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Herpes simplex virus type 1 encephalitis

Herpes simplex virus type 1 encephalitis
Robyn S Klein, MD, PhD
Section Editor:
Martin S Hirsch, MD
Deputy Editor:
Jennifer Mitty, MD, MPH
Literature review current through: Dec 2022. | This topic last updated: Aug 05, 2022.

INTRODUCTION — Herpes simplex virus type 1 (HSV-1) encephalitis is the most common cause of sporadic fatal encephalitis worldwide. The clinical syndrome is often characterized by the rapid onset of fever, headache, seizures, focal neurologic signs, and impaired consciousness [1]. HSV-1 encephalitis is a devastating disease with significant morbidity and mortality, despite available antiviral therapy.

The pathogenesis, clinical manifestations, diagnosis, and treatment of HSV-1 encephalitis will be reviewed here. Neonatal encephalitis and other manifestations of HSV-1 infection are discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection".)

EPIDEMIOLOGY — HSV-1 encephalitis is the most common cause of fatal sporadic encephalitis in the United States, accounting for approximately 10 to 20 percent of the 20,000 annual viral encephalitis cases [2,3]. The infection arises in all age groups, with one-third of all cases occurring in children and adolescents [4]. HSV-1 is also the most commonly identified pathogen among hospitalized patients diagnosed with encephalitis in Australia [5]. In a nationwide retrospective study of the incidence of HSV-1 encephalitis in Sweden over a 12-year period (1990 to 2001), the incidence of confirmed cases was 2.2 per million population per year [6], which is similar to what was reported in the United States between 2000 and 2010 [7]. In the United States, the incidence of HSV-1 encephalitis has been reported to be 1 in 100,000 to 150,000 individuals [8,9].

PATHOGEN — In nearly all cases of herpes encephalitis beyond the neonatal period, the etiologic agent is herpes simplex virus type 1 (HSV-1), with less than 10 percent of cases attributable to HSV-2 [10]. In neonates, herpes encephalitis may be caused by either HSV-1 or HSV-2.

In up to 50 percent of HSV-1 encephalitis cases, the strains detected in the central nervous system and the skin differ in the same patients [11]. Thus, in patients with a prior history of herpes labialis, primary infection with a different strain may cause HSV-1 encephalitis.


Routes of infection — HSV infection of the central nervous system (CNS) appears to arise via one of three routes, each accounting for approximately one-third of infections [2]:

Immediate CNS invasion via the trigeminal nerve or olfactory tract following an episode of primary HSV-1 of the oropharynx; most patients with primary infection are younger than 18 years of age.

CNS invasion as a result of viral reactivation in patients with history of recurrent infection; this rarely occurs in conjunction with oral lesions.

CNS infection without primary or recurrent HSV-1 infection, which is felt to represent reactivation of latent HSV in situ within the CNS; in rare cases, this may be triggered by recent manipulation of brain parenchyma at a site of prior infection [12].

Virus gains access to the brain along axons from the face to the trigeminal ganglia [13]. In most cases, necrosis occurs in the temporal lobe with clinical deficits consistent with the areas damaged.

Various animal models have been developed that attempt to mimic these possible routes of infection. One murine model demonstrated that installation of HSV-1 into the nares of certain strains of mice produces focal lesions localized to the temporal lobe, similar to those observed in human cases of HSV-1 encephalitis [14]. Another murine model has shown that inoculation of HSV into the murine tooth pulp leads to an encephalitis primarily affecting the temporal cortex and limbic system [15]. This manner of inoculation selectively infects the mandibular division of the trigeminal nerve, which is both the most commonly infected division of the trigeminal nerve and the most common site of viral latency in humans with HSV-1 infections. Animal studies also indicate that HSV-1 can spread to contralateral sites via the anterior commissure [16].

Another possible mechanism of nervous system invasion is viremia. HSV has been identified by culture in the blood of neonates and immunocompromised patients and, by polymerase chain reaction, in the blood of immunocompetent adults with gingivostomatitis [17,18].

Latent infections with neurovirulent strains of HSV-1 can be reactivated in trigeminal ganglia and central nervous system olfactory centers of rabbits by the administration of cyclophosphamide and dexamethasone in another model system [19]. Although this model mimics human disease with focal brain necrosis restricted to the temporal lobes, it requires immunosuppressive drugs to initiate infection [19]. However, in humans HSV-1 encephalitis is not more common in immunosuppressed than immunocompetent hosts [2].

Host susceptibility — There are several factors that contribute to host susceptibility. These include:

Toll-like receptors (TLRs) are important in the innate immune response. TLR3 is expressed in the CNS, where it may prevent spread of HSV from the epithelium to the brain via cranial nerves through the generation of interferons. Defects in various signaling molecules in the TLR3 pathway can predispose children to HSV encephalitis. (See "Toll-like receptors: Roles in disease and therapy", section on 'TLR signaling defects in primary immunodeficiency' and "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

Studies of regulators of host innate and adaptive immunity indicate that the risk of symptomatic HSV-1 infection is modified by major histocompatibility complex (MHC) class I allotypes (B*18, C*15, and the group of alleles encoding A19), the high-affinity receptor/ligand pair KIR2DL2/HLA-C1, and the CD16A-158V/F dimorphism [20]. (See "Major histocompatibility complex (MHC) structure and function".)

Patients receiving certain immunomodulatory therapies may be at increased risk for HSV encephalitis [21-25]. As an example, in a series of 20 patients receiving natalizumab (a recombinant humanized monoclonal antibody used to treat multiple sclerosis and Crohn disease), 5 cases of HSV-1 encephalitis were reported as well as 3 cases of HSV encephalitis that were nontyped [21]. The patients with HSV encephalitis usually presented with seizures, altered mental status, and fever.

HSV-1 encephalitis has also been reported in patients taking tumor necrosis factor-alpha (TNF-alpha) inhibitors [22,26]. Although the use of TNF-alpha inhibitors has been associated with tuberculosis and other infections, the relationship of HSV-1 infection to these medications is unclear. (See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

Tissue injury — Much of the brain damage from CNS HSV-1 infection may be immune mediated [14], which may explain the observation that HSV-1 encephalitis is not more common among the immunosuppressed despite the frequency and extension of mucocutaneous HSV-1 infections and dissemination to visceral organs in these hosts [27]. Indeed, HSV encephalitis in immunocompromised patients sometimes follows a different clinical course characterized by a slow evolution with only mild histopathologic changes observed on biopsy specimens [28]. However, immunocompromised patients with HSV-1 encephalitis may exhibit more extensive brain damage despite limited signs of inflammation detected within CSF specimens [29].

Although the pathogenesis of HSV encephalitis is not fully understood, it is felt that both direct virus-mediated and indirect immune-mediated mechanisms play a role in producing CNS damage [2]. It is unclear whether the extent of CNS viral load is directly related to the severity of tissue damage. In one study of eight patients with HSV encephalitis, the level of HSV-1 viremia in CSF, as determined by PCR, did not correlate with the severity of clinical signs and symptoms [30].

A number of lines of evidence support immune-mediated damage in the pathogenesis of HSV-1 encephalitis.

HSV-1 encephalitis is characterized by focal inflammatory lesions that are thought to result from the expression of a virus-specific T cell response [31]. As an example, cytotoxic T cells that specifically lyse HSV-infected targets in vitro predominate at focal sites of infection in murine models [15].

Other animal models have demonstrated correlation between production of cytokines and nitric oxide and brain injury [32].

Administration of exogenous interleukin- (IL) 4 to mice intranasally infected with HSV-1 increases the severity of subsequent encephalitis through the increased production of IL-4 from local CD4+ T cells [33].

Correlations have been noted between the infiltration of immune cells into the CNS during herpes virus infection and demyelination in the mouse model [31].

HSV-1 IgM immune complexes were localized in cerebrovascular walls in the brain of a patient with herpes encephalitis [34].

In a retrospective study, N-methyl-D-aspartate receptor (NMDAR) IgA, IgG, or IgM antibodies were detected in the serum and/or CSF of 13 of 44 patients (30 percent) with herpes simplex encephalitis, whereas these antibodies were not detected in any patients with enterovirus or varicella-zoster encephalitis [35]. NMDAR antibodies are also associated with a distinct clinical syndrome unrelated to HSV encephalitis, anti-NMDAR encephalitis. (See "Paraneoplastic and autoimmune encephalitis", section on 'Anti-NMDA receptor encephalitis'.)


Symptoms and signs — Patients with HSV-1 encephalitis typically present with altered mentation and level of consciousness for more than 24 hours, fever, new onset seizures, and/or focal neurologic deficits. Focal neurologic findings are usually acute (<1 week in duration) and include focal cranial nerve deficits, hemiparesis, dysphasia, aphasia, or ataxia [2,36]. Over 90 percent of patients will have one of the above symptoms plus fever [2]. Other associated neurologic symptoms include urinary and fecal incontinence, aseptic meningitis, localized dermatomal rashes, and Guillain-Barré syndrome [37]. Later in the clinical course, patients may have diminished comprehension, paraphasic spontaneous speech, impaired memory, and loss of emotional control [38].

Various behavioral syndromes have been reported in association with HSV-1 encephalitis including:


Klüver-Bucy syndrome (KBS)

Varying states of amnesia

Hypomanic symptoms often occur in patients during the initial phase of HSV-1 encephalitis, presumably from inflammation of the inferomedial temporal lobe or limbic system [39]. Behavior alterations may include an elevated mood, excessive animation, decreased need for sleep, inflated self-esteem, and hypersexuality [38,39].

KBS is a behavioral syndrome of varying etiologies, originally described in Rhesus macaques after bilateral temporal lobectomy, which includes "psychic blindness," loss of normal anger and fear responses, and increased sexual activity [38]. KBS and amnesia are thought to occur secondary to HSV's affinity for the temporal lobe and limbic structures [38].

HSV-1 CNS infection has also been implicated in cases of recurrent brainstem encephalitis. This condition is characterized by upward gaze palsy and facial numbness, as well as signs of involvement of corticospinal, spinothalamic, lemniscal, and brainstem cerebellar pathways [37].

Focal granulomatous encephalitis has also been described in association with herpes encephalitis. In a case report, two adult patients presented with cognitive symptoms progressing over weeks, despite acyclovir treatment, with temporal lobe abnormalities reported on magnetic resonance imaging (MRI) with gadolinium enhancement [40]. HSV-1 polymerase chain reaction (PCR) analysis was negative in cerebrospinal fluid (CSF) but positive in brain biopsies, which demonstrated vasocentric granulomatous inflammation. Paired blood and CSF samples showed intrathecal synthesis of HSV-1 type-specific IgG. The patients improved clinically only after immunosuppression and, despite profound cognitive impairment, recovered fully.

Laboratory abnormalities — Examination of the CSF typically shows a lymphocytic pleocytosis with counts ranging from 10 to 400 cells/microL, an elevated protein, and an increased number of erythrocytes (in 84 percent of patients) [41]. However, a normal CSF profile can occur early in the course of the disease; this observation has been made in immunocompetent hosts and in a small case series of patients taking tumor necrosis factor (TNF-alpha) inhibitors [22,42]. Repeat testing can be helpful when the clinical suspicion is high. Low glucose is uncommon and may suggest an alternative diagnosis [41].

Most patients have serologic evidence of prior infection with HSV-1, consistent with reactivation disease [2].

Imaging studies — MRI with or without contrast is the study of choice to evaluate HSV-1 encephalitis, and in the majority of cases, is abnormal. Findings may include asymmetric hyperintense lesions on T2-weighted sequences corresponding to areas of edema in the mesiotemporal and orbitofrontal lobes and the insular cortex [43]. Diffusion restriction on diffusion-weighted imaging (DWI) is detected in the anterior temporal lobes and the insular cortex early in the course of HSV encephalitis [44], even prior to detection of CSF viral DNA in some cases [45]. A large retrospective study comparing DWI with fluid-attenuated inversion recovery (FLAIR) found that DWI performed early in the course of illness (<2 weeks from symptom onset) revealed as many or more lesions, with improved visualization compared with FLAIR signal abnormalities, which appeared more prominent late in the course of disease [46].

Temporal lobe lesions are predominantly unilateral and may have associated mass effect [2]. In a study that reviewed 251 cases of temporal lobe encephalitis, of which 60 were due to HSV, a multivariate model found that bilateral temporal lobe involvement and lesions outside the temporal lobe, insula, or cingulate were associated with a significantly lower odds of herpes simplex encephalitis [47]. However, extratemporal abnormalities were noted in 11 of 20 patients in one retrospective study [48]. In general, focal radiographic findings are found more often in older patients [49].

Cranial computed tomography (CT) scans of the brain have only 50 percent sensitivity early in the disease, and the presence of abnormalities is generally associated with severe damage and poor prognosis [2]. In contrast, MRI is the most sensitive and specific imaging method for HSV encephalitis, especially in the early course of the disease (image 1) [45,50]. However, normal MRI findings have been also reported in the setting of disease. Several recent studies indicate that MRI with diffusion-weighted imaging (DWI) may be helpful early in the diagnosis of HSV-1 encephalitis; however, DWI is not superior to conventional MRI for follow-up [51-53].

In situations with limited access to MRI, single-photon emission computed tomography (SPECT) imaging can also be used to help establish a diagnosis of HSV encephalitis. Most of the data using SPECT scanning are based upon small case series. In one series of 14 patients with viral encephalitis and CSF antibodies to HSV, SPECT scanning showed an increased accumulation of radiotracer in the affected temporal lobe [54]. A subsequent series evaluated the utility of dynamic Tc-ECD SPECT in the evaluation of patients with suspected viral encephalitis (as assessed via MRI) [55]. Of the nine patients studied, accumulation of tracer was only observed in the three cases of HSV encephalitis but not in the cases of viral encephalitis due to other etiologies.

Electroencephalogram — Focal electroencephalogram (EEG) findings occur in >80 percent of cases, typically showing prominent intermittent high amplitude slow waves (delta and theta slowing), and, occasionally, continuous periodic lateralized epileptiform discharges in the affected region [56,57]. Many EEG findings, however, are nonspecific.

DIFFERENTIAL DIAGNOSIS — The diagnosis of HSV encephalitis should be considered in the febrile encephalopathic patient with new onset seizures, with or without focal findings. However, these clinical findings are not pathognomonic because numerous other infections can mimic HSV encephalitis [4].

In a classic study of 432 patients who underwent brain biopsy for a presumed diagnosis of herpes encephalitis, 45 percent had HSV isolated from brain tissue, 22 percent had other identifiable causes of their symptoms, and 33 percent remained undiagnosed [36].

It is extremely important that the diagnosis of HSV encephalitis be entertained early in any patient who presents with suggestive signs, symptoms, laboratory, and imaging studies since it is among the more treatable of the infectious etiologies of encephalitis.

The differential diagnosis is extensive and can include [36,58]:

Encephalitis from other viral etiologies such as arbovirus infections (West Nile encephalitis, St. Louis encephalitis, Western equine encephalitis, California encephalitis, Eastern equine encephalitis, Japanese encephalitis), other herpesviruses (CMV, EBV, VZV) and other miscellaneous viruses (enteroviruses, influenza A, mumps, adenovirus, lymphocytic choriomeningitis virus, progressive multifocal leukoencephalopathy caused by JC virus) [59].

Brain abscess or subdural empyema caused by a variety of organisms including bacteria, mycobacteria, fungi, rickettsiae, mycoplasma, or protozoa.

Post-infectious conditions such Reye syndrome.

Acute disseminated encephalomyelitis.

Subacute sclerosing panencephalitis secondary to defective measles virus.

Neurosyphilis [60,61].

Primary or secondary brain tumors [62].

Paraneoplastic and autoimmune encephalitis. (See "Paraneoplastic and autoimmune encephalitis".)

Other noninfectious causes such as subdural hematoma, systemic lupus erythematosus, adrenal leukodystrophy, vasculitis, neuro-Behçet and toxic encephalopathy [63].


Polymerase chain reaction — The gold standard for establishing the diagnosis is the detection of herpes simplex virus DNA in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR). The test has extremely high sensitivity (98 percent) and specificity (99 percent) and is positive early in the course of illness. While awaiting results of PCR testing, treatment for HSV encephalitis should be initiated. When present, HSV DNA is detectable via PCR analysis of the CSF for at least two weeks and up to one month after the onset of clinical disease [10,64]. A CSF white blood cell count of ≥5 cells/microL together with fever, a virus-specific rash, or headaches have been reported as independent predictors of a positive PCR result for HSV DNA [65,66], whereas CSF with normal protein and cell counts had a negative predictive value [67].

The use of PCR for the diagnosis of HSV-1 encephalitis has also led to the identification of atypical forms of HSV-1 encephalitis formerly attributed to alternative viruses including brainstem encephalitis, myelitis, or diffuse encephalitis without temporal lobe involvement [68].

This topic is discussed in detail elsewhere. (See "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis".)

Brain biopsy — Prior to the availability of PCR testing, brain biopsy was considered to be the only way to accurately diagnose herpes encephalitis [1,69]. Brain biopsy still has a role in patients who have clinical deterioration despite antiviral therapy or when alternative diagnoses are being considered [69].

Brain specimens are examined for the presence of HSV by culture, HSV antigens by immunohistochemistry, or viral DNA by in situ hybridization [70]. Pathological examination of involved regions may show areas of mononuclear inflammation with perivascular cuffs and focal infiltrates of inflammatory cells [56]. Glial nodules, neuronophagia, and intense lymphocytic infiltrates with regions of necrosis and macrophages may also be observed [56]. However, the procedure is invasive and can lead to neurologic sequelae such as intracranial hemorrhage and edema at the biopsy site [2].

CSF antigen and antibody determinations — CSF antigen and antibody determinations are not helpful in the early diagnosis of HSV encephalitis.

The use of purified HSV glycoprotein B to detect CSF antibodies has a sensitivity of 97 percent and a specificity of 100 percent [71]. However, viral antibody titers, which rise fourfold over the course of the illness, are first positive after 10 days to 2 weeks of illness and are thus only helpful retrospectively [41].

HSV antigen can also be detected in CSF, but sensitivity and specificity of this test is lower than PCR assays [72].

Viral culture — Viral culture of CSF is rarely positive in the early stages of infection and is only positive later in about 4 to 5 percent of patients with brain biopsy-proven HSV encephalitis [41,58].


Empiric therapy – We recommend empiric therapy with IV acyclovir (10 mg/kg IV every 8 hours with dose adjustment for renal insufficiency) as soon as the diagnosis of HSV encephalitis is considered (see 'Clinical features' above). Oral antiviral therapy (eg, valacyclovir) should not be used for the treatment of HSV encephalitis.

Overall, IV acyclovir is well tolerated. However, it must be infused slowly and with a fluid bolus to prevent crystalluria and renal failure [2]. Neurologic toxicity has been reported, but has only been observed at extremely high doses (>10 mg/kg every 8 hours) or in cases of renal failure without dose adjustment [2]. The mechanism of action and toxicity profile of acyclovir are discussed in detail separately. (See "Acyclovir: An overview" and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

Early antiviral therapy (eg, before loss of consciousness, within 24 hours of the onset of symptoms, Glasgow Coma Scale score of 9 to 15) can reduce mortality and limit the severity of chronic postencephalitic behavioral and cognitive impairments [38,73]. Since acyclovir is only effective in halting viral replication, early therapy can prevent extensive replication and subsequent CNS damage. However, even with early administration of therapy after onset of disease, nearly two-thirds of survivors will have significant neurologic deficits [4]. In a study that included over 200 patients with PCR confirmed HSV-1 encephalitis, the mortality of patients who were treated with fever and altered mental status upon presentation was between 5 to 10 percent [9].

Shortages of intravenous (IV) acyclovir have occurred. If IV acyclovir is not available, alternative agents must be used. Specific recommendations are presented separately. (See "Acyclovir: An overview", section on 'If there is an acyclovir shortage'.)

The decision to discontinue empiric treatment is discussed below. (See 'Discontinuation of therapy based on PCR results' below.)

Duration for those with HSV encephalitis – The duration of treatment of HSV encephalitis in immunocompetent patients should be 14 to 21 days. Although the original trials used only 10 days [74,75], shorter time periods have been associated with occasional relapse with acyclovir-sensitive HSV [57,76,77]. This phenomenon has been mainly observed in children [76,77]. The low toxicity profile of the drug makes longer duration of therapy possible.

Efficacy of IV acyclovir – IV acyclovir was shown to be the treatment of choice for the reduction of mortality and morbidity from HSV encephalitis in the mid-1980s. A series of trials compared its efficacy with vidarabine, which had earlier been shown to be better than placebo [74,75]:

Patients who underwent brain biopsy for presumptive HSV encephalitis were randomly assigned to treatment with either vidarabine or acyclovir for ten days. One-third of the patients had biopsy-proven disease. Mortality was significantly reduced in the acyclovir-treated patients (28 percent versus 54 percent) [74].

In another study, 127 patients with suspected HSV encephalitis were randomized to a 10-day course of acyclovir versus vidarabine [78]. The diagnosis of HSV encephalitis was verified by brain biopsy and/or antibody responses in serum and CSF in 53 patients. Mortality was significantly decreased in the acyclovir group compared to the vidarabine group (19 percent versus 50 percent).

In both of the above studies, six-month assessments confirmed that functional status was significantly better in the acyclovir-treated patients compared to those assigned to the vidarabine arm [74,78].

Further study is necessary before other agents (eg, oral valacyclovir) can be recommended for HSV encephalitis. One study evaluated the pharmacokinetics of orally administered valacyclovir (1 g orally three times daily for 21 days) in four patients with HSV encephalitis [79]. Although the patients achieved and maintained therapeutic concentrations of valacyclovir in the CSF for the duration of therapy, the CSF concentrations dropped over time, likely reflecting a reduction in blood-brain barrier permeability with healing of the infection.

DISCONTINUATION OF THERAPY BASED ON PCR RESULTS — In patients with a low prior probability of HSV encephalitis (normal neuroimaging, <5 cells/mm2 in CSF, normal mental status), a negative CSF HSV PCR result reduces the likelihood of disease to <1 percent [10]. Antiviral therapy may thus be discontinued if a negative CSF HSV PCR result is obtained after 72 hours following onset of neurological signs and symptoms.

In contrast, in patients with a high prior probability of HSV encephalitis (suggestive neuroimaging findings, CSF pleocytosis, positive EEG findings, or seizures), a negative PCR result reduces the disease likelihood to approximately 5 percent. In addition, clinicians must consider alternative reasons for a false-negative CSF PCR result, including early testing after the onset of symptoms, antiviral therapy, or presence of PCR inhibitors (eg, hemoglobin degradation products in bloody CSF) [64].

OUTCOMES — Untreated, the fatality in herpes encephalitis can approach 70 percent and most of the survivors have serious neurologic deficits [2,3]. Survivors can also have significant neuropsychiatric and neurobehavioral issues [80].

Mortality – Even with appropriate diagnosis and treatment, mortality may still be as high as 20 to 30 percent [2,74,78]. A large retrospective multicenter study of 93 adult patients with HSV encephalitis who were treated with acyclovir assessed outcome and prognostic factors for morbidity and mortality [81]. Among 85 patients assessed at six months, 13 died (15 percent) and 17 (20 percent) had a severe disability. A multivariate analysis identified two factors associated with poor outcome: a Simplified Acute Physiology Score >27 at admission and a delay of greater than two days between presentation to the hospital and initiation of acyclovir therapy.

Morbidity – Survivors may have significant long-term morbidity after HSV encephalitis. Severe behavioral abnormalities, anterograde amnesia, features of KBS, and severe cognitive impairment are potentially chronic aspects of the postencephalitic syndrome [38,82]. Long-term follow-up of treated patients may show residual neurologic deficits on either clinical or formal neurologic testing [80]. The most common residua are dysnomia and impaired new learning for both verbal and visual material, despite normal performances on a standard mental status examination [73]. One study from Sweden highlighted that rehospitalization was frequent among 236 survivors with confirmed HSV encephalitis (occurring in 87 percent of patients) [6]. Reasons for hospital admission included seizure disorder, neuropsychiatric illness, or thromboembolic phenomena.

Autoimmune encephalitis – HSV encephalitis is also associated with an autoimmune encephalitis mediated by autoantibodies against the N-methyl-D-aspartate receptor (NMDAR) for the neurotransmitter glutamate [83,84]. The hallmark symptoms include prominent neuropsychiatric changes, decreased consciousness, seizures, dyskinesias including choreoathetosis, and autonomic instability [85]. Thus, recurrent neurological symptoms in patients with a recent history of HSV encephalitis should prompt CSF evaluation of viral DNA and anti-NMDAR antibodies. (See "Paraneoplastic and autoimmune encephalitis", section on 'Anti-NMDA receptor encephalitis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Infectious encephalitis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Encephalitis (The Basics)")


Epidemiology – Herpes encephalitis is the most common cause of fatal sporadic encephalitis in the United States and involves all age groups. In nearly all cases of herpes encephalitis beyond the neonatal period, the etiologic agent is herpes simplex virus type 1 (HSV-1). In neonates, herpes encephalitis may be caused by either HSV-1 or HSV-2. (See 'Pathogen' above and 'Epidemiology' above.)

Clinical features – The clinical syndrome is often characterized by the rapid onset of fever, headache, seizures, focal neurologic signs, and impaired consciousness. (See 'Symptoms and signs' above.)


We recommend lumbar puncture for cerebrospinal fluid analysis and polymerase chain reaction (PCR) testing for HSV in any patient with encephalitis. The detection of herpes simplex virus DNA in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) testing is considered the gold standard for establishing the diagnosis. (See 'Diagnosis' above.)

We also recommend brain magnetic resonance imaging (MRI) to assess signs of temporal lobe involvement, which would support the diagnosis. Absence of this finding does not alter decisions regarding empiric therapy. Brain MRI would also eliminate other alternative causes of mental status changes, such as brain abscess. (See 'Imaging studies' above.)

Although a brain biopsy is generally not needed to establish the diagnosis, it should be considered if the patient clinically deteriorates on appropriate therapy and PCR testing is negative for HSV. (See 'Brain biopsy' above.)

Treatment – For patients with suspected HSV encephalitis, we recommend empiric therapy with acyclovir (10 mg/kg intravenous [IV] every 8 hours) (Grade 1B). Treatment should be initiated as soon as the diagnosis is considered since delays in treatment can lead to significant neurologic sequelae. If the evaluation supports the diagnosis of HSV encephalitis, treatment should be continued for 14 to 21 days. (See 'Treatment' above and 'Discontinuation of therapy based on PCR results' above.)

  1. Hanley DF, Johnson RT, Whitley RJ. Yes, brain biopsy should be a prerequisite for herpes simplex encephalitis treatment. Arch Neurol 1987; 44:1289.
  2. Levitz RE. Herpes simplex encephalitis: a review. Heart Lung 1998; 27:209.
  3. Whitley RJ. Viral encephalitis. N Engl J Med 1990; 323:242.
  4. Whitley RJ, Kimberlin DW. Herpes simplex encephalitis: children and adolescents. Semin Pediatr Infect Dis 2005; 16:17.
  5. Huppatz C, Durrheim DN, Levi C, et al. Etiology of encephalitis in Australia, 1990-2007. Emerg Infect Dis 2009; 15:1359.
  6. Hjalmarsson A, Blomqvist P, Sköldenberg B. Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality. Clin Infect Dis 2007; 45:875.
  7. George BP, Schneider EB, Venkatesan A. Encephalitis hospitalization rates and inpatient mortality in the United States, 2000-2010. PLoS One 2014; 9:e104169.
  8. Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future. F1000Res 2018; 7.
  9. Whitley R, Baines J. Clinical management of herpes simplex virus infections: past, present, and future. F1000Res 2018; 7.
  10. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes 2004; 11 Suppl 2:57A.
  11. Whitley R, Lakeman AD, Nahmias A, Roizman B. Dna restriction-enzyme analysis of herpes simplex virus isolates obtained from patients with encephalitis. N Engl J Med 1982; 307:1060.
  12. Alonso-Vanegas MA, Quintero-López E, Martínez-Albarrán AA, Moreira-Holguín JC. Recurrent Herpes Simplex Virus Encephalitis After Neurologic Surgery. World Neurosurg 2016; 89:731.e1.
  13. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res 2006; 71:141.
  14. Hudson SJ, Dix RD, Streilein JW. Induction of encephalitis in SJL mice by intranasal infection with herpes simplex virus type 1: a possible model of herpes simplex encephalitis in humans. J Infect Dis 1991; 163:720.
  15. Barnett EM, Jacobsen G, Evans G, et al. Herpes simplex encephalitis in the temporal cortex and limbic system after trigeminal nerve inoculation. J Infect Dis 1994; 169:782.
  16. Jennische E, Eriksson CE, Lange S, et al. The anterior commissure is a pathway for contralateral spread of herpes simplex virus type 1 after olfactory tract infection. J Neurovirol 2015; 21:129.
  17. Stanberry LR, Floyd-Reising SA, Connelly BL, et al. Herpes simplex viremia: report of eight pediatric cases and review of the literature. Clin Infect Dis 1994; 18:401.
  18. Harel L, Smetana Z, Prais D, et al. Presence of viremia in patients with primary herpetic gingivostomatitis. Clin Infect Dis 2004; 39:636.
  19. Stroop WG, Schaefer DC. Production of encephalitis restricted to the temporal lobes by experimental reactivation of herpes simplex virus. J Infect Dis 1986; 153:721.
  20. Moraru M, Cisneros E, Gómez-Lozano N, et al. Host genetic factors in susceptibility to herpes simplex type 1 virus infection: contribution of polymorphic genes at the interface of innate and adaptive immunity. J Immunol 2012; 188:4412.
  21. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. Clin Infect Dis 2013; 57:849.
  22. Bradford RD, Pettit AC, Wright PW, et al. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 2009; 49:924.
  23. Perini P, Rinaldi F, Puthenparampil M, et al. Herpes simplex virus encephalitis temporally associated with dimethyl fumarate-induced lymphopenia in a multiple sclerosis patient. Mult Scler Relat Disord 2018; 26:68.
  24. Sharma K, Ballham SA, Inglis KE, et al. Does natalizumab treatment increase the risk of herpes simplex encephalitis in multiple sclerosis? Case and discussion. Mult Scler Relat Disord 2013; 2:385.
  25. Pfender N, Jelcic I, Linnebank M, et al. Reactivation of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis. Neurology 2015; 84:2377.
  26. Crusio RH, Singson SV, Haroun F, et al. Herpes simplex virus encephalitis during treatment with etanercept. Scand J Infect Dis 2014; 46:152.
  27. Tan IL, McArthur JC, Venkatesan A, Nath A. Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised. Neurology 2012; 79:2125.
  28. Pepose JS, Hilborne LH, Cancilla PA, Foos RY. Concurrent herpes simplex and cytomegalovirus retinitis and encephalitis in the acquired immune deficiency syndrome (AIDS). Ophthalmology 1984; 91:1669.
  29. Herget GW, Riede UN, Schmitt-Gräff A, et al. Generalized herpes simplex virus infection in an immunocompromised patient--report of a case and review of the literature. Pathol Res Pract 2005; 201:123.
  30. 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 virus encephalitis. Neurology 1997; 48:1341.
  31. Hudson SJ, Streilein JW. Functional cytotoxic T cells are associated with focal lesions in the brains of SJL mice with experimental herpes simplex encephalitis. J Immunol 1994; 152:5540.
  32. Koprowski H, Zheng YM, Heber-Katz E, et al. In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci U S A 1993; 90:3024.
  33. Ikemoto K, Pollard RB, Fukumoto T, et al. Small amounts of exogenous IL-4 increase the severity of encephalitis induced in mice by the intranasal infection of herpes simplex virus type 1. J Immunol 1995; 155:1326.
  34. Hayashi K, Yanagi K, Takagi S. Detection of herpes simplex virus type 1-IgM immune complexes in the brain of a patient with prolonged herpes encephalitis. J Infect Dis 1986; 153:56.
  35. Prüss H, Finke C, Höltje M, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 2012; 72:902.
  36. Whitley RJ, Cobbs CG, Alford CA Jr, et al. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA 1989; 262:234.
  37. Tyler KL, Tedder DG, Yamamoto LJ, et al. Recurrent brainstem encephalitis associated with herpes simplex virus type 1 DNA in cerebrospinal fluid. Neurology 1995; 45:2246.
  38. Hart RP, Kwentus JA, Frazier RB, Hormel TL. Natural history of Klüver-Bucy syndrome after treated herpes encephalitis. South Med J 1986; 79:1376.
  39. Fisher CM. Hypomanic symptoms caused by herpes simplex encephalitis. Neurology 1996; 47:1374.
  40. Varatharaj A, Nicoll JA, Pelosi E, Pinto AA. Corticosteroid-responsive focal granulomatous herpes simplex type-1 encephalitis in adults. Pract Neurol 2017; 17:140.
  41. Nahmias AJ, Whitley RJ, Visintine AN, et al. Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. J Infect Dis 1982; 145:829.
  42. Razavi B, Razavi M. Herpes simplex encephalitis--an atypical case. Infection 2001; 29:357.
  43. Misra UK, Kalita J, Phadke RV, et al. Usefulness of various MRI sequences in the diagnosis of viral encephalitis. Acta Trop 2010; 116:206.
  44. Sawlani V. Diffusion-weighted imaging and apparent diffusion coefficient evaluation of herpes simplex encephalitis and Japanese encephalitis. J Neurol Sci 2009; 287:221.
  45. McCabe K, Tyler K, Tanabe J. Diffusion-weighted MRI abnormalities as a clue to the diagnosis of herpes simplex encephalitis. Neurology 2003; 61:1015.
  46. Renard D, Nerrant E, Lechiche C. DWI and FLAIR imaging in herpes simplex encephalitis: a comparative and topographical analysis. J Neurol 2015; 262:2101.
  47. Chow FC, Glaser CA, Sheriff H, et al. Use of clinical and neuroimaging characteristics to distinguish temporal lobe herpes simplex encephalitis from its mimics. Clin Infect Dis 2015; 60:1377.
  48. Wasay M, Mekan SF, Khelaeni B, et al. Extra temporal involvement in herpes simplex encephalitis. Eur J Neurol 2005; 12:475.
  49. Lakeman FD, Whitley RJ. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis 1995; 171:857.
  50. Domingues RB, Fink MC, Tsanaclis AM, et al. Diagnosis of herpes simplex encephalitis by magnetic resonance imaging and polymerase chain reaction assay of cerebrospinal fluid. J Neurol Sci 1998; 157:148.
  51. Hatipoglu HG, Sakman B, Yuksel E. Magnetic resonance and diffusion-weighted imaging findings of herpes simplex encephalitis. Herpes 2008; 15:13.
  52. Heiner L, Demaerel P. Diffusion-weighted MR imaging findings in a patient with herpes simplex encephalitis. Eur J Radiol 2003; 45:195.
  53. Küker W, Nägele T, Schmidt F, et al. Diffusion-weighted MRI in herpes simplex encephalitis: a report of three cases. Neuroradiology 2004; 46:122.
  54. Launes J, Nikkinen P, Lindroth L, et al. Diagnosis of acute herpes simplex encephalitis by brain perfusion single photon emission computed tomography. Lancet 1988; 1:1188.
  55. Kataoka H, Inoue M, Shinkai T, Ueno S. Early dynamic SPECT imaging in acute viral encephalitis. J Neuroimaging 2007; 17:304.
  56. Rose JW, Stroop WG, Matsuo F, Henkel J. Atypical herpes simplex encephalitis: clinical, virologic, and neuropathologic evaluation. Neurology 1992; 42:1809.
  57. VanLandingham KE, Marsteller HB, Ross GW, Hayden FG. Relapse of herpes simplex encephalitis after conventional acyclovir therapy. JAMA 1988; 259:1051.
  58. Rowley AH, Whitley RJ, Lakeman FD, Wolinsky SM. Rapid detection of herpes-simplex-virus DNA in cerebrospinal fluid of patients with herpes simplex encephalitis. Lancet 1990; 335:440.
  59. Whitley RJ, Gnann JW. Viral encephalitis: familiar infections and emerging pathogens. Lancet 2002; 359:507.
  60. Marano E, Briganti F, Tortora F, et al. Neurosyphilis with complex partial status epilepticus and mesiotemporal MRI abnormalities mimicking herpes simplex encephalitis. J Neurol Neurosurg Psychiatry 2004; 75:833.
  61. Szilak I, Marty F, Helft J, Soeiro R. Neurosyphilis presenting as herpes simplex encephalitis. Clin Infect Dis 2001; 32:1108.
  62. Giglio P, Bakshi R, Block S, et al. Primary central nervous system lymphoma masquerading as herpes encephalitis: clinical, magnetic resonance imaging, and pathologic findings. Am J Med Sci 2002; 323:59.
  63. Hasegawa T, Kanno S, Kato M, et al. Neuro-Behçet's disease presenting initially as mesiotemporal lesions mimicking herpes simplex encephalitis. Eur J Neurol 2005; 12:661.
  64. Boivin G. Diagnosis of herpesvirus infections of the central nervous system. Herpes 2004; 11 Suppl 2:48A.
  65. Minjolle S, Arvieux C, Gautier AL, et al. Detection of herpesvirus genomes by polymerase chain reaction in cerebrospinal fluid and clinical findings. J Clin Virol 2002; 25 Suppl 1:S59.
  66. Simko JP, Caliendo AM, Hogle K, Versalovic J. Differences in laboratory findings for cerebrospinal fluid specimens obtained from patients with meningitis or encephalitis due to herpes simplex virus (HSV) documented by detection of HSV DNA. Clin Infect Dis 2002; 35:414.
  67. Tang YW, Mitchell PS, Espy MJ, et al. Molecular diagnosis of herpes simplex virus infections in the central nervous system. J Clin Microbiol 1999; 37:2127.
  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.
  69. Soong SJ, Watson NE, Caddell GR, et al. Use of brain biopsy for diagnostic evaluation of patients with suspected herpes simplex encephalitis: a statistical model and its clinical implications. NIAID Collaborative Antiviral Study Group. J Infect Dis 1991; 163:17.
  70. Burns J, Redfern DR, Esiri MM, McGee JO. Human and viral gene detection in routine paraffin embedded tissue by in situ hybridisation with biotinylated probes: viral localisation in herpes encephalitis. J Clin Pathol 1986; 39:1066.
  71. Kahlon J, Chatterjee S, Lakeman FD, et al. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis 1987; 155:38.
  72. Lakeman FD, Koga J, Whitley RJ. Detection of antigen to herpes simplex virus in cerebrospinal fluid from patients with herpes simplex encephalitis. J Infect Dis 1987; 155:1172.
  73. Gordon B, Selnes OA, Hart J Jr, et al. Long-term cognitive sequelae of acyclovir-treated herpes simplex encephalitis. Arch Neurol 1990; 47:646.
  74. Whitley RJ, Alford CA, Hirsch MS, et al. Vidarabine versus acyclovir therapy in herpes simplex encephalitis. N Engl J Med 1986; 314:144.
  75. Jeffries DJ. Clinical use of acyclovir. Br Med J (Clin Res Ed) 1985; 290:177.
  76. Valencia I, Miles DK, Melvin J, et al. Relapse of herpes encephalitis after acyclovir therapy: report of two new cases and review of the literature. Neuropediatrics 2004; 35:371.
  77. De Tiège X, Rozenberg F, Des Portes V, et al. Herpes simplex encephalitis relapses in children: differentiation of two neurologic entities. Neurology 2003; 61:241.
  78. Sköldenberg B, Forsgren M, Alestig K, et al. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet 1984; 2:707.
  79. Pouplin T, Pouplin JN, Van Toi P, et al. Valacyclovir for herpes simplex encephalitis. Antimicrob Agents Chemother 2011; 55:3624.
  80. Arciniegas DB, Anderson CA. Viral encephalitis: neuropsychiatric and neurobehavioral aspects. Curr Psychiatry Rep 2004; 6:372.
  81. Raschilas F, Wolff M, Delatour F, et al. Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study. Clin Infect Dis 2002; 35:254.
  82. Grydeland H, Walhovd KB, Westlye LT, et al. Amnesia following herpes simplex encephalitis: diffusion-tensor imaging uncovers reduced integrity of normal-appearing white matter. Radiology 2010; 257:774.
  83. Morris NA, Kaplan TB, Linnoila J, Cho T. HSV encephalitis-induced anti-NMDAR encephalitis in a 67-year-old woman: report of a case and review of the literature. J Neurovirol 2016; 22:33.
  84. Ellul MA, Griffiths MJ, Iyer A, et al. Anti-N-Methyl-D-Aspartate Receptor Encephalitis In A Young Child With Histological Evidence On Brain Biopsy Of Coexistent Herpes Simplex Virus Type 1 Infection. Pediatr Infect Dis J 2016; 35:347.
  85. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7:1091.
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