Congenital Human Cytomegalovirus Infection and Neurologic Diseases in Newborns

Human cytomegalovirus (CMV), a member of the beta-herpesvirus family, is the largest and most complex human herpesvirus. It is highly species-specific, with humans being the only known hosts. CMV can infect almost every cell type, including epithelial cells, endothelial cells, smooth muscle cells, neurocytes, and sustentacular cells of the central nervous system (CNS), as well as retinal epithelial cells, dermal fibroblasts, and monocytes/macrophages. The production of infectious virions varies widely among different cell types, ranging from very low in macrophages to very high in fibroblasts.

Congenital CMV (cCMV) infection is a significant cause of neonatal malformation, affecting approximately 0.2% to 2.2% of neonates in the United States, with an average prevalence of 1%. While only about 10% of infected newborns exhibit obvious clinical manifestations, 10% to 15% of asymptomatic infections result in long-term neurologic sequelae. The pathogenesis of cCMV infection in the CNS during fetal development is not fully understood, but it is known that CMV can infect the fetal encephalon during early gestation, compromising neurodevelopment and leading to various degrees of neurologic damage.

Neurologic Diseases Caused by cCMV Infection

Sensorineural Hearing Loss

Sensorineural hearing loss (SNHL) is the most common long-term sequela of cCMV infection. Approximately 700 million people worldwide have moderate or higher degrees of deafness, with CMV infection being a major cause of nongenetic SNHL in developed countries. Studies have shown that the prevalence of cCMV infection is 0.58%, with 9.8% of cases being symptomatic and 90.2% asymptomatic. Deafness accounts for 32.8% of symptomatic CMV infections and 9.9% of asymptomatic infections, making cCMV infection the leading cause of SNHL.

The degree of hearing loss caused by cCMV infection can range from unilateral to bilateral and may persist or worsen after the perinatal period. Early screening, diagnosis, and prophylactic treatment are essential for children with cCMV infection. Methods for screening include auditory brainstem response, urinary CMV-DNA viral load, and dried blood spot (DBS) tests. However, the effectiveness of DBS tests in predicting SNHL remains controversial.

Treatment options for hearing loss caused by cCMV infection include ganciclovir, hearing aids, and cochlear implants. Early cochlear implants can significantly improve language comprehension in children with cCMV-induced hearing loss, although they cannot fully correct the language delays caused by the infection.

Neurodevelopmental Disorders

Neurodevelopmental defects are abnormalities in structure, function, metabolism, mind, behavior, and inheritance caused by disorders of embryonic development. cCMV infection can lead to microcephaly, mental retardation, hydrocephalus, brain tumors, seizures, and autism. The severity of these defects is often related to the timing of maternal CMV infection, with early gestation infections being more likely to cause severe neurodevelopmental defects.

Diagnostic methods for neurodevelopmental disorders include B-ultrasound and MRI examinations. Intravenous ganciclovir treatment for 6 weeks in children with CNS cCMV infection may improve neurodevelopmental delay. Monitoring the state of neurodevelopment during the perinatal period and early treatment can improve the prognosis of these disorders.

Ophthalmic Complications

Ocular diseases caused by CMV infection mainly include retinochoroiditis, which manifests as strabismus, optic atrophy, microphthalmia, cataract, retinal necrosis and calcification, blindness, and malformation of the atria and optic disc. Infants with symptomatic cCMV infection account for approximately 14% of cases of chorioretinitis at birth.

Diagnosis of related ophthalmic diseases depends on ophthalmologic examination. Currently, no definitive treatment is available for choroidal retinitis caused by cCMV infection, although antiviral treatment with ganciclovir can improve the progression of the disease.

Cerebral Neoplasms

CMV gene products are frequently observed in cerebral neoplasms, such as glioblastoma and medulloblastoma. The CMV infection rates and the expression of IE proteins are high in primary medulloblastoma, medulloblastoma cells, and allograft medulloblastoma. The high expression of CMV gene US28 results in STAT3 phosphorylation, activation of the Wnt pathway, enhancement of COX-2 expression, and increased production of vascular endothelial growth factor, prostaglandin E2, and interleukin-6.

CMV and its gene products can exert both oncogenic and oncomodulatory effects, promoting tumor formation by activating oncogenic signaling pathways such as the PI3K/Akt/mTOR pathway, MAPK/Erk pathway, Wnt pathway, and NF-kB pathway.

Infantile Autism

Autism, also known as autistic disorder, is a pervasive developmental disorder characterized by social dysfunction, communication disorders, language delays, stereotyped behavioral repetitions, and significant limitations of interest. cCMV infection is involved in the occurrence of autism, especially CMV infection during the third trimester of gestation, which may increase the risk of autism.

The incidence of autism is rapidly increasing, and the long-term prognosis is not promising. Early studies have shown that congenital rubella virus infection is associated with autism, and the rubella vaccine can reduce the incidence of autism, providing new perspectives for research on the pathogenesis and early prevention of autism.

Other Neurologic Abnormalities

cCMV infection can also cause microlesions and mild brain injuries, which may accumulate and lead to severe dysfunctions. Early studies suggested a possible association of CMV infection with abnormal electroencephalograms and neurologic dysfunction after febrile convulsions and epilepsy. Additionally, CMV virus titers were associated with decreased cognitive ability in healthy adults, and CMV seroprevalence and antibody levels may be related to hippocampal volume.

In patients with acquired immunodeficiency syndrome (AIDS), CMV mainly causes five distinct neurologic syndromes: retinitis, myelitis polyradiculopathy, encephalitis with dementia, ventriculoencephalitis, and multiple mononeuritis. Detection of CMV-DNA through cerebrospinal fluid PCR has been demonstrated to be a useful tool for diagnosing CMV-related CNS disease in patients with AIDS.

Pathogenesis of CMV-Related Nervous System Diseases

The pathogenesis of CMV infection and the associated damage to the development of the fetal CNS are not fully understood due to the insufficient number of cases in autopsy studies and species specificity limiting the establishment of related animal models. The murine CMV infection model is useful for studying the pathogenesis of CMV infection in the CNS, but murine CMV does not cause cCMV infection in mice.

Human embryonic tissue is also an effective tool for studying the mechanism of cCMV infection in neurodevelopment. Studies have shown that cCMV infection-induced CNS developmental defects mainly through the following mechanisms: in the encephalon, CMV infection can directly cause inappropriate immune responses, and in the placenta, CMV infection leads to placental dysfunction and fetal hypoxia, which indirectly compromise encephalon development.

CMV can inhibit the proliferation and differentiation of neural stem cells, and CMV’s gene products are involved in neural stem cell apoptosis and autophagy abnormalities, leading to nervous system infections and neurodevelopmental disorders. Severe deafness was associated with moderate vestibular dysfunction, and widespread cell degeneration, fibrosis, and calcification have been reported in the cochlea and vestibular system of patients with extensive sequelae due to cCMV infection.

Conclusion

Human CMV compromises neurodevelopment directly by infecting the fetal encephalon and inducing neuroimmune responses to damage nerve cells or by its gene products inhibiting the proliferation and differentiation of neural progenitor cells. It can also indirectly trigger placental inflammation, disrupting the oxygen supply to the fetus and causing neurodevelopmental abnormalities such as developmental defects, mental retardation, ophthalmic complications, cerebral neoplasms, infantile autism, and epilepsy.

Currently, studies on the pathogenesis of neurodevelopmental disorders and hearing loss in infants with cCMV infection are lacking. Neurologic damage in the CNS is mostly irreversible, complicating treatment and the achievement of breakthroughs in related studies. Therefore, improving prenatal diagnosis and diagnosis of acquired perinatal infection, increasing newborn hearing screening and testing, and early intervention are essential for improving the prognosis of cCMV infection and reducing corresponding neurologic injuries.

doi.org/10.1097/CM9.0000000000000404

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