Herpes simplex virus encephalitis (ORPHA:1930)
A rare disorder caused by infection of the central nervous system by Herpes simplex virus (HSV) that could have a devastating clinical course and a potentially fatal outcome particularly with delay or lack of treatment. This disorder often involves the frontal and temporal lobes, usually asymmetrically, resulting in personality changes, cognitive impairment, aphasia, seizures, and focal weakness.
Epidemiology
HSVE accounts for 20 % of encephalitis cases and its annual incidence is 1/250,000-1/500,000 in industrialized nations and is presumed to be the same across the globe.
Clinical description
HSVE usually peaks in childhood (between 3 months and 6 years during primary infection with HSV-1) and in older people (bimodal distribution). The manifestations of HSVE include low-grade pyrexia accompanied by severe headache, nausea, vomiting, and lethargy, followed by neurological features, which may include cognitive dysfunction (confusion, acute memory disturbances and disorientation), behavioral changes (irritability, hallucinations, psychosis, personality changes, agitation), focal neurological abnormalities (such as focal weakness, anomia, aphasia, dysphasia,), hemiparesis and seizures. There may be marked temporal lobe edema and occasionally brainstem herniation. 20 % of HSVE cases may present a relatively mild or atypical disease.
Etiology
HSV-1 causes 90 % of cases of HSVE with 10 % of cases caused by HSV-2; the latter is a common cause in neonates (during vaginal delivery) and the immunosuppressed. HSVE results from primary infection in 1/3 of cases and reactivation in 2/3. Mutations in genes such as TLR3 (4q35) and TRAF3 (14q32.32) have been observed suggesting an influence of genetic factors, presumably by an impaired type I and type III IFN production in response to HSV-1. In 7 % of patients with HSVE, antibodies against NMDAR (N-methyl-D-aspartate receptor), may be detected. Post-HSVE, abnormal movements or relapse of symptoms may be related to these antibodies.
Diagnostic methods
The mainstay of diagnosis is detection of HSV in cerebrospinal fluid (CSF) by Polymerase Chain Reaction (PCR), although it may be negative for HSV-1 during the first 3 days of illness or after 10-14 days. CSF examination shows lymphocytosis (≥10-200/mm3) and raised protein (> or equal to 0.5-1.0 g/l). Magnetic resonance imaging findings show the characteristic abnormalities of edema and/or abnormal enhancement in one or both temporal and frontal lobes, the insular cortex, and the angular gyrus.
Differential diagnosis
Differential diagnosis includes: other viral causes of encephalitis, (varicella zoster virus, enteroviruses etc); bacterial infections, including ricketsial disease, mycoplasma pneumonia, chlamydophila infections; autoimmune diseases, such as paraneoplastic limbic encephalitis, acute disseminated encephalomyelitis, Rasmussen subacute encephalitis; and other causes including space occupying lesion and non-infectious encephalopathy.
Genetic counseling
HSVE occurs sporadically.
Management and treatment
The mainstay of treatment is intravenous injection (IV) of acyclovir (10mg/kg) 3 times daily for 14 days-21 days. CSF examination could be repeated at the end of that period to check if the virus has been cleared. Dosage should be adjusted in cases of renal malfunction. In immunocompromised patients, acyclovir should be continued for at least 21 days. Corticosteroids such as dexamethasone have been used in patients with HSVE, but the benefits are uncertain. The beneficial effects of methylprednisolone in children with antibodies against the NMDAR have yet to be established, as well as the possible benefits of steroid therapy or oral valacyclovir following IV acyclovir.
Prognosis
If untreated, mortality rates are 70 % that can be reduced to 28% following treatment. However morbidity remains high and survivors often have residual deficit such as chorea or epilepsy. A delay of 48 hours or more in starting acyclovir is associated with poor outcome.

                            Last update: 
                            June 2015


                            - Expert reviewer(s): 
                            Dr Jeoffrey SEGURA  - Pr Tom SOLOMON