Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
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Cytomegalovirus (CMV) is a ubiquitous agent responsible for most intrauterine infections. Besides well-known symptoms and findings such as hearing loss and microcephaly, congenital cytomegalovirus infection can also underlie certain cerebral anomalies and static leukodystrophies. In this article, the authors discuss uncommon presentations of asymptomatic congenital cytomegalovirus, predicted outcomes of congenital multi-strain cytomegalovirus infection, and updates on potential cytomegalovirus vaccines.
• Cytomegalovirus is the most common infection of the developing brain.
• Congenital cytomegalovirus infection can cause a host of cerebral abnormalities, including calcifications, ventriculomegaly, white matter lesions, cortical atrophy, and cortical migration abnormalities.
• Affected children can have neurologic impairments that range from sensorineural hearing loss to profound mental and motor deficits.
In 1904, Ribbert described a stillborn infant with congenital syphilis who had large inclusion-bearing cells in the kidney (45). A similar report followed (30). These are probably the first cases of congenital cytomegalovirus described in literature. By 1921, it was postulated that the inclusions were due to an infectious agent, most likely a virus (24; 35). The agent was subsequently called "salivary gland virus," and the infection was referred to as "cytomegalic inclusion disease.” Murine cytomegalovirus was successfully grown in tissue culture in 1954 (51). Two years later, human cytomegalovirus was isolated from congenitally infected children using similar techniques (52; 62). The name "cytomegalovirus" was accepted in 1960 (61).
Only 5% to 12% of infected infants are symptomatic at birth. However, more symptoms appear on longer follow-up because congenital cytomegalovirus is a chronic persistent infection.
Symptomatic neonatal infection. The most common abnormalities at birth are jaundice, thrombocytopenia, petechiae, purpura, hepato- or splenomegaly, intrauterine growth retardation, microcephaly, and sensorineural hearing loss (5% to 10% at birth and up to 40% during childhood). Less common are hemolytic anemia, ascites, hydrops, prematurity, inguinal hernia, pneumonitis, and ocular problems (chorioretinitis, microphthalmos). The presence or absence of microcephaly predicts nervous system involvement (23). Various neurologic problems can occur: encephalitis, mental retardation, seizures, abnormal tone or movements, hydrocephalus, leukodystrophy, or migration abnormalities such as lissencephaly or schizencephaly (57).
CT scan is abnormal in 70% of symptomatic children, most commonly showing parenchymal calcifications, and correlates with neurologic outcome. As an alternative to CT, ultrasonography can be combined with magnetic resonance imaging in the newborn period.
Asymptomatic neonatal infection. Approximately 85% of infected infants will fall into this group (40). Some will be diagnosed as a result of neonatal screening for hearing or with late sequelae, such as hearing loss (6% to 25%) or permanent neurologic impairment (13.5%). Of interest, a unique case of leukemoid reaction (> 100,000 WBCs) as the only presenting feature of congenital cytomegalovirus infection in an otherwise asymptomatic preterm infant has been described (29).
Hearing should be assessed periodically during childhood because hearing loss is the most common sign of congenital cytomegalovirus infection, especially first trimester infections, and can progress. Of all affected symptomatic and asymptomatic infants, 5% have hearing loss at birth and 15.4%, at 6 years (23).
Prognosis relates to the timing of in utero infection as well as the presence or absence of symptoms at birth and the type of maternal infection. Primary maternal cytomegalovirus infection and symptomatic congenital infection increase the likelihood of significant problems. Children symptomatic at birth have a mortality rate of 10% to 20% and are more likely to develop permanent sequelae than asymptomatic ones (50% vs. 13%) (16). Ascites and hepatosplenomegaly are associated with an increased death rate. Ventriculomegaly, microcephaly, and calcification are associated with neurologic damage (36). Cortical migration disorders such as lissencephaly or polymicrogyria can occur, but largely depend on the timing of the in utero infection. Lissencephaly is observed if the infection occurs prior to 16 to 18 weeks of gestation (04). Polymicrogyria may occur if the fetus is infected between 18 and 24 weeks of gestation. Frontal and temporal polymicrogyria are the most common patterns of migrational disorder (63). Death within the first month results from severe hepatic disease, disseminated intravascular coagulation, or secondary bacterial infections; death in the first year results from progressive liver disease or severe failure to thrive. Death after 1 year of age is seen in those with severe neurologic damage and usually results from complications of infection, aspiration, or malnutrition. Subsequent and significant additional deficits occur in up to 95% of symptomatic infections. These include hearing loss (bilateral in up to 70%), neurologic impairment (mental retardation, motor deficits, seizures, and behavioral or cognitive deficits), dental defects (abnormal enamel, severe caries, crumbling primary teeth), and vision loss due to chorioretinitis or optic atrophy. Hearing loss occurs in one fifth of asymptomatic and one third of symptomatic congenitally infected infants. It can improve, worsen, or fluctuate during childhood. It must be noted that congenital co-infection with multiple cytomegalovirus strains is not currently shown to be predictive of either severity of symptoms or sensorineural hearing loss at birth (42).
Asymptomatic infection does not carry a risk of death, but it can lead to morbidity. Hearing loss and (according to some studies) neurodevelopmental defects develop in 5% to 17% of these patients.
A combination of imaging characteristics, cerebrospinal fluid profile and head circumference adjusted for weight, can be helpful in predicting neurologic outcomes after congenital infection. Imaging-based predictive scales based on the presence of destructive lesions (dilated ventricles, germinolysis, calcifications, and atrophy), teratogenic abnormalities (cerebellar hypoplasia, dysgenesis of the corpus callosum), and white matter signal abnormality on MRI can be useful (01).
A 3-month-old girl was admitted for pneumonia and anemia. She was born at term as the first child of healthy parents with a birthweight of 2200 g. The pregnancy and delivery were uneventful. On physical examination she had microcephaly, jaundice, respiratory difficulty, and hepatosplenomegaly. Laboratory tests revealed elevated liver enzymes, hemolytic anemia, and thrombocytopenia. Chest x-ray showed interstitial pneumonia. Congenital cytomegalovirus infection was diagnosed on the basis of specific IgM in the serum, the presence of inclusion bodies in urinary epithelial cells, and a positive polymerase chain reaction with high viral load in the urine.
Human cytomegalovirus is an enveloped double-stranded DNA member of the herpes virus group. It is ubiquitous and infects only humans. Like other herpes agents, cytomegalovirus becomes latent in the host after primary infection and may reactivate to cause secondary infection. Different cytomegalovirus strains exist, and reinfections also occur.
Congenital cytomegalovirus is due to fetal infection by maternal virus. Both primary and secondary maternal infections can involve the fetus at any time during pregnancy. Congenital cytomegalovirus produces a chronic infection: virus is recoverable months to years after birth.
Congenital cytomegalovirus is an intrauterine infection, distinct from perinatal cytomegalovirus infection. In perinatal infections, virus is transmitted to the newborn at the time of birth, or shortly after, by way of infected birth canal, breast milk, or blood transfusion. Congenital infection probably results from virus acquired by susceptible women immediately before or during early pregnancy followed by viremia, placental infection, and hematogenous and transplacental spread to the fetus. Alternative postulated, but unproven, mechanisms include: reactivation of latent virus within uterine tissue, transovarian infection, or spermatozoan infection. Preexisting maternal immunity protects considerably from virus transmission. Only 1.5% of secondary maternal infections involve the fetus, compared to 30% to 40% of primary infections. Still, more than 60% of all the infants infected in utero are born to mothers with preconception immunity and who have a secondary infection by new strains during pregnancy. However, severe symptoms, and specifically severe and progressive hearing loss, are more frequent during primary infection (47).
The extent of damage due to cytomegalovirus varies widely and is correlated with viral load (09), as well as immune-mediated damage by virus-specific cytotoxic T lymphocytes and consequent hypoxic cerebral damage (22). Tumor necrosis factor receptor UL144 polymorphisms have been suggested as a predisposing factor affecting virus load (02). Gap junction protein beta-2 (GJB2) mutations are more frequent in patients with cytomegalovirus and hearing loss than those without (21% vs. 3%) (48).
Cytomegalovirus can infect many different cell types and all major organs. The cochlea is frequently involved, as is the central nervous system. There is a predilection for periependymal neurons and glia, with focal encephalitis and periependymitis. Necrotic periependymal tissue subsequently calcifies. Calcifications are typically periventricular but may also be scattered throughout the brain. Cytomegalovirus produces cytolysis, with focal necrosis and a localized mononuclear inflammatory response. Tissue damage results from direct effects of the inflammatory response as well as an associated vasculopathy resulting in ischemia and encephalomalacia, immune-mediated reactions, and apoptosis (14).
Typical pathology involves cytomegalic brain cells with intranuclear inclusions. When cytomegalovirus infects developing CNS tissue, it can produce microcephaly with neuronal migration defects. Severe destructive changes lead to more severe brain abnormalities such as porencephalic cysts, cerebellar hypoplasia, aqueductal stenosis, and hydrocephalus. Postnatally, MRI can detect white matter abnormalities that occur in several patterns: predominantly parietal lobe lesions, multifocal white matter lesions with polymicrogyria, and diffuse white matter lesions with polymicrogyria (58).
An in vitro model using neural stem cells showed that CMV activates the peroxisome proliferator-activated receptor γ (PPARγ), which inhibits neural stem cell differentiation into neurons and, thus, may underlie one of the key pathogenic mechanisms behind CMV-associated neurologic sequelae (12). Cytomegalovirus can induce specific chromosomal damage that requires viral entry into the cell, but not de novo viral protein expression, a probable mechanism for damage in the developing fetal brain (19). Another mechanism in the pathogenesis might be related to down regulation of the EGF receptor on the cell surface by cytomegalovirus (06). A murine model of cytomegalovirus-induced sensorineural hearing loss showed that the activation of the inflammasome pathways as well as reactive oxygen species formation are some of the mechanisms of damage to the spiral ganglion neurons (65).
Congenital cytomegalovirus is a persistent chronic infection. Half of infected children show viremia for months and viruria for 6 years or more. Cytomegalovirus may be excreted in saliva for 2 to 4 years. Late sequelae reflect this chronic infection of developing tissue. In addition, some abnormalities that are present at birth may not be detectable until the infant is older.
The prevalence of congenital cytomegalovirus infection varies from 0.15% to 2.0% in different countries. Approximately 40,000 congenitally infected infants are born in the United States each year. Polymerase chain reaction of dried blood samples demonstrated that 0.7% of newborns in California were positive for cytomegalovirus; however, not all newborns with congenital infection can be identified, even by this sensitive method (40). Ten to twenty percent show signs of neurologic damage; approximately half will manifest problems within the first 6 years of life. Congenital cytomegalovirus is the most common cause of nonhereditary sensorineural hearing loss in children.
Seropositivity varies with age, geographic location, cultural and socioeconomic background, and childrearing practices. In the United States, seroprevalence is 40% to 60% among middle and upper income people, compared with 80% in lower income groups. Seroconversion rates during pregnancy range from 0.7% to 4.1%. Primary maternal infection carries a higher risk for fetal damage, but recurrent maternal infection may also be associated with symptomatic infection in the infant. The rate of transmission to infants born to mothers who had a primary infection or a recurrent infection during pregnancy was 32% and 1.4%, respectively. Neurologic symptoms have occasionally been observed in infants born to mothers with preconceptional immunity. Nonwhite race, low-socioeconomic status, premature birth, and neonatal intensive care unit admittance were risk factors for congenital cytomegalovirus infection (31). Significant epidemiological associations were found between congenital cytomegalovirus infection and the following: caring for school children in the year before delivery; onset of sexual activity less than 2 years before delivery; sexually transmitted diseases during pregnancy; household size of more than 3 people; and maternal age of less than 25 years. Women who carried both of the first 2 factors were at greatest risk for delivering an infected baby (21).
The goal of preventing congenital cytomegalovirus infection with a vaccine is of the highest priority. The presence of cytomegalovirus genes that encode proteins that lead to evasion of the immune system complicates vaccine design. In addition, the immunological basis for prevention is not sufficiently identified.
Currently there are no effective vaccines available, although several potential candidates are emerging (54). A phase II trial studying recombinant genetically modified gB, which is an immunodominant envelope protein, in an adjuvant (MF59) versus placebo in cytomegalovirus seronegative women proved to be immunogenic and showed a 50% reduction in the rate of maternal infection (41). It must, however, be noted that most of the efficacy was observed in the first 12 to 15 months. Despite being moderately efficacious, this vaccine ultimately failed to induce a durable and robust cellular and humoral immunity (60). Another potential vaccine that underwent phase I trials combined gB protein and pp65/IE1 fusion protein was successful at neutralizing antibody response (05). In a phase II trial, this vaccine (TransVax, also known as ASP0113) reduced posttransplant cytomegalovirus viremia in patients undergoing hematopoietic cell transplant. However, in the randomized, double-blind, placebo controlled phase III trial (HELIOS), ASP0113 failed to reduce mortality and cytomegalovirus-related end-organ disease (primary endpoints of the study) as well as did not reach its secondary endpoints (“time to first protocol-defined cytomegalovirus viremia and time to first use of adjudicated CMV-specific antiviral therapy”) (59). The cytomegalovirus vaccine CymVectin combines plasmids that express pp65/IE1 fusion protein with gB formulated with Vaxfectin, an adjuvant that helps induce a robust humoral and cellular response. It is currently in phase I trial.
A mRNA vaccine (mRNA-1647) by Moderna, consisting of 6 mRNAs, of which 5 encode the subunits of the cytomegalovirus pentamer complex and 1 mRNA encodes the glycoprotein B (gB) protein, is completing phase II trial (NCT04232280). The interim results showed that the vaccine was able to significantly boost neutralizing antibodies in both cytomegalovirus seropositive and seronegative patients. Phase III trial began in 2021. Many other candidate vaccines are currently in development as well. These combine peptides, subunits, or all multi-subunit complexes of the pentameric complex necessary for the endothelial and epithelial cell entry by the virus (37).
At this time, neither primary prevention, nor standardized, high-throughput screening tests or follow-up protocols for secondary and tertiary prevention are available. Therefore, current preventive measures include counseling young women, assessing their serologic status to identify those at risk for primary infection, and recommending appropriate hygiene measures in situations with risk of cytomegalovirus exposure, such as daycare centers. Recommendations for pregnant women include avoidance of iatrogenic transmission through blood transfusion and adherence to hygiene measures. Infants actively excrete virus. Awareness of this fact, with appropriate contact isolation and proper hygienic measures, minimizes risk of cytomegalovirus transmission.
Although a large percentage of pregnant women shed the virus during pregnancy, their infants do not develop congenital infection (13). Therefore, prenatal diagnosis of intrauterine infection is accomplished by serologic studies (ie, detection of virus-specific IgG in a previously seronegative pregnant woman or of specific IgM with low IgG avidity) and most reliably by PCR of the amniotic fluid collected at least 7 weeks after the presumed time of maternal infection and after 21 weeks of gestation (64). A low avidity index indicates recent infection and may help to distinguish pregnancies in which invasive prenatal diagnosis is necessary. Ebina and colleagues showed that a cut-off value of less than 40% IgG avidity index carried a specificity of 96.1% and a sensitivity of 64.3% for prediction of congenital infection (18).
IgM-positivity, seroconversion, or anti-CMV antibodies of low/moderate avidity are observed for approximately 18 to 20 weeks after primary infection.
Yinon and colleagues assessed the quality of evidence for diagnosis of intrauterine infection (64). Routine screening of pregnant women for cytomegalovirus by serologic testing is currently not recommended – a practice that is not without some controversy (15). Screening is advised when an influenza-like illness is experienced during pregnancy; when ultrasonographic findings suggesting infection are detected; and for seronegative pregnant women who work in child care or health care. In the case of primary maternal infection, there is a 30% to 40% risk for fetal infection and 20% to 25% risk for sequelae. In cases of proven secondary infection (high IgG avidity), counselors should estimate a lower transmission rate. Ultrasonography findings that show an abnormal pattern of periventricular echogenicity, ventriculomegaly, and various parenchymal abnormalities may support the diagnosis of suspected cytomegalovirus infection in mid or late pregnancy and may indicate the need for serological tests. However, ultrasound abnormalities predict symptomatic congenital infection in only a third of cases (25).
Risk factors for asymptomatic infants developing late hearing loss include an intense and prolonged maternal antibody response, which suggests infection early in pregnancy and continuing antigenic stimulation. Genetic mutations predisposing the child to hearing loss due to cytomegalovirus, if confirmed in larger populations, may be screened to identify infants at risk.
A targeted screening of newborns for evidence of hearing loss may be important, may provide early access to interventions, and may alter these neonates’ developmental outcomes (33). A large multicenter trial evaluated 99,945 babies and showed that testing those infants who fail their newborn hearing screen for cytomegalovirus can identify the majority (57%) of those with sensorineural hearing loss due to cytomegalovirus infection (20). Universal screening for cytomegalovirus at birth may also help detect those children who are at risk for late onset of sensorineural hearing deficits.
The differential diagnosis of congenital cytomegalovirus includes other congenital infections (rubella, toxoplasmosis, syphilis, herpes simplex, hepatitis, and varicella zoster). Both cytomegalovirus and intrauterine parvovirus B19 infection can cause fetal hydrops. Rubella produces heart defects, cataracts, a salt-and-pepper retinopathy (rather than chorioretinitis), and, rarely, produces cerebral calcifications. Toxoplasmosis typically has scattered, rather than periventricular, calcifications, and its associated skin rash is maculopapular. Congenital syphilis produces long-bone changes (osteochondritis, epiphysitis), rhinitis, and mucous membrane lesions; brain calcifications are unusual. Herpes simplex may produce skin and mucous membrane vesicles. Neonatal herpes is generally a perinatal infection, and presents acutely 1 to 3 weeks after birth.
Bacterial sepsis is also in the differential, as are noninfectious disorders such as hemolytic diseases (due to blood type or factor incompatibilities or primary red cell defects), metabolic disorders (galactosemia, tyrosinemia), immune thrombocytopenia, reticuloendotheliosis, and congenital leukemia. The differential diagnosis widens dramatically when congenital cytomegalovirus produces only mild or single organ disease.
Metabolic disorders, particularly respiratory chain defects, can cause cortical migration abnormalities and cerebral calcifications similar to congenital cytomegalovirus infection. Severe lactic acidosis in the neonate suggests a metabolic disturbance that can be proven by measurement of mitochondrial enzyme activities.
Attention has been drawn to the resemblance between congenital cytomegalovirus and autosomal recessive cystic leukoencephalopathy without megalencephaly. In the latter, children are asymptomatic at birth but show developmental delay within the first year of life, with a normal or small head circumference. Bilateral cystic lesions in the anterior temporal lobes, enlarged inferior horns, and multifocal white matter alterations can be seen on brain MRI. Brain computed tomography demonstrates intracranial calcifications that can mimic congenital cytomegalovirus infection (26).
Congenital cytomegalovirus should be suspected in any newborn with signs suggesting this diagnosis or when there has been maternal seroconversion during pregnancy. In pregnant women, the diagnosis is essentially based on the detection of IgG and IgM antibodies. The presence of the cytomegalovirus DNA by PCR in the maternal uterine cervical secretions may be predictive of congenital cytomegalovirus infection (56). The detection of viral DNA in the amniotic fluid confirms congenital infection. However, amniocentesis must be performed after 21 weeks’ gestation and at least 6 weeks after seroconversion in order to reliably detect cytomegalovirus. A high cytomegalovirus load in the amniotic fluid on quantitative PCR correlates with symptomatic infection.
The gold standard for diagnosing congenital cytomegalovirus infection is isolation of the virus from newborn babies’ urine, saliva, conjunctival or rectal swabs, or leukocytes through conventional or rapid cell culture techniques. All samples should be obtained within the first 2 weeks of life because later samples do not allow differentiation between intrauterine and intra- or postpartum infection. Detection of viral DNA by PCR is the most widely used diagnostic test and can be performed even retrospectively on blood, saliva, or urine samples obtained around birth. Quantitative PCR methods can be useful to distinguish between cytomegalovirus infection and cytomegalovirus disease; a significantly higher viral load is seen in symptomatic infants. A urine-based screening program can identify asymptomatic cases with low viral loads in the blood (28). Real-time PCR in neonatal blood samples showed a lower sensitivity than the rapid culture of saliva, limiting its value as a screening test (10). According to the data derived from the CMV and Hearing Multicenter Screening (CHIMES) study, real-time PCR of saliva and urine are as reliable as virus culture, and provide a good diagnostic tool for high-volume screening (46).
Less-established virus detection techniques include electron microscopy, enzyme-linked immunosorbent assay detection of antigen, cytologic examination on sloughed cells in urine, or immunohistochemistry or in situ hybridization in tissue samples, especially in the case of stillbirth or abortion.
Serologic tests are not a substitute for virus isolation or histopathology, but are useful adjuncts for diagnosis. The absence of IgG against cytomegalovirus in cord or infant blood rules out congenital infection, and the presence of IgM supports this diagnosis; however, false-positive and false-negative reactions do occur. One study suggested that the neonatal serum IgM has a poor sensitivity (40.7%) for the diagnosis of congenital cytomegalovirus infection, being positive in only 48.8% of those with a symptomatic infection and 22.1% of those asymptomatic (07).
Other common laboratory findings are increased cord blood IgM level, atypical lymphocytosis, thrombocytopenia, anemia, direct hyperbilirubinemia, and increased aspartate transaminase. Cerebrospinal fluid may show increased protein in cases with neurologic damage or hearing loss and mild mononuclear pleocytosis. A variety of imaging approaches have been used to detect and confirm congenital cytomegalovirus infection (34). Neuroimaging may show intracranial (particularly periventricular) calcifications in 25% to 50%, multicentric encephalomalacia, leukodystrophy, ventriculomegaly, or migration abnormalities. Although pachygyria and lissencephaly can also be seen, the most typical findings are polymicrogyria, cerebellar hypoplasia, hippocampal malformations, and temporal lobe lesions (17). The latter typically consist of dilatation of temporal horns, white matter hyperintensity, and cysts in the temporal poles. For most abnormalities, including migrational defects, MRI is preferred. In suspected cases, fetal or postnatal MRI may be helpful in understanding the extent of cerebral damage. In this way the MRI may help decide the need for prenatal or postnatal antiviral therapy, or in some severely affected cases, the need for discussion about the possible termination of pregnancy as an option (03).
Prenatal management. Pregnant women with documented primary cytomegalovirus infection are offered termination, but the possibility of asymptomatic fetal infection can cause major difficulties in the decision process. At present, there is no recommended treatment for pregnant women with cytomegalovirus infection.
A randomized, double-blind, placebo-controlled study evaluated the efficacy of valaciclovir in the first trimester for preventing congenital cytomegalovirus infection evaluated via amniocentesis, and it showed a 71% reduction in infections (11% in valaciclovir group vs. 30% in placebo; P = 0.027), highlighting that valaciclovir may be effective at reducing the rate of fetal cytomegalovirus infection after maternal primary infection acquired early in pregnancy, and that early treatment of pregnant women with primary infection may prevent termination of pregnancies or delivery of infants with congenital cytomegalovirus (50).
Hyperimmune IgG against cytomegalovirus was initially thought to lower the risk of congenital infection (49), a randomized trial of hyperimmune globulin administered to 128 women showed that it did not significantly modify the course of primary infection. However, the power of the study to detect the difference was small, at 33%. It must also be noted that the rate of obstetrical adverse events was higher in the hyperimmune globulin group than in the placebo group (13% vs. 2%) (44).
An observational multicenter study involving 36 women administered hyperimmune IgG also corroborated the lack of significant efficacy of this approach (08).
A multicenter, double-blind trial evaluated efficacy of cytomegalovirus hyperimmune immunoglobulins administered to pregnant women with primary cytomegalovirus infection diagnosed before 24 weeks' gestation. This approach failed to lower incidence of a composite of congenital cytomegalovirus infection or perinatal death compared placebo (27).
A study of in-utero symptomatic cytomegalovirus infections evaluated the effects of combined fetal therapy (FT) and neonatal therapy (NT) consisting of immunoglobulin therapy administered into the fetal peritoneal cavity and/or maternal blood and post-natal administration of valacyclovir/valganciclovir. At 18 months of age at follow-up, the proportion of infants with severe impairments in the fetal therapy group was significantly lower than that in neonatal therapy alone group (18.2 % vs. 64.3 %, p < 0.05) (55).
International Congenital Cytomegalovirus Recommendations Group’s most recent guideline does not recommend the use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus in pregnant women with primary cytomegalovirus. The guidelines also do not recommend the use of valganciclovir for congenital cytomegalovirus during pregnancy (43).
The most recent best practice guideline from the American Society for Maternal-Fetal Medicine does not recommend antenatal treatment with ganciclovir or valacyclovir (53). The guideline specifies that these options or cytomegalovirus hyperimmune immunoglobulin should be offered only as a part of a research protocol.
Postnatal treatment. Infants with severe symptomatic infections require supportive care for systemic disease, eye problems, or seizures. Ganciclovir appears to preserve or improve hearing and neurodevelopmental status (39). Although intravenous ganciclovir and oral valganciclovir are used in the treatment of congenital cytomegalovirus infection, their use is limited by the potential for toxicity, especially neutropenia (38). A randomized, placebo-controlled trial of valganciclovir administered to infants with symptomatic cytomegalovirus infection showed that 6 months of treatment was superior to 6 weeks of treatment in improving long-term hearing and development outcomes (32). Oral treatment with valganciclovir appears preferable because of easier administration, high bioavailability, and efficacy on clinical and virological parameters (23); however, because of significant toxicity associated with valganciclovir, only moderately to severely affected infants older than 32 weeks of gestation but younger than 1 month of age should be administered valganciclovir (43). The combined use of antiviral agents and anticytomegalovirus immunoglobulin in severe disease may be more efficient than either agent alone. Cytomegalovirus-induced infantile spasms are not treated with adrenocorticotropic hormone to avoid a disseminated infection. Infected infants require serial medical, audiologic, psychometric, and eye examinations to detect late sequelae. Older children may require specific therapeutic interventions and educational assistance. Cochlear implants are effective for hearing loss. Gandhi and colleagues published an evidence-based review and algorithm for the management of cases of suspected of congenital cytomegalovirus infection (23).
A study evaluated whether cytomegalovirus-specific CD8 + T-cell responses in neonates with congenital cytomegalovirus using QuantiFERON®-CMV assay, within day 14 of life (T0) and during the second month of life (T1), could be used to predict symptomatic infection (11). Reactive QuantiFERON®-cytomegalovirus results at T0 and T1 correlated with lack of neonatal symptoms (P = .0001).
Congenital cytomegalovirus involves maternal infection during pregnancy. Primary maternal infections during the first half of pregnancy carry the greatest risk of fetal damage. Pregnant women should avoid contact with suspected cases.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Elena Grebenciucova MD
Dr. Grebenciucova of Northwestern University has no relevant financial relationships to disclose.See Profile
John E Greenlee MD
Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.See Profile
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