Herpes Simplex Encephalitis (HSE)

Overview

Herpes simplex encephalitis is the most common sporadic and treatable fatal encephalitis in adults; the majority of cases are caused by HSV-1, and the virus affects the temporal and inferior frontal lobes and the limbic system through a hemorrhagic-necrotizing process. This pattern of involvement is the result of the virus reaching the central nervous system via retrograde axonal spread through the trigeminal or olfactory nerve pathways, and the tissue damage caused directly by viral cytolysis is combined with secondary inflammatory edema that develops afterward.

The typical clinical picture consists of fever, headache, altered consciousness or personality change, aphasia, focal seizures, and focal neurological deficits; however, all of these findings are not present together in every patient, and the diagnosis can be delayed in immunosuppressed patients where the clinical presentation may be much more subtle. Magnetic resonance imaging shows T2/FLAIR signal increase in the temporal and limbic regions and sometimes hemorrhagic foci; this imaging method is the most sensitive among neuroimaging tools and can detect abnormal findings even in the early stages of the disease.

Cerebrospinal fluid examination shows lymphocytic pleocytosis, elevated protein levels, usually normal glucose, and often erythrocytes or xanthochromia; these findings reflect the hemorrhagic-necrotizing process in the CSF. The basis for diagnosis is CSF HSV polymerase chain reaction testing, and the reported sensitivity-specificity values for this test vary across sources; some series report approximately 96% sensitivity and 99% specificity, while others report 94-98% sensitivity and 94-98% specificity.

Despite this variability, the common point is: in the very early stages of the disease, particularly within the first 72-96 hours after symptom onset, the viral load may still be below the detection threshold, so PCR can yield false-negative results, and therefore a single negative result does not exclude the diagnosis in cases of high clinical suspicion. Periodic lateralized epileptiform discharges seen on electroencephalography are sharp-slow wave complexes originating from the unilateral or bilateral temporal region, occurring approximately two to fifteen days after the onset of the disease, and repeating at intervals of two to three seconds, and are detected in about two-thirds of confirmed cases; the absence of this pattern does not exclude the diagnosis and should not be considered absolutely specific, as it can also be seen in some other infectious or inflammatory processes outside of seizures (such as bacterial meningoencephalitis, neurosyphilis).

In untreated cases, mortality reaches approximately 70%, while with early acyclovir treatment, this rate is significantly reduced and the risk of neurological sequelae decreases; this difference forms the clinical justification for starting antiviral treatment empirically before diagnostic test results are available. The basis for this justification is a randomized study conducted in 1986 by the NIAID Collaborative Antiviral Study Group, which compared acyclovir with vidarabine in biopsy-proven HSE cases; in this study, mortality was 54% in those receiving vidarabine and 28% in those receiving acyclovir, and this difference established acyclovir treatment as the standard.

Key considerations

• Bacterial meningitis or meningoencephalitis may not be clinically distinguishable from HSE, and therefore simultaneous empirical antibacterial treatment may be necessary against this condition, in which survival is measured in minutes.
• Other viral encephalitides include varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus-6, and enteroviruses; most of these cannot be definitively distinguished from HSE based on clinical and imaging findings, and diagnosis is made with a broad panel PCR.
• Autoimmune or paraneoplastic encephalitis, particularly anti-NMDA receptor encephalitis, can be triggered by HSE and typically recurs with psychiatric symptoms, movement disorders, and seizures days to weeks after recovery from the initial infection; at this stage, CSF HSV PCR is usually negative.
• Brain abscess, subdural empyema, or septic encephalopathy can mimic HSE by causing fever and focal neurological findings; contrast imaging showing ring-like lesions or empyema collections suggests these diagnoses.
• Status epilepticus and prolonged postictal state may cause impaired consciousness and transient focal deficits; excluding active seizure activity with EEG plays a critical role in this distinction.
• Metabolic or toxic encephalopathies, for example hepatic encephalopathy, uremic encephalopathy, Wernicke's encephalopathy, and severe hyponatremia, cause fluctuating consciousness disturbances but typically do not produce focal deficits or imaging findings specific to temporal lobe involvement.
• Acute ischemic stroke, particularly in the territory of the left middle cerebral artery, can mimic HSE with acute aphasia and hemiparesis; however, stroke usually occurs without fever and imaging shows the boundaries of the vascular territory.
• Autoimmune limbic encephalitis (associated with anti-LGI1, anti-CASPR2, or other neuronal surface antibodies) can lead to a presentation similar to HSE with subacute memory impairment, seizures, and behavioral changes; however, the course is generally slower and fever is not prominent.
• Opportunistic central nervous system infections such as cytomegalovirus encephalitis or progressive multifocal leukoencephalopathy in immunosuppressed patients should also be considered in the differential diagnosis; in these patients, HSE clinical presentation may be more subtle, making the differentiation more difficult.

Why it matters

Acyclovir selectively inhibits viral DNA polymerase, thereby stopping HSV replication, and when started early significantly reduces both mortality and the risk of neurological sequelae; since delayed antiviral treatment is associated with poor neurological outcomes, empiric treatment before diagnostic tests (CSF PCR, MRI) are available is an established standard and is included in the Infectious Diseases Society of America's 2008 encephalitis guideline. The dose is 10 mg/kg given every eight hours; in obese patients, ideal body weight rather than actual body weight is used, based on observational data showing that obesity increases the risk of acyclovir-induced nephrotoxicity.

Because acyclovir can crystallize in renal tubules, it is recommended that the infusion be completed over at least one hour, concentrations be kept low, and aggressive hydration be provided, especially in febrile or volume-depleted patients; as creatinine levels may rise in the first 24-48 hours of treatment, kidney function should be closely monitored and the dosing interval adjusted according to creatinine clearance. Although CSF HSV PCR is a highly sensitive test, it can give false-negative results in the very early stage of the disease, so a single negative PCR result is not sufficient to discontinue antiviral treatment in cases with a high pretest probability; in this situation, the IDSA approach recommends continuing treatment and repeating the lumbar puncture within three to seven days to renew the PCR.

The duration of treatment in adults typically ranges from 14 to 21 days; durations closer to 21 days may be preferred depending on the severity of central nervous system involvement, but there is no definite consensus among sources on this matter, and some sources also cite the 10-day duration recommended by the manufacturer — due to this discrepancy, the duration decision should be individualized based on clinical response and neuroimaging findings. The use of adjuvant corticosteroids is a controversial issue: the GACHE study conducted in Germany, Austria, and the Netherlands, although designed to investigate the effect of adding dexamethasone to acyclovir, was terminated early due to low patient enrollment and was completed with only 41 patients without sufficient power; therefore, no evidence has been produced strong enough to support or exclude the routine use of corticosteroids, and routine application is not recommended.

If clinical deterioration, psychiatric symptoms, or movement disorders develop days to weeks after the completion of HSE treatment, HSV-triggered anti-NMDA receptor encephalitis should be considered; this secondary process is confirmed by the detection of NMDAR antibodies in the CSF, and in this stage, HSV PCR is usually negative, with treatment directed towards immunotherapy rather than antivirals.

Critical complications

• Acyclovir-induced acute kidney injury occurs when the drug crystallizes in the renal tubules and is recognized by an increase in creatinine within the first 24-48 hours of treatment; prevention involves adequate hydration, at least a one-hour infusion duration, and dosing based on ideal body weight in obese patients, and if it occurs, hydration is increased and the dosing interval is extended according to creatinine clearance.
• Acyclovir neurotoxicity occurs in the form of confusion, myoclonus, hallucination, and lethargy, especially in patients with renal failure or those receiving high doses; since this condition can be confused with the encephalitis itself, it should be kept in mind in the differential diagnosis, and when detected, the dose should be reduced and the drug discontinued if necessary.
• Cerebral edema and the associated increase in intracranial pressure can develop in cases where temporal lobe necrosis is widespread, and manifest with papilledema, unilateral pupil dilation, or a Cushing response; management includes head elevation, osmotherapy, and neurosurgical consultation if necessary.
• Status epilepticus can develop as a direct result of temporal and limbic involvement and may be difficult to recognize because the nonconvulsive form is only detected through continuous EEG monitoring; it requires aggressive antiepileptic treatment and intensive care support if needed.
• HSV-triggered anti-NMDA receptor encephalitis emerges days to weeks after treatment of the initial infection with psychiatric symptoms, movement disorders, and seizures; diagnosis is confirmed with CSF NMDAR antibodies and managed with immunotherapy (corticosteroids, intravenous immunoglobulin, or plasmapheresis).
• Persistent neurological and cognitive sequelae, particularly memory impairment, aphasia, personality changes, and seizure disorders, can develop even in a significant proportion of treated patients; these sequelae require long-term neuropsychological rehabilitation.
• Hyponatremia can develop due to the syndrome of inappropriate antidiuretic hormone secretion and may worsen consciousness impairment; serum sodium needs to be monitored regularly and corrected with fluid restriction or hypertonic saline if necessary.
• In neonates, neutropenia due to high-dose acyclovir therapy is common and can lead to treatment interruption; therefore, regular complete blood count monitoring should be performed during treatment, and in cases of significant neutropenia, the dose or duration should be reassessed together with hematology/neonatology specialists.

Special considerations

• Acyclovir in pregnancy is considered safe when the potential benefit outweighs the risk, and there is no consistent data showing teratogenic effects in humans; in life-threatening conditions such as encephalitis, pregnancy should not be a justification for delaying treatment or reducing the dose.
• In neonates with central nervous system or disseminated disease, the dose differs from adults and is administered as 20 mg/kg IV every eight hours for 21 days; since the introduction of high-dose therapy, mortality in disseminated disease has decreased from approximately 57% to 31%, and in central nervous system disease from about 20% to the 6–14% range, demonstrating that early and adequate dosing directly determines the outcome in this age group.
• In children (between three months and twelve years of age), an adult dose of 10 mg/kg is insufficient, and a dose of 20 mg/kg IV every eight hours should be used; applying the adult dose may lead to inadequate treatment and poor neurological outcomes.
• In elderly patients, the clinical presentation may be milder compared to young adults, and classical symptoms such as fever and headache may be less prominent; since this may cause diagnostic delay, a lower threshold should be maintained in elderly patients with unexplained acute confusion or behavioral changes.
• In patients with renal failure, the acyclovir dose is not changed but the dosing interval is extended (every twelve hours for creatinine clearance of 25-50 mL/min, every twenty-four hours for 10-25 mL/min); the dose is only halved for patients with creatinine clearance below 10 mL/min; if this distinction is improperly applied, either inadequate treatment or risk of neurotoxicity may occur.
• In immunosuppressed patients (organ transplant recipients, those with HIV infection, or those undergoing chemotherapy), the clinical picture may be milder and mortality is higher; in these patients, opportunistic infections such as cytomegalovirus encephalitis should also be considered in the differential diagnosis, and the diagnostic threshold should be lowered.
• In obese patients, dosing should be based on ideal body weight rather than actual body weight; observational studies have shown that dosing according to actual weight significantly increases the risk of nephrotoxicity.

Follow-up plan

Renal function, especially serum creatinine and urine output, should be monitored daily during the initial days of treatment because acyclovir-related acute kidney injury typically occurs within the first 24-48 hours; in patients receiving high-dose pediatric or neonatal regimens, neutropenia should also be monitored with regular complete blood counts. If the initial CSF HSV PCR result is negative but there is high clinical suspicion, acyclovir should not be stopped and lumbar puncture should be repeated within three to seven days for PCR testing.

Magnetic resonance imaging and electroencephalography should be used to support the diagnosis and evaluate seizure activity, and antiepileptic treatment should be initiated if seizures are detected. Before discharge, it should be confirmed that the patient's neurological examination is stable, oral intake is adequate, and the patient or family is informed about possible long-term sequelae (memory impairment, personality changes, seizures).

If new psychiatric symptoms, movement disorders, or neurological deterioration develop within days to weeks after the completion of treatment, the patient or their relatives should seek urgent medical attention, and in this case, a CSF autoantibody test for anti-NMDA receptor encephalitis should be sent and neurology and immunotherapy should be initiated. In recovering patients, neurological and cognitive rehabilitation should be planned, and outpatient neurology follow-up should be arranged for cognitive functions and seizure control.