Viral CNS Infections — Questions

Why C

JC virus attaches to a sialylated glycan and depends on the serotonin 5-HT2A receptor, expressed on glial cells, to enter; this helps explain its tropism for the brain and underlies the trial of serotonin antagonists such as mirtazapine. CD4 is the HIV receptor, the nicotinic acetylcholine receptor is used by rabies virus, CR2 by Epstein-Barr virus, and the epidermal growth factor receptor by other viruses.

Cerebrospinal fluid PCR is positive in only about 30% of cases of VZV vasculopathy, so a negative result does not exclude it. Demonstrating intrathecal synthesis of anti-VZV immunoglobulin G is the more sensitive approach, and the same principle applies to other rash-free neurological presentations of the virus.

HSV-1 establishes latency chiefly in the trigeminal ganglion, the source of recurrent orolabial herpes, while HSV-2 favours the sacral ganglia.

The other options invert or invent the site: HSV-2 latency is sacral rather than trigeminal or in the olfactory bulb, and HSV does not reside in anterior horn cells as its principal reservoir.

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.

Natalizumab blocks lymphocyte entry into the brain, removing the immune surveillance that contains JC virus, so PML is its defining hazard.

Risk stratification

Three factors set the risk. The serum JC virus antibody index: seronegative patients are at low risk, while a high index (conventionally above about 1.5) marks substantially higher risk. Prior use of immunosuppressant drugs raises risk further. So does duration of treatment, with risk climbing markedly beyond about two years. A patient who is seropositive with a high index, has had previous immunosuppression and has been treated for several years sits in the highest-risk group.

Monitoring

Seronegative patients are retested periodically, because seroconversion on therapy raises their risk. Higher-risk patients undergo more frequent magnetic resonance surveillance, every few months rather than annually, to detect early or presymptomatic lesions, since outcome is far better when PML is caught before it becomes symptomatic.

Management if PML develops

Stop natalizumab and accelerate its clearance with plasma exchange or immunoadsorption to restore normal lymphocyte trafficking. There is no specific antiviral. Restoring immune surveillance almost inevitably provokes an immune reconstitution inflammatory syndrome, which is then managed in its own right, with corticosteroids reserved for severe inflammation with raised intracranial pressure.

• How and when it is produced: after amplification is complete, the product is heated gradually while fluorescence from a double-stranded-DNA-binding dye (or probe) is monitored. As the duplex denatures, fluorescence falls steeply at the melting temperature (Tm); plotting the negative first derivative of fluorescence against temperature gives a peak at the Tm. It is a post-amplification step.
• Why HSV-1 and HSV-2 differ: their amplicons differ in sequence and guanine-and-cytosine content, so they melt at different temperatures and give distinct peaks.
• Why it is useful: it allows single-tube typing of HSV-1 versus HSV-2 without separate probes or gels, detects mixed infection, and confirms that the signal is the specific amplicon rather than primer-dimer or non-specific product.

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.

PML is a directly cytopathic disease that emerges only when cellular immunity fails.

Reactivation under immunosuppression

Most adults carry JC virus as a lifelong, low-level persistent infection of the kidney and lymphoid tissue, controlled by T-cell immunity. PML is reactivation of this infection, not a new one: almost all patients are already seropositive, and disease appears only with profound immunosuppression, classically advanced HIV with a low CD4 count or treatment with agents such as natalizumab. Loss of JC-virus-specific CD8 cytotoxic T cells is the decisive failure.

Reaching and damaging the brain

Two molecular changes license neurovirulence: rearrangement of the non-coding control region from the urinary archetype to the disease-associated prototype, which raises replication in glial cells, and mutation of the VP1 receptor-binding site favouring the serotonin 5-HT2A receptor on glia. Infected B-lineage cells are thought to carry the virus across the blood-brain barrier. There it replicates lytically in oligodendrocytes, the myelin-producing cells. Because each oligodendrocyte myelinates many axons, their destruction produces expanding, coalescing demyelination of the subcortical white matter, with the histological triad of enlarged oligodendrocyte nuclei, bizarre reactive astrocytes and foamy macrophages, and little inflammation until immune reconstitution supervenes.

A complete answer covers the immune-mediated mechanism, the clinical syndrome, and why the extensor plantar response localises the lesion.

Pathogenesis. HAM/TSP is an immune-mediated inflammatory myelopathy, not a direct cytopathic infection. A high proviral load drives persistent expression of viral antigen in circulating infected T-cell clones, and a vigorous but ineffective cytotoxic T-lymphocyte (CTL) response to these cells provokes chronic inflammation. Cytokine-mediated injury and lymphocytic infiltration fall on the thoracic spinal cord, producing demyelination and axonal loss in the lateral corticospinal tracts.

Clinical presentation. A slowly progressive spastic paraparesis of the lower limbs, with upper motor neuron signs (spasticity, brisk reflexes, clonus), bladder and sphincter dysfunction, sensory disturbance and low back pain. It is commoner in women, is chronic and disabling, and is not malignant.

Significance of the extensor plantar response. A bilateral extensor plantar (positive Babinski sign) is an upper motor neuron sign. It confirms the lesion is in the corticospinal tracts of the cord rather than in the lower motor neurons or peripheral nerves, consistent with a myelopathy, and supports the clinical picture of a spastic rather than flaccid paraparesis.

A complete answer traces how a virus reaches the central nervous system, how it crosses into it, and how it injures it.

Reaching the central nervous system. Most encephalitic viruses arrive through the blood, after a primary infection and viraemia seed the cerebral vasculature. Two haematogenous routes exist: virus in the vessels of the meninges or choroid plexus crosses into the cerebrospinal fluid and infects the ependyma and underlying brain, or virus crosses the blood-brain barrier directly. It may infect the endothelium, be carried across inside infected leukocytes (as with the human immunodeficiency virus, HIV, and measles), or, as with West Nile virus, exploit a barrier made leaky by inflammatory cytokines. The alternative is the neural route: retrograde axonal transport along peripheral nerves, used by rabies virus and, on reactivation, by herpes simplex and varicella-zoster virus.

Injuring the brain. Disease arises from direct neuronal infection and from the immune response to it. The histological hallmarks are neuronal necrosis, neuronophagia (engulfment of dying neurons), and perivascular cuffing by mononuclear cells, the last reflecting the immune response itself. The balance of direct and immune-mediated injury varies: rabies virus is barely cytopathic yet uniformly lethal through functional neuronal failure, herpes simplex produces necrotising temporal-lobe damage, and in others the immune infiltrate drives much of the harm.

Outcome depends on the virus, the region infected, and the vigour and timing of the immune response, which is also why oedema in the closed cranial compartment is so dangerous.

A complete answer links each laboratory test to the clinical and radiological picture, since the diagnosis is made on the combination rather than on any single result.

Cerebrospinal fluid JC virus PCR

The central test is detection of JC virus DNA in cerebrospinal fluid by polymerase chain reaction. In a patient with compatible neurology and characteristic imaging, a positive result confirms the diagnosis (laboratory-confirmed PML) and removes the need for brain biopsy. Detection in the cerebrospinal fluid is meaningful because the virus is not normally present there, unlike urine and blood, where asymptomatic shedding is common. Quantification is useful for monitoring. The key limitation is sensitivity: the assay misses roughly a quarter of histologically proven cases, particularly at low viral load or after antiretroviral therapy has reduced it, so a negative result does not exclude PML. Routine cerebrospinal fluid is usually otherwise normal, which helps separate PML from the meningoencephalitides that produce a pleocytosis.

When the PCR is non-informative

Where the result is negative but suspicion persists, the options are to repeat the test, to measure an intrathecal anti-JC virus antibody response, or to proceed to stereotactic brain biopsy. Biopsy remains the definitive test, showing the histological triad of demyelination, enlarged oligodendrocyte nuclei and bizarre astrocytes, with confirmation by viral protein on immunohistochemistry or viral genome by in situ hybridisation.

Putting it together

The laboratory does not diagnose PML in isolation: it supplies the virological confirmation that, set against the clinical syndrome and the magnetic resonance imaging appearance, allows the case to be graded as possible, probable or laboratory-confirmed. The serum JC virus antibody index has no role in diagnosing an established case; it is a risk-stratification tool in the natalizumab setting.

A complete answer spans the complications of primary varicella and of zoster, and notes that severity concentrates where cell-mediated immunity is immature or failing.

Skin and soft tissue

• Secondary bacterial infection, the commonest, from group A streptococci and Staphylococcus aureus, occasionally reaching necrotising fasciitis.
• Haemorrhagic varicella, around days 2 to 3 of the rash, with epistaxis, melaena or haematuria, mainly in the immunocompromised.

Pulmonary

• Varicella pneumonia, the leading cause of varicella death, affecting ~1 in 200 adults and far fewer children, typically 1 to 6 days after the rash; greatly increased in the immunocompromised and in pregnancy.

Neurological

• Cerebellar ataxia, benign and self-limiting, and the more serious encephalitis (~3 to 4 per 100,000), some 4 to 8 days after the rash.
• Guillain–Barré syndrome, and after zoster, postherpetic neuralgia.

Ocular

• Keratitis, uveitis, iritis and retinitis, mainly with zoster ophthalmicus and threatening sight; progressive outer retinal necrosis occurs in advanced HIV.

Other

• Reye syndrome if aspirin is given, and disseminated disease with visceral involvement in the immunocompromised.

Greatest severity falls on neonates, pregnant women, adults and the immunocompromised.

The result is meaningful precisely because the site is privileged.

A positive result signifies central nervous system disease

JC virus is not normally present in cerebrospinal fluid, unlike urine and blood, where most healthy adults shed or harbour the virus without consequence. Detection of JC virus DNA in the cerebrospinal fluid therefore indicates replication within the central nervous system rather than incidental persistence. In a patient with a compatible clinical picture and characteristic magnetic resonance imaging, a positive PCR confirms the diagnosis as laboratory-confirmed PML and removes the need for brain biopsy. Viral load can be quantified to support monitoring.

Interpret with the clinical and radiological context

The result is read together with the syndrome and the imaging, not alone. A positive PCR without compatible clinical or radiological features should prompt review rather than an immediate diagnosis. The converse caveat also matters: because the assay misses about a quarter of proven cases, a negative result does not exclude PML, so the positive result is the more decisive of the two.

A complete answer defines what a prion strain is, explains how distinct strains can exist in an agent that carries no genome, and notes the supporting evidence and clinical relevance.

Definition. A prion strain is a distinct, stably transmissible prion phenotype, recognised by a reproducible combination of incubation period, clinical signs and neuropathological lesion profile (the distribution and severity of spongiform change). Strains behave this way despite an identical prion protein (PrP) amino acid sequence in the host, which is the central puzzle they pose.

Structural basis. Because the agent has no nucleic acid, strain information is held in the conformation of the misfolded protein, the scrapie-type prion protein (PrP-Sc), itself. Strains differ in their folding, in the ratio of the di-, mono- and un-glycosylated bands, and in the size of the protease-resistant core fragment. These are read out by Western blot glycoform and fragment typing (for example type 1 versus type 2), which, combined with the codon 129 genotype, defines the molecular subtypes of sporadic Creutzfeldt-Jakob disease (such as MM1 and VV2).

Evidence. Serial transmission into inbred mice of identical prion gene (PRNP) genotype reproduces each strain’s incubation time and lesion profile, showing the phenotype is a property of the agent and not the host. Strain also governs the species barrier: the bovine spongiform encephalopathy agent and variant Creutzfeldt-Jakob disease share the same strain signature, which is how the cattle-to-human link was established.

Clinical relevance. Strain, together with the codon 129 polymorphism, predicts the incubation period, clinical picture and lesion distribution, and underlies the molecular classification of human prion disease.

Epidemiology

SSPE is a rare, delayed, invariably fatal complication of measles caused by persistent CNS infection with defective measles virus.

• Incidence: historically quoted as ~1 in 10,000 measles cases; NEJM 2025 cites 7–11 per 100,000 cases, and recent surveillance suggests it may be more common than previously estimated (Wendorf et al., 2017).
• Latent period: typically 6–10 years after primary infection (range 1 to >30 years).
• Major risk factor: measles infection at <2 years of age — the immature immune response permits establishment of persistent CNS infection.
• Host: previously immunocompetent individuals — contrast with MIBE, which occurs in the immunocompromised.
• Outcome: progressive, with periodic remissions; death within 1–3 years of onset in most patients.
• Public-health pattern: SSPE incidence falls as measles is suppressed by vaccination, and rises 5–10 years after major measles outbreaks — vaccination is the only meaningful prevention.

Clinical course

Insidious onset over months, progressing through four stages:

1. Subtle behavioural changes — personality change, declining school performance.
2. Motor signs — awkwardness, stumbling, then myoclonic jerks and seizures.
3. Progressive cortical decline — ataxia, dementia, extrapyramidal signs (choreoathetosis, dystonic posturing).
4. Late — visual loss (chorioretinitis, optic atrophy, cortical blindness), spasticity, coma.

Diagnosis — the classic triad

1. Clinical — gradual, progressive behavioural change, myoclonus, dementia, visual disturbance, and pyramidal/extrapyramidal signs.
2. EEG — periodic high-amplitude slow-wave complexes (Radermecker complexes) at 4–20 second intervals, typically synchronised with myoclonus.
3. CSF measles-specific antibody — exceptionally high MeV-specific IgG, with oligoclonal bands on electrophoresis, and a markedly elevated CSF:serum MeV antibody ratio indicating intrathecal synthesis.

Supporting investigations: MRI shows progressive white-matter abnormalities and later cortical atrophy. Brain biopsy (rarely needed) shows diffuse encephalitis with intranuclear and intracytoplasmic inclusion bodies. RT-PCR may detect MeV RNA but is unreliable.

Pathology. Diffuse encephalitis of grey and white matter with perivascular cuffing, lymphocytic infiltration, microglial proliferation, and patchy demyelination. Inclusion bodies contain MeV ribonucleocapsids; infectious virus cannot be recovered — the defective MeV in SSPE brains has mutations throughout the genome, especially in the M, H and F genes, preventing virion assembly.

Differential

Other progressive encephalopathies: prion disease (CJD), HIV encephalopathy, autoimmune encephalitis, leukodystrophies.

A complete answer covers what makes one molecular assay better than another, then how that claim is checked first from documentation and then on local samples.

Characteristics of a superior assay

• Higher analytical sensitivity (a lower limit of detection), which matters greatly in cerebrospinal fluid where viral loads are low.
• High specificity with detection and typing of both HSV-1 and HSV-2, ideally as part of a syndromic multiplex panel.
• Built-in controls: an internal extraction and amplification control to flag inhibition or failed extraction.
• Validated across the required specimen types (cerebrospinal fluid, genital and mucocutaneous swabs, blood) and robust to inhibitors such as blood in cerebrospinal fluid.
• Operational advantages: faster turnaround, automation, higher throughput, lower cost per test, and ease of use.

Evaluation on paper

• Review the manufacturer’s validation data, regulatory approvals and independent peer-reviewed evaluations.
• Examine the stated limit of detection, analytical sensitivity and specificity, linearity, reproducibility and cross-reactivity, and compare them against the current assay.

Evaluation in practice

• Method comparison against the current assay or reference standard on local samples, reporting concordance, sensitivity, specificity and an agreement statistic such as Cohen’s kappa.
• Verify the limit of detection with dilution panels, and assess precision within and between runs.
• Run external quality assessment and proficiency panels.
• Assess the practical fit: workflow, turnaround, cost, training needs and likely clinical impact.

Decision

The new assay is adopted if it improves sensitivity, specificity, turnaround or cost without loss of accuracy, and is then kept under ongoing internal quality control and external quality assessment.

The Far-Eastern subtype has a predilection for the anterior horn cells of the cervical cord, producing a poliomyelitis-like flaccid paralysis of the shoulder girdle and arms.

Retinitis, a purely sensory neuropathy, a hepatic haemorrhagic fever and isolated facial palsy are not the characteristic pattern.

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.

Ramsay Hunt syndrome is reactivation of VZV in the geniculate ganglion of the facial nerve, producing an ipsilateral facial palsy with vesicles in the ear, sometimes with hearing loss and altered taste.

Ophthalmic-division zoster affects the eye and forehead rather than the ear and facial nerve, and a facial palsy without the characteristic vesicular rash and dermatomal distribution would not point to VZV.

VZV cerebral vasculopathy, an inflammation of the cerebral arteries that follows reactivation, raises the risk of ischaemic and haemorrhagic stroke for months after an episode of zoster. The risk is particularly increased after herpes zoster ophthalmicus, rising around 4.5-fold.

Herpes simplex encephalitis is a medical emergency, so intravenous aciclovir is started empirically the moment it is suspected, because delay worsens outcome and the drug is safe; the standard course is 10 mg/kg every 8 hours for 14 to 21 days.

Waiting for PCR loses critical time, oral therapy gives inadequate central nervous system levels, and ganciclovir and foscarnet are neither first-line for HSV nor free of greater toxicity.

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.

Why B

Cerebrospinal fluid JC virus PCR misses roughly a quarter of histologically proven cases, especially at low viral load, so a negative result does not exclude PML when the clinical and radiological picture is typical. The appropriate next steps are to repeat the PCR, consider an intrathecal antibody index, or proceed to brain biopsy, not to abandon the diagnosis.

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.

The incubation period is about 7 to 14 days after a tick bite, and tends to be shorter after milk-borne infection.

The other intervals are too short or too long for tick-borne encephalitis.

Tick-borne encephalitis can be acquired by drinking unpasteurised milk or dairy from an infected goat, sheep or cow, which sheds virus during its viraemia.

Sexual, respiratory, rodent-excreta and waterborne routes are not features of the virus.

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.

The cellular prion protein is predominantly alpha-helical. Disease arises when it refolds into a beta-sheet-rich, aggregation-prone and protease-resistant form, which then templates the conversion of further normal protein.

The defining change is in secondary structure, not the amino acid sequence, so the glycosylation, membrane-anchoring and dimerisation options all miss the point.

Diagnosis rests on serology, with virus-specific IgM in serum and cerebrospinal fluid and a rising IgG on paired sera, because the viraemia is usually past by the time encephalitis appears; reverse-transcription PCR helps early, especially in Venezuelan infection.

Agar culture, urinary antigen, electroencephalography alone and skin biopsy are not the approach.

HAM/TSP (human T-lymphotropic virus type 1 [HTLV-1]-associated myelopathy / tropical spastic paraparesis) is a slowly progressive inflammatory myelopathy. It presents as a spastic paraparesis with brisk reflexes, bladder dysfunction and back pain, driven by immune-mediated infiltration of the thoracic spinal cord.

It is not a flaccid or acute process, not a peripheral neuropathy, not an optic neuritis, and not a cerebellar syndrome.

The differential of a rapidly progressive dementia spans other neurodegenerative dementias, infection, vascular disease and tumours, but the priority is to identify the autoimmune and paraneoplastic limbic encephalitides, because they are treatable and must not be mistaken for an untreatable prion disease.

The other options are themselves untreatable neurodegenerative conditions.

An extensor plantar response (a positive Babinski sign), with hyperreflexia and clonus, is a sign of upper motor neuron damage and localises the lesion to the corticospinal tracts, the lateral funiculi of the thoracic cord that are the core casualty in HAM/TSP.

It separates this myelopathy from a lower motor neuron or peripheral-nerve process, which instead reduces tone and reflexes. The neuromuscular junction, cerebellum and dorsal columns produce different signs and none gives an extensor plantar response.

With a very high ratio of subclinical to clinical infection (on the order of 250 to 1), most people in endemic areas are infected and immune by adulthood, so clinical disease falls mainly on children.

The other groups are not the predominant affected population in highly endemic settings.

Western equine encephalitis is generally mild in adults but can be severe in infants, with seizures and a substantial risk of permanent brain damage in survivors.

The other groups are at lower risk.

Japanese encephalitis virus is the prototype of the Japanese encephalitis serocomplex, which also contains West Nile, St Louis encephalitis and Murray Valley encephalitis viruses, and shares their neurotropism.

Dengue, Spondweni (which holds Zika), tick-borne encephalitis and yellow fever form separate serogroups.

Madariaga virus is the species into which the South American strains formerly called Eastern equine encephalitis virus were reclassified, and it is generally much less virulent in people.

It is not a vaccine strain, not tick-borne, not the most virulent member, and not Western virus.

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).

A common PRNP polymorphism at codon 129 encodes either methionine or valine, and homozygosity predisposes to disease. All but one variant Creutzfeldt-Jakob disease case identified to date has occurred in methionine homozygotes, which is why the codon 129 genotype is determined in suspected cases.

E200K and octapeptide insertions cause genetic rather than variant disease, and heterozygosity is relatively protective.

On diffusion-weighted magnetic resonance imaging, sporadic disease shows cortical ribboning and high signal in the deep grey nuclei, whereas variant Creutzfeldt-Jakob disease shows a hyperintense posterior thalamus, the pulvinar sign.

This sign is uncommon in the other prion diseases listed.

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).

Human prion disease is sporadic in about 85% of cases (almost all sporadic Creutzfeldt-Jakob disease), genetic in about 15% (autosomal dominant PRNP mutations), and acquired in a small and declining remainder (kuru, iatrogenic and variant disease).

Overall incidence is roughly one to one and a half cases per million people per year.

The European and Siberian subtypes classically run a biphasic course: a grippe-like first phase, a symptom-free remission, then in a minority a neurological second phase. The Far-Eastern subtype is usually monophasic, progressing straight into severe disease.

The course is not confined to laboratory-acquired or milk-borne cases.

Eastern equine encephalitis virus cycles between passerine birds and the mosquito Culiseta melanura in freshwater hardwood swamps of eastern North America, with less host-specific bridge vectors carrying it to people and horses.

The rodent cycle belongs to Venezuelan virus, and the other pairings are wrong.

Sporadic Creutzfeldt-Jakob disease is a rapidly progressive dementia: cognitive decline over weeks to months, far faster than Alzheimer’s disease, with ataxia and, as it advances, myoclonus, ending in akinetic mutism. This tempo is the single most useful clinical clue.

The other options point to dementia with Lewy bodies, a parkinsonian disorder, normal-pressure hydrocephalus, and a relapsing demyelinating disease.

The incubation period is about two to ten days, varying by virus, followed by a febrile prodrome that may progress to encephalitis.

The other intervals are far too short or too long.

Prions are not viruses or any conventional microbe but a misfolded, self-propagating form of the cellular prion protein. The agent contains no nucleic acid, which is why it resists nucleases and radiation and provokes no immune response, the protein-only hypothesis.

The distractors describe a virus, a bacterial variant and an autoantibody, none of which fit an agent that carries no genome and triggers no inflammation.

Diagnosis rests on serology, chiefly IgM-capture ELISA on serum and cerebrospinal fluid, with a fourfold titre rise in paired sera confirming; serum IgM can persist for several months.

Virus is rarely isolated once neurological disease has begun, and the other options are not diagnostic tests for the virus.

Why D

There is no specific antiviral for JC virus; the single effective principle is to restore JC-virus-specific immunity, which in HIV means starting or optimising antiretroviral therapy. Aciclovir has no activity against polyomaviruses, cidofovir has not shown benefit, corticosteroids are reserved only for severe immune reconstitution inflammation, and mirtazapine is unproven and not a treatment in its own right.

Japanese encephalitis virus has a predilection for the deep grey matter, especially the substantia nigra and basal ganglia, producing extrapyramidal features and a Parkinson-like syndrome that often appears in convalescence.

The cerebellum, occipital cortex, hippocampus and pituitary are not the characteristic targets.

Culex tritaeniorhynchus, which breeds in rice paddies and other ground pools, is the principal vector, linking the disease to irrigated rice agriculture across Asia.

Tree-hole and container-breeding Aedes transmit yellow fever, dengue and Zika, not Japanese encephalitis.

IgM-capture ELISA on serum and cerebrospinal fluid is the standard test, with sensitivity approaching 100% when both are tested one to two weeks after onset; cerebrospinal-fluid IgM indicates central nervous system infection. Flavivirus cross-reactivity is the main limitation.

Virus is rarely isolated, blood is cleared early, and electroencephalography and biopsy are not confirmatory.

Most people with Venezuelan equine encephalitis have a self-limited influenza-like febrile illness, and only a minority, mainly children, develop encephalitis.

It is not usually fatal, arthritic, haemorrhagic, or silent in everyone.

Ixodes ricinus transmits tick-borne encephalitis in Europe and Ixodes persulcatus in Russia and Asia; Ixodes ricinus also transmits Lyme borreliosis, so co-infection can occur.

Hyalomma ticks transmit Crimean-Congo haemorrhagic fever, and the other genera are not the vectors of tick-borne encephalitis.

Variant Creutzfeldt-Jakob disease is lymphotropic, with prion protein in tonsil and appendix as well as brain, and has been transmitted by blood transfusion; this underlies the leucoreduction and donor-deferral measures applied to the blood supply.

Sporadic disease, by contrast, has not been shown to transmit by transfusion.

Epidemics arise when mutation of an enzootic strain produces a variant that replicates to high titre in horses, which then amplify the virus for floodwater mosquitoes to spread.

It is not spread person-to-person, through water, by ticks, or between birds.

The equine encephalitis viruses are New World agents not found in South Africa, so their relevance is as an imported differential in a traveller returning from the Americas.

The locally important alphaviruses are instead Sindbis, Middelburg and Ndumu; these viruses are not endemic, tick-borne, or locally eliminated.

There is no specific antiviral for tick-borne encephalitis, so management is supportive, with neurological intensive care for severe encephalitis and attention to respiratory function where cervical-cord or bulbar involvement threatens breathing.

Acyclovir treats herpes simplex encephalitis and doxycycline treats the tick-borne bacterium of Lyme disease, neither of which is tick-borne encephalitis virus.

Pigs are the key amplifying host, developing a high viraemia and living close to people in rural Asia, while ardeid wading birds are natural maintenance hosts; humans and horses are dead-end hosts.

Primates, rodents and bats are not the amplifying hosts for Japanese encephalitis.

Small rodents are the principal reservoir, sustaining the cycle with Ixodes ticks, including through co-feeding between infected and uninfected ticks on the same host. Large mammals maintain the tick population but rarely transmit the virus.

Pigs, birds and primates are reservoirs for other flaviviruses, not for tick-borne encephalitis.

Eastern equine encephalitis has the highest case-fatality, of the order of 30% or more, with frequent severe neurological sequelae in survivors, especially children.

The others are considerably less lethal.

Ardeid wading birds, such as herons and egrets, are the natural maintenance hosts, with pigs as the amplifying host that drives human exposure.

Poultry, songbirds and waterfowl are not the recognised maintenance hosts, and birds are integral to the cycle.

Western equine encephalitis virus arose by recombination, its genome descended from an Eastern-equine-encephalitis-like ancestor with the structural genes of a Sindbis-like virus.

The others are not recombinants.

Western equine encephalitis virus, isolated from horse brains in California in 1930, was the first alphavirus ever grown in culture.

The three viruses were recovered from encephalitic horses in the Americas during the 1930s, not from African birds, not after 2000, and not before 1900.

Human Western equine encephalitis has all but vanished, with no North American case for many years, for reasons that appear ecological rather than a loss of virulence.

Its vector is Culex tarsalis, not Culiseta melanura; it is a New World, mosquito-borne virus.

Prions resist formalin, alcohol, ultraviolet and ionising radiation, and standard autoclave cycles. Reliable decontamination needs protein-denaturing methods: immersion in sodium hydroxide followed by autoclaving, sodium hypochlorite, or porous-load autoclaving at 134°C.

Formalin, 70% alcohol, a routine 121°C cycle and ultraviolet irradiation all leave infectivity intact. For high-risk procedures, single-use instruments that are then incinerated are preferred.

LDLRAD3, a low-density lipoprotein receptor-related protein, is a key entry receptor for Venezuelan equine encephalitis virus.

MXRA8 serves the arthritogenic Old World alphaviruses, and the others are not its receptor.

Bilateral thalamic lesions are characteristic of Japanese encephalitis on CT or MRI, in keeping with its deep grey-matter tropism.

Temporal-lobe necrosis suggests herpes simplex encephalitis, and the other patterns are not typical of Japanese encephalitis.

All three viruses are neurotropic, invading the brain and infecting neurons, and Eastern equine encephalitis virus is the most neurovirulent.

Susceptibility to fatal disease is highest at the extremes of age, and neuroinvasion can occur by several routes, not only along nerves.

Effective inactivated (for example the Vero-cell IXIARO) and live-attenuated (SA14-14-2) vaccines drive routine childhood immunisation across endemic Asia and are recommended for at-risk travellers; because the virus is a single serotype, they protect across genotypes.

The mouse-brain vaccine is largely phased out, vaccines are not genotype-restricted, and children are the main target group.

There is no licensed human vaccine; veterinary vaccines protect horses, and Venezuelan equine encephalitis virus is highly infectious by aerosol and a recognised biothreat.

Human vaccines remain investigational, the laboratory-aerosol hazard is real, and equine vaccination is central to outbreak control.

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).

Effective inactivated whole-virus vaccines based on the European subtype cross-protect against all three subtypes, with efficacy above 95%; they are given as a multi-dose primary series with periodic boosters.

There is no single-dose lifelong tick-borne encephalitis vaccine, and protection is not restricted to the European subtype.

VZV establishes lifelong latency in neurons, and not only in the dorsal-root sensory ganglia but also in cranial-nerve, autonomic and enteric ganglia.

In the latent state the virus shuts down almost all gene expression, restricting itself largely to a non-coding latency-associated transcript that suppresses ORF61 and so blocks the cascade that would otherwise drive replication.

The Far-Eastern subtype is the most severe, with a case-fatality of roughly 20% to 40%, compared with about 6% to 8% for the Siberian and 0.5% to 2% for the European subtype.

Kunjin is a subtype of West Nile virus, not of tick-borne encephalitis virus.

The real-time quaking-induced conversion assay amplifies and detects the misfolded prion protein directly in cerebrospinal fluid, with a specificity around 98%, so a positive result carries real diagnostic weight.

The 14-3-3 and total tau assays measure non-specific markers of neuronal injury, and the periodic sharp waves and cortical ribboning are supportive findings rather than detection of the protein itself.

Powassan virus is a member of the tick-borne encephalitis serocomplex, which also contains Kyasanur Forest disease, Omsk haemorrhagic fever and louping ill viruses.

Japanese encephalitis and West Nile viruses form the mosquito-borne Japanese encephalitis serocomplex, and dengue and yellow fever are separate groups.

Human viraemia is too low to infect feeding mosquitoes, so people cannot sustain the cycle, which is maintained by pigs and wading birds; there is no human-to-human spread.

Humans are fully susceptible and are bitten in the field, so the other options are incorrect.

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.

a. Tick-borne encephalitis in its biphasic form: a grippe-like first phase, a remission, then a neurological second phase of meningitis or meningoencephalitis, typical of the European subtype.

b. The unpasteurised goat’s milk, because tick-borne encephalitis virus can be acquired by the alimentary route from the milk of infected goats, sheep or cattle, an additional exposure to the tick bite.

c. Serology, with IgM-capture ELISA on serum and cerebrospinal fluid and a rising titre in paired sera; virus is rarely isolated once neurological disease has begun.

d. Tick-borne encephalitis vaccination before travel (with tick-bite avoidance and avoiding unpasteurised dairy as supporting measures).

Clinical and radiological features

PML presents subacutely over weeks with focal deficits that reflect lesion location rather than a single syndrome: limb weakness, visual field loss, cognitive or behavioural change, speech disturbance and ataxia. Fever and headache are characteristically absent. Magnetic resonance imaging shows one or more areas of subcortical white matter that are hyperintense on T2-weighted and FLAIR sequences and hypointense on T1, without mass effect and, in the untreated HIV setting, usually without contrast enhancement.

Differential diagnosis

The differential is the rest of the advanced-HIV brain. HIV encephalitis causes a more diffuse, symmetrical leukoencephalopathy with cognitive decline. Cerebral toxoplasmosis and primary central nervous system lymphoma both produce mass lesions with oedema and ring or homogeneous enhancement, unlike PML. Cytomegalovirus encephalitis tends to be periventricular. The lack of mass effect and enhancement, the multifocal white-matter pattern, and a positive cerebrospinal fluid JC virus PCR distinguish PML, with biopsy reserved for unresolved cases.

• European (Western) subtype: the mildest, with a case-fatality of about 0.5% to 2%; transmitted by Ixodes ricinus.
• Siberian subtype: intermediate severity, case-fatality about 6% to 8%, and associated with chronic progressive disease.
• Far-Eastern subtype: the most severe, case-fatality about 20% to 40%, often monophasic with prominent paralysis.

Measles produces a spectrum of central nervous system (CNS) complications defined by when they appear after the acute illness, the host’s immune status, and whether active or defective measles virus (MeV) is present in the brain.

Key discriminators. Time after rash separates them first: ADEM in days to weeks, MIBE in months, SSPE in years. Host status separates them next: MIBE is the encephalitis of the immunocompromised, whereas SSPE strikes the previously immunocompetent young child. Presence of virus in the brain distinguishes the three pathologies: absent in ADEM (autoimmune), actively replicating in MIBE, and defective in SSPE. All three are largely preventable by measles vaccination.

Why A

JC virus is a polyomavirus: a small non-enveloped icosahedral particle with a circular double-stranded DNA genome of about 5 kilobases, whose large T antigen drives the cell into S phase to support replication. Option C describes a parvovirus, B a picornavirus or similar, E an orthomyxovirus, and D an enveloped DNA virus such as a herpesvirus.

Why E

Restoring immunity can provoke an immune reconstitution inflammatory syndrome, in which the returning T-cell response attacks JC-virus-infected cells; the formerly non-enhancing PML lesions develop enhancement and oedema and the patient worsens even as infection is being controlled. The timing after antiretroviral therapy and the new enhancement point to PML-IRIS rather than drug toxicity, simple progression, abscess or haemorrhage.