Technical Articles

The Role of "Slow Virus" Infections in Neurological Disease

M. B. WEBER, MD which the agent continues to multiply, slowly producing progressive abnormality over the course of months and SUMMARY years, usually with a very long incubation period, and often with a localization of the infectious process to a single The conventional concept of an acute virus organ.2 The second source was the Soviet virologists whose infection is contrasted with the newer concept claims of isolation of transmissible agents from of a "slow virus infection". The author amyotrophic lateral sclerosis and multiple sclerosis, describes several neurological diseases of although unconfirmed, awakened new interests in this area. animals and man with a "proven" slow viral The third source has been the many recent observations of etiology. The epidemiological, clinical labora- both virologists and morphologists of the relationships of a tory and pathological features of these diseases variety of viruses to human neurological disease. Examples are placed parallel to several idiopathic of these include the elucidation of the chronic nature of degenerative and demyelinating diseases ofman rubella infection of the fetus and newborn, the newer and remarkable similarities are noted. Dr. theories of the pathogenesis of herpes zoster, the repeated Weber suggests that diseases such as Parkin- electron microscopic observation of virus-like particles in sonism, Creutzfeldt-Jakob disease, amyotrophic progressive multifocal leukoencephalopathy and in lateral sclerosis and multiple sclerosis may subacute sclerosing panencephalitis, and the transmission of result viral infections. kuru and Creutzfeldt-Jakob diseases to chimpanzees. from slow Although many links are missing in the chain of proven slow viral infections to idiopathic degenerative and demyelinating diseases of man, there are similarities among these slow viral infections described first, and several idiopathic chronic neurological disease of man described THE CONVENTIONAL CONCEPT of a virus infection afterwards. is that of an acute self-limiting disease with a relatively short incubation period, usually well under a month. There Scrapie, Visna is a rapid proliferation of the virus, just before the acute From the standpoint of neurology and neuropathology, phase of the disease which usually lasts no more than a few the two "slow infections" of sheep of greatest interest are days or weeks. Disappearance of the virus and clinical scrapie and visna. They produce totally dissimilar symptoms promptly ensues upon the appearance of specific pathologic changes, the former appearing to be a antibody. Pathologically, the common denominator is an degenerative disease, and the latter having features of a inflammatory reaction. demyelinating disease. Thus, they provide important The concept that viruses can cause diseases with long experimental models for the study of mechanisms of slow incubation periods, with no apparent proliferation of the infections of the nervous system. virus, with an episodic or chronic nature measured in terms Visna is a central nervous system disease of sheep first of years, with progression of disease despite antibody observed in Iceland during the late 1930s. In 1952, visna production, or the failure to induce antibody production, was successfully transmitted by intracerebral innoculation or diseases with varied pathologic reactions, is not new. One of affected sheep brain into other sheep. The early clinical need only recall the long incubation periods of rabies, or signs included stumbling and lagging behind the flock. This serum hepatitis, the recurrent nature of herpes labialis, or was followed by paralysis of the hind legs, trembling of the the chronicity and non-inflammatory neoplastic pathology lips and tilting of the head. These signs progressed over a of warts. What is new is a resurgence of interest in viruses as period of months to paraplegia or total paralysis. The possible causes of relapsing, subacute, or chronic disease was inexorably progressive and remissions or neurological disorders of man.' survival were never seen. In the experimentally transmitted The stimuli for this renewed interest come from several disease, one to four years elapsed before the signs of sources. The first, and probably most significant source, has paralytic disease developed. During this incubation period, been the veterinary research on the viral etiology of such animals developed significant amounts of neutralizing chronic neurological diseases as scrapie and visna in sheep antibodies to the agent, yet the clinical disease progressed. and the chronic encephalopathy of mink. It is in this area Icelandic workers have conclusively documented that the that the concept of "slow infections" was introduced, and potentially important experimental models for subacute or chronic degenerative or demyelinating diseases of the Dr. Weber is a neurologist at Toronto's North York General nervous system were first uncovered. The Icelandic Hospital and a clinical teacher in neurology, University of veterinarian, Sigurdsson, working with Icelandic sheep, Toronto, Sunnybrook HospitaL defined "slow infection" as an infection of the host in

CANADIAN FAMILY PHYSICIAN * APRIL, 1971 39 transmissible agent is a virus. Neuropathologically, the hemiparesis, visual loss, aphasia and dementia. There is a disease produces a patchy demyelination. Persistence of reasonably acute onset, but the disease has a subacute, infection in the presence of circulating antibody during the progressive course. Spinal fluid shows little if any incubation period suggests that the virus remains confined abnormality. The pathological picture is unique with to the cells without causing cell necrosis. It has been multiple foci of cerebral demyelination of various sizes, and postulated that the virus-host relationship is held in in different stages of evolution. Within these foci, there is a equilibrium by immune mechanisms of the host; but with loss of myelin sheaths with relative sparing of axons. disruption of the equilibrium, disease develops. This disease Surrounding the foci of demyelination, bizarre disordered is a promising model for experimental studies of slow oligodendroglia are found with characteristic eosinophilic infections, and the investigation of the possible role of slow nuclear inclusions. Despite the lack of inflammatory infections in demyelinating disease (multiple sclerosis). changes, the presence of inclusion bodies and the Scrapie is an invariably fatal condition of adult sheep occurrence of this disorder in the course of systemic following a chronic course of months, or even years. diseases capable of interfering with immunological activity, Affected animals develop progressive ataxia, tremor, led Richardson to speculate that a virus infection might be hyper-excitability or lethargy, weakness or wasting. Scrapie implicated. Electron microscopic studies have demonstrated was transmitted experimentally in 1936 by injecting brain virus-like particles that are consistent morphologically with and spinal cord of affected sheep into healthy ones. The the virions of Papova viruses. The theoretical questions are disease has been transmitted to goats, mice, hamsters and raised whether these virus-like particles might represent the rats, and after serial passage in these hosts it can then be reactivation or dissemination of a latent agent such as wart transmitted back to sheep. The incubation period of scrapie virus or an as yet unknown human polyonia virus, or is prolonged, ranging from nine months to four years in whether they might represent a primary infection with a sheep. Pathologically, hypertrophy and proliferation of normally nonpathogenic agent. astroglia is the first abnormality to develop. Degenerative changes occur in the neurons. Spongiform degeneration of Kuru central grey matter masses and of the cerebellar cortex is a This unusual disease which affects the Fore tribe of the late finding. Mink encephalopathy, a disease producing New Guinea Highlands is perhaps the most convincing similar neuropathological changes, may be due to the same example of a slow virus infection in man.5 The disease was or a similar agent, that produces scrapie. One of the most responsible for over half of all deaths among the 7,000 singular features of scrapie has been the inability to South Fore people. It is primarily a disease of adult demonstrate any antibody formation against the agent in females, and male and female children over the age of five. any host. The clinical and pathological features of scrapie The disease begins insidiously with titubation of the head are reminiscent of several chronic neurological diseases of and mild truncal ataxia. The ataxia follows a progressive, man. relentless course until the patient is unable to walk and is unable to make the slightest movement without wild ataxic Rubella tremors. The scanning speech evolves to aphonia. In the late Rubella is known as an acute exanthematous disease. stages of the disease, there are abnormalities of extraocular The rubella syndrome of newborn infants, first described in movements and mental changes. The disease progresses for 1941 by Gregg, produced a concept of rubella as a chronic three to six months until death results from aspiration infection. The infection which begins in the first trimester associated with dysphagia, starvation or sepsis. The CSF has of pregnancy persists and progresses for months with been found to be normal. affected infants continuing to excrete virus in some cases for more than a year after birth. Surprisingly, this persistent Creutzfeldt-Jakob Disease tissue infection continues in the presence of large amounts In the original pathological description of kuru, the of serum neutralizing antibody. Chronicity of this fetal resemblance to Creutzfeldt-Jakob disease was emphazised. infection, its persistence in the presence of maternal and Clinically, dementia and myoclonus are far more prominent later host antibody, its capacity to produce malformations in this sporadic disease than the cerebellar ataxia seen in as well as inflammatory lesions and the apparent chronic kuru. Neuropathologically, however, there is a remarkable infection of histologically normal cells, all indicate the need similarity, with prominent astrocytosis, neural loss and to modify our conventional ideas of pathogenesis of human variable spongiform changes in the cortex. Recently Gibbs viral infection. has reported the possible transmission of Creutzfeldt-Jakob disease to the chimpanzee 13 months after intracerebral Cytomegalovirus innoculation of cerebral biopsy tissue from a patient.6 The The human cytomegalovirus produces Cowdry Type A chimpanzee developed similar clinical features of the intranuclear inclusions and results in persistent active disease. At autopsy, neuropathological features resembled infection lasting months to years involving localized areas those of Creutzfeldt-Jakob disease. Further studies by of the kidneys or saliva glands. Although post-natal Gibbs and Gajdusek show that the disease can be infection is not apparent, pre-natal infection can cause transmitted from chimpanzee to chimpanzee. serious neurological disease including chorioretinitis, seizures, intracranial calcifications and mental retardation. Parkinson's Disease, Epilepsia Partialis, Amyotrophic Lateral Sclerosis Progressive Multifocal Leukoencephalopathy A viral etiology for Parkinson's disease has long been In 1958, Astrom, Mancall and Richardson described suspected since it was known that Parkinsonism would be a three patients with an unusual demyelinating disease frequent sequela for the first five years after encephalitis complicating chronic lymphocytic leukemia and Hodgkin's lethargica or von Economo's encephalitis. The neuro- disease.3 They termed this disorder progressive multifocal pathological findings in patients dying of this disease in the leukoencephalopathy. Neurological abnormalities consist of acute phase were consistent with a viral encephalitis. The 40 CANADIAN FAMILY PHYSICIAN * APRIL, 1971 applicable concept here is that a virus can persist in the A new discipline, geographical medicine, has given us a brain following acute encephalitis and lead to sequelae by new and unique insight into the cause of multiple continued localized activity. Further definition of the sclerosis.7 Geographical medicine involves the intensive etiology of post-encephalitis Parkinsonism is impaired by study of the epidemiology of a disease in populations that the disappearance of the clinical disease, encephalitis have migrated from one environment to another. lethargica, in the 1930s. The prevalence of multiple sclerosis in native born The concept that virus can persist in the brain following whites of Great Britain and Northern Europe is high, and in acute encephalitis and lead to sequelae by continued native born whites of South Africa it is low. Multiple localized activity has been a popular one in the U.S.S.R. sclerosis in South Afr ca occurs in immigrants from Soviet neurologists have considered progressive mental Northern Europe who arrived after their 15th birthday, disorders, Parkinsonism, amyotrophic lateral- sclerosis, with their first symptoms often occuring long after their multiple sclerosis and epilepsia partialis continua sequelae arrival. From these data, one could postulate that multiple from persistent infection. Tic-borne encephalitis virus has sclerosis is a slow virus infection contacted in one's youth been isolated from brain tissue surgically removed from two while living in an endemic area. A prolonged incubation patients with epilepsia partialis continua. In 1962 Zilber et period permits symptoms to appear long after emigration. al reported the isolation of a transmissible agent in rhesus The more time one spends in his youth before age 15 years monkeys, from patients dying with amyotrophic lateral in an endemic area, the more likely he is to carry his disease sclerosis. After a latent period of one to three years, in latent form to a non-endemic area upon emigration. This monkeys innoculated intracerebrally with homogenates of same principle is duplicated in Israel where native Israelis human medulla and spinal cord developed asymmetrical demonstrate a low prevalence of multiple sclerosis, whereas wasting in the upper and lower extremities, and worsened Jews who emigrate to Israel from Northern Europe carry over a period of eight months to three years. Innoculations the same high prevalence of multiple sclerosis as exists in from these monkeys produced similar disease in two their countries of origin. Genetic and dietary factors are subsequent passages in monkeys. Attempts to reproduce controlled in the South African and Israeli examples and these results at the National Institutes of Health in the therefore would not seem to be important in the etiology United States have been unsuccessful. of multiple sclerosis. Although climate has long been considered to play an important role, the disease prevalence Multiple Sclerosis of multiple sclerosis in South Africa and Australia cannot In 1946, Margulis and co-workers in the Soviet Union be reconciled with their very similar climate. Moreover, it reported the isolation of a virus from mice innoculated with has long been realized that the disease, once established, human brain. While these Soviet workers now accept that does not remit or improve if one moves from a temperate this was a rabies virus, they believe that it represents a climate where the disease is common, to a tropical climate variation capable of causing multiple sclerosis in man. where the disease is uncommon. Gudnadottir reported the isolation of a herpes virus from If the diseases I have described are indeed due to a "slow the brain of a patient with multiple sclerosis, and a virus infection", our traditional views concerning the statistically significant higher incidence of neutralizing spectrum of neurological diseases that might be related to antibodies to this agent in the serums of patients with viruses needs to be modified. This spectrum must now multiple sclerosis than in healthy adults. Ross and include meningitis, encephalitis, poliomyelitis, intrauterine co-workers in Scotland found no increase in herpes malformations, degenerative and demyelinating diseases and antibodies in patients with multiple sclerosis but they did viral induced neoplasia. Even inborn errors of metabolism find significantly more serums from multiple sclerosis that are clinically silent might take on pathological patients who had complement fixing antibodies to significance when slow virus infections slightly alter varicella-zoster virus. metabolism synergistically with the genetic error. As a Homogenates from a patient who died of acute multiple corollary, a slow virus infection may assume clinical sclerosis in England were innoculated into sheep in Iceland, significance only when genetic factors are such as to and scrapie developed in all four innoculated animals. provide fertile ground for viral infectivity. While it is Attempts to reproduce this finding in England and illogical to propose that viruses will emerge as the causal Northern Ireland were unsuccessful. agents in the entire gamut of idiopathic neurological The finding in multiple sclerosis that has been diseases, it is tempting to assume that in diseases such as substantiated in many laboratories is that the serums of Parkinsonism, amyotrophic lateral sclerosis and multiple patients with multiple sclerosis contain greater amounts of sclerosis, this approach is hot on the trail of the etiological antibody to measles virus than do serums of control groups. agents. 4 The measles antibody is not more prevalent in cases of multiple sclerosis but is of higher titres than in control groups. The levels of antibody to measles virus are by no means as striking as those observed in patients with References subacute sclerosing panencephalitis, but they do represent a 1. Johnson, R. T., and Johnson, K. P. Recent Advances in statistically significant elevation of titre of measles Neurology. F. A. Davis Co. 33-78, 1969. antibody in the absence of increased levels of antibody to 2. Sigurdsson, B., Brit. Vet. J. 110: 7-9, 255-270, 307322 other viruses. The finding cannot be dismissed but its and 341-354, 1954. interpretation is elusive. 3. Astrom, K. E. et al, Brain. 81: 93, 1958. A viral etiology for multiple sclerosis is not incompatible 4. Dawson, J. R. Jr., Amer. J. Path. 9: 7, 1933. with an auto-immune theory of etiology. A virus could 5. Gajdusek, D. C., New Engi. J. Med. 276: 392-400, (Feb. slightly modify a myelin protein so that the host would 16) 1967. then recognize his own myelin as "foreign" and produce 6. Gibbs, C. J. Jr., etal, Science. 161: 388, 1968. antibodies against myelin, resulting in demyelination. 7. Dean, G., Scientific American. 40-46, (July) 1970. CANADIAN FAMILY PHYSICIAN * APRIL, 1971 41