Ograve;²ªÊ ENCEPHALITIS

Synonyms: spring-summer, Far East tick encephalomyelitis. Tick encephalitis is typical seasonaJ natural-focal transmissive infection, cuused by Flavivirus species in ecological group Arboviruses.

Historic reference

As a new nozologic form tick encephalitis was discovered in 1937 in the Far East by Chumakov, Chubladze and other during special expedition. The leader of this expedition was famous scientist L.A. Zilber. During a short period agent and the factor of transmission of the disease were discovered. The epidemiological features of tick encephalitis, clinical manifestations, pathomorphology were studied, also methods of specific prophylaxis and treatment were elaborated. The original course of the disease as two-wave-like type (milk fever) was described by Smorodincev and Chumakov in 1951-1954. In this case the agent of the disease was isolated from goat and cow milk.

Etiology

The agent of tick encephalitis belongs to Flavivirus species in ecological group of Arboviruses. This is RNA-virus, covered by a protein membrane. In connection with the peculiarities in antigenic structures viruses are divided on west and east types, causing various nozogeographical forms of tick encephalitis.

Virus is very well cultivated at the hen's embryos and also on the different cell's cultures. The white mices, monkeys, goat, sheep and horses may be used as laboratory .models for study of infection. Virus is unfirm to high temperature and different physical and chemical agents.

Epidemiology

Tick encephalitis is typical seasonal natural-focal transmissive infection. The basic reservoir and carrier of Arbovirus is ixodes ticks of varies types. The tick becomes infected through 6-7 days after sucking of blood from infected organism (different types of mammals, squirrels, moles, porcupines, rats, field mousses and also a man). The viruses are in the lymphatic system of the tick. Then they spread and concentrate in the sexual organs and salivary glands. Viruses are preserved during all life of the tick (till 4 years). The tick transfers viruses transovarially to the next generations of the ticks.

The infection of the ticks is supported with help of many forest mammals. There is an alimentary way of the transmission of infection in tick encephalitis due to use of unboiled goat or cow milk.

There are 3 types of focuses of the disease: natural focuses, transitional focuses with changes of biocenosis in certain territory, antropurgic. Tick encephalitis is registered in antropurgic focuses in 70 % of all cases. The morbidity has seasonal character (May-June). The focuses of tick encephalitis are known in Central Europe, Scandinavia, Russia.

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Pathogenesis

Penetration gate is mainly the skin, but the intestinal mucous membrane may be also a place of the entrance. Virus enters the lymphatic nodes, internal organs and central nervous system. Viruses multiply in the cells of the central nervous system. The virus causes the degeneration of the cells,multiplies in the mesenchymal cells and supports the inflammation. The inflammatory process is concentrated mainly in the gray matter of the brain and spinal cord, especially in the motile neurones of the brain and cervical part of the spinal cord. The middle brain, thalamus, hypothalamus and cerebellum are also involved into the process.

Anatomic pathology

Edema of the cerebral membranes and the brain matter is marked and also the dilatation and hyperemia of the vessels of the various calibres, hemorrhages occur. The extensive proliferation of the glial cells, necrobiosis of the frontal corns of the cervical part of the spinal cord, reticular formation and nucleus of cranial nerves are also observed. Hemorrhages are observed in mucous membranes of the stomach, intestine, extensive hyperemia of the internal organs occur.

Clinical manifestations

Incubation period is 10-14 days, but it may be from 3 till 60 days. The onset of the disease is acute, with high temperature till 40.0 - 41.0 °Ñ. The disease is accompanied by chill, severe headache, pains in the loin, region pains in the eyeballs. In some cases short prodromal period occurs: weakness, fatigue, headache, sleeplessness, sometimes psychic violations. The next phases are differented in the course of the disease: initial phase with predominance of general toxic syndrome; the phase of neurological disorders with different variants of the central nervous system lesion; the phase of outcomes (recovery or residual manifestations - pareses, paralyses).

There are 5 principal forms of the disease:

1. Feverish form.

2. Meningeal form.

3. Meningoencephalitic form.

4. Meningoencephalomyelytic form.

5. Polyradiculoneuritic form.

It's worth to underline that the severe paralytic forms of tick encephalitis occur more frequently due to eastern variant of the course (Far East,Siberia), In accordance with gravity of the course of the disease the next types of tick encephalitis are differented:

1. Mild form with fever during 3-5 days, signs of the serious meningitis and! recovery during 3-5 weeks.

2. Middle serious form with meningeal symptoms and recovery during 1.5-2 month.

1.

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3. Serious forms with high lethal rate, lingering course, uncomplete recovery with pareses and paralyses.

The fulminate forms are known too. The fulminate forms may be finished by death of the patient during the first day of the disease.

In usual course of tick encephalitis the signs of the damage of the central nervous system are noted from the first days or sometimes from the first hours (pareses, paralyses of the limbs, cramps, disorders of the cerebral nerves.

The violation of the consciousness is observed. It is possible delirium, soporotic state, coma. There is hyperemia of the face, neck and chest, conjunctivitis. The decreased arterial pressure, bradycardia, muffed heart tones are marked. In serious course of the disease myocardiodystrophy develops. It may be development of acute heart failure. Frequently, the disorders of the respiratory center are revealed. It may lead to respiratory failure. It is possible the development of edema of lungs on the background of disorder of myocardium.

In alimentary infection the disorders of intestine is noted. It is accompanied by meteorism, constipations, hepatolienalic syndrome. In the peripheral blood expressive neurotrophilic leukocytosis with the shift of the formula to the left, increased ESR are observed.

Feverish form of tick encephalitis is characterized by the rapid course with development of general toxic syndrome.

Meningeal form is characterized by development of general toxic syndrome and signs of serous meningitis. The severe headache, fever, vomiting are noted. The meningeal signs are revealed: rigidity of occipital muscles, Brudsyndky's symptoms, Kernig's symptom. In some cases the cramps and loss of conciousness may observed. In cerebrospinal puncture the increased pressure of liquor is noted. During testing cerebrospinal liquor the lymphocytic pleocytosis,increased of containment of protein, sugar and chlorides are determined.

Meningoencephalitic form is accompanied by diffusive or local disorder of the brain. In diffusive disorder the manifestations of brain's coma come out on the first plan. The gravity of the state increases due to progressing of edema of brain: from light soporosic state till deep coma. In state near coma the hallucinations may be observed and also delirium, psychomotoric excitement. Cramps of skeletal muscles are marked. During local damage of the nervous system the neurological symptoms are determined in zone of the damage of the substance of central nervous system. Thus in damage of the white substance of the cerebral brain spastic paralysis and pareses of the extremities may arise depending on localization of the pathological process and damages of the cranial nerves and also disorder of the speech. Frequently, hyperkinesises and attacks of the cramps are observed.

Besides that the signs of the violations of innervation of the eyes (diplopia, ptosis,squint) and damages of the nucleuses of the cranial nerves may observed depending on localization of viral damages of the brain.

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Bulbaric symptoms (dysphonia, dysarthria, dysphagia) arise due to damage of the basis of the brain. In increase of bulbaric signs lethal outcomes may be due to disorder of the breath and asphyxia.

Meningoencephalopolyomyelitic form of the disease is characterized by general toxic, meningeal syndromes and sings of diffusive encephalitis, local encephalitis and damage of grey matter of spinal cord. Due to this flabby pareses develop from 3-4 days of the disease, especially of the muscles of the neck, upper extremities and shoulder belt. Rarely the intercostal muscles and diaphragm are damaged. Subsequently the atrophy of the muscles of the neck,shoulder belt and hands develop. The head turns down towards the chest. The volume of the movements of the upper extremities is limited harshly, till full loss of the functions. In rare cases, the damages of the lower extremities may occur too, with violation of the function of the pelvic organs.

Polyradicyloneurotic form of tick encephalitis is manifested by general toxic, meningeal symptoms and signs of the damage of the radices and peripheral nerves.

Two-wave meningoencephalitis (two-wave milk fever) is registered in European focuses of tick encephalitis. This form is characterized by development of two phases of the temperature reaction. The duration of every wave is 2-15 days with interval 1-2 weeks. The first wave of the temperature is accompanied by predominance of general toxic syndrome. The second wave is characterized by development of meningeal signs with frequent positive dynamics and complete recovery without residual appearances.

Complications

The most common complications are asymmetric lower motor neuron paralyses and others neuropsychiatric residua.

Diagnosis

The diagnosis of tick encephalitis is based on the epidemiological and laboratory data.

The specific diagnosis is concluded in detachment of the virus from the blood and cerebrospinal liquor in the early periods of the disease (4-7 day). The different cultures are used for this purpose - chicken's embryo, kidney's epithelium and other. Besides that, the biological method of the of infection by material from the sick infant white mouses is used. The identification of the viruses may be performed also with help of the method of the fluorescence antibodies. The diagnosis may be confirmed serologically by method of pair serums with help of the complement fixation reaction, indirect hemagglutination and neutralization.

Differential diagnosis

The differential diagnosis of tick encephalitis is performed with meningites and encephalites of other etiology (meningococcal infection, tuberculosis, viral diseases), with polyomyelitis, vascular damages of the brain, with coma of different

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genesis (uremic coma, diabetic coma), tumors of the central nervous system, abscess of the brain. It's worth to underline the leading role of the epidemiological anamnesis.

Treatment

The specific treatment of tick encephalitis is performed with help antiencephalitic donor's gammaglobulin, which is injected in a dose of 5-10 mL intramuscularly during 3 days. The course of the treatment is necessary to repeat in case of severe form of encephalitis.

The pathogenetic therapy plays the great role. The remedies for desintoxication, dehydration, sedative remedies and hyperbarric oxygenation are used. In severe cases the artifical ventilation of the lungs is necessary.

Prophylaxis

The prophylaxis of tick encephalitis is performed in the area of the disease. The active specific prophylaxis is performed by epidemic indications over 1 month till appearance and activity of the ticks. The living or killed attenuative vaccines are used. The vaccine is injected subcutaneosly in a dose of 1.0 mL three times with interval of 3-4 months. The revaccination is performed one time every year (1.0 mL of vaccine, subcutaneously). Besides that the measures of the individual prevention are used - special clothes, repellents.

Control questions:

1. Classification of viral encephalitises.

2. Etiology and epidemiology of Japanese encephalitis.

3. Pathogenesis of Japanese encephalitis.

4. Anatomic pathology of disease.

5. Main clinical symptoms and signs of Japanese encephalitis.

6. Complications of encephalitis.

7. The methods of diagnosis of Japanese encephalitis.

8. Differential diagnosis of Japanese encephalitis.

9. Treatment of Japanese encephalitis.

10. Etiology and epidemiology of tick encephalitis.

11. Pathogenesis of tick encephalitis.

12. Main clinical symptoms and signs of tick encephalitis.

13. Complications of tick infection.

14. The methods of diagnosis of tick encephalitis.

15. Differential diagnosis of tick encephalitis.

16. Treatment of tick encephalitis.

17. Preventive measures against encephalitises.

Rabies 263

RABIES

An acute infectious disease of mammals, especially carnivores, characterized by central nervous system wrilation followed by paralysis and death.

Historic reference

Rabies in dogs and the importance of saliva in its transmission may have been recognized in Pharaonic times and in China at least seven centuries BC. But it now seems doubtful whether much-quoted passages from the Babylonian pre-Mosaic Eshnunna code (around 2300 BC) and those attributed to Democritus (500-400 BC) referred specifically to rabies. Aristotle (322 BC) described rabies in animals but seems to deny that humans could be infected or could die from the disease. Celsus in "De medicina" (1st century) described hydrophobia in afflicted humans and recognized that the disease was spread by saliva, although his use of the Latin word "virus" did not imply.a specifically infective origin. He discussed local treatment for the wound, including cupping, suction and cauterization, and the immersion of the patient in sea water. Other persistent myths that arose at that time were the idea that surgical excision of a dog's "tongue worm" (frenulum linguae) would protect it from rabies (as pointless and malicious an operation as that for "tongue tie" in children) and the belief that rabies could be generated spontaneously in dogs. In the sixteenth century, Fracastoro strengthened the concept of rabies as a contagious disease. A scientific or experimental approach to rabies was delayed until 1793, when John Hunter published his very important paper "Observations and heads of enquiry on canine madness". Hunter suggested that the transmission of rabies should be studied by inoculating saliva from rabid animals and humans into dogs and that attempts should be made to inactivate the "poison" in the saliva. These ideas may have inspired the experiments by Zinke (1804) and Magendie and Breschet (1813). Zinke used a paintbrush to introduce saliva from rabid dogs into incisions made in the skin of dogs, cats, rabbits, and chickens, which duly developed signs of rabies. In the same year Magendie and Breschet infected dogs with saliva from human patients with hydrophobia.

Galtier (1879) was responsible for an important technical advance. He found that rabbits could be infected with rabies and were far more convenient experimental animals than dogs. Pasteur adopted the use of rabbits in his studies of rabies beginning in 1880. He was the first to recognize that the major site of infection was the CNS. "Street virus" from a naturally infected dog was passaged through a series of rabbits to produce "fixed virus" with a consistent minimum incubation period of 6 or 7 days. Attenuation of the fixed virus was achieved by desiccation of rabbit

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spinal cord for up to 14 days."Pasteur was able to protect dogs from challenge by immunizing them with the desiccated material, and in 1885 he used his vaccine for the first time in Joseph Meister, a boy severely bitten by a rabid dog. In 1891 passive immunization, using whole blood from vaccinated dogs and humans, was studied by Babes and Cerchez. Negri (1903) described his diagnostic inclusion body, which allowed the laboratory diagnosis of rabies. The introduction of the more specific and sensitive immunofluorescence method by Goldwasser and Kissling in 1958 has now largely replaced the Seller's stain for Negri bodies. The nature of the infective agent was further elucidated by Remlinger (1903), who showed that it would pass through a Berkefeld filter. It was not until 1936 that the size of the virus was established by reliable ultrafiltration studies (Galloway and Elford), and it was first seen as a bullet-shaped particle by electron microscopy in 1962 (Almeida and colleagues).

Improvements in Pasteur's vaccine were achieved by Semple and Fermi, who killed the virus rather than attenuated it, and by Fuenzalida and Palacios, who developed a suckling mouse brain vaccine which carried a lower risk of

neuroparalytic complications.

Successful growth of rabies virus in tissue culture was achieved by Kissling in 1958, leading to the development of human diploid cell strain vaccine by Wiktor and his colleagues in 1964 and of other safe and highly potent tissue culture vaccines. The use of passive immunization with equine hyperimmune serum has been vindicated by the famous natural experiment following an attack by a rabid wolf on 29 people in Iran in 1954.

Etiology

The Rhabdoviruses (Greek "rhabdos" - rod) are a group of about 140 RNA viruses of plants, arthropods, fish, reptiles, birds, and mammals. Rabies and its five related viruses constitute the genus Lyssavirus. The rabies virion is

approximately 180 x 80 nm.

Rabies virus is rapidly inactivated by heat: at 56 °Ñ the half-life is less than 1 minute and, experimentally, the titer decreased by 105 infectious doses within 15 minutes. At 37 °Ñ the half-life is prolonged to several hours in moist conditions.

Repeated intracerebral passage in animals of "street virus" from naturally infected animals results in a "fixed virus" of uniformly shortened incubation period and reduced pathogenicity which is used in vaccine production.

Epidemiology

Rabies is enzootic in mammal populations in most countries. Rabies-free countries include the British Isles, Norway, Sweden, Iceland, Mediterranean and Atlantic islands, Australia, New Guinea, Borneo, New Zealand, Malaysia, Singapore, Japan, Taiwan, and Antarctica. Rabies is spread among animals by bites, ingestion of infected prey, inhalation of aerosols

Important reservoirs of sylvatic rabies include skunks, foxes, raccoons, and insectivorous bats in North America, foxes in the Arctic, mongooses in Granada

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and Puerto Rico, vampire bats in Trinidad, Mexico, Central and South America; wolves, jackals, and small carnivores in Africa and Asia; foxes, wolves, raccoon dogs, insectivorous bats in Europe. Rodents are unlikely to be important. Transmission is mainly by species such as foxes and bats in Europe and foxes, skunks, raccoons, and bats in North America. A separate strain of rabies virus may be peculiar to each mammalian host species.

Domestic dogs, and to a much lesser extent cats, are the main reservoir of urban rabies, which is responsible for more than 90 % of human cases worldwide..

Bat rabies was discovered in the Ukraine in 1964 when a rabid animal was found in Kiev, and two girls have died of bat-transmitted rabies, one in 1977 in Voroshilovograd and the other in 1985 in Belgorod.

The true global incidence of human rabies has been obscured by underreporting. Recently, a figure of 50,000 human deaths per year in India alone was suggested. Other countries reporting a high incidence of human rabies include Pakistan, Bangladesh, Sri Lanka, Philippines, Thailand, Indonesia, Brazil, Colombia, El Salvador, Peru, Ecuador, Mexico and China.

Intact skin is an adequate barrier to the infection,but broken skin and intact mucosa can admit the virus. Human infections usually result from inoculation of virus-laden saliva through the skin by the bite of a rabid dog or other mammal. Scratches, abrasions, and other wounds can be contaminated with infected saliva.

The following are very unusual routes of human infection:

1. Inhalation. This has been reported in caves densely populated with insectivorous bats, which can create an aerosol of rabies virus from infected nasal secretions and possibly urine. In the United States there have been two laboratory accidents involving the inhalation of fixed virus during vaccine preparation.

2. Vaccine-induced rabies (rage de laboratoire). In the worst incident, 18 people developed paralytic rabies in Fortaleza, Brazil, in 1960. The incubation period was 4 to 13 days after inoculation of a vaccine in which the virus had not been inactivated.

3. Corneal transplant grafts. Seven cases have been reported in France, the United States, Thailand, Morocco, and India in which infected comeae were transplanted from donors who had died of unsuspected rabies. Six of the recipients developed rabies and died.

4. Transplacental infection. This has been observed in animals but until recently had not been reported in humans, whereas a number of women who developed rabies encephalitis in late pregnancy were delivered of healthy babies. Transmission of rabies by breast milk is well documented in animals and has been suspected in at least one human case.

Animals can be infected through the gastrointestinal tract (per os and per rectum). In the previrologic era, there were claims that eating infected meat and sexual intercourse could transmit rabies to humans, but these routes remain unproven.

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Pathogenesis

In experimental animals, injected rabies virus replicates locally in striated muscle but is soon detectable at neuromuscular junctions and neuromuscular and neurotendinal spindles. Direct invasion of nerve cells may also occur without prior infection of muscle. Various possible cell surface receptors for attachment of the rabies virus have been suggested, such as phosphatidylserine, carbohydrates, phospholipids, and sialylated gangliosides. At neuromuscular junctions and in the CNS, the postsynaptic nicotinic acetylcholine receptor is an important attachment site for the virus. Binding at these sites is competitive with cholinergic ligands, including the snake venom neurotoxin, alphabungarotoxin, which shows sequence homology with rabies virus glycoprotein.

' Once inside peripheral nerves,the virus is carried centripetally by the flow of axoplasm to the dorsal root ganglia where there is further replication, explaining perhaps the characteristic prodromal symptom of paresthesia at the site of the inoculation. Spread along peripheral nerves can be blocked experimentally by local anesthetics, metabolic inhibitors, and section of the nerves. Spread is rapid through the spinal cord and brain, and there is massive viral replication on membranes of neurons and glial cells and direct transmission of virus from neuron to neuron via the synapses. Virus also exists free and spreads within extracellular spaces such as the CSF. In the early stages of the encephalomyelitis, there is selective infection of certain neuronal populations. Finally, there is a phase of passive centrifugal spread of virus from the nervous system in the axoplasm of many efferent nerves, including those of the autonomic nervous system. Virus has been found in many tissues including skeletal and cardiac muscle, intestine, kidney, liver, pancreas, and brown fat. Extraneural viral replication has been observed in salivary glands, brown fat, and cornea. Virus is shed from salivary and lacrimal glands, taste buds, respiratory tract, and rarely in urine and milk. Viremia has rarely been detected in animals and is not thought to be involved in pathogenesis or spread.

Anatomic pathology

Rabies is an acute nonsuppurative meningoencephalomyelitis. By the time the patient dies, ganglion cell degeneration, perineural and perivascular mononuclear cell infiltration, neuronophagia, and glial nodules may be widespread throughout the brain, spinal cord, and peripheral nerves. However, considering the clinical severity, changes are often surprisingly mild. Inflammatory changes are most marked in the midbrain and medulla in furious rabies and in the spinal cord in paralytic rabies. The diagnostic intracytoplasmic inclusion bodies (Negri bodies) contain viral ribonucleoprotein and probably fragments of cellular organelles such as ribosomes, giving the essential internal structure. They are found in up to 80 % of human cases and are most numerous in the pyramidal cells of Ammon's horn in the hippocampus, in cerebellar Purkinje cells, and in

Rabies 267

the medulla and ganglia. Apart from these inclusion bodies there are no histologic features that distinguish rabies from poliomyelitis or other forms of viral encephalitis. The brain stem, limbic system, and hypothalamus appear to be most severely affected. A spongiform encephalopathy has been demonstrated in skunks and foxes. It probably represents an immunologic effect of infection. Extraneural changes include focal degeneration of salivary and lacrimal glands, pancreas, adrenal medulla, and lymph nodes. An interstitial myocarditis with round cell infiltration has been described. This may be associated with cardiac arrhythmias. The brain of a fatal human case of Mokola virus encephalitis showed perivascular cuffing with lymphocytes and lymphoblastoid cells. Neurons contain large numbers of homogeneous cytoplasmic inclusion bodies,which were quite different in size and appearance from Negri bodies.

Clinical manifestation

The incubation period is between 20 and 90 days and more than two-thirds of cases, with an extreme range of 4 days to more than 20 years. In some animals, latent infections can be reactivated by corticosteroids and stress, providing a possible explanation for the rare authentic reports of very long incubation periods in humans. Facial and severe multiple bites, transmission by corneal transplant, and accidental inoculation of live virus (rage de laboratoire) are associated with relatively short incubation periods. A few days of prodromal symptoms may precede the development of definite signs of rabies encephalomyelitis. These may consist of fever, changes of mood, and nonspecific "flulike" symptoms, but in more than one-third of cases itching, neuritic pain, or paresthesia at the site of the healed bite wound suggests impending rabies. The existence of two distinct clinical patterns of rabies, furious (agitated) and paralytic ("dumb", "rage mue" or "rage muette"), depends on whether the brain or spinal cord is predominantly infected and may reflect differences in the infecting strain of rabies virus or in the host's immune response.

*

Furious rabies, the more common presentation in humans except those infected by vampire bats, is characterized by hydrophobia, aerophobia, and episodic generalized arousal interspersed with lucid intervals of normal cerebration. Hydrophobia is a reflex series of forceful jerky inspiratory muscle spasms provoked by attempts to drink water and associated with an inexplicable terror. A draft of air on the skin produces a similar reflex response, "aerophobia".

Initially, the spasms affect the diaphragm, sternomastoideus, and other accessory muscles of inspiration, but a generalized extension response may be produced ending in opisthotonos and generalized convulsions with cardiac or respiratory arrest. Without supportive care, about one-third of patients with furious rabies die during a hydrophobic spasm in the first few days of their illness. There is hyperesthesia and periods of generalized excitation during which the patient becomes hallucinated, wild, and sometimes aggressive. These grotesque symptoms are explained by a selective

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encephalitis involving the brain stem and limbic system. In rabies, unlike most other encephalitides, patients may remain intermittently conscious and rational. Hypersalivation, lacri-mation, sweating, and fluctuating blood pressure and body temperature result from disturbances of hypothalamic or autonomic nervous system function. Conventional neurologic examination may fail to disclose any abnormality unless a hydrophobic spasm is observed. Physical findings include meningism, cranial nerve and upper motor neuron lesions, muscle fasciculation, and involuntary movements. Increased libido, priapism, and frequent spontaneous orgasms may be the presenting symptom in some patients, suggesting involvement of the amygdaloid nuclei. Furious rabies naturally progresses to coma and death within a week, but some patients have been kept alive for several months in intensive care units.

Paralytic rabies is apparently much less common than the furious form in humans but is frequently undiagnosed. The paralytic form of rabies was also seen in patients with postvaccinal rabies. It seems more likely to develop in patients who have received antirabies vaccine. After the prodromal symptoms (see above), paralysis, fasciculation, pain, and paresthesia start in the bitten limb and ascend symmetrically or asymmetrically. There is progression to paraplegia with sphincter involvement, quadri paresis, and finally paralysis of bulbar and respiratory muscles. Hydrophobia is usually absent. Patients with paralytic rabies may survive for several weeks even without intensive care.

Complications

A large number of complications have been documented in rabies, most occur during the coma phase. Neurologic complications reported in addition to those previously noted include increases in intracranial pressure that may occur during the late neurologic or coma phases; hypothalamic involvement producing inappropriate secretion of antidiuretic hormone and/or diabetes insipidus, and autonomic dysfunction leading to hypertension, hypotension, cardiac arrhythmias, or hypothermia. Seizures are common, may be generalized or focal, and may be accompanied by cardiac arrhythmias, cardiac arrest, or respiratory dysfunction. Respiratory complications occur in all cases. Hyperventilation and respiratory alkalosis appear to be common during the prodrome and early neurologic phase, whereas hypoventilation and respiratory depression develop routinely during the acute neurologic phase. Progressive hypoxia, which is not corrected by increasing the inspired oxygen concentration, and decreased pulmonary compliance also develop later. Cardiac supraventricular arrhythmias are common, and severe bradycardia and cardiac arrest may occur in association with hypoxia. Histologic evidence of myocarditis has been reported. The hypotension that accompanies these problems aggravates preexisting hypoxia, and death follows.

Diagnosis

In the mammal responsible of the bite, rabies can be confirmed within a few hours by immunofluorescence of acetone-fixed brain or spinal cord impression

Rabies 269

smears,a technique that has replaced the classic Seller's stain for Negri bodies which is notoriously difficult to interpret. A simple ELISA test can be used if fluorescence microscopy is not available, and a sensitive avidin-biotin peroxidase method has recently been developed for use with formalin-fixed histologic sections. Rapid examination of CNS tissue in animals suspected of being rabid is now preferred to observing them in captivity for 10 days. In patients, rabies can be confirmed during life by immunofluorescence of skin, and brain biopsies, but the corneal impression smear technique is falsely negative too often to be useful. Early in the illness, rabies virus can be isolated from saliva, brain, CSF, and even spun urine but not blood. Virus isolation in neuroblastoma cell cultures can produce a result in 2 to 4 days instead of the 2 to 3 weeks required for the traditional intracerebral inoculation of mice. In patients who have not been vaccinated or given rabies immune globulin, rabies antibody in serum and especially in the CSF is diagnostic of rabies encephalitis. Rabies-neutralizing antibody leaks across the blood-CSF barrier in patients with postvaccinal encephalomyelitis, but a very high titer suggests a diagnosis of rabies. The only reliable method for distinguishing rabies from postvaccinal encephalomyelitis during life is by the immunofluorescence of skin biopsies. In rabies, lymphocyte pleocytosis rarely exceeds a few hundred cells per microliter. A neutrophil leukocytosis is commonly found in the blood.

Differential diagnosis

The spasms of pharyngeal tetanus may resemble hydrophobia, and this disease can also complicate an animal bite. Severe tetanus is distinguished by its shorter incubation period, the presence of trismus, the persistence of muscular rigidity between spasms, the absence of pleocytosis, and a better prognosis. The rare encephalopathy complicating serum sickness and anaphylactic reactions to Hymenoptera venoms are said to resemble rabies encephalitis. Rabies phobia is an hysterical response to the fear of rabies. It differs from true rabies in its shorter incubation period, often a few hours after the bite, by the emphasis on aggressive and dramatic symptoms, and by its excellent prognosis. Few hysterics could accurately simulate a hydrophobic spasm.

Paralytic rabies should be considered in patients with rapidly ascending flaccid paralysis, suspected Guillain-Barre syndrome, and transverse myelitis. In tropical developing countries that are still dependent on Semple-type and suckling mouse brain rabies vaccines, the most important differential diagnosis is postvaccinal encephalomyelitis. This usually develops within 2 weeks of the first dose of vaccine but has no clinical or laboratory features that reliably distinguish it from rabies while the patient is still alive, except for the absence of demonstrable rabies antigen in skin biopsies (see below). In poliomyelitis there are no sensory abnormalities. Herpes simiae (B virus) encephalomyelitis, which is transmitted by monkey bites, has a shorter incubation period than rabies (3 to 4 days).

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Vesicles may be found in the monkey's mouth and at the site of the bite. The diagnosis can be confirmed virologically and the patient treated with acyclovir.

Treatment

Human rabies remains virtually incurable. Intensive care offers the only hope of prolonging life and, perhaps in a very few cases of paralytic rabies or infection with attenuated virus, of survival. Problems arising during intensive care include a variety of respiratory complications such as aspiration pneumonia, pneumothorax, and respiratory arrest, cardiac arrhythmias, hypertension, pulmonary edema and effects of myocarditis including congestive cardiac failure, generalized convulsions, cerebral edema, inappropriate secretion of antidiuretic hormone or diabetes insipidus, polyneuropathy, hyper- and hypothermia, and hematemesis associated with ulceration or tears in the mucosa of the upper gastrointestinal tract. Heavy sedation and analgesia should be given to relieve the agonizing symptoms. Immunosuppressant agents, including corticosleroids, rabies hyperimmune serum (which may have accelerated death), antiviral agents such as ribavirin, and alpha-interferon have not proved useful. Studies of intrathecal live attenuated vaccines in animals suggest the possibility of applying the treatment in human cases.

Prophylaxis

In rabies endemic areas, those at high risk of exposure to rabid animals should be given pre-exposure vaccination. These include veterinarians, health care personnel, laboratory workers, and dog catchers. In areas where animal rabies is highly prevalent, especially among domestic dogs, there may even be a case for including rabies vaccine in the expanded programs of immunization for children. In nonendemic areas those who come into contact with imported mammals in quarantine, who work with rabies virus in laboratories, or who intend to travel to rabies endemic areas should be vaccinated. Travelers at particular risk of exposure to rabies are zoologists and other field workers, foresters, cave explorers, and those whose work involves walking and cycling in urban and rural areas of India, Southeast Asia, and Latin America. Only tissue culture vaccines are safe enough to use for pre-exposure prophylaxis.

Postexposure prophylaxis. Cleaning the wound as soon as possible after a bite or other contact with a rabid animal is essential first aid and is particularly effective for superficial wounds. The wound should be scrubbed with soap or detergent and generously rinsed under a running tap for at least 5 minutes. Foreign material and dead tissue should be removed under anesthesia. The wound should be irrigated with a viricidal agent such as soap solution, povidone iodine, 0.1 % aqueous iodine, or 40 to 70 % alcohol. Quaternary ammonium compounds, hydrogen peroxide, and mercurochrome are not recommended. Suturing may inoculate virus deeper into the tissues and so should be avoided or delayed when possible. The risk of other viral, bacterial, fungal, and protozoal infections must be considered after bites by animals and humans.

Rabie

Control questions:

1. Etiology, epidemiology and incidence of rabies.

2. Pathogenesis of rabies.

3. Anatomic pathology of disease.

4. Immunology response to rabies encephalomyelitis.

5. Response to vaccination.

6. Main clinical symptoms and signs of human rabies encephalomyelitis

7. Laboratory methods of rabies diagnosis.

8. Differential diagnosis of rabies.

9. Treatment of human rabies encephalomyelitis.

10. Prevention and control of rabies.

11. Pre- and postexposure prophylaxis.

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Date: 2014-12-21; view: 1143