Although both primary herpes simplex virus (HSV) infection and reactivation. Update on Herpes Simplex Encephalitis DIAGNOSIS AND TREATMENT UPDATE

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1 DIAGNOSIS AND TREATMENT UPDATE Update on Herpes Simplex Encephalitis Kenneth L. Tyler, MD Departments of Neurology, Medicine, Microbiology, and Immunology, University of Colorado Health Sciences Center, and the Neurology Service of the Denver Veterans Affairs Medical Center, Denver, CO Herpes simplex encephalitis is the most common identified cause of sporadic viral encephalitis in the United States. Early diagnosis is critical because treatment with the antiviral drug acyclovir dramatically decreases morbidity and mortality. The use of polymerase chain reaction (PCR) techniques to amplify the genome of herpes simplex virus (HSV) from cerebrospinal fluid (CSF) has become the diagnostic procedure of choice. False-positive CSF HSV PCR results are rare when testing is performed in experienced laboratories. Negative CSF HSV PCR results should always be interpreted in the context of the timing of specimen collection and the likelihood of disease. Negative CSF HSV PCR tests can occur within the first 72 hours of illness, with subsequent tests becoming positive. Patients with HSV encephalitis will typically have a negative CSF HSV PCR after 14 days of acyclovir treatment, and a persisting positive PCR should prompt consideration of additional or revised antiviral therapy. Quantitative PCR testing provides information about HSV viral load in CSF, but the potential correlation of viral load with prognosis or other clinical features of disease remains uncertain. Although the neuroimaging abnormalities seen in HSV encephalitis are not unique, more than 90% of patients with proven HSV encephalitis will have magnetic resonance imaging (MRI) abnormalities involving the temporal lobes. Special MRI techniques, including fluid-attenuated inversion recovery and diffusion-weighted imaging, might reveal abnormalities not seen with conventional imaging sequences. Neuroimaging patterns in infants and children differ significantly from those seen in adults and include a higher frequency of extratemporal lesions. [Rev Neurol Dis. 2004;1(4): ] 2004 MedReviews, LLC Key words: Herpes simplex Encephalitis Polymerase chain reaction Cerebrospinal fluid Magnetic resonance imaging Acyclovir Although both primary herpes simplex virus (HSV) infection and reactivation are extremely common and affect millions of individuals in the United States each year, HSV encephalitis remains an extraordinarily rare event. Encephalitis caused by HSV is the most common cause of sporadic (nonepidemic) encephalitis in the United States, with an incidence of approximately 4 cases per million population. In most recent large series, the majority VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES 169

2 Herpes Simplex Encephalitis continued (60%-70%) of cases of suspected viral encephalitis are of unknown etiology. Of those cases in which a specific cause is identified, HSV typically accounts for 35% to 55%. 1,2 HSV isolates are grouped into 2 major serotypes (HSV-1 and HSV-2). Primary exposure to HSV-1 outside the neonatal period usually results in gingivostomatitis, and by adulthood 60% to 80% of individuals are HSV-1 seropositive. Exposure to HSV-2 is typically associated with genital herpes, and acquisition of HSV-2 seropositivity generally parallels onset of sexual activity, with 25% to 35% of individuals becoming seropositive by adulthood. At least 80% of cases of neonatal and infantile herpes encephalitis or neonatal encephalitis associated with disseminated herpes infection are due to HSV-2. 3 Neonatal infection typically results from passage of the infant through an infected birth canal during parturition. Conversely, more than 90% of HSV encephalitis cases in adults are caused by HSV-1 (see below). Approximately one third of all HSV encephalitis cases occur in those younger than 20 years, and the majority of these likely reflect primary infection. By contrast, it is likely that the majority of cases of HSV encephalitis in older individuals results from viral reactivation. HSV infection is an important cause of encephalitis in the elderly, accounting for more than one third of all cases of encephalitis in those older than 60 years. 4 HSV encephalitis occurs at all seasons of the year and in adults affects both sexes equally. HSV encephalitis in infants and children may show a male predominance. 5 The overwhelming majority of patients with HSV encephalitis do not have identifiable risk factors predisposing them to disease. However, isolated cases have occurred after The overwhelming majority of patients with HSV encephalitis do not have identifiable risk factors predisposing them to disease. intracranial surgery. It has also been suggested that the apolipoprotein ε2 allele is over-represented in patients with HSV encephalitis compared with the general population. 6 Pathogenesis The exact pathogenesis of adult HSV encephalitis remains unknown. It has been suggested that invasion of the central nervous system (CNS) Just over half the patients presented initially with headache, fever, and alteration of consciousness. during primary infection might result from viral entry through the nose, with subsequent infection of olfactory bulb neurons and retrograde spread to enterorhinal and parahippocampal and hippocampal cortex. In the case of encephalitis due to reactivation of latent virus, virus reactivating in trigeminal ganglion may spread to the frontal and temporal lobes via tentorial nerves. Several recent postmortem studies have shown that portions of the HSV genome can be detected in brain and brainstem tissues from asymptomatic individuals, although it remains unknown whether this is indicative of the presence of fully reactivationcompetent latent virus in CNS neurons that is capable of reactivation to induce encephalitis. 7 Clinical Features Much of what is currently known about the clinical and laboratory features of HSV encephalitis is the result of multicenter collaborative studies coordinated by the Collaborative Antiviral Study Group (CASG), directed by Richard Whitley, MD, at the University of Alabama (Birmingham, AL). Enrollment in the original CASG clinical trials required patients to undergo brain biopsy to unequivocally establish the diagnosis of HSV encephalitis. Patients with biopsyproven HSV encephalitis 8 typically had a history of alteration of consciousness (97%), fever (90%), and headache (81%). At the time of hospital presentation, fever was present in 92% and focal neurologic findings in 85%. Common neurologic abnormalities at the time of presentation included personality change (85%), aphasia (76%), ataxia (40%), hemiparesis (38%), and cranial nerve deficits (32%). Many patients (38%) had seizures, which could be focal (65%), generalized (23%), or both (12%). Autonomic dysfunction was also particularly common (80%). In a Scandinavian study of 53 cases of HSV encephalitis, 9 of which approximately 40% had diagnosis confirmed by isolation of virus or detection of antigen at biopsy or necropsy, the most common clinical features were fever (100%), altered consciousness (100%), personality change (87%), headache (74%), seizures (62%), hemiparesis (40%), and aphasia (36%). These basic features were also confirmed in a study from Glasgow, 10 in which 87% of patients had the diagnosis established by brain biopsy either by virus isolation or detection of viral antigen by immunofluores- 170 VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES

3 Herpes Simplex Encephalitis cence. In this study just over half the patients presented initially with headache, fever, and alteration of consciousness. Meningismus was present in 65%, and 48% had an influenza-like prodromal illness preceding the development of encephalitis. Approximately half the patients were mute or aphasic, and one third were in deep coma at the time of admission. 10 In recent years, the use of brain biopsy as the definitive diagnostic test for HSV encephalitis has been supplanted, except in rare instances, by the use of polymerase chain reaction (PCR) techniques to amplify specific HSV genome fragments from cerebrospinal fluid (CSF) (reviewed by DeBiasi and colleagues 11 and Kleinschmidt-DeMasters and colleagues 12 ). The clinical features of PCR-defined HSV encephalitis are generally similar to those identified in studies using brain biopsy, although patients tend to be less severely ill at time of diagnosis. Fever, CSF pleocytosis, and some degree of alteration in mental status/level of consciousness occur in more than 90% of cases Other frequent symptoms in PCRproven HSV encephalitis include personality change (40%-60%), seizures (33%-50%), motor deficits (approximately 33%), and aphasia (31%). The severity of mental status changes is considerably less in PCR-based studies than in the earlier biopsy-dependent ones In the biopsy era, only approximately one third of patients had a Glasgow Coma Scale (GCS) score greater than 10, whereas this proportion has increased to approximately 80% in studies using CSF PCR for diagnosis. Data on the clinical presentation of HSV encephalitis in children are more limited than those on adults. Investigators in Israel 16 reviewed the presentation and outcome of 28 children aged 9 months to 16 years in whom the diagnosis of HSV encephalitis was made by a variety of means, including CSF antibody studies and PCR. Symptoms at or before admission included fever above 38 C (79%), altered consciousness (68%), seizures (68%), vomiting (57%), headache (50%), and personality change (43%). The lower incidence of reported headache and personality change might have reflected in part the inclusion of young children (21% in the study were age 1 year or younger), in whom detection of these symptoms might have been more difficult. Cerebrospinal Fluid Almost all patients with suspected HSV encephalitis will have a CSF examination. The basic CSF profile in HSV encephalitis is a lymphocytic pleocytosis, a normal or mildly elevated protein level, and normal glucose levels. In 1 series of 93 patients, 17 the average cell count was 237 ± 477 leukocytes/mm 3 (range, leukocytes/mm 3 ) and the average protein level 83 ± 56 mg/dl (range, mg/dl). In a smaller study, 18 investigators found essentially similar results, with a mean leukocyte count of 202 leukocytes/mm 3 (range, leukocytes/mm 3 ) and protein level of 73 mg/dl (range, mg/dl). Unfortunately, this profile is not specific and occurs in many CNS viral infections, as well as in acute disseminated encephalomyelitis and even in noninfectious conditions. A normal CSF cell count is seen in less than 5% of immunocompetent adults, 17 although this number is likely higher in those immunocompromised by human immunodeficiency virus infection or other causes. In infants and children with HSV encephalitis, approximately 20% of CSF specimens obtained on the first day of hospitalization might contain fewer than 10 cells/mm 3. 5 A lymphocytic pleocytosis is characteristic of HSV encephalitis, and a predominance of polymorphonuclear neutrophils occurs only in approximately 2% of cases. A CSF glucose concentration of less than 50% of the serum glucose is seen in less than 5% of patients. Patients with a normal CSF cell count, a CSF polymorphonuclear pleocytosis, or a depressed CSF glucose level only rarely have HSV encephalitis, and the presence of any of these findings should prompt a careful search for alternative diagnostic possibilities. Unfortunately, the basic CSF profile for HSV encephalitis is not specific and occurs in many CNS viral infections. Cerebrospinal Fluid Polymerase Chain Reaction CSF PCR is the diagnostic procedure of choice in HSV encephalitis, but care needs to be taken in interpreting the results obtained. CSF PCR has been reported to have a sensitivity of approximately 96% to 98% and a specificity of approximately 94% to 99% for diagnosis of adult HSV encephalitis when CSF is obtained in the appropriate clinical setting and testing is performed in an experienced laboratory. 19,20 The sensitivity and specificity of PCR for diagnosis of neonatal and infantile HSV encephalitis have been more variable, with reported sensitivities ranging from 75% to 100% and specificity approaching 100% if positive results in patients with herpetic skin-eyemouth disease are considered to reflect occult CNS disease rather than false-positive studies (see Kimberlin VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES 171

4 Herpes Simplex Encephalitis continued and colleagues 3 ). It is important to recognize that there is no standard protocol for CSF HSV PCR. Different laboratories use different primer sets designed to amplify different HSV genes, different reaction conditions, and different methods for confirming the specificity of amplified products. Gene targets for primers include the viral thymidine kinase and DNA polymerase genes, as well as the genes encoding glycoproteins B, C, D, or G and a DNA binding protein, 21 with the DNA polymerase and glycoprotein D genes being the most common targets. Interpretation of PCR results is critically influenced by both the timing of the test in relation to the onset of clinical illness and the pretest probability that a patient has HSV encephalitis. In 1 study, 3 of 11 patients tested within 72 hours of symptom onset had a negative CSF PCR result that subsequently became positive when they were retested 4 to 7 days later. 22 In a recent retrospective study in children with HSV encephalitis, 5 investigators found that 8 of 33 CSF samples (24%) obtained during the first 3 days of illness were negative. In 5 cases in which a second CSF sample was obtained at 5 to 11 days of illness, 4 were positive. 5 The presence of fewer than 10 leukocytes/mm 3 in CSF was associated with a higher likelihood of a negative CSF HSV PCR result. Similarly, approximately 80% of treated patients will have a negative CSF PCR result at greater than 14 days of illness (no data are available for untreated patients). 19 Thus, negative CSF PCR results obtained either early (< 3 days) or late (> 14 days) in infection should be interpreted with caution. CSF PCR results should also be interpreted according to the likelihood (prior probability) that the patient being tested has the disease being tested for (Bayesian analysis). For example, in a patient with a high (eg, 60%) pretest probability of herpes encephalitis according to clinical and laboratory studies, a negative CSF PCR result dramatically reduces Interpretation of PCR results is critically influenced by both the timing of the test in relation to the onset of clinical illness and the pretest probability that a patient has HSV encephalitis. the likelihood of HSV encephalitis (post-test probability 6%) but does not exclude it entirely. Conversely, in a patient with a low pretest probability of disease (eg, 5%), a negative PCR test result reduces the post-test probability to approximately 0.2%. 20 A clinician would likely choose not to stop therapy in the first instance but might discontinue therapy in the second case. In these 2 scenarios, a positive test would increase the probability of HSV encephalitis to 99% (high pretest probability) and 83.5% (low pretest probability), and in both situations treatment would certainly be continued. False-Negative Results In addition to occurring when CSF specimens are obtained too early or too late after infection (see above), false-negative CSF PCR results can also occur when CSF contains components that interfere with PCR reactions. Fortunately, this situation False-negative CSF PCR results can also occur when CSF contains components that interfere with PCR reactions. seems to be rare for HSV PCR. In a study comparing PCR with brain biopsy, 53 of 54 biopsy-positive specimens were also PCR positive (98%). 19 An additional 164 CSF specimens were tested for inhibitory activity by spiking them with HSV DNA (200 copies) and then testing them by PCR. HSV DNA was successfully amplified from 162 specimens (99%), suggesting that only approximately 1% of CSF specimens might contain nonspecific PCR inhibitory activity. 19 Other investigators 21 have suggested that 1% to 5% of CSF specimens might contain inhibitors that interfere with PCR. High concentration of porphyrin compounds, which can be derived from hemolysis of red cells, can interfere with PCR reactions. These studies suggest that, although false-negative HSV PCR results are rarely due to PCR inhibitory activity in CSF, care should be taken in interpreting negative HSV PCR results obtained on blood-contaminated CSF specimens. The low rate of apparent false-negative CSF HSV PCR results is consistent with a retrospective study of 799 CSF HSV PCR-negative patients with encephalitis, in which it was suggested (using other tests for diagnosis of HSV infection) that 3 patients might have had PCR-negative HSV encephalitis. 23 False-Positive Results False-positive HSV CSF PCR results seem to be rare when tests are performed in experienced laboratories with accepted methods for avoiding inadvertent contamination of samples. In the series by Lakeman and colleagues, 19 in which CSF HSV PCR 172 VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES

5 Herpes Simplex Encephalitis was compared with brain biopsy, 3 of 47 patients (6%) with negative brain biopsy results for HSV had positive CSF HSV PCR results. However, it is likely that some or even all of these cases represent examples in which, owing to sampling error or other technical issues, the brain biopsy was falsely negative rather than the CSF PCR being falsely positive. In another study that included 116 cases of non- HSV viral infections of the CNS and 82 nonviral infections of the CNS, none had a positive CSF HSV PCR. No positive HSV PCR results were found in more than 500 other samples from patients with a variety of noninfectious CNS diseases (eg, stroke) or systemic diseases with CNS symptoms. 23 Confirmation of Results Because HSV PCR testing methodology is not standardized, it is important to understand the criteria being used by a specific reporting laboratory in determining whether an HSV PCR result is considered positive. It is essential that laboratories confirm not only that PCR has amplified a reaction product of the predicted size for the primers being used, but also that methods are used to confirm that this product actually represents amplification of the target gene. This is often done by Southern blotting and DNA probe hybridization, in which the amplification products are transferred to nitrocellulose paper and then hybridized with a labeled probe specific for the target gene. A PCR enzyme-linked immunosorbent assay (ELISA) system has also been developed, in which PCR amplification products are mixed with a labeled DNA probe specific for the target gene of interest and the probe is then captured onto a streptavidin-coated ELISA plate and detected colorimetrically. 21 Nucleotide sequence analysis of the amplification product also confirms its specificity, but this technique is used primarily for research rather than routine clinical applications. Failure to adequately confirm the specificity of amplification products might account for some cases of false-positive CSF PCR results. Finally, it is important to recognize that most studies of the sensitivity and specificity of CSF PCR testing have been done in defined clinical settings (eg, patients with suspected meningitis or encephalitis). Care should always be taken when interpreting a positive test result obtained in an unexpected or unusual setting different from that used to initially validate the test. Care should also be taken when extrapolating sensitivity/specificity values obtained in a particular set of patients to a very different clinical situation (eg, a CSF specimen sent for HSV PCR testing obtained in a patient with no evidence to suggest an acute CNS infection). Viral Load In some CNS viral infections, such as those caused by human immunodeficiency virus, measuring the exact amount of virus present in CSF ( viral load ) by quantitative PCR testing provides valuable prognostic and therapeutic information. There are few studies of the utility of quantitative PCR tests in HSV encephalitis It was suggested in 1 study that patients with higher HSV viral loads (> 100 copies/ml of CSF) have poorer outcomes than those with low copy numbers. 25 However, a study in children found no correlation between viral load and outcome. 24 In the study by Domingues and colleagues, 25 patients with higher copy numbers were symptomatic longer (6.6 ± 3 days vs 3.9 ± 3 days) and were more likely to have reduced consciousness (100% vs 43%) and computed tomography (CT) scan abnormalities (100% vs 14%) than those with low copy numbers. Patients with high copy numbers also had a higher mortality rate (63%) compared with those with low copy numbers (11%). Viral loads do not seem to differ significantly in patients with HSV encephalitis due to primary infection as compared with reactivation. 27 There are few studies of the utility of PCR tests in HSV encephalitits. Real-Time PCR Recently, real-time PCR has been increasingly used to detect HSV genome in CSF. 28 The advantages of this technique include reduced handling and manipulation of specimens with associated reduction in risk of contamination, and enhanced speed and ease of use compared with conventional PCR techniques. Real-time PCR also provides semiquantitative information about the amount of viral genome present in the sample and can be easily configured with use of appropriate primer sets to identify the serotype of virus (HSV-1 or HSV- 2). Sensitivity has been reported to be 2000 to 5000 HSV genome equivalents per milliliter of CSF for HSV-1 and 20,000 to 50,000 HSV genome equivalents per milliliter for HSV-2. These values were approximately 10- fold greater than those obtained by the same laboratory for standard nested PCR. Other laboratories 19,20,22 using conventional PCR techniques generally report detection levels of 10 to 200 HSV-1 genome copies per milliliter, suggesting that real-time PCR might be less sensitive than conventional PCR in detecting HSV genome in CSF. VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES 173

6 Herpes Simplex Encephalitis continued CSF Antibody Studies HSV infections of the CNS are often associated with increased intrathecal synthesis of HSV antibodies. In one study of 53 patients with HSV encephalitis, 9 86% of those who had virus isolated or antigen detected at either biopsy or autopsy also had evidence of intrathecal synthesis of HSV antibody. This percentage dropped to 63% in the subgroup of patients with No EEG pattern is specific for HSV encephalitis. positive immunocytochemistry but no virus isolation. 9 CSF HSV antibody titers generally increase over the first week of illness, peaking 2 or more weeks after onset. 29 For this reason, studies of HSV-specific intrathecal antibody responses are generally insensitive for early diagnosis of HSV encephalitis and are of limited utility and are rarely used in this setting. Both the specificity and sensitivity of intrathecal antibody tests are considerably less than those of CSF PCR, and as a result use of these tests is generally of limited diagnostic value except under special circumstances. In the Scandinavian study cited above, 9 24% of encephalitis patients with negative HSV biopsy results had evidence of intrathecal synthesis of HSV antibody a potential 24% false-positive rate. As discussed earlier, the prevalence of positive HSV CSF PCR tests declines sharply after the first week of illness, and less than 20% of specimens obtained after 2 or more weeks are typically PCR positive. In this setting, when the only CSF specimens available are from late in the course of illness, intrathecal antibody studies might complement PCR testing in establishing a diagnosis. The specificity of intrathecal antibody testing can be enhanced by obtaining paired CSF and serum samples, correcting the CSF/serum HSV antibody ratio with the CSF/serum albumin ratio (a measure of blood brain barrier integrity), and by performing parallel studies measuring antibodies against another virus. The demonstration of an increased CSF/serum HSV antibody ratio suggests that there is intrathecal synthesis of HSV antibody. Under certain circumstances there might be a generalized increase in intrathecal synthesis of antibodies against a variety of viral antigens (eg, in some patients with multiple sclerosis). Showing that increased intrathecal antibody synthesis is limited to HSV-specific antibodies suggests that HSV was the cause of disease. CSF Culture CSF culture is of extremely low sensitivity for diagnosis of HSV encephalitis. Positive cultures have been reported in less than 5% of cases. 30 Electroencephalogram Electroencephalogram (EEG) abnormalities occur in approximately 75% of patients with either biopsy- or PCRproven HSV encephalitis. 31 Common abnormalities include generalized slowing with frontotemporal predominance, focal arrhythmic delta activity, periodic lateralized epileptiform discharges, and temporal sharp or spike activity. No EEG pattern is specific for HSV encephalitis, although the appearance of abnormalities suggestive of focal dysfunction in the temporal and/or inferior frontal lobes in a patient with suspected viral encephalitis should always raise the possibility of HSV infection. Neuroimaging Virtually all patients with suspected encephalitis will have neuroimaging studies done. CT scans are abnormal in more than 60% of either biopsyor PCR-proven cases of HSV encephalitis. 8,13,15,17 However, CT is of limited utility because abnormalities typically develop late and are nonspecific. Common findings include hypodensity in the temporal and orbital frontal areas often associated with mass effect and heterogenous enhancement after contrast administration. Small areas of hemorrhage might appear in affected areas and on rare occasions even frank hematomas. Magnetic resonance imaging (MRI) is more sensitive and specific than CT, and abnormalities appear earlier. MRI is the neuroimaging procedure of choice in patients with suspected HSV encephalitis. More than 90% of PCR-proven HSV encephalitis cases have abnormal MRI findings, with increased T2 and decreased T1 signal in the temporal lobes. 13,15 Associated lesions in the In one report, 2 of 5 patients were found to have chronic progressive MRI changes on studies obtained 6 months after hospital discharge, despite clinical improvement. frontal lobes occur in more than one third of cases. In adults, lesions in parietal or occipital lobes are extremely unusual and occur in less than 10% of cases. 15,17 Extratemporal lesions are more common in infants and children (see below). Enhancement frequently occurs in T1-weighted images after administration of gadolinium. The sensitivity of MR is enhanced by the use of specialized imaging techniques, 174 VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES

7 Herpes Simplex Encephalitis including fluid-attenuated inversion recovery (FLAIR) and diffusionweighted imaging (DWI) (Figures 1 and 2). The heavily T2-weighted FLAIR images with long echo times diminish the intensity of CSF signal, reduce volume averaging between CSF and brain parenchyma, and allow for better visualization of cerebral gray matter DWI reflects molecular motion of water within tissues and might reveal areas of abnormally increased signal reflecting restricted water diffusion in areas of cytotoxic or vasogenic edema and tissue injury that are not seen on other imaging modalities The corresponding apparent diffusion coefficient values are usually decreased in studies obtained in the acute phase of illness, when cytoxic edema predominates. Long-term neuroimaging studies in patients surviving HSV encephalitis are limited. In one report, 2 of 5 patients were found to have chronic progressive MRI changes on studies obtained 6 months after hospital discharge, despite clinical improvement. 40 It is important to recognize that the MR appearance of HSV encephalitis in young children and infants might differ significantly from that seen in adults. 41 Neonates with HSV encephalitis may have prominent abnormalities in periventricular white matter. Both infants and young children may have lesions that resemble infarcts and that can occur outside the frontotemporal area and in the absence of frontotemporal lesions (eg, in parietal or occipital lobes or cerebellum) features that would be almost unheard of in adults. In a recent study, 5 only 60% of infants and children with HSV encephalitis showed characteristic temporal lobe lesions, with the remaining 40% having involvement of extratemporal areas. Treatment, Prognosis, and Sequelae Data from studies performed before the advent of effective antiviral therapy for HSV encephalitis suggest that the mortality in untreated HSV encephalitis was approximately 70%, with less than 3% of untreated individuals returning to normal function. The first drug shown to be effective in treatment was vidarabine, which reduced mortality to Deaths among patients surviving acute infection continue to keep mortality measured at 1-year postinfection at approximately 28%. 44% at 6 months postinfection. Acyclovir was subsequently shown to be even more effective than vidarabine and reduced mortality to 19% at 6 months and 28% at 18 months postinfection. 42 Essentially identical results were obtained in a Scandinavian study. 9 More recent studies, using PCR as the basis for diagnosis, have typically reported mortality rates of 6% to 15% at 6 months postinfection, 13,17,25 although late deaths among patients surviving acute infection continue to keep mortality measured at 1-year postinfection at approximately 28%, 17 nearly equivalent to that reported earlier. 42 Studies in children suggest that mortality rates might be lower than in adults (7%-8%). 43 Moderate or severe sequelae have been reported in 32% to 56% of adult survivors 9,42 and approximately 40% of children surviving HSV encephalitis. 43 Common sequelae include cognitive deficits, aphasia, seizures, and focal weakness. In adults, several Figure 1. Fluid-attenuated inversion recovery coronal MRI image from a 61-year-old man with PCR-proven HSV encephalitis taken on the fourth day after onset of neurologic symptoms. There is increased signal in the right temporal lobe. Note the asymmetry between the abnormal right temporal lobe (left side of figure) and the relatively normal appearing left temporal lobe (right side of figure). MRI, magnetic resonance imaging; PCR, polymerase chain reaction; HSV, herpes simplex virus. prognostic factors have been identified that influence morbidity and mortality associated with HSV encephalitis. In the CASG trial that demonstrated the efficacy of acyclovir, 42 mortality and morbidity were dramatically influenced by both the Figure 2. Diffusion weighted images from a 52-yearold man with PCR-proven HSV encephalitis taken 2 days after hospitalization. Note the abnormal increased signal in the left anterior and medial temporal lobes (A, B, right side of figures). Compare to standard T2- weighted MR images taken at the same time, which show only subtle and ill-defined areas of increased signal in the left medial temporal lobe (C, arrow) and in both insula (D, arrows). PCR, polymerase chain reaction; HSV, herpes simplex virus; MR, magnetic resonance. Reprinted with permission from McCabe K et al. 37 VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES 175

8 Herpes Simplex Encephalitis continued age of the patients and by their level of consciousness (as measured by the GCS) at the time of institution of treatment. No patient less than age 30 with a GCS score greater than 6 died, and approximately 60% recovered with no or only minor sequelae. By contrast, in those with a GCS score of 6 or less, mortality exceeded 30% and approximately 70% of survivors had moderate or severe disability. 42 In children, the GCS score was a predictor of both mortality and morbidity, with patients having a GCS score of less than 6 dying, between 6 and 10 surviving with moderate sequelae, and greater than 10 surviving with no sequelae. 43 Both the Acute Physiology and Chronic Health Evaluation and Simplified Acute Physiology Score results have also been shown to correlate with prognosis. 17 Several studies have suggested that time delay between hospital admission and institution of acyclovir therapy might also influence prognosis. In general, patients treated within 2 days of admission do better than those treated later. 17,44 Cognitive impairment, and particularly memory difficulties, remain major sequelae of HSV encephalitis and have been reported in up to 65% of patients. 45,46 In a study of neuropsychologic outcome in 22 adult patients, 6 (27%) were found to be normal, 13 (59%) had mild impairment, and 3 (14%) had moderate or severe impairment. 47 Findings can include dense amnesia and severe anterograde memory impairment. The severity of amnesia correlates with severity of damage to limbic system structures, particularly the hippocampus, with bilateral injury typically resulting in more severe deficits than unilateral impairment. 45 Older individuals and those with lower level of consciousness at start of treatment tended to have more severe cognitive deficits. 47 Patients with a delay of fewer than 5 days between symptom onset and start of acyclovir therapy did better than those with longer delay. Cognitive Relapse after completion of a minimal 10-day course of acyclovir is unusual in adults. deficits typically improve after hospital discharge, and compared with the level of impairment seen acutely, recovery can be substantial. 46 In initial studies with acyclovir, a dose of 10 mg/kg every 8 hours given for a total of 10 days was used. 9,42 Although there have been no controlled trials in which the efficacy of longer treatment regimens was examined, it is now generally recommended that treatment be maintained for a minimum of 10 to 14 days. It has also been suggested that in immunocompromised patients or patients in whom HSV encephalitis seems to be the result of primary infection rather than reactivation (ie, those who are HSV seronegative at presentation) treatment be continued for 21 days. 48 A consensus report from Europe has suggested that CSF PCR might be useful for guiding duration of therapy. This report suggested that patients whose PCR result is negative after completion of a standard course (10-14 days) of intravenous acyclovir can have treatment stopped. Patients with a persistently positive PCR should have a repeat cycle of treatment and their PCR rechecked. 49 There are currently no data supporting the role of additional oral antiviral therapy after a standard course of intravenous acyclovir, although in an ongoing multicenter, randomized, placebo-controlled, double-blind trial (CASG 204), investigators are studying the efficacy of treating patients for an additional 90 days with oral valacyclovir after completion of standard intravenous acyclovir. Although there has been one case report describing the successful use of oral valacyclovir in the treatment of HSV encephalitis, intravenous acyclovir remains the only treatment of proven efficacy. Recent studies suggest that a new class of antiviral drugs that inhibits the HSV helicase primase might be more effective than currently available nucleoside analogues in inhibiting HSV replication in vitro 50 ; however, these agents have not yet entered clinical trials. Relapse after completion of a minimal 10-day course of acyclovir is unusual in adults. In one series of 53 patients treated for 10 days, there were 2 relapses (4%), which occurred 8 and 14 days after completion of treatment. 9 In the CASG trial of vidarabine versus acyclovir, no relapses were seen in the 28 acyclovirtreated patients who survived acute illness. 42 Relapses might be a more significant problem in pediatric patients, in whom rates as high as 26% have been reported in some series. 51 Relapses might either be the result of postinfectious immune-mediated processes (HSV CSF PCR negative), or true viral recurrences (HSV CSF PCR positive). 52 Fortunately, the majority of cases of true viral relapse respond to a repeat course of acyclovir. 51 In addition to specific antiviral therapy, patients with HSV encephalitis often need treatment for associated problems, including seizures and raised intracranial pressure. In extreme cases, patients with severe increases in intracranial pressure who do not respond to conventional therapy with steroids and hyperosmotic agents might require 176 VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES

9 Herpes Simplex Encephalitis surgical decompression and/or resection of necrotic areas of temporal lobe. 53,54 Although steroids are used by some physicians in routine treatment of HSV encephalitis, there are no controlled trials supporting their efficacy. However, the mortality rates in a Scandinavian study of HSV encephalitis, 9 in which 75% of patients received corticosteroids (dose and duration not specified) in addition to acyclovir, were identical to those in a contemporaneous US study of acyclovir alone, 42 suggesting that the addition of steroids did not have a positive or negative impact on mortality in acyclovirtreated patients. Dr. Tyler is supported by the Reuler-Lewin Family Professorship of Neurology and receives research grants from the Department of Veterans Affairs (MERIT, REAP), NIH, and Department of Defense. References 1. Glaser CA, Gilliam S, Schnurr D, et al. In search of encephalitis etiologies: diagnostic challenges in the California encephalitis project, Clin Infect Dis. 2003;36: Davison KL, Crowcroft NS, Ramsay ME, et al. Viral encephalitis in England, : What did we miss? Emerg Infect Dis. 2003; 9: Kimberlin DW, Lakeman FD, Arvin AM, et al, and the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis. 1996;174: Koskiniemi M, Piiparinen H, Mannonen L, et al. Herpes encephalitis is a disease of middle aged and elderly people: polymerase chain reaction for detection of herpes simplex virus in the CSF of 516 patients with encephalitis. J Neurol Neurosurg Psychiatry. 1996;60: De Tiege X, Heron B, Lebon P, et al. Limits of early diagnosis of herpes simplex encephalitis in children: a retrospective study of 38 cases. Clin Infect Dis. 2003;36: Lin W-R, Wozniak MA, Esiri MM, et al. Herpes simplex encephalitis: involvement of apolipoprotein E genotype. J Neurol Neurosurg Psychiatry. 2001;70: Baringer JR, Pisani P. Herpes simplex virus genomes in human nervous system tissue analyzed by polymerase chain reaction. Ann Neurol. 1994;36: Whitley RJ, Soong S-J, Linneman C, et al. Herpes simplex encephalitis. Clinical assessment. JAMA. 1982;247: Skoldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicenter study in consecutive Swedish patients. Lancet. 1984; 2: Kennedy PG. A retrospective analysis of fortysix cases of herpes simplex encephalitis seen in Glasgow between 1962 and Q J Med. 1988;68: DeBiasi RL, Kleinschmidt-DeMasters BK, Weinberg A, Tyler KL. Use of PCR for the diagnosis of herpesvirus infections of the central nervous system. J Clin Virol. 2002; 25(suppl 1): S5-S Kleinschmidt-DeMasters BK, DeBiasi RL, Tyler KL. Polymerase chain reaction as a diagnostic adjunct in herpesvirus infections of the nervous system. Brain Pathol. 2001;11: Domingues RB, Tsanaclis AM, Pannuti CS, et al. Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis. 1997;25: Domingues RB, Lakeman FD, Pannuti CS, et al. Advantage of polymerase chain reaction in the diagnosis of herpes simplex encephalitis: presentation of five atypical cases. Scand J Infect Dis. 1997;29: Domingues RB, Fink MC, Tsanaclis AMC, et al. Diagnosis of herpes simplex encephalitis by Main Points Encephalitis caused by herpes simplex virus (HSV) is a rare event, with an incidence of approximately 4 cases per million in the United States; HSV encephalitis occurs at all seasons of the year and in adults affects both sexes equally. Patients with HSV encephalitis typically have a history of alteration of consciousness, fever, and headache; common neurologic abnormalities at the time of presentation include personality change, aphasia, ataxia, hemiparesis, and cranial nerve deficits. The basic cerebrospinal fluid (CSF) profile in HSV encephalitis is a lymphocytic pleocytosis, a normal or mildly elevated protein level, and normal glucose levels; patients with a normal CSF cell count, a CSF polymorphonuclear pleocytosis, or a depressed CSF glucose level only rarely have HSV encephalitis. CSF polymerase chain reaction (PCR) is the diagnostic procedure of choice in HSV encephalitis, with high sensitivity and specificity; false-positive results seem to be rare when tests are performed in experienced laboratories with accepted methods for avoiding inadvertent contamination of samples. Tests for HSV-specific intrathecal antibody response are generally insensitive for early diagnosis of HSV encephalitis, and both the specificity and sensitivity of intrathecal antibody tests are considerably less than those of CSF PCR; thus these tests are generally of limited diagnostic value. Magnetic resonance imaging (MRI) is the neuroimaging procedure of choice in patients with suspected HSV encephalitis; more than 90% of PCR-proven HSV encephalitis cases have abnormal MRI findings, with increased T2 and decreased T1 signal in the temporal lobes. Treatment of HSV encephalitis with the antiviral acyclovir has been shown to reduce mortality to 19% at 6 months and 28% at 18 months postinfection; it is now generally recommended that treatment be maintained for a minimum of 10 to 14 days. Moderate or severe sequelae have been reported in 32% to 56% of adult survivors and approximately 40% of children surviving HSV encephalitis; common sequelae include cognitive deficits, aphasia, seizures, and focal weakness. VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES 177

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Application of competitive PCR to cerebrospinal fluid samples from patients with herpes simplex encephalitis. J Clin Microbiol. 1998;36: Wildemann B, Ehrhart K, Storch-Hagenlocher B, et al. Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex encephalitis. Neurology. 1997;48: Revello MG, Baldanti F, Sarasini A, et al. Quantitation of herpes simplex virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis by the polymerase chain reaction. Clin Diagn Virol. 1997;7: Kessler HH, Muhlbauer G, Rinner B, et al. Detection of herpes simplex virus DNA by realtime PCR. J Clin Microbiol. 2000;38: Aurelius E, Johansson B, Skoldenberg B, et al. Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet. 1991;337: Nahmias AJ, Whitley RJ, Visintine AN, et al. Collaborative Antiviral Study Group. 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Rev Neurol Dis ;4: Reviews in Neurological Diseases is a copyrighted publication of MedReviews, LLC. All rights reserved. 178 VOL. 1 NO REVIEWS IN NEUROLOGICAL DISEASES