The profile of epilepsy and its characteristics in children with neurocutaneous syndromes

INTRODUCTION

Neurocutaneous syndromes are a group of inherited disorders with a multitude of abnormalities involving the central nervous system, skin, and visceral organs. Neurofibromatosis 1 (NF1), tuberous sclerosis complex (TSC), and Sturge–Weber syndrome (SWS) are the prototypical neurocutaneous syndromes with genetic mutations in cell growth regulation pathways.^[1] Neurological presentation ranges from mild behavioral abnormalities to drug-resistant epilepsy.^[2-5] In these children, there is a high prevalence of neurodevelopmental disorders and epilepsy.^[6,7] The frequency of epilepsy is estimated at 6–10% in NF1, 70–90% in TSC, and 70–90% in SWS.^[1,3-5,8,9] Although the mechanisms resulting in epileptogenesis differ between the neurocutaneous disorders, there is an overlap in the molecular pathways, especially mammalian targets of rapamycin (mTOR) signaling pathways.^[1] The possible contributors to cellular hyperexcitability in NF1 can be cortical malformations, neurotransmitter defects, alterations in ion channels, or synaptic plasticity.^[10] The epileptogenesis in TSC is due to the dysfunction of mTOR signaling pathways resulting in abnormal cellular excitation and hyperexcitable circuits due to neuropathological substrates.^[11,12] The possible contributors to cellular hyperexcitability in TSC are neuron dysplasia, dendritic spine dysgenesis, reduced GABAergic inhibition, increased glutamatergic excitation, and glial dysgenesis.^[1] In SWS, the possible contributors are blood vessel dysgenesis, calcification, and cell death.^[13] In these children, seizures can cause sleep disturbances which, in turn, cause behavioral issues and further reduce the threshold of seizures.^[14] The management is challenging as these children have significant comorbidities that impact their quality of life. With a better molecular understanding of the mechanisms, therapy can be targeted with the help of “Precision medicine” based on unique molecular pathways. The profile of seizures in children with neurocutaneous syndromes is variable, and this study aimed to evaluate the characteristics of epilepsy in these children.

MATERIALS AND METHODS

This cross-sectional study was conducted for an 18-month study period in the Department of Pediatrics at a North Indian tertiary care referral hospital after obtaining prior ethical approval.

RESULTS

Of 119 children with neurocutaneous syndromes, 94 (79%) had epilepsy, 8/21 (38.1%) children with NF1 had epilepsy, 69/72 (95.8%) children with TSC had epilepsy, 14/16 (87.5%) children with SWS had epilepsy, and 26/119 (21.8%) children fulfilled the criteria of West Syndrome [Table 1].

DISCUSSION

The higher proportion of epilepsy in our study population may be due to the enrollment of patients from neurodevelopment and epilepsy clinics with significant neurological comorbidities. In a study by Santoro et al.,^[20] seizures were found in 4.3% of the general population, and in Hsieh et al.,^[21] the prevalence was 5.87%. The most common seizure type in the index study was generalized tonic-clonic seizure (GTCS) (23.8%). In the previous studies, focal seizures were more common, followed by GTCS.

Among the studies on NF1, Khair et al. reported epilepsy in 13.5% of their cohort of children with NF1, with focal onset seizures in 11 patients, followed by GTCS in five patients.^[5] In a retrospective study by Hsieh et al. with 630 children and adults, focal-onset seizures in 2.6% and GTCS in 2.4% of the cohort.^[21] In a study by Santoro et al. on NF1 children, 11/19 (58%) had focal seizures; however, 10/19 children with seizures had structural epilepsy, all of whom had focal seizures.^[20] In the index study, all children had non-structural seizures and among the children with NF1, generalized motor tonic-clonic seizures were the most common type (62.5%).

Among the studies on TSC, Nabbout et al. reported a prevalence of epilepsy in 83.6%, with 38.9% presenting with epileptic spasms and 67.5% with focal seizures.^[22] In another study by Vignoli et al., epilepsy was reported in 72.5% with TSC.^[23] In another study by Chu-Shore et al., 85.2% of 291 patients with TSC had seizures, with focal onset seizures in 76%.^[24] Similar to the previous studies, focal seizures and generalized onset epileptic spasms were the most common seizure types in the index study. In a study by Alkonyi et al., all 110 patients with SWS enrolled had seizures.^[25]

In our cohort, 26/119 (21.8%) children fulfilled the criteria of West syndrome. Five children were follow-up cases of West syndrome more than 10 years old and continued to have epileptic spasms. Many patients might have had West syndrome before enrolment in our study and might have evolved into another type of seizure, as reported in the previous studies.^[26] In a study by Fukushima et al. with 50 TSC patients monitored and analyzed after 10 years, the outcome was unfavorable for patients with generalized seizures.^[26] Capal et al. reported that in patients with epileptic spasms, developmental outcomes were poor on assessments at 12, 18, and 24 months of age.^[27]

Among the studies on SWS, the prevalence of epilepsy reported was 90% in patients with bilateral cerebral involvement.^[1] The common seizure type reported in SWS was focal seizures.^[1] In the index study, more than 90% of children with SWS had focal seizures, in concordance with the previous studies.

Among the 16 children with ASD, 13 (81.3%) had epilepsy, but the association was not statistically significant in our study population. In the index study, there was a significant association between epilepsy and ASD in children with TSC (P < 0.01), similar to the study by Vignoli et al., where epilepsy has been considered a significant risk factor for ASD in TSC.^[28] The higher proportion in our cohort can be attributed to more children presenting with epilepsy in the pediatric neurology clinic. The index study found statistically significant associations between epilepsy and ID (P = 0.02) and behavioral problems (P = 0.00).

CONCLUSION

The prevalence of epilepsy in neurocutaneous syndromes is very high. Profiling seizures in children with neurocutaneous syndromes is paramount in devising target-specific treatments as the epileptogenesis in each syndrome differs in the molecular pathways leading to the hyperexcitability state.