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ORIGINAL ARTICLE |
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| Ahead of print
publication |
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Profile of central nervous system malformations in children from a tertiary care center in southern India
Vykuntaraju K Gowda1, Kiruthiga Sugumar2, Dhananjaya K Vamyanmane3, Sanjay K Shivappa2
1 Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India
2 Department of Pediatric Medicine, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India
3 Department of Pediatric Radiology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka, India
| Date of Submission | 12-Sep-2021 |
| Date of Decision | 28-Nov-2021 |
| Date of Acceptance | 26-Dec-2021 |
| Date of Web Publication | 12-Jul-2022 |
Correspondence Address:
Vykuntaraju K Gowda,
Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bangalore, Karnataka 560029
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpn.JPN_181_21
 Abstract | | |
Background: Malformations of the central nervous system (CNS) include a wide range of disorders characterized by neurodevelopmental delay and seizures. They are multifactorial in etiology. There is a lack of data in India; hence, this study was planned to study the clinical profile and type of CNS malformations in children. Materials and Methods: This is a retrospective chart review of CNS malformation between January 2018 and December 2018. Details of clinical and laboratory data were analyzed. Results: Of 110 cases, males were 65. The most common age group was 1–5 years accounting for 50%. Various clinical features were developmental delay (72), seizures (58), microcephaly (57), and dysmorphism (28). History of birth asphyxia was present in 12 cases. The various malformations were neuronal migration defects (36.36%); congenital hydrocephalus (24.54%), with aqueductal stenosis being the most common etiology; neural tube defects (13, 11.8%); and posterior fossa malformation (10 of which two were Joubert syndrome). Others were five cases of agenesis of corpus callosum, one case each of hemimegalencephaly and arteriovenous malformation, and four cases of complex mixed malformations. Conclusion: The most common presentation was global developmental delay and seizures. The most common malformation of CNS observed was neuronal migration defect followed by hydrocephalus. They can present as birth asphyxia.
Keywords: Central nervous system malformation, developmental delay, neural tube defects, seizures
| Introduction | |  |
Congenital malformation of the central nervous system (CNS) is due to the abnormal development of the brain, spinal cord, and other neural structures that are formed in the embryonic period. It is the most common malformation detected among others, with the incidence of 3.32/1000 live births.[1] The CNS anomalies can be classified based on the developmental stage at which they occur[2] or can be classified as disorders of dorsal induction (3–4 weeks of gestation), disorders of ventral induction (5–10 weeks of gestation), disorders of neuronal proliferation and differentiation (2–5 months of gestation), disorders of neuronal migration (2–5 weeks), disorders of myelination, secondarily acquired injury of normally formed structures (7 months of gestation–1 year of age), and unclassified.[3]
There are diverse etiologies for the CNS malformations including nutritional, periconceptional folate deficiency; genetic causes; medications like anti-seizure drugs; maternal infections; maternal diseases like diabetes mellitus; multiple pregnancies; and previous pregnancy with neural tube defects.[4],[5] The most common manifestation includes developmental delay and seizures. There may be features of other system involvement in the case of syndromic association.[6] There is a dearth of studies about the etiology of CNS malformations in southern India; hence, this study was undertaken to provide the clinical and etiological profile of the malformations of the CNS.
| Materials and Methods | | |
This is a retrospective review of children presenting to the pediatric neurology department in a tertiary care pediatric hospital between January 2018 and December 2018. The following information was obtained from the medical records of each patient: age, sex, mode of presentation (seizures, developmental delay, abnormal movements or behavior, focal neurological deficit), family history, antenatal and perinatal history, developmental history, neuroimaging: computed tomography (CT)/magnetic resonance imaging (MRI), duration of admission, genetic reports, and final diagnosis. Children between day 1 to 18 years, with or without perinatal insult, with imaging evidence of malformation, were included. The final diagnosis and etiology of each child were confirmed with neuroimaging—CT/MRI or by genetic testing. The clinical, radiological findings were collected and tabulated. Simple descriptive statistics were used to analyze the data in the form of frequencies with percentages and median as applicable. The ethical clearance was obtained by the institutional ethical committee.
| Results | | |
In this study, a total of 110 children were analyzed, aged between 0 and 18 years. [Table 1] shows various clinical features and [Table 2] shows the type of various malformations. The youngest in this study was a 3-day-old neonate and the oldest was 16 years. The mean age in this study was 2 years. There was male preponderance (65, 59.09%). The family history of similar malformations was observed in three families: one child each with Joubert syndrome, pontocerebellar hypoplasia, and agenesis of the corpus callosum. The various clinical features were global developmental delay in 72 (65.45%), seizures in 58 (52.72%), facial dysmorphism in 28 (25.45%), large head size in 25 (22.72%), nystagmus in 10 (9.09%), autistic features in seven (6.3%), cortico-visual impairment in three (2.72%), and oculomotor apraxia in two children (1.8%). A history of perinatal insult was present in 12 patients (10.9%). Twenty (18%) of them presented to the emergency department initially as seizures. Other system involvements such as congenital heart disease, dysplastic kidneys, and congenital talipes equinovarus were noted in 2%. The antenatal scan detected hydrocephalus in four, spinal dysraphism in three, and agenesis of the corpus callosum in two children.
The most common malformation observed was neuronal migration disorders (n = 40), followed by hydrocephalus (n = 27); neural tube defects such as spinal dysraphism, meningomyelocele, and diastematomyelia (n = 13); and posterior fossa malformations (n = 10). Complex mixed malformations were observed in four patients. Focal cortical dysplasia was present in 13 patients (11.8%), detected by MRI brain, in those with normal CT scans.
[Figure 1] shows severe microcephaly and hydrocephalus. [Figure 2] shows occipital encephalocele, lumbar myelomeningocele, the tuff of hair, and sinus tract with swelling in the lumbar region. [Figure 3] shows swelling of the left side of the check with hypopigmented macule, CT, and MRI of the brain showing left-sided hemimegalencephaly. In [Figure 4], MRI of the brain shows pachygyria/agyria complex and pontocerebellar hypoplasia. [Figure 5] shows open-lip schizencephaly, pontocerebellar hypoplasia, and molar tooth sign in Joubert syndrome. | Figure 1: Clinical photographs showing severe microcephaly (A and B) and hydrocephalus (C and D)
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 | Figure 2: Clinical photographs showing occipital encephalocele (A and B), lumbar myelomeningocele (C), the tuft of hair in the lumbar region (D and E), and sinus tract with swelling in the lumbar region (F)
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 | Figure 3: Clinical photograph of a child showing swelling of the left side of the cheek with hypopigmented macule (A). Contrast-enhanced CT of the brain with axial sections (B and C) showing enlarged left cerebral hemisphere, hypodense white matter (arrowhead), thickening of the cortex (thick white arrow), and ipsilateral dilatation of lateral ventricle (thin white arrow) suggestive of hemimegalencephaly. Axial T1-weighted MRI brain showing the enlarged left cerebral hemisphere. Diffuse thickening of the left cerebral cortex with absence of sulci and gyri (thick white arrow in D). The altered signal intensity of left cerebral white matter (arrowhead) and ipsilateral dilatation of lateral ventricle (thin white arrows in E and F)
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 | Figure 4: Axial T1-weighted MRI brain showing absence of sulci and gyri with thickening of the cortex in bilateral frontal, temporal, and parieto-occipital lobes (thick white arrow in A). Bilateral dilated lateral ventricles (thin white arrows in B and C), suggestive of pachygyria/agyria complex. Sagittal T1-weighted brain MRI demonstrates large posterior fossa with cerebellar vermian hypoplasia and enlargement of the retrocerebellar subarachnoid space that communicates with the fourth ventricle (thick white arrow in C). Hypoplasia of pons (thin white arrows in C and D) and cerebellar hemispheres with normal ventricular system and other midline structures
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 | Figure 5: Axial T1-weighted MRI brain showing gray matter lined CSF cleft extending from the right lateral ventricle to the right frontotemporal cortex (thick white arrow in A) and axial T2-weighted MRI brain showing gray matter lined CSF cleft extending from the right lateral ventricle to the right frontotemporal cortex (thick white arrow in B) suggestive of open-lip schizencephaly. The sagittal T1-weighted brain MRI demonstrates large posterior fossa with cerebellar vermian hypoplasia (arrowhead in C) and enlargement of the retrocerebellar subarachnoid space (arrow in C) that communicates with the fourth ventricle. Mild hypoplasia of pons (arrow) with normal ventricular system and other midline structures suggestive of pontocerebellar hypoplasia. MRI brain T1-weighted (A) and diffusion-weighted images axial sections (B) through the junction of the midbrain and the hindbrain (isthmus region) show abnormally deep interpeduncular fossa (thin white arrow). Elongated and mal-oriented superior cerebellar peduncles give the appearance of a “molar tooth” (thick white arrow). MRI brain T1-weighted sagittal section (C) showing horizontal peduncle
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Genetic testing was done in seven children, out of whom only three cases showed pathogenic variants. One pathogenic variant of c.100C>T p.Gln34Ter in the INPP5E gene in homozygous status responsible for Joubert syndrome and another pathogenic variant of c.1296T>G p.Tyr432Ter in the AHI1 gene in homozygous status for Joubert syndrome 3 were noted. One pathogenic variant of c.1001A>G (p.Tyr334Cys) in the SEPSECS gene in homozygous status responsible for pontocerebellar hypoplasia type 2D was noted in one case of pontocerebellar hypoplasia.
| Discussion | | |
This was a hospital-based retrospective study conducted at a tertiary care hospital. In this study, 110 children were included between day 1 and 18 years with the mean age of presentation being 2 years. Male preponderance was noted (59.09%) as in Sailaja.[7] The most common mode of presentation was developmental delay (65.45%) and seizures (52.72%), as in Mohammed et al.[8] and Hadzagić-Catibusić et al.[9] but seizures were more common in Sailaja.[7]
Macrocephaly was observed in 22.72% of children, whereas it was observed in 51.81% of children in Sailaja[7] and 17.1% of children in Mohammed et al.[8] These differences probably represent the management of hydrocephalus being taken care of at a smaller center and may not have been further referred to the tertiary care center. Twelve (10.9%) children had a history of perinatal insult. These 12 cases were later diagnosed as lissencephaly in four, pachygyria in four, and one case each of Joubert syndrome, pontocerebellar hypoplasia, holoprosencephaly, and focal cortical dysplasia. This highlights the importance of neuroimaging in confirming the diagnosis of birth asphyxia and looking for underlying malformations that may be predisposing for birth asphyxia and also helpful for genetic counseling.
Dysmorphic features were observed in 28 children (25.45%), like 27 in Sailaja. Associated features such as cortical visual impairment (n = 3), autistic features (n = 7), nystagmus (n = 10), and oculomotor apraxia (n = 2) were also noted. Other system involvements such as congenital heart disease, dysplastic kidneys, and congenital talipes equinovarus were also noted in 2% of the subjects, which is relatively less in comparison with a study done by Barros et al.[10]
[Table 3] shows comparison of various causes in the present study and those reported in the literature. The most common malformation observed in the present study was neuronal migration defects (36.36%), followed by hydrocephalus (24.54%), neural tube defects (11.8%), and posterior fossa malformations (9.09%). Neural tube defects were the most common malformation observed in studies by Sailaja (46.7%), and Hadzagić-Catibusić et al. (38.6%), whereas corpus callosal dysgenesis/hypoplasia (23.3%) was the most common malformation observed in Mohammed et al. Complex brain malformation was noted in 3.6% of children in the present study, whereas it was 8.6% in Mohammed et al. | Table 3: Comparison of various causes in the present study and those reported in the literature
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Of the neuronal migration defects, cortical dysplasia was the most common type in 13 children (11.8%). Most of them presented in the later age with focal seizures. Development was normal in the majority with cortical dysplasia, except for a few who had mild developmental delay. Lissencephaly was seen in 10 children, and there was one child with a porencephalic cyst.
Aqueductal stenosis was the most common cause of hydrocephalus observed. Dandy–Walker malformation was seen in 10 children, which was comparable to that in Mohammed et al. where there were eight children with the Dandy–Walker variant. Of the neural tube defects, seven children (6.36%) had spinal dysraphism, three had lumbar meningomyelocele, and one had meningoencephalocele in the present study, whereas lumbar meningomyelocele (n = 9) was the most common neural tube defect in Sailaja.
There were five cases of agenesis of the corpus callosum, three cases each of colpocephaly and holoprosencephaly, two cases of craniovertebral junction anomaly, and one case each of persistent septum pellucidum, arteriovenous malformation, and hemimegalencephaly. There were two cases of Joubert syndrome diagnosed in our present study.
Results revealed that the neuronal migration defects were the most common congenital brain malformation observed, which is quite different from previous studies that showed neural tube defects were the most observed malformation. It may be due to increased antenatal care and supplementation with folic acid to prevent neural tube defects and also as there are no inborn deliveries, anencephaly, and other severe malformations seen in our hospital. It was also evident that MRI brain was more sensitive in diagnosing parenchymal anomalies. Most of the cortical dysplasia (n = 13, 11.8%) that had normal CT brain was picked up in MRI brain,[11] emphasizing the importance of the choice of neuroimaging modality when congenital brain malformation is suspected. We were able to identify three pathogenic variants on genetic testing of two cases of Joubert syndrome and one case of pontocerebellar hypoplasia, out of seven cases analyzed. The limitations of this study were that it was a retrospective review and a genetic test was not done in all cases.
| Conclusion | | |
Congenital brain malformations commonly present with global developmental delay and/or seizures. The most common malformation of CNS observed was neuronal migration defect. Focal cortical dysplasia should be considered when there is a late presentation of focal seizures, even in a developmentally normal child where CT of the brain can be normal.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3]
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