Worldwide, herpes simplex virus (HSV) causes the most common form of sporadic, potentially fatal encephalitis in adults and children older than 6 months. In the United States, herpes simplex encephalitis (HSE) may account for up to 20% of all encephalitis cases. 88 HSE occurs in all age groups and strikes both sexes equally in any season. The annual incidence is 1 per 250,000 to 500,000.89 HSV infection of the central nervous system (CNS) is divided into two groups:
Approximately half of neonatal HSV infections have CNS involvement, either as part of disseminated infection or as encephalitis alone. Neonatal HSV infection is usually contracted by vertical transmission from infected mother to neonate, mainly via fetal intrapartum contact with genital HSV infection (85% of cases).13 Congenital infection rarely occurs; the remaining infections are due to postpartum virus exposure.
Newborns with disseminated disease present within 1 week. Neonatal encephalitis alone presents at an average age of 2 weeks. The slightly older age at presentation in the group with isolated encephalitis and the observation that this group usually does not develop skin lesions suggest a different pathogenesis from the cutaneous or disseminated forms of the disease.90 Access of HSV to CNS in neonatal encephalitis is thought to occur via intraneuronal routes. Brain disease is initially localized to one or both temporal lobes and then may progress to involve all brain regions.88
HSE in older children and adults is caused by both primary and recurrent HSV infection. Approximately two-thirds of cases are caused by virus reactivation. The route of access of the virus to the CNS in primary infections is under exploration. It has been documented to occur via the trigeminal nerve after tooth pulp inoculation,91 and by olfactory bulb involvement.92 Such infection paths are consistent with the temporal and orbitofrontal localization of the resulting encephalitis.
HSV-1 strains vary widely with regard to their neurovirulence and epileptogenesis. Stroop and Schaefer used clonally related strains (gram-positive cocci [+GC] and gram-negative cocci [GC]) of HSV-1 to determine the pathophysiologic basis of neurovirulence in a rabbit model. After intranasal inoculation, +GC infection was nearly uniformly fatal, whereas GC infection was asymptomatic. The +GC infected animals developed EEG abnormalities that preceded severe motor seizures, and +GC antigens were found in the first cortical layer of animals that developed seizures. These results suggest that the ability of HSV-1 to induce electrophysiologic brain abnormalities is associated with its ability to replicate within specific brain centers.93
The pathophysiology of epileptogenesis is unclear. Competing theories include:88
HSE is characterized by intense meningitis and destructive changes in brain parenchyma. Inflammation with accompanying necrosis and hemorrhage occur, often maximally involving frontal and temporal lobes. Temporal brain regions are most involved quantitatively in autopsy studies.88
HSE presents as a focal encephalitis. Neurologic signs found early in the disease course include aphasia, confusion, and behavioral changes. These can progress to a fulminant illness characterized by recurrent focal or generalized seizures, coma, and death.88 Hemiparesis is evident at the time of presentation in approximately one-third of cases.90
Partial seizures that can secondarily generalize are frequent in HSE, occurring in up to 40% of cases.13 Abnormal brain electrophysiology occurs in most patients, even those without clinical seizure expression.13
The possibility that HSE underlies a variety of epilepsy syndromes, including epilepsy associated with chronic encephalitides, is being investigated. For example, Jay and colleagues reported two patients presenting with intractable seizures in whom HSV-1 eventually was detected.94 In one patient, an intrauterine infection was suspected as the underlying basis for the seizure disorder and extensive cerebral calcification and gliosis. The other patient underwent temporal lobectomy for medically refractory seizures at age 3 years, and pathologic examination revealed chronic encephalitis. Although immunohistochemical, ultrastructural, and culture studies were negative for viral pathogens, PCR revealed HSV-1 DNA sequences in both cases.94
In another report, the same researchers detected HSV-1 in the brains of three patients who presented with intractable seizures.95 All three patients had a previous history of HSV-1 encephalitis and went on to develop a medically refractory seizure disorder requiring surgical intervention. Pathologic examination revealed chronic encephalitis in all three cases. Although immunohistochemical and ultrastructural studies were negative for viral pathogens, PCR analysis revealed HSV-1 genome. These cases exemplify chronic encephalitis associated with a seizure disorder in which a definitive viral etiology was documented by PCR, demonstrating the persistence of viral genome in brain parenchyma long after the initial episode of treated herpes encephalitis.
Routine blood tests reveal peripheral leukocytosis.
Lumbar puncture demonstrates:
Virus is rarely recovered from CSF, and detection of HSV antibodies in CSF is not sensitive or specific enough to make a treatment decision.88,96 PCR has become the mainstay of noninvasive diagnosis, but the isolation of HSV from a brain biopsy specimen remains the diagnostic gold standard.
CT can demonstrate temporal hypodensity and contrast enhancement but is often normal during the first week of disease. MRI can reveal temporal lobe pathology, including loss of gray-white differentiation, edema, and hemorrhagic components, during the first week.88,96
HSE produces dramatic EEG changes that are highly suggestive (80% of biopsy-proven cases), although not pathognomonic.88,96 EEG patterns include focal slowing, spiking, and paroxysmal lateralizing epileptiform discharges.13 Focal-temporal or lateralized polymorphic delta activity is the earliest change. Diffuse slowing soon follows, with a persistence of temporal predominance. Pseudoperiodic complexes, present on serial EEGs in two-thirds of biopsy-proven cases, appear over temporal regions early in the disease course, usually within 1 month of disease onset.13
Pseudoperiodic lateralized epileptiform discharges in a patient with herpes encephalitis.
Morphologically, complexes are sharp waves or sharply contoured slow waves. They repeat at intervals of 1 to 5 seconds. Pseudoperiodic complexes can be high-amplitude and obvious, but they also may be low-amplitude and subtle. Bilaterally independent complexes can occur, with a predominance concordant with the severity of the involved side. If bilateral, complexes can be synchronous or asynchronous, with a time-locked relationship between lateralized discharges.13,88,96
Seizure patterns can evolve from pseudoperiodic complexes. Over time, complexes become less frequent and disappear, leaving low-amplitude polymorphic slowing in their place.13
Neonatal HSE also produces these EEG complexes. In the neonate population, they are often multifocal and shift from side to side.
Acyclovir is the drug of choice. The recommended dosage is 10 mg/kg every 8 hours for 1014 days.88
Seizures should be managed routinely with anticonvulsants as needed. The seizure relapse rate is approximately 510%.13
The mortality rate is 15% at 3 months. Fewer than 40% of patients survive with minimal or no long-term neurologic sequelae, even with acyclovir treatment.13,88,96 The outcome is more favorable for patients who are younger than 30 years old, have been ill for fewer than 4 days, and have little impairment of consciousness at the start of treatment.
The association of seizures with HSE morbidity and mortality has been studied via animal models. In a study using rabbits, different strains of HSV-1 were injected to induce focal HSE. (Subsequent histopathologic analysis confirmed infection focality.) Virus strains resulting in greater than 70% mortality produced seizures, and all animals that seized became moribund or died. In contrast, a virus strain resulting in 20% mortality produced no seizures. Administration of daily phenobarbital reduced mortality significantly in animals given epileptogenic virus strains. Although only animal studies, these results emphasize the clinical significance, and specifically the negative prognostic potential, of comorbid seizures complicating infection and underscore the importance of seizure control within infectious states.97
Reviewed and revised March 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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