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Neuro-Anatomical Study of a Rare Brain Malformation: Lissencephaly, a Report of Eleven Patients

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Neuro-Anatomical Study of a Rare Brain Malformation: Lissencephaly, a Report of Eleven Patients Original Research Article Neuro-Anatomical Study of a Rare Brain Malformation: Lissencephaly, A Report of Eleven Patients Kataria Sushma K1, Gurjar Anoop S2,*, Parakh Manish3, Gurjar Manisha4, Parakh Poonam5, Sharma Rameshwar P6 1Professor, 2Assistant Professor, 6Resident, Dept. of Anatomy, 3Professor, Dept. of Paediatric Medicine, 4Assistant Professor, Dept. of Biochemistry, 5Assistant Professor, Dept. of Obs. and Gyn., Dr S.N. Medical College, Jodhpur, Rajasthan *Corresponding Author Gurjar Anoop S Assistant Professor, Dept. of Obs. & Gyn., Dr. S.N. Medical College, Rajasthan E-mail: [email protected] Abstract Background and Objectives: Clinical data and magnetic resonance imaging (MRI) / Computerised Tomography (CT) scans of patients with lissencephaly were reviewed. The clinico-anatomic profile and type of lissencephaly in patients attending the Paediatric Neurology Clinic in Western Rajasthan was determined. The major comorbid conditions, maternal and fetal factors associated with lissencephaly were also studied. Methods: Patients with radiologically proven lissencephaly were included in the study. A detailed epidemiologic profile, clinical history, neurologic examination and neuro-imaging details (CT/MRI) were recorded. The data collected was analyzed. Results and Interpretation: The prevalence of lissencephaly amongst the patients attending the clinic was 0.49%. All patients had anatomical features compatible with impaired neuronal migration. Seizure was the most common comorbid (90.9%) condition associated with lissencephaly. Conclusion: MRI and appropriate genetic studies as feasible should be done to aid in accurate clinco-anatomic and genetic diagnosis in all patients suspected of having a congenital Central Nervous System (CNS) malformation such as lissencephaly. Key words: CNS Malformations, Heterotopias, Lissencephaly, Neuronal Migration, Seizures. Introduction disorganised layers rather than six normal layers. Lissencephaly, which literally means smooth In the variants of classical lissencephaly, extra- brain, is a rare brain malformation caused by cortical anomalies are also present (total or impaired neuronal migration of post-mitotic subtotal agenesis of the corpus callosum and/or neurons from the ventricular zone to the cortical cerebellar hypoplasia). plate during 12th to 24th weeks of gestation. The classical lissencephalies and the variant Lissencephaly is manifested as a smooth cerebral forms on the basis of their genetic etiology can be surface due to absence of cerebral convolutions / further divided into four groups: Anomalies in gyri, abnormally thick cortex with four abnormal the LIS1 gene (isolated lissencephaly and Miller- layers that includes a deep zone of diffuse Dieker syndrome), anomalies in the TUBA3 neuronal heterotopia and enlarged dysplastic and DCX genes, and lissence-phalies caused by ventricles1. It encompasses the pathologic terms mutations in the ARX gene (XLAG syndrome, X- agyria (absent gyri), pachygyria (broad gyri) and linked lissencephaly with agenesis of the corpus subcortical band heterotopia. callosum). In addition to these four entities, There are around 20 different types of isolated lissencephalies without a known lissencephaly and different systems for classifying genetic defect, lissencephalies with severe lissencephaly exist. Based on the associated microcephaly (microlissencephaly) and lissencep- malforma-tions and underlying etiology two large halies associated with polymalformative syndro- groups can be distinguished: classical lissencep- mes are also included in the group of classical haly (and its variants) and cobblestone lissenceph- lissencephalies.2 aly. In classical lissencep-haly (or type I), the Cobblestone lissencephaly is a severe brain cortex appears thickened, with four more or less malformation observed in three overlapping Indian Journal of Neurosciences, January-March,2016;2(1): 1-5 1 Kataria Sushma K et al. Neuro-Anatomical Study of a Rare Brain Malformation: Lissencephaly, A Report of…… syndromes, all genetic with autosomal-recessive lissencephaly. This study made a fresh attempt to inheritance: the Walker-Warburg, Fukuyama and evaluate both the anatomic and the clinical profile MEB (Muscle-Eye-Brain) syndromes. It is of these patients presenting exclusively in a characterised by global disorganisation of Pediatric Neurology clinic of tertiary care centre in cerebral organogenesis with an uneven cortical Western Rajasthan, India. surface (with a pebbled or cobblestone appeara- nce). The brain malformation consists of Material and Method cobblestone cortex, abnormal white matter, The study was conducted in the Department of enlarged ventricles, often with hydrocephalus, Anatomy and the Pediatric Neurology Clinic at the small brainstem and small dysplastic cerebellum3. Department of Pediatrics, Umaid Hospital for The abnormal cortex is severely disorganized with Women and Children attached to Dr. S. N. no recognizable layers and with disruption by Medical College, Jodhpur, Rajasthan. Over the abnormal vascular channels and fibroglial bands study period 2255 patients attended the Pediatric that extend into and often obstruct the Neurology clinic. MRI/CT Scans and clinical subarachnoid space. The changes are widespread records of patients with lissencephaly were in the most severe syndrome (Walker-Warburg reviewed. A detailed epidemiologic profile, syndrome) but are less extensive in the other clinical history, neurologic examination and syndromes.3 results of electrophysiology were recorded. Major Children with lissencephaly have feeding and Comorbid conditions such as seizures, global swallowing problems, muscle tone anomalies developmental delay (GDD), gross motor delay (early hypotonia and subsequently limb (GMD), speech and language delay (SLD), autism, hypertonia), seizures (in particular, infantile microcephaly and hydrocephalus associated with spasms) and severe psychomotor retardation. this anomaly was evaluated. The epilepsy is often resistant to treatment. The encephalopathy associated with lissencephaly is Results and Discussion often very severe and affected children are Out of the two thousand two hundred and fifty completely dependent on the carer.4 five patients that attended the clinic during the All forms of lissencephaly and subcortical study period thirty three patients had different band heterotopias are genetic, and genetic testing congenital CNS malformations. Lissencephaly is currently available for at least 80% of patients was the most predominant anomaly and was with lissencephaly or subcortical band detected in eleven patients (33.3%). The heterotopias. The most productive order of testing prevalence of lissencephaly among the patient is chromosome analysis and fluorescence in situ attending the clinic was 0.49%. Sanghvi et al7 hybridization searching for deletions of identified seventy six cases with epileptogenic chromosome 17p13.3 that include the LIS1 gene, brain malformations based on neuro imaging. followed by sequencing of LIS1, then DCX, and Lissencephaly was reported in nine cases. finally ARX. Patients with Walker-Warburg Barkovich et al6 reported incidence of various syndrome or muscle-eye-brain disease have CNS anomalies. Incidence of lissencephaly was 1 greatly enlarged lateral ventricles and many have to 4 per 100,000 births. frank hydrocephalus. Thus can be detected on Table 1 presents the spectrum of lissencephaly prenatal ultrasound examination in the mid- to late with relevant clinical features and radiologic second trimester. findings. 58.3% cases with lissencephaly had other The genetic and congenital disorder is the associated CNS abnormalities, which included second most common cause of infant and Dandy-Walker variants, heterotopia, agyria, childhood mortality and occurs with a prevalence pachygyria, agenesis of corpus callosum and of 25-60 per 1000 births.5 The incidence of all closed lip schizencephaly. Similar to our findings forms of type I lissencephaly is around 1 in Sanghvi et al7 also reported that 55.5% cases with 100,000 births.6 Malformations represent an lissencephaly had other associated CNS important contribution to the total disease burden abnormalities, which included colpocephaly, seen in pediatric neurology. An extensive review Dandy-Walker variants, cysts, heterotopia, FCD, of the literature has revealed that there is a paucity polymicrog-yria and pachygyria. of literature from India and especially Western Rajasthan regarding the prevalence of Indian Journal of Neurosciences, January-March,2016;2(1): 1-5 2 Kataria Sushma K et al. Neuro-Anatomical Study of a Rare Brain Malformation: Lissencephaly, A Report of…… Of the total patients with lissencephaly and its Maharashtra twenty two of the thirty seven variants 36.4% were males where as 63.6% were malformed babies (59.4%) were full term whereas females. The female to male ratio was 1.75: 1 40.5% (15/37) were pre terms. Thirteen of the showing female preponderance. The mean age of thirty seven congenitally malformed babies presentation was 4.72 years with the age range of (35.1%) were very low birth weight (mean ± SD; 2.5 month to 11 years. Similar to our results 1314.2 ± 175 g); 13/37 (35.1%) were low birth Parmar et al8 reported that incidence of congenital weight (mean ± SD; 1938.4 ± 268.8 g)11. malformation were slightly more in female with F: Of the total patients with congenital CNS M ratio of 1.6:1. In contradiction to our study malformation 9.0 % of subjects had icterus, 18.2 Sanghvi et al7 reported a male preponderance
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