INTRODUCTION

The importance of disordered nervous system maturation in causing chronic abnormalities of brain function has become fully apparent. The frequency of developmental defects ranges from 2% to 3% of all newborns. Among all the congenital anomalies, disorders of the central nervous system (CNS) are the most severe, difficult to detect its etiology, and predict its clinical presentation and course. Seventy five percent of fetal deaths and 40% of deaths within the first year of life are secondary to CNS malformations. Furthermore, 5% to 15% of pediatric neurology hospital admissions appear to be primarily related to cerebral and spinal cord anomalies.¹

Genetic and non-genetic interactions are responsible for 20% of CNS malformations; monogenic malformations, whether autosomal or X-linked, account for 7.5% of malformations; chromosomal factors account for 6%; and environmental factors including maternal infections, maternal diabetes, irradiation, and drugs (e.g., thalidomide, valproic acid, methyl mercury, excessive vitamin A or retinoic acid) account for at least another 3.5%. In the remainder, more than 60% of cases, the cause of the CNS malformation are uncertain.²

Developmental CNS malformations are a complex group of congenital malformations often presenting with variable neuro-developmental dysfunctions. These anomalies include dysgenetic corpus callosum  (DCC), disorders of neuronal migration as [lissencephaly, focal cortical dysplasia (FCD), pachygyria, polymicrogyria, heterotopia ,schizencephaly, proencephaly, hydrancephaly ,holoprosencephaly], neural tube defects as [anencephaly, encephalocele] , hemimegalencephaly, Chiari malformation, neurocoetaneous syndromes as [Sturge Weber syndrome, linear coetaneous nevus syndrome and tuberous sclerosis], Dandy-Walker malformation and, Klippel-Fiel syndrome.³

The aim of this work is to study the clinical manifestations of various types of congenital CNS malformations (early and late onset cases) in relation to their neuroimaging finding and to detect frequency of congenital CNS malformations among the patients attending the pediatric neurology outpatient's clinic, Children’s hospital, Cairo University.

SUBJECTS AND METHODS

This is a prospective study which was carried out on patients attending the neuro-pediatric Unit, Children's Hospital, Cairo University over a period of 3 months from October 2008 to January 2009. Patients suspected of having congenital CNS malformations were selected and further studied via neuroimaging (CT and MRI).

Inclusion criteria:

·           Patients presenting with motor or mental delay or both and no definite history of hypoxic ischemic insult.

·           Microcephaly with dysmorphic features.

·           Neuro-cutaneous manifestations as cafe au lait spots, hypopigmented patches etc…

·           Spinal cord anomalies that may suggest CNS malformations.

Magnetic resonance imaging (MRI) was performed for suspected patients and was the clue for definite diagnosis. All patients needed sedation during imaging. Sedation by chloral hydrate was given for infants while I.V. diazepam for older children. MRI was performed on 1.0 Tesla unit (Signa, GE, Milwaukee) using a head coil. Some MR examinations were performed on 1.0 Tesla (Gyroscan NT 10; Philips Medical systems). FLAIR sequence (Fluid attenuated inversion recovery sequence) was obtained in all cases.

Interictal scalp EEG was performed to 30 patients using the Nihon Kohden 14-channel EEG machine. The electrodes were placed according to 1-8 and 1-20 international system of electrodes placements. Bipolar as well as referential montages were applied. Sleep records were obtained using chloral hydrate (50 mg/kg/body weight). Awake records were also obtained for older children using hyperventilation and photic stimulation as provocative methods. In some patients digital EEG was available.

Patients with congenital CNS were further subdivided into 4 groups; Group1 with Dysgenesis of corpus callosum (DCC) in 7 cases (22%); Group2  with neural tube defects (NTD) in 12 cases (37.5%); Group3 with malformations of cortical development (MCD) in 9 cases (28%); Group4 with neurocutaneous syndromes (NCS) were found in 4 cases (12.5%).

Statistical Analysis

Statistical analysis of this data were collected, checked, revised and entered the computer. Data were analyzed by SPSS statistical package version 17. Excel computer program was used to tabulate the results, and represent it graphically. Qualitative variables were expressed as Count and percentages. The significant difference between any two proportion groups for the qualitative variables from normal distribution were tested by using   Z-test at p<0.05.⁴

RESULTS

Among  3280 Egyptian children patients (total group) who attended the Pediatric Neurology outpatient clinic in Children's Hospital, Cairo University over a period of three months from October 2008 to January 2009, 32 patients (0.97%) (Study group) were found to have the final diagnosis of congenital central nervous system (CNS) malformations.

The frequency of congenital central nervous system malformations among the whole number of patients who had attended the clinic was 9.7/1000.

Sex distribution:

Male & female distribution among all patients who attended the clinic was 1894 males (58%) and 1386 females (42%) with ratio of 6:4. Similarly males outnumber the females in the study subgroup (n=32), where males were 19 patients (59%) while females were 13 patients (41%).

Among the study group, patients were sub-categorized according to clinical and neuroimaging findings as shown in Table (1).

Age of presentation and clinical picture:

The DCC group had the earliest age of onset while the latest belonged to group4 with NCS. In group 1 with DCC, mean age on presentation was 15 months, while in group 2 with NTD, mean age was 17 months, whereas the mean age of presentation in group 3 (MCD) and group 4 (NCS) was 20 and 30 months respectively

Comparison between the clinical picture of the 4 groups as regards to seizures, developmental milestones, abortion, positive consanguinity, dysmorphism, micro- and macrocephaly and EEG findings is shown in Table (2). It also shows the statistical difference between them.

Seizures were one of the most common encountered symptoms in the study group [19 cases (59%)]. Seventy nine percent of patients having seizures had their onset in the first year of life. Seizures occurred with highest frequency in NCS, followed by MCD, then DCC and lastly NTD and this was statistically significant (p<0.05) (Table2).

The developmental milestones: Most of the patients of MCD (66.7%) had both motor and mental delay, while most of patients of NCS (75%) had only motor delay (p<0.05).

Family history of abortion or still birth was encountered in 11 cases (34%). Thirteen cases (40%) had history of positive consanguineous marriage, the majority of cases belonged to group 2 with NTD.  Dysmorphic features were found in 12 cases (37%). Microcephaly was highest in (MCD) (66.7%) and this percentage was significantly different from other groups (p<0.05). Surprisingly no patient from group 4 with NCS had any of the previous features and this was statistically significant (p<0.05)

Electroencephalography (EEG):

EEG recording was done only to 30 patients. It showed; normal EEG in 12 cases (37.5%), hypoactive record in 6 cases (18.7%), focal epileptogenic activity in 7 cases (22%), generalized epileptogenic activity in 4 cases (12.5%), burst suppression pattern in 1 case (diagnosed as lissencephaly) (Table3).

EEG was normal with highest percentage in NCS (100%), however NTD was the least causing focal discharge (10%) and this was statistically significant from other groups (p <0.05) (Table 2).

Magnetic resonance imaging (MRI):

MRI was the most important diagnostic modality in our study group. Figure 1 shows samples of different congenital anomalies found in the study.

Table 1. Frequency & categorization of the patients according to the final diagnosis.

Table  2. Comparison between the clinical picture of the 4 groups of patients.

Percentage of freq.= (count / freq).

Different letters means that there is a significant difference between each two column percentages by using z-test for comparing two proportions at p<0.05.

 Table 3.  EEG results of the study group.

* One patient died few hours after birth, and the other refused to do EEG.

Figure 1. MRI brain from different cases showing (A) Lissencephaly, (B) Chiari II malformation, with agenesis of corpus callosum, (C) Dandy Walker malformation (D) Rt tempo parietal schizencephaly, cortical dysplasia, microcephaly with incomplete lissencephaly and agenesis corpus callosum, (E) Holoprosencephaly, (F) Polymicrogyria.

DISCUSSION

The current study was carried out on 3280 patients, 32 patients (0.97%) were diagnosed as congenital central nervous system (CNS) malformations. Among them neural tube defects (NTD) were the most common (37.5%) followed by malformations of cortical development (MCD) (28%) while isolated dysgenesis of corpus callosum (DCC) was less common (22%)and neurocutaneous syndrome (NCS) was the least one (12.5%).

These results are in agreement with that of Dolk et al, who reported that neural tube defects were among the most common human malformations, with an incidence of 1–5 per 1,000 live births⁵.  Hadzagic-Catibusic et al, reported that CNS malformation, isolated or multiple, have been diagnosed in 100 patients (0.61%). Lethal outcome was established in (9%). The most frequent CNS malformations were neural tube defects (38.6%). Hydrocephalus was seen in (26.8%), microcephaly in (18.9%), agenesis of corpus callosum in (7.9%), Dandy Walker malformation in (4.7%) and other CNS malformations in (3.1%).⁶

In this study male to female ratio was 6:4. These results are in agreement with that of Adeyemo et al, who reported the pattern of major congenital malformations at University College Hospital, Ibadan, Nigeria among admitted children over a period of 5 years where the male: female ratio was 1.6:1.⁷

In this study age at presentation ranged from 1 day to 7 years, 45.6% of the patients with congenital CNS malformations represented before the age of one year of life. This result is similar to that of Adeyemo et al, who reported that the age of presentation ranged from a few hours to 13 years, and the majority (72.7%) presented in infancy. Leventer et al, reported that the age at initial imaging was 8 days to 18 years (mean age= 5 years).^7,8

In this study seizures were found in 59% with the majority (79%) had their seizure onset before the first year of life. The most common type of seizures was generalized in (33%). Focal type was less common and was reported in patients with (DCC) & less extensive forms of (MCD) as polymicrogyria and heterotopia. Overall seizures were controlled on antiepileptic medications except in some patients with either lissencephaly or Sturge Weber syndrome. These results are similar to that of Sanghvi et al, who reported that 46 out of 76 cases (60.5%) had their first seizure in infancy, and included 13 neonates. The seizures were generalized in 31/76 cases (40.7%) and partial in 27/76 (35.6%). Multiple seizure types were seen in 38.2% cases. Serdal et al, reported that; in 101 cases included in his study; epileptic seizures were present in (71.3%). Generalized seizures were present in (32.7%), complex partial in (25.7%) and secondary generalized in (11%). ^1,10

Regarding age at onset of seizures; in our study the majority was in the first year of life (79% of cases).This is in agreement with that of Serdal et al, who reported that seizures started in the first year of life in (48.6%) of the cases in general. Complete seizure control was achieved in (30.6%) of cases, while seizures continued in (69.5%) of the cases with varying frequencies.¹⁰

One third of the patients in our study had history of positive consanguineous marriage, while similar conditions as (mental subnormality, epilepsy) were described in (9%). Similarly, Sanghvi et al,  reported that out of 76 patients , 8% were born of a consanguineous marriage including 2.6% with family history of lissencephaly and 8% had a family history of epilepsy.¹

On measuring the head circumference, it was found that (39%) were microcephalic, while (9%) were macrocephalic. This result is similar to that of Leventer et al, who reported macrocephaly in (8.3%), and microcephaly in (5.5%), while Sanghvi et al, reported that 22 patients out of 76 patients (28.9%) had microcephaly. ^8,1

Global delay in milestones was reported in 76% of patients; one third (10 cases) showed delayed motor milestones mainly in neurocutaneous syndromes. Delayed both motor & mental milestones were found in 45% of patients mainly seen in (MCD) & (DCC). This result is in agreement with that of Leventer et al, who reported developmental delay or intellectual disability in (68%).  Sanghvi et al, reported that at presentation, (19 %) patients had normal neuro-developmental assessment, 64%patients had global delay in milestones, and (17%) had motor delay.^8,1

Regarding EEG recording, it was done only to 30 patients (one died and the other refused). Normal EEG was found in 12 cases (37.5%), non epileptiform activity in 22% (7 cases) [whether hypoactive record (6cases) or burst suppression pattern (1 case)], however epileptiform activity was encountered in 34% [whether focal (7cases) or generalized (4cases)]. Patients with (NTD) had abnormal EEG record in 70 % of patients which was mainly generalized hypoactivity in two third of cases. Inspite of the presence of seizures in all patients with (NCS), their EEG records were normal. Similarly Serdal et al, reported that EEG recordings were obtained in 96 of 101 cases; (56.3%) of them had epileptiform abnormality and non-epileptiform abnormality in (22.9%). In (20.8%) of the cases normal EEG findings was found. Slowing of baseline activity was present in diffuse malformations such as lissencephaly, diffuse polymicrogyria and diffuse band heterotopias. On the other hand Sanghvi et al, reported that (84.2%) patients had abnormal EEG, whereas (15.8%) had a normal EEG. ^10,1

Conclusion

Congenital CNS malformations show wide spectrum of clinical manifestations so it should be suspected in patients presenting with seizures, developmental delay, microcephaly, macrocephaly, or dysmorphic features especially during first year of life. Definite diagnosis depends on both relevant history and clinical data integrated with specific MRI findings.

REFERENCES

1.      Sanghvi J, Surekha B, Ursekar M. Spectrum of Congenital CNS Malformations in Pediatrics.  Indian Pediatr. 2004; 41(8):831-8.

2.      Herman TE, Siegel MJ. Miller—Dieker syndrome, type 1 lissencephaly. J Perinatol. 2008; 28(4): 313-5.

3.      Johnston MV, Kinsmen S. Congenital anomalies of central nervous system. In:  Kligman B, Stanton G, editors. Nelson text book. 18^th ed .Philadelphia: Saunders; 2007. p.1983-90.

4.      Armitage P. Statistical Methods in Medical Research. London: Blackwell Scientific Publications; 1971.

5.      Dolk H, de Wals P, Gillerot Y. Heterogeneity of neural tube defects in Europe: the significance of site of defect and presence of other major anomalies in relation to geographic differences in prevalence. Teratology. 1991; 44:547–59.

6.      Hadzagic-Catibusic F, Maksic H, Uzicanin S. Congenital malformations of the central nervous system: clinical approach. Bosn J Basic Med Sci.  2008; 8(4): 356-60.

7.      Adeyemo AA, Okolo CM, Omotade OO. Major congenital malformations among paediatric admissions at University College Hospital, Ibadan, Nigeria. Ann Trop Paediatr.  1994; 14(1): 75-9.

8.      Leventer RJ, Phelan EM, Coleman LT. Clinical and imaging features of cortical malformations in childhood. Neurology. 1999; 53(4): 715-22.

9.      Alorainy IA. Pattern of congenital brain malformations at a referral hospital in Saudi Arabia: an MRI study. Ann Saudi Med. 2006; 26(1): 28-37.

10.    Gungor S, Yalnızoglu D, Turanli G. Malformations of cortical development and epilepsy: evaluation of 101 cases. Epilepsy. 2007, 49(2): 131-40

11.    Copp AJ, Bernfield M. Etiology and pathogenesis of human neural tube defects: Insights from mouse models. Curr Opin Pediatr. 1994; 6: 624–31.