Current Diagnosis & Treatment in Infectious Diseases

Section IV - Viral Infections

43. Viral Infection of the Central Nervous System

Lawrence W. Drew MD, PhD

Many viruses causing infection of the central nervous system (CNS) are covered in chapters devoted to each type of virus. For example, enteroviruses, the agents most frequently causing meningitis and occasionally encephalitis, are covered in Chapter 27. The herpes viruses that cause meningitis, encephalitis, or both, especially herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV), are discussed in Chapter 33. This chapter considers viruses that cause CNS diseases (Box 43-1) as their primary manifestations.


Essentials of Diagnosis

  • Summer and fall cases, especially if in a cluster or outbreak, suggest arboviruses or enteroviruses.
  • History of exposure to mosquitoes suggests arbovirus infection, especially in geographic areas of high endemicity (eg, swamps of Florida).
  • Maculopapular rash suggests enterovirus disease.
  • Lymphocytic pleocytosis in cerebrospinal fluid (CSF) with normal glucose and protein concentrations suggests viral meningitis.

General Considerations

Arthropod-borne (arbo) viruses causing encephalitis are members of the toga-, flavi-, and bunyavirus families. The medically important togaviruses include rubella virus, which is discussed in Chapter 36, and the equine encephalitis viruses. The flavivirus family, which includes St. Louis encephalitis (SLE) and West Nile viruses, also includes dengue and yellow fever viruses; the latter described in detail in Chapter 44. The bunyaviruses causing CNS disease are members of the California encephalitis (CE) virus group, but other pathogenic bunyaviruses include the hantaviruses, which are discussed in Chapter 44. The older term, arbovirus, refers to those encephalitis-causing viruses that have an arthropod vector, eg, mosquitoes or ticks. These viruses have a very broad host range, including mammals, birds, amphibians, and reptiles.

  1. Epidemiology

Togaviruses and flaviviruses are prototypical arboviruses. As arboviruses, they infect both vertebrates and invertebrates, and they initiate a viremia in a vertebrate host and a persistent, productive infection of the salivary gland of the invertebrate to provide virus for infection of other host animals. If the virus is not in the blood, the arthropod vector cannot pick it up. The infection cycle involves transmission of the virus by the arthropod vector and amplification in a susceptible, natural host to allow reinfection of other arthropods. Humans are usually dead-end hosts that cannot spread the virus back to the vector because a persistent viremia is not maintained. Table 43-1 lists vectors, natural hosts, and a geographic distribution for representative togaviruses and flaviviruses.

These viruses are usually restricted to a specific genus of arthropod vector and its vertebrate host. The most common vector is the mosquito, but some arboviruses are also spread by ticks and sand flies. Not all arthropods can act as good vectors for each virus. For example, Culex quinquefasciatus is resistant to infection by western equine encephalitis (WEE) virus (a togavirus) but is an excellent vector for SLE virus (a flavivirus). As with mosquito-borne viruses, the life cycle of the tick dictates the pattern of spread of tick-borne viruses.

In endemic regions, the risk of arbovirus infection increases during the rainy season. Pools of standing water, drainage ditches, and sumps in cities can provide breeding grounds for mosquitoes, such as Culex spp., the vector of SLE and West Nile virus. During the summer months the arboviruses are cycled between a host (eg, bird) and an arthropod (eg, mosquito). This cycle maintains and increases the amount of virus in the environment. In the winter neither the normal host nor the vector remains to maintain the virus. The virus may persist in arthropod larvae or eggs or in reptiles or amphibians that remain in the locale, or it may be blown by the winds or migrate with the birds and then return during the summer.

Birds and small mammals are the usual hosts for the togaviruses and flaviviruses, but reptiles, amphibians, and, rarely, humans can also act as hosts. Development of a large population of viremic animals can occur in these species to continue the infection cycle of the virus. Although some of these viruses are called equine encephalitis viruses, the horse sometimes is a dead-end host. However, as with humans, the horse may develop clinical disease.

CE viruses are arthropod-borne members of the bunyavirus family. Bunyaviruses were known as arboviruses until the discovery of hantaviruses, members of the family that are transmitted to humans without the aid of arthropod vectors. Despite its name, CE occurs almost exclusively in the eastern half of the United States and especially in the North Central States. The name derives from the fact that the first representative of this virus group was isolated in Kern County, Calif., but the most common type causing disease in the United States is the La Crosse virus, which was first isolated in Wisconsin. This virus causes the most prevalent arbovirus infection in children in the United States.

The age distribution of patients with arthropod-borne encephalitis is striking. SLE and West Nile virus cause clinical illness in older adults, CE in school-aged children, and western and eastern equine encephalitis (WEE and EEE) predominately in infants and young children.

  1. Microbiology

The toga- and flaviviruses are enveloped, single-stranded ribonucleic acid (RNA) viruses. Until recently the flaviviruses were included in the Togaviridaefamily, but differences in size, morphology, gene sequence, and replication have made it necessary to classify them as an independent virus family.

The flaviviruses also have plus-strand RNA and an envelope. However, the virions are slightly smaller than those of the togaviruses (37–50 nm in diameter). All the flaviviruses are serologically related, and antibodies to one virus may cross-neutralize another virus.

CE viruses are intermediate-sized RNA viruses (90-120 nm in diameter) in the bunyavirus genus that are spherical in appearance. They are enveloped and contain three separate pieces of negative-strand RNA of differing lengths.

  1. Pathogenesis

The togaviruses and flaviviruses can cause lytic or persistent infections of both vertebrate and invertebrate hosts. Infections of invertebrates are usually persistent, with continued virus production.

Female mosquitoes acquire the togaviruses and flaviviruses on taking a blood meal from a viremic vertebrate host. The virus infects the epithelial cells of the mid-gut of the mosquito, spreads through the basal lamina of the mid-gut to the circulation, and then infects the salivary glands. The virus sets up a persistent infection and replicates to high titers in these cells. The salivary glands can then release virus into the saliva; however, certain strains of WEE virus are limited to the mid-gut and cannot infect the salivary glands.

After biting a host, the female mosquito regurgitates virus-containing saliva into the victim's bloodstream. The virus circulates freely in the plasma and comes into contact with susceptible target cells such as the endothelial cells of the capillaries, macrophages, and monocytes.

Table 43-1. Arthropod-borne viruses causing CNS disease.

Virus Family and Type










   Eastern equine encephalitis (EEE)

Aedis culiseta


North America (East and Gulf Coasts); South America

Mild systemic or severe encephalitis

   Western equine encephalitis (WEE)

Culex culiseta


North and South America

Mild systemic encephalitis

   Venezuelan equine encephalitis

Aedes culex

Small mammals; horses

North, South, and Central America

Mild systemic or severe encephalitis






   St. Louis encephalitis

Culex spp.


North America



Ixodes ticks

Small mammals

North America


   Japanese encephalitis

Culex spp.

Pigs; birds



   West Nile

Culex spp.


Africa, Europe, U.S.

Fever, encephalitis, hepatitis

   Russian spring summer encephalitis

Ixodes and Dermacentor ticks





   California (La Crosse Virus)

Aedes spp.

Small mammals

Eastern one-half of North America

Mild systemic encephalitis


Following replication of the virus in these cells, the initial viremia produces systemic symptoms such as fever, chills, headaches, backaches, and flulike symptoms within 3–7 days of infection. Some of these symptoms can be attributed to the interferon produced after infection of these target cells. This is considered a mild systemic disease, and most virus infections do not progress beyond this point.

After replication in cells of the reticuloendothelial system, a secondary viremia may result. This can produce sufficient virus to infect target organs such as the brain, liver, skin, and vasculature, depending on the tissue tropism of the virus. Access to the brain is provided by infection of the endothelial cells lining the small vessels of the brain or choroid plexus.

The vertebrate-invertebrate cycle of CE viruses is very similar to that for toga- and flaviviruses and includes Aedes triseriatus as the vector mosquito and the squirrel or chipmunk as the usual host.

BOX 43-1 Other Viral Infections of the CNS




More Frequent



Less Frequent


WEE, EEE, VEE, West Nile Virus


Progressive multifocal leukoencephalopathy, rabies

Progressive multifocal leukoencephalopathy Creutzfeldt-Jakob disease, rabies

Clinical Findings

  1. Signs and Symptoms.Infection by the togaviruses usually causes a low-grade disease characterized by flulike symptoms (ie, chills, fever, rash, and aches) that correlate with systemic infection during the initial viremia. EEE, WEE, and Venezuela equine encephalitis (VEE) virus infections can progress to encephalitis (as the names imply) in humans and horses, with EEE causing the most severe disease. These viruses are usually more of a problem to livestock than to humans.

Most infections with flaviviruses are relatively benign, although encephalitic or hemorrhagic disease can occur. The encephalitis viruses include St. Louis, Japanese, Murray Valley, and Russian spring-summer viruses. Infections with West Nile and other viruses usually are limited to a mild systemic disease, possibly with a hemorrhagic rash, but the 1999 outbreak on the East Coast of the United States with cases of fatal encephalitis underscores the potential severity of infection with West Nile virus.

Inapparent, mild illnesses or aseptic meningitis occur with CE virus infection, the latter after an incubation period of approximately 48 h. Encephalitis caused by CE occurs approximately 1 week after exposure and is manifested by seizures and generalized cerebral dysfunction mimicking herpes simplex encephalitis. It is most common in school-aged children.

  1. Laboratory Findings.The togaviruses, flaviviruses, and CE viruses can be grown in both vertebrate and mosquito cell lines but are difficult and dangerous to isolate. When isolation of the virus is necessary, the best systems are suckling mice and mosquito cell lines. In addition to cytopathology, the viruses grown in culture can be detected by immunofluorescence or by hemadsorption of avian erythrocytes. After isolation, the viruses can be distinguished by analysis of the genomic RNA or by monoclonal antibodies.

A variety of serologic methods can be used to diagnose arbovirus infections. Seroconversion or a fourfold increase in titer between acute and convalescent sera is used to indicate a recent infection. The serologic cross-reactivity between viruses in a group or complex limits identification of the actual viral species in many cases.

  1. Imaging

Magnetic resonance imaging (MRI) may help to distinguish HSV encephalitis from other types; HSV characteristically causes temporal lobe lesions, whereas arboviruses cause focal lesions in basal ganglia and thalami.

Differential Diagnosis

The arthropod-borne encephalitides are similar to each other, but the specific etiology may be suggested by geographic location and age of the patient as well as the severity of the illness. For example, WEE is more apt to occur in the far western United States, Colorado, and Texas; EEE is endemic along the entire East Coast; SLE in the eastern states, Texas, and Mississippi; and CE in the Midwest. The 1999 outbreak of West Nile virus infections in New York was originally thought to be due to SLE, but this virus is now endemic in the Eastern United States. West Nile attacked adults and had a fatality rate of 10%. WEE has its highest attack rate in infants < 1 year of age and is most severe in this age group. EEE is more severe than WEE, with a mortality rate of ≥ 20% in infants and children. SLE is similar in severity to WEE, with 5% mortality in those with encephalitis, but SLE tends to attack adults rather than infants or children. CE, in contrast, attacks patients aged 5–18 years.

Arbovirus encephalitis must be distinguished from that caused by herpes simplex viruses (HSV, VZV, and EBV), especially since the latter infections can be treated with antiviral agents. Herpesvirus encephalitis occurs sporadically without any seasonal pattern and occurs with or without mosquito exposure. HSV and VZV encephalitis may be preceded or accompanied by characteristic vesiculopustular skin lesions. HSV tends to be localized to the temporal lobe, causing EEG and imaging abnormalities in this location.


In infants < 1 year old with encephalitis, death may occur in up to 20% and neurologic sequelae in > 50% of survivors. The rates of these complications are less in older children and adults.


No treatments exist for arbovirus diseases other than supportive care.


Attack rates for encephalitis are approximately 1 per 1000 infections. In older children and adults, ≥ 95% recover from encephalitis, and sequelae are uncommon, but in infants there is high mortality and frequent residua in survivors.

Prevention & Control

The easiest means to prevent the spread of any arbovirus is elimination or avoidance of its vector and breeding grounds (Box 43-2). Killed vaccines against Japanese encephalitis, EEE, WEE, and Russian spring-summer encephalitis viruses are available. These vaccines are for individuals working with the specific virus or at risk of contact. A live vaccine against VEE virus is available but only for use in domestic animals.


Lymphocytic choriomeningitis (LCM) virus is an arenavirus, the same family as Lassa virus. All arenaviruses have a common reservoir in animals, especially small rodents. The infected animals may be asymptomatic or minimally diseased but excreting the virus in their secretions.


LCM virus infects hamsters and mice; chronic infection is common in these animals and leads to chronic viremia and virus shedding in saliva, urine, and feces. Infection of humans may occur by way of aerosols, contamination of food, or fomites. Bites are not a usual mechanism of spread. Persistently infected rodents do not usually exhibit illness. The incubation period for LCM infections averages 10–14 days.


Arenaviruses are pleomorphic and enveloped with lipid; the virion has a mean diameter of 120 nm. They contain two-stranded RNA in a linear or circular configuration. The total molecular weight of this RNA is 3.2 × 106 daltons–4.8 × 106 daltons.


Arenaviruses are able to infect macrophages and possibly cause the release of mediators of cell and vascular damage. In certain laboratory animals the clinical severity of arenavirus disease appears to be directly related to the host's immunologic response. The greater the immune (especially T lymphocyte) response, the worse the disease. Whether these mechanisms are operative in human infection is not clear. LCM virus may actually produce an encephalitis as well as meningitis. Perivascular mononuclear infiltrates may be seen in neurons of all sections of brain as well as in the meninges.

BOX 43-2 Control of Arthropod–borne Viral Encephalitis

Prophylactic Measures

· Avoid mosquito and tick bites

· Vaccines for certain arboviruses

Isolation Precautions

· None

Clinical Syndrome

LCM illness occurs in most infected individuals but is usually nonspecific or influenzalike. Current estimates show that ~35% of infected persons exhibit clinical evidence of CNS infection. The name of the virus suggests that meningitis is a typical clinical event, but actually a febrile illness, if it occurs, may be subacute and persist for several months. Encephalitis occurs in approximately one-third of patients with CNS manifestations.

Laboratory Diagnosis

The diagnosis of LCM virus infection is usually made through serologic tests, although the virus can be recovered by inoculation of blood (early) or CSF (late in illness) into suckling mice or Vero monkey cells.

Treatment & Prevention

Only supportive therapy for patients with LCM infection is currently available. Prevention of these rodent-borne infections rests on control of the vector's contact with humans. Most human cases of LCM in the United States have resulted from contact with pet hamsters or in rodent-breeding facilities. If hamsters must be kept as pets, scrupulous hand washing is recommended after contact.


Essentials of Diagnosis

  • Subacute onset of neurologic abnormalities including hallucinations, combativeness, muscle spasms, seizures, and focal paralysis.
  • Detection of negri bodies or rabies antigen in animal or human brain tissue (70–90%).
  • Rabies-neutralizing antibody in serum or CSF diagnostic in an unimmunized patient.

General Considerations

Rabies is an acute fatal viral illness of the CNS. It can affect all mammals and is transmitted between them by infected secretions, most often by bite. It was first recognized more than 3000 years ago and has been among the most feared of infectious diseases. It is said that Aristotle recognized that rabies could be spread by a rabid dog.

  1. Epidemiology

Rabies exists in two epizooic forms: the urban form is associated with unimmunized dogs or cats and is essentially nonexistent in the United States; the sylvatic form occurs in wild skunks, foxes, wolves, raccoons, bats, and mongooses. Throughout the world there are striking geographic differences in specific animals. For example, raccoons are a significant reservoir of rabies in the southwestern United States but not on the West Coast; the bat is a frequent vector in Latin America, and the wolf in Eastern Europe. Rodents are not important vectors of rabies. Human or cattle infection is incidental, and does not contribute to maintenance or transmission of the disease.

Human exposures may be from wild animals or from unimmunized dogs or cats. Domestic animal bites are the most frequent vectors in developing countries because of lack of enforcement of animal immunization. Infection in domestic animals usually represents a spillover from infection in wildlife reservoirs. Human infection tends to occur where animal rabies is common and where there is a large population of unimmunized domestic animals. Worldwide, the occurrence of human rabies is estimated to be about 15,000 cases per year, with the highest attack rates in Southeast Asia, the Philippines, and the Indian subcontinent. In the United States, fewer than five cases of human rabies are reported yearly.

  1. Microbiology

The rabies virus is a bullet-shaped, enveloped, single-stranded RNA virus of the rhabdovirus group. The virion is large, with a diameter of ~180 nm. Knoblike glycoprotein excrescences or projections, which elicit neutralizing and hemagglutination-inhibiting antibodies, cover its surface.

In the past, a single antigenically homogeneous virus was believed responsible for all rabies; however, differences in cell culture growth characteristics of isolates from different animal sources, some differences in virulence for experimental animals, and antigenic differences in surface glycoproteins have indicated strain heterogeneity among rabies virus isolates. These studies may help to explain some of the biological differences noted, as well as the occasional case of vaccine failure.

  1. Pathogenesis

The essential first event in human or animal rabies infection is the introduction of virus through the epidermis, usually as a result of an animal bite. Inhalation of heavily contaminated material, such as bat droppings, eg, by cave explorers, can also cause infection. Rabies virus first replicates in striated muscle tissue at the site of inoculation. It then enters the peripheral nervous system at the neuromuscular junctions and spreads up the nerves to the CNS, where it replicates exclusively within the gray matter. It then passes centrifugally along autonomic nerves to reach other tissues, including the salivary glands, adrenal medulla, kidneys, and lungs.

Passage into the salivary glands in animals explains transmission of the disease by infected saliva. The incubation period ranges from 10 days to a year, depending on the amount of virus introduced, the amount of tissue involved, the host immune mechanisms, and the distance the virus must travel from the site of inoculation to the CNS. Thus the incubation period is generally shorter with face wounds than with leg wounds. Immunization early in the incubation period frequently aborts the infection.

The neuropathology of rabies resembles that of other viral diseases of the CNS, with infiltration of lymphocytes and plasma cells into CNS tissue and nerve cell destruction. The pathognomonic lesion is the negri body, an eosinophilic cytoplasmic viral inclusion distributed throughout the brain, particularly in the hippocampus, cerebral cortex, cerebellum, and dorsal spinal ganglia.

Clinical Findings

  1. Signs and Symptoms.Rabies in humans usually results from a bite by a rabid animal or contamination of a wound by an animal's saliva. It presents as an acute, fulminant, fatal encephalitis; human survivors have been reported only occasionally. The disease begins as a nonspecific illness marked by fever, headache, malaise, nausea, and vomiting. Abnormal sensations at or around the site of viral inoculation occur frequently and probably reflect local nerve involvement. The onset of encephalitis is marked by periods of excess motor activity and agitation. Hallucinations, combativeness, muscle spasms, signs of meningeal irritation, seizures, and focal paralysis occur. Periods of mental dysfunction are interspersed with completely lucid periods; as the disease progresses, however, the patient lapses into coma. Autonomic nervous system involvement often results in increased salivation.

Brain stem and cranial nerve dysfunction is characteristic, with double vision, facial palsies, and difficulty in swallowing. The combination of excess salivation and difficulty in swallowing produces the traditional picture of foaming at the mouth. Hydrophobia, the painful, violent involuntary contractions of the diaphragm and accessory respiratory, pharyngeal, and laryngeal muscles initiated by swallowing liquids, is seen in about 50% of cases. Involvement of the respiratory center produces respiratory paralysis, the major cause of death. The median survival after onset of symptoms is 4 days, with a maximum of 20 days unless artificial supportive measures are instituted. Recovery is rare and has been seen only in partially immunized individuals.

  1. Laboratory Findings.Laboratory diagnosis of rabies in animals or deceased patients is accomplished by demonstration of virus in brain tissue. As negri bodies are not seen in at least 20% of rabies victims, their absence does not rule out the diagnosis. Viral antigen can be demonstrated rapidly by immunofluorescence procedures. Intracerebral inoculation of infected brain tissue or secretions into suckling mice results in death in 3–10 days. Histologic examination of their brain tissue shows negri bodies; both negri bodies and rhabdovirus particles may be demonstrated by electron microscopy. Specific antibodies to rabies virus can be detected in serum, but generally only late in the disease.

Differential Diagnosis

Rabies may initially be mistaken for Guillain-Barré syndrome, an ascending peripheral polyneuritis, but encephalitic symptoms and signs do not develop in the latter illness.


Pneumonia and other infectious complications of intensive care are almost invariable. Respiratory paralysis results from infection of the respiratory center.


In the late 1800s Pasteur, noting the long incubation period of rabies, suggested that a vaccine to induce an immune response before the development of disease might be useful in prevention. He apparently successfully vaccinated Joseph Meister, a boy severely bitten and exposed to rabies, with multiple injections of a crude vaccine made from dried spinal cords of rabies-infected rabbits. This treatment emerged as one of the most noteworthy accomplishments in the annals of medicine (Box 43-3 and Prevention & Control section below for more information).


Of patients with rabies, > 90% die owing to complications of the illness or progressive neurologic dysfunction, especially respiratory paralysis.

Prevention & Control

Prevention is the mainstay of controlling human rabies. Intensive supportive care has resulted in two or three long-term survivors; despite the best modern medical care, however, the mortality still exceeds 90%. In addition, because of the infrequency of the disease, many cases die without definitive diagnosis. Human hyperimmune antirabies globulin interferon and vaccine do not alter the disease once symptoms have developed. Currently, the prevention of rabies is divided into preexposure and postexposure prophylaxis.

BOX 43-3 Treatment of Rabies




First Choice

Treatment consists of immune enhancement: immune globulin and vaccine (see Box 43-5 for dosages)

Treatment consists of immune enhancement: immune globulin and vaccine (see Box 43-5 for dosages)

  1. Preexposure prophylaxis.This type of prophylaxis is recommended for individuals at high risk of contact with rabies virus, such as veterinarians, spelunkers, laboratory workers, and animal handlers. The vaccine currently used in the United States for preexposure prophylaxis uses an attenuated rabies virus grown in human diploid cell culture and inactivated with beta-propriolactone. Preexposure prophylaxis consists of two subcutaneous injections of vaccine given 1 month apart, followed by a booster dose several months later.
  2. Postexposure prophylaxis.This type of prophylaxis requires careful evaluation and judgment. Every year more than 1 million Americans are bitten by animals, and in each instance a decision must be made whether to initiate postexposure rabies prophylaxis. In this decision the physician must consider (1) whether the individual came into physical contact with saliva or another substance likely to contain rabies virus; (2) whether there was significant wounding or abrasion; (3) whether rabies is known or suspected in the animal species and area associated with the exposure; (4) whether the bite was provoked or unprovoked (ie, the circumstances surrounding the exposure); and (5) whether the animal is available for laboratory examination. Any wild animal or ill, unvaccinated, or stray domestic animal involved in a possible rabies exposure, such as an unprovoked bite, should be captured and killed. The head should be sent immediately to an appropriate laboratory, usually at the state health department, for search for rabies antigen by immunofluorescence. If examination of the brain by this technique is negative for rabies virus, it can be assumed that the saliva contains no virus and that the exposed person requires no treatment. If the test is positive, the patient should be given postexposure prophylaxis.

Postexposure prophylaxis consists of immediate, thorough washing of the wound with soap and water; passive immunization with 20 IU per kg hyperimmune globulin, of which at least half the dose should be infiltrated around the wound site; and active immunization with antirabies vaccine (Box 43-4). With human diploid vaccine, five doses given on days 1, 3, 7, 14, and 28 are recommended. Physicians should always seek the advice of the local health department when the question of rabies prophylaxis arises.


In 1998, a newly emergent paramyxovirus was identified as the cause of an outbreak of encephalitis, with the first death occurring in the village of Nipah, Malaysia. The cases occurred in farmers and abattoir workers who had close contact with diseased pigs that had a respiratory illness. Nipah virus is closely related to another recently emerged paramyxovirus known as Hendra virus. Thus, the potential for new viral pathogens to emerge continues unabated.

BOX 43-4 Control of Rabies

Prophylactic Measures

· Postexposure: immune globulin 20 IU per kg; infiltrate ½ into wound; vaccine 1.0 ml of human diploid cell vaccine (HDCV) or inactivated vaccine (RVA) on days 0, 3, 7, 14, and 28.

· Pre-exposure: vaccine

Isolation Precautions

· Not necessary for infected patient


Essentials of Diagnosis

  • Progressive cerebral deterioration in an immunocompromised patient, leading to paralysis and death in < 1 year.
  • Multiple lesions in white matter, as revealed by MRI.
  • Virions visible on brain biopsy.
  • Normal CSF findings (cell count, glucose, protein).
  • JC virus (JCV) DNA detectable in CSF by PCR.

General Considerations

  1. Epidemiology

Progressive multifocal leukoencephalopathy (PML) is a rare syndrome that occurs in immunocompromised patients, including those with AIDS, and is caused by a papovavirus known as JC virus (JCV). The virus was first recovered by coculturing of brain tissue from a patient with progressive multifocal leukoencephalopathy and Hodgkin's disease. Polyomavirus infections are ubiquitous, and most humans are infected with JCV by the age of 15 years.

  1. Microbiology

The polyomaviruses are small (44 nm in diameter), icosahedral, and lack an envelope. The double-stranded DNA is a circular, supercoiled molecule.

  1. Pathogenesis

Respiratory transmission is the probable mode of spread. Immune suppression after organ transplantation or during pregnancy is capable of reactivating latent infections.

Clinical Findings

  1. Signs and Symptoms.Clinical symptoms develop insidiously but progress relentlessly. Patients may have multiple neurologic symptoms unattributable to a single anatomic lesion. Impairment of speech, vision, coordination, mentation, or some combination of these occurs and is followed by paralysis of the arms and legs and finally death in approximately 1 year.
  2. Laboratory Findings.CSF is normal and does not contain antibody to JCV but may be positive for JCV by PCR. Histologic examination of brain tissue from cases of progressive multifocal leukoencephalopathy reveals cytologic changes within the oligodendrocytes. These cells are adjacent to areas of demyelination. There is little if any inflammatory cell response. Electron microscopy can be used to visualize viral particles in brain tissue, and immunofluorescence can confirm the identity of viral antigen.

JCV grows best in primary human fetal glial cells, which are not readily available. Culture of JCV is therefore performed only in a few research laboratories.

  1. Imaging

MRI is characteristic with multiple high signal-intense lesions predominantly in white matter.

Differential Diagnosis

Although the MRI is characteristic, similar clinical and radiologic findings can occur with VZV infections in AIDS patients.


There is progressive worsening of cerebral and neurologic function with death usually occurring 3–6 months from onset.


No specific treatment is available, but some stabilization or improvement may occur if the immunosuppression can be reduced, eg, control of HIV infection.


Rarely there may be regression of symptoms especially if immunosuppression can be reduced. Otherwise the disease is fatal and may be especially rapid in AIDS patients.

Prevention & Control

The ubiquitous nature of polyomaviruses and the lack of understanding of their modes of transmission make preventing primary infection unlikely. Minimizing the duration and degree of immunosuppression can decrease reactivation of polyomavirus and the development of PML.



Evidence has accumulated during the past 30 years that a variety of progressive neurologic diseases in both animals and humans are caused by viral or other filterable agents that share some of the properties of viruses. These illnesses have been termed slow viral diseases because of the protracted period between infection and the prolonged course of the illness, but a better term is persistent viral infection. Most persistent viral infections involve well-differentiated cells, such as lymphocytes and neuronal cells. These diseases are associated with unconventional viruses that are small, filterable infectious agents transmissible to certain experimental animals, but that do not appear to be associated with immune or inflammatory responses by the host and have not been cultivated in cell culture.

Viral persistence can result from integration of viral nucleic acid into the host genome, mutations that interfere with or severely limit viral replication or antigenicity, failure of host immune systems to recognize virus or infected cells, or some combination of these.

A group of progressive degenerative diseases of the central nervous system with similar pathology has been described. Two of the illnesses, Creutzfeldt-Jakob disease and kuru, occur in humans; two others, scrapie in sheep and goats and progressive encephalopathy in mink, occur in animals. Although the pathogenesis of these four illnesses is not well understood, there are various degrees of neuronal loss, spongiform neurologic changes, and astrocyte proliferation. The incubation periods are months to years, and the diseases have protracted and inevitably fatal courses.

The causes of these diseases are transmissible agents with unusual physical and chemical properties, but their nature is still obscure. They are small and filterable to diameters of 5 nm or less, multiply to high titers in the reticuloendothelial system and brain, produce characteristic infections, and can remain viable even in formalinized brain tissue for many years. They are resistant to ionizing radiation, boiling, and many common disinfectants. Recognizable virions have not been found in tissues, and the agents have not been grown in cell culture. Treatment of infectious material with proteases and nucleases does not decrease infectivity.

Brain extracts from scrapie-infected animals contain a glycoprotein called PrP that is not found in the brains of normal animals. PrP has been termed a prion (proteinaceous infectious particle), and purified proteinaceous extracts of brain tissue in very high dilutions have been shown to transmit disease to experimental animals. Repeated attempts to find associated nucleic acids have been generally unrewarding. PrP is encoded in a host gene, and specific prion mRNA has been found in both normal and infected tissue. Why the mRNA is translated in the disease and how prion production is apparently initiated by an external source of infectious PrP remain unanswered. During scrapie infection, prion protein may aggregate into birefringent rods and form filamentous structures termed scrapie-associated fibrils, which are found in membranes of scrapie-infected brain tissues.


Essentials of Diagnosis

  • Progressive mentation abnormalities leading to disorders of gait and myoclonus.
  • Occurs in sixth and seventh decades in previously normal patients.
  • May be history of corneal transplant, neurosurgical procedures, or use of human growth hormone.
  • Characteristic brain biopsy abnormalities of spongiform degeneration, neuron loss, and astrogliosis.

General Considerations

Creutzfeldt-Jakob disease is a progressive, fatal illness of the central nervous system that is seen most frequently in the sixth and seventh decades of life. The disease is sporadic and found worldwide, with an incidence of disease of 1 case/million people per year. The mode of acquisition is unknown, but a higher incidence of the disease among Israelis of Libyan origin who eat sheep eyeballs has led to speculation that the disease may be transmitted by the ingestion of scrapie-infected tissue. Infection has been transmitted by corneal transplants, by contact with infected electrodes used in a neurosurgical procedure, and by pituitary-derived human growth hormone. In these cases, the incubation period of the disease was ~15–20 months.

Other evidence suggests that a longer latency may follow natural infection. It has been transmitted to chimpanzees, mice, and guinea pigs by inoculation of infected brain tissue, leukocytes, and certain organs. High levels of infectious agent have been found, especially in the brain, where they may reach 107infectious doses per gram of brain. Nonpercutaneous transmission of disease has not been observed, and there is no evidence of transmission by direct contact or airborne spread.

Clinical Findings

  1. Signs and Symptoms.The initial clinical manifestation is a change in cerebral function, usually diagnosed initially as a psychiatric disorder. Forgetfulness and disorientation progress to overt dementia, with the development of changes in gait, increased tone in the limbs, myoclonus, and seizures. The disorder runs a course of 12 months to 4–5 years, eventually leading to death.
  1. Laboratory Findings.Brain biopsy provides definitive diagnosis and includes spongiform degeneration, neuron loss, and astrogliosis. There are also birefringent rods and fibrillar structures similar to those in scrapie. Identification of Creutzfeldt-Jakob prion protein (PrP CjD) by fluorescent antibody directed against it is a useful diagnostic adjunct to neuropathologic examination of brain tissue.
  2. Imaging

EEG is abnormal and characteristic in more than 75% of patients with periodic, symmetric, biphasic or triphasic sharp wavers. Computed tomography (CT) scan or MRI reveals brain atrophy.

Differential Diagnosis

Cases of Creutzfeldt-Jakob disease may resemble PML, but the latter occurs in immunocompromised patients, including those with AIDS, whereas Creutzfeldt-Jakob disease occurs in older, nonimmunocompromised individuals.


There is no effective therapy of Creutzfeldt-Jakob disease, and all cases have been fatal.


The small risk of nosocomial infection is related only to direct contact with brain tissue. Stereotactic neurosurgical equipment, especially that used in patients with undiagnosed dementia, should not be reused. In addition, organs from patients with undiagnosed neurologic disease should not be used for transplants. Growth hormone from human tissue has now been replaced by a recombinant genetically engineered product. The agent of Creutzfeldt-Jakob disease has not been transmitted to animals by inoculation of body secretions, and no increased risk of disease has been noted in family members or medical personnel caring for patients. Disinfection of potentially infectious material can be accomplished by treatment for 1 h with 0.5% sodium hypochlorite solution or by autoclaving at 121°C for 1 h.


Kuru was a subacute, progressive neurologic disease of the Fore people of the Eastern Highlands of New Guinea. In the local Fore dialect, kuru means to tremble with fear or to be afraid. The disease was brought to the attention of the western world by Gadjusek and Zigas in the mid-1950s. Although the illness was localized and decreasing in incidence, its study has thrown light on the infectious nature of similar transmissible encephalopathies. Epidemiologic studies indicated that kuru usually afflicted adult women or children of either sex. The disease was rarely observed outside of the Fore region, and outsiders in the region did not contract the disease. The symptoms and signs were ataxia, hyperreflexia, and spasticity, which led to progressive starvation and death. Mental alertness was unaffected until the late stages of illness.

Pathologic examination revealed changes only in the CNS, with diffuse neuronal degeneration and spongiform changes of the cerebral cortex and basal ganglia. No inflammatory response was noted. Inoculation of infectious brain tissue into primates produced a disease that caused similar neurologic symptoms and pathologic manifestations after an incubation period of approximately 40 months.

Epidemiologic studies indicated that transmission of the disease in humans was associated with ritual cannibalism, practiced mainly by women and young children and occasionally by men. This ritual involved the handling and ingestion of organs of deceased relatives. Inoculation through lesions in the skin and mucous membranes was shown to be the most likely mode of transmission, with clinical disease developing 4–20 years after exposure. Since the elimination of cannibalism from the Fore culture, kuru has disappeared.


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