Disclosure
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. 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. For excellent patient education resources, visit eMedicine's Teeth and Mouth Center and Brain and Nervous System Center. Also, see eMedicine's patient education articles Oral Herpes and Encephalitis. 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. 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:
Mortality/Morbidity: Untreated patients with HSV-1 have a 70% mortality rate.
Race: No race predisposition is noted in the literature. Sex: No sex predisposition is 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. Clinical Details: In adults, 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 empiric 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. In some patients, a brain biopsy may be required for a definitive diagnosis. EEG also can reveal focal temporal abnormalities, which are seen in 80% of patients; a normal EEG is believed to exclude the diagnosis. Periodic lateralized epileptiform discharges 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. An RNA polymerase test of CSF 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. 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 turn-around 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. Note that the results remain positive during the first week of antiviral therapy. Prompt therapy with acyclovir inhibits the herpes simplex polymerase and stops the virus from replicating. 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. 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:
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, and/or 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 underway to develop an effective vaccine. However, to date, this has not been possible. Preferred Examination: MRI is the preferred modality for evaluating the brain. 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.
Brain, Abscess
West Nile Virus
Findings: Plain radiographs are not useful in assessing HSV encephalitis. |
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Findings: In adults, CT classically reveals hypodensity in the temporal lobes either unilaterally or bilaterally, with or without frontal lobe involvement. Hemorrhage is usually not observed. A gyral or patchy parenchymal pattern of enhancement is observed. Contrast enhancement generally occurs later in the disease process. The herpes virus preferentially involves the temporal lobe and orbital surfaces of the frontal lobes. This involvement may extend to the insular cortex, posterior occipital cortex, and the cerebral convexity; however, the basal ganglia are spared. Bilateral involvement is frequent. Involvement of the cingulate gyrus occurs later in the disease. The classic involvement of the medial temporal and frontal lobes is consistent with intracranial spread along the small meningeal branches of the fifth cranial nerve. Cingulate gyrus involvement may arise from efferent hippocampal connections. A rhomboencephalitis resulting from pontine involvement may occur and likely arises from retrograde viral transmission along the cisternal portion of the trigeminal nerve to the brainstem. In neonates, involvement is in the periventricular white matter, sparing the medial temporal and inferior frontal lobes. In addition, meningeal enhancement may be observed following contrast. Degree of Confidence: Late in the disease process, when temporal and frontal lobe involvement is seen, CT findings may be characteristic. Reports exist of patients with normal CT results and CSF studies in the presence of abnormal MRI and EEG, indicating that MRI is more sensitive. Early in the disease process, limited sensitivity of approximately 50% was noted. When typical findings of HSV encephalitis are observed on CT, they often are associated with severe brain damage and a poor prognosis. False Positives/Negatives: Because of bone artifact, the temporal lobes can be difficult to assess on CT. Early in the disease process, CT may be normal. Other causes of encephalitis, tumor, or lymphoma may appear similar.
Findings: In adults, T2-weighted MRI reveals hyperintensity corresponding to edematous changes in the temporal lobes (Image 1), inferior frontal lobes, and insula, with a predilection for the medial temporal lobes. Foci of hemorrhage occasionally can be observed on MRI (Image 2). MRI is preferred for imaging and follow-up studies of herpes encephalitis. Typically, temporal lobe T2 hyperintensity spares the basal ganglia. Although this appearance was previously believed pathognomonic for herpes involvement, similar findings can be observed in progressive multifocal leukoencephalopathy and primary CNS lymphoma. Patchy parenchymal or gyral enhancement can be observed (Image 3). Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape. Reports of restricted diffusion in herpes encephalitis exist (Image 4), with corresponding T2 hyperintensity reflecting edema (Image 5). Reports suggest diffusion-weighted imaging may be more sensitive in the detection of HSV involvement than conventional MRI sequences, and may mimic an infarct with involvement of the cortical regions of the temporal lobe. In neonates, T2-weighted MRI shows hyperintensity of the periventricular white matter, with the medial temporal and inferior frontal lobes spared. Meningeal enhancement also may be observed. MR spectroscopy using proton spectroscopic MRI has demonstrated a reduction of the N-acetylaspartate (NAA)-to-choline ratio. A decreased NAA peak has been reported 7-14 weeks after onset, and in some cases, an elevated choline peak is seen. Occasionally, the lactate peak may be elevated. The NAA decrease is believed to reflect neuronal injury. NAA recovery has been noted to parallel clinical improvement. Degree of Confidence: The diagnosis can be strongly suggested by the typical appearance of medial temporal abnormalities that do not respect hippocampal borders.
Findings: The role for sonography in herpes encephalitis is limited. For in utero or neonatal evaluation, ultrasonography may have a limited role in identifying the periventricular destructive process.
Findings: The use of technetium Tc 99m hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT in evaluating herpes encephalitis is limited. Results demonstrate that the encephalitis matches the distribution of hyperintensity on T2-weighted MRIs, with increased HMPAO uptake in the acute stage. Late sequelae are characterized by decreased HMPAO uptake and postnecrotic widening of the temporal horns. Degree of Confidence: When abnormal uptake involves the temporal lobes, with characteristic involvement of the limbic system, the diagnosis of herpes encephalitis is likely.
Findings: Angiography has no significant role in the diagnosis of herpes encephalitis.
Intervention: Radiologic interventionNo radiologic interventions for herpes encephalitis have been described to date. Medical intervention with acyclovirDrug description Acyclovir exerts an antiviral effect on HSV by interfering with DNA synthesis and inhibiting viral replication. Acyclovir is a synthetic purine nucleoside analogue and highly selective in its affinity for thymidine kinase encoded by HSV. In vitro studies indicate that acyclovir triphosphate is the active form and competes with deoxyguanosine triphosphate for viral DNA polymerase and then incorporated predominantly into viral DNA. Viral DNA polymerase has a 10- to 30-fold or greater affinity in vitro for acyclovir phosphatase than does cellular DNA polymerase. The mechanism of action includes competitive inhibition of viral DNA polymerase, incorporation into and subsequent termination of the growing viral DNA chain, and inactivation of DNA polymerase. Its highest antiviral activity in vitro is against HSV-1, then HSV-2 and varicella-zoster virus. Acyclovir-resistant mutants have been described and occur in immunocompromised patients who have thymidine kinase-deficient HSV. Consider the possibility of viral resistance in patients with a poor response. Adult dosage In patients with normal renal function, administer 10 mg/kg infused at a constant rate for a minimum of 1 hour, every 8 hours, for a total of 15 mg/kg/d, for 14-21 days. Rapid infusion of acyclovir can cause crystalluria and subsequent renal failure. A therapeutic duration of 10 days may result in a relapse rate of up to 10%. Consequently, longer therapy of 3 weeks has been suggested. Pediatric dosage In children younger than 12 years, administer 250 mg/m2 at a constant intravenous rate over 1 hour, every 8 hours, for a total of 750 mg/m2/d for 7 days. Drug interactions
Pregnancy Acyclovir is a category C drug; its safety for use during pregnancy has not been established. Animal reproduction studies at standard doses did not result in teratogenic effects, but doses at 5-10 times human levels resulted in rat fetal head and tail anomalies and maternal toxicity. Although acyclovir is not teratogenic in standard animal studies, a potential for chromosome damage at high concentrations may exist. A prospective epidemiologic registry of acyclovir use in pregnancy has been ongoing since 1984. As of June 1996, in 494 woman exposed to systemic acyclovir in the first trimester, the occurrence rate of birth defects was approximately that of the general population; however, this is a small sample. To monitor maternal-fetal outcomes in the setting of systemic acyclovir, GlaxoSmithKline established an Acyclovir in Pregnancy Registry in 1984, which was completed in 1999. Physicians and healthcare providers may obtain a final study report by calling the GlaxoSmithKline Customer Response Center at 1-888-825-5249. Precautions Adjust the dosage when acyclovir is administered to patients with renal impairment. Take precautions when administering the medication concurrently with nephrotoxic drugs, which may increase risk of renal dysfunction and/or the risk of CNS symptoms (confusion, dizziness, hallucinations, paresthesia, seizure, somnolence). Demonstrable levels of acyclovir have been reported in women after the oral administration of acyclovir and have ranged from 0.6-4.1 times the plasma level. This potentially exposes a nursing infant to a dose of 0.3 mg/kg/d. Consequently, nursing is not advised while patients are taking acyclovir. Contraindications Acyclovir is contraindicated in patients who develop hypersensitivity or intolerance to the formulation. Medical/Legal Pitfalls:
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