Cytomegalovirus Encephalitis in HIV 

HIV-associated cytomegalovirus (CMV) encephalitis is one of several central and peripheral nervous system infections seen in late-stage disease.^[1] Neurologic manifestations of CMV infection include encephalitis, ventriculitis, myelitis, retinitis, radiculoganglionitis, and peripheral neuropathies. These infections usually occur in patients with severe immunodeficiency: CD4⁺ lymphocyte counts typically are lower than 50/µL.

Prior to the development of highly active antiretroviral therapy (HAART), 2% of HIV-infected patients with CD4⁺ counts less than 50/µL developed CMV neurologic disease. The incidence has decreased since HAART became available. CMV infection of the CNS is recognized at autopsy in 18-28% of patients with AIDS. Histologic findings include ventriculoencephalitis, microglial nodules, focal parenchymal necrosis, isolated cytomegalic cells, and nuclear inclusions.

Cerebrospinal fluid (CSF) analysis not only can point to the correct diagnosis but also permits exclusion of other diagnostic considerations. Prompt initiation of antiviral drugs is essential. If left untreated, HIV-associated CMV encephalitis typically progresses to death in days to weeks. Death may result from other complications of advanced AIDS rather than the neurologic condition.

For more information, see the Medscape Reference topics HIV Disease, Encephalitis, Cytomegalovirus, and Viral Encephalitis.

HIV-associated cytomegalovirus (CMV) encephalitis can present in different ways, including the following:

• CMV encephalitis may be asymptomatic
• CMV encephalitis characterized by ventriculoencephalitis manifests with abrupt onset and rapidly progressive confusion and lethargy
• Cranial nerve palsies, most often oculomotor and facial, and other focal neurologic deficits occur
• CMV encephalitis characterized by microglial nodules and focal parenchymal necrosis manifests with a more indolent change in mental status, very similar to AIDS dementia complex (ADC)

CMV encephalitis may occur in conjunction with CMV-associated colitis, esophagitis, retinitis, myelitis, radiculoganglionitis, neuropathy, or adrenal insufficiency, often in patients already receiving ganciclovir. A strong association between CMV retinitis and encephalitis is apparent. In an autopsy series of 47 patients with AIDS, 75% of those with CMV retinitis involving the peripapillary area also had encephalitis.^[2]

Findings on physical examination may include the following:

• Confusion, cognitive decline
• Rare focal neurologic signs
• Cranial nerve palsies

The differential diagnosis of cytomegalovirus (CMV) encephalitis includes the following:

• Herpes simplex encephalitis
• HIV-1 cerebrovascular complications
• HIV-1 CNS cryptococcosis
• HIV-1 CNS toxoplasmosis
• HIV-1 progressive multifocal leukoencephalopathy
• HIV-1 CNS lymphoma
• HIV-1 encephalopathy
• HIV-1 AIDS dementia complex

Metabolic encephalopathies should also be considered.

Cerebrospinal fluid (CSF) analysis not only can point to the correct diagnosis but also permits exclusion of other diagnostic considerations. Typical CSF findings are an elevated protein level and mononuclear leukocytosis. Cytomegalovirus (CMV) can be detected by means of culture, polymerase chain reaction (PCR), CMV antigen testing, or cytology. In patients without CMV infection, CMV is rarely detected by PCR in the CSF. PCR of the CSF may help confirm the diagnosis.

Electrolyte disturbances (eg, hyponatremia) consistent with adrenal insufficiency may be observed.

Computed tomography (CT) and magnetic resonance imaging (MRI) can aid in the diagnosis and can exclude other diagnostic considerations (eg, absence of parenchymal enhancement, evidence of increased intracranial pressure [ICP]). Head CT and MRI findings include encephalitis involving the cerebral hemispheres and brainstem, ventriculitis, meningitis, and infarcts. Hydrocephalus and cerebral atrophy have been reported. Periventricular calcification, a marker of congenital CMV infection, is not seen.

Mass lesions due to CMV have been reported but are rare. T2-weighted MRI may show diffuse white matter hyperintensity similar to that seen in HIV encephalopathy and other HIV-associated central nervous system (CNS) disorders. Gadolinium contrast MRI may reveal meningeal and ependymal enhancement, as well as ring enhancing lesions.

Prompt initiation of antiviral drugs is essential for treatment of cytomegalovirus (CMV) encephalitis.^[3] These agents inhibit viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase, inhibiting DNA synthesis. Medical support is required in cooperation with the primary care physician and an infectious diseases specialist.

Because the clinical presentation, cerebrospinal fluid (CSF) studies, and imaging studies may not provide a definitive diagnosis, a high level of suspicion is necessary to avoid a delay in proper therapy. Delayed diagnosis and treatment can lead to death.

Ganciclovir and foscarnet

Ganciclovir and foscarnet are indicated for CMV infections in the induction phase. The 2 agents may be used in combination, although this combination results in substantial rates of adverse effects.^{[4, 3]} Long-term intravenous (IV) maintenance therapy may be indicated for patients who have a clinical response.

Valganciclovir

Oral valganciclovir has very good bioavailability and can be used for long-term prophylaxis. Patients not responding to ganciclovir should be evaluated for ganciclovir resistance, a common cause of treatment failure. Most of these patients remain sensitive to foscarnet.

The goal of pharmacotherapy is to shorten the clinical course and prevent or decrease complications, latency, recurrences, transmission, and established latency. Highly active antiretroviral therapy (HAART) is effective in reconstituting the immune system and preventing CMV reactivation.^[5] Current guidelines recommend discontinuation of secondary prophylaxis in HAART recipients with a sustained (>6 mo) increase in CD4⁺ T cells to greater than 100-150 cells/µL.^[3]

Without antiviral therapy, mortality approaches 100%. With antiviral therapy, more than 50% of patients stabilize or improve.

Overall, the prognosis is usually poor even with immune reconstitution and antivirals against cytomegalovirus (CMV). This disappointing expected outcome is in part determined by the stage of HIV infection and the overall health of the patient.^[6]