Cytomegalovirus Encephalitis in HIV

Cytomegalovirus (CMV) is a double-stranded DNA virus in the herpes virus family that can cause disseminated or localized end-organ disease in HIV-infected patients with advanced immunosuppression. 

In patients with HIV, CMV encephalitis is one of the opportunistic infections that can be seen in late stages of 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. Other risk factors for CMV encephalitis include prior history of opportunistic infections, high levels of plasma HIV RNA (>100,000 copies/mL), and high levels of CMV as measured by polymearase chain reaction (PCR).[2]  Most infections occur in the setting of prior CMV disease (seropositive), reactiviation of latent CMV virus, or infection with a novel strain.[3]

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.

Encephalitis and meningitis have different but overlapping clinical features. Patients with meningitis may be lethargic or distracted by headache, but cerebral function usually remains normal. Patients with encephalitis commonly present with altered mental status, motor or sensory deficits, altered behavior, personality changes, and speech or movement disorders. 

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.[4]

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. CMV PCR in the CSF is the recommended method to diagnose and confirm CMV with neurologic involvement. CSF analysis will typically show low glucose, elevated protein, and can have either a neutrophilic or mononuclear pleocytosis.[5]

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]). MRI is preferred to CT in the diagnosis of CMV encephalitis.

MRI findings are typically non-specific and demonstrate T2 FLAIR hyperintensities in the periventricular white matter. The presence of enhancement suggests ventriculitis, which can occur in CMV encephalitis.

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.[6] 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.[7, 6] Long-term intravenous (IV) maintenance therapy may be indicated for patients who have a clinical response.

Suggested dosing: IV gancyclovir (5 mg/kg every 12 hours) plus foscarnet (90 mg/kg every 12 hours).[8]

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.[9] 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.[6]

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.[10]

Prior to the introduction of potent antiretroviral therapy (ART), the median survival of patients with cytomegalovirus (CMV) neurologic disease was less than three months.[11]  However, ART has altered the natural history of CMV neurologic disease, and long-term survival has been reported in some patients, even if patients initiate ART after being diagnosed with CMV disease.