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Slow Virus" Infections in Neurological Disease

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Slow Virus 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
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