Human herpesvirus 6 (HHV-6) infects nearly 100 percent of humans in early childhood, and the infection then lasts for the rest of a person’s life. Viral infections such as human herpes virus 6 (HHV-6) which results in roseola infantum may contribute to developing seizure. Ninety-six of 228 patients (42.1%) showed HHV-6 reactivation in peripheral blood and 129 of 228 (56.6%) demonstrated HHV-6 in at least one of the specimens tested. Many aspects of this syndrome suggest close similarities between DIHS and graft-versus-host disease (GVHD). Specific serologic assays showed marked seroconversion against human herpesvirus-6 but not to measles virus. Thus, it is likely that HHV-6 is associated with some dermatological disorders. The 44-year old patient presented with fever, sore throat, abdominal pain, vomiting, facial and hand edema, diffuse macular and pruritic rash, ascites and hepatosplenomegaly.
The best model for human postinfectious encephalomyelitis (acute disseminated encephalomyelitis), however, is not a viral infection but experimental autoimmune encephalomyelitis (EAE) induced by injection of myelin proteins with Freund’s adjuvant. Roseola has a sudden onset of a high fever, sometimes as high as 105 degrees Fahrenheit. Progressive multifocal leucoencephalopathy (PML) in macaque monkeys caused by SV40 virus is the animal equivalent of PML in man caused by the related JC virus. As in the human disease, the disease evolves in latently infected animals when other infections or illnesses cause immunodeficiencies. Four naturally occurring infections in their native hosts have been the most widely studied models of virus-induced demyelination. Theiler’s virus, a picornavirus, and JHM virus, a murine coronavirus, were both originally recovered from paralyzed mice; canine distemper, a morbillivirus closely related to measles virus, has long been recognized to cause demyelination in a subacute encephalitis called “old dog disease”; and visna virus, a natural retrovirus infection of sheep, causes relapsing and remitting disease with multifocal demyelinating lesions after a long incubation period. Recent research has suggested that HHV-6 may also be associated with diseases in people with apparently healthy immune systems: encephalitis, mesial temporal lobe epilepsy, multiple sclerosis, myocarditis, and idiopathic cardiomyopathy.
Febrile convulsion is the most common type of seizure in children between 3-60 months old (1-2). 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 ). 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. HHV-6 has been associated with portal necrosis in transplant recipients with reactivated HHV-6 and liver failure, but biopsy analysis may be required because HHV-6 DNA is often at normal levels in the peripheral blood in spite of active infection in the liver (Buyse 2013). 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.
However, most of the time neither virus causes disease; only about 20% of infected children develop symptoms of roseola. 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. For the approximately 1 percent of the population born with viral DNA in every cell in their body, several questions arise. Primers designed based on conserved part of U22 gene of HHV-6 genome.
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. 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. Two cases (2%) had rash at the time of febrile convulsion. 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. 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 ). Recovery of viruses from tissues or spinal fluid of patients has been repeatedly reported (see ), but not with the consistency of serological tests. Indeed most have proved to be contaminants picked up from cell cultures or laboratory animals. 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.