Herpes simplex encephalitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Saad, M.B.B.S.[2] Cafer Zorkun, M.D., Ph.D. [3], Anthony Gallo, B.S. [4]

Synonyms and keywords: HSE; Herpes viral encephalitis; Herpes meningoencephalitis; HSV encephalitis; Herpes simplex virus encephalitis

Herpes simplex encephalitis is a severe viral infection of the central nervous system and the most common cause of sporadic fatal encephalitis worldwide. It may be classified according to the causative virus into HSV-1 and HSV-2 disease; HSV-1 causes more than 90% of cases beyond the neonatal period, while HSV-2 predominates in neonates. The exact pathogenesis is not fully understood, but the disease is believed to result from retrograde transmission of virus along nerve axons to the brain after reactivation of latent virus in the trigeminal ganglion, producing a necrotising, often haemorrhagic encephalitis of the medial temporal lobes and insular cortex.

Herpes simplex encephalitis constitutes a medical emergency. If left untreated, approximately 70% of patients progress to mortality. It must be differentiated from other diseases causing fever, headache, seizures and altered mental status, including bacterial meningitis, other viral encephalitides, brain abscess, subarachnoid haemorrhage, stroke, metabolic and toxic encephalopathies and autoimmune encephalitis. Physical examination findings are generally non-specific.

Diagnosis rests on cerebrospinal fluid examination obtained by lumbar puncture, which typically shows a lymphocytic pleocytosis, together with detection of HSV DNA by polymerase chain reaction. A negative PCR taken very early does not exclude the diagnosis. Magnetic resonance imaging is the imaging modality of choice.

The mainstay of therapy is prompt intravenous antiviral treatment, and the drug of choice is aciclovir, which must be started empirically before microbiological confirmation. Adjunctive dexamethasone does not improve verbal memory outcome, and prolonged oral valaciclovir after intravenous therapy confers no benefit. Surgery is reserved for refractory raised intracranial pressure. Approximately one quarter of survivors develop autoimmune encephalitis after completing antiviral therapy, most often associated with NMDA receptor antibodies. Even with prompt treatment, mortality remains substantial and most survivors are left with neuropsychological sequelae, particularly impairment of memory.

Before effective antivirals, herpes simplex encephalitis was diagnosed by brain biopsy and was fatal in approximately 70% of cases.^[1] Two randomised controlled trials in the 1980s established aciclovir as the treatment of choice. In the NIAID Collaborative Antiviral Study Group trial, 208 patients undergoing brain biopsy for presumptive herpes simplex encephalitis were randomised to vidarabine or aciclovir; 69 patients (33%) had biopsy-proved disease, and mortality was 54% in vidarabine recipients compared with 28% in aciclovir recipients (P = 0.008).^[2] A parallel randomised Swedish multicentre study reached the same conclusion.^[3]

Detection of HSV DNA in cerebrospinal fluid by polymerase chain reaction subsequently replaced brain biopsy as the diagnostic standard.^[4] More recent milestones include the recognition of inborn errors of the TLR3–type I interferon pathway as a cause of childhood disease,^[5] the identification of post-infectious autoimmune encephalitis as a frequent complication,^[6] and completion of the first randomised controlled trial of corticosteroids in this disease.^[7]

Herpes simplex encephalitis may be classified according to the causative virus type and the affected host.

The exact pathogenesis of herpes simplex encephalitis is not fully understood. It is believed to result from retrograde transmission of the virus from a peripheral site on the face to the brain along a nerve axon following HSV-1 reactivation.^[1] The virus lies dormant in the ganglion of the trigeminal or fifth cranial nerve, but the exact mechanism of reactivation and neuroinvasion remains unknown. The olfactory nerve may also be involved, providing a direct route from the nasal mucosa to the orbitofrontal and medial temporal structures.^[9] Primary infection with direct neuroinvasion accounts for a minority of cases, chiefly in children and young adults.^[10]

Host genetic susceptibility contributes to disease in a subset of patients. A dominant-negative TLR3 allele was identified in otherwise healthy children with HSV-1 encephalitis; TLR3 is expressed in the central nervous system, where it is required to control HSV-1, but appears redundant for host defence against most other microbes.^[5] Subsequent work has extended this to other defects of the TLR3–type I interferon axis, and the intensity and persistence of the interferon signature, together with specific HLA alleles, correlate with the risk of post-infectious autoimmune complications.^[11]

The resulting pathology is an asymmetric necrotising, frequently haemorrhagic encephalitis with a predilection for the medial temporal lobe, insular cortex, cingulate gyrus and orbitofrontal cortex, accompanied by perivascular lymphocytic cuffing, microglial nodules and Cowdry type A intranuclear inclusions. Cytotoxic and vasogenic oedema, raised intracranial pressure and seizures follow, and the anatomical distribution of injury explains the characteristic residual deficits in memory, language and behaviour.^[10]

Herpes simplex encephalitis is caused by HSV-1 or HSV-2. HSV-1 accounts for more than 90% of cases outside the neonatal period, whereas HSV-2 is the predominant cause of neonatal central nervous system disease and is over-represented among immunocompromised patients.^[8][10]

Herpes simplex encephalitis must be differentiated from other diseases that cause fever, headache, seizures and altered mental status.^{[12][13][14][15]}

Herpes simplex encephalitis must also be differentiated from other causes of headache, altered mental status and seizures, including brain tumours and delirium tremens.

In a Swedish nationwide study covering the 12-year period 1990-2001, 638 patients hospitalised in Sweden received a primary diagnosis of herpes simplex encephalitis, of whom 236 had confirmed central nervous system infection due to herpes simplex virus type 1, corresponding to an incidence of confirmed disease of 2.2 cases per million population per year.^[8] Herpes simplex virus is consistently the most commonly identified infectious cause of encephalitis in population-based studies from high-income settings.^[16] Approximately 90% of cases are caused by HSV-1, with the remainder caused by HSV-2; HSV-2 infection is most commonly observed among immunocompromised individuals and neonates.^[8][10]

Herpes simplex encephalitis affects all ages. The age distribution is bimodal, with peaks in young children and in adults over 50 years of age.^[24] Increasing age is an independent predictor of unfavourable outcome (odds ratio 1.04; 95% confidence interval 1.02 to 1.05).^[25]

There is no consistent gender predilection to the development of herpes simplex encephalitis.^[16]

There is no established racial predilection to the development of herpes simplex encephalitis.^[10]

Unlike arboviral and enteroviral encephalitis, there is no seasonal predilection to the development of herpes simplex encephalitis, which occurs sporadically throughout the year.^[24]

Most patients with herpes simplex encephalitis are previously healthy, and no risk factor is identified in the majority of cases. Recognised associations include:^[10][5][11]

• Extremes of age (young children and adults over 50 years)
• Inborn errors of the TLR3-type I interferon pathway, which underlie a proportion of childhood cases and confer a risk of recurrence
• Immune deficiency, including HIV infection, haematological malignancy, transplantation and exposure to immunomodulatory or immunosuppressive therapy, which is associated with atypical presentation and poorer outcome
• Neonatal exposure to maternal genital HSV-2 infection, particularly primary maternal infection near delivery

Herpes simplex encephalitis constitutes a medical emergency. Illness typically evolves over hours to a few days with fever, headache and progressive alteration of consciousness, behaviour or language, frequently punctuated by focal or generalised seizures. If left untreated, approximately 70% of patients progress to mortality.^[1] Time from symptom onset to initiation of antiviral therapy is one of the few modifiable determinants of outcome.^[26][25]

Common complications of herpes simplex encephalitis include:^[10][27][8]

• Seizures and status epilepticus
• Meningeal involvement (meningoencephalitis)
• Cerebral oedema and raised intracranial pressure, with risk of herniation
• Coma and respiratory failure requiring mechanical ventilation
• Aspiration pneumonia and shock
• Venous thromboembolism, the incidence of which was 5-14 times higher than that in the general population in the Swedish nationwide cohort
• Epilepsy, which was the most common diagnosis at readmission among survivors
• Post-infectious autoimmune encephalitis
• Persistent amnesia, aphasia, executive dysfunction and personality change

The prognosis of herpes simplex encephalitis remains guarded even with prompt treatment. Among patients treated with aciclovir, the mortality rate is approximately 14%-19%, and among survivors, 45%-60% have neuropsychological sequelae at 1 year.^[28] In the Swedish nationwide cohort, 1-year mortality among patients with confirmed HSV-1 disease was 14% (33 of 236 patients died), which was 8 times higher than expected, and 87% of survivors were readmitted to hospital.^[8]

In a multinational study of 438 evaluable adults with molecularly confirmed herpetic meningoencephalitis, 232 (52.9%) experienced an unfavourable outcome, 44 died and 188 survived with sequelae. Independent predictors of unfavourable outcome were age (odds ratio 1.04; 95% confidence interval 1.02 to 1.05), Glasgow Coma Scale score (odds ratio 0.84; 95% confidence interval 0.77 to 0.93) and duration of symptoms before treatment of 2 to 7 days (odds ratio 1.80; 95% confidence interval 1.16 to 2.79) and more than 7 days (odds ratio 3.75; 95% confidence interval 1.72 to 8.15).^[25] In the original NIAID trial, 6-month mortality varied by Glasgow Coma Scale score at the onset of therapy: for scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46 and 67 percent among patients treated with vidarabine, compared with 0, 25 and 25 percent among those treated with aciclovir; at 6 months, 5 of 37 patients receiving vidarabine (14 percent) compared with 12 of 32 receiving aciclovir (38 percent) were functioning normally (P = 0.021).^[2]

There are no criteria specific to herpes simplex encephalitis. Diagnosis is made within the framework of the International Encephalitis Consortium consensus case definition, which requires altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) lasting 24 hours or longer with no alternative cause identified, together with minor criteria including documented fever of 38 degrees Celsius or greater within 72 hours, generalised or partial seizures not attributable to a pre-existing seizure disorder, new onset of focal neurological findings, cerebrospinal fluid white blood cell count of 5 per cubic millimetre or greater, neuroimaging abnormality suggestive of encephalitis, and electroencephalographic abnormality consistent with encephalitis. Confirmed disease requires laboratory confirmation, which for herpes simplex encephalitis is a positive cerebrospinal fluid HSV PCR.^[13][29]

The dominant principle is that neither neuroimaging nor lumbar puncture should delay empiric aciclovir.^[27][29][25]

If possible, a detailed and thorough history from the patient and from a collateral informant is necessary, since altered cognition frequently prevents accurate self-report. Symptoms of herpes simplex encephalitis include:^[10][26][27]

• Fever
• Headache
• Decreased alertness, drowsiness and lethargy
• Confusion and personality or behavioural change
• Inability to produce or comprehend language
• Memory impairment
• Seizures, often focal with temporal lobe semiology
• Nausea and vomiting
• Difficulty swallowing
• Olfactory or gustatory hallucinations

Symptom duration before treatment is prognostically important, and a history extending beyond 7 days before initiation of antiviral therapy is independently associated with unfavourable outcome.^[25]

Physical examination findings for herpes simplex encephalitis are generally non-specific and no finding is sufficiently sensitive or specific to establish or exclude the diagnosis. Common physical examination findings include:^[10][27]

• Fever
• Confusion and reduced Glasgow Coma Scale score
• Aphasia and other focal cortical signs
• Focal or generalised seizures
• Hemiparesis and cranial nerve abnormalities
• Coma in advanced disease
• Nuchal rigidity when there is meningeal involvement
• Papilledema when intracranial pressure is raised

Mucocutaneous herpetic lesions are usually absent and their absence has no diagnostic value; when present, associated findings may include genital or oral ulcers, conjunctivitis, chorioretinitis or erythema multiforme.

Cerebrospinal fluid obtained by lumbar puncture characteristically shows a lymphocytic pleocytosis with increased leukocytes, often accompanied by red blood cells reflecting the necrotising and haemorrhagic nature of the process, mildly to moderately elevated protein and a normal glucose.^[24][10] Cerebrospinal fluid may be acellular very early in the illness and in immunocompromised patients, and a normal cell count does not exclude the diagnosis.

Polymerase chain reaction of cerebrospinal fluid is the diagnostic test of choice. In the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluation against brain biopsy, HSV DNA was detected by PCR in cerebrospinal fluid of 53 (98%) of 54 patients with biopsy-proven disease and was detected in all 18 cerebrospinal fluid specimens obtained before brain biopsy; 4 of 19 specimens remained positive after 2 weeks of antiviral therapy. Reported sensitivity and specificity against brain biopsy were 98% and 94%, respectively.^[4] A negative result obtained within the first 72 hours of symptom onset, or from a specimen with a bland cerebrospinal fluid profile, does not exclude the diagnosis, and guidelines recommend continuing aciclovir and repeating the lumbar puncture when clinical suspicion persists.^[27][29]

Multiplex syndromic panels shorten time to an aetiological result but do not replace targeted PCR and culture. In a systematic review and meta-analysis, the summary sensitivity and specificity of the BioFire FilmArray meningitis/encephalitis panel were 90% (95% confidence interval 86-93%) and 97% (95% confidence interval 94-99%), respectively, with both false-positive and false-negative detections reported.^[30][31]

The following table summarises cerebrospinal fluid findings in herpes simplex encephalitis compared with the principal differential diagnoses.^[10][13][27]

Computed tomography is insensitive early in the illness and a normal scan does not exclude the diagnosis; its principal role is to exclude a mass lesion or haemorrhage before lumbar puncture when indicated. Findings on CT suggestive of herpes simplex encephalitis include subtle low density within the anterior and medial temporal lobe and the insular cortex.^[32] Subtleties become more apparent over time, may progress to haemorrhage and may eventually spread to the contralateral temporal lobe after 7-10 days.^[24]

Magnetic resonance imaging is the imaging modality of choice for herpes simplex encephalitis and is substantially more sensitive than computed tomography, particularly with diffusion-weighted sequences.^[29][10] Findings on MRI suggestive of herpes simplex encephalitis include:^[33]

• T1
  • General oedema in the affected region
  • Hyperintense signal if complicated by subacute haemorrhage
• T1 C+ (Gd)
  • Early: enhancement is generally absent
  • Later: enhancement is variable and may appear as gyral, leptomeningeal, ring or diffuse enhancement
• T2 and FLAIR
  • Hyperintensity of affected white matter and cerebral cortex, typically asymmetric and involving the medial temporal lobe, insular cortex, cingulate gyrus and orbitofrontal cortex, characteristically sparing the basal ganglia
• DWI/ADC
  • More sensitive than T2-weighted images
  • Restricted diffusion is common due to cytotoxic oedema
• GE/SWI
  • May demonstrate blooming if haemorrhagic

The following video demonstrates herpes simplex encephalitis on MRI:

{{#ev:youtube|OLQlsDCcD3Y}}

Electroencephalography is abnormal in the great majority of patients and, although non-specific, supports the diagnosis and detects non-convulsive seizures. Characteristic findings are lateralised temporal slowing and periodic lateralised epileptiform discharges.^[29][27] Brain biopsy is no longer routinely required and is reserved for patients with progressive undiagnosed encephalitis despite comprehensive non-invasive investigation.^[29][13]

Suspected herpes simplex encephalitis is a medical emergency and the following steps are performed in parallel rather than in sequence.^{[27][29][10][25]}

• Assess and support airway, breathing and circulation; admit to a high-dependency or critical care environment if consciousness is reduced or seizures are recurrent
• Administer intravenous aciclovir as soon as encephalitis is suspected, ideally within 6 hours of presentation and before microbiological confirmation; delay beyond 2 to 7 days from symptom onset is independently associated with unfavourable outcome
• Obtain blood cultures, blood glucose, electrolytes, renal and hepatic function, coagulation screen and HIV testing
• Perform lumbar puncture unless contraindicated; if imaging is required first, do not interrupt or withhold aciclovir
• Add empiric antibacterial therapy where bacterial meningitis cannot be excluded
• Treat seizures and monitor for non-convulsive status epilepticus
• Ensure adequate hydration and monitor serum creatinine, since aciclovir is nephrotoxic and may crystallise in renal tubules
• Correct hyponatraemia, hypoglycaemia and hypoxaemia, which aggravate secondary brain injury

The mainstay of therapy for herpes simplex encephalitis is antiviral therapy, and the drug of choice is aciclovir.^[2][3][29]

Adjunctive and unproven therapies:

• Corticosteroids. In the DexEnceph trial, 94 adults aged 16 years or older with PCR-confirmed HSV-1 or HSV-2 encephalitis were enrolled between September 2016 and February 2022 across 53 hospitals in the UK and randomly assigned to intravenous dexamethasone 10 mg four times daily for 4 days plus intravenous aciclovir 10 mg/kg three times daily for at least 14 days (47 patients), or intravenous aciclovir alone (47 patients); 81 patients were included in the modified intention-to-treat analysis. Dexamethasone was started a median of seven days after hospital admission. Verbal memory at 26 weeks, measured by the Wechsler Memory Scale-IV auditory memory index, did not differ significantly between groups. Adverse events and serious adverse events occurred at similar rates in both arms, seizures requiring readmission and thrombotic events were uncommon and not in excess with dexamethasone, there were no treatment-related deaths, and corticosteroid use was not associated with increased viral persistence in cerebrospinal fluid.^[7] Adjunctive dexamethasone is therefore not recommended routinely to improve cognitive outcome, but the absence of demonstrable harm is clinically relevant when corticosteroids are given empirically to a patient with suspected encephalitis in whom an autoimmune cause remains possible. Corticosteroids retain a role in the management of severe cerebral oedema with mass effect and in confirmed post-infectious autoimmune encephalitis.
• Prolonged oral antiviral therapy. Following completion of a standard course of intravenous aciclovir, 87 adults with PCR-confirmed herpes simplex encephalitis were randomised to valaciclovir 2 g three times daily (40 patients) or placebo (47 patients) for 90 days. There was no clinical benefit, and routine prolonged oral antiviral suppression is not recommended.^[28]

Supportive therapy includes airway protection and mechanical ventilation where required, intravenous fluids with attention to sodium balance, anticonvulsant medication for seizures, management of raised intracranial pressure, venous thromboembolism prophylaxis, nutrition and early rehabilitation.^[27][10]

Aciclovir may be discontinued before completion of a full course when an alternative diagnosis is established, or when cerebrospinal fluid HSV PCR is negative on two occasions 24 to 48 hours apart in a patient with a normal level of consciousness, cerebrospinal fluid white cell count below 5 per cubic millimetre and neuroimaging that is not characteristic of herpes simplex encephalitis.^[27]

Surgical intervention is not required for uncomplicated herpes simplex encephalitis. Procedural and surgical management is reserved for specific complications.^[27][10][29]

• Management of raised intracranial pressure: head elevation, osmotherapy, ventilatory control of PaCO₂ and, in selected patients, invasive intracranial pressure monitoring within a neurocritical care pathway
• Decompressive craniectomy: considered as a rescue measure for refractory intracranial hypertension or impending uncal herniation from massive temporal lobe swelling; supported only by observational data and case series
• External ventricular drainage: for obstructive hydrocephalus, which is uncommon but may complicate severe brain swelling
• Continuous EEG monitoring: indicated in patients with unexplained persistent depression of consciousness to detect non-convulsive status epilepticus
• Repeat lumbar puncture: diagnostic rather than therapeutic; indicated when the initial PCR is negative but suspicion persists, at the end of therapy in neonates, and when post-infectious autoimmune encephalitis is suspected
• Brain biopsy: reserved for progressive undiagnosed encephalitis despite comprehensive non-invasive investigation
• Epilepsy surgery: considered in selected survivors with medically refractory post-encephalitic focal epilepsy

• Surveillance for post-infectious autoimmune encephalitis. In the prospective cohort of the Spanish Herpes Simplex Encephalitis Study Group, 27% of patients with herpes simplex encephalitis developed symptoms of autoimmune encephalitis within 3 months of completing treatment with aciclovir. Presentation varied by age: patients aged 4 years or younger developed choreoathetosis, decreased level of consciousness and frequent seizures or infantile spasms, whereas children older than 4 years and adults predominantly developed behavioural and psychiatric change.^[6] Persistently elevated interferon-stimulated gene signatures and specific HLA alleles identify patients at higher risk.^[11] Any new or worsening neurological or psychiatric symptom after completion of antiviral therapy should prompt repeat MRI, repeat lumbar puncture with HSV PCR and testing for neuronal surface antibodies including NMDA receptor antibodies. Confirmed cases are treated with immunotherapy, not with further antiviral therapy.
• Neuropsychological assessment and cognitive rehabilitation. Among survivors treated with aciclovir, 45%-60% have neuropsychological sequelae at 1 year, predominantly affecting memory.^[28] Formal neuropsychological evaluation should be arranged before or shortly after discharge and repeated during follow-up.
• Epilepsy management. Epilepsy was the most common diagnosis at hospital readmission in the Swedish nationwide cohort, and 87% of survivors were readmitted.^[8] Anticonvulsant therapy should be reviewed periodically and refractory cases referred for specialist assessment.
• Thromboprophylaxis and vascular surveillance. The incidence of venous thromboembolism, including pulmonary embolism, was 5-14 times higher than that in the general population in the Swedish cohort.^[8]
• Multidisciplinary rehabilitation. Physiotherapy, occupational therapy, speech and language therapy, educational and vocational support, and psychological support for patients and families.
• Investigation for inborn errors of immunity in children with herpes simplex encephalitis, particularly after recurrent disease, given the recognised contribution of TLR3 and type I interferon pathway defects.^[5][11]

The following algorithm summarises the approach to neurological deterioration after completion of antiviral therapy.

There is no proven strategy for the primary prevention of herpes simplex encephalitis caused by HSV-1, because disease in most patients results from reactivation of a latent virus that is acquired near-universally in childhood and carried asymptomatically.^[10][1] Vaccines against herpes simplex virus have been developed but remain experimental and none is licensed for the prevention of central nervous system disease.

Measures that reduce transmission of HSV-2 are relevant to the prevention of neonatal central nervous system disease and of HSV-2 disease in adults, and include abstinence from sexual contact, a long-term mutually monogamous relationship with an uninfected partner, correct and consistent use of latex condoms, and disclosure of infection status between sexual partners. In pregnancy, recognition of maternal genital herpes and appropriate obstetric management reduce the risk of intrapartum transmission.^[29]

Because no primary preventive intervention exists for the great majority of cases, the practical priority is secondary prevention of poor outcome through early recognition and immediate empiric antiviral therapy.^[25][26]

Secondary prevention is directed at limiting neurological injury and detecting complications:^{[27][25][6][28]}

• Immediate empiric intravenous aciclovir in every patient with suspected encephalitis, since delay of 2 to 7 days and of more than 7 days from symptom onset independently predicts unfavourable outcome
• Completion of a full 14 to 21 day intravenous course, since relapse has been described after abbreviated therapy; prolonged oral valaciclovir maintenance is not indicated
• Structured follow-up with repeat clinical, imaging and antibody assessment for post-infectious autoimmune encephalitis, which occurred in 27% of patients in prospective follow-up
• Audiological, neuropsychological and epilepsy surveillance in survivors
• Evaluation for underlying inborn errors of immunity in children, particularly after a second episode

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