Herpes Simplex Encephalitis: Accurate Early Diagnosis and Effective Treatment
ABSTRACTS & COMMENTARY
Synopsis: Except for immunosuppressed patients, early diagnosis and acyclovir therapy initiated 24 hours after first symptom of Herpes simplex virus encephalitis, determined early by PCR, appears to prevent severe long-term cognitive damage.
Sources: Cinque P, et al. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: A consensus report. J Neurol Neurosurg Psychiatry 1996;61:339-345; Hokkanen L, et al. Amnesia in acute herpetic and nonherpetic encephalitis. Arch Neurol 1996;53:972-978.
The symptom complex of acute viral enceph- alitis is relatively uncommon, even in tertiary medical centers with large numbers of admissions. In the absence of small, viral-specific epidemics, most examples of acute inflammatory encephalopathy-encephalitis are difficult to diagnose specifically by clinical signs alone, although brain imaging, standard CSF analysis, and EEG usually help nonspecifically to categorize the illness. Within this framework, Herpes simplex viruses 1 (90%) and 2 (10%) cause an estimated 100-150 cases per year in the United States. The incidence of acute encephalitis of other causes is harder to come by but probably amounts to about 100 overall. Characteristic findings include acute, out-of-the-blue fever, headache, confusion, convulsions, stupor, coma, or temporary amnesia. The CSF usually contains up to 500 cells, mostly mononuclear. Brain images usually remain normal during early hours, and serum immunologic analyses are not diagnostic for several days or more. Prior to the availability of the antiviral agent acyclovir, mortality in herpes simplex encephalitis (HSE) reached about 70%, with a high incidence of severe neurologic deficits in survivors. A few years ago, a number of centers in the United States and abroad resorted to brain biopsy in an effort to make an early diagnosis in HSE and administer a hopeful treatment. Fortunately, the capacity of acyclovir to halt HSE as well as other viral encephalitides with a minimal adverse drug risk almost entirely eliminated the need for brain biopsy. Nevertheless, accurate, specific diagnosis remained highly desirable since a negative test would promptly stimulate a search for non-viral causes of the severe acute encephalopathy.
Which brings us to the above reports. The first, deriving from the European Concerted Action on Virus Meningitis and Encephalitis, certifies the reliability and swiftness of diagnosing HSE by employing a polymerase chain reaction (PCR) test of CSF in combination with a specific intrathecal antibody response. Controlled studies show that PCR correctly identified HSV 1 or 2 in the CSF in 88 of 93 patients, a sensitivity of 95%. Similar testing in non-HSE produced no positive results, indicating a 100% specificity. Similar results have been previously reported (Lakeman FD, et al. J Infect Dis 1995;171:857-863; reviewed in Infect Dis Alert 1995;14:142). Concurrent identification of a proportional increase in CSF herpes antibody compared to serum antibody during the initial days of illness supports the PCR diagnosis but is nonspecific, since such differential changes can occur in acute zoster illnesses as well as in relapses of multiple sclerosis.
The report goes on from the above to recommend a 10-day course of intravenous acyclovir (ACV) 10 mg/kg every eight hours. Since the above protocol has been followed by occasional relapses of encephalitis, some investigators recommend either giving ACV 15 mg/kg/8 h or employing the new (but incompletely tested) agents, famcyclovir or valacyclovir. Current mortality/morbidity rates are not supplied, but controlled trials from the mid 80s indicate that ACV therapy has brought HSE mortality from 50-55% down to 19% and ultimate cognitive disability from 87% down to about 50%.
The report by Hokkanen et al from Finland provides a broader clinical picture of outcomes from acute herpetic and non-herpetic encephalitis. Between January 1, 1990, and December 31, 1994, 45 patients out of a total population of one million developed acute encephalitis. CSF serum antibody ratios provided diagnostic affirmation during the first three years, and PCR was also applied during 1993-1994. Ultimate diagnoses were HSE, 8; HSV (zoster), 7; 9 miscellaneous but established (see original text), and 21 unknown cause. In addition to disease-specific antibiotics, 43 patients (including all HSE) received ACV. Apparently, none died, and the HSE patients received ACV within 24 hours (5), 48 hours (2), and 96 hours (1) after first symptoms. Of the total patients, 24 had no detectable decline of intelligence on a battery of tests administered as quickly as five days after onset. Of the remaining 21, six of seven patients with HSE and 15 with other than HSE disease showed cognitive deterioration early after illness. At re-evaluation after 4-5 years, three of the original patients still suffered an apparently isolated abnormality of severe global amnesia. One originally had HSE. The manuscript is unclear about the extent of other cognitive impairments among the total patient group but it appears that at least four of the patients with HSE and seven of the non-HSE suffered at least some permanent impairment of memory several years after the original illness.
COMMENT BY FRED PLUM, MD
The above papers describe a modern miracle. Fifteen years ago, about half of all patients with acute, severe encephalitis turned out to have Herpes simplex disease. Diagnosis was impossible except by brain biopsy, and specific therapy was unknown, although early anecdotal reports suggested a value for ACV. Large controlled trials, based on brain biopsy diagnosis, confirmed the value of ACV, which subsequently turned out also to inhibit H. zoster as well as providing minimal activity against Epstein-Barr virus and cytomegalovirus. Except for immunosuppressed patients, early diagnosis and ACV therapy delivered within 24 hours after first symptom appears to prevent severe long-term cognitive damage. Prompt PCR analysis, however, is imperative. (Dr. Plum is Neurologist-in-Chief, New York Hospital-Cornell Medical Center.)