NEUROLOGICAL DISEASES CAUSED BY VIRUSES

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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.

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Acute neurological syndromes

There are four main syndromes:

• 1. Encephalitis
• 2. Flaccid paralysis
• 3. Aseptic meningitis
• 4. Post infectious encephalo-myelitis

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.

[For more information, see lecture notes on viral haemorrhagic fevers].

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 causitive agents.

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.

This uncommon complication may develop in the convalescent phase of a number of common virus infections, including: measles, mumps, rubella and primary varicella-zoster virus infection, 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 tissue (molecular mimicry).

Gillain 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.

• Subacute-sclerosing panencephalitis (SSPE)
• Progressive multifocal leuco-encephalopathy (PML)
• Retrovirus disease
• Spongiform encephalopathies

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

Virology

The Papovavirus family contains two main groups:-

Papilloma viruses (which cause warts), See electronmicrographs
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 inco-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.

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.

Diseases falling into this category include:

Scrapie - sheep, goats

Bovine spongiform encephalopathy - cattle

Transmissable Mink encephalopathy - mink

Creutzfeldt-Jakob disease - man, sporadic and familial

Gerstmann-Streussler disease - man, familial

Fatal Familial Insomnia - man, familial

Kuru - man, Fore people, New Guinea

Properties of Prions:

• 1. Infectivity is associated with a novel infectious protein, termed prion (PrP)
• 2. Infectious particles are very small - about 20-30 nm in size.
• 3. No nucleic acid has yet been found to form part of the agent
• 4. Prions are extremely resistent to inactivation by: ultra-violet light, formaldehyde and heat.
• 5. Prions can be transmitted by intra-cerebral or sub-cutaneous inoculation of material from infected brain.

Pathogenesis of prion diseases
The pathogenesis of prion diseases is still a great mystery. The pathology appears to be both infectious as well as genetic.

Recent evidence has demonstrated that the prion protein has the same primary amino acid sequence as a host protein which is normally present at low levels in healthy brain tissue. The cellular protein has been termed PrPc. Although the amino acid sequence is the same as the cellular one, the prion protein, has an abnormal conformation, due to different post translational modification. Exposure to the abnormal form triggers a conversion of the cellular isoform to the infectious form. This is followed by progressive accumulation of the abnormal form (prion protein) in the brain, which is deposited as amyloid.

Scrapie is a neurological disease occurring in sheep and goats. It was first identified in Britain, but it is now known to occur world wide. It is the prototype disease of the spongiform encephalopathies; the scrapie prion is termed PrPsc. The disease is clearly infectious as it can be transmitted to sheep, mice and hamsters by intra-cerebral or sub cutaneous inoculation of material from the brains of infected sheep. Susceptibility to infection appears to be genetically determined.

Clinical features
The disease is transmitted by contact in flocks of sheep and also vertically, from ewes to lambs. In natural infection, the incubation period is 2 to 5 years. Following intra- cerebral inoculation, however, the incubation is much shorter, only 3 to 24 months.

Affected sheep develop ataxia, tremor and muscular in co-ordination; the symptoms progress to paralysis and death.

Similar disease to scrapie which occurs in cattle. It is believed that scrapie was introduced into cattle herds fed on feeds containing scrapie-infected sheep offal. The condition is now epidemic in cattle herds in England and Wales ("Mad Cow Disease"). There is concern that the infection may be transmitted to humans, and a report of an increased number of cases of CJD in young people linked to the consumption of beef burgers sparked a world wide furore.

Transmissable Mink encephalopathy

Scrapie has been introduced into minks, bred in captivity through feeds containing sheep brains.

Creutzfeldt-Jakob disease (CJD)

In 1920, Creutzfeldt described a progressive dementing illness in a 22 year old woman. The following year, Jakob described four older patients with a clinically similar presentation and course. Since then, numerous cases of CJD have been described. CJD occurs world wide. It is very rare, with an incidence of about 1 case per million population. While most cases are sporadic, 5-10% are familial. In the familial form, CJD is inherited as an autosomal dominant condition.

Clinical features
The onset of the disease typically occurs between the ages of 50 and 65 years. There are two main modes of presentation:

• 1. Chronic dementing illness
• 2. Progressive cerebellar dysfunction

The condition is relentlessly progressive and patients usually die within a year of presentation.

Transmission:
The natural route of infection is not known, but CJD has been accidently transmitted by:
1. Corneal grafts - where the corneas were harvested from cadavers that died of CJD.
2. Growth hormone preparations, derived from human pituitary glands.
3. In two patients who received grafts of dura mater, prepared from cadavers, and
4. through electrodes used for electro-encephalography which had previously been used in a patient with CJD.

The prion detected in the brains of patients with CJD is termed PrPCJD. The disease has also been experimentally transmitted to chimpanzees and other primates. Following intracerebral inoculation, the incubation period is 11-14 months. The disease can also be transmitted peripherally (IV, intra peritoneal or intramuscular routes). But transmission is much less efficient and the incubation period is much longer (many years).

Decontamination procedures:
Prions are extremely resistent to inactivation by ultra-violet light, forrmaldehyde and heat.

Recommended methods of decontaminating infected material include:

1. Autoclaving for 4.5 hours (121oC, 15 p.s.i)

2. 1N NaOH followed by autoclaving for 1.5 hours

Gerstmann-Streussler Syndrome

Rare familial neurodegenerative disease which usually manifests in the third to the seventh decade of life. The condition is both infectious and genetic: the predisposition is inherited as an autosomal dominant condition; while, in addition, the disease can be transmitted to non human primates by intra cerebral inoculation with brain tissue from cases of GSS.

Recent genetic studies have revealed that affected individuals have a point mutation in their PrPc gene. The altered amino-acid sequence of the PrPC protein may make it more susceptible to transformation to the abnormal conformation.

Fatal Familial Insomnia

Another rare familial disorder. Predisposed individuals also have a mutation in their PrPc gene.

This is a transmissable prion disease found only in the Fore people of New Guinea. It first appeared about 60 years ago and the incidence increased until the late 1950's. The disease is now known to have been transmitted through ritual cannibalism: until the late 1950's it was the practice of women and children to eat the brains and viscera of dead relatives, including those who had themselves died of Kuru. Cannibalism stopped in 1957 and the incidence of Kuru has declined sharply since then.

Clinical features:
The incubation period varied from 4-20 years.
Patients presented with progressive cerebellar dysfunction. Death usually occurred within a year of initial presentation.

Transmission studies:
Intra-cerebral inoculation of brain tissue from Kuru victims into non human primates leads to the development of symptoms within two years.

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

Oncovirinae

HTLV 1 - Tropical spastic paraparesis