Chapter 20: Persistent Viral Infections of the Central Nervous System

The molecular mechanisms of persistent viral infections are not clearly understood, but three broad conditions must be satisfied for a virus to establish a persistent infection in a host:

1. Virus must be able to infect host cells without being cytolytic or cytopathic. Viruses have found various cell types such as nonpermissive cells in a host to infect and remain less cytopathic or noncytolytic to maintain persistence. For example, HSV remains latent in sensory neurons; HIV is less cytopathic to resting T cells or monocytes/macrophages.

2. Viral genome must be maintained by various mechanisms. Viral genomes can be maintained in several ways, including integration of retroviral DNA (HIV) and extrachromosomal episomes for DNA viruses (HSV). However, the mechanisms of viral RNA genome maintenance are not known.

3. Virus must avoid detection and elimination by the host’s immune system. Viruses have evolved several evasion strategies such as infection of immunologically privileged sites that are not easily accessible to the immune system (central nervous system [CNS] and other sites), antigenic variation, downregulation of immune components, and others. Several viruses cause persistent infection of the CNS because they are not easily detected and eliminated by the host immune response. Many of the persistent viruses employ some or all strategies to avoid elimination by the immune system.

Evidence has accumulated 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 (Tables 20–1, 20–2, and 20–3). These illnesses have been termed “slow viral diseases” because of the protracted period between infection and the onset of disease as well as 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. They can be classified as (1) diseases associated with “conventional” viral agents that possess nucleic acid genomes and protein capsids and/or envelopes induce immune responses and can be grown in cell culture systems; and (2) diseases associated with “unconventional” agents that are small, filterable infectious agents, known as “prions,” which are transmissible to certain experimental animals, but do not contain nucleic acids, do not appear to be associated with immune or inflammatory responses by the host, and have not been cultivated in cell culture.

Persistence of conventional viruses can result from infection of a nonpermissive cell in the host with restrictive cytolytic effects, preservation of viral nucleic acid in infected host’s cells, and mutations that interfere with or severely limit viral replication or antigenicity.

The following conditions are the major persistent infections caused by conventional viral agents. They are summarized in Table 20–1.

Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is discussed in Chapter 10. It is a rare chronic measles virus infection of children that usually appears 2 to 10 years after measles virus infection and produces progressive neurologic disease characterized by an insidious onset of personality change, progressive intellectual deterioration, and both motor and autonomic nervous system dysfunctions.

Progressive Postrubella Panencephalitis

Even more rarely, a degenerative neurologic disorder similar to SSPE is associated with persistent rubella virus infection of the CNS. This condition is seen most often in adolescents who have had the congenital rubella syndrome. Rubella virus has been isolated from brain tissue in these patients using cocultivation techniques.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a subacute, degenerative disease of the brain found primarily in adults with (1) immunosuppressive diseases, especially acquired immunodeficiency syndrome (AIDS) and hematologic malignancies; or (2) diseases requiring therapy with immunosuppressive agents. PML is due to a polyomavirus (JC virus) and is considered in Chapter 19.

Persistent Enterovirus Infection

Persons with congenital or severe acquired immunodeficiency, especially those with agammaglobulinemia, may develop a chronic CNS infection due to an echovirus or other enterovirus. Headache, confusion, lethargy, seizures, and cerebrospinal fluid (CSF) pleocytosis are common manifestations. The virus can be isolated from the CSF. Clinical improvement may be achieved by the administration of human hyperimmune globulin to the infecting virus type. Relapse, however, occurs when therapy is discontinued, indicating persistence of virus despite the therapy.

AIDS Dementia Complex or HIV-Associated Dementia

Human immunodeficiency virus (HIV) causes a persistent infection of the CNS in many patients with symptomatic AIDS known as AIDS dementia complex (ADC) or HIV-associated dementia (HAD). The virus does not directly infect the nerve cells but the virus produced by perivascular macrophages and/or microglia may produce a bystander effect causing inflammation that may damage brain and spinal cord. The clinical course may vary from a mild subacute illness (early stage of HIV infection) to severe progressive dementia (late stages of HIV infection). HAD primarily occurs with more advanced HIV infection and symptoms include encephalitis, behavioral changes, and a gradual decline in cognitive function. HAD is more common in HIV-infected infants than infected adults. For more on HIV/AIDS, see Chapter 18.

Latent Herpes Simplex Virus Infection

Herpes simplex viruses, HSV-1 and HSV-2, following primary infection ascend in the trigeminal and sacral root ganglia and establish persistent/latent infection. There might be HSV replication in the ganglia but then it becomes latent and oncolytic. Reactivation of HSV due to sunlight, stress, immune suppression, trauma, etc. passes viral genome anterograde in axons to the epithelium to cause replication and disease (see Chapter 14 for details).

Latent Varicella-Zoster Virus Infection

Varicella-Zoster virus (VZV) causes primary chickenpox and after recovery from acute infection, the virus establishes latency in dorsal root ganglia. After some time, several years or in many instances above aged 50 years, the virus is reactivated and the skin lesions are seen in the same area of the dermatome. Clinically, this disease is called shingles and it is usually unilateral. In immunocompromised patients, the reactivated form could disseminate and cause serious problems. Details are described in Chapter 14.

A group of progressive degenerative diseases of the CNS has been shown to be caused by infectious agents with unusual physical and chemical properties, which are now known as prions. The Nobel Prize in Medicine for 1997 was awarded to Stanley Prisoner for his work in identifying the role of prions in disease. Prions cause bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, and five fatal CNS diseases in humans (Table 20–2). Prions can be the etiologic agents of inherited, communicable, or sporadic diseases. The pathogenesis of these illnesses is not well understood, but the pathologic and clinical features are similar. Varying degrees of neuronal loss and astrocyte proliferation occur. The diseases are known as “spongiform” encephalopathies or transmissible spongiform encephalopathies (TSE) because of the vacuolar changes in the cortex and cerebellum (Figures 20–1 and 20–2). The incubation periods for these diseases are months to years, and their courses are protracted and inevitably fatal.

A prion is a “small proteinaceous infectious particle” that is not inactivated by procedures that destroy nucleic acids (Table 20–3). They have diameters of 5 to 100 nm or less 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 by electron microscopy, and the agents have not been grown in cell culture.

A prion is composed of a protein encoded by a normal cellular gene, PrP, in the brain which is located on chromosome 20. The protein, designated PrPc, is converted from a normal form (designated as NP in Figure 20–3) into a disease-causing form by a change in posttranslational conformational process to a protein designated PrPsc (designated as PP in Figure 20–3). Brain extracts from scrapie-infected animals contain PrPsc, which is not found in the brains of normal animals; PrPsc is the prion that is responsible for transmission and infection. The conformational change is also the way in which prions increase in number; that is, contact with PrPsc results in a conformational change of the normal prion host cell protein, PrPc or NP, and the formation of additional abnormal or infectious prion protein, PrPsc or PP (Figure 20–3). Production of PrPsc prions and the consequent pathology result from this process. During scrapie infection, prion protein may aggregate into amyloid-like birefringent rods and filamentous structures termed scrapie-associated fibrils (Figure 20–4), which are found in membranes of scrapie-infected brain tissues. The amino acid sequence of different prion proteins in different animal species differ from one another and transmission across species usually does not occur. Specifically, ingestion of tissue from sheep or elk infected with abnormal prions has not been documented to lead to human disease. Tissue from infected cows did, however, transmit variant CJD (see following text).

Kuru

Kuru was a subacute, progressive neurologic disease of the Fore people of the Eastern Highlands of New Guinea. The disease was brought to the attention of the Western world by Gadjusek and Zigas in 1957. Although the illness was localized and decreasing in incidence, its study has thrown light on the transmissibility and infectious nature of similar encephalopathies. Epidemiologic studies indicated that kuru usually afflicted adult women, or children of either sex. The disease was rarely observed outside 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 dementia, starvation, and death. 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 apparent. 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 ingestion of a soup made from the brains of dead relatives and eaten in honor of the deceased. Clinical disease developed 4 to 20 years after exposure. Since the elimination of cannibalism from the Fore culture, kuru has disappeared.

Creutzfeldt-Jakob Disease

Creutzfeldt-Jakob disease (CJD) is a progressive, fatal illness of the CNS that is seen most frequently in the sixth and seventh decades of life. The initial clinical manifestations are a change in cerebral function, usually diagnosed initially as a psychiatric disorder. Forgetfulness and disorientation progress to overt dementia and the development of changes in gait, increased tone in the limbs, involuntary movement, and seizures. These manifestations resemble those of kuru. The disorder usually runs a course of 4 to 7 months, eventually leading to paralysis, wasting, pneumonia, and death.

CJD is found worldwide, including the United States, with an incidence of disease of one to two case(s) per million per year. The mode of acquisition is unknown, but it occurs both sporadically (85%) and in a familial pattern (15%). Infection has also been transmitted by dura mater grafts and corneal transplants, by contact with contaminated electrodes or instruments used in neurosurgical procedures, and by pituitary-derived human growth hormone. The latter was responsible for more than 100 cases. The incubation period of the disease is approximately 3 years to more than 20 years. The agent of CJD 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.

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 107 infectious doses per gram of brain tissue. Nonpercutaneous transmission of CJD has not been observed, and there is no evidence of transmission by direct contact or airborne spread.

Brains from patients with CJD have the birefringent rods and fibrillar structures noted in kuru and scrapie (Figure 20–4). Identification of PrPsc and antibodies directed against it may become a useful diagnostic adjunct to neuropathologic examination of brain tissue. Pathologic examination of brain tissue is the only definitive diagnostic test.

Therapy

There is no effective therapy for CJD, and all cases have been fatal.

Prevention

The small risk of nosocomial infection is related only to direct contact with infected tissue. Stereotactic neurosurgical equipment, especially which was 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. Recommendations for disinfection of potentially infectious material include treatment for 1 hour with 2N NaOH or by autoclaving at 132°C for 60 to 90 minutes. Others recommend even more extensive treatment such as combining these two procedures to ensure inactivation.

Bovine Spongiform Encephalopathy (“Mad Cow Disease”) and “Variant Creutzfeldt-Jakob Disease”

BSE was identified in 1986 in cow in the United Kingdom, causing them to become uncoordinated and unusually apprehensive. The source of the emerging epidemic was soon traced to a food supplement that included meat and bone meal from dead sheep. Between 1986 and 2004, 180 000 cases of BSE in cattle were confirmed in the United Kingdom. To combat BSE, the British government banned the use of animal-derived feed supplements in 1988, and the epidemic among cattle, which peaked at nearly 40 000 cases in 1992, decreased to less than 4000 new cases in 1997. By February 2002, most European countries had reported cases of BSE, but new infections have ceased as a result of imposing tight controls on cattle feed. The United States had been spared, as measured by over 19 000 cattle brain examinations. The incubation period in cattle was determined to be 2 to 8 years. In addition to the incoordination and apprehension, the cows exhibited hyperesthesia, hyperreflexia, muscle fasciculations, tremors, and weight loss. Autonomic dysfunction was frequently manifested as reduced rumination, bradycardia, and other cardiac arrhythmias. Unfortunately, the prion that causes BSE survived the heat of cooking and was transmitted to humans who inadvertently consumed infected bovine neural tissue or bone marrow (both are sometimes found in processed meats, depending on the rendering procedures used).

Globally, over 220 humans with “variant CJD,” have been reported, with a majority of them, 177 cases, in the United Kingdom, 27 cases in France, and 4 cases in the United States. In all the four cases reported in the United States, infection most likely occurred outside the United States, including United Kingdom (two cases), Saudi Arabia (one case), and Europe and/or the Middle East (one case). The cases frequently present in young adults as psychiatric problems progressing to neurologic changes and dementia, with death in an average of 14 months. It appears that destruction of diseased cattle and the changes in livestock feeds have prevented further cases.

Gerstmann-Straüssler-Scheinker Disease

Gerstmann-Straüssler-Scheinker (GSS) disease is similar to CJD, but occurs at a younger age (fourth to fifth decade). Cerebellar ataxia and paralysis are common, but dementia is less often seen. The disease evolves over an average of 5 years. It was originally thought to be familial, but it also occurs sporadically, very rarely. GSS has been transmitted to experimental animals. The familial nature of this disease raises the question of vertical transmission versus inherited susceptibility.

Fatal Familial Insomnia

This is a recently recognized familial (inherited) prion disease in which a syndrome of sleeping difficulty is followed by progressive dementia. It occurs in patients aged 35 to 61 years, culminating in death within 13 to 25 months. In almost all cases, this disease is caused by a specific mutation in the prion protein. The infectious agent has been transmitted to experimental animal models.