Postinfectious Encephalomyelitis or Acute Disseminated Encephalomyelitis (ADEM)

This is an acute perivenular demyelinating disease of the brain and spinal cord that usually follows viral infections, but on occasions follows some bacterial infections and vaccines, particularly those containing nervous system tissues. Historically, the disorder was also known as post-exanthematous encepahlomyelitis, since it was most frequent after viral diseases characterized by rashes. In the 1950s, ADEM constituted one-third of all cases of encephalitis (see Table 1-4). With the discontinuation of vaccinia virus immunization against smallpox and introduction of vaccines to prevent measles, mumps, rubella, and chickenpox, ADEM constitutes less than one-tenth of the cases of acute encephalitis and now is most common after nonspecific upper respiratory infections.

TABLE 1-4

Postinfectious Encephalomyelitis Associated with Exanthematous Viral Infections.

The hazard of ADEM after inoculation of vaccinia virus to protect against smallpox has returned as an issue, since resumption of vaccination is being considered to counter the possible use of smallpox as a terrorist weapon. A very high rate of complications in one Dutch vaccination program was presumably due to use of a more encephalitogenic strain; the low rates during the mass vaccination in New York in 1947 probably reflects poor surveillance. In Great Britain, during the more recent outbreak of smallpox in 1962, a rate of postvaccinal encephalomyelitis of 1 per 20,000 was estimated, and CDC retrospective surveys estimated 1 per 200,000 in the United States prior to the discontinuation of vaccination. However, the risk of ADEM when starting vaccination after a hiatus of 30 years is uncertain, since neurologic complications are more frequent with primary vaccination and higher in persons over the age of 20 years.

The clinical presentation of ADEM usually follows the antecedent exanthem or respiratory or gastrointestinal symptoms by 5 to 21 days. Typically postmeasles encephalomyelitis occurs 5 to 7 days after the rash when the child is returning to normal activity. There is the abrupt recurrence of fever, depression of consciousness, and appearance of multifocal neurological findings. The spinal fluid usually contains myelin basic protein, often shows increased pressure and a mild pleocytosis (but in about one-third of cases, no increased cellularity is found). The MRI may show very dramatic changes with multiple enhancing lesions in the white matter.

The histopathology of fatal cases shows perivenular inflammation and demyelination throughout the brain and spinal cord. In most instances, virus is not found within the nervous system. For example, in measles, virus is seldom recoverable after the rash which corresponds with the humoral immune response. In measles, deaths occurring at or before the time of rash, measles virus has been found in cerebrovascular endothelial cells by in situ PCR; but no virus antigen or nucleic acid has been found in cells of the CNS in patients dying of encephalomyelitis.

The pathogenesis of ADEM is related to infection of immunocompetent cells and the alteration of immune responses. In both postmeasles and postvaricella disease activated peripheral blood lymphocytes responsive to myelin basic protein have been demonstrated. The autoimmune response against CNS myelin appears to occur without the prerequisite of infection of CNS cells. ADEM appears to be an autoimmune disease very similar to experimental autoimmune encephalomyelitis.

Progressive Multifocal Leucoencephalopathy (PML)

PML is a subacute demyelinating disease originally described as a rare complication of leukemia and Hodgkin's disease. Prior to 1982, PML was an extraordinarily rare disease. With the emergence of AIDS over the past two decades, PML has become a common opportunistic infection causing death in 3-5 percent of AIDS patients.

The clinical presentation is on a background of severe immunosuppression. Multifocal neurological symptoms and signs develop insidiously and usually follow an ingravescent course to death. With introduction of HAART therapy and recovery of T4 counts, stabilization and even improvement has been reported. There is no fever, no nuchal rigidity, and usually no pleocytosis. A very characteristic MRI pattern is seen, however, with nonenhancing multifocal lesions in the subcortical white matter.

The neuropathological changes are unique. Plaques of demyelination are seen preferentially in the grey-white junction. Histologically inflammation is slight or absent. In areas of demyelination, axons are relatively spared and oligodendrocytes are lost. Surrounding these foci, oligodendrocytes are enlarged and contain intranuclear inclusions. Astocytosis is intense, and many astrocytes contain bizarre mitotic figures and multiple nuclei resembling malignant cells.

Electron microscopic examination of the oligodendrocyte inclusions reveal profuse pseudocrystalline arrays of papovaviruses. Only occasional viral particles are seen in astrocytes but they express papovavirus T antigen. JC virus, an ubiquitous human papovavirus, has been associated with almost all cases.

The pathogenesis of demyelination in PML is the opposite of that in ADEM. JC virus causes an asymptomatic persistent infection in most persons. With intense immunosuppression the virus in some patients is transported to brain, probably in B cells. With massive replication in oligodendrocytes these cells are destroyed with secondary loss of myelin. There is no evidence of infection of neurons. Semipermissive infection of astrocytes leads to limited virus production but many astrocytic changes and proliferation resemble transformation. The tat protein of HIV may transactivate JC virus accounting for the unique frequency of PML in HIV-infected patients.

Multiple Sclerosis

A viral cause for multiple sclerosis has been postulated for over 100 years. Over the past half century this speculation has been highlighted by 3 types of studies. First, epidemiological evidence implicates childhood exposure factors (possibly viral infections) in the genesis of multiple sclerosis, and natural history studies have related “virus-like illnesses” to exacerbations of the disease. Second, studies of human and animal viral infections have documented that these infections can have incubation periods of years, cause remitting and relapsing disease and can cause myelin destruction mediated by a variety of mechanisms. Third, laboratory studies of patients with multiple sclerosis consistently show that such patients have greater antibody responses to a variety of viruses than controls and this includes intrathecal antibody synthesis. This is not to deny the clear-cut genetic susceptibility factor (a concordance of over 30 percent in monozygotic twins) or the immunologic abnormalities (which may be caused by infection or be the cause of the unusual viral immune responses in patients).

The unique geographical distribution in temperate zones may in part be explained by Nordic susceptibility genes, but because many immigration studies show that migrants after about age 13 take their risk of early homeland with them and very young migrants acquire the risk of their new land, these findings suggest a childhood exposure. Apparent outbreaks are recorded such as the increase in incidence of multiple sclerosis in the Faroe Islands following the British occupation in World War II. Little evidence is present in these studies to implicate a specific agent; but there are examples of viruses that show different ages of acquisition. For example, varicella occurs at earlier ages in temperate climates and Epstein-Barr virus infections at later ages; in addition the severity or presentation of infection may be age dependent. Early childhood Epstein-Barr virus infection is asymptomatic whereas young adult infection gives rise to infectious mononucleosis.

Specific viral infections have been suggested by serological and virus isolation studies. Over 30 studies have documented the higher levels of antibody to measles in serum and spinal fluid in multiple sclerosis patients than in controls. Although the most striking, measles is not alone as antibodies to many viruses have been found higher in multiple sclerosis patients (see Table 1-5).

TABLE 1-5

Higher Anti-Viral Antibodies in Multiple Sclerosis Than in Controls.

Recovery of viruses from tissues or spinal fluid of patients has been repeatedly reported (see Table 1-6), but not with the consistency of serological tests. Indeed most have proved to be contaminants picked up from cell cultures or laboratory animals.

TABLE 1-6

Viruses Recovered from Patients with Multiple Sclerosis.

Recent interest has focused on Chlamydia pneumoniae, herpesvirus 6, Epstein-Barr virus, and endogenous retroviruses as latent or persistent agents implicated in multiple sclerosis. While they are all normal flora of the human body, they seem to change in quantity or topography in multiple sclerosis. Again this raises the tough question of causation versus an epiphenomenon secondary to the immunological changes in the disease.

Chlamydia commonly causes chronic infection of macrophages, so its recovery from an inflammatory lesion may only reflect the ingress of macrophages. Similarly Epstein-Barr is latent in B cells, and in a disease such as multiple sclerosis, where intrathecal antibody synthesis is taking place, finding it in spinal fluid or brain by PCR is not surprising. Human herpesvirus 6 has similar latency and may be nonspecifically activated by a disease exacerbation. Endogenous retrovirus sequences are present in all our cells, but again nonspecific activation of macrophages increases the translation of these sequences.

In conclusion, patients with multiple sclerosis have abnormally active immune responses to many viruses, and these responses include intrathecal responses. Viral infections precede exacerbations of disease more often than can be explained by chance. The pathogenetic role of viruses in the cause of multiple sclerosis and the precipitation of exacerbations remain a mystery.