Imaging in Herpes Encephalitis 

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. Magnetic resonance imaging (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]} See the image below.

On pathology, herpes viruses cause a fulminant hemorrhagic and necrotizing meningoencephalitis, with typical gross findings of severe edema and massive tissue necrosis, with petechial hemorrhages and hemorrhagic necrosis. Often, the petechial hemorrhage is not observed on computed tomography (CT) scanning 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. Taira et al found that a lower Glasgow Coma Scale score and a greater number of lesions detected on CT scanning were predictors of prolonged acyclovir therapy.^[13]

Preferred examination

MRI is the preferred modality for evaluating the brain.^{[14, 15, 16]} However, early in the clinical course of the disease, MRI results may be negative. A negative MRI does not rule out HSV encephalitis. Therapy should be empirically continued until laboratory tests definitely exclude the diagnosis. A case report of West Nile Virus causing focal temporal lobe findings was described in the literature.^[17]

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

In adults, CT scans classically reveal 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.^{[15, 18]}

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 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.^{[19, 20]}

Taira et al analyzed specific variables as predictors of a need for a prolonged course of acyclovir therapy in 23 patients with HSV encephalitis and reported a lower Glasgow Coma Scale score and a greater number of lesions detected on CT scans were predictors of prolonged therapy.^[13] The investigators 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.^[13]

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 cerebrospinal fluid (CSF) studies in the presence of abnormal MRI and EEG findings, 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 scan, they often are associated with severe brain damage and a poor prognosis.^[15]

Because of bone artifact, the temporal lobes can be difficult to assess on CT scanning. Early in the disease process, CT scanning may be normal. Other causes of encephalitis, tumor, or lymphoma may appear similar.

The diagnosis of herpes encephalitis can be strongly suggested by the typical appearance of medial temporal abnormalities that do not respect hippocampal borders.

In adults, T2-weighted MRI reveals hyperintensity corresponding to edematous changes in the temporal lobes (see the first 2 images below), inferior frontal lobes, and insula, with a predilection for the medial temporal lobes. Foci of hemorrhage occasionally can be observed on MRI (see the third image below).

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 to be 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 (see the image below).^{[21, 22, 23, 24, 25, 26]}

Reports of restricted diffusion in herpes encephalitis exist (see the first image below), with corresponding T2 hyperintensity reflecting edema (see the second image below). 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.^[27]

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.^{[28, 29]}

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have 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.

NSF/NFD 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. 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 FDA Information on Gadolinium-Based Contrast Agents or Medscape.

The role for ultrasonography in herpes encephalitis is limited. For in utero or neonatal evaluation, ultrasonography may have a limited role in identifying the periventricular destructive process.

The use of technetium-99m (^99m Tc) hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT) scanning 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. When abnormal uptake involves the temporal lobes, with characteristic involvement of the limbic system, the diagnosis of herpes encephalitis is likely.