Herpes Simplex Encephalitis

Herpes simplex encephalitis is the commonest identified cause of sporadic, non epidemic viral encephalitis in immunocompetent adults and children beyond the neonatal period. It is caused almost exclusively by herpes simplex virus type one. Untreated mortality historically approached 70 percent, making it the single most important treatable cause of encephalitis to recognise and treat immediately.

It arises either from reactivation of latent virus within the trigeminal ganglion, with retrograde spread to the temporal and frontal lobes, or, less commonly, from primary infection.

The disease has a characteristic predilection for the medial temporal lobes, orbital frontal cortex and insular cortex. This underlies much of the distinctive clinical and radiographic picture.

Pathophysiology

The virus establishes latency within sensory ganglia following primary mucocutaneous infection. Encephalitis is believed to result from reactivation, with spread along the olfactory or trigeminal pathways directly into the temporal and frontal lobes.

This explains the striking and diagnostically important asymmetry and localisation of the resulting necrotising, haemorrhagic inflammation. It contrasts with the more diffuse pattern typical of many other viral encephalitides.

Fever, headache and altered mental status developing over several days characterise the typical onset.

Behavioural and personality change is often the earliest and most striking feature. It reflects the characteristic frontal and temporal lobe involvement. It is frequently misattributed initially to a primary psychiatric disturbance if the underlying infective process is not considered.

Focal neurological signs occur commonly and reflect the specific anatomical localisation of the disease process. They include dysphasia (reflecting dominant temporal lobe involvement) and olfactory or gustatory hallucinations. Focal or generalised seizures are also common.

Progressive decline in consciousness, from confusion through to coma, occurs over subsequent days if untreated. A substantial proportion of untreated or delayed treatment cases progress to severe permanent neurological disability or death.

A preceding or concurrent history of herpes labialis or other mucocutaneous herpetic lesions is present in only a minority of patients. Its absence should never be used to lower clinical suspicion in an otherwise compatible presentation.

Cerebrospinal fluid polymerase chain reaction testing for herpes simplex virus deoxyribonucleic acid is the essential diagnostic test. Sensitivity approaches 100 percent when performed after the first 72 hours of illness.

A false negative result can occur if testing is performed very early in the illness course. A single negative result obtained within the first day or two of symptoms should be repeated after 24 to 72 hours if clinical suspicion remains high. It should not be used to discontinue treatment prematurely.

Cerebrospinal fluid analysis typically shows a lymphocytic pleocytosis, mildly to moderately raised protein, and normal or only mildly reduced glucose. Red blood cells or xanthochromia are sometimes present, reflecting the haemorrhagic nature of the underlying necrotising process. A normal opening cerebrospinal fluid white cell count does not exclude the diagnosis in a small proportion of cases.

Magnetic resonance imaging is considerably more sensitive than computed tomography and is the imaging modality of choice. It characteristically shows asymmetric signal change on T2 and fluid attenuated inversion recovery sequences involving the medial temporal lobes, insular cortex and orbital frontal cortex, sometimes with associated haemorrhage.

These changes may be absent very early in the illness but typically become apparent within the first 48 hours.

Electroencephalography frequently shows characteristic periodic lateralised epileptiform discharges arising from one or both temporal regions. This finding is not specific but supports the diagnosis. It is also valuable for detecting non convulsive seizure activity contributing to depressed consciousness.

Brain biopsy was historically the diagnostic reference standard before reliable polymerase chain reaction testing. It is now reserved for the rare cases where diagnostic uncertainty persists despite full non invasive testing and the patient is failing to respond to empirical treatment as expected.

Start intravenous aciclovir 10 mg per kg every 8 hours immediately on clinical suspicion, before any confirmatory testing is available. Infuse over at least one hour to reduce the risk of nephrotoxicity, with adequate concurrent hydration. Treatment delay bears a direct and substantial relationship to both mortality and long term neurological outcome.

Dose adjustment is required according to renal function, with the dosing interval extended in renal impairment. Monitor renal function regularly throughout treatment, given the recognised risk of aciclovir induced crystalline nephropathy, particularly in the context of dehydration or rapid intravenous administration.

Treatment is continued for a total of 14 to 21 days. The longer duration of 21 days is generally preferred, given evidence of reduced relapse rates compared with shorter courses.

Some specialists recommend a repeat cerebrospinal fluid polymerase chain reaction test toward the end of the treatment course, to confirm viral clearance before discontinuing therapy. This applies particularly to immunocompromised patients or where the clinical response has been slower than expected.

Do not discontinue treatment on the basis of an early negative polymerase chain reaction result obtained within the first 72 hours of illness if clinical and radiological features remain strongly suggestive of herpes simplex encephalitis. The false negative rate is recognised at this early stage. Repeat testing after 24 to 72 hours before treatment is stopped in this circumstance.

Supportive management includes:

• standard anticonvulsant therapy for seizures (levetiracetam or sodium valproate as first line agents in this context, avoiding phenytoin where possible given interaction concerns and a less favourable adverse effect profile in this population)
• careful monitoring and correction of sodium, given the recognised risk of inappropriate antidiuretic hormone secretion
• intensive care admission with consideration of intracranial pressure monitoring for patients with significantly reduced consciousness or evidence of raised intracranial pressure

A relapsing course is a recognised phenomenon. It presents as clinical deterioration or new neurological features some weeks after apparently successful initial treatment. It may reflect true viral relapse, warranting a further course of aciclovir.

Increasingly, it is recognised as a post infectious autoimmune encephalitis, most often anti N methyl D aspartate receptor encephalitis, triggered by the preceding herpes simplex infection. This requires immunotherapy rather than further antiviral treatment.

Repeat cerebrospinal fluid testing is therefore essential in any patient who deteriorates after initial improvement. Include autoimmune antibody panels alongside repeat herpes simplex virus polymerase chain reaction.

Full neuropsychological assessment and rehabilitation input are essential components of longer term management. The risk of persistent memory impairment, personality change, dysphasia and epilepsy is substantial even in patients who receive prompt and complete treatment. This reflects the destructive nature of the underlying necrotising process in the affected temporal and frontal regions.