I. What every physician needs to know.

Herpes simplex virus (HSV) is a common cause of encephalitis that is associated with significant morbidity and mortality. Early diagnosis and treatment with acyclovir is essential to prevent complications. Nearly all cases in adults are associated with HSV Type 1 (HSV-1). It is the most common cause of fatal sporadic encephalitis in the United States.

Three methods are postulated for the infection of the CNS. The first is CNS invasion via the trigeminal nerve or olfactory tract after an episode primary HSV-1 of the oropharynx. The second is peripheral reactivation after an episode of recurrent HSV-1 infection of the oropharynx. The final is reactivation of virus latent in brain tissue, not accompanied by oropharyneal HSV.

II. Diagnostic Confirmation: Are you sure your patient has herpes encephalitis?

A. History Part I: Pattern Recognition:

The rapid onset of fever, headache, and change in mental status should make the clinician concerned for HSV encephalitis. Behavior changes and changes in personality can be seen. Seizures may be present due to temporal lobe involvement of infection. Focal neurological changes such as cranial nerve deficits, ataxia, and weakness can occur. If untreated, obtundation usually occurs.

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B. History Part 2: Prevalence:

All age groups are affected. HSV encephalitis is the most common cause of fatal sporadic encephalitis in the US. Environmental or genetic predisposing factors have not been identified.

C. History Part 3: Competing diagnoses that can mimic herpes encephalitis.

Differential diagnosis based on fever, headache, and change in mental status:

  • ) Other causes of viral encephalitis

    Arbovirus (West Nile encephalitis, Western Equine encephalitis, Eastern Equine encephalitis, St. Louis encephalitis)


    Ebstein-Barr virus


  • ) Bacterial meningitis

  • ) Abscess or subdural empyema from bacterial, fungal, mycobacterial, or rickettsial causes

  • ) Leukoencephalopathy (JC virus)

  • ) Noninfectious causes



    Toxic Encephalopathy

    Systemic lupus erythematosus


Diagnostic testing as below helps to distinguish HSV encephalitis from the above diagnoses.

D. Physical Examination Findings.

  • Fever

  • Focal neurological changes including diminished mental status, cranial nerve deficits

E. What diagnostic tests should be performed?

Lumbar puncture should be performed in patients with suspected viral encephalitis. Computed tomography (CT) Brain is often performed before lumbar puncture, but do not often show abnormalities associated with HSV encephalitis. Magnetic Resonance Imaging (MRI) of the brain is more sensitive and specific for diagnosis of HSV encephalitis.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Lumbar puncture sent for fluid analysis shows a lymphocytic pleocytosis. The Cerebrospinal Fluid (CSF) protein is often elevated, and red blood cells can be seen in both Tubes 1 and 4. The CSF may not have these characteristics early in disease onset.

CSF polymerase chain reaction (PCR) testing has become the diagnostic standard for HSV-1 encephalitis. It has a high sensitivity (94%) and specificity (98%) for the disease. Treatment should be initiated while testing is pending if clinical suspicion is high.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Because patients need a lumbar puncture (LP) for diagnosis, most patients receive a noncontrast CT of the brain prior to the LP. The CT is often nondiagnostic, especially early in disease. Temporal lobe abnormalities are classic for the disease. MRI has increased sensitivity and specificity compared to a CT scan. A contrasted MRI may be more helpful in the diagnosis, but if a patient cannot receive contrast due to allergy or ESRD, FLAIR and diffusion-restricted imaging can be considered.

An electroencephalogram (EEG) is often abnormal in patients with HSV encephalitis. The EEG can show slowing in the temporal and frontal regions. It is helpful in identifying patients with nonconvulsive seizure activity.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Viral cultures are often not useful in diagnosis given yield and time to identification.

III. Default Management.

Immediate therapy is essential to prevent further neurological complications and mortality.

A. Immediate management.

Intravenous acyclovir should be started at 10mg/kg every 8 hours in a patient with normal renal function. If there is no contraindication to therapy, acyclovir should be started while awaiting PCR results. Total therapy of 14-21 days with IV acyclovir is recommended.

B. Physical Examination Tips to Guide Management.

Improvement in neurological exam to include mental status may be seen.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Creatinine should initially be monitored daily in patients receiving acyclovir therapy.

Repeat CSF sampling and Polymerase Chain Reaction (PCR) testing can be considered in patients in whom there is a high clinical suspicion with a negative initial PCR.

D. Long-term management.

Repeat CSF sampling for HSV PCR can be performed at the end of therapy. Continued positive PCR may be an indication for continuing therapy.

There is a low risk of relapse, up to 5%, but data for chronic suppression is controversial.

E. Common Pitfalls and Side-Effects of Management

Intravenous acyclovir can crystallize in the urine. IV hydration should be considered in patients without contraindication.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Reduction in acyclovir dose must be made in patients with renal insufficiency.

  • For CrCl 25-50: Change dosing interval to q12h

  • For CrCl 10-25: Change dosing interval to q24h

  • For CrCl less than 10: Reduce dose by 50% and change dosing interval to q24h

For intermittent hemodialysis, reduce dose by 50% and change dosing interval to q24h, ensuring that dosing is done after hemodialysis.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

IV hydration in the setting of IV acyclovir therapy is needed. Judicious use of fluids in heart failure is needed.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

High risk for neurologic changes. Change in mental status may warrant electroencephalogram (EEG) to evaluate for nonconvulsive seizure activity.

B. Anticipated Length of Stay.

Length of stay is determined by the level of neurological change and morbidity seen. Therapy of 14-21 days with IV acyclovir is recommended but if stable can be done via peripherally inserted central catheter (PICC) line.

C. When is the Patient Ready for Discharge.

Neurologic stability needs to be ensured prior to discharge. IV acyclovir therapy can be continued at skilled nursing facility.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

  • Follow-up with infectious disease physician should be arranged prior to discontinuing IV acyclovir therapy.

  • Follow-up with neurology can be considered depending on level of neurologic change.

  • Primary care follow-up should occur within one week.

2. What tests should be conducted prior to discharge to enable best clinic first visit.


3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Renal function should be monitored on at least twice weekly basis while on acyclovir.

E. Placement Considerations.

As there is a high neurologic morbidity associated with the disease, placement in a skilled nursing facility or long-term acute care hospital may be needed. PICC line should be inserted for IV acyclovir therapy.

F. Prognosis and Patient Counseling.

Mortality approaches 70% in untreated patients and remains as high as 20 to 30% even in treated patients. Significant neurological complications may persist including behavioral abnormalities and cognitive impairment.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.


B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

  • Falls precautions given potential neurologic changes

  • Venous thromboembolism prophylaxis is indicated

VII. What's the evidence?

Baringer, JR. “Herpes simplex infections of the nervous system.”. Neurol Clin.. vol. 26. 2008. pp. 657-74.

Levitz, RE. ” Herpes simplex encephalitis: a review.”. Heart Lung.. vol. 27. 1998. pp. 209-12.

Tunkel, AR, Glaser, CA, Bloch, KC. ” The management of encephalitis: Clinical practice guidelines by the Infectious Diseases Society of America.”. . vol. 47. 2008. pp. 303-27.

Whitley, RJ. “Herpes simplex encephalitis: adolescents and adults.”. Antiviral Research.. vol. 71. 2006. pp. 141-48.

Whitley, RJ. ” Viral encephalitis.”. . vol. 323. 1990. pp. 242-50.

Whitley, RL, Lakeman, F. ” Herpes Simplex Virus infections of the central nervous system: therapetuci and diagnostic considerations.”. Clin Infect Dis.. vol. 20. 1995. pp. 414-20.

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