Herpes simplex encephalitis

(Redirected from Herpesviral encephalitis)
Jump to navigation Jump to search


Template:DiseaseDisorder infobox

Sexually transmitted diseases Main Page

Herpes simplex Microchapters

Home

Patient Information

Genital Herpes
Congenital Herpes

Overview

Classification

Orofacial Infection
Anogenital Infection
Ocular Infection
Herpes Encephalitis
Neonatal Herpes
Herpetic Whitlow
Herpes Gladiatorum
Mollaret's Meningitis

Pathophysiology

Epidemiology and Demographics

Asymptomatic Shedding

Recurrences and Triggers

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

Direct detection of Genital Lesions

Treatment

Antiviral Therapy

Overview
Antivirals for First Episode of Genital Herpes
Antivirals for Recurrent Genital Herpes

Primary Prevention

Counseling

Herpes simplex encephalitis On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Herpes simplex encephalitis

CDC on Herpes simplex encephalitis

Herpes simplex encephalitis in the news

Blogs on Herpes simplex encephalitis

Directions to Hospitals Treating Herpes simplex

Risk calculators and risk factors for Herpes simplex encephalitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Muhammad Saad, M.B.B.S.[2] Cafer Zorkun, M.D., Ph.D. [3], Anthony Gallo, B.S. [4]

Synonyms and keywords: HSE; Herpes viral encephalitis; Herpes meningoencephalitis; HSV encephalitis; Herpes simplex virus encephalitis

Overview

Herpes simplex encephalitis is a severe viral infection of the central nervous system and the most common cause of sporadic fatal encephalitis worldwide. It may be classified according to the causative virus into HSV-1 and HSV-2 disease; HSV-1 causes more than 90% of cases beyond the neonatal period, while HSV-2 predominates in neonates. The exact pathogenesis is not fully understood, but the disease is believed to result from retrograde transmission of virus along nerve axons to the brain after reactivation of latent virus in the trigeminal ganglion, producing a necrotising, often haemorrhagic encephalitis of the medial temporal lobes and insular cortex.

Herpes simplex encephalitis constitutes a medical emergency. If left untreated, approximately 70% of patients progress to mortality. It must be differentiated from other diseases causing fever, headache, seizures and altered mental status, including bacterial meningitis, other viral encephalitides, brain abscess, subarachnoid haemorrhage, stroke, metabolic and toxic encephalopathies and autoimmune encephalitis. Physical examination findings are generally non-specific.

Diagnosis rests on cerebrospinal fluid examination obtained by lumbar puncture, which typically shows a lymphocytic pleocytosis, together with detection of HSV DNA by polymerase chain reaction. A negative PCR taken very early does not exclude the diagnosis. Magnetic resonance imaging is the imaging modality of choice.

The mainstay of therapy is prompt intravenous antiviral treatment, and the drug of choice is aciclovir, which must be started empirically before microbiological confirmation. Adjunctive dexamethasone does not improve verbal memory outcome, and prolonged oral valaciclovir after intravenous therapy confers no benefit. Surgery is reserved for refractory raised intracranial pressure. Approximately one quarter of survivors develop autoimmune encephalitis after completing antiviral therapy, most often associated with NMDA receptor antibodies. Even with prompt treatment, mortality remains substantial and most survivors are left with neuropsychological sequelae, particularly impairment of memory.

Historical Perspective

Before effective antivirals, herpes simplex encephalitis was diagnosed by brain biopsy and was fatal in approximately 70% of cases.[1] Two randomised controlled trials in the 1980s established aciclovir as the treatment of choice. In the NIAID Collaborative Antiviral Study Group trial, 208 patients undergoing brain biopsy for presumptive herpes simplex encephalitis were randomised to vidarabine or aciclovir; 69 patients (33%) had biopsy-proved disease, and mortality was 54% in vidarabine recipients compared with 28% in aciclovir recipients (P = 0.008).[2] A parallel randomised Swedish multicentre study reached the same conclusion.[3]

Detection of HSV DNA in cerebrospinal fluid by polymerase chain reaction subsequently replaced brain biopsy as the diagnostic standard.[4] More recent milestones include the recognition of inborn errors of the TLR3–type I interferon pathway as a cause of childhood disease,[5] the identification of post-infectious autoimmune encephalitis as a frequent complication,[6] and completion of the first randomised controlled trial of corticosteroids in this disease.[7]

Classification

Herpes simplex encephalitis may be classified according to the causative virus type and the affected host.

Category Usual host Typical features
HSV-1 encephalitis Children beyond the neonatal period, adolescents and adults; immunocompetent hosts Focal necrotising encephalitis of the medial temporal lobe, insular cortex and orbitofrontal cortex; accounts for more than 90% of non-neonatal cases[8]
HSV-2 encephalitis Neonates; immunocompromised adults Diffuse rather than focal involvement in neonates; in adults HSV-2 more often causes meningitis (including recurrent Mollaret's meningitis) than encephalitis
Neonatal HSV central nervous system disease Neonates infected intrapartum or postnatally Occurs as isolated CNS disease or as part of disseminated disease; requires higher-dose and longer antiviral therapy
Post-herpes simplex encephalitis autoimmune encephalitis Survivors of any age, within weeks to months of treatment Neuronal surface antibody-mediated relapse, most often NMDA receptor antibodies; requires immunotherapy, not further antivirals[6]

Pathophysiology

The exact pathogenesis of herpes simplex encephalitis is not fully understood. It is believed to result from retrograde transmission of the virus from a peripheral site on the face to the brain along a nerve axon following HSV-1 reactivation.[1] The virus lies dormant in the ganglion of the trigeminal or fifth cranial nerve, but the exact mechanism of reactivation and neuroinvasion remains unknown. The olfactory nerve may also be involved, providing a direct route from the nasal mucosa to the orbitofrontal and medial temporal structures.[9] Primary infection with direct neuroinvasion accounts for a minority of cases, chiefly in children and young adults.[10]

Host genetic susceptibility contributes to disease in a subset of patients. A dominant-negative TLR3 allele was identified in otherwise healthy children with HSV-1 encephalitis; TLR3 is expressed in the central nervous system, where it is required to control HSV-1, but appears redundant for host defence against most other microbes.[5] Subsequent work has extended this to other defects of the TLR3–type I interferon axis, and the intensity and persistence of the interferon signature, together with specific HLA alleles, correlate with the risk of post-infectious autoimmune complications.[11]

The resulting pathology is an asymmetric necrotising, frequently haemorrhagic encephalitis with a predilection for the medial temporal lobe, insular cortex, cingulate gyrus and orbitofrontal cortex, accompanied by perivascular lymphocytic cuffing, microglial nodules and Cowdry type A intranuclear inclusions. Cytotoxic and vasogenic oedema, raised intracranial pressure and seizures follow, and the anatomical distribution of injury explains the characteristic residual deficits in memory, language and behaviour.[10]

Causes

Herpes simplex encephalitis is caused by HSV-1 or HSV-2. HSV-1 accounts for more than 90% of cases outside the neonatal period, whereas HSV-2 is the predominant cause of neonatal central nervous system disease and is over-represented among immunocompromised patients.[8][10]

Differentiating Herpes Simplex Encephalitis from Other Diseases

Herpes simplex encephalitis must be differentiated from other diseases that cause fever, headache, seizures and altered mental status.[12][13][14][15]

Disease Similarities Differentials
Meningitis Classic triad of fever, nuchal rigidity and altered mental status Photophobia, phonophobia, rash associated with meningococcemia, concomitant sinusitis or otitis, swelling of the fontanelle in infants; neutrophilic CSF pleocytosis with low glucose in bacterial disease; encephalopathy and focal deficits are not typical of uncomplicated meningitis
Other viral encephalitides Fever, headache, seizures, lymphocytic CSF pleocytosis Varicella zoster virus, enterovirus, West Nile virus and other arboviruses, mumps, measles; exposure, travel and vector history; anterior horn cell involvement with West Nile virus; distinguished by CSF PCR and serology[16]
Autoimmune encephalitis Subacute memory loss, psychiatric change, seizures, MRI medial temporal signal change More gradual onset, frequent movement disorder (chorea, orofacial dyskinesia), autonomic instability, absent or low-grade fever, extreme delta brush on EEG; neuronal surface antibodies in CSF and serum; may arise de novo or as a complication of herpes simplex encephalitis[6]
Brain abscess and subdural empyema Fever, headache, hemiparesis Varies with location; papilledema, focal sensory loss, parameningeal source; ring-enhancing lesion with central restricted diffusion or extra-axial collection on imaging; lumbar puncture often contraindicated
Demyelinating diseases Ataxia, lethargy, focal deficits Multiple sclerosis: nystagmus, internuclear ophthalmoplegia, Lhermitte's sign; well-demarcated ovoid lesions with T1 hypointensities. Acute disseminated encephalomyelitis: somnolence, myoclonic movements and hemiparesis; diffuse or multifocal enhancement with indistinct lesion borders
Substance abuse and drug toxicity Tremor, headache, altered mental status Varies with substance; prior history, paranoia, sudden panic, anxiety, hallucinations; lithium, sedatives, phenytoin and carbamazepine toxicity; toxicology screen and drug levels
Electrolyte disturbance Fatigue, headache, nausea, confusion Varies with deficient ion; edema, constipation, hallucinations; abnormalities of T wave, P wave and QRS complex on EKG; arrhythmia, dehydration, renal failure; afebrile with non-inflammatory CSF
Stroke Ataxia, aphasia, dizziness Abrupt maximal onset in a vascular territory; positional vertigo, high blood pressure, extremity weakness; afebrile; infarct on computed tomography or diffusion-weighted MRI
Intracranial haemorrhage Headache, coma, dizziness Lobar hemorrhage, numbness, tingling, hypertension, hemorrhagic diathesis; blood on non-contrast CT
Trauma Headache, altered mental status Amnesia, loss of consciousness, dizziness, concussion, contusion; history of injury; extra-axial collection or contusion on imaging

Herpes simplex encephalitis must also be differentiated from other causes of headache, altered mental status and seizures, including brain tumours and delirium tremens.

Disease Key clinical features CT / MRI CSF findings Gold standard test Other findings
Herpes simplex encephalitis Fever, headache, altered mental status, seizures, aphasia, personality change over hours to days Asymmetric medial temporal lobe, insular cortex and orbitofrontal T2/FLAIR hyperintensity with restricted diffusion; haemorrhage on GRE/SWI; CT normal early Lymphocytic pleocytosis, red blood cells common, mildly raised protein, normal glucose; may be acellular very early or in immunosuppression CSF HSV-1/HSV-2 PCR[4] Temporal periodic lateralised epileptiform discharges on EEG; mucocutaneous herpes usually absent
Autoimmune encephalitis Subacute psychiatric and behavioural change, seizures, movement disorder, autonomic instability; often afebrile Normal or bilateral medial temporal signal change; no necrosis or haemorrhage Mild lymphocytic pleocytosis, oligoclonal bands, normal glucose Neuronal surface antibodies in CSF and serum (e.g. NMDA receptor) May follow herpes simplex encephalitis by weeks to months; responds to immunotherapy[6]
Brain tumour Progressive headache, focal deficit, seizures; usually afebrile Mass lesion with surrounding vasogenic oedema and enhancement Malignant cells on cytology; may show raised protein[17] Contrast-enhanced MRI and histopathology Cachexia, gradual progression of symptoms
Delirium tremens Agitation, hallucinations, tremor 48-96 hours after cessation of alcohol Normal Normal Clinical diagnosis Tachycardia, diaphoresis, hypertension, mydriasis, tachypnoea; history of alcohol use with sudden withdrawal or reduction
Subarachnoid haemorrhage Thunderclap headache maximal at onset, neck stiffness, often afebrile Subarachnoid blood on non-contrast CT Uniformly blood-stained fluid that does not clear between tubes; xanthochromia[18] CT scan without contrast, followed by lumbar puncture if CT negative[19][20] Confusion, dizziness, nausea, vomiting; trauma or aneurysm
Stroke Sudden focal deficit in a vascular territory; afebrile Infarct on CT or diffusion-weighted MRI Normal CT scan without contrast and vascular imaging Transient ischaemic attacks, hypertension, diabetes mellitus; speech difficulty, gait abnormality
Neurosyphilis Chronic course, cranial nerve palsy, uveitis, cognitive decline[21][22] Variable; infarcts, meningeal enhancement or mesiotemporal change Raised leukocytes and protein Reactive serum treponemal test with CSF VDRL[23] Blindness, confusion, depression, abnormal gait; unprotected sexual intercourse, other STIs
Other viral encephalitis Viral prodrome, fever, encephalopathy; extreme lethargy Often normal or non-temporal (thalamic, basal ganglia or brainstem in arboviral disease) Mononuclear lymphocytosis, raised protein, normal glucose CSF PCR and pathogen-specific serology[16] Tick or mosquito bite, travel; rash, hepatosplenomegaly, lymphadenopathy
Wernicke's encephalopathy Ophthalmoplegia, ataxia, confusion; afebrile Mammillary body and periaqueductal signal change on MRI Normal Clinical assessment and response to thiamine History of alcohol use disorder or malnutrition
CNS abscess High-grade fever, progressive headache, focal deficit, papilledema Ring-enhancing lesion with central restricted diffusion Variable pleocytosis, raised protein; lumbar puncture often contraindicated Contrast-enhanced MRI; culture of aspirated pus Drug use, endocarditis, immunosuppression, parameningeal focus; fatigue, nausea, vomiting
Subdural empyema Fever, headache, rapidly progressive focal deficit and seizures Crescentic extra-axial collection with restricted diffusion and rim enhancement Sterile pleocytosis; lumbar puncture generally avoided Contrast-enhanced MRI and surgical drainage Antecedent sinusitis, otitis or mastoiditis
Drug toxicity Altered consciousness, ataxia, nystagmus; usually afebrile Normal Normal Serum drug levels and toxicology screen Lithium, sedatives, phenytoin, carbamazepine
Conversion disorder Non-anatomical deficits, inconsistent examination; afebrile Normal Normal Diagnosis of exclusion Tremors, blindness, difficulty swallowing; antecedent psychosocial stressor
Electrolyte disturbance and hypoglycemia Confusion, seizures, palpitations, sweating, dizziness Normal (osmotic demyelination if sodium corrected too rapidly) Normal Serum sodium, potassium, calcium, glucose and HbA1c History of diabetes mellitus, diuretic use, vomiting or diarrhoea
Febrile seizures Brief generalised seizure with fever in a child aged 6 months to 5 years, with rapid return to baseline Normal Not routinely performed in a simple febrile seizure; must be performed if encephalopathy persists Clinical diagnosis; EEG if atypical Family history of febrile seizures; intercurrent viral illness or gastroenteritis

Epidemiology and Demographics

Incidence

In a Swedish nationwide study covering the 12-year period 1990-2001, 638 patients hospitalised in Sweden received a primary diagnosis of herpes simplex encephalitis, of whom 236 had confirmed central nervous system infection due to herpes simplex virus type 1, corresponding to an incidence of confirmed disease of 2.2 cases per million population per year.[8] Herpes simplex virus is consistently the most commonly identified infectious cause of encephalitis in population-based studies from high-income settings.[16] Approximately 90% of cases are caused by HSV-1, with the remainder caused by HSV-2; HSV-2 infection is most commonly observed among immunocompromised individuals and neonates.[8][10]

Age

Herpes simplex encephalitis affects all ages. The age distribution is bimodal, with peaks in young children and in adults over 50 years of age.[24] Increasing age is an independent predictor of unfavourable outcome (odds ratio 1.04; 95% confidence interval 1.02 to 1.05).[25]

Gender

There is no consistent gender predilection to the development of herpes simplex encephalitis.[16]

Race

There is no established racial predilection to the development of herpes simplex encephalitis.[10]

Season

Unlike arboviral and enteroviral encephalitis, there is no seasonal predilection to the development of herpes simplex encephalitis, which occurs sporadically throughout the year.[24]

Risk Factors

Most patients with herpes simplex encephalitis are previously healthy, and no risk factor is identified in the majority of cases. Recognised associations include:[10][5][11]

  • Extremes of age (young children and adults over 50 years)
  • Inborn errors of the TLR3-type I interferon pathway, which underlie a proportion of childhood cases and confer a risk of recurrence
  • Immune deficiency, including HIV infection, haematological malignancy, transplantation and exposure to immunomodulatory or immunosuppressive therapy, which is associated with atypical presentation and poorer outcome
  • Neonatal exposure to maternal genital HSV-2 infection, particularly primary maternal infection near delivery

Natural History, Complications and Prognosis

Natural History

Herpes simplex encephalitis constitutes a medical emergency. Illness typically evolves over hours to a few days with fever, headache and progressive alteration of consciousness, behaviour or language, frequently punctuated by focal or generalised seizures. If left untreated, approximately 70% of patients progress to mortality.[1] Time from symptom onset to initiation of antiviral therapy is one of the few modifiable determinants of outcome.[26][25]

Complications

Common complications of herpes simplex encephalitis include:[10][27][8]

Prognosis

The prognosis of herpes simplex encephalitis remains guarded even with prompt treatment. Among patients treated with aciclovir, the mortality rate is approximately 14%-19%, and among survivors, 45%-60% have neuropsychological sequelae at 1 year.[28] In the Swedish nationwide cohort, 1-year mortality among patients with confirmed HSV-1 disease was 14% (33 of 236 patients died), which was 8 times higher than expected, and 87% of survivors were readmitted to hospital.[8]

In a multinational study of 438 evaluable adults with molecularly confirmed herpetic meningoencephalitis, 232 (52.9%) experienced an unfavourable outcome, 44 died and 188 survived with sequelae. Independent predictors of unfavourable outcome were age (odds ratio 1.04; 95% confidence interval 1.02 to 1.05), Glasgow Coma Scale score (odds ratio 0.84; 95% confidence interval 0.77 to 0.93) and duration of symptoms before treatment of 2 to 7 days (odds ratio 1.80; 95% confidence interval 1.16 to 2.79) and more than 7 days (odds ratio 3.75; 95% confidence interval 1.72 to 8.15).[25] In the original NIAID trial, 6-month mortality varied by Glasgow Coma Scale score at the onset of therapy: for scores of greater than 10, 7 to 10, and less than or equal to 6, mortality was 42, 46 and 67 percent among patients treated with vidarabine, compared with 0, 25 and 25 percent among those treated with aciclovir; at 6 months, 5 of 37 patients receiving vidarabine (14 percent) compared with 12 of 32 receiving aciclovir (38 percent) were functioning normally (P = 0.021).[2]

Diagnosis

Diagnostic Criteria

There are no criteria specific to herpes simplex encephalitis. Diagnosis is made within the framework of the International Encephalitis Consortium consensus case definition, which requires altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) lasting 24 hours or longer with no alternative cause identified, together with minor criteria including documented fever of 38 degrees Celsius or greater within 72 hours, generalised or partial seizures not attributable to a pre-existing seizure disorder, new onset of focal neurological findings, cerebrospinal fluid white blood cell count of 5 per cubic millimetre or greater, neuroimaging abnormality suggestive of encephalitis, and electroencephalographic abnormality consistent with encephalitis. Confirmed disease requires laboratory confirmation, which for herpes simplex encephalitis is a positive cerebrospinal fluid HSV PCR.[13][29]

Diagnostic Algorithm

The dominant principle is that neither neuroimaging nor lumbar puncture should delay empiric aciclovir.[27][29][25]

 
 
 
 
 
 
 
Suspected encephalitis: febrile illness with new seizure, new focal neurological signs, or altered consciousness, cognition, personality or behaviour
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start intravenous aciclovir immediately; take blood cultures, glucose, electrolytes and HIV test
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No contraindication to lumbar puncture
 
 
 
 
 
Contraindication present: reduced consciousness, focal deficit, papilledema, seizures uncontrolled, coagulopathy, immunosuppression
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immediate lumbar puncture
 
 
 
 
 
Computed tomography or MRI first, then lumbar puncture when safe; do not interrupt aciclovir
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSF analysis: opening pressure, cell count and differential, protein, glucose with paired serum glucose, HSV-1/HSV-2 PCR, VZV and enterovirus PCR, bacterial culture; plus MRI brain and EEG
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV PCR positive: continue aciclovir 14-21 days
 
 
 
 
 
 
 
 
 
HSV PCR negative
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If clinical, MRI or EEG features remain suggestive, continue aciclovir and repeat lumbar puncture at 24-48 hours; test for neuronal surface antibodies and alternative pathogens
 


History and Symptoms

If possible, a detailed and thorough history from the patient and from a collateral informant is necessary, since altered cognition frequently prevents accurate self-report. Symptoms of herpes simplex encephalitis include:[10][26][27]

Symptom duration before treatment is prognostically important, and a history extending beyond 7 days before initiation of antiviral therapy is independently associated with unfavourable outcome.[25]

Physical Examination

Physical examination findings for herpes simplex encephalitis are generally non-specific and no finding is sufficiently sensitive or specific to establish or exclude the diagnosis. Common physical examination findings include:[10][27]

Mucocutaneous herpetic lesions are usually absent and their absence has no diagnostic value; when present, associated findings may include genital or oral ulcers, conjunctivitis, chorioretinitis or erythema multiforme.

Laboratory Findings

Cerebrospinal fluid obtained by lumbar puncture characteristically shows a lymphocytic pleocytosis with increased leukocytes, often accompanied by red blood cells reflecting the necrotising and haemorrhagic nature of the process, mildly to moderately elevated protein and a normal glucose.[24][10] Cerebrospinal fluid may be acellular very early in the illness and in immunocompromised patients, and a normal cell count does not exclude the diagnosis.

Polymerase chain reaction of cerebrospinal fluid is the diagnostic test of choice. In the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluation against brain biopsy, HSV DNA was detected by PCR in cerebrospinal fluid of 53 (98%) of 54 patients with biopsy-proven disease and was detected in all 18 cerebrospinal fluid specimens obtained before brain biopsy; 4 of 19 specimens remained positive after 2 weeks of antiviral therapy. Reported sensitivity and specificity against brain biopsy were 98% and 94%, respectively.[4] A negative result obtained within the first 72 hours of symptom onset, or from a specimen with a bland cerebrospinal fluid profile, does not exclude the diagnosis, and guidelines recommend continuing aciclovir and repeating the lumbar puncture when clinical suspicion persists.[27][29]

Multiplex syndromic panels shorten time to an aetiological result but do not replace targeted PCR and culture. In a systematic review and meta-analysis, the summary sensitivity and specificity of the BioFire FilmArray meningitis/encephalitis panel were 90% (95% confidence interval 86-93%) and 97% (95% confidence interval 94-99%), respectively, with both false-positive and false-negative detections reported.[30][31]

The following table summarises cerebrospinal fluid findings in herpes simplex encephalitis compared with the principal differential diagnoses.[10][13][27]

Cerebrospinal fluid parameter Normal Herpes simplex encephalitis Other viral encephalitis Bacterial meningitis Tuberculous meningitis Autoimmune encephalitis
Cells per µL < 5 10-500 (may be < 5 in the first 24-48 hours or in immunosuppression) 10-1000 Typically > 1000 50-500 0-100
Predominant cell Lymphocyte and monocyte Lymphocyte; red blood cells commonly present Lymphocyte Neutrophil Lymphocyte Lymphocyte
Total protein (mg/dL) 15-45 60-100, occasionally higher Normal or mildly elevated Typically 100-500 Typically 100-500 Normal or mildly elevated
Glucose ratio (CSF/plasma) > 0.6 Normal, occasionally mildly reduced > 0.6 < 0.4 < 0.5 Normal
Confirmatory test Not applicable HSV-1/HSV-2 PCR; intrathecal antibody synthesis late in the illness Pathogen-specific PCR and serology Gram stain and culture Xpert MTB/RIF Ultra and mycobacterial culture Neuronal surface antibodies with oligoclonal bands

CT

Computed tomography is insensitive early in the illness and a normal scan does not exclude the diagnosis; its principal role is to exclude a mass lesion or haemorrhage before lumbar puncture when indicated. Findings on CT suggestive of herpes simplex encephalitis include subtle low density within the anterior and medial temporal lobe and the insular cortex.[32] Subtleties become more apparent over time, may progress to haemorrhage and may eventually spread to the contralateral temporal lobe after 7-10 days.[24]

MRI

Magnetic resonance imaging is the imaging modality of choice for herpes simplex encephalitis and is substantially more sensitive than computed tomography, particularly with diffusion-weighted sequences.[29][10] Findings on MRI suggestive of herpes simplex encephalitis include:[33]

  • T1
  • T1 C+ (Gd)
    • Early: enhancement is generally absent
    • Later: enhancement is variable and may appear as gyral, leptomeningeal, ring or diffuse enhancement
  • T2 and FLAIR
  • DWI/ADC
    • More sensitive than T2-weighted images
    • Restricted diffusion is common due to cytotoxic oedema
  • GE/SWI

The following video demonstrates herpes simplex encephalitis on MRI:

{{#ev:youtube|OLQlsDCcD3Y}}

Other Diagnostic Studies

Electroencephalography is abnormal in the great majority of patients and, although non-specific, supports the diagnosis and detects non-convulsive seizures. Characteristic findings are lateralised temporal slowing and periodic lateralised epileptiform discharges.[29][27] Brain biopsy is no longer routinely required and is reserved for patients with progressive undiagnosed encephalitis despite comprehensive non-invasive investigation.[29][13]

Treatment

Initial Management

Suspected herpes simplex encephalitis is a medical emergency and the following steps are performed in parallel rather than in sequence.[27][29][10][25]

  • Assess and support airway, breathing and circulation; admit to a high-dependency or critical care environment if consciousness is reduced or seizures are recurrent
  • Administer intravenous aciclovir as soon as encephalitis is suspected, ideally within 6 hours of presentation and before microbiological confirmation; delay beyond 2 to 7 days from symptom onset is independently associated with unfavourable outcome
  • Obtain blood cultures, blood glucose, electrolytes, renal and hepatic function, coagulation screen and HIV testing
  • Perform lumbar puncture unless contraindicated; if imaging is required first, do not interrupt or withhold aciclovir
  • Add empiric antibacterial therapy where bacterial meningitis cannot be excluded
  • Treat seizures and monitor for non-convulsive status epilepticus
  • Ensure adequate hydration and monitor serum creatinine, since aciclovir is nephrotoxic and may crystallise in renal tubules
  • Correct hyponatraemia, hypoglycaemia and hypoxaemia, which aggravate secondary brain injury

Medical Therapy

The mainstay of therapy for herpes simplex encephalitis is antiviral therapy, and the drug of choice is aciclovir.[2][3][29]

Population Aciclovir regimen Duration Comment
Adults 10 mg/kg intravenously every 8 hours 14-21 days Dose on ideal body weight in obesity; adjust for renal impairment; maintain hydration and monitor creatinine[29][27]
Children 3 months to 12 years 10-15 mg/kg (or 500 mg/m2) intravenously every 8 hours 21 days Higher weight-based dosing reflects more rapid clearance in children[29]
Neonates 20 mg/kg intravenously every 8 hours 21 days Repeat cerebrospinal fluid PCR near the end of therapy; treatment is extended if PCR remains positive[29]
Aciclovir intolerance or resistance Foscarnet, with cidofovir as a further alternative As guided by response Resistance is rare and is largely confined to immunocompromised hosts with prolonged prior exposure[29]

Adjunctive and unproven therapies:

  • Corticosteroids. In the DexEnceph trial, 94 adults aged 16 years or older with PCR-confirmed HSV-1 or HSV-2 encephalitis were enrolled between September 2016 and February 2022 across 53 hospitals in the UK and randomly assigned to intravenous dexamethasone 10 mg four times daily for 4 days plus intravenous aciclovir 10 mg/kg three times daily for at least 14 days (47 patients), or intravenous aciclovir alone (47 patients); 81 patients were included in the modified intention-to-treat analysis. Dexamethasone was started a median of seven days after hospital admission. Verbal memory at 26 weeks, measured by the Wechsler Memory Scale-IV auditory memory index, did not differ significantly between groups. Adverse events and serious adverse events occurred at similar rates in both arms, seizures requiring readmission and thrombotic events were uncommon and not in excess with dexamethasone, there were no treatment-related deaths, and corticosteroid use was not associated with increased viral persistence in cerebrospinal fluid.[7] Adjunctive dexamethasone is therefore not recommended routinely to improve cognitive outcome, but the absence of demonstrable harm is clinically relevant when corticosteroids are given empirically to a patient with suspected encephalitis in whom an autoimmune cause remains possible. Corticosteroids retain a role in the management of severe cerebral oedema with mass effect and in confirmed post-infectious autoimmune encephalitis.
  • Prolonged oral antiviral therapy. Following completion of a standard course of intravenous aciclovir, 87 adults with PCR-confirmed herpes simplex encephalitis were randomised to valaciclovir 2 g three times daily (40 patients) or placebo (47 patients) for 90 days. There was no clinical benefit, and routine prolonged oral antiviral suppression is not recommended.[28]

Supportive therapy includes airway protection and mechanical ventilation where required, intravenous fluids with attention to sodium balance, anticonvulsant medication for seizures, management of raised intracranial pressure, venous thromboembolism prophylaxis, nutrition and early rehabilitation.[27][10]

Aciclovir may be discontinued before completion of a full course when an alternative diagnosis is established, or when cerebrospinal fluid HSV PCR is negative on two occasions 24 to 48 hours apart in a patient with a normal level of consciousness, cerebrospinal fluid white cell count below 5 per cubic millimetre and neuroimaging that is not characteristic of herpes simplex encephalitis.[27]

Procedural / Surgical Therapy

Surgical intervention is not required for uncomplicated herpes simplex encephalitis. Procedural and surgical management is reserved for specific complications.[27][10][29]

  • Management of raised intracranial pressure: head elevation, osmotherapy, ventilatory control of PaCO2 and, in selected patients, invasive intracranial pressure monitoring within a neurocritical care pathway
  • Decompressive craniectomy: considered as a rescue measure for refractory intracranial hypertension or impending uncal herniation from massive temporal lobe swelling; supported only by observational data and case series
  • External ventricular drainage: for obstructive hydrocephalus, which is uncommon but may complicate severe brain swelling
  • Continuous EEG monitoring: indicated in patients with unexplained persistent depression of consciousness to detect non-convulsive status epilepticus
  • Repeat lumbar puncture: diagnostic rather than therapeutic; indicated when the initial PCR is negative but suspicion persists, at the end of therapy in neonates, and when post-infectious autoimmune encephalitis is suspected
  • Brain biopsy: reserved for progressive undiagnosed encephalitis despite comprehensive non-invasive investigation
  • Epilepsy surgery: considered in selected survivors with medically refractory post-encephalitic focal epilepsy

Long-Term Management

  • Surveillance for post-infectious autoimmune encephalitis. In the prospective cohort of the Spanish Herpes Simplex Encephalitis Study Group, 27% of patients with herpes simplex encephalitis developed symptoms of autoimmune encephalitis within 3 months of completing treatment with aciclovir. Presentation varied by age: patients aged 4 years or younger developed choreoathetosis, decreased level of consciousness and frequent seizures or infantile spasms, whereas children older than 4 years and adults predominantly developed behavioural and psychiatric change.[6] Persistently elevated interferon-stimulated gene signatures and specific HLA alleles identify patients at higher risk.[11] Any new or worsening neurological or psychiatric symptom after completion of antiviral therapy should prompt repeat MRI, repeat lumbar puncture with HSV PCR and testing for neuronal surface antibodies including NMDA receptor antibodies. Confirmed cases are treated with immunotherapy, not with further antiviral therapy.
  • Neuropsychological assessment and cognitive rehabilitation. Among survivors treated with aciclovir, 45%-60% have neuropsychological sequelae at 1 year, predominantly affecting memory.[28] Formal neuropsychological evaluation should be arranged before or shortly after discharge and repeated during follow-up.
  • Epilepsy management. Epilepsy was the most common diagnosis at hospital readmission in the Swedish nationwide cohort, and 87% of survivors were readmitted.[8] Anticonvulsant therapy should be reviewed periodically and refractory cases referred for specialist assessment.
  • Thromboprophylaxis and vascular surveillance. The incidence of venous thromboembolism, including pulmonary embolism, was 5-14 times higher than that in the general population in the Swedish cohort.[8]
  • Multidisciplinary rehabilitation. Physiotherapy, occupational therapy, speech and language therapy, educational and vocational support, and psychological support for patients and families.
  • Investigation for inborn errors of immunity in children with herpes simplex encephalitis, particularly after recurrent disease, given the recognised contribution of TLR3 and type I interferon pathway defects.[5][11]

Special Populations

Population Key considerations
Neonates Predominantly HSV-2; may present as isolated central nervous system disease, skin-eye-mouth disease or disseminated disease. Aciclovir 20 mg/kg intravenously every 8 hours for 21 days; cerebrospinal fluid PCR repeated near the end of therapy, with treatment extended if still positive. Neuroimaging shows diffuse rather than focal temporal involvement[29]
Children Higher weight-based aciclovir dosing and 21-day duration. Consider inborn errors of the TLR3-type I interferon pathway, particularly after recurrence. Children aged 4 years or younger who develop post-infectious autoimmune encephalitis characteristically present with choreoathetosis and decreased level of consciousness[5][6]
Immunocompromised patients Atypical presentations with fewer localising features, more diffuse or brainstem imaging abnormality, and cerebrospinal fluid that may show minimal pleocytosis despite severe disease; outcome is worse. Consider concurrent VZV, CMV, HHV-6, fungal and mycobacterial causes, and test for HIV in all patients[10][29]
Pregnancy Aciclovir is used at standard therapeutic doses; treatment must not be delayed. Coordinate obstetric and neonatal care, and plan delivery with attention to the risk of neonatal HSV transmission when genital lesions are present
Renal impairment Aciclovir dose interval must be extended according to creatinine clearance; ensure adequate hydration, monitor renal function during therapy and be alert to aciclovir-induced neurotoxicity, which may mimic worsening encephalitis[27]
Patients deteriorating after completing aciclovir Distinguish true virological relapse (repeat cerebrospinal fluid HSV PCR positive) from post-infectious autoimmune encephalitis (PCR negative, neuronal surface antibodies positive); the latter is treated with immunotherapy rather than further antiviral therapy[6][11]

The following algorithm summarises the approach to neurological deterioration after completion of antiviral therapy.

 
 
 
 
 
New or worsening neurological or psychiatric symptoms after completing aciclovir
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Repeat MRI brain, EEG and lumbar puncture with HSV PCR and neuronal surface antibody testing in CSF and serum
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV PCR positive: virological relapse - resume intravenous aciclovir
 
 
 
 
 
 
 
HSV PCR negative, neuronal antibodies positive: post-herpes simplex encephalitis autoimmune encephalitis - treat with immunotherapy
 


Primary Prevention

There is no proven strategy for the primary prevention of herpes simplex encephalitis caused by HSV-1, because disease in most patients results from reactivation of a latent virus that is acquired near-universally in childhood and carried asymptomatically.[10][1] Vaccines against herpes simplex virus have been developed but remain experimental and none is licensed for the prevention of central nervous system disease.

Measures that reduce transmission of HSV-2 are relevant to the prevention of neonatal central nervous system disease and of HSV-2 disease in adults, and include abstinence from sexual contact, a long-term mutually monogamous relationship with an uninfected partner, correct and consistent use of latex condoms, and disclosure of infection status between sexual partners. In pregnancy, recognition of maternal genital herpes and appropriate obstetric management reduce the risk of intrapartum transmission.[29]

Because no primary preventive intervention exists for the great majority of cases, the practical priority is secondary prevention of poor outcome through early recognition and immediate empiric antiviral therapy.[25][26]

Secondary Prevention

Secondary prevention is directed at limiting neurological injury and detecting complications:[27][25][6][28]

  • Immediate empiric intravenous aciclovir in every patient with suspected encephalitis, since delay of 2 to 7 days and of more than 7 days from symptom onset independently predicts unfavourable outcome
  • Completion of a full 14 to 21 day intravenous course, since relapse has been described after abbreviated therapy; prolonged oral valaciclovir maintenance is not indicated
  • Structured follow-up with repeat clinical, imaging and antibody assessment for post-infectious autoimmune encephalitis, which occurred in 27% of patients in prospective follow-up
  • Audiological, neuropsychological and epilepsy surveillance in survivors
  • Evaluation for underlying inborn errors of immunity in children, particularly after a second episode

References

  1. ↑ 1.0 1.1 1.2 1.3 Whitley RJ (2006). "Herpes simplex encephalitis: adolescents and adults". Antiviral Res. 71 (2–3): 141–148. doi:10.1016/j.antiviral.2006.04.002. PMID 16675036.
  2. ↑ 2.0 2.1 2.2 Whitley RJ, Alford CA, Hirsch MS, Schooley RT, Luby JP, Aoki FY, Hanley D, Nahmias AJ, Soong SJ (1986). "Vidarabine versus acyclovir therapy in herpes simplex encephalitis". N Engl J Med. 314 (3): 144–149. doi:10.1056/NEJM198601163140303. PMID 3001520.
  3. ↑ 3.0 3.1 Sköldenberg B, Forsgren M, Alestig K, Bergström T, Burman L, Dahlqvist E, Forkman A, Frydén A, Lövgren K, Norlin K (1984). "Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients". Lancet. 2 (8405): 707–711. doi:10.1016/s0140-6736(84)92623-0. PMID 6148470.
  4. ↑ 4.0 4.1 4.2 Lakeman FD, Whitley RJ (1995). "Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease". J Infect Dis. 171 (4): 857–863. doi:10.1093/infdis/171.4.857. PMID 7706811.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 Zhang SY, Jouanguy E, Ugolini S, Smahi A, Elain G, Romero P, Segal D, Sancho-Shimizu V, Lorenzo L, Puel A, Picard C, Chapgier A, Plancoulaine S, Titeux M, Cognet C, von Bernuth H, Ku CL, Casrouge A, Zhang XX, Barreiro L, Leonard J, Hamilton C, Lebon P, Héron B, Vallée L, Quintana-Murci L, Hovnanian A, Rozenberg F, Vivier E, Geissmann F, Tardieu M, Abel L, Casanova JL (2007). "TLR3 deficiency in patients with herpes simplex encephalitis". Science. 317 (5844): 1522–1527. doi:10.1126/science.1139522. PMID 17872438.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, Llufriu S, Muchart J, Erro ME, Abraira L, Moris G, Monros-Giménez L, Corral-Corral Í, Montejo C, Toledo M, Bataller L, Secondi G, Ariño H, Martínez-Hernández E, Juan M, Marcos MA, Alsina L, Saiz A, Rosenfeld MR, Graus F, Dalmau J (2018). "Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis". Lancet Neurol. 17 (9): 760–772. doi:10.1016/S1474-4422(18)30244-8. PMID 30049614.
  7. ↑ 7.0 7.1 Solomon T, Hooper C, Easton A, Rosala-Hallas A, Facer B, Moore P, Keller SS, Whitfield T, Fernandez C, Kneen R, Griffiths MJ, Das K, Moore SC, Davies K, Wheatley D, Stahl JP, Hardwick B, Defres S, Michael BD, Burnside G, Ellul MA (2026). "Safety and efficacy of adjunct dexamethasone in adults with herpes simplex virus encephalitis in the UK (DexEnceph): a multicentre, observer-blind, randomised, phase 3, controlled trial". Lancet Neurol. 25 (2): 136–146. doi:10.1016/S1474-4422(25)00454-5. PMID 41579900 Check |pmid= value (help).
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 Hjalmarsson A, Blomqvist P, Sköldenberg B (2007). "Herpes simplex encephalitis in Sweden, 1990-2001: incidence, morbidity, and mortality". Clin Infect Dis. 45 (7): 875–880. doi:10.1086/521262. PMID 17806053.
  9. ↑ Dinn JJ (1980). "Transolfactory spread of virus in herpes simplex encephalitis". Br Med J. 281 (6252): 1392. doi:10.1136/bmj.281.6252.1392. PMID 7437807.
  10. ↑ 10.00 10.01 10.02 10.03 10.04 10.05 10.06 10.07 10.08 10.09 10.10 10.11 10.12 10.13 10.14 10.15 10.16 Venkatesan A, Michael BD, Probasco JC, Geocadin RG, Solomon T (2019). "Acute encephalitis in immunocompetent adults". Lancet. 393 (10172): 702–716. doi:10.1016/S0140-6736(18)32526-1. PMID 30782344.
  11. ↑ 11.0 11.1 11.2 11.3 11.4 Armangué T, Olivé-Cirera G, Martínez-Hernandez E, Rodes M, Peris-Sempere V, Guasp M, Ruiz R, Palou E, González A, Marcos MA, Erro ME, Bataller L, Corral-Corral Í, Planagumà J, Caballero E, Vlagea A, Chen J, Bastard P, Materna M, Marchal A, Abel L, Cobat A, Alsina L, Fortuny C, Saiz A, Mignot E, Vanderver A, Casanova JL, Zhang SY, Dalmau J (2023). "Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies". Brain. 146 (10): 4306–4319. doi:10.1093/brain/awad238. PMID 37453099 Check |pmid= value (help).
  12. ↑ Kennedy PG (2004). "Viral encephalitis: causes, differential diagnosis, and management". J Neurol Neurosurg Psychiatry. 75 Suppl 1: i10–i15. doi:10.1136/jnnp.2003.034280. PMID 14978145.
  13. ↑ 13.0 13.1 13.2 13.3 Venkatesan A, Tunkel AR, Bloch KC, Lauring AS, Sejvar J, Bitnun A, Stahl JP, Mailles A, Drebot M, Rupprecht CE, Yoder J, Cope JR, Wilson MR, Whitley RJ, Sullivan J, Granerod J, Jones C, Eastwood K, Ward KN, Durrheim DN, Solbrig MV, Guo-Dong L, Glaser CA (2013). "Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium". Clin Infect Dis. 57 (8): 1114–1128. doi:10.1093/cid/cit458. PMID 23861361.
  14. ↑ Eckstein C, Saidha S, Levy M (2012). "A differential diagnosis of central nervous system demyelination: beyond multiple sclerosis". J Neurol. 259 (5): 801–816. doi:10.1007/s00415-011-6240-5. PMID 21932127.
  15. ↑ De Kruijk JR, Twijnstra A, Leffers P (2001). "Diagnostic criteria and differential diagnosis of mild traumatic brain injury". Brain Inj. 15 (2): 99–106. doi:10.1080/026990501458335. PMID 11260760.
  16. ↑ 16.0 16.1 16.2 16.3 Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, Cunningham R, Zuckerman M, Mutton KJ, Solomon T, Ward KN, Lunn MP, Irani SR, Vincent A, Brown DW, Crowcroft NS (2010). "Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study". Lancet Infect Dis. 10 (12): 835–844. doi:10.1016/S1473-3099(10)70222-X. PMID 20952256.
  17. ↑ Weston CL, Glantz MJ, Connor JR (2011). "Detection of cancer cells in the cerebrospinal fluid: current methods and future directions". Fluids Barriers CNS. 8 (1): 14. doi:10.1186/2045-8118-8-14. PMID 21371327.
  18. ↑ Lee MC, Heaney LM, Jacobson RL, Klassen AC (1975). "Cerebrospinal fluid in cerebral hemorrhage and infarction". Stroke. 6 (6): 638–641. doi:10.1161/01.str.6.6.638. PMID 1198628.
  19. ↑ Birenbaum D, Bancroft LW, Felsberg GJ (2011). "Imaging in acute stroke". West J Emerg Med. 12 (1): 67–76. PMID 21694755.
  20. ↑ DeLaPaz RL, Wippold FJ, Cornelius RS, Amin-Hanjani S, Angtuaco EJ, Broderick DF (2011). "ACR Appropriateness Criteria on cerebrovascular disease". J Am Coll Radiol. 8 (8): 532–538. doi:10.1016/j.jacr.2011.05.010. PMID 21807345.
  21. ↑ Liu LL, Zheng WH, Tong ML, Liu GL, Zhang HL, Fu ZG (2012). "Ischemic stroke as a primary symptom of neurosyphilis among HIV-negative emergency patients". J Neurol Sci. 317 (1–2): 35–39. doi:10.1016/j.jns.2012.03.003. PMID 22482824.
  22. ↑ Berger JR, Dean D (2014). "Neurosyphilis". Handb Clin Neurol. 121: 1461–1472. doi:10.1016/B978-0-7020-4088-7.00098-5. PMID 24365430.
  23. ↑ Ho EL, Marra CM (2012). "Treponemal tests for neurosyphilis--less accurate than what we thought?". Sex Transm Dis. 39 (4): 298–299. doi:10.1097/OLQ.0b013e31824ee574. PMID 22421697.
  24. ↑ 24.0 24.1 24.2 24.3 Whitley RJ, Gnann JW (2002). "Viral encephalitis: familiar infections and emerging pathogens". Lancet. 359 (9305): 507–513. doi:10.1016/S0140-6736(02)07681-X. PMID 11853816.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 25.5 25.6 25.7 Erdem H, Cag Y, Ozturk-Engin D, Defres S, Kaya S, Larsen L, Poljak M, Barsic B, Argemi X, Sørensen SM, Bohr AL, Tattevin P, Gunst JD, Baštáková L, Jereb M, Johansen IS, Karabay O, Pekok AU, Sipahi OR, Chehri M, Beraud G, Shehata G, Del Vecchio RF, Maresca M, Karsen H, Sengoz G, Sunbul M, Yilmaz G, Yilmaz H, Sharif-Yakan A, Kanj SS, Parlak E, Pehlivanoglu F, Korkmaz F, Komur S, Kose S, Ulug M, Bolukcu S, Coskuner SA, Ince N, Akkoyunlu Y, Halac G, Sahin-Horasan E, Tireli H, Kilicoglu G, Al-Mahdawi A, Nemli SA, Inan A (2015). "Results of a multinational study suggest the need for rapid diagnosis and early antiviral treatment at the onset of herpetic meningoencephalitis". Antimicrob Agents Chemother. 59 (6): 3084–3089. doi:10.1128/AAC.05016-14. PMID 25779579.
  26. ↑ 26.0 26.1 26.2 Raschilas F, Wolff M, Delatour F, Chaffaut C, De Broucker T, Chevret S, Lebon P, Canton P, Rozenberg F (2002). "Outcome of and prognostic factors for herpes simplex encephalitis in adult patients: results of a multicenter study". Clin Infect Dis. 35 (3): 254–260. doi:10.1086/341405. PMID 12115090.
  27. ↑ 27.00 27.01 27.02 27.03 27.04 27.05 27.06 27.07 27.08 27.09 27.10 27.11 27.12 27.13 Solomon T, Michael BD, Smith PE, Sanderson F, Davies NW, Hart IJ, Holland M, Easton A, Buckley C, Kneen R, Beeching NJ (2012). "Management of suspected viral encephalitis in adults--Association of British Neurologists and British Infection Association National Guidelines". J Infect. 64 (4): 347–373. doi:10.1016/j.jinf.2011.11.014. PMID 22120595.
  28. ↑ 28.0 28.1 28.2 28.3 Gnann JW, Sköldenberg B, Hart J, Aurelius E, Schliamser S, Studahl M, Eriksson BM, Hanley D, Aoki F, Jackson AC, Griffiths P, Miedzinski L, Hanfelt-Goade D, Hinthorn D, Ahlm C, Aksamit A, Cruz-Flores S, Dale I, Cloud G, Jester P, Whitley RJ (2015). "Herpes simplex encephalitis: lack of clinical benefit of long-term valacyclovir therapy". Clin Infect Dis. 61 (5): 683–691. doi:10.1093/cid/civ369. PMID 25956891.
  29. ↑ 29.00 29.01 29.02 29.03 29.04 29.05 29.06 29.07 29.08 29.09 29.10 29.11 29.12 29.13 29.14 29.15 Tunkel AR, Glaser CA, Bloch KC, Sejvar JJ, Marra CM, Roos KL, Hartman BJ, Kaplan SL, Scheld WM, Whitley RJ (2008). "The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America". Clin Infect Dis. 47 (3): 303–327. doi:10.1086/589747. PMID 18582201.
  30. ↑ Tansarli GS, Chapin KC (2020). "Diagnostic test accuracy of the BioFire FilmArray meningitis/encephalitis panel: a systematic review and meta-analysis". Clin Microbiol Infect. 26 (3): 281–290. doi:10.1016/j.cmi.2019.11.016. PMID 31760115.
  31. ↑ Leber AL, Everhart K, Balada-Llasat JM, Cullison J, Daly J, Holt S, Lephart P, Salimnia H, Schreckenberger PC, DesJarlais S, Reed SL, Chapin KC, LeBlanc L, Johnson JK, Soliven NL, Carroll KC, Miller JA, Dien Bard J, Mestas J, Bankowski M, Enomoto T, Hemmert AC, Bourzac KM (2016). "Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens". J Clin Microbiol. 54 (9): 2251–2261. doi:10.1128/JCM.00730-16. PMID 27335149.
  32. ↑ Zimmerman RD, Russell EJ, Leeds NE, Kaufman D (1980). "CT in the early diagnosis of herpes simplex encephalitis". AJR Am J Roentgenol. 134 (1): 61–66. doi:10.2214/ajr.134.1.61. PMID 6766039.
  33. ↑ Bulakbasi N, Kocaoglu M (2008). "Central nervous system infections of herpesvirus family". Neuroimaging Clin N Am. 18 (1): 53–84. doi:10.1016/j.nic.2007.12.001. PMID 18319155.


Template:WikiDoc Sources

Retrieved from "https://www.wikidoc.org/index.php?title=Herpes_simplex_encephalitis&oldid=1745584"