Epstein-Barr virus infections of the nervous system
Nov. 11, 2023
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Herpes simplex virus infections are common, and the virus is latent in ganglia in a large portion of the population. The virus may spread to the brain along a trigeminal or olfactory pathway and produce an encephalitis with characteristic localization in the temporal and frontal lobes. Early diagnosis and initiation of therapy with intravenous acyclovir are important in reducing the morbidity and mortality of herpes simplex encephalitis, so clinical suspicion must always be high for this disease. In this article, the author reviews the clinical features, pathogenesis, epidemiology, diagnosis, and management of herpes simplex encephalitis.
• Herpes simplex encephalitis is a sporadic encephalitis that often presents with focal neurologic symptoms and signs reflecting frontal and temporal lobe involvement.
• MR brain imaging and CSF studies (if no contraindications), including detection of herpes simplex virus DNA with polymerase chain reaction amplification, are important diagnostic investigations.
• Delays in initiation of intravenous acyclovir are associated with increased morbidity and mortality, with an untreated mortality rate of 70%.
• Intravenous acyclovir should be initiated as soon as possible on the basis of a clinical suspicion of herpes simplex encephalitis and continued for 14 to 21 days for confirmed disease or discontinued as soon as the diagnosis is excluded.
Herpes simplex virus infections were described in ancient Greece. The term "herpes," which means to creep or crawl, was used to describe the spreading cutaneous lesions in the infections (22). The Romans associated mouth and lip lesions with fever and used the term “herpes febrilis.” The ability of herpes simplex virus to travel from a peripheral site of inoculation to sensory ganglion cells and centrally into the CNS has been recognized since the early work of Goodpasture and Teague (39). Herpes simplex encephalitis was first reported in a 4-week-old infant in 1941 (103) and, shortly afterward, in an adult patient (128); intranuclear inclusions were demonstrated in brain tissue, and herpes simplex virus was isolated. Nahmias and Dowdle identified the two antigenic subtypes of herpes simplex virus (79), which led to observations that herpes simplex virus-1 was primarily responsible for infections "above the belt,” whereas herpes simplex virus-2 was responsible for infections "below the belt." Over the past 30 years, there have been many advances in our understanding of herpes simplex virus and herpes simplex encephalitis. Herpes simplex encephalitis is a viral disease in which antiviral therapy has been demonstrated to have a dramatic beneficial effect on outcome.
The clinical features of herpes simplex encephalitis have largely been defined on the basis of autopsy-confirmed fatal cases and from clinical trials performed by the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group; these findings were based on diagnostic brain biopsy proven cases of focal encephalitis. Hence, the clinical features in these patients may reflect severe disease and perhaps not the entire spectrum of disease. The disease is of acute onset, usually less than a week. The main features include headache, fever, and alteration of consciousness, which may develop over a period of hours or more slowly over days. Headache is a prominent early symptom and is present in about 90% of cases. Fever is almost always present, and its absence should normally cast doubt on the diagnosis. Focal neurologic features may be present, including aphasia, hemiparesis, and visual field defects (superior quadrant). Focal or generalized seizures are very common (98), and olfactory or gustatory hallucinations may occur as well. Behavioral disturbances (sometimes bizarre), personality changes, or psychotic features may occur and be prominent, and psychiatric disease is sometimes suspected. Signs of autonomic dysfunction are also often present. Focal piloerection has been described (16). Papilledema is present in a minority of patients. Mild or atypical forms of herpes simplex encephalitis have been recognized without focal features; they are associated with herpes simplex virus-1 and virus-2 infections, immunosuppression with corticosteroids or coexisting HIV infection, or disease predominantly involving the nondominant temporal lobe (28; 34; 106). Herpes simplex encephalitis has been recognized during treatment with monoclonal antibody tumor necrosis factor-alpha inhibitors for rheumatological disorders (15) and with therapy of multiple sclerosis with fingolimod (83). Unusual clinical presentations, including the opercular syndrome (facio-pharyngo-glosso-masticatory diplegia) (02), may be difficult to recognize as herpes simplex encephalitis. A history of cold sores is no more common in patients with herpes simplex encephalitis than in patients with nonherpes simplex encephalitis (125). Herpes simplex virus-2 encephalitis occurs in elderly immunosuppressed patients, may be indistinguishable from that caused by herpes simplex virus-1, and the prognosis may be unfavorable even when antiviral therapy is given (73). Herpes simplex encephalitis may develop in hospitalized patients, particularly in critical care units (50).
Early clinical recognition of the disease and prompt initiation of antiviral therapy clearly lead to a more favorable outcome. Herpes simplex encephalitis is a severe brain infection; in the absence of effective antiviral therapy, mortality is in excess of 70%, and only about 2.5% of patients overall regained normal neurologic function (65). Postencephalitic epilepsy is common after herpes simplex encephalitis (98). The prognosis is better when antiviral therapy is initiated relatively early in the course of disease; a French study showed a favorable outcome in 65% of patients (55 of 85) and complete recovery in 14% (12 of 85) (88). A study by Schloss and colleagues showed that quantitation of herpes simplex virus genomes in CSF is not a useful prognostic marker of herpes simplex encephalitis (96). Severe underlying disease, chronic alcohol abuse, and atypical CSF findings are all independent risk factors for late initiation of acyclovir in hospitalized patients (85). Young patients (less than 30 years old) also have a more favorable outcome than older patients. Treatment initiated after consciousness is severely impaired is unlikely to result in a good clinical outcome (124). Even with appropriate acyclovir therapy, only 38% of patients had mild or no neurologic impairment (118). Persistent cognitive and memory impairment, aphasia, and motor deficits are common after herpes simplex encephalitis. Chronic seizure disorders may also occur. Recurrent or relapse of herpes simplex encephalitis occurs rarely, and 15 late relapse cases (over 3 months after the first episode) have been reported (90). This condition occurs by poorly defined mechanisms, but herpes simplex virus reactivation or immune-mediated mechanisms (90) may play a role. The CSF may be negative for herpes simplex virus DNA by polymerase chain reaction in this condition. It is likely that a longer course of therapy with intravenous acyclovir (14 to 21 days) has reduced the incidence of this complication. Of eight patients with relapse, Armangue and colleagues found that five (63%) had CSF antibodies against the N-methyl-D-aspartate (NMDA) receptor and immunotherapy showed efficacy (05). Although anti-NMDA receptor autoimmune encephalitis usually occurs less than 90 days (mean 48 days) after herpes simplex encephalitis (94), cases have been reported 7 and 12 months afterwards (29). In 48 patients with herpes simplex encephalitis, 27 (56%) were anti-NMDA receptor positive with IgG (12/48, 25%), IgM (14/48, 29%), or IgA (13/48, 27%) antibodies in serum or CSF; only IgG anti-NMDA receptor serostatus correlated with impaired recovery of cognitive performance (115). Autoimmune encephalitis after herpes simplex encephalitis is more common in younger children, with relapses occurring in 14% to 27% of children and in 7% to 13% of adults (32).
Cerebrovascular complications of herpes simplex encephalitis occur in about 17% of cases, and some have evidence of vasculitis (33). Delayed acute intracerebral hemorrhage involving the initial encephalitic region in medial temporal lobe structures has been reported as a rare complication of herpes simplex encephalitis (99). Acute retinal necrosis may occur after herpes simplex encephalitis; there was a mean latency of 21 months (14 days to 5 years) in seven patients (112). There is evidence that the cumulative effects of repeated mild herpes simplex virus brain infections may result in neuronal damage similar to that found in neurodegenerative disorders such as Alzheimer disease (71).
A 20-year-old female university student presented with a history of a few days of headache. She then experienced increased headache, nausea and vomiting, and visual hallucinations. On the next day, she developed a low-grade fever and confusion. On admission to the hospital, her temperature was 38.2°C. She demonstrated word-finding difficulty and made paraphasic errors. Motor examination was normal, with symmetrical reflexes and downgoing toes. An MRI scan of her head showed expansion of the medial left temporal lobe. Hyperintense signal was observed in the medial left temporal lobe and left insular cortex on T2-weighted images and fluid-attenuated inversion recovery sequences.
No gadolinium enhancement was observed. An EEG showed high-voltage slow waves over the left frontotemporal region without epileptiform activity. CSF showed 185 mononuclear cells, five polymorphonuclear leukocytes, and three erythrocytes per µL. CSF protein was mildly elevated, and CSF glucose was normal. Herpes simplex virus DNA was detected in CSF using polymerase chain reaction amplification. The patient was treated with 10 mg/kg of intravenous acyclovir every 8 hours for 21 days. She had persistent impaired recent verbal memory and mild word-finding difficulty, and she made paraphasic errors. She was not able to return to the university.
Herpes simplex virus is a member of a family of viruses that consists of a single large double-stranded DNA molecule and encodes at least 84 different polypeptides and viral surface glycoproteins, which mediate attachment and penetration of the virus into cells and provoke host immune responses (123). Herpes simplex virus-1 is usually associated with orofacial infections and encephalitis; herpes simplex virus-2 usually causes genital infections. However, there is overlap in the epidemiology and clinical manifestations of infections caused by these viruses. A Korean study showed that a similar proportion (approximately 50%) of patients had herpes simplex encephalitis due to herpes simplex-1 and herpes simplex virus-2, but neurologic sequelae were more frequent in cases due to herpes simplex virus-1 (77). Brain tissue obtained from diagnostic brain biopsy or autopsy in herpes simplex encephalitis may demonstrate typical histopathologic changes, including hemorrhagic necrosis with characteristic intranuclear inclusions. Herpes simplex virus can be demonstrated in infected brain by using electron microscopy, antigen-detection techniques, and viral culture.
Primary infection with herpes simplex virus in susceptible (seronegative) individuals occurs after exposure of the virus to a mucosal surface or abraded skin. The virus is subsequently transported along axons via retrograde transport to nuclei of neurons in local peripheral sensory (trigeminal or dorsal root) ganglia. The viral genome remains in a latent state in peripheral sensory ganglia for the life of the host. A variety of stimuli, including physical or emotional stress, fever, menstruation, or ultraviolet light, cause reactivation of the virus with viral gene expression and the development of recurrent infections, most commonly skin lesions (eg, cold sores). The majority of the population becomes infected with herpes simplex virus-1 by 40 years of age. Most herpes simplex virus-2 infections are sexually transmitted; women and African Americans have higher infection rates than men and Caucasians, respectively.
The localization of herpes simplex encephalitis in temporal lobes and orbitofrontal cortex may, in part, reflect the route of entry of the virus into the host. In primary infection, the virus may enter by an olfactory route and spread along olfactory fibers through the cribriform plate into the olfactory bulbs. Subsequently, viral spread could occur along the base of the brain. At least half of cases of herpes simplex encephalitis are caused by a different viral strain than the one responsible for cold sores (121). In reactivation of herpes simplex virus infection, it has been hypothesized that the virus may spread from the trigeminal ganglion along branches of the trigeminal nerve in tentorial nerves that innervate the meninges of the anterior and middle cranial fossae (23). In situ reactivation of latent virus from brain tissue, where it sometimes can be detected, remains another possibility (11). Rarely, neurosurgery may be a triggering factor for reactivation with the development of herpes simplex encephalitis (61). There is evidence of novel mutations in the Toll-like receptor (TLR) 3 signaling pathway and also involving other innate signaling molecules, suggesting that there is impaired innate immunity to herpes simplex virus in herpes simplex encephalitis (78). Five patients (two adults and three children) with herpes simplex encephalitis were found to have variants of SNORA31 (snoRNA31 is thought to be a guide RNA directing the chemical modification of target uridine residues into pseudouridine in rRNA and small nuclear RNA), which renders increased susceptibility of cortical neurons to herpes simplex virus 1 infection (64). Deficiency of mannan-binding lectin serine proteinase 2 (MASP-2) due to substitution in a gene encoding a key protease in the lectin pathway of the complement system, results in reduced in vivo antiviral activity, was recognized in two adult patients with herpes simplex encephalitis (13).
Pathologically, herpes simplex encephalitis is characterized by a necrotizing meningoencephalitis associated with edema, hemorrhage, and encephalomalacia. Apoptotic cell death of neurons and glia has been observed in areas of productive viral infection, and this may be an important contributing factor to the brain injury in herpes simplex encephalitis (24; 07). Interestingly, about 30% of patients with herpes simplex encephalitis develop NMDA receptor antibodies (86). It has been recognized that herpes simplex encephalitis can trigger the development of anti-NMDA receptor encephalitis (67; 05).
Herpes simplex virus is worldwide in distribution and infects only humans under natural conditions (123). There is no gender preference and no seasonal variation in the incidence of infection. Herpes simplex encephalitis is the most common identified cause of severe sporadic encephalitis in the Western world and has an incidence of about 6.4 cases per million adults per year in the United States (76). Herpes simplex virus causes only about 5% to 10% of cases of acute viral encephalitis in the United States (18), and a study in hospitals in England showed that 19% of cases of encephalitis were due to herpes simplex virus (41). The projected costs (direct and indirect) for all cases of presumed herpes simplex encephalitis in the United States are estimated at about U.S. $500 million per year (65). About 90% of herpes simplex encephalitis is due to herpes simplex virus-1; 10% is due to herpes simplex virus-2 (08). In encephalitis due to herpes simplex virus-1, about two thirds of cases result from reactivation of latent infection (121). Herpes simplex encephalitis is not more frequent in immunodeficient patients, but when it does occur, the presentation may be atypical with a subacute and progressively deteriorating course (117). Patients who have received immune checkpoint inhibitors may also have atypical clinical features (66). Typical herpes simplex encephalitis may follow recent SARS-CoV-2 infection, particularly if treated with injectable corticosteroids (44). Familial herpes simplex encephalitis has been reported infrequently (56). The apolipoprotein E2 allele has been reported to be a risk factor for herpes simplex encephalitis (68), whereas the apolipoprotein E4 allele is a risk factor for recurrent herpes labialis (cold sores) (55). A 19-year-old French patient was reported who had herpes simplex encephalitis at the age of 8 and was found to have two compound heterozygous mutations in his TLR 3 gene, resulting in complete TLR 3 deficiency (43).
There are no useful measures for the prevention of herpes simplex encephalitis; herpes simplex virus infections are common, and the virus is latent in ganglia in a large portion of the population. A high index of clinical suspicion, appropriate investigations, and early treatment with intravenous acyclovir are all important in obtaining the best possible clinical outcome.
Other causes of viral encephalitis are in the differential diagnosis of herpes simplex encephalitis. Herpes simplex encephalitis should be strongly suspected when there are focal features with localization in the temporal lobe or orbitofrontal cortex. Cases with bilateral temporal lobe lesions and lesions outside of the temporal lobe and limbic region have a reduced probability of being due to herpes simplex encephalitis (20). Other viruses occasionally cause encephalitis with marked focal features, including arboviruses (03; 84; 104) and Epstein-Barr virus. MRI of Japanese encephalitis may show temporal lobe lesions, typically involving the hippocampus with sparing of other temporal lobe structure, and with associated involvement of the thalamus, substantia nigra, and, less frequently, the basal ganglia (46). Human herpesvirus-6 has been associated with meningitis and encephalitis, and it can produce focal encephalitis that mimics herpes simplex encephalitis in immunocompromised patients with exclusive involvement of the medial temporal lobes on MR imaging (81). Nonviral infections, including infections caused by bacteria (cerebritis or brain abscesses), rickettsia, fungi, and parasites, as well as other conditions such as postinfectious encephalitis, CNS lymphoma, vascular disease, and mitochondrial disease may also have a similar clinical presentation (10). In particular, neurosyphilis can have similar clinical and MR imaging findings (105). A nonherpetic acute limbic encephalitis has been described (69).
Early diagnosis of herpes simplex encephalitis is important for initiation of antiviral therapy at the earliest possible time, and therapy should be initiated even before the diagnostic investigations are completed. Basaran and colleagues reported hyponatremia (< 135 mEq/L) in 56% of patients with herpes simplex encephalitis due to herpes simplex virus-1 versus 20% of patients with nonherpes simplex virus-1 viral encephalitis (12). Focal electroencephalographic abnormalities are present in about 80% of cases (125). Sharp and slow wave activity is usually localized to the temporal region, and periodic complexes may be present (111; 54; 102; 19). Brain imaging studies, particularly MRI, usually show abnormalities in involved areas including the temporal lobes, although rare patients with normal MRI studies have been reported (27; 52; 48). Technetium brain scans and CT head scans have much lower sensitivity than MRI. CT shows hypodense lesions in the temporal lobe and orbitofrontal region, which may demonstrate mass effect, regions of hemorrhage, and irregular contrast enhancement. A CT perfusion study reported a focal increase in blood flow (70). On MRI, hyperintense signal intensities are typically seen on T2-weighted images in typical sites, including one or both inferomedial temporal lobes, insular cortex, inferior frontal lobes, cingulate gyrus, and thalamus, with foci of hemorrhage due to the presence of degradation products of hemoglobin (25). T1-weighted images show hypointense signal in the same areas, and meningeal enhancement may be demonstrated following administration of gadolinium (25), but one study found that pre- and postcontrast T1-weighted images were the least informative sequences compared with others (49). FLAIR sequences demonstrate superior definition of temporal lobe abnormalities compared with standard T1- and T2-weighted images (34). It is not yet clear how MRI abnormalities evolve over a period of months after herpes simplex encephalitis associated with clinical improvement (36). Diffusion MRI studies may also be useful for early detection of lesions with diffusion-weighted imaging changes preceding FLAIR changes (74; 89). Resolution of the restricted diffusion abnormalities may correlate with clinical improvement (30). Diffusion tensor imaging in the earliest phase may show slight reduction of mean diffusivity, but in later stages it is increased in keeping with inflammatory vasogenic edema (51). Rarely, patients may have lesions in atypical locations in the brain (82; 113; 14), especially immunocompromised patients (106; 45). The early localization of lesions can be predominantly or exclusively in the frontal lobes (107). MRI lesions are more heterogeneous in herpes simplex encephalitis caused by herpes simplex virus type 2 (100). A study using diffusion-tensor imaging has shown reduced integrity of normal-appearing white matter tracts contralateral to unilateral lesions in herpes simplex encephalitis patients, which likely contribute to memory impairment (42). Rarely, herpes simplex encephalitis may present with intracerebral hemorrhage involving a temporal lobe, and disease progression occurs with ongoing hemorrhagic necrosis and hematoma expansion (62).
Serological diagnosis of herpes simplex virus infection is not useful clinically. A lumbar puncture may show an elevated opening pressure. CSF examination usually shows a mononuclear cell pleocytosis with a mildly elevated protein and a normal glucose. A CSF pleocytosis is present in about 97% of cases (125) but may be absent in either immunocompetent or immunosuppressed patients (95; 57; 106; 92). Cell counts are often around 100 white cells/µL, and counts above 500 white cells/µL are found in less than 10% of patients. The presence of erythrocytes in the CSF in a nontraumatic lumbar puncture is encountered with similar frequency in patients with encephalitis of other causes (125). Herpes simplex virus can be cultured only from CSF in about 4% of cases (80; 101). Intrathecal synthesis of herpes simplex virus-specific antibodies occurs in 94% to 97% of cases, but not usually until 3 to 10 days or more after the onset of symptoms (80; 58). An intrathecal immune response may be absent when antiviral therapy is started early (93).
A number of reports have demonstrated high sensitivity and specificity of polymerase chain reaction amplification assays for the detection of herpes simplex virus DNA in the CSF of patients with suspected herpes simplex encephalitis. Because polymerase chain reaction assays can be performed within a few hours, the results can be helpful in making decisions about antiviral therapy. However, it is important that the polymerase chain reaction assay is performed by a reliable laboratory because PCR assays developed in-house are known to have variable sensitivity and specificity (38). Primers from a herpes simplex virus sequence that is common to both herpes simplex viruses-1 and -2 (either the glycoprotein or herpes simplex virus DNA polymerase) identify herpes simplex virus DNA in the CSF (120). CSF specimens from patients with brain biopsy-proven herpes simplex encephalitis, and those with other proven diseases, indicate a diagnostic sensitivity of 98% at the time of clinical presentation as well as a specificity that approaches 100% (65). False-negative results may occur when there is contamination of CSF by medical or laboratory staff or by the presence of inhibitors. Inhibitory activity for the Taq polymerase used in polymerase chain reaction amplification can be assessed by assays after "spiking" CSF specimens with multiple copies of herpes simplex virus DNA (65). Inhibitory activity may be due to porphyrin compounds from degradation of hemoglobin, or it may be present without any evidence of hemolysis of erythrocytes in the CSF (09; 26). The specificity of positive polymerase chain reaction assays can be confirmed with restriction enzyme analysis, hybridization, and sequencing; false positive results may be a problem in some laboratories (110). False positive results are rare and are most likely due to laboratory cross-contamination (38). A negative polymerase chain reaction assay for herpes simplex virus DNA on the first or second day of illness should, if clinical suspicion is high, be repeated after 48 to 72 hours because initial negative results may become positive on testing of a subsequent CSF specimen (114). Although PCR is the gold standard for the diagnosis of herpes simplex encephalitis, there is significant variability in test performance between diagnostic laboratories (119). Clinicians should be very cautious about discontinuing acyclovir therapy after receiving a negative result for PCR herpes simplex virus DNA in the CSF, particularly if the clinical features are typical (91). Repeat PCR testing should be done on CSF 3 to 7 days after an initial negative result if there is a high clinical suspicion of herpes simplex encephalitis (109). Also, there is always the possibility of a false negative result due to laboratory error. A report indicated that the CSF remains positive for herpes simplex virus DNA by polymerase chain reaction in more than 80% of patients at the end of 1 week of antiviral therapy (65). A retrospective study showed that about half of cases become negative for herpes simplex virus DNA a median of 7 days later (17). Quantitative assays on CSF herpes simplex virus DNA showed that the viral burden in the CSF did not correlate with the severity of clinical signs, imaging findings, or outcome, suggesting the importance of indirect mechanisms of brain injury in the infection (126). Patients treated with tumor necrosis factor-alpha inhibitors may initially have normal MRI brain scans and negative results of CSF herpes simplex virus DNA PCR results, so there should be a higher threshold for discontinuing acyclovir therapy in these patients (15). Patients with cancer, particularly patients who have received cranial radiotherapy, may have an increased risk of developing herpes simplex encephalitis and may have misleading CSF results (lack of pleocytosis or negative PCR results) (40).
Prior to the development of polymerase chain reaction technology and widespread use of MRI, brain biopsy was an important diagnostic test for herpes simplex encephalitis. The utility of diagnostic brain biopsy for the management of encephalitis is presently controversial, especially in light of empirical antiviral drugs and the rivaling sensitivity and specificity of polymerase chain reaction-based assays. At the present time, diagnostic brain biopsy is normally reserved for only a minority of cases of undiagnosed encephalitis that fails to respond to initial therapy.
Antiviral therapy with intravenous acyclovir is standard therapy for herpes simplex encephalitis. Acyclovir is a synthetic nucleoside analogue with low toxicity. Nephrotoxicity with precipitation of the drug in the renal tubules can be reduced by slow infusion and by ensuring adequate hydration. Also, the dosing interval should be increased in patients with impaired creatinine clearance. Acyclovir inhibits DNA synthesis by competing with deoxyguanosine triphosphate as a substrate for DNA polymerase, and DNA chain termination results because acyclovir lacks a 3'-hydroxyl group (65). Acyclovir is converted to its monophosphate derivative by the herpes simplex virus thymidine kinase, and subsequent phosphorylation takes place by cellular enzymes. Hence, the drug is concentrated in infected cells. With acyclovir therapy (10 mg/kg every 8 hours) in the study by the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group, the mortality of herpes simplex encephalitis was reduced from 70% to 28% (124; 118). Therapy with acyclovir was continued for 10 days in this study. However, because of subsequent recognition of recurrent (or relapse) herpes simplex encephalitis, there has been a trend to extend therapy for a total of 14 to 21 days. The acyclovir dosage should be adjusted with renal impairment. A clinical trial showed no benefit of valacyclovir therapy for 90 days after a standard course of acyclovir therapy (37). Immunocompetent (97) and immunodeficient (60) patients with herpes simplex encephalitis have been reported with resistance to acyclovir due to mutations in the thymidine kinase gene and with improvement after foscarnet therapy. Delays in initiation of intravenous acyclovir therapy in herpes simplex encephalitis are common (53). Therapy with intravenous acyclovir should be initiated based on the clinical picture as soon as a diagnosis of herpes simplex encephalitis is seriously considered; delays in initiation of therapy while waiting for the results of investigations should be avoided. Antiepileptic medications should be used to control seizures, and usually seizures are not difficult to control in this setting.
Corticosteroids probably have a role in the treatment of vasogenic edema from the inflammatory process, particularly when there is mass effect with risk of brain herniation. There is support for a beneficial effect of corticosteroids from studies in a mouse model (75). Apart from the management of mass effect, it is unknown whether corticosteroids have a beneficial effect on the disease when combined with acyclovir. A small, nonrandomized study suggested the possibility of improved outcome with corticosteroid administration (59), but this needs confirmation. A randomized controlled clinical trial by German, Austrian, and Dutch investigators comparing acyclovir plus adjuvant dexamethasone with acyclovir plus placebo in adult patients with herpes simplex encephalitis was discontinued because of poor recruitment (72). At the present time it is unknown if there is a benefit from adjunctive therapy with corticosteroids in herpes simplex encephalitis (87) and there are no solid data supporting this therapy. A randomized, open-label, observer-blind multicenter trial is now in progress in the United Kingdom to determine whether dexamethasone in addition to standard antiviral therapy improves clinical outcomes versus antiviral therapy alone (116).
Intracranial pressure monitoring and other measures for the management of increased intracranial pressure may also be useful in these patients, and surgical decompression is occasionally necessary (127; 01). Therapeutic hypothermia has been reported for management of increased intracranial pressure in herpes simplex encephalitis (63).
About 25% of patients with herpes simplex encephalitis develop autoimmune encephalitis, predominantly anti-NMDA receptor encephalitis, within 3 months of the acute illness (06). Aggressive immunotherapy is needed for autoimmune encephalitis after herpes simplex encephalitis.
The morbidity and mortality of herpes simplex encephalitis remain high. The 30-day mortality of herpes simplex encephalitis is as low as 5% to 10% but increases to about 20% by day 180; 20% of survivors have severe neurologic sequelae, 20% have moderate neurologic sequelae, and 40% have minimal impairment (119). Severe impairment of memory and naming are particularly prominent in herpes simplex encephalitis (47). There are important social consequences for survivors and, for many cases, a lack of adequate support systems (21). Neurologic improvement may be delayed over many months. Patients are at risk of developing acute retinal necrosis after herpes simplex encephalitis, particularly within a period of 2 years (108).
More than 20 cases of herpes simplex encephalitis in pregnancy have been reported (31). Because of the natural history of untreated disease, there is no alternative but to treat with intravenous acyclovir as in patients who are not pregnant. Acyclovir crosses the placenta and is excreted by the fetal kidney and concentrated in the amniotic fluid, but there is no accumulation of the drug in the fetus (35). The Acyclovir in Pregnancy Registry has prospectively gathered data on prenatal exposure to acyclovir; no increase in the number of birth defects and no consistent pattern of abnormalities have been noted (04).
No anesthetic agents are contraindicated in patients with herpes simplex encephalitis. Acyclovir therapy should be continued without adjustment of the dosage throughout a perioperative period.
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