestic animals and humans; however, the control of wildlife rabies still remains a practical problem for which adequate methods do not currently exit. In less developed countries where dogs, cats, bats, foxes and wild carnivores are the most important reservoirs, there are still a large number of cases of rabies in human populations. The risk of the rabies virus infection in humans can be reduced by decreasing contact with domestic or wild rabid animals, and by rapid intervention with prophylactic measures, such as active and passive immunization. Rabies Vaccine For more than 70 years after Pasteur’s work, vaccines containing nerve tissue have been available. Adverse reactions to nerve tissue vaccines such as neurologic complications have been attributed to the presence of myelinated tissue in the vac- cine. The nerve tissue vaccine is reported to induce a neuroparalytic reaction in one out of 200 to 2,000 persons vaccinated. At present, Semple vaccines made in sheep or goat brains are used throughout Asia and Africa, but they are associated with definite risk of post-vaccinal encephalitis. Suckling mouse brain vaccines have also been developed and have a lower risk of autoimmune allergic encephalitis in ap- proximately 1 in 8,000 persons. Although 14 to 23 daily inoculations were recom- mended for these nerve tissue vaccines, the efficacy of nerve tissue vaccines used in humans has not been evaluated by controlled studies. In addition, post-exposure treatment with these vaccines in patients who have been severely exposed to the rabies virus does not always protect against rabies. The introduction of the duck embryo vaccine (DEV) prepared from virus propagated in embryonic duck eggs has greatly reduced the number of post-vaccinal reactions; however, it is less immuno- genic than the nerve tissue vaccine. 3 The answer to these problems of rabies vaccine safety and antigenicity has been the development of a vaccine prepared from the rabies virus grown in tissue culture free of neuronal tissue. There have been intense efforts worldwide to produce a vaccine at a low cost that is of safe and efficacious. Table 9.1 lists the rabies vaccines that are used worldwide and all formulations with cell or avian culture vaccines currently licensed for use are considered equally safe and efficacious. Many of these new tissue culture vaccines are not exported, but purified Vero cell rabies vaccines (PVRV) and purified chick embryo cell (PCEC) vaccines are available in many tropical endemic areas. The potency of one dose of a tissue culture vaccine is >2.5 international units (IU) per dose, as per WHO stan- dard. Despite the aforementioned developments, cell culture rabies vaccines are still used less commonly throughout the world than nerve tissue vaccines. 163 Human Rabies 9 Table 9.1. Important rabies vaccines for humans Vaccine Name Virus Strain Substrate Type Where Used Cell-culture Human diploid cell culture (HDCV) PM-strain Human culture β-Propiolactone United States, Europe, fibroblasts -inactivated ROW Purified chick embryo cell (PCEVC) Flury LP Chick embryo cell β-Propiolactone Germany, United States, -inactivated ROW Rabies vaccine absorbed (RVA) Kissling Fetal rhesus lung β-Propiolactone United States diploid cell -inactivated Purified Vero cell (PVRV) PM-strain Vero cell β-Propiolactone France, Europe, ROW -inactivated Primary hamster kidney cell (PHKCV) Beijing, or Vnokovo Primary Syrian Formalin China, Russia hamster kidney cell -inactivated A vian Purified duck embryo cell (PDEV) PM-strain Duck embryo β-Propiolactone Europe, ROW -inactivated Nerve-tissue Semple Several Sheep, goat or Phenol Asia, Africa rabbit brain -inactivated Fuenzalida Several Suckling mouse Inactivated Asia, Africa brain Abbreviation: ROW, rest of world [...]... cells express Bcl-2, an anti-apoptosis factor Further immunohistochemical studies have suggested the importance of very late antigen -4 (VLA -4 ) / \vascular cell adhesion molecule-1 (VCAM-1) interactions as the major pathway for lymphocyte recruitment into the chronic inflammatory regions and an involvement of monocyte chemo-attractant protein-1(MCP-1) and lymphocyte functionTropical Neurology, edited... neurophysiological and neuropathological findings Neurology 19 74; 24( 3):21 1-2 18 Nagano I, Nakamura S, Yoshioka M et al Expression of cytokines in brain lesions in subacute sclerosing panencephalitis Neurology 19 94; 44 :71 0-7 15 Prabhakar S, Mathen DK Subacute sclerosing panencephalitis In: Chopra JS, Sawhney IMS eds Neurology in Tropics New Delhi: BI Churchill Livingstone, 1999:21 4- 2 26 Jabbour JT, Garcia JH Lemmi H... 1969; 207:2 24 8-2 2 54 Gascon G, Yamani S, Crowell J et al Combined oral isoprinosine-intraventricular alpha interferon therapy for subacute sclerosing panencephalitis Brain Dev (Tokyo) 1993; 15: 34 6-3 55 Dyken PR, Swift A, Durant RH et al Longterm followup of patients with subacute sclerosing panencephalitis treated with inosiplex Ann Neurol 1982; 11:35 9-3 64 10 1 84 Tropical Neurology 12 13 14 15 16 17 18... Inc., 1997:57 3-6 00 Bear GM, Shaddock JH, Quirion R, Dam TV, Lentz TL Rabies susceptibility and acetylcholine receptor Lancet 1990; 335:66 4- 6 65 9 1 74 Tropical Neurology 6 7 8 9 10 11 12 13 14 15 16 9 17 18 Hemachudha T, Phuapradit P Rabies Curr Opinion Neuro1997; 10:26 0-2 67 Hemachudha T Human rabies: Clinical aspects, pathogenesis and potential therapy Curr Top Microbiol Immunol 19 94; 187:12 1-1 43 Warrell... Argentina Total 2 1 1 6 100 38 1 8 1 1 6 100 280 1 8 60 21 1 1 63 10 5 4 7 1 1 1 1 22 1 22 5 70 100 4 4 15 45 0 350 100 4 4 15 45 1188 3150 These are an estimated or reported minimum number of patients with HAM/TSP 11 188 Tropical Neurology A B Fig 11.3 Immunohistological demonstration of CD4+ and CD8+ cells a) HAM patient in active phase with a 4. 5 years disease duration, b) patient in chronic phase with 9... 197 6-1 990 Int J Epidemiol 1992; 21:58 3-5 88 Anlar B, Yalaz K, Oktem F et al Longterm followup of patients with subacute sclerosing panencephalitis treated with intraventricular interferon Neurology 1997; 48 :52 6-5 28 Miller C, Farrington CP, Hasbert K The epidemiology of subacute sclerosing panencephalitis in England and Wales 197 0-1 989 Int J Epidemiol 1992; 21:99 8-1 006 CHAPTER 1 CHAPTER 11 HTLV-I-Associated... endemic areas in the world for adult T-cell leukemia-lymphoma (ATLL) caused by HTLV-I; moreover, Japan is free from malnutrition and yaws, which have been considered possible causes of tropical spastic paraparesis Investigators in other areas of the world have also found a similar association between HTLV-I and myelopathy (Fig 11.1) Tropical spastic paraparesis and HTLV-I-associated myelopathy are thought... different areas: the Caribbean Basin3 and Japan .4 In tropical spastic paraplegia, 59% of patients have antibodies to HTLV-I In Japan, an association of HTLV-I with spastic paraparesis has been found, but these patients resided in a temperate zone We proposed the term HTLV-I-associated myelopathy (HAM) Occurrence of such patients in Japan suggests HTLV-I as a cause of spastic paraparesis because Japan... HLTV-I-associated myelopathy is a chronic inflammatory disease of the spinal cord associated with immunological abnormalities related to HTLV-I infection The clinical features are characterized by slowly progressive spastic paraparesis and positive anti-HTLV-I antibody both in serum and in cerebrospinal fluid.1,2 The association of spastic paraparesis with human T-lymphotropic virus type I (HTLV-I)... response So the patients who have received a non-cell culture rabies vaccine without a documented neutralizing antibody response must undergo the full post-exposure prophylaxis, including RIG, if indicated Human Rabies 171 Pre-Exposure Prophylaxis for Rabies The risk for rabies virus infection can be significantly diminished by pre-exposure prophylaxis in high-risk individuals, such as laboratory personnel . -inactivated A vian Purified duck embryo cell (PDEV) PM-strain Duck embryo β-Propiolactone Europe, ROW -inactivated Nerve-tissue Semple Several Sheep, goat or Phenol Asia, Africa rabbit brain -inactivated Fuenzalida Several. 7, 14 and 28. This is the only US-FDA approved method for post-exposure treatment in the United States. In some European countries, a sixth dose is recommended to be used at 90 days. The “ 2-1 -1 ”. without preservative should be used within 6-8 h if kept at 4 to 8 o C. 14 169 Human Rabies 9 Table 9.3. Standard WHO post-exposure regimens The eight-site intradermal regimen (Oxford regimen):