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VIRAL INFECTIONS OF THE NERVOUS SYSTEM

J. Richard Baringer, M.D.

Lecture Objectives:

1.                  Learn the signs, symptoms and most common etiologies of viral meningitis

2.                  Learn viruses which cause acute encephalitis

3.                  Learn the treatment of Herpes Simplex Encephalitis

4.                  Learn the types of viral infections which occur in immunosuppressed patients

5.                  Learn the features of Creutzfeldt-Jakob Disease

Lecture Outline

A. VIRAL MENINGITIS

1. SIGNS AND SYMPTOMS

Headache

Fever

Stiff Neck

2. ETIOLOGIES

Mumps

Coxsackie

Echo

LCM

HSV

AIDS

Other (drugs mimicking)

3. PATHOLOGY

4. CSF FINDINGS

5. COURSE

6. TREATMENT

B. ACUTE ENCEPHALITIDES

1. SIGNS AND SYMPTOMS

Meningeal

Confusion – Coma

Seizures

Focal abnormalities

2. ETIOLOGIES

a. Arbovirus – (Togaviruses) Epidemics

St. Louis

Eastern equine

Western equine

California

Course

Treatment

b. Herpes Simplex Virus

Sproadic, necrotizing

HSV-1

Pathology – Temporal – Frontal

EEG

CSF

X-ray/MRI

Other diagnoses

Treatment

Course

C. VIRAL INFECTIONS IN IMMUNOSUPPRESSED

1. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML)

Host factors

Clinical Presentation

Etiology

Pathology

CSF

X-ray/MRI

2. AIDS – HIV

Immunosuppression

Viral

Bacterial

Fungal

Parasitic

Tumor

Direct infection of CNS and PNS

Meningitis

Subacute encephalitis

Demyelinating polyneuropathy

Distal sensory neuropathy

D. SLOW VIRAL INFECTIONS

1. Subacute sclerosing panencephalitis (SSPE)

Course

Measles

Pathology

CSF

E. UNCONVENTIONAL INFECTIONS

1. CREUTZFELDT-JAKOB DISEASE

2. CLINICAL FEATURES

3. PATHOLOGY

4. “PRION DISEASES” – SCRAPIE/TME/KURU/CJD/BSE

5. AGENT Resistance

Nature

6. TRANSMISSION

Iatrogenic – cornea/electrode/surgical instruments/dura/HGH

Natural

Bovine spongiform encephalopathy

New Variant CJD

VIRAL INFECTIONS OF THE NERVOUS SYSTEM

J. RICHARD BARINGER, M.D.

Viruses, usually the cause of acute self limited infections in other organs of the body, present a spectrum of disease processes in the nervous system varying from brief benign conditions to diseases which have incubations periods of several years followed by slowly progressive courses over months to years with eventual fatality. We will consider, in this discussion: 1) the acute viral meningitides in which the infection process is usually brief and confined to the meninges and the subarachnoid space; 2) the acute encephalitides in which infection of the brain parenchyma with attendant confusion, coma, or focal abnormalities becomes dominant; 3) viral infections in the immunosuppressed host in which viruses may be reactivated from a latent or commensal state to one of pathogenicity; 4) slow viral infections due to conventional viral agents acting in unusual ways in the nervous system, and; 5) the viral-like processes due to unconventional agents whose nature and pathogenesis remain unknown.

1. VIRAL MENINGITIS

Virus induced or “aseptic” meningitis is a common phenomenon encountered sporadically throughout the year but often in the form of communal epidemics. The clinical process is that of an acutely developing headache, stiff neck, fever, and photophobia in a previously healthy, usually young individual. The onset, typically over a period of a few hours, may occasionally be quite explosive, simulating that of a subarachnoid hemorrhage. In the majority of cases, there are few signs such as obtundation or seizures to point to an affection of the underlying brain parenchyma.

A number of viral agents are recognized as causes of outbreaks of aseptic meningitis. Among these are mumps virus, Coxsackie virus, echovirus, poliovirus, herpes simplex virus Type 2, the human immunodeficiency virus (HIV), and the virus of lymphocytic choriomeningitis. The culture of these viral agents from the cerebrospinal fluid is often quite difficult. Recent advances in PCR technology have made it possible to identify many of the enteroviruses and HSV-2 with great sensitivity. The enteroviruses can often be recovered from stool specimens or demonstrated by PCR. The diagnosis should be confirmed on the basis of acute and convalescent serologic assays. In a significant proportion of cases of acute viral or “aseptic” meningitis, extensive virologic and serological testing does not turn up a specific etiologic agent.

The pathology of these processes is largely that of an acute lymphocytic pleocytosis in the cerebrospinal fluid with infiltration of lymphocytes in the pia and arachnoid layers without any affection of the underlying brain. The cerebrospinal fluid typically contains up to a few hundred cells and though a transient predominance of polymorphonuclear leukocytes may be seen within the first few hours, the CSF formula usually quickly changes to one of a predominant lymphocytosis accompanied by a slight rise in protein. Glucose values are usually within the normal range. In the case of mumps meningitis, a transient and partial lowering of the CSF glucose value has frequently been seen.

The course of these infections is usually quite brief and the prognosis usually excellent. Despite the initial presence of severe headache, the patient’s mental status is usually unaffected, and there are no focal or lateralizing signs pointing to disturbance of the brain parenchyma. If the initial cerebrospinal fluid contains a predominance of polymorphonuclear leukocytes or lowering of the blood glucose, the differential diagnosis between an acute viral meningitis and an acute bacterial meningitis may become difficult, and in such instances a repeat spinal tap in 12 to 24 hours may serve to resolve the issue. Most patients are substantially improved within 2 to 3 days, but occasional patients may have lingering headache, photophobia, and pleocytosis in the cerebrospinal fluid for a period of a few weeks or more.

It is important to keep in mind that the “aseptic meningitis syndrome” can be seen in other circumstances. Drugs including trimethoprim sulfa, ibuprofen, Naprosyn and carbamazepine have been implicated in the syndrome. It has also been seen after administration of OKT-3 antibodies.

The treatment of an acute viral meningitis is purely supportive with bedrest, parenteral fluids as may be required, and analgesics sufficient to make the patient comfortable.

2. ACUTE ENCEPHALITIDES

The acute virus induced encephalitides present a much more serious picture. The patient may exhibit the same signs and symptoms as are present in a viral meningitis, but these are often overshadowed by signs pointing to parenchymal affection of the brain consisting of states of confusion or obtundation progressing to coma, the appearance of focal or generalized seizures, and the presence of focal deficits due to inflammatory pathology within the brain substance.

The range of viral agents which may be responsible for acute encephalitides is large but tends to be geographically delimited. The most frequently encountered viral encephalitides in the United States are those resulting from arthropod borne viruses (Togaviruses) which have produced seasonal epidemics in various parts of the country. The epidemics are usually related to the mosquito populations and thus tend to occur characteristically in the summer or early fall. They occur prominently in clusters in urban areas and at times at which the normal cycle of the virus through mosquitos and animal hosts is accidentally interrupted by man. St. Louis encephalitis is commonly seen in Mississippi and Missouri river valleys and in the western United States. Eastern equine encephalitis is an uncommon disease of great severity that is periodically seen in small outbreaks along the eastern seaboard. Western equine encephalitis is usually of somewhat milder intensity. California encephalitis is frequently of mild severity and paradoxically is a disease that is seen most often in the midwest. Because all of these illnesses are the result of Togaviruses for which there is no specific antiviral agent, the treatment is purely supportive and expectant. Patients in coma must be tended carefully in regard to their fluid balance, bladder and bowel care, skin care, and pulmonary toilet. The effective management of such patients depends heavily on skilled nursing support.

The most frequent non-epidemic necrotizing encephalitis in the United States is that due to herpes simplex virus. The process can be seen in two distinct circumstances, that of an acute widespread necrotizing infection of the newborn in which the skin, eyes, viscera, and brain are involved with an acute infection more often due to HSV Type 2 but sometimes due to HSV Type 1. This infection is, in most cases, related to infection of the maternal cervix and while it is usually thought that the infection is acquired in passage of the infant through the birth canal, it is clear that in some cases the infection is intrauterine, presumably from retrograde infection through the cervix. It is a devastating destructive process within the brain resulting in a very high frequency of death and in survivors a high frequency of severe retardation.

In children and adults who are immune competent, herpes encephalitis is always due to the Type 1 virus, the type that causes the common cold sore. It is a process that is restricted to the brain with no evidence of herpetic infection in other tissues of the body. Within the brain, the pathology is strikingly limited to the temporal and subfrontal lobes and adjacent portions of the insula. The condition presents as an acute disturbance in memory and attention followed by obtundation, seizures, and frequently focal disturbances consisting of hemipareses or aphasia. The diagnosis of herpes encephalitis can be quite difficult and its distinction from cerebrovascular events, other infections, abscesses, or tumors often can tax the clinician’s ability. The EEG is universally abnormal but may not be characteristic for the disease. The cerebrospinal fluid picture is that of a lymphocytic pleocytosis with or without some elevation of the protein and rarely a slight lowering of the CSF sugar. Occasionally the CSF cell count is normal when the patient is first seen. CT scans of the brain may often reveal the temporal and frontal pathology with enhancing lesions, but in may cases, the CT scans early in the illness are entirely normal. MRI scans are usually abnormal very early in the illness and show the characteristic temporal and subfrontal localization to great advantage. There are practical difficulties with obtaining MRI scans in severely obtunded or combative patients which place some practical limitations on its use.

Because there is effective treatment in the form of acycloguanosine (Acyclovir) for herpes infections of the brain, establishing the diagnosis of this condition is imperative at the earliest possible time. HSV genomes often can be identified in early CSF specimens using the polymerase chain reaction. The PCR reaction for HSV in the spinal fluid has both high sensitivity and specificity and has come to be regarded as the “gold standard” for the diagnosis of HSV induced encephalitis. It occasionally may be falsely negative: 1) on the first day or two of clinical illness; 2) in the presence of blood in the CSF and; 3) after the second week of illness. Antibodies to HSV appear in the CSF near the end of the first week and persist for many months, hence are of more use for retrospective diagnosis.

In rare instances where the clinical picture is unclear, it may be necessary to resort to biopsy of an affected part of the brain to establish the diagnosis. Herpes antigen usually can be demonstrated in brain biopsy specimens, and the virus can be detected by culture or PCR amplification of viral DNA.

The treatment consists of the supportive treatment that is necessary for any patient with viral encephalitis to which is added intravenous Acyclovir in a 10 to 14 day course. Treatment has reduced the mortality of the process from 70% to approximately 40%, but a significant morbidity among survivors is still the rule. The use of steroids to reduce inflammatory edema has been somewhat controversial because of the known ability of steroids to impair viral clearance; against this must be weighed the hazards of increased intracranial pressure and mass effect resulting in herniation and death. Steroids should be used when significant brain swelling occurs.

3. VIRAL INFECTION IN THE IMMUNOSUPPRESSED

A variety of virus induced diseases of the brain have been recognized in recent years in patients who are immunosuppressed, either through underlying disease processes or in the situation of iatrogenic immunosuppression. Perhaps the best known of these is progressive multifocal leukoencephalopathy (or PML) described 40 years ago by workers at the Massachusetts General Hospital. The disease is a slowly progressive demyelinative disease of the brain which presents with progressive weakness, visual involvement or aphasia in patients who are immunosuppressed. The most frequent underlying diseases until recently have been Hodgkin’s disease, lymphoma, or leukemia, but in the last several years the incidence of PML in the acquired immunodeficiency syndrome has been substantial. The pathology of the disease is that of a demyelinating process involving the white matter of the cerebral hemispheres which has two striking histologic characteristics: 1) the presence of inclusions within oligodendrocytes and 2) the presence of large pleomorphic hyperchromatic astrocytes. The inclusions within oligodendrocyte nuclei consist of aggregates of viral particles belonging to the human papova virus group represented by JC virus, the latter being the initials of the patient from whom the virus was first isolated. Antibody to JC virus is present in 80% or more the normal adult population. The site of viral latency is uncertain but preliminary evidence has suggested that the kidneys and/or bone marrow may be the sites in which the virus lies dormant until it is permitted to spread by virtue of the immunosuppressive state. The diagnosis of the disease can be made most easily by MR or CT scan which demonstrates the demyelinative process in the cerebral hemispheres in the immunosuppressed patient. Cerebrospinal fluid studies are usually completely normal.

Within the last few years, it has become recognized that patients with the acquired immunodeficiency syndrome have a very high incidence of opportunistic infections of the brain including multifocal leukoencephalopathy, cytomegalovirus encephalitis, herpes virus encephalitis, cryptococcal fungal infections, toxoplasmosis, and unusual bacterial infections. In addition, the incidence of lymphomas of the central nervous system is exceedingly high in AIDS patients. It is felt that all of these conditions basically result from the profound immunosuppression which results from the infection of T helper cells with AIDS virus. If this were not enough, it is now clear that the human immunodeficiency virus also has the potential to produce a direct infection of central and peripheral nerve structures. The virus (HIV) is undoubtedly the cause for the dementia that takes place in AIDS. In addition, the virus has been isolated from the spinal cord and peripheral nerve where it is in all likelihood responsible for the vacuolar myelopathy (in the spinal cord) and the various forms of peripheral neuropathy that may be seen in AIDS. Thus the AIDS patient may bear a double infectious burden in the nervous system, that of the direct HIV infection of the nervous system at every level, and the opportunistic infections conferred by the immunosuppressive state.

4. SLOW VIRAL INFECTIONS

A variety of slowly progressive viral infections of the nervous system due to conventional viral agents have been recognized over the course of the last several years. These include slowly progressive virus diseases due to JC virus as outlined above, but in “normal” hosts diseases such as subacute sclerosing panencephalitis and progressive rubella panencephalitis. Subacute sclerosing panencephalitis is perhaps the best understood of this category of diseases. It is a disease of young children characterized initially by behavioral abnormalities followed by progressive demential, myoclonus, seizures, spasticity, obtundation, and death taking place over periods ranging from a few weeks to several months. It is now recognized that the disease is associated with the presence of measles virus and often occurs in children who have had measles at an unusually young age, i.e., under the age of one year. The disease characteristically has its onset in the first decade or in early teenage. The pathology is that of a progressive inflammatory and gliotic process within the brain, characterized by the presence of intranuclear inclusions. The inclusions have been recognized on the basis of fluorescent antibody and electron microscopic studies to represent measles virus nucleocapsids. The patients have extraordinarily high levels of antibody to measles both in the serum and in the cerebrospinal fluid and the diagnosis can be established on the basis of these abnormal antibody levels. Biochemical studies of virus isolated from the brains of patients with subacute sclerosing panencephalitis have indicated that in many cases the virus appears to lack an M protein, the protein that is necessary for alignment and budding of the measles virus nucleocapsid from the cell surface membrane. The precise circumstances that lead to the development of this virus variant are not yet fully understood, but it is thought that this abnormality may in some way lead to the development of this slowly progressive inflammatory brain disease years after the initial measles virus infection.

5. UNCONVENTIONAL AGENTS AND CNS DISEASE

During the course of the last 30 years, a fascinating story has evolved concerning a rare disease of humans called Creutzfeldt-Jakob disease and its relationship to an exceedingly unusual transmissible agent. Creutzfeldt-Jakob disease has been recognized for over 100 years as a rapidly progressive dementia usually in middle aged or elderly adults which is associated with myoclonic jerks, a distinctive EEG abnormality, and a course leading to death usually within 6 months to 1 year. Although there are variations on the theme, the usual picture is that of a rapidly evolving dementia with or without focal signs to which is added the myoclonic jerks or seizures. The patients are usually severely demented within a few weeks to months from the onset of the first clinical signs, and the majority of patients die under one year from the onset of the disorder. For decades the disorder was viewed as a peculiar “degenerative” disease of the brain occurring only rarely (incidence = 0.5 to 1 per million).

In the late 1960’s, Dr. Carlton Gajdusek was investigating a peculiar degenerative disease of the brain called Kuru in a remote tribe in the New Guinea highlands. When he showed the brain pathology to Dr. William Hadlow at the Rocky Mountain National Laboratories in Hamilton, Montana, Dr. Hadlow immediately recognized the similarity of the Kuru brain pathology to that of scrapie, a transmissible disease of sheep which had been known for many years. The transmissible nature of scrapie was then known but the agent had not been identified.

These observations led to the inoculation of Kuru brain specimens into chimpanzees and the subsequent development of Kuru pathology in the chimpanzees. It was subsequently recognized by Dr. Igor Klatzo at the National Institutes of Health that the pathology of Kuru and the pathology of Creutzfeldt-Jakob disease were very similar, and this led to the inoculation of specimens of brain from patients with Creutzfeldt-Jakob disease into chimpanzees with the development of an identical pathologic process after incubation periods varying from one to two years.

Subsequent studies have identified the presence of an agent in Creutzfeldt-Jakob brain which replicates to high titers and which has unusual physical chemical properties including resistance to inactivation by heat or chemical agents and a failure to induce any immunologic or inflammatory response in the brain. The agent has never been confidently visualized in tissue sections by electromicroscopy, and there is no evidence to date that it contains either DNA or RNA. Dr. Stanley Prusiner at the University of California has suggested that the agent may be in the form of a low molecular weight (27-30KD) protein; he has coined the term PRION for the agent. Subsequent studies have indicated that the gene coding for this protein is present in normal cells of humans and other animals.

The list of natural diseases related to prions continues to grow.

In non-humans:

1. Scrapie of sheep and goats

2. Transmissible mink encephalopathy

3. Chronic wasting disease (deer and elk)

4. Bovine spongiform encephalopathy (“mad cow disease”)

In humans:

1. Kuru

2. Creutzfeldt-Jakob disease

3. Gerstmann-Straussler-Scheinker syndrome

4. Familial fatal insomnia

5. “New Variant” Creutzfeldt-Jakob disease

Work from Prusiner’s laboratory has identified a 27-30 KD protein in the brains of mice infected with the scrapie agent; this protein is the protease-resistant core of a normal 33-35 KD product of the prion protein (PrP) gene. In humans, the PrP gene is localized in chromosome 20. In the Gerstmann-Straussler-Scheinker syndrome, a dominantly inherited dementia, and in the familial cases of Creutzfeldt-Jakob disease, point mutations in the human PrP gene have been found repeatedly. In sporadically occurring Creutzfeldt-Jakob disease, it is thought that the disease may arise from a spontaneous conversion of PrP (cellular) to PrP (Creutzfeldt) due either to a somatic mutation or a rare event involving modification of the cellular PrP protein.

How the prion protein multiplies is uncertain. In scrapie infected mice, the PrP^sc isoform multiples to 10⁹ while the cellular form (PrP^c) remains unchanged. It is has been hypothesized that a PrP^sc molecule might combine with a PrP^c molecule to produce a dimer that is somehow transformed into two PrP^sc molecules. The process might then proceed exponentially to replicate the protein to high titers.

A number of puzzles remain in this unique disease constellation. While it seems likely that the disease is related to the presence (and titer) of the PrP^sc protein, the mechanism by which it replicates itself and the mechanism by which it produces CNS disease have yet to be elucidated.

Of practical importance in regard to the transmissibility of Creutzfeldt-Jakob disease is the fact that the disease has been accidentally transmitted from patient to patient by: 1) corneal transplantation from a donor not suspected to have Creutzfeldt-Jakob disease; 2) the use of gold intracerebral electrodes which had been previously used in patients with Creutzfeldt-Jakob disease and sterilized only by exposure to gas; 3) the contamination by the Creutzfeldt agent of human pituitary growth hormone produced from pooled human pituitary glands and administered parenterally; and 4) the contamination of dural grafts by Creutzfeldt-Jakob disease agent. Despite these alarming examples of iatrogenic transmission of the disease, there is little evidence that medical personnel in contact with Creutzfeldt disease patients are subjected to an increased risk of contracting the disease. Although the illness has been known to be present in one neurosurgeon and two histology technicians, it has yet to be reported in pathologists, neurologists, or with increased frequency among medical personnel. Although 10% of patients with Creutzfeldt-Jakob disease have a family history of Creutzfeldt-Jakob disease, the afflicted relatives are always parents, siblings, or children and virtually never the spouses. Thus, the risk of accidental transmission by casual or even intimate contact with the patient would seem to be quite remote.

Recently a new form of prion disease has surfaced in England. This disease differs clinically from classical CJD disease in affecting young individuals and presenting with a combination of psychiatric disorder, painful extremities and ataxia with dementia a late feature. The disease, called “New Variant Creutzfeldt-Jakob Disease” is in all likelihood the result of ingestion of beef from cattle affected by “mad cow” disease. The latter arose from a change in the composition of a nutritional feed supplement composed in part of sheep offal. A change to a less expensive method of processing the food supplement apparently resulted in the failure to inactive sheep scrapie prions from the material. Thus the cross species transmission of scrapie prions from sheep to cattle (resulting in “mad cow” disease), has been furthered by apparent transmission across another species barrier to man. At present there are approximately 30 cases identified of this “NVCJD”, all (with one exception in France) in England. Destruction of hundreds of thousands of affected British cattle has reduced the incidence of mad cow disease dramatically. Because the incubation period of NVCJD is unknown, the number of additional cases that may occur in humans is presently unknown.

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