Congenital Cytomegalovirus (CMV) Infection

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Background    Neuroimaging    Gross Pathology    Histopathology & Immunohistochemistry Differential Diagnosis    Reference

BACKGROUND AND CLINICAL INFORMATION: Head

Summary    Clinical features    Pathogenesis

Summary: In congenital CMV infections, over 90% of the newborns are asymptomatic at the time of birth but the consequences of in utero CMV infection such as hearing loss will show up as the infant gets older. The most morphological abnormalities is microcephaly and periventricular calcification. Death that occurs shortly after birth tends to be resulted from hepatic failure. CMV infections due to primary infections produce more severe damage than those resulted from reactivation of latent infection. [Non-congenital CMV infection]

The virus: A member of the Herpesviruses and contain double-stranded DNA. CMV has the largest genome (229 kb) of the viruses know to infect man.

Transmission:  CMVis spread by vertical transmission (mother to fetus), direct personal contact or through the blood. CMV infections are the most common viral infection known to be transmitted in utero. Humans are believed to be the only reservoir for human CMV infection. 

Primary infection is much more likely to produce serious fetal disease than reactivation of latent infection during pregnancy. Maternal antibodies may be protective. Infection during early gestation is more likely to have poorer outcome.

Incidence: Ranges fom 0.2% to 2.2% among all live birth and has no seasonal variation.

Clinical feature:

• Over 90% of infected newborns are asymptomatic at the time of birth. About 5-15% of infected babies who are asymptomatic at birth will develop seuqelae within the first two years of life, most commonly hearing loss. Other features of silent congenital CMV infection include low intelligence, microcephaly and chorioretinitis.

• In symptomatic newborns, the observed illness varies in severity. The approximately order of decending frequency, the most prominent manifestations include hepatosplenomegaly, jaundice, purpura, microcephaly, cerebral calcifications, and chorioretinitis (but visual loss is infrequent). Involvement of the CNS is the most common and important manifestation of congenital CMV infection. Ocular and hearing defects are common. Other common neurologic abnormalities include microcephaly, periventricular calcification, severe psychomotor retardation, strabismus, seizures and low birth weight.

• In contrast to the neurologic damage, extraneural involvement of the liver, spleen, lungs, and kidney is usually reversible with relatively little chance of permanent malfunction. Babies may also have imparied cell-mediated immunity.

• Cause of death: The mortality among congenitally infected infants may be as high as 20-30%. Death that occur early in life is usually a consequence of hepatic dysfunction, bleeding or secondary bacterial infection. Death after the first year of life is usually the result of complications secondary to neurological dysfunction.

• Definitive diagnosis: serology, viral culture or demonstration of CMV in tissue. Prenatal diagnosis by ultrasound is possible.

Pathogenesis: possible mechanisms include

• Direct cellular loss through viral infection, both of individual cells and of larger foci both inside and outside cortex.

• Loss of primitive neuroectodermal cells in the ventricular zone boht neuornal and glial if the fetal brain is infected before migration is completed. This will lead to a migration disorder.

• Loss of intergrity of the pial-glial border.

• Systemic hypoxic-ischemic insult due to systemic hypotension.

• Local hypoxic-ischemic insult due to damage to capillaries.

• Immunologic injury involving antigen-antibody complex deposition may be involved in organs such as kidney.

NEUROIMAGING: Head

• Intracranial calcification is seen in 20-30% of symptomatic congenital CMV infection.

• Ventriculomegaly and microcephaly.

GROSS PATHOLOGY: Head

Microcephaly: Seen in at least 50% of all cases. Other pathologic changes include polymicrogyria, ventriculomegaly, and necrosis.

Relation with morphologic changes:

• CMV is known to persist for months in the fetus. The most obvious, but not necessarily the most important, pathogenic mechanism is continuous viral replication in affected organs. Excretion of CMV into urine and saliva persists for years.

• Variable CNS damage: The pathology of intracerebral disease ranges from incidental to widespread destruction. The final morphologic changes are dependent on when the fetus is infected and how long the baby lived after the infection. Knowledge of pre-existing CNS malformation before the onset of infection is also of critical help.

• Early fetal incetion: Infection at a very early stage will probably lead to embryonic death. Presence of abnomalities suggestive of teratogenic events at very early gestational age, such as cyclopia, may suggest a coincidence rather than a true CMV induced malformation.

HISTOPATHOLOGY AND IMMUNOHISTOCHEMISTRY: Head

Inclusions: Findings varies from small and scattered microglia nodules to small infarcts to cavitary, necrotic lesions. The amount of CMV inclusion may not be proportional to the degree of destruction and may be difficult to be found. Inclusions can be found in all kinds of neuroglial cells with the periventricular areas being the most fruitful site; inclusion bodies are also found in choroid plexus, meninges, and blood vessel walls.

Calcification can occur in anywhere with necrosis. Subependymal calcification is, however, most common. Ventriculomegaly may be due to widespread destruction or obstruction of the aqueduct secondary to ependymitis.

Loss of primitive cells in the ventricular zone (germinal matrix) can be marked. This may be the cause of microcephaly and polymicrogyria.

Migration disorder: features suggestive of migration disorder including accumulation of primitive neuroepithelial cells and polymicrogyria may be seen.

Polymicrogyria: if polymicrogyria and CMV inclusion is seen in an infant, CMV may be causal. If the inclusion is seen in polymicrogyria in patients older than one year old, the CMV infections may be recent because CMV inclusions are not usually found after after the first year in congenital infection. The CMV infection in these cases, therefore, is more likely to be coincidental.

Ocular pathology is CMV chroioretinitis and deafness (sensorineural) is due to infection of the epithelium in the inner ear by CMV.

DIFFERENTIAL DIAGNOSIS: Head

Facial-scapulo-humeral dystrophy (Landouzy-Déjerine): In a minor proportion of cases, there is extensive inflammatory cell infiltration. Invasion of necrotic fibers by mononuclear cells (a phenomenon in polymyositis and inclusion body myositis) is not present but “degenerating” and “partially degenerating” fibers are invaded by histiocytes.

Hereditary body myopathies: The onset is in adolesence or early adulthood. Other than that they have no inflammation, they have histoligical features almost identical to that of inclusion body myositis. Late onset cases must be distinguished from inclusion body myositis.

REFERENCE: Head

Carpenter S. JNEN 1996 55:1105, general review.

Askanas V and Engel WK JNEN 2001 60:1-14, pathogenesis and its relation to Alzheimer’s disease.

Moslemi AR, Lindberg C, Oldfors A. Analysis of multiple mitochondrial DNA deletions in inclusion body myositis. Hum Mutat. 1997;10(5):381-6.

Schroder JM, Molnar M. Mitochondrial abnormalities and peripheral neuropathy in inflammatory myopathy, especially inclusion body myositis. Mol Cell Biochem. 1997 Sep;174(1-2):277-81.