





















































Nepas Journal 28-1


-10-

Introduction:
Developmental Central Nervous System (CNS)

malformations are a complex group of congenital
malformations often presenting with variable neuro-
developmental dysfunction and seizures 1. Among them
Neuronal Migrational Disorders (NMDs) is the result of
disturbed brain development due to defective neuroblast
migration in the early gestation. In such disorders, neurones
are abnormally located or there is an absence of migration of
neurobalst 2. They have been recognized for more than 100
years 3. NMDs of the brain have recently been identified as a
major cause of Cognitive Developmental Delay (CDD) and
intractable epilepsy 4,5. NMDs include; Schizencephaly
(unilateral or bilateral grey matter line cleft of lateral cerebral
wall extending from periventricular zone to the meninges),
Lissencephaly (brain appears smooth with few gyri),
Pachygyria  (thickened gyri), Polymicrogyria (excessive small
windings), Neuronal Heterotopia (collections of neuronal
arrests in the subcortical white matter), Periventricular Nodular
Heterotopia (absence of migration of Neuroblast from
periventricular region), Brain Warts (marginal glioneural
heterotopia), Non-neoplastic Ventricular Mass, Double Cortex
or Band Heterotopia and Hemimegalencephaly (dysplastic
enlargement of the lateral ventricles on the affected side
associated with gray and white matter malpositioning l,5,6.
Computed Tomography (CT) Scan and Magnetic Resonance
Imaging (MRI) of brain have revolutionized our understanding

of these malformations, providing a good anatomic diagnosis.
However, accurate pathological diagnosis can be done by
histopathology only. We conducted the present study to
evaluate clinical spectrum of NMD’s in children as diagnosed
by neuro-imaging in the western region of Nepal.

Methods:
All the children with the diagnosis of NMD over a seven

years period from 2001 to 2007 at the Manipal College of
Medical Sciences and Teaching Hospital (a tertiary care
hospital), Department of Paediatrics in the western region of
Nepal were included in study. These children were evaluated
for age at seizure onset, sex, risk factors, parental
consanguinity, family history, antenatal history, gestational
period, developmental delay, dysmorphic features, seizure
semiology, neurological examination and other associated
clinical conditions. CT scan of brain was done in all the total
of eighteen (18) cases and MRI was done for further
confirmation in two (2) cases only, which was because MRI is
not available in this region. The same neuro-radiologist
reviewed all the CT scans. Electroencephalograms (EEG) was
performed in cases with doubtful seizure semiology, to identify
the seizure type and concomitant EEG abnormality.  Brain
CT scans were performed on a GE Helical CTE; CT scanner
with systematic study from vertex to foramen magnum at
9-mm intervals. EEGs were obtained using the international

Original Article

Clinico-Radiological Spectrum of Neuronal Migrational Disorders: A
Study of Paediatric Patients in the Western Region of Nepal.
Swain PK, 1 Dhaliwal MS2, Thapalial A3 ,Tiwari PK4.
1. Dr. Pradeep Kumar Swain, Associate Professor, 2. Dr. M. S. Dhaliwal, Assistant Professor, 3. Dr. Anna Thapalia, Professor and
HOD, Department of Paediatrics, 4. Dr. P. K. Tiwari, Professor and HOD, Department of Radiodiagnosis, Manipal College of
Medical Sciences (MCOMS), Pokhara, Nepal.

Address of correspondence: pkswain1 @rediffmail.com

Abstract:
Objective: This study was conducted in a tertiary care paediatric hospital to ascertain the spectrum of clinical

and radiological features of Neuronal Migrational Disorders in children. The role of inheritance in Neuronal
Migrational Disorders is under intense investigation. Studies on Neuronal Migrational Disorders (NMDs) in children
from developing countries are lacking. Method: Retrospective analysis of records of diagnosed cases by neuro-
imaging as Neuronal Migrational Disorders in the Department of Paediatrics. Results: Eighteen Children (2days to
8years age) with different types of neuronal migrational disorder based on neuro-imaging were included. Observed
anomalies included Lissencephaly (33.3%), Pachygyria (16.6%), Polymicrogyria (5.5%), Heterotopia (11.1%),
Schizencephaly (22.2%) and Hemimegalencephaly (5.5%). Focal Seizure in 5 (27.7%) cases, Generalised Tonic
Clonic Seizures in 3 (16.6%) and Myoclonic Seizure in 2 (11.1%) cases were the types of seizure present in 10
(55.5%) patients. Five patients presented with Quadriparesis, two with Hemiplegia and one with Congenital Talipes
Equinovarus. All the eighteen patients had some degree of Cognitive Developmental Delay. Conclusion:
Lissencephaly is the most common type of Neuronal Migrational Disorder followed by Schizencepahly. Focal
Seizure and Quadriparesis were the common manifestations. Family history of similar cases with parental
consanguinity in Schizencephaly cases gives a clue to the autosomal recessive mode of inheritance. Family history
of similar cases of Schizencephaly without any history of consanguinity indicates an autosomal pattern of inheritance.

Key words: Neuronal Migrational Disorders, Lissencephaly, Schizencephaly, Cognitive Developmental Delay and
Neuro-imaging.



-11-

10-20 system and recorded on a 23 Specialized Laboratory
Equipment machine in ten (10) patients having seizures.

Results:
A total Of 18 patients were included in the study. There

were 10 boys and 8 girls. Mean age at onset of clinical
presentations was 1.6 years (2 days—8years). Distribution of
different types of NMD’s in the study series were
Lissencephaly 6 (33.33%), Schizencephaly 4 (22.22%),
Pachygyria 3 (16.67%), Polymicrogyria 1 (5.56%),
Heterotopia 2 (11.11%) and Hemimegalencephaly 2 (11.11%).
Two of the Lissencephaly cases had Complete Agenesis of
the Corpus Callosum. One of the Schizencephaly had unilateral
parietal lobe closed lip and other three had unilateral open lip
Schizencephaly. Four patients had other associated anomalies
(Table-I). All 18 patients had some degree of cognitive
developmental delay, 10 (55.55%) had seizures, 5 (27.77%)
had Quadriparesis, one (5.55%) had Congenital Talipes
Equinovarus [CTEV] and 2 (11.11%) had Hemiplegia.

Table-I: Clinical Data’s and Investigations in 18 Patients with NMD.

Case number(n)-18 Associated Clinical presentations MRI EEG Family Consanguinity

conditions Seizure others history

Lissencephaly Agenesis of GTCS-2* Quadriparesis(4) 4 4 3
n=6(33.33%), corpus callosum(2)

Schizencephaly FS-2 Hemiplegia(2) 2 2

n=4(22.22%),

Pachygyria Microcephaly(1) MS-2‡ Quadriparesis(1) 1 1

n=3(16.67%),

Heterotopia FS-2 † 1 1 2

n=2(11.11%)

Polymicrogyria CTEV(1) § 1 1

n= 1(5.56%)

Hemimegalencephaly, Hydrocephaly(1) GTCS-1 1

n=2(11.11%) FS-1

NB: *GTCS – Generalized Tonic Clonic Seizure, †FS-Focal Seizure, ‡MS-Myoclonic Seizure, § CTEV – Congenital Talipes Equino
Varus.

Age at onset of seizure was in the neonatal period in 3
patients, 2-8 months in 2 patients and after 1 year in 5 patients.
Seizure at the onset was Myoclonic in 2, Generalized Tonic
Clonic in 3 patients and Focal in 5 patients. 2 patients had
Myoclonic Seizure and 3 patients with Generalized Tonic-
Clonic seizure subsequently developed Infantile Spasm. Focal
Epilepsy was the predominant type of seizure followed by
GTCS 7 Myoclonic seizure. Pattern of seizure and other
clinical presentations in relation to the CT findings is shown
as in Table-I. During the same period 204 Cognitive
Developmental Delay (CDD) alone, 268 seizures alone and
98 CDD and seizures both were diagnosed in the paediatrics
department. Incidence of NMD’s was 8.8% in CDD alone,
6.0% in seizure alone and 18.3% in both the CDD and seizure.

EEG was done in all the 10 seizure cases.
Hypsarrythmia and high voltage fast activity were the
commonest abnormality in 6 cases followed by Multifocal
Epileptiform activities in 2 cases and Generalized Polyspike
slow waves in 2 cases.

 All patients were diagnosed by brain CT scan and MRI
further confirmed the diagnosis in 2 patients only (Table-I).
Parental consanguinity was documented in 6 (33.33%) patients
of whom 3 (16.66%) had Lissencephaly, 2 (11.11%)
Heterotopia and one (5.55%) had pachygyria. Family history
of similar cases was documented in 6 patients (4 in
Lissencephaly along with 2 in Schizencephaly) which
suggested an autosomal recessive pattern of inheritance in
Lissencephaly patients and autosomal dominant pattern in
Schizencepahly.

Figure I : CT scan images showing Schizencephaly (closed
lip type)



-12-

Discussion:
NMDs represent abnormalities of neuronal migration

occurring in the period 2-5 months post-conception 2. Nearly
all malformations of the brain are direct results of faulty
migration or at least a secondary impairment of migration.
Imperfect cortical lamination, abnormal gyral development,
subcortical heterotopia and other focal dysplasia are related
to some factor that interferes with neuronal migration, whether
vascular, traumatic, metabolic or infectious . All the NMDs
occur mostly during the 8 weeks to 20 weeks of gestation .
Incomplete neuroblast migration in the early pregnancy leads
to Heterotopias. Smooth cerebral cortex without convolutions
is called as Lissencephaly or agyria which occurs at the mid-
gestation due to genetic causes and also in intrauterine
infections. Schzencephaly is a unilateral or bilateral deep cleft
usually in general position of sylvian fissure but is not a sylvian
fissure and occurs as a genetic traits & sporadically also 6.

The exact aetiology behind NMDs is not known, but
pathological processes disruptive to migration include
hypoxic-ischaemic encephalopathies, inborn errors of
metabolism, congenital infections, chromosomal
abnormalities, genetic defects, and prenatal exposure to
cocaine and other street drugs 7,8. Volpe stated that sporadic
cases of Lissencephaly are more common than familial
varieties, contrary to Barth who stated that Lissencephaly is
usually due to Mendelian Inheritance or Chromosomal
Disorders 9,10. The extremely high rate of parental
consanguinity among Lissencephalic patients (66.66%) and
family history of possible similar cases with autosomal
recessive inheritance (50.00%) in the present study support
the genetic etiology of lissencephaly. The genes responsible
for two types of Lissencephaly were mapped to chromosome
9q31-33 and chromosome Xq22.3 11,12. Mutations of the XLIS
(or DCX) gene and of the LIS1 gene on chromosome 17
recently found in the cases of Lissencepahly 23.

Familial occurrence of Schizencephaly in 50.00% of
cases was found in this study. Familial cases of schizencephaly
have been reported, raising the possibility of an autosomal
dominant inheritance with incomplete penetrance and variable
expression 13. The role of inheritance in other non-
lissencephalic NMDs is not clear in the literature and the small
number of patients in the present study does not allow definite
suggestions (Table I). Parental consanguinity was also found
in cases of Pachygyria and Heterotopia. Straussberg et al 14.
Reported a case of autosomal recessive Pachygyria.

Technically optimal CT is effective in detecting
different types neuronal migartional disorder  but MRI is more
specific than CT 15. All patients in the present study were
investigated by Spiral-CT and only two of them had their
diagnosis further confirmed by MRI.

Seizure disorder and cognitive developmental delay
which was the major clinical presentations in this study was
reported by other workers also 16,17,18,19. With a small sample
size in the present study NMDs still represent 8.8% in CDD
alone, 6.0% in seizure alone and 18.3% in both the CDD and
seizure. The results of the present study are comparable to
those of Brodtkorb et al. who found that 4.3% of patients with
epileptic seizures and 13.7% of patients with seizures and
mental retardation had NMDs 20. All patients in the present
study had some degree of cognitive developmental delay of
variable severity. Fifty percent of seizures were in the neonatal
period in the study which was in accordance with the Gestaut
et al 21. Quadriparesis and GTCS was the predominant
manifestation in Lissencephaly patients which was similar to
the report by Guerrini et al 22.

Schizencephaly has a wide anatomo-clinical spectrum
(closed lip and open lip), including focal epilepsy in most
patients, which was also reflected in our study 23. Familial
occurrence is rare but in our study it was 50% among four
patients without any history of consanguinity thus indicating
an autosomal dominant pattern of inheritance, which needs
further study. However at present, there is no clear indication
on the possible pattern of inheritance and on the practical
usefulness that mutation detection in an individual with
schizencephaly would carry in terms of genetic counseling 23.

Conclusion:
In conclusion this present study reflects the incidence

of possibly inherited NMDs like Lissencepahly is much higher
than other forms. Neuronal Migrational Disorder in children
is still the predominant cause of epilepsy and developmental
delay. Association of Schizencephaly in families without
parental consanguinity indicative of autosomal dominant
pattern of inheritance but which needs further evaluation and
study in a larger scale. Parental consanguinity is also present
in other types of NMDs including Lissencephaly. More genetic
work is required to determine their etiologies.

References:
1. Osborn AG. Normal Brain Development and General

Classification of Congenital Malformations. In: Osborn
AG, editor. Diagnostic Neuroradiology. 1st ed. St Louis,
Mosby-Yearbook, 1994. p 3-14.

2. Schaefer BG, Sheth RD, Bondensteincr JB. Cerebral
Dysgenesis. Neurologic Clinics  1994; 12: 773-88.

3. Martell M. Ein Fall Von Heterotopic Der Frauen
Substance in Den Beiden Hemispherens Des
Gronsshirns. Arch    Psychiatr Nervenkr 1893; 25: 124-
36.

4. Barth PG. Migrational Disorders Of The Brain. Curr
Opin Neural Neurosurg 1992; 5: 339-43.



-13-

5. Hanefeld F. Pediatric and Developmental Neurology.
Curr Opin Neural Neurosurg 1992; 5: 331-2.

6. Walter G. Bradley,Robert B.Daroff, Gerald M.Fenichel
& Joseph Jankovic, Neuology in Clinical Practice ,VolI;
    4th edition ,p-1763- 1786.

7. Barth PG. Schizencephaly and Nonlissencephalic
Cortical Dysplasia. Am J Neural 1992; 13: 104-8.

8. Domingues R, Aguirre Vila-Coro, Slopis JM, Bohan TP.
Brain and Abnormalities In Infants With In Utero
Exposure to Cocaine and other Street Drugs. Am J Dis
Child 1991; 145: 688-95.

9. Barth PG. Schizencephaly and Nonlissencephalic
Cortical Dysplasia. Am J Neural 1992; 13: 104-8.

10. Volpe JJ. Neuronal Proliferation, Migration,
Organization And Myelination. Major Problems In
Clinical Pediatrics. In: Volpe JJ (Ed.) Neurology of the
Newborn, 2nd edn. W.B. Saunders Co, Philadelphia,
1987; 22: 37-60.

11. Toda T, Segawa M, Namuray, el al. Localization of Gene
for Fukuyama Type Congenital Muscular Dystrophy to
Chromosome 9q31-33. Nature Genet 1993; 5: 283-6.

12. Dobyns WB, Andermann E, Andermann F, el al. X-
Linked Malformations of Neuronal Migration.
Neurology 1996; 47: 331-9.

13. F. Haverkamp, K. Zerres, B. Ostertun, D. Emons and
M.J. Lentze, Familial Schizencephaly: Further
Delineation of a Rare Disorder. J Med Genet 32 (1995),
pp. 242–244.

14. Straussberg R, Gross S, Amir J, Gadoth N. A New
Autosomal Recessive Syndrome of Pachygyria. Clin
Genet 1996; 70: 155-8.

15. Gao PY, Zhonghua fang she xue za zhi. CT Diagnosis
Of Neuron Migration Anomalies; Chinese Journal of
Radiology 1989 Feb;23(1):2-4.

16. Turjman F, Massoud TF, Sayre JW, Vinuela F, Guglielmi
G, Duckwiler G. Epilepsy Associated with Cerebral
Arteriovenous Malformations. Multivariate Analysis of
Angioarchitectural Characteristics. Am J Neuroradiol
1995; 16: 345-50.

17. Sperling MR. Neuroimaging in Epilepsy: Recent
Developments in MR Imaging, Positron-Emission
Tomography, and Single Photon Emission Tomography.
Neurologic Clinics 1993; 11:883-903.

18. Smith AS, Weinstein MA, Quencer RM, el al.
Association of Heterotopic Gray Matter with Seizures,
MR Imaging. Radiology 1988; 168: 195-8.

19. Altman N, Birchansky S, Goldstein R, el al. Preliminary
Report of Neuroimaging And Pathological Correlations
in Children Operated on for Intractable Focal Epilepsy.
Int Pediatr 1994; 9 : 85-93.

20. Brodtkorb E, Nilsen G, Smevik O, Rinck PA. Epilepsy
and Anomalies of Neuronal Migration: MRI and Clinical
Aspects. Acta Neural Scand 1992; 86: 24-32.

21. Gastaut H, Pinsard N, Raybaud C, Aicardi J, Zifkin B.
Lissencephaly (Agyria-Pachygyria) Clinical Findings
and Serial EEG Studies. Dev Med Child Neurol 1987;
2: 167-80.

22. Guerrini R, Sicca F, parameqqiani L. Epilepsy and
Malformation of CNS. Epileptic Disord,2003;sept. 5
suppl 2: s 9-26.

23. Guerrini R and Carrozzo R. Epileptogenic Brain
Malformations: Clinical Presentation, Malformative
Patterns and Indications for Genetic Testing ,Seizure.
2002 Apr;11 Suppl A:532-43; quiz 544-7.


