eMedicine Specialties > Radiology > Brain/Spine

Herpes Encephalitis

Author: Mahesh R Patel, MD, Chief, MRI, Department of Diagnostic Imaging, Santa Clara Valley Medial Center
Contributor Information and Disclosures

Updated: Feb 24, 2009

Introduction

Background

Herpes encephalitis is the most common cause of sporadic viral encephalitis, with a predilection for the temporal lobes and a range of clinical presentations, from aseptic meningitis and fever to a severe rapidly progressive form involving altered consciousness. In adults, herpes simplex virus type 1 (HSV-1) accounts for 95% of all fatal cases of sporadic encephalitis and usually results from reactivation of the latent virus. The clinical findings and neuroimaging appearance are both consistent with spread of the virus from a previously infected ganglion.

More recently, sporadic cases of human herpesvirus 6 (HHV6) have been described in immunocompromised patients or those with lymphoproliferative disorders.  In children and neonates, herpes simplex virus type 2 (HSV-2) accounts for 80-90% of neonatal and almost all congenital infections. An isolated case report of an immunocompromised adult patient developing HSV-2 infection has been described. MRI can play an important role in determining the diagnosis and extent of disease.^{1,2,3,4,5,6,7,8,9,10,11,12}

Pathophysiology

Herpes encephalitis can occur either through hematogenous spread or neuronal transmission. In the typical adult infected with HSV-1, the neuronal spread of the latent virus occurs from the peripheral neuron in retrograde fashion to the brain, usually through the trigeminal or olfactory tract.¹³

In addition to retrograde propagation of the latent virus in the peripheral ganglion, reactivation of latent virus within the brain has also been postulated in cases of encephalitis. Among neonatal patients, the initial infection occurs in the birth canal and spreads hematogenously, with the virus gaining access to the neuronal tissue by diffusing through the blood-brain barrier or by infecting the endothelial cells in the blood vessels.

Herpes viruses consist of a double-stranded DNA core with a surrounding envelope of distinguishing glycoproteins.

On pathology, herpes viruses cause a fulminant hemorrhagic and necrotizing meningoencephalitis. Typical gross findings include severe edema and massive tissue necrosis, with petechial hemorrhages and hemorrhagic necrosis. Often, the petechial hemorrhage is not observed on CT or MRI. On microscopy, a focal necrotizing vasculitis is observed with perivascular and meningeal lymphocytic infiltration and eosinophilic intranuclear inclusions in glial cells and neurons.

Frequency

United States

Although adult herpes encephalitis accounts for 10-20% of viral encephalitis in the United States, the disease is rare. The incidence is 3 cases per 100,000 persons per year.¹⁰

In the United States, millions of women of childbearing age have genital HSV-2.

Approximately 1500-2200 neonatal patients with HSV are identified each year. The risk of HSV in a neonate born to a mother with primary infection is at least 20%, and most often the infection is primary. Neonates born of women with chronic HSV infection have a small risk of recurrent infection, which is estimated to be 1 case per 2000 births. In these patients, passively acquired maternal antibodies may protect against primary infection.^4,14,8

International

The international occurrence for herpes encephalitis cannot be determined.

Mortality/Morbidity

• Untreated patients with HSV-1 have a 70% mortality rate.
• With early treatment, 40% of patients recover without significant neurologic deficits; however, despite appropriate diagnosis and therapy, the mortality rate remains at 30%.
• Interestingly, HSV does not appear to be more common in immunocompromised patients than in normal hosts. HSV-1 is rarely associated with pregnancy.
• HSV mortality in neonates with isolated CNS disease is 15%, and in those with disseminated CNS disease, the rate is 57%. Morbidity for these groups is also high.
• Mejias et al found that detection of HSV DNA in the CSF of 4 neonates with HSV encephalitis following 15-21 days of high-dose acyclovir therapy may be a risk factor for worse neurodevelopmental outcome.¹⁵
• Taira et al analyzed specific variables as predictors of a need for a prolonged course of acyclovir therapy in 23 patients with HSV encephalitis. A lower Glasgow Coma Scale score and a greater number of lesions detected on CT were predictors of prolonged therapy. The investigators therefore concluded that standard initial ACV treatment may not be sufficient for patients with such predictors and that initial treatment modifications may be necessary in such patients.¹⁶

Race

No racial predisposition for herpes encephalitis has been noted in the literature.

Sex

No sex predisposition for herpes encephalitis has been noted in the literature.

Age

HSV-1 typically affects the adult population, while HSV-2 typically affects neonates.

Anatomy

Adult HSV-1 encephalitis often results from reactivation of latent HSV in the trigeminal ganglion. The virus spreads along the orbitofrontal and temporal meningeal branches of this cranial nerve and then to the anterior and middle cranial fossa. Atypical spread can occur when cranial nerves IX and X are involved. The virus has a predilection for the limbic system, involving one or both temporal lobes, and often involving the hippocampus, parahippocampus, and amygdala. Frontal and parietal spread also can occur.

In neonates, HSV-2 typically involves the periventricular white matter and the meninges, with sparing of the medial temporal and inferior frontal lobes.¹⁷

Presentation

In adults with HSV-1, the most common early symptoms are headache and fever. Additional symptoms include intellectual impairment, aphasia, meningeal signs, seizures, and paresthesias. Early treatment is crucial to a good outcome, and empirical acyclovir therapy can be initiated before a definitive diagnosis is established. The virus cannot be cultured routinely from CSF, though lymphocytic pleocytosis and elevations in protein concentrations are observed. CSF viral cultures are positive for HSV in fewer than 5% of patients. Anti-HSV antibodies often do not appear until 1-3 weeks after symptom onset; therefore, antibody culture is helpful only in retrospective diagnosis. Although previously, a brain biopsy was often performed to obtain a definitive diagnosis, this is rarely done any longer.^18,19

EEG also can reveal focal temporal abnormalities, which are seen in 80% of patients; a normal EEG is believed to exclude the diagnosis.¹³ Periodic lateralized epileptiform discharges (PLEDs) also support the diagnosis, but this finding is nonspecific. Historically, a brain biopsy provided a definitive diagnosis, but this procedure is not highly sensitive and can result in complications, including hemorrhage and edema at the biopsy site.²⁰

An RNA polymerase test of CSF, polymerase chain reaction (PCR),^21,22 permits a more definitive diagnosis because it is both sensitive and specific. In this test, 2 sets of oligonucleotide primers amplify gene products from HSV-1 and HSV-2. This is the diagnostic test of choice. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group reported a sensitivity of 94% and a specificity of 98% when compared with HSV culture from brain biopsy.^20,23

After DNA amplification, a Southern blot technique can be used to identify the characteristic herpes simplex banding. The results are positive early in the disease, and the test has a turnaround time of approximately 24 hours. This test is now considered the criterion standard for the diagnosis of HSV. Rare false-positive reports result from cross-contamination. False-negative reports have been described in neonates and young infants, perhaps because of the presence of heme or other inhibitors. In addition, false-negative assays can occur early in the disease. A repeat assay should be considered. Note that the results remain positive during the first week of antiviral therapy.

The HHV6 virus exists in 2 subtypes, HHV6A and HHV6B, with the B subtype primarily responsible for primary infection and reactivation. Diagnosis is made by PCR analysis for HHV6 DNA in samples of CSF. It has, however, been postulated that PCR detection of HHV6 DNA in patients past the age of primary infection may reflect chromosomal integration of viral DNA rather than active infection.

Prompt therapy with acyclovir inhibits the herpes simplex polymerase and stops the virus from replicating. Improved survival rates are present when treatment is started within 4 days after the onset of illness. Patients with possible HSV should receive acyclovir 10 mg/kg intravenously every 8 hours. Rapid infusion can cause crystalluria and subsequent renal failure. The dose should be given slowly over at least 1 hour by pump infusion techniques. A therapeutic duration of 10 days is suggested, but this may result in up to a 10% relapse rate. A longer therapeutic period of 3 weeks has been proposed.

Of note is that immunocompromised patients with HHV6 infection are ineffectively treated with acylovir, although their clinical presentation is similar to that seen in patients with HSV-1. Early identification can be helpful, because patients with HHV6 infection respond to ganciclovir and foscarnet.

Neonatal herpes simplex encephalitis (typically HSV-2 and rarely HSV-1) should be viewed as a different entity. Infants with HSV develop symptoms in the first week of life and typically present at 10-17 days. Newborns tend to present with 3 patterns, as follows:

• Category 1: The disease is limited to the skin, mouth, and eyes.
• Category 2: Primary CNS involvement is present.
• Category 3: Disseminated disease involving the CNS, lung, liver, skin, and eyes is observed.

The only neonatal patients with good prognoses are those with category 1, or limited, disease. Isolated CNS disease tends to be diagnosed later and has a high incidence of permanent neurologic complications. Treatment is similar to that of adults, with an acyclovir dosage of 30 mg/kg/d.

Neonatal HSV can be prevented by performing cesarean delivery, providing contact drainage, and taking secretion precautions, as well as by providing third-trimester therapy for the mother with acyclovir 400 mg 3 times per day.

With therapy, and if HSV is confined to the skin, the prognosis is good, with 98% of babies showing normal development at age 1 year. However, 75% of patients with CNS involvement or disseminated disease either die or have permanent neurologic impairment.

Attempts are under way to develop an effective vaccine. However, to date, this has not been possible.

Preferred Examination

MRI is the preferred modality for evaluating the brain.^22,24,25

Limitations of Techniques

Early imaging with CT or radionuclide studies may reveal normal findings. CT may not reveal abnormalities until 3-5 days after symptom onset, by which time the patient may be stuporous and comatose. In the acute setting, even contrast-enhanced MRIs may be negative.

Differential Diagnoses

Other Problems to Be Considered

West Nile Virus
Other causes of encephalitis
Brain infarction
Brain vasculitis
Progressive multifocal leukoencephalopathy
Paraneoplastic syndromes

• Search for CME/CE on This Topic »

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• Oral Herpes Treatment
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