Neurological disease is one of the most serious complications of virus infection. Clinically, viral neurological disease can be divided into acute diseases and chronic syndromes.  The pathology may be due either to viral multiplication in the cells of the brain, or due to the (misdirected) immune response of the host - post infectious encephalo-myelitis. Where virus replicates in the brain, virus can usually be isolated from brain tissue or from cerebrospinal fluid. This is not the case with the post infectious syndromes.

Acute neurological syndromes
Virus may reach the brain either by the blood stream or by spread along peripheral nerves. Asymptomatic infection of the brain is common.
There are four main syndromes:
1. Encephalitis
2. Flaccid paralysis
3. Aseptic meningitis
4. Post infectious encephalo-myelitis

Acute viral encephalitis
Viral replication occurs in the brain tissue itself, causing destructive lesions in the grey matter. The main symptoms include: fever, drowsiness, confusion, convulsions and focal neurological signs. Morbidity and mortality is very high. Viruses that cause encephalitis include Herpes Simplex, Rabies and some of the Arboviruses.

The Arboviruses include a miscellaneous group of enveloped, RNA viruses that are transmitted from one vertebral host to another via blood sucking arthropods. The main reservoirs are wild birds and small mammals. Man may be infected if bitten by the insect vector. Arboviruses cause two types of disease:
1. Encephalitis, and
2. Fever (often with haemorrhagic manifestations)

Arboviral encephalitis occurs in most parts of the world; but different agents are responsible for disease in different areas. In South Africa, there are no endemic arboviruses that specifically cause encephalitis. Rarely, however, encephalitis may occur as part of the clinical course of infection with: West Nile virus, Rift Valley Fever virus, Sinbis virus, Crimean-Congo haemorrhagic fever or Chickengunya virus. These viruses are endemic in livestock herds in certain parts of the country and farm workers or vets may occasionally be infected.

Flaccid paralysis
Due to direct infection of motor neurones. Patients present with fever and flaccid paralysis of a group of muscles. The lower limbs tend to be involved more commonly than the upper limbs. Signs of meningitis such as headache and neck stiffness are frequent accompanying features. The most common aetiological agents include the polioviruses 1-3, but with the reduction in prevalence of wild type polio, a number of non-polio enteroviruses have also been implicated as rare causative agents.

Aseptic meningitis
Infection of the meninges. A relatively mild disease with a good prognosis. Patients present with fever, headache, neck stiffness and photophobia. Common viral agents include:enteroviruses, mumps virus and lymphocytic choriomeningitis virus.

Post infectious encephalomyelitis
This uncommon complication may develop in the convalescent phase of a number of common virus infections, including: measles, mumps, rubella and primary varicella-zoster virusinfection, as well as following the administration of certain vaccines, such as: vaccinia virus and the older neurotissue rabies vaccines.
Wide spread demyelinating lesions develop in the brain and spinal cord, associated with lymphocytic infiltration and perivascular cuffing of adjacent blood vessels. Virus cannot be isolated from brain tissue or CSF. The aetiology is somewhat obscure, but it is believed to be an auto-immune phenomenon, triggered by exposure to foreign antigens which are closely related to host proteins normally expressed in brain issue (molecular mimicry).

Guillain Barre syndrome
Poly-neuritis which develops a few days after the acute phase of a viral infection. The disease is due to demyelination of peripheral nerves. Patients present with an ascending paralysis, associated with paraesthesia. Like post infectious encephalomyelitis, it is believed to be an immunological phenomenon. Patients usually recover spontaneously over a few weeks or months. There is no specific treatment.

Chronic Neurological Conditions:
A number of viruses and virus-like agents can cause chronic neurological disaese. Characteristically, these conditions have a long incubation period followed by slow development of symptoms and a progressive, uniformly fatal course.
Subacute-sclerosing panencephalitis (SSPE)
Progressive multifocal leuco-encephalopathy (PML)
Retrovirus disease
Spongiform encephalopathies
Subacute Sclerosing Pan Encephalitis
This is a rare, slowly progressive degenerative disease of the brain which develops six to eight years following a primary uncomplicated infection with measles virus. It is due to persistent measles virus infection in the CNS.

Clinical Features
Patients usually present with personality and behavioural changes followed by progressive intellectual impairment, convulsions, myoclonic movements, coma and death.

Pathogenesis
It is thought that the virus gains entry into the CNS during the viraemia that occurs at the time of the primary infection.

The pathology is due to infection of the brain with a measles virus mutant that lacks an essential structural gene and cannot therefore undergo complete cycles of replication. This has two effects:
1.) It enables the virus to establish a persistent infection in the brain - because there is limited expression of viral antigens on the surface of infected neurones, an effective immune response cannot be mounted against the infected cells.
2.) The disease proceeds very slowly - because, as no infectious virus particles are released, spread of infection to new cells only occurs through fusion with adjacent infected cells.

Epidemiology
Occurs in about 1 per million cases of measles. The incidence has declined sharply since the introduction of vaccination against measles.

Laboratory diagnosis
Affected individuals have high titres of measles specific antibodies in their serum and CSF. Measles virus antigens can be demonstrated in brain tissue.

Progressive multifocal leuco-encephalopathy
There are two members of the Papovavirus family which are known to infect man, namely JC virus, which replicates in neural tissue and BK virus which has been isolated from the urinary tract. Neither of them cause any pathology in healthy people.
JC virus - is associated with progressive multifocal leuco-encephalopathy
Virology

The Papovavirus family contains two main groups:-
Papilloma viruses (which cause warts), Polyoma viruses, these are slightly smaller than papilloma viruses, and in animals are sometimes associated with tumours.
The two known human polyoma viruses are:
JC - Progressive multifocal leuco-encephalopathy
BK - isolated from urine of immunosuppressed patients
dsDNA genome
small icosahedral particles, 42-45 nm grows in human foetal glial cell cultures (JC) Progressive multifocal leuco-encephalopathy is a progressive neurological disorder caused by reactivation of JC virus in the brain. Infection is common, but neurological disease is rare; it only occurs in immunosuppressed patients.

Clinical Features
Patients may present with a variety of neurological signs, including: hemiparesis, dementia, dysphagia, muscular in co-ordination or impaired vision. The condition is progressive and invariably fatal.

Pathology
Multiple foci of demyelination are found throughout the cerebral hemispheres and cerebellum. The virus infects oligodendrocytes, which have a bizzare histological appearance.

Epidemiology
Infection with JC virus is common, but invariably asymptomatic: Seroprevalence surveys have shown that about 50-60% of adults have antibodies.
Spongiform Encephalopathies
(Prion diseases)
A number of transmissable neurological syndromes, caused by unconventional virus-like agents, have been identified in man and other animals. These diseases are characterized by the following features:

1. Confined to the CNS
2. Long incubation period
3. Progressive, uniformly fatal course
4. Typical brain histology: reactive gliosis, vacuolation of neurones, deposition of amyloid protein in the brain and the absence of an inflammatory response.
5. Infection is believed to be transmitted by means of a novel infectious protein, termed prion or PrP.

Retrovirus Disease
Lentivirinae:
Lentiviruses characteristically establish a persistent infection in the host and cause chronic wasting disorders which are uniformly fatal. Members of this family that typically cause CNS pathology include:
Pathology
Inflammatory cell infiltration, perivascular cuffing of blood vessels, demyelination, necrosis and reactive gliosis.

Pathogenesis
The pathogenesis of the neuropathology is not very clear. Virus is probably introduced into the CNS by infected monocytes which cross the blood brain barrier. Differentiation of the infected monocytes into microglial cells is thought to trigger viral replication. None of these viruses appear to infect neuro-ectodermal cells directly, and damage to brain tissue is therefore thought to occur indirectly by cytokines released during inflammation. It is also thought that certain viral proteins, such as the gp160 of HIV, may be directly toxic to neurones.

In addition to the above (where the neurological damage arises directly as a result of HIV infection) CNS pathology in patients with AIDS may also be caused by opportunistic infectious agents such as: JC virus (PML), HCMV, VZV as well as a number of bacterial and fungal diseases.

Diana Hardie
University of Cape Town

University of Cape Town