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CASE REPORT Table of Contents   
Year : 2008  |  Volume : 51  |  Issue : 3  |  Page : 402-404
Cytomegalovirus infection with lissencephaly

1 Department of Pathology, Sri Ramachandra University, Chennai, Tamil Nadu, India
2 Department of Obstetrics and Gynaecology, Sri Ramachandra University, Chennai, Tamil Nadu, India

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Lissencephaly is a malformation of the brain in which the brain surface is smooth, rather than convoluted. Among the various causes of lissencephaly, infection by a virus during pregnancy plays an important role. Cytomegalovirus (CMV) is an important pathogen causing this anomaly. We present this case of a young female with 24-week-gestation diagnosed on ultrasound as carrying an anomalous fetus with lissencephalic features. At autopsy, there were multiple intra-nuclear CMV inclusions in the brain and the kidneys. This case is presented for its rarity and for the documentation of the tissue localization of CMV inclusions at autopsy.

Keywords: Cytomegalovirus, inclusions, lissencephaly, ultrasound

How to cite this article:
Joseph LD, Pushpalatha, Kuruvilla S. Cytomegalovirus infection with lissencephaly. Indian J Pathol Microbiol 2008;51:402-4

How to cite this URL:
Joseph LD, Pushpalatha, Kuruvilla S. Cytomegalovirus infection with lissencephaly. Indian J Pathol Microbiol [serial online] 2008 [cited 2021 Dec 4];51:402-4. Available from: https://www.ijpmonline.org/text.asp?2008/51/3/402/42534

   Introduction Top

Lissencephaly is a malformation of the brain in which the surface of the brain is devoid of gyri and sulci. Among the various causes of lissencephaly, gestational insults by infection during pregnancy play an important role, particularly, cytomegalovirus. Lissencephaly is a congenital defect in neuronal migration which occurs between 12 and 16 weeks of gestation.

   Case history Top

A 22-year-old female patient at 24-week-gestation was diagnosed to have an anomalous baby and ultrasound technique also showed features suggestive of lissencephaly in the brain. The patient gave a history of previous abortion. The pregnancy was terminated by extra-amniotic instillation of ethacridine lactate. She delivered a dead male fetus with ascites. Autopsy examination revealed the presence of approximately 500 ml of ascitic fluid. All the other organs were normal on gross examination, with the exception of the brain which showed a smooth surface with the absence of gyri and sulci [Figure 1].

Microscopic examination of the lungs showed immaturity and features suggestive of a canalicular phase of development. Both the kidneys showed multiple inclusions of cytomegalovirus (CMV) [Figure 2] with interstitial mononuclear cell infiltrates composed of lymphocytes and plasma cells. The brain showed autolytic changes with focal areas of dystrophic calcification. CMV inclusions were seen in the sections of the cerebral cortex. Sections from the placenta showed features of villitis, villous edema, perivillous fibrin deposition, congestion and chorioamnionitis in the membranes.

   Discussion Top

Lissencephaly, first described by Owen in 1868, means "smooth brain" to describe the gross appearance of the brain. It is a developmental disorder of brain characterized by the lack of normal convolutions and is caused by a defective neuronal migration, the process in which nerve cells move from their place of origin to their permanent location which usually occurs between 12- and 16-week-gestation. When the brain forms, the neurons are generated in a region of the brain known as ventricular zone. From there, they travel by crawling outward along other cells, known as radial glia, to reach the cortical zone. A disruption of this normal migration results in disorders like heterotopia, agyria-pachyria, lissencephaly, polymicrogyria, vascular malformations, teratomas and phakomatosis. [1] de Rijk-van Andel reported a prevalence rate of 11.7 per million births in the Netherlands for lissencephaly. [2]

Lissencephaly may be caused by intra-uterine viral infection and insufficient blood supply to the fetal brain, in early pregnancy or as a genetic disorder. Among the viral infections, CMV is a very important etiological factor in the causation of lissencephaly. Other causes of central nervous system infections are toxoplasmosis, rubella, herpes simplex, human immunodeficiency virus and syphilis. CMV is caused by a species-specific, double-stranded herpes virus which causes mild to severe congenital infections. CMV has a particular affinity for the developing germinal matrix of the brain, but it can infect other organs too, with the development of characteristic cytoplasmic or nuclear inclusion bodies. The severity of the brain changes is directly related to the gestational age of the fetus at the time of infection. Early infection leads to more severe migrational and developmental anomalies. Early second trimester infection leads to complete lissencephaly, while late second trimester infection causes polymicrogyria. CMV may cause multifocal but usually less-extensive areas of brain necrosis, especially ependymal and subependymal, because of intra-uterine infection. This can result in spontaneous abortions, stillbirths, prematurity, microencephaly, polymicrogyria, hydrocephalus and intra-cranial calcifications. Characteristic hematoxyphilic to amphophilic owl's eye intra-nuclear (Cowdry type A) and other amphophilic intra-cytoplasmic inclusions distinguish CMV infections from others. Lissencephaly is usually diagnosed on the basis of either CT or MRI scan of the brain. It can be suspected based on the sonologic findings. Antenatal sonogram helps in identifying fetus with CMV infection by suggestion of an abnormal periventricular echogenicity in association with diffuse lissencephaly or cortical dysplasia or cerebellar hypoplasia. The other features to suggest CMV infection includes abnormal ventricular signals, intra-parenchymal echogenic foci, intra-ventricular adhesions, ventriculomegaly, altered sulcation and gyral pattern and cerebellar anomalies. [3] Other systemic features like ascites, bilateral pleural effusions and cardiac anomalies can also be detected. Twickler reported the antenatal sonographic findings of cerebral ventriculomegaly and decreased head circumference in two cases, secondary to CMV infection. [4] Extensive literature search did not reveal any definite epidemiological data as regards the incidence rate of CMV with lissencephaly.

Soussotte et al. reported a case of fetus with decreased cephalic dimensions at 32 weeks on routine ultrasonography later to be followed by a transvaginal sonography which revealed echogenic vessels in the thalami and lesions in the subependymal region. The pregnancy was terminated and the cause was confirmed to be due to CMV infection. [5] CT scan of the brain showed atrophy, ventricular dilatation and parenchymal calcification. MR findings include migrational anomalies like lissencephaly and polymicrogyria, encephalomalacia with non-specific ventricular enlargement, prominent sulci, subependymal paraventricular cysts and calcifications. [6]

Cytomegalovirus is diagnosed by other laboratory parameters, which can yield positive CMV cultures of body fluids, by positive serum titers of CMV-specific immunoglobulin M, demonstration of large intra-nuclear inclusions in CMV-infected cells. [7] CMV DNA can be detected in the cerebrospinal fluid of the patients affected by lissencephaly. Kohyama et al. studied the involvement of human CMV infections in conditions of neurological impairment in 45 neurologically affected children aged 1 month to 17 years by means of polymerase chain reactions. [8] Several serologic assays are used to detect the CMV-specific IgM antibodies both in the whole serum and serum fractions obtained by sucrose density gradient centrifugation or column chromatography. These include complement fixation, anti-complement immunofluorescence, indirect hemagglutination and radio immuno assay (RIA). More recently ELISA has also been widely used. The anti-genemia assay detects and quantifies peripheral blood leukocytes which are positive for CMV lower-matrix phosphoprotein pp65. Detection and quantification of CMV DNA in blood can be achieved by PCR and hybridization technique. There is also a "shell vial" assay for the determination and quantification of the viremia.

Currently, there is no cure for lissencephaly. Treatment of individual depends on the manifesting symptoms, like anti-convulsant drug therapy for the treatment of seizures. Muscle relaxants may be useful for the symptoms of increased tone. Nigro et al. [9] have shown that treatment of pregnant women with CMV-specific hyperimmunoglobulin is safe. Most of these patients die at an early age due to failure to thrive or infections like pneumonia.

An accurate diagnosis of lissencephaly and CMV infection is mandatory as appropriate preventive measures may be instituted in high-risk pregnancies.

This case has been reviewed to highlight the causal relationship of CMV and lissencephaly with an accent on the variety of developmental anomalies and morphological changes associated with gestational insults by this virus. Documentary evidence of histopathological detection of CMV inclusions in the brain and kidney are very sparse in literature. The importance of genetic counseling in case of these high-risk pregnancies and the diagnostic modalities has also been emphasized.

   References Top

1.Barkowich AJ, Gressens P, Evrard P. Formation maturation, disorders of the brain neocortex. AJNR Am J Neuroradiol 1992:13:423-46.  Back to cited text no. 1    
2.de Rijk-van Andel JF, Art WF, Hofman A, Staal A, Niermeijer MF. Epidemiology of lissencephaly type I. Neuroepidemiology 1991;10:200-4.  Back to cited text no. 2    
3.Malinger G, Lev D, Zahalka N, Ben Aroia Z, Watemberg N, Kidron D, et al . Fetal cytomegalovirus infection of the brain: The spectrum of sonographic findings. Am J Neuropathol 2003;24:28-32.  Back to cited text no. 3    
4.Twickler DM, Perlman J, Maberry MC. Congenital cytomegalovirus infection presenting as a cerebral ventriculomegaly on antenatal sonography. Am J Perinatol 1993;10:404-6.  Back to cited text no. 4  [PUBMED]  
5.Soussotte C, Maugey-Laulom B, Carles D, Diard F. Contribution of transvaginal ultrasonography and fetal cerebral MRI in a case of congenital cytomegalovirus infection. Fetal Diagn Ther 2000;15:219-23.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Alonso A, Alvarez A, Seara MJ, Linares M, Villalon J. Unusual manifestations of postnatally acquired cytomegalovirus infections: Finding on CT and MR. Pediatr Radiol 1996;26:772-4.  Back to cited text no. 6    
7.Donnor C, Liesnord C, Content J. Prenatal diagnosis of 52 pregnancies at risk for congenital cytomegalovirus infection. Obstet Gynecol 1993;82:481-6.  Back to cited text no. 7    
8.Kohyama J, Kajiwara M, Shimohira M, Iwakawa Y, Okawa H. Human cytomegalovirus DNA in cerebrospinal fluid. Arch Dis Child 1994;71:414-8.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Nigro G, Adler SP, La Torre R, Best AM; Congenital Cytomegalovirus Collaborating Group. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]

Correspondence Address:
Sarah Kuruvilla
Department of Pathology, Sri Ramachandra University, Porur, Chennai - 600 116, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.42534

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  [Figure 1], [Figure 2]

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