Cytomegalovirus

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Epidemiology and Risk Factors. Cytomegalovirus (CMV) is the most common life- and sight-threatening opportunistic viral infection in patients with AIDS. '127' Central nervous system infection by CMV in patients with AIDS may take the form of one or more of five distinct neurological syndromes: retinitis, polyradiculomyelitis, encephalitis with dementia, ventriculoencephalitis, and mononeuritis multiplex. '128' Organ transplant recipients are also at risk for encephalitis due to CMV. Newborns with congenital CMV infection may have seizures, spasticity, microcephaly, chorioretinitis or optic atrophy, and neuroradiographic evidence of intracerebral calcifications and cerebral atrophy. '129'

Cytomegalovirus is a DNA virus and a member of the herpesvirus group, which includes VZV, herpes simplex virus types 1 and 2, and Epstein-Barr virus. All of these viruses have a propensity to assume a latent state in humans and to undergo reactivation. '129' Primary infection with CMV is usually benign; approximately 80 percent of adults in the United States have complement fixation (CF) antibodies to CMV by the age of 40, but under conditions of immune suppression, latent virus may be reactivated, producing a variety of systemic and neurological syndromes.

Pathogenesis and Pathophysiology. CMV is acquired by close personal contact through saliva, cervical secretions, and semen, and through blood transfusion. In congenital CMV infections, the fetus acquires the infection transplacentally. Symptomatic congenital CMV infection is a complication only of primary maternal infection; infants born to immune mothers may be infected but appear to be asymptomatic in the newborn period. Perinatal infection in infants occurs either through contact with CMV-infected uterine cervical secretions or through transmission of CMV in breast milk. Infection of the CNS results from viremia, and CMV has a predilection to infect the ependymal cells lining the ventricles and the gray matter in the cortex, basal ganglia, brain stem, and cerebellum. '128' , '129' The CNS symptoms and neuropathological abnormalities observed in CMV-infected fetuses have been attributed to chronic intrauterine CMV encephalitis. '129'

Clinical Features and Associated Findings. As stated earlier, CMV may cause congenital disease, retinitis, lumbosacral polyradiculopathy and myelitis, encephalitis with dementia, ventriculoencephalitis, mononeuritis multiplex, and infectious polyneuritis--the Guillian-Barre syndrome.

Congenital CMV Infection. The clinical spectrum of congenital CMV infection varies from an asymptomatic

infant to one who has the signs and symptoms of disseminated disease. In the most severe form of congenital CMV infection, the virus affects multiple organs, and the infant has hepatitis, splenomegaly, pneumonitis, jaundice, thrombocytopenia, chorioretinitis, hemolytic anemia, petechial or purpuric rash, seizures, spasticity, microcephaly, optic atrophy, and neuroimaging evidence of intracerebral calcifications and cerebral atrophy. '129'

Retinitis. The presenting complaint of CMV retinitis is usually unilateral "floaters" or decreased visual acuity. Ophthalmological examination demonstrates large white-colored areas with perivascular exudates and hemorrhages. Initially these abnormalities are found at the periphery of the fundus, but if left untreated, lesions progress to involve the macula and the optic disk. '130'

Lumbosacral Polyradiculopathy and Myelitis. The presentation of this syndrome is characterized by a subacute onset of weakness, areflexia, and sensory loss in the legs in association with bladder- or anal-sphincter dysfunction. The disease evolves as an ascending paraparesis. '128' Clinical evidence of lower extremity weakness, areflexia, and bilateral Babinski's signs (if the spinal cord is involved) suggests this syndrome.

Encephalitis. Patients with AIDS and encephalitis due to CMV present with forgetfulness, memory impairment, apathy, and withdrawal like patients with HIV encephalitis, except that patients with CMV encephalitis have had AIDS longer and have lower mean CD4 lymphocyte counts at presentation. Patients with CMV encephalitis also have rapidly progressive cognitive impairment, and their survival is markedly shorter than that of patients with HIV dementia. CMV encephalitis is characterized by multifocal, diffusely scattered, small microglial nodules and inclusion- bearing cytomegalic cells that are concentrated in the gray matter in the cortex, basal ganglia, brain stem, and cerebellum. There is a strikingly high incidence of hyponatremia, hyperkalemia consistent with an Addisonian state, dilutional hyponatremia with hypo-osmolality, or hypernatremia due to dehydration in patients with CMV encephalitis. W

Ventriculoencephalitis. A distinction is made between CMV encephalitis, described earlier, and CMV ventriculoencephalitis, which is characterized by necrosis of the cranial nerves and of the periventricular parenchyma. '128' This syndrome presents as a rapidly fatal delirium with oculomotor palsies and nystagmus, and a linear homogeneous increased signal on T2-weighted MRI scans around the ventricles with ventriculomegaly.

Mononeuritis Multiplex. CMV mononeuritis results from focal necrotizing vasculitis of the epineural arteries and presents as a multifocal or asymmetrical sensory or motor deficit in the distribution of a peripheral or cranial nerve. '12a'

Differential Diagnosis. The diagnosis of congenital CMV infection is made by recovery of infectious virus from urine, saliva, buffy coat leukocytes, or CSF. Demonstration of seroconversion or a fourfold increase in CMV antibody titers between the acute and convalescent sera strongly supports recent CMV infection. CT scan demonstrates intracerebral calcifications and cerebral atrophy in newborns with CNS symptoms. '129' The diagnosis of CMV retinitis is made clinically because it is impractical to obtain fluid or tissue from the eye for culture or microscopic examination. Blood, urine, or semen can be cultured to document active CMV infection in the patient, but the relevance of these cultures is questionable because patients without retinitis have positive cultures. '130' In patients with CMV lumbosacral polyradiculopathy, the cerebrospinal fluid often demonstrates a pleocytosis with a neutrophilic predominance, the protein concentration is elevated, and the glucose concentration may be low or normal. Culture of CSF for CMV is the gold standard, but this test is insensitive (positive in 60 percent of patients), and CSF should also be analyzed by the PCR technique.'«! , '132' Magnetic resonance imaging may reveal enlargement of the conus medullaris, clumping of lumbosacral rootlets, or enhancement (with gadolinium) of the leptomeninges of the lower spinal cord. '128' In patients with CMV encephalitis there may be a mild mononuclear pleocytosis and an elevated protein concentration. CSF should be analyzed for CMV DNA by PCR. In patients with CMV ventriculoencephalitis, magnetic resonance imaging (as described above) may demonstrate increased periventricular signal intensity on T2-weighted images. In all patients in whom a CMV neurological syndrome is suspected, culture of the CSF and analysis of CSF by PCR to detect CMV DNA should be performed.

Management. Ganciclovir and foscarnet are the two antiviral agents that have been proved effective in the treatment of CMV retinitis. CMV polyradiculopathy, encephalitis, and ventriculoencephalitis have been treated with dosing regimens that are identical to those used for CMV retinitis, although their clinical efficacy has not been established (see Tâble..,..4..1-6 ). Ganciclovir 5 mg/kg intravenously is given twice daily during "induction" therapy for a minimum of 2 to 3 weeks. This is followed by maintenance therapy at a dose of 6 mg/kg intravenously qd. Foscarnet is given in a dose of 60 mg/kg administered intravenously every 8 hours for induction therapy for a minimum of 2 to 3 weeks, followed by maintenance therapy of 100 to 120 mg/kg given intravenously qd. The doses of ganciclovir and foscarnet must be reduced when renal function is impaired or renal toxicity develops. A reversible leukopenia is an adverse effect of ganciclovir, as is a thrombocytopenia. Adverse effects of foscarnet include renal toxicity, anemia, hypocalcemia, hypopophosphatemia, and seizures. '130] Both CMV encephalitis and ventriculoencephalitis have been reported in patients receiving maintenance therapy for CMV retinitis even when the retinitis remains under control. '127] , '128

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