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Herpes Simplex Encephalitis
Article Last Updated: Mar 13, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Wayne E Anderson, DO, Assistant Professor of Internal Medicine/Neurology, Western University of Health Sciences; Assistant Professor of Family Medicine, Touro University College of Osteopathic Medicine; Consulting Staff in Pain Management, Department of Neurology, California Pacific Medical Center
Wayne E Anderson is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American Medical Association, American Society of Law Medicine and Ethics, California Medical Association, and San Francisco Medical Society
Editors: Ramon Diaz-Arrastia, MD, PhD, Assistant Professor, Department of Neurology, Comprehensive Epilepsy Center, University of Texas Southwestern; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Author and Editor Disclosure
Synonyms and related keywords:
herpes, genital herpes, herpes encephalitis, encephalitis, HSE, HSV-1, HSV-2, cold sores, fever blisters, herpes simplex virus, human herpesvirus, HHV, HHV-1, herpes simplex virus type 1, herpes simplex virus type 2, herpes simplex encephalitis
Background
The human herpesvirus (HHV) family includes 2 clinically important strains, also known as herpes simplex virus (HSV). Human herpesvirus 1 (HHV-1), also called herpes simplex virus type 1 (HSV-1), causes oral lesions (so-called fever blisters); these are common and may respond to antiviral medications, although they spontaneously remit in most cases. Human herpesvirus 2 (HHV-2), also known as herpes simplex virus type 2 (HSV-2), causes genital lesions. It was previously thought to appear within 1-2 weeks of primary infection, then to recur with lessening severity. That lesions may appear clinically at any interval after primary infection is now known. HSV-2 may be treated with antiviral medications.
Patients with HSV may require long-term antiviral treatment if they have recurrent lesions or involvement of other organ systems (eg, herpes simplex keratitis). HSV remains dormant in the nervous system; rarely, it presents as encephalitis, possibly by direct transmission through peripheral nerves to the CNS. This encephalitis is a neurologic emergency and the most important neurologic sequela of HSV.
Pathophysiology
Besides causing local outbreaks, HSV-1 and HSV-2 are associated with encephalitis. HSV-1 is the more common cause of adult encephalitis. HSV-2 is the more common cause of newborn encephalitis, which is associated with maternal genital infections. Pathophysiology of this encephalitis is poorly understood in humans. Animal models suggest that the virus enters the CNS via peripheral nerves. Virus-induced apoptosis may play a role in the molecular pathogenesis of herpes simplex encephalitis (HSE). HSV is an enveloped, double-stranded DNA virus. It is part of the herpes family, which also includes varicella-zoster virus (VZV, or HHV-3) and cytomegalovirus (CMV, or HHV-5).
The encephalitis affects the temporal lobes of the brain in most cases. Wasay et al report temporal lobe involvement in 60% of patients. Fifty-five percent of patients demonstrated temporal and extratemporal pathology, and 15% of patients demonstrated extratemporal pathology exclusively.
Frequency
United States
HSE is the most common nonepidemic encephalitis. Incidence is 2 cases per million population per year. HSE may occur year-round. HSV-1 is ubiquitous and HSV-2 is also common.
International
International incidence is similar to that in the United States.
Mortality/Morbidity
HSV-1 and HSV-2 infections often recur. HSE rarely occurs. Untreated HSE is progressive and often fatal in 7-14 days. However, significant morbidity exists among those treated. A landmark study by Whitley et al in 1977 revealed a 70% mortality rate in untreated patients and severe neurologic deficits in most of the survivors (Whitley, 1977). The following demonstrate the variety of complications.
- Elbers and colleagues followed properly treated children for 12 years after the HSE. They found seizures in 44% of the children and developmental delay in 25% of the children. They concluded that HSE continues to be associated with poor long-term neurologic outcomes despite appropriate therapy (Elbers, 2007).
- Shelley and colleagues reported a case of intracerebral hematoma occurring in a patient successfully treated with a full course of acyclovir after apparent eradication of the virus. The hematoma occurred in the region of the encephalitis (Shelley, 2007).
- Marschitz and colleagues reported a case of chorea after HSE (Marschitz, 2007).
Sex
- Herpes affects both sexes equally.
- Genital herpes may be more apparent in the male because of anatomy.
Age
One third of HSE cases occur in children.
History
- In HSE, patients may have a prodrome of malaise, fever, headache, and nausea.
- This is followed by acute or subacute onset of an encephalopathy whose symptoms include lethargy, confusion, and delirium.
- Headaches, seizures, aphasia, and other focal deficits also may occur.
Physical
- On neurological examination, global and focal neurologic findings include encephalopathy, delirium, aphasia, cranial nerve deficits, and hemiparesis.
- Meningeal signs may be present.
- Unusual presentations occur. Both HSV-1 and HSV-2 may produce a more subacute encephalitis, apparent psychiatric syndromes, and benign recurrent meningitis. Less commonly, HSV-1 may produce a brain stem encephalitis and HSV-2, a myelitis.
- Ku et al discussed the unique presentation of HSE in a bilingual patient. He developed global aphasia for 1 language (his most recently learned language) but retained most of his birth language ability.
- McGrath et al reported on 4 patients with confirmed HSE, each with an anterior opercular syndrome. The syndrome (ie, paralysis of the masticatory, facial, pharyngeal, and lingual muscles) occurred as the primary manifestation of HSE in 2 patients and as part of the encephalitis picture in the other 2 patients. The authors suggested that unique presentations, such as the anterior opercular syndrome, should alert the clinician to the possibility of HSE.
Causes
- In adults, the host immune response, combined with viral factors, determines invasiveness and virulence.
- Mitchell et al showed that invasiveness of HSV-1 glycoprotein variants is controlled by host response.
- Geiger et al used interferon-gamma–knockout mice to show how interferon-gamma protected against HSV-1–mediated neuronal death.
- These data suggested that the presentation and severity of encephalitis vary.
- Evidence from a European study suggested that socioeconomic status and geography might affect levels of virus seropositivity. However, clinical correlation is difficult because HSE can occur at any time, regardless of the patient's socioeconomic status, age, race, or sex.
- In children, encephalitis often results from primary infection with HSV. Approximately 80% of children with HSE do not have a history of labial herpes.
- In newborns, a preexisting but recurrent maternal genital herpes infection results in 8% risk of symptomatic infection, usually transmitted at the second stage of labor via direct contact. Should the mother acquire genital herpes during pregnancy, the risk increases to 40%.
- Cathomas et al report a case of HSE as a complication of chemotherapy for breast cancer.
Acute Disseminated Encephalomyelitis
Aphasia
Aseptic Meningitis
Benign Childhood Epilepsy
Benign Neonatal Convulsions
Childhood Migraine Variants
Complex Partial Seizures
Confusional States and Acute Memory Disorders
Dissection Syndromes
Early Myoclonic Encephalopathy
EEG in Common Epilepsy Syndromes
EEG in Dementia and Encephalopathy
EEG in Status Epilepticus
Epileptiform Discharges
Frontal Lobe Epilepsy
Frontal Lobe Syndromes
Generalized EEG Waveform Abnormalities
Haemophilus Meningitis
HIV-1 Associated CNS Complications (Overview)
Intracranial Epidural Abscess
Intracranial Hemorrhage
Lennox-Gastaut Syndrome
Leptomeningeal Carcinomatosis
Migraine Headache
Migraine Headache: Pediatric Perspective
Migraine Variants
Neurosyphilis
Paraneoplastic Encephalomyelitis
Seizures and Epilepsy: Overview and Classification
Simple Partial Seizures
Status Epilepticus
Temporal Lobe Epilepsy
Other Problems to be Considered
Complex partial status epilepticus
Myoclonus
Partial seizures with secondary generalization
Seizure, partial (focal)
Benign epilepsy syndromes
Management of increased intracranial pressure in the neuro ICU
Management of intracranial hemorrhage in the neuro ICU
EEG in coma
Increased intracranial pressure
Neuro-Behçet disease
Lab Studies
- In suspected HSE, the workup must be initiated rapidly and should not delay treatment.
- General laboratory studies are not helpful in diagnosis but may show evidence of infection or detect renal disease (in which case, treatment must be adjusted).
Imaging Studies
- CT scan
- Low-density lesions may be found in two thirds of cases, especially in the temporal lobes, but they may not appear until 3-4 days after onset.
- Edema and hemorrhages may be present.
- After 1 week, contrast enhancement may be detectable.
- MRI
- Being more sensitive than CT scan, MRI is now the imaging study of choice.
- Temporal lobe involvement, sometimes hemorrhagic, and early involvement of white matter are typical. The inferomedial portion of the temporal lobe is most commonly affected on MRI, sometimes in association with abnormalities of the cingulate gyrus.
- Proton-density and T2 images may be more helpful than T1 images.
Other Tests
- Electroencephalography
- EEG is quite sensitive and shows abnormalities in four fifths of biopsy-proven cases of HSE.
- Focal temporal changes or diffuse slowing may be observed.
- Periodic complexes and periodic lateralizing epileptiform discharges (PLEDs), in the proper clinical context, are strongly suggestive of HSE.
- However, Beneto et al reported 9 patients with confirmed HSE who had no PLED activity or had other EEG patterns.
Procedures
- Once a space-occupying lesion has been excluded by imaging, lumbar puncture always should be performed in suspected HSE.
- Acutely, a typical "viral profile" is identified, with mildly elevated protein, normal glucose, and a moderate pleocytosis (mostly mononuclear cells).
- Red blood cells and xanthochromia may be seen.
- The fluid should be sent for HSV-1 and HSV-2 polymerase chain reaction (PCR) to detect HSV DNA.
- In general, cerebrospinal fluid (CSF) yield is proportional to the volume analyzed; an adequate volume of CSF should be obtained (>10 mL).
- PCR is highly specific. Importantly, it remains positive up to 5 days after initiation of treatment.
- Intrathecal antibodies can be quantified, thus giving evidence for a CNS antibody response.
Histologic Findings
Orbitofrontal or limbic encephalitis may be seen. One hallmark of the condition is significant hemorrhage in these locations. Cowdry A inclusions are seen.
Medical Care
- General nutritional and fluid support is important. Universal precautions are appropriate. Monitor for increased intracranial pressure and seizures.
- Increased intracranial pressure
- Treatment of brain edema ranges from simple measures (eg, elevating head of bed, gentle diuresis with medication such as furosemide) to more complex measures (eg, mannitol and steroids, intubation with hyperventilation).
- Seizures
- Behavioral manifestations of HSE may resemble seizures, which are also common.
- Should seizure activity become apparent or should the EEG show evidence of nonconvulsive seizures, begin anticonvulsant therapy.
- Benzodiazepines may be useful for aborting status epilepticus but, because of their short duration, are ineffective at preventing further seizures.
- A longer-acting agent is preferable.
Surgical Care
- When HSE diagnosis cannot be established, brain biopsy can yield definitive diagnosis. Biopsy may be considered when lumbar puncture is precluded or nondiagnostic but is rarely used today with the availability of nontoxic and effective antiviral medications.
Consultations
- HSE is a neurologic emergency. Consultation with a neurologist is required.
- Neurosurgical consultation is helpful only if a brain biopsy is being considered.
- An infectious disease consultation may be appropriate.
- An evaluation for rehabilitation is often appropriate to deal with the long-term neurological sequelae of HSE.
The goals of therapy are to reduce morbidity and to prevent complications.
Pharmacotherapy for HSE is available in the form of acyclovir and vidarabine.
Patient outcome is improved when treated with either of these agents. Acyclovir is more effective and less toxic.
When the diagnosis of HSE is suspected or has been established, IV acyclovir should be initiated immediately.
Drug Category: Antivirals
The goals of using antivirals are to shorten the clinical course, prevent complications, prevent development of latency and subsequent recurrences, decrease transmission, and eliminate established latency.
| Drug Name | Acyclovir (Zovirax) |
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| Description | Has demonstrated inhibitory activity against both HSV-1 and HSV-2 and is taken up selectively by infected cells; rate of mortality from HSE before use of acyclovir was 60-70%—since acyclovir, it is approximately 30%.
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| Adult Dose | 10 mg/kg/dose IV or 500 mg/m2/dose IV q8h |
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| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Half-life prolonged and toxicity increased by concomitant probenecid or zidovudine |
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| Pregnancy | B - Usually safe but benefits must outweigh the risks.
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| Precautions | Use caution in patients with renal failure or receiving other nephrotoxic drugs concurrently |
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Drug Category: Anticonvulsants
These agents are used to terminate clinical and electrical seizure activity as rapidly as possible and prevent seizure recurrence.
| Drug Name | Carbamazepine (Tegretol) |
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| Description | Effective in treatment of complex partial seizures; appears to act by reducing polysynaptic responses and blocking posttetanic potentiation.
Once a response is attained, attempt to reduce dose to minimum effective level or to discontinue drug at least once q3mo. |
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| Adult Dose | 200 mg PO bid or 100 mg suspension PO qid; increase at weekly intervals by no more than 200 mg/d tid/qid (bid with extended release) until best response obtained; not to exceed 1600 mg/d |
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| Pediatric Dose | <6 years: 10-20 mg/kg/d PO bid/tid (qid with suspension); increase weekly to achieve optimal clinical response administered tid/qid
6-12 years: 100 mg PO bid or 50 mg suspension PO qid; increase at weekly intervals by gradually adding another 100 mg/d on tid/qid schedule (bid with extended release) until best response obtained; not to exceed 1000 mg/d
>12 years: Administer as in adults; not to exceed 1000 mg/d in children aged 12-15 y or 1200 mg/d in patients >15 y |
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| Contraindications | Documented hypersensitivity, history of bone marrow depression, concomitant MAOIs, concomitant danazol |
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| Interactions | May decrease primidone and phenobarbital levels; serum concentrations may be increased by concurrent primidone or phenobarbital; plasma levels and toxicity may increase with concurrent cimetidine—interaction of greatest clinical importance when cimetidine added to carbamazepine during first 4 wk of therapy; levels increase 38-123% within 30 d of danazol administration |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Do not use concomitantly with MAOIs; discontinue MAOIs for >14 d before carbamazepine administration
This drug is not a simple analgesic; do not use for relief of minor aches or pains; use caution in patients with increased intraocular pressure
Obtain complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron, as baseline; monthly CBC, differential, platelets during the first 2 mo and thereafter yearly or every other year
May produce drowsiness, dizziness, or blurred vision; patients should observe caution while driving or performing other tasks requiring alertness, coordination, or physical dexterity |
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| Drug Name | Phenytoin (Dilantin) |
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| Description | A hydantoin, its primary site of action appears to be motor cortex, where it may inhibit spread of seizure activity; may reduce maximal activity of brain stem centers responsible for tonic phase of grand mal seizures.
Dose should be individualized; if daily dosage cannot be divided equally, larger dose should be given before bedtime.
Phosphorylated formulation, fosphenytoin, available for parenteral use (IV/IM). |
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| Adult Dose | Initial: 100 mg PO/IV tid or 125 mg suspension PO tid
Maintenance: 300-400 mg/d PO/IV divided tid (qd/bid if extended release); increase to 600 mg/d (625 mg/d suspension) prn; not to exceed 1500 mg/d |
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| Pediatric Dose | Initial: 5 mg/kg/d PO/IV divided bid/tid
Maintenance: 4-8 mg/kg PO/IV divided bid/tid; not to exceed 300 mg/d
> 6 years: May require minimum adult dose (300 mg/d); not to exceed this dose |
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| Contraindications | Documented hypersensitivity; SA block, sinus bradycardia, second- and third-degree AV block, Adams-Stokes syndrome (because of effects on ventricular automaticity) |
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| Interactions | Toxicity may be increased by amiodarone, benzodiazepines, chloramphenicol, cimetidine, disulfiram, ethanol (acute ingestion), fluconazole, isoniazid, metronidazole, miconazole, omeprazole, phenacemide, phenylbutazone, succinimides, sulfonamides, trimethoprim, and valproic acid; effects may be decreased by barbiturates, carbamazepine, diazoxide, ethanol (chronic ingestion), rifampin, theophylline, antacids, charcoal, and sucralfate; may decrease effects of acetaminophen, amiodarone, carbamazepine, cardiac glycosides, corticosteroids, dicumarol, disopyramide, doxycycline, estrogens, haloperidol, methadone, metyrapone, mexiletine, oral contraceptives, quinidine, theophylline, and valproic acid |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Death from cardiac arrest has occurred after too-rapid IV administration, sometimes preceded by marked QRS widening; discontinue if hepatic dysfunction occurs; discontinue if skin rash appears—do not resume if rash is exfoliative, bullous, or purpuric; use caution in patients with diabetes (may raise blood glucose) or acute intermittent porphyria
May cause blood dyscrasias; obtain baseline CBC and urinalysis, repeat monthly for several months thereafter |
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Further Inpatient Care
- ICU care may be required, especially if seizure activity or increased intracranial pressure is present.
- Hospitalization is not routine for uncomplicated HSV-1 or HSV-2 infection.
Further Outpatient Care
- Depending on the neurologic deficits, rehabilitation services may be required after HSE.
- Education may help reduce spread of HSV-2.
In/Out Patient Meds
- If chronic suppressive therapy is needed, acyclovir or famciclovir can be used orally.
Complications
- Common sequelae among survivors include motor deficits, seizure disorders, and changes in mental status.
- If treatment of HSE is delayed, permanent neurological deficits may occur in survivors.
- Even in treated cases of HSE, complications and sequelae are not uncommon.
- Both focal and global sequelae may occur, and survivors may require permanent assistance.
- Cognitive and memory deficits are particularly common, as are recurrent seizures.
Prognosis
- Anterograde memory often is impaired even with successful treatment of HSE.
- Retrograde memory, executive function, and language ability also may be impaired. A study by Utley et al showed that patients who had a shorter delay ( <5 d) between presentation and treatment had better cognitive outcomes.
Patient Education
Medical/Legal Pitfalls
- Because delayed diagnosis increases morbidity and mortality, failure to diagnose and treat early could result in litigation. With the availability of potentially beneficial therapy, initiating treatment before a definitive diagnosis of HSE (ie, during the workup) should be considered. However, the literature demonstrates that even with appropriate therapy, significant morbidity is the rule rather than the exception.
- The belief that HSV-2 lesions appear initially 2 wk after primary infection can lead to false accusations of infidelity. The physician should emphasize that initial outbreak of lesions may occur at any time, possibly years, after infection.
- Athmanathan S, Vydehi BV. Neuronal apoptosis in herpes simplex virus-1 encephalitis (HSE). Medical Microbiology. 2001;19:127-131.
- Baxter P, Forsyth R, Eyre J. Relapse and movement disorder after herpes simplex encephalitis. J Child Neurol. Jun 1997;12(4):283. [Medline].
- Beneto A, Gomez E, Rubio P, et al. [Periodical EEG pattern modifications in herpetic encephalitis treated with acyclovir]. Rev Neurol. Jul 1996;24(131):829-32. [Medline].
- Brown ZA, Vontver LA, Benedetti J, et al. Effects on infants of a first episode of genital herpes during pregnancy. N Engl J Med. Nov 12 1987;317(20):1246-51. [Medline].
- Cathomas R, Pelosi E, Smart J. Herpes simplex encephalitis as a complication of adjuvant chemotherapy treatment for breast cancer. Clin Oncol (R Coll Radiol). Jun 2005;17(4):292-3. [Medline].
- Cinque P, Cleator GM, Weber T, et al. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry. Oct 1996;61(4):339-45. [Medline].
- Elbers JM, Bitnun A, Richardson SE. A 12-year prospective study of childhood herpes simplex encephalitis: is there a broader spectrum of disease?. Pediatrics. Feb 2007;119(2):e399-407. [Medline].
- Geiger KD, Nash TC, Sawyer S, et al. Interferon-gamma protects against herpes simplex virus type 1-mediated neuronal death. Virology. Nov 24 1997;238(2):189-97. [Medline].
- Hasegawa T, Kanno S, Kato M, et al. Neuro-Behçet's disease presenting initially as mesiotemporal lesions mimicking herpes simplex encephalitis. Eur J Neurol. Aug 2005;12(8):661-2. [Medline].
- Jereb M, Lainscak M, Marin J, Popovic M. Herpes simplex virus infection limited to the brainstem. Wien Klin Wochenschr. Jul 2005;117(13-14):495-9. [Medline].
- Ku A, Lachmann EA, Nagler W. Selective language aphasia from herpes simplex encephalitis. Pediatr Neurol. Sep 1996;15(2):169-71. [Medline].
- Marschitz I, Rodl S, Gruber-Sedlmayr U. Severe chorea with positive anti-basal ganglia antibodies after herpesencephalitis. J Neurol Neurosurg Psychiatry. Jan 2007;78(1):105-7. [Medline].
- McGrath NM, Anderson NE, Hope JK, et al. Anterior opercular syndrome, caused by herpes simplex encephalitis. Neurology. Aug 1997;49(2):494-7. [Medline].
- Mitchell BM, Stevens JG. Neuroinvasive properties of herpes simplex virus type 1 glycoprotein variants are controlled by the immune response. J Immunol. Jan 1 1996;156(1):246-55. [Medline].
- Preiser W, Weber B, Klos G, et al. Unusual course of herpes simplex virus encephalitis after acyclovir therapy. Infection. Sep-Oct 1996;24(5):384-9. [Medline].
- Shelley BP, Raniga SB, Al-Khabouri J. An unusual late complication of intracerebral haematoma in herpes encephalitis after successful acyclovir treatment. J Neurol Sci. Jan 31 2007;252(2):177-80. [Medline].
- Shian WJ, Chi CS. Magnetic resonance imaging of herpes simplex encephalitis. Zhonghua Min Guo Xiao Er Ke Yi Xue Hui Za Zhi. Jan-Feb 1996;37(1):22-6. [Medline].
- Utley TF, Ogden JA, Gibb A, et al. The long-term neuropsychological outcome of herpes simplex encephalitis in a series of unselected survivors. Neuropsychiatry Neuropsychol Behav Neurol. Jul 1997;10(3):180-9. [Medline].
- Wasay M, Mekan SF, Khelaeni B, et al. Extra temporal involvement in herpes simplex encephalitis. Eur J Neurol. Jun 2005;12(6):475-9. [Medline].
- Whitley RJ, Soong SJ, Dolin R, et al. Adenine arabinoside therapy of biopsy-proved herpes simplex encephalitis. National Institute of Allergy and Infectious Diseases collaborative antiviral study. N Engl J Med. Aug 11 1977;297(6):289-94. [Medline].
- Whitley RJ, Soong SJ, Linneman C Jr, et al. Herpes simplex encephalitis. Clinical Assessment. JAMA. Jan 15 1982;247(3):317-20. [Medline].
- Whitley RJ. Viral encephalitis. N Engl J Med. Jul 26 1990;323(4):242-50. [Medline].
Herpes Simplex Encephalitis excerpt Article Last Updated: Mar 13, 2007
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