Viral Diseases of the Central Nervous System — Questions

a. The picture is a viral (aseptic) meningitis: a lymphocytic pleocytosis with normal glucose and mildly raised protein, and a positive herpes simplex virus type 2 (HSV-2) PCR (polymerase chain reaction) confirms HSV-2 as the cause.

b. This is HSV-2 aseptic meningitis, which commonly accompanies a primary genital HSV-2 infection (in up to a quarter of affected women). When such episodes recur over time the condition is called Mollaret meningitis.

c. Supportive care with analgesia; intravenous aciclovir for a severe presentation, stepping down to oral valaciclovir to complete a course of about 10 to 14 days; and counselling about genital HSV and recurrence. The prognosis is good and the illness self-limiting, unlike HSV-1 encephalitis.

Cause. Almost always herpes simplex virus type 1 (HSV-1). It follows either a primary infection or, more often, reactivation of latent virus.

Route to the brain. Virus reaches the central nervous system along the trigeminal or olfactory nerve pathways, seeding the medial temporal lobes and orbitofrontal cortex.

Localisation. The characteristic, usually unilateral, involvement of the temporal lobe gives the typical clinical and imaging picture.

Mechanism of injury. Lytic infection of neurons and glia provokes intense inflammation, producing a haemorrhagic, necrotising encephalitis with oedema and raised intracranial pressure.

Host susceptibility. Inborn errors of the Toll-like receptor 3 (TLR3) interferon pathway (TLR3, UNC93B1, TRIF, TBK1) impair control of HSV in the central nervous system and predispose, especially in children.

Consequences. Untreated mortality exceeds 70%, and survivors often have memory, language and behavioural deficits. A post-infectious anti-N-methyl-D-aspartate (anti-NMDA) receptor autoimmune encephalitis can follow weeks later.

• Aetiology: a benign recurrent lymphocytic (aseptic) meningitis, usually caused by herpes simplex virus type 2 (HSV-2) (occasionally HSV-1).
• Clinical features: repeated, self-limiting episodes of meningitis (headache, fever, neck stiffness) over months to years, each resolving spontaneously over a few days; large activated mononuclear “Mollaret cells” were the historical hallmark.
• Cerebrospinal-fluid findings: lymphocytic pleocytosis, raised protein and normal glucose, with HSV-2 DNA detectable by PCR (polymerase chain reaction) during an attack.
• Management: episodes are self-limiting; aciclovir or valaciclovir is used for severe acute attacks. The benefit of long-term suppressive therapy is uncertain and not clearly established.

Post-infectious encephalomyelitis, also called acute disseminated encephalomyelitis, appears one to two weeks after a systemic infection or, formerly, after vaccination. Its pathology is perivascular demyelination with no virus demonstrable in the brain, which is why it is an immune-mediated, probably autoimmune, attack on myelin rather than direct viral replication. Measles is its leading trigger worldwide, complicating roughly 1 in 1000 infections.

A proportion of patients develop antibodies to the N-methyl-D-aspartate (NMDA) receptor one to four weeks after herpes simplex encephalitis, producing a relapsing, immune-mediated encephalitis that complicates recovery. The clue is the biphasic course: improvement after treatment, then fresh deterioration. This is neither a failure of aciclovir nor a new infection (options A and B), and it follows rather than precedes the viral illness.

Neuroinvasiveness is the capacity to enter the nervous system and neurovirulence the capacity to harm it once there; their product is neurotropism. Mumps virus is the clearest example of high neuroinvasiveness with low neurovirulence: it reaches the meninges and alters the cerebrospinal fluid in about half of infections but seldom causes lasting damage. Herpes simplex virus is the opposite (option A), rarely invading but devastating when it does. The other combinations do not match the description.

In sporadic herpes simplex encephalitis only about 4% of cerebrospinal-fluid cultures are positive, so culture misses almost every case. Polymerase chain reaction on cerebrospinal fluid has replaced it, with a sensitivity above 95% and a specificity approaching 100%, and has removed the former reliance on brain biopsy (against option C). Culture neither cross-reacts with varicella-zoster virus nor over-detects the virus (options A and E).

Non-polio enteroviruses can invade the anterior horn of the spinal cord and cause an acute flaccid paralysis indistinguishable from poliomyelitis. Enterovirus D68 was implicated in the clusters of acute flaccid myelitis seen where poliovirus has been eliminated, for example in California in 2012 and 2013, and is unusual among enteroviruses in causing substantial morbidity. Such cases trigger acute-flaccid-paralysis surveillance to detect and exclude poliovirus.

After crossing a body surface and replicating locally, a virus seeds the blood as a primary viraemia, then amplifies in highly vascular organs, above all the liver and spleen, to generate a sustained, high-titre secondary viraemia. It is this later wave that delivers virus across the vascular barrier into the central nervous system. Neuronal routes (option C) are used by only a few viruses, such as herpes simplex and rabies, and the blood-brain barrier in fact opposes entry rather than allowing diffusion (option D).

Progressive multifocal leukoencephalopathy is caused by reactivation of JC polyomavirus in advanced HIV (human immunodeficiency virus) infection or other immunosuppression. Unlike the neuronotropic viruses that kill neurons, JC virus infects oligodendrocytes and destroys them, demyelinating the white matter. It is a virus rather than a prion (option E), is not vector-borne (option A), and provokes an immune response, emerging chiefly when immunity fails (against option B).

Rabies is the prototype of neuronal spread. The virus replicates at the inoculation site, binds acetylcholine receptors to enter peripheral nerve endings, and travels by axonal transport to the brainstem and limbic system, shielded from circulating immunity. Spread along the olfactory route (option E) is a feature of herpes simplex virus, not rabies, and rabies does not depend on a viraemia (option A).

The viral and bacterial cerebrospinal-fluid pictures overlap. Although viral meningitis is classically lymphocytic, about 40% of cases show a neutrophil predominance in the first day or two before shifting to lymphocytes, and about 15% of bacterial cases are lymphocytic, so neither pattern is decisive (against option C).

The typical viral profile is a modest pleocytosis (usually 30 to 300, up to 500/mm³), a protein under 100 mg/dL (against option D), and a glucose above 40% of the serum value (against option A).

The distinction is between sporadic and epidemic disease. Herpes simplex virus is the commonest cause of sporadic encephalitis, the isolated, non-seasonal case, and the one that most demands treatment. The larger numbers worldwide, however, are epidemic and vector-borne: the arboviruses are the leading cause of encephalitis globally, with Japanese encephalitis virus foremost among them. Rabies, an animal-bite infection rather than an arbovirus, is the other major global cause.