Neurological manifestations. distemper virus infect& INTRODUCTION ABSTRACT ~~~ REVIEW

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1 REVIEW Neurological manifestations F 0 01 canine distemper virus infect& A. Tipold, M. Vandevelde and A. Jaggy Institute of Animal Neurology, University of Berne, Bremgartenstrasse 109a, 3001 Bern, Switzerland [ournal ofsmol1 Animul Pructice (1992) 33, ABSTRACT ~~~ Canine distemper virus causes a multisystemic disease in dogs often with severe neurological signs. These signs are the result of viral replication in neurons and glial cells leading to grey matter lesions and demyelination. Inflammation leads to further destruction of the tissue. As extraneural signs are often lacking and only one localisation may be found on neurological examination, distemper may be 'difficult to diagnose. Myoclonus is almost pathognomonic for this disease but occurs in less than half of the cases. The inflammation of the central nervous system that occurs during the chronic stage of the disease can be detected on examination of the cerebrospinal fluid, in particular by determination of the IgG index. Viral antigen can be demonstrated in cerebrospinal fluid cells by fluorescent antibody techniques. The prognosis of nervous distemper is generally poor although dogs can recover from this disease. Treatment is largely supportive and symptomatic. The importance of regular vaccination is stressed. INTRODUCTION Canine distemper was first reported in Europe in 1761 (Fankhauser 1982). For a long time distemper was a major cause of neurological disease in dogs. Although widespread use of vaccination since the 1950s and 1960s markedly reduced the incidence of distemper, outbreaks still occur and neurological manifestations of distemper are by no means rare. Canine distemper is a highly contagious disease caused by a morbillivirus that is closely related to the measles and rinderpest viruses (Appel and Gillespie 1972). Canine distemper virus (CDV) can infect a wide range of carnivores, including members of the Canidae, Procyonidae and Mustelidae (Appel and Gillespie 1972). Dogs with acute systemic CDV infection shed the virus in their faeces, saliva, urine and conjunctival and nasal exudates. The virus enters the host usually by way of an aerosol infection (Appel and others 1981). Virus replication starts in the lymphoid tissues. When lymphatic tissue infection becomes widespread, viraemia develops and an initial rise in body temperature and leucopenia is observed. Viral antigen can be found in buffy coat preparations during this time. Ten to 14 days after inoculation the virus invades various epithelial tissues and the central nervous system. CDV enters the brain parenchyma through the cerebrospinal fluid pathways (Higgins and others 1982) or crosses the blood-brain barrier by way of infected lymphoid cells (Summers and others 1979). In the central nervous system it replicates in neurons and in glial cells, resulting in grey matter and white matter lesions with demyelination. In many cases demyelination is the most important finding. The initial lesions in the white matter are not inflammatory and are the result of viral replication in glial cells (Vandevelde and others 1985). These lesions are characterised by demyelination and occur in predilection sites such as the cerebellum, optic system and spinal cord. A chronic course can result from a late or insufficient immune response against CDV (Krakowka and others 1975, Appel and others 1982). Inflammation in the demyelinating lesions during the chronic disease may lead to further damage of the white matter (Vandevelde and others 1982). The virulence of the viral strain, the age and the immunocompetence of the dog determine the course and outcome of the disease. Strain variations have been studied in experimental distemper, in which the Snyder Hill strain caused a polioencephalomyelitis and the A and R 252 strains of CDV a demyelinating disease

2 Neurological manifestations of canine distemper virus infection (Summers and others 1984). It is uncertain whether Snyder Hill CDV-like viruses occur in nature: the current authors found no evidence that a CDV-induced polioencephalitis, like the Snyder Hill-induced disease, occurs spontaneously. In the acute stage of the infection a severe immunosuppressive effect of CDV is observed (Krakowka and others 1980). Without an effective antiviral immune response infected dogs will develop a rapidly progressive disease and die. Dogs which are able to respond immunologically early to CDV infection will recover with little or no clinical signs. Dogs with a delayed immune response tend to develop a chronic neurological disease (Appel and others 1982). The inflammation is often associated with worsening of the tissue damage and progression of the neurological signs. At this stage of the disease there is intrathecal production of antibodies by infiltrating lymphocytes. These antibodies are directed against CDV as well as against myelin antigens, mainly myelin basic protein (Vandevelde and others 1986). It has been shown in vitro that antiviral antibodies can stimulate macrophages with secretion of free radicals of oxygen (Griot and others 1989). In vitro it has been shown that these radicals are highly toxic to oligodendrocytes, the myelin producing cells (Griot and others 1990). This mechanism could be responsible for the severe tissue damage seen in chronic demyelinating lesions in distemper. CDV is able to persist in the central nervous system despite the presence of an intrathecal immune response providing a continuous source of viral antigen to maintain such tissue damaging reactions. CLINICAL SIGNS ~ Despite the relatively large experimental and neuropathological literature on nervous distemper there are only a few indepth studies on the clinical neurology of distemper. The present authors have studied about 100 well documented cases of nervous distemper during the past few years. Much of what follows is based on this experience. According to most clinical textbooks CDVinfected dogs develop a systemic disease, including fever, gastrointestinal and respiratory signs, followed by neurological disease two or three weeks later. However, such classical presentation is not the rule. It has been claimed in various publications that neurological signs in distemper may occur much later (months or years) after the systemic infection as a post infectious encephalitis. However, there is neither experimental evidence nor any conclu- sive clinicopathological observations in the spontaneous disease to support this notion. According to the owners of the animals in this series, systemic signs were often very mild or absent. Only in a third of the present cases was extraneural involvement such as gastrointestinal or respiratory signs, fever and conjunctivitis noted by the owner, either preceding the neurological signs or occurring simultaneously. On clinical examination two-thirds of the animals were presented with (often mild) extraneural signs, including conjunctivitis and fever, respiratory signs, gastrointestinal involvement, tonsillitis, cachexia and hyperkeratosis of the footpads or of the nose. In a third of the dogs no extraneural signs were found at all. There was neither a breed nor sex predisposition in this material and none has been reported. Although a little more than a half of the cases were younger than one year of age (about a third less than four months of age), distemper was often seen in adult dogs. The duration of the neurological disease varied from a few days to more than one month. Consistent with the literature, which shows that distemper is generally a monophasic disease (Greene and Appel 1990), only one of the present dogs had a chronic relapsing course. Neurological signs vary widely in canine distemper. The signs should reflect the distribution of the virus and lesions in the central nervous system. In the experience of the present authors, a clinicopathological correlation is often lacking in neurological distemper. On histological examination the lesions are mostly multifocal, but often only one localisation is found on clinical examination. For example, in about a third of these cases spinal cord signs with paresis and ataxia of the limbs were the only neurological findings. Other common signs included central vestibular disease (head tilt, nystagmus, tendency to fall, cranial nerve and conscious proprioceptive deficits) and cerebellar disease (ataxia with hypermetria and head bobbing) and generalised or partial seizures. Uni- or bilateral blindness, sometimes with dilated pupils, caused by the frequent involvement of the optic nerves and tracts is present. In some animals, mild swelling of the optic disc or a retinitis may be found on fundic examination. Generalised muscle atrophy is rare as is a clinical presentation of a focal cortical lesion. Myoclonus, that is, rhythmic jerking of single muscles or muscle groups, is a common sign in canine distemper and was found in 40 per cent of these cases, involving mostly the muscles of the limbs, the head and rarely the trunk. Although myoclonus is often considered to be a pathognomonic sign in distemper, it is also observed in other inflammatory diseases of the central ner- 467

3 A. TIPOLD AND OTHERS vous system in dogs. The pathogenesis of myoclonus remains uncertain; experimental studies suggest that focal spinal cord lesions may be responsible. Another possibility is that a basal nucleus lesion may initiate this sign and establish a pacemaker in the spinal cord or brainstem, which maintains the involuntary muscle activity (DeLahunta 1983). It has been reported before that distemper can occur together with other infections in the central nervous system (Greene and Appel 1990). The massive immunosuppression caused by CDV can lead to activation of a latent protozoal infection. In six cases in this series a combined infection of distemper with Toxoplasma gondii or Neospora caninum was found. Such animals had lower motor neuron signs, electromyographic changes including fibrillation potentials and positive sharp waves, slowed nerve conduction velocity and severe myositis as detected on muscle biopsies (Wolf and others 1991). LABORATORY FINDINGS A frequent haematological finding is lymphopenia, sometimes combined with leucopenia or leucocytosis with left shift, anaemia, monocytosis and rarely thrombocytopenia (Greene and Appel 1990). Lymphopenia, a sign of immunosuppression in CDV infection, is also combined with a decrease of lymphocyte responsiveness to lectin stimulation (Cerruti-Sola and others 1983). Serum biochemical findings including electrophoresis are non-specific and rarely useful for diagnosis in this disease. Examination of the cerebrospinal fluid can be a very useful diagnostic procedure in distemper. However, during the acute demyelinating stage of the disease, inflammatory reactions are lacking and protein and cell content of the cerebrospinal fluid may be normal (Vandevelde and others 1986). In the chronic stage of the disease, inflammation occurs with invasion of mononuclear cells in the lesions and the cerebrospinal fluid. In such cases pleocytosis is frequently but not always found (Bichsel and others 1984). Many of the invaded cells are immunoglobulin-producing lymphocytes. By measuring the IgG content in cerebrospinal fluid and serum and using the corresponding albumin values as a reference, the so called IgG index can be determined (Bichsel and others 1984, Tipold and others 1992). The IgG index is elevated in most cases with inflammatory distemper, even in those cases in which no significant pleocytosis can be found. However, the index is normal in most dogs with acute non-inflammatory distemper. The demonstration of an elevated IgG index is very helpful to detect the presence of inflammation of the central nervous system but is not specific for distemper (Tipold and others 1992). DIAGNOSIS A clinical diagnosis of distemper is often difficult when the typical presentation of the disease with neurological signs developing after systemic symptoms is lacking. Likewise, myoclonus, which is highly suggestive of nervous distemper, is lacking in more than half of the cases. When multifocal neurological signs are found, an inflammatory disease of the central nervous systtem is suspected and can be confirmed by cerebrospinal fluid examination. CDV infection should be considered in the differential diagnosis in such cases. As described above, frequently only one localisation is found. Such cases of distemper with focal signs and in which other typical findings such as extraneural signs or myoclonus are lacking, are a diagnostic challenge for the veterinary surgeon. Other focal lesions have to be excluded by a variety of imaging techniques. Careful cerebrospinal fluid examination in such animals may reveal the presence of inflammation suggesting the possibility of CDV infection. A final diagnosis is based on the demonstration of viral antigens in scrapings and body fluids such as conjunctival smears, tracheal washing, urine sediment and cerebrospinal fluid cells. Viral antigen can be hard to find in the extraneural tissues in cases with neurological distemper without systemic signs. Viral antigen can be detected in cerebrospinal fluid cells with an indirect fluorescent antibody test using anti- CDV antibodies. For this technique the cerebrospinal fluid cells have to be concentrated first by sedimentation or centrifugation (Vandevelde and Spano 1977). Frequently, only small numbers of cells can be obtained. The demonstration of anti-cdv antibodies in serum is of limited diagnostic value. Comparing serum antibody titres with intrathecally produced anti-cdv IgG may help diagnostically, however, severely immunosuppressed animals may not have any detectable antibody at all. PROGNOSIS The prognosis of CDV-infection with neurological signs is generally guarded, especially in cases with severe immunosuppression and rapidly progressing clinical signs. Seizures in CDVinfection are an unfavourable prognostic sign because they are generally difficult to control 468

4 Neurological manifestations of canine distemper virus infection with anticonvulsants. Dogs in which the immune response recovers in the early stage of the disease have a better prognosis. When the neurological signs are not debilitating, the animal need not be euthanased as soon as a diagnosis of distemper is established. Because dogs have a chance to recover from the disease, supportive treatment is recommended for one or two weeks to study the course of the condition. TREATMENT The lack of an effective antiviral treatment for CDV infection requires the need for supportive care and symptomatic treatment. The patients should be kept clean, warm and quiet. Fluid therapy should be given to dogs with altered hydration status. Sometimes a parenteral nutrition programme is necessary. Dogs with respiratory signs and with secondary bacterial bronchopneumonia must be given antibiotics. Vitamin B may counteract anorexia. In patients with seizures, anticonvulsants such as phenobarbitone should be administered, but the response is often poor. Corticosteroids are used because of the immunopathological basis of the neural lesions and their potential to combat brain oedema. The immunosuppressive effect of steroids can also be a disadvantage, because the inflammatory response does lead to clearance of the virus (Bollo and others 1986). Many drugs have been used for the treatment of myoclonus, such as procainamide or clonazepam, without much success and it is thought that myoclonus is probably an irreversible condition. Passive administration of canine hyperimmune serum may be beneficial to combat viraemia and perhaps viral replication in extraneural tissues. However, it is very doubtful that significant amounts of the administered antibodies cross the blood-brain barrier. Therefore, serotherapy is probably not useful in CDV infection of the central nervous system. As macrophages and their products, especially free radicals of oxygen, are important in the induction of tissue damage in distemper (Griot and others 1989), antioxidants such as vitamin E, vitamin C, superoxide dismutase and iron chelators should perhaps be used therapeutically, but clinical trials with such drugs have not yet been performed. It is clear that prevention of the disease is possible through active immunisation. Maternal antibodies are responsible for a period of temporary immunity that varies in duration from a few days to four months (Shell 1990). During this time these anti-cdv antibodies prevent both infection and successful immunisation with canine distemper vaccine. In most pups, the concentration of maternal antibodies reaches low levels at six to eight weeks of age, but they may be found until 14 weeks of age. As it is usually not practical to determine the concentration of maternal antibody, vaccination against CDV every three to four weeks between six to 16 weeks of age is recommended, followed by periodic boosters (Greene and Appel 1990). However, vaccination breakthroughs may occur. More than half of the current dogs with neurological distemper had been vaccinated against CDV. In addition, post vaccinal encephalitis has been reported after distemper vaccination (Hartley 1974). REFERENCES APPEI., M. J. G. & GILLESPIE, J. H. (1972) Canine distemper virus. Virology Monographs 11, Springer, Vienna, New York APPEL, M. J. G., GIBBS, E. P. J., MARTIN, S. J., TER MEULEN, V., RIMA, B. K., STEPHENSON, J. R. & TAYLOR, W. P. (1981) Morbillivirus diseases of animals and man. Comparative Diagnosis of Viral Diseases 6, APPEL, M. G. J., SHEK, W. R. & SUMMERS, B. A. (1982) Lymphocyte-mediated immune cytotoxicity in dogs infected with virulent canine distemper virus. Infection and Immunity 37, BICHSEL, P., VANUEVELDE, M., VANDEVELDE, E. & AFFOLTER, U. (1984) Immunoelectrophoretic determination of albumin and IgG in serum and cerebrospinal fluid in dogs with neurological diseases. Research in Veterinary Science 37, BOLLO, E., ZURBRIGGEN, A., VANDEVELDE, M. & FANKHAUSER, R. (1986) Canine distemper virus clearance in chronic inflammatory demyelination. Acta Neuropathologica 72, CERRUTI-SOLA, S., KRISTENSEN, F., VANDEVELDE, M., BICHSEL, P. & KIHM, U. (1983) Lymphocyte responsiveness to lectin and myelin antigens in canine distemper infection in relation to the development of demyelinating lesions. Journal of Neuroimrnunology4, DELAHUNTA, A. (1983) Veterinary Neuroanatomy and Clinical Neurology. 2nd edn. W. B. Saunders, Philadelphia. p 145 FANKHAUSER, R. (1982) Hundestaupe - Geschichte einer Krankheit. Schweizer Archiv fur Tierheilkunde 124, GREENE, C. E. & APPEL, M. J. G. (1990) Canine distemper. In: Infectious Diseases of the Dog and Cat. Ed C. E. Greene, W. B. Saunders, Philadelphia. pp GRIOT, C., BURGE, T., VANJJEVELDE, M. & PETERHANS, E. (1989) Antibody-induced generation of reactive oxygen radicals by brain macrophages in canine distemper encephalitis: a mechanism for bystander demyelination. Acta Neuropathologics 78, GRIOT, C., VANDEVELDE, M., RICHARD, A., PETERHANS, E. & STOCKER, R. (1990) Selective degeneration of oligodendrocytes mediated by reactive oxygen species. Free Radical Research Communications 11, HARTLEY, W. J. (1974) A post-vaccinal inclusion body encephalitis in dogs. Veterinary Pathology 11, HIGGINS, R. J., KRAKOWKA, S. G., METZLER, A. E. & KOESTNER, A. (1982) Primary demyelination in experimental canine distemper virus induced encephalomyelitis in gnotobiotic dogs. Acta Neuropathologica 58,

5 A. TIPOLD AND OTHERS I KKAKOWKA, S., OLSEN, R., CONFER, A., KOESTNER, A. & MCCUL- LOUGH, B. (1975) Serologic response to canine distemper viral antigens in gnotobiotic dogs infected with canine distemper virus. Journal of Infectious Diseases 132, KKAKOWKA, S., HIGGINS, R. J. & Koestner, A. (1980) Canine distemper virus: review of structural and functional modulations in lymphoid tissues. American Journal of Veterinary Research 41, SHELL, L. G. (1990) Canine distemper. Compendium on Continuing Education, Small Animal Practice 12, SIIMMERS, B. A,, GREISEN, H. A. & APPEL, M. J. G. (1979) Early events in canine distemper demyelinating encephalomyelitis. Acta Neuropathologica 46, 1-10 SUMMERS, B. A., GREISEN, H. A. & APPEL, M. J. (1984) Canine distemper encephalomyelitis: variation with virus strain. Journal of Comparative Pathology 94, TIPOLD, A., PFISTER, H. & VANDEVELDE, M. (1992) Determination of the IgG index for the detection of intrathecal immunoglobulin synthesis in dogs using an ELISA. Research in Veterinary Science (In press) VANDEVELDE, M. & SPANO, J. S. (1977) Cerebrospinal fluid cytology in canine neurologic disease. American Journal of Veterinary Research 38, VANDEVELDE, M., KRISTENSEN, F., KRISTENSEN, B., STECK, A. 1. & KIHM, U. (1982) Immunological and pathological findings in demyelinating encephalitis associated with canine distemper virus infection. Acta Neuropafhologica 56, 1-8 VANDEVELDE, M., ZURBRIGGEN, A., HIGGINS, R. J. & PALMER, D. (1985) Spread and distribution of viral antigen in nervous canine distemper. Acta Neuropathologica 67, VANDEVELDE, M., ZURBRIGGEN, A., STECK, A. & BICHSEL, P. (1986) Studies on the intrathecal humoral immune response in canine distemper encephalitis. Journal of NeuroimmunolOgy11, WOLF, M., CACHIN, M., VANDEVELDE, M., TIPOLD, A. & DUBEY, J. P. (1991) Zur klinischen diagnostik des protozoaren myositissyndroms (Neospora caninum) des welpen. Tierh'rztliche Praxis 19, VIDEO REVIEW Diagnosis in Small Animal Dermatology: Part 3, Four Easy Cases (26 minutes) and Part 4, Four Difficult Cases (32 minutes). Written by D. H. Scarff and I. S. Mason. Produced and distributed by the Royal Veterinary College Unit for Veterinary Continuing Education. Price each (plus p&p and VAT). THESE two videos provide a follow-up to the guidance offered in the first two of the series which dealt with the basics of dermatological diagnosis ie, history, physical examination and laboratory tests. The presentations talk the viewer through a series of progressively more difficult diagnoses. In each video the cases are presented in a similar format with a brief introduction and a summary of the case history. The pertinent details of the clinical examination are demonstrated and the viewer is then requested to stop the tape and suggest a differential diagnosis. This is then discussed and the viewer is then prompted again, this time to list the investigative tests that will eliminate the differentials. The information is then collated and the definitive diagnosis briefly discussed. Treatment and case management are not detailed. The four easy cases presented are scabies, flea allergic dermatitis, hyperadrenocorticism and feline plasma cell pododermatitis. The choice of the latter two as easy cases may cause raised eyebrows on some circles. Feline plasma cell pododermatitis in particular is very rare, but, notwithstanding, the choice of this condition to illustrate diagnostic work-up is, perhaps, surprising, as the presenters admit. The definitive dia- gnosis of this condition is only achieved by biopsy (unless one has seen it before). The four difficult cases which are discussed are atopy, drug eruption, pemphigus foliaceus and vasculitis. This last case nicely illustrates the point that although the pathological process may be identified the underlying cause may still be elusive. In both of these videos the authors talk the viewer through their thought processes, and with a fair degree of success. One must accept that videos can never capture the essence of a diagnosis; only being in the consulting room can achieve that. On the whole the format is successful and the productions are useful. The photography is good and the close-ups of the lesions particularly so. The use of overlays to summarise the case history or laboratory tests, for example, is very effective. Some aspects of the production are less pleasing. In particular the cutting between besuited clinician in the office to clinicians in consulting tunic. This gives a somewhat disjointed feel to the flow of the material and this reviewer and one suspects the clinicians, would have felt more comfortable with the discussions taking place in the consulting room. The tapes are supplied with a small booklet which contains a few questions and seven summarised case histories. The presumption is that the viewer will be in a position to answer these if the information in the video productions has been understood. These two video productions will prove useful to clinicians who require guidance on how to apply investigative dermatological techniques to clinical case material and the production is to be commended. RICHARD HARVEY 470

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