Approach Considerations
A high index of suspicion is required to make the diagnosis of herpes simplex encephalitis (HSE), and expeditious evaluation is indicated after the diagnosis is considered. In the absence of any other identifiable cause, consider HSE in any febrile patient with encephalopathy and CSF pleocytosis. Start empiric acyclovir therapy promptly in patients with suspected HSE pending confirmation of the diagnosis because acyclovir, the drug of choice, is relatively nontoxic and because the prognosis for untreated HSE is poor.
Failure to consider the possibility of HSE can result in delayed diagnosis and treatment, with subsequent increased risks of mortality and morbidity. A single-center study from a high-volume academic emergency department (ED) reported that only 29% of patients with a presentation suggestive of viral encephalitis (fever, neuropsychiatric abnormalities, cerebrospinal fluid [CSF] pleocytosis, and a negative CSF Gram stain) received acyclovir in the ED. [40]
See the following for more information:
Initial Management
Prehospital care consists of supportive management of the patient’s airway, breathing, and circulation (ABCs). General nutritional and fluid support is important. Universal precautions are appropriate. Monitor for increased intracranial pressure (ICP) and seizures.
Intensive care unit (ICU) care may be required, especially if seizure activity or increased ICP is present. Depending on the availability of local expertise (eg, infectious disease, neurology, neurosurgery specialists), transfer to a tertiary care facility may be appropriate. Hospitalization is not routine for uncomplicated herpes simplex virus type 1 (HSV-1) or herpes simplex virus type 2 (HSV-2) infection.
Management of increased intracranial pressure
Treatment of brain edema ranges from simple measures (eg, elevating head of bed, gentle diuresis with medication such as furosemide) to more complex measures (eg, mannitol and steroids, intubation with hyperventilation).
Management of seizures
Behavioral manifestations of HSE may resemble seizures, which are also common. Should seizure activity become apparent or should electroencephalography (EEG) show evidence of nonconvulsive seizures, begin anticonvulsant therapy.
Benzodiazepines may be useful for aborting status epilepticus but, because of their short duration, are ineffective at preventing further seizures. A longer-acting agent is preferable.
Antiviral Therapy
Pharmacotherapy for HSE is available in the form of acyclovir. Patient outcome is improved after treatment with this agent. Acyclovir is the treatment of choice for HSE. [1, 3, 41] When the diagnosis of HSE is suspected or has been established, acyclovir (typically 30 mg/kg/d intravenously [IV] in adults) should be initiated immediately.
Through a series of in vivo reactions catalyzed by viral and host cellular enzymes, acyclovir is converted to acyclovir triphosphate, a potent inhibitor of HSV DNA polymerase, without which viral replication cannot occur. Human cells are not affected.
Acyclovir has relatively few serious adverse effects. Because of its high pH, IV acyclovir may cause phlebitis and local inflammation if extravasation occurs. Gastrointestinal (GI) disturbances, headache, and rash are among the more frequent adverse reactions.
The drug is excreted by the kidney, and the dose should be reduced in patients with renal dysfunction. Crystal-induced nephropathy may occur if the maximum solubility of free drug is exceeded. Risk factors for this are IV administration, rapid infusion, dehydration, concurrent use of nephrotoxic drugs, underlying renal disease, and high doses. The risk of renal toxicity is reduced by adequately hydrating the patient (eg, 1 mL/d of fluid for each 1 mg/d of acyclovir).
Acyclovir is considered appropriate for serious infections during pregnancy. The manufacturer cautions that it should be used in pregnancy only when the potential benefits outweigh the potential risks. However, a prospective registry of acyclovir use in pregnancy between 1984 and 1999, including 756 first-trimester exposures, demonstrated a 3.2% rate of birth defects, similar to that expected in the general population. [42]
In immunocompetent patients, viral resistance to acyclovir has been clinically insignificant, with a reported prevalence of less than 1%. [43] However, in immunocompromised patients, this figure rises to 6%. Degree of immunosuppression and duration of exposure to acyclovir appear to be the most important risk factors for the development of resistant strains.
Since most relapses occur within 3 months of completing an initial course of IV acyclovir, a prolonged course of an oral antiviral agent (eg, valacyclovir) has been suggested after initial treatment. An ongoing clinical trial is currently evaluating a 90-day course of valacyclovir versus placebo after treatment with acyclovir in patients with HSE. [44]
A 2009 Cochrane database review of data from 17 trials that compared interventions used for the prevention and treatment of HSV in patients being treated for cancer concluded that acyclovir is effective in preventing and treating HSV infections. Valacyclovir was not found to be more effective than acyclovir, nor did a higher dose of valacyclovir make a difference. Some evidence indicated that placebo, as a prophylaxis, is more effective than prostaglandin E, but the risk of bias was unclear in all trials. [45]
If long-term suppressive therapy is needed, acyclovir or famciclovir can be used orally.
Neonatal herpes simplex encephalitis
Acyclovir in doses of 20 mg/kg IV every 8 hours (60 mg/kg/d) is currently recommended for neonatal HSE. This dosage is higher than that used in older children and adults (30 mg/kg/d), but, in neonates, it has been shown to improve mortality and morbidity when compared with the lower dosage. Because the higher dosage is associated with neutropenia, the white blood cell (WBC) count should be monitored closely.
Steroid Therapy
The role of steroids in the treatment of HSE remains uncertain. To the extent that cellular damage in HSE is the result of immune-mediated inflammatory processes triggered by the viral infection, the anti-inflammatory effects of steroids may be beneficial. However, there is also concern that steroids might suppress immune responses of the host that are necessary to limit viral replication.
Animal studies have demonstrated a beneficial effect of steroids on outcome, without evidence of increased viral replication or dissemination. [46, 47] Steroids have been used to reduce cerebral edema in patients with severe HSE.
One nonrandomized, retrospective human study compared the outcomes of patients with HSE who received steroids in addition to acyclovir with the outcomes of those who received acyclovir alone. [48] The steroid group had improved outcomes at 3 months. Although these results suggest a possible role for steroids in HSE, definitive recommendations must await the results of larger prospective studies.
The German trial of Acyclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE), a multicenter, randomized, placebo-controlled trial, is currently enrolling patients with HSE in a study designed to assess the outcomes of treatment with acyclovir against the outcomes of treatment with acyclovir plus dexamethasone. [49]
Prevention
No measures are known to be effective for preventing HSE in adults and older children. Person-to-person transmission does not occur. Prophylactic treatment of close contacts and special isolation precautions are unnecessary.
Preventive measures for neonatal HSE include cesarean delivery in women with active herpetic genital infections at the time of delivery and protection of neonates from persons with active herpetic infections. Some authorities recommend a course of suppressive acyclovir therapy near the time of delivery in mothers with a history of genital herpes.
Consultations and Additional Care
HSE is a neurologic emergency. Consultation with a neurologist is required. Neurosurgical consultation is helpful only if a brain biopsy is being considered. An infectious disease consultation may be appropriate.
An evaluation for rehabilitation is often appropriate to deal with the long-term neurologic sequelae of HSE. Depending on the nature and degree of any neurologic deficits present, rehabilitation services may be required.
-
Axial proton density-weighted image in 62-year-old woman with confusion and herpes encephalitis shows T2 hyperintensity involving right temporal lobe.
-
Axial gadolinium-enhanced T1-weighted image reveals enhancement of right anterior temporal lobe and parahippocampal gyrus. At right anterior temporal tip is hypointense, crescentic region surrounded by enhancement consistent with small epidural abscess.
-
Axial diffusion-weighted image reveals restricted diffusion in left medial temporal lobe consistent with herpes encephalitis. This patient also had positive result on polymerase chain reaction assay for herpes simplex virus, which is both sensitive and specific. In addition, patient had periodic lateralized epileptiform discharges on electroencephalography, which supports diagnosis of herpes encephalitis.
