AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Despite advances in antiviral therapy over the past 2 decades, herpes simplex encephalitis (HSE) remains a serious illness with significant risks of morbidity and death.^{1, 2, 3} HSE occurs as 2 distinct entities.

• In children older than 3 months and in adults, HSE is usually localized to the temporal and frontal lobes and is caused by herpes simplex virus type 1 (HSV-1).
• In neonates, however, brain involvement is generalized, and the usual cause is herpes simplex virus type 2 (HSV-2), which is acquired at the time of delivery.

Unless noted otherwise, this article describes HSE as it occurs in older children and adults. (See Special Concerns for a discussion of neonatal HSE.) HSE must be distinguished from herpes simplex meningitis, which is more commonly caused by HSV-2 than by HSV-1, and which often occurs in association with a concurrent herpetic genital infection. Like other forms of viral meningitis, herpes simplex meningitis usually has a benign course and is not discussed in this article.

Pathophysiology

The pathogenesis of HSE is poorly understood. Neurons are quickly overwhelmed by a lytic and hemorrhagic process distributed in an asymmetric fashion throughout the medial temporal and inferior frontal lobes. Involvement of the basal ganglia, cerebellum, and brainstem is uncommon. The exact mechanism of cellular damage is unclear, but it may involve both direct virus-mediated and indirect immune-mediated processes. The ability of HSV-1 to induce apoptosis (programmed cell death, or "cellular suicide") in neuronal cells, a property not shared by HSV-2, might explain why the former causes virtually all cases of HSE in immunocompetent older children and adults.^{4, 5}

A vivid description of the temporal course of tissue destruction is given in an immunohistological autopsy study of patients succumbing to HSE over periods of days to weeks in the era prior to acyclovir:

The impression gained is of a rapidly spreading wave of viral infection within limbic structures, probably starting on one side of the brain and spreading within it and to the other side, lasting about 3 weeks and leaving in its wake a trail of devastatingly severe necrosis and inflammation in infected parts of the brain.⁶

Brain infection is thought to occur by means of direct neuronal transmission of the virus from a peripheral site to the brain via the trigeminal or olfactory nerve. Factors that precipitate HSE are unknown. The prevalence of HSE is not increased in immunocompromised hosts, but the presentation may be subacute or atypical in these patients.  HSV-2 may cause HSE in patients with HIV-AIDS. ^{7, 8, 9}

HSE represents a primary herpes simplex virus (HSV) infection in about one third of cases. The remaining cases occur in patients with serologic evidence of preexisting HSV infection and are due to reactivation of a latent peripheral infection in the olfactory bulb or trigeminal ganglion, or reactivation of a latent infection in the brain itself. A substantial number of neurologically asymptomatic individuals may have latent HSV present in the brain. In a postmortem study, HSV was present in the brains of 35% of patients with no evidence of neurological disease at the time of death.¹⁰

Frequency

United States

HSE is the most common cause of sporadic lethal encephalitis, occurring in about 1 person per 250,000-500,000 population per year.

Mortality/Morbidity

The mortality rate in untreated patients is 70%. Among treated patients, the mortality rate is 19%, and more than 50% of survivors are left with moderate or severe neurological deficits.

Race

No predilection for race exists.

Sex

The male-to-female ratio is 1:1.

Age

HSE has a bimodal distribution by age, with the first peak occurring in those younger than 20 years and a second occurring in those older than 50 years. HSE in younger patients usually represents primary infection, whereas reactivation of latent infection occurs in older persons.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

HSE is an acute or subacute illness, causing both general and focal signs of cerebral dysfunction. It is sporadic and occurs without a seasonal pattern. Although the presence of fever, headache, behavioral changes, confusion, focal neurological findings, and abnormal CSF findings are suggestive of HSE, no pathognomonic clinical findings reliably distinguish HSE from other neurological disorders with similar presentations (eg, non-HSV encephalitis, brain abscess, tumor).¹¹ Confirmation of the diagnosis depends on the identification of HSV in the CSF by means of a polymerase chain reaction (PCR) or on the identification of HSV in brain tissue by means of brain biopsy (see Workup).

Typical symptoms include the following:¹²

• Fever (90%)
• Headache (81%)
• Psychiatric symptoms (71%)
• Seizures (67%)
• Vomiting (46%)
• Focal weakness (33%)
• Memory loss (24%)

Physical

The most frequent findings on physical examination are fever and mental status abnormalities. Meningismus is uncommon.

Typical findings on presentation include the following:¹²

• Alteration of consciousness (97%)
• Fever (92%)
• Dysphasia (76%)
• Ataxia (40%)
• Seizures (38%)
• • Focal (28%)
  • Generalized (10%)
• Hemiparesis (38%)
• Cranial nerve defects (32%)
• Visual field loss (14%)
• Papilledema (14%)

A causal or temporal relationship between peripheral lesions (eg, herpes labialis) and HSE does not exist. Also, many febrile diseases may precipitate herpes labialis. Therefore, the presence or absence of such lesions neither confirms nor excludes the diagnosis.

Causes

• In children older than 3 months and in adults, HSV-1 is responsible for virtually all cases.
• HSV-2 causes a small number of cases, particularly in the immunocompromised host.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Serologic analysis
• • Serologic evaluation of blood or CSF may be useful for retrospective diagnosis, but it has no role in the acute diagnosis and treatment of patients.
  • Strategies based on increases in antibody levels and on the ratio of antibody levels in serum and CSF have not proven to be clinically useful.
• CSF analysis
• • Patients with HSE typically have mononuclear pleocytosis of 10-500 WBCs/µL (average, 100 WBCs/µL).
  • As a result of the hemorrhagic nature of the underlying pathologic process, the RBC count may be elevated (10-500 RBCs/µL).
  • Protein levels are elevated to the range 60-700 mg/dL (average, 100 mg/dL).
  • Glucose values may be normal or mildly decreased (30-40 mg/dL).
  • In about 5-10% of patients, especially children, initial CSF results may be normal. However, on serial examinations, the cell counts and protein values increase.
  • Viral cultures of CSF are rarely positive and should not be relied on to confirm the diagnosis.
• Polymerase chain reaction^{13, 14}
• • PCR analysis of CSF for the detection of HSV DNA has virtually replaced brain biopsy as the criterion standard for diagnosis.
  • PCR is highly sensitive (94-98%) and specific (98-100%).
  • Results become positive within 24 hours of the onset of symptoms and remain positive for at least 5-7 days after the start of antiviral therapy.
  • Clinical severity and outcome appear to correlate with viral load as assessed by quantitative PCR techniques,¹⁵ but not all investigators have confirmed this.¹⁶
  • False-negative findings may occur early in the course of the disease when viral DNA levels are low (within 72 h of the onset of symptoms) or when blood is present in the CSF, as hemoglobin may interfere with PCR.¹⁷
  • Pretest probability should be considered in interpretation of results. A negative result obtained less than 72 hours after the onset of symptoms in a patient with a high pretest probability (fever, focal neurological abnormalities, CSF pleocytosis) should be repeated.
  • False-positive test results are rare and usually reflect accidental contamination of the specimen in the laboratory.

Imaging Studies

• Magnetic resonance imaging
• • MRI of the brain is the preferred imaging study. Abnormalities are found in 90% of patients with HSE; MRI may be normal early in the course of illness.
  • Findings of localized temporal abnormalities are highly suggestive of HSE, but confirmation of the diagnosis depends on the identification of HSV by means of PCR or brain biopsy.
  • MRI can noninvasively establish many of the potential alternative diagnoses of HSE.
• Computed tomography
• • Head CT may show changes in the temporal and/or frontal lobe, but CT is less sensitive than MRI.
  • Approximately one third of patients with HSE have normal CT findings on presentation.

Other Tests

• Electroencephalography
• • Electroencephalography (EEG) shows focal abnormalities, such as spike and slow- or periodic sharp-wave patterns over the involved temporal lobes.
  • EEG is 84% sensitive to abnormal patterns in HSE but lacks specificity (32%).

Procedures

• Brain biopsy
• • Historically, brain biopsy has been considered the only definitive means of diagnosing HSE. With the advent of PCR technology, the role of brain biopsy is diminishing.
  • Brain biopsy carries a complication rate of about 3%.
  • The results of brain biopsy can establish alternative diagnoses, both treatable (eg, brain tumor) and nontreatable (eg, non-HSV viral encephalitis).
  • Studies have demonstrated that PCR testing of CSF is as accurate as brain biopsy in confirming the diagnosis of HSE.
• Lumbar puncture (see Lab Studies)

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prehospital Care

Prehospital care consists of supportive management of the patient's airway, breathing, and circulation (ABCs).

Emergency Department Care

• A high index of suspicion is required to make the diagnosis.
• No pathognomonic clinical findings are associated with HSE.
• The diagnosis of HSE should be considered in any patient with a progressively deteriorating level of consciousness, fever, abnormal CSF findings, and focal neurological abnormalities in the absence of any other causes.
• Proceed with expeditious evaluation after the diagnosis is considered.
• Empiric treatment of patients with suspected HSE is recommended pending confirmation of the diagnosis because acyclovir, the drug of choice, is relatively nontoxic and because the prognosis for untreated HSE is poor.
• Rapid initiation of acyclovir therapy is crucial to reduce mortality and morbidity risks.

Consultations

• Neurologist
• Infectious disease specialist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Goals of therapy are to shorten the clinical course of the disease, to prevent complications, and to prevent recurrences.

Drug Category: Antiviral agents

The treatment of choice for HSE is acyclovir.^{1, 3, 18} Through a series of in vivo reactions catalyzed by viral and host cellular enzymes, acyclovir is converted to acyclovir triphosphate, a potent inhibitor of HSV DNA polymerase, without which viral replication cannot occur. Human cells are not affected.

Acyclovir has relatively few serious adverse effects. The drug is excreted by the kidney, and the dose should be reduced in patients with renal dysfunction. Crystal-induced nephropathy may occur if the maximum solubility of free drug is exceeded. Risk factors for this are intravenous administration, rapid infusion, dehydration, concurrent use of nephrotoxic drugs, underlying renal disease, and high doses. The risk of renal toxicity is reduced by adequately hydrating the patient (eg, 1 mL fluid per day for each 1 mg/d of acyclovir).

Because of its high pH, intravenous acyclovir may cause phlebitis and local inflammation if extravasation occurs. Gastrointestinal disturbances, headache, and rash are among the more frequent adverse reactions. Acyclovir is considered appropriate for serious infections during pregnancy. The manufacturer cautions that it should be used in pregnancy only when the potential benefits outweigh the potential risks. However, a prospective registry of acyclovir use in pregnancy between 1984 and 1999, including 756 first trimester exposures, demonstrated a 3.2% rate of birth defects, similar to that expected in the general population.¹⁹

Since most relapses occur within 3 months of completing an initial course of intravenous acyclovir, a prolonged course of an oral antiviral agent (eg, valacyclovir) has been suggested following initial treatment. An ongoing clinical trial is currently evaluating a 90-day course of valacyclovir versus placebo post treatment with acyclovir in patients with HSE.²⁰

The role of steroids in the treatment of HSE remains uncertain. To the extent that cellular damage in HSE is the result of immune-mediated inflammatory processes triggered by the viral infection, the anti-inflammatory effects of steroids may be beneficial. However, there is also concern that steroids might suppress immune responses of the host that are necessary to limit viral replication. Animal studies have demonstrated a beneficial effect of steroids on outcome, without evidence of increased viral replication or dissemination.^{21, 22} Steroids have been used to reduce cerebral edema in patients with severe HSE.

One nonrandomized, retrospective human study compared the outcomes of patients with HSE who received steroids in addition to acyclovir versus those receiving acyclovir alone.²³ The steroid group had improved outcomes at 3 months. While these results suggest a possible role for steroids in HSE, definitive recommendations must await the results of larger prospective studies.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• All patients require admission to an intensive care unit.
• Monitoring of intracranial pressure may be needed.

Transfer

• Depending on availability of local expertise (eg, infectious disease, neurology, neurosurgery specialists), transfer to a tertiary care facility may be appropriate.

Deterrence/Prevention

• No measures are known to be effective for preventing HSE.
• Person-to-person transmission does not occur.
• Prophylactic treatment of close contacts and special isolation precautions are unnecessary.

Complications

• Seizures are common, and some authorities recommend prophylactic treatment with anticonvulsant drugs in patients with severe HSE.
• Patients with HSE are subject to the same complications as those of all seriously ill and immobilized patients with depressed levels of consciousness (eg, aspiration, deep venous thromboses, decubiti).

Prognosis

• The mortality rate in patients treated with acyclovir was 19% in the comparative trials that established its superiority to vidarabine. More recent trials have reported lower mortality (6-11%), perhaps because they included patients diagnosed by PCR rather than brain biopsy who thus may have been identified earlier with milder disease.^{1, 3}
• Sequelae among survivors are significant and depend on the patient's age and neurological status at time of diagnosis.
• • Patients who are comatose at diagnosis have a poor prognosis regardless of their age.
  • In noncomatose patients, the prognosis is age related, with better outcomes occurring in patients younger than 30 years.
• Neurological outcomes in survivors treated with acyclovir are as follows:
• • No deficits or mild deficits - 38%
  • Moderate deficits - 9%
  • Severe deficits - 53%
• Relapses following HSE have been reported to occur in 5–26% of patients, with most relapses occurring within the first 3 months after completion of treatment. Relapses are more frequent in children than adults. It is unclear whether such relapses represent recurrence of viral infection or an immune-mediated inflammatory process. Some of the relapses reported in earlier studies may have been due to inadequate duration of treatment rather than true recurrences of HSE. A recent long-term follow-up study of patients with HSE suggests that different pathogenic mechanisms are present during relapses than during the initial infection.²⁴ Serial measurements of inflammatory markers as well as HSV viral load in the CSF of relapsing patients demonstrated increased inflammatory markers without detectable HSV during relapses. This suggests that immune-mediated events, rather than direct viral-mediated neuronal toxicity, may predominate in relapses.

Patient Education

• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Encephalitis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider the possibility of HSE can result in delayed diagnosis and treatment, with subsequent increased risks of mortality and morbidity. In a recent single-center study from a high volume academic emergency department, the authors reported that only 29% of patients with a presentation suggestive of viral encephalitis (fever, neuropsychiatric abnormalities, CSF pleocytosis, and a negative CSF Gram stain) received acyclovir in the ED.²⁵
• • No pathognomonic clinical findings are associated with HSE.
  • The diagnosis can be confirmed only by means of PCR or brain biopsy.
  • In the absence of any other identifiable cause, consider HSE in any febrile patient with encephalopathy and CSF pleocytosis.
  • Start empiric acyclovir therapy promptly in such patients pending confirmation of the diagnosis.
• Initial presentation may be mild or atypical in immunocompromised patients (eg, those with HIV infection or those receiving steroid therapy).
• • Focal neurological deficits, CSF pleocytosis, and CT abnormalities may be absent initially.
  • A high index of suspicion is required in all immunocompromised patients with febrile encephalopathy.

Special Concerns

• Neonatal HSE^{26, 27}
• • The predominant pathogen is HSV-2 (75% of cases), which is usually acquired by maternal shedding (frequently asymptomatic) during delivery. The absence of a maternal history of prior genital herpes does not exclude risk; in 80% of cases of neonatal HSE, no maternal history of prior HSV infection is present. Prolonged rupture of the membranes (>6 h) and intrauterine monitoring (eg, attachment of scalp electrodes) are risk factors.
  • In about 10% of cases, HSV (often type 1) is acquired postpartum by contact with an individual who is shedding HSV from a fever blister, finger infection, or other cutaneous lesion.
  • HSE may occur as an isolated CNS infection or as part of disseminated multiorgan disease.
  • The mortality rate is substantial, even with appropriate treatment; 6% in patients with isolated HSE and 31% in those with disseminated infection.
  • Signs and symptoms of HSE develop about 6-12 days after delivery, at which time lethargy, poor feeding, irritability, tremors, or seizures may be noted.
  • • Those with disseminated disease also have abnormal liver function test results and thrombocytopenia.
    • In contrast to older patients, neonates often have herpetic skin lesions.
  • Diagnostic modalities are similar to those in older children and adults. However, HSV can sometimes be confirmed by Tzanck preparations taken from vesicular lesions, and HSV can be cultured from the CSF in about one third of affected neonates.
  • Acyclovir in doses of 20 mg/kg IV q8h (60 mg/kg/d) is currently recommended. This dose is higher than that used in older children and adults (30 mg/kg/d), but, in neonates, it has been shown to improve mortality and morbidity when compared with the lower dose. The higher dose is associated with neutropenia, so the white blood cell count should be monitored closely.
  • Preventive measures include cesarean delivery in women with active herpetic genital infections at the time of delivery and protection of neonates from persons with active herpetic infections. Some authorities recommend a course of suppressive acyclovir therapy near the time of delivery in mothers with a history of genital herpes.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Whitley RJ. Herpes simplex encephalitis: adolescents and adults. Antiviral Res. Sep 2006;71(2-3):141-8. [Medline].
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3. Tyler KL. Herpes simplex virus infections of the central nervous system: encephalitis and meningitis, including Mollaret's. Herpes. Jun 2004;11 Suppl 2:57A-64A. [Medline].
4. Aurelian L. HSV-induced apoptosis in herpes encephalitis. Curr Top Microbiol Immunol. 2005;289:79-111. [Medline].
5. DeBiasi RL, Kleinschmidt-DeMasters BK, Richardson-Burns S, Tyler KL. Central nervous system apoptosis in human herpes simplex virus and cytomegalovirus encephalitis. J Infect Dis. Dec 1 2002;186(11):1547-57. [Medline].
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9. Osih RB, Brazie M, Kanno M. Multifocal herpes simplex virus type 2 encephalitis in a patient with AIDS. AIDS Read. Feb 2007;17(2):67-70. [Medline].
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13. 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 Gr. J Infect Dis. Apr 1995;171(4):857-63. [Medline].
14. Cinque P, Cleator GM, Weber T, Monteyne P, Sindic CJ, van Loon AM. The role of laboratory investigation in the diagnosis and management of patients with suspected herpessimplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry. Oct 1996;61(4):339-45. [Medline].
15. Domingues RB, Lakeman FD, Mayo MS, Whitley RJ. Application of competitive PCR to cerebrospinal fluid samples from patients with herpes simplex encephalitis. J Clin Microbiol. Aug 1998;36(8):2229-34. [Medline].
16. Wildemann B, Ehrhart K, Storch-Hagenlocher B, Meyding-Lamadé U, Steinvorth S, Hacke W, et al. Quantitation of herpes simplex virus type 1 DNA in cells of cerebrospinal fluid of patients with herpes simplex virus encephalitis. Neurology. May 1997;48(5):1341-6. [Medline].
17. Weil AA, Glaser CA, Amad Z, Forghani B. Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result. Clin Infect Dis. Apr 15 2002;34(8):1154-7. [Medline].
18. Rathmann K, Scott SA. Acyclovir. In: Drug Evaluation Monographs. Micromedex:2005.
19. Stone KM, Reiff-Eldridge R, White AD, Cordero JF, Brown Z, Alexander ER. Pregnancy outcomes following systemic prenatal acyclovir exposure: Conclusions from the international acyclovir pregnancy registry, 1984-1999. Birth Defects Res A Clin Mol Teratol. Apr 2004;70(4):201-7. [Medline].
20. National Institute of Allergy and Infectious Diseases. A Phase III Double-Blind, Placebo-Controlled Trial of Long Term Therapy of Herpes Simplex Encephalitis (HSE): An Evaluation of Valacyclovir (CASG-204). ClinicalTrials.gov. Available at http://clinicaltrials.gov/ct/show/NCT00031486?order=1. Accessed August 8, 2007.
21. Sergerie Y, Boivin G, Gosselin D, Rivest S. Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice. J Infect Dis. Mar 15 2007;195(6):817-25. [Medline].
22. Thompson KA, Blessing WW, Wesselingh SL. Herpes simplex replication and dissemination is not increased by corticosteroid treatment in a rat model of focal Herpes encephalitis. J Neurovirol. Feb 2000;6(1):25-32. [Medline].
23. Kamei S, Sekizawa T, Shiota H, Mizutani T, Itoyama Y, Takasu T, et al. Evaluation of combination therapy using aciclovir and corticosteroid in adult patients with herpes simplex virus encephalitis. J Neurol Neurosurg Psychiatry. Nov 2005;76(11):1544-9. [Medline].
24. Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F, Forsgren M, Andersson B, et al. Incidence and pathogenesis of clinical relapse after herpes simplex encephalitis in adults. J Neurol. Feb 2006;253(2):163-70. [Medline].
25. Benson PC, Swadron SP. Empiric acyclovir is infrequently initiated in the emergency department to patients ultimately diagnosed with encephalitis. Ann Emerg Med. Jan 2006;47(1):100-5. [Medline].
26. Kohl S. Herpes Simplex Virus. In: Behrman RE, Kliegman RM, Jenson HB. Behrman: Nelson Textbook of Pediatrics. 17^th ed. Philadelphia: Saunders; 2004.
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Article Last Updated: Oct 11, 2007