Diagnostic evaluation of patients with epileptic spasms in the era of next-generation sequencing.

OBJECTIVE: Epileptic spasms (ES) can be caused by a variety of etiologies. However, in almost half of cases, the etiology is unidentified. With the advent of next-generation sequencing (NGS), the recognition of genetic etiologies has increased. METHODS: We retrospectively reviewed the medical records of patients with ES who were evaluated in the comprehensive epilepsy program at King Fahad Specialist Hospital Dammam between 2009 and 2022. RESULTS: Our data show that in 57.7% of patients with ES, the etiology was unidentified after a standard clinical evaluation and neuroimaging. Of these patients, n = 25 (35.2%) received a genetic diagnosis after some form of genetic testing, and 3.1% of patients from specialized metabolic work indicated the need for genetic testing to confirm the diagnosis. Karyotyping led to a diagnosis in 3.6% of patients, and chromosomal microarray led to a diagnosis in 7.1%. An NGS epilepsy gene panel (EP) was done for 45 patients, leading to a diagnosis in 24.4% (n = 11). Exome sequencing was done for 27 patients, including n = 14 with non-diagnostic panel testing; it led to a diagnosis in 37.3% (n = 10). Exome sequencing led to a diagnosis in 61.5% of patients without a previous panel test and in only two patients who had previously had a negative panel testing. SIGNIFICANCE: In this article, we present the diagnostic evaluations of ES for a cohort of 123 patients and discuss the yield and priority of NGS for evaluating ES. Our findings suggest that exome sequencing has a higher diagnostic yield for determining the etiology of ES in patients for whom the etiology is still unclear after an appropriate clinical assessment and a brain MRI.

Constitutional Mismatch Repair Deficiency Syndromes, a Neurofibromatosis 1 Mimicker That Hinders Timely Management.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) is a rare, autosomal recessive disease caused by a biallelic germline mutation in one of the DNA mismatch repair genes ( MLH1 , MSH2 , MSH6 and PMS2 ). In addition to colorectal, brain, and hematological malignancies, many additional premalignant and non-malignant features that can point toward the diagnosis of CMMRD have been reported. The report from the CMMRD consortium revealed that all children with CMMRD have café-au-lait macules (CALMs) but the number of CALMs does not reach > 5 in all CMMRD patients, which is one of the diagnostic criterions of NF1. About half of the patients with CMMRD develop brain tumors and up to 40% develop metachronous second malignancies. METHODS: This is an observational retrospective case series describing five pediatric patients with CMMRD. RESULTS: All the five patients in our cohort developed brain tumors and showed a predilection to the frontal lobe. In our cohort, multiple Mongolian spots, coloboma, obesity, CHD, dysmorphism, and clubfoot were also encountered. In all our patients, NF1 and other tumorigenic predisposing syndromes were initially suspected. CONCLUSION: Increasing awareness of this condition and its shared reminiscent NF1 features, particularly CALMs among child neurologists, oncologists, geneticists, and dermatologists can help uncover the tip of the iceberg of CMMRD that carries an important consequence on management.

Continuous Spikes and Waves During Sleep (CSWS), Severe Epileptic Encephalopathy, and Choreoathetosis due to Mutations in FRRS1L.

Background. Biallelic pathogenic variants in the FRRS1L gene are now known to cause developmental and epileptic encephalopathy-37 (DEE37). It can also be associated with chorea and continuous spikes and waves during sleep (CSWS). CSWS is a rare age-related epileptic encephalopathy syndrome of childhood that is characterized by seizures, neurocognitive regression and electrical status epilepticus during sleep (ESES) on electroencephalogram (EEG) that evolves in four stages. Seizures start during the prodromal phase but the ESES on EEG appears only during acute stage and this is the stage when the diagnosis of CSWS can be made. Methods. We present two patients with FRRS1L mutation causing DEE37 with CSWS. We also review twenty-nine cases of DEE37 described in the literature before and discuss its association with CSWS in the total cohort of thirty-one cases. Results. Developmental regression was found in 80% of the patients, mean age of seizure onset was 18 months, ESES or slow spike and wave on the EEG were reported mostly in the older patients (median age of 11 years) and hypsarrhythmia was reported in younger patients (median age of 4 years). This could suggest that if the younger patients were followed longer their EEG would have evolved into ESES during the acute stage of this syndrome and a diagnosis of CSWS could be made. Conclusion. Recognizing ESES and the natural evolution of CSWS is important in diagnosis and proper management of these patients. More detailed report of EEG findings and the evolution of epilepsy and development are needed to further characterize this syndrome.

Faciobrachial Dystonic Seizures as a Sign of Relapse in a Child with LGI-1 Encephalitis.

We report an interesting case of a young girl with LGI1-antibody encephalitis who presented at 7 years old with very frequent seizures and severe neurocognitive decline. She responded very well to high dose corticosteroids and intravenous immunoglobulin (IVIG) initially but relapsed after 7 months. The relapse included frequent faciobrachial dystonic seizures (FBDS) that were successfully treated with rituximab. This case report highlights a few important points about LGI1-antibody encephalitis in children to help clinicians recognize this condition early and start prompt treatment with immunosuppressants. Data is lacking about LGI1-antibody encephalitis in children as it is mostly reported in adults. Our patient presented with frequent drug-resistant seizures including FBDS, along with amnesia, confusion, medial temporal lobe involvement, and hyponatremia similar to the presentation in adults. In contrast, none of the patients in the recent systematic review had FBDS or hyponatremia, making our case unique and suggesting variability in clinical presentation in children similar to adults. To our knowledge, FBDS have never been reported in children and our patient was initially misdiagnosed as having Childhood Epilepsy with Centrotemporal spikes. Since receiving rituximab, our patient is seizure-free for 1 year and 9 months and was successfully weaned of topiramate. She is going to school and has normal attention, concentration, memory, and mood. We propose early consideration of rituximab to accelerate recovery and prevent relapse.

A systematic review of the efficacy of perampanel as treatment for myoclonic seizures and symptomatic myoclonus

Epileptic myoclonus or myoclonic seizures can occur in idiopathic generalized epilepsy (IGE) and progressive myoclonus epilepsy (PME). However, symptomatic myoclonus which is stimulus-sensitive and provoked by movement is typically seen in PME and Lance-Adams syndrome. Symptomatic myoclonus is not always associated with epileptiform discharges on the electroencephalogram. Therapeutic interventions such as anti-seizure medications (ASMs), the ketogenic diet and vagus nerve stimulation are not always effective. There is emerging evidence that perampanel (PER), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, may be effective for the treatment of myoclonic seizures and symptomatic myoclonus. We performed a systematic review of the literature to assess the efficacy of PER as treatment for myoclonic seizures and symptomatic myoclonus. Twenty-seven studies with a total sample size of 260 patients were included. The efficacy of PER was analysed separately for myoclonic seizures and symptomatic myoclonus. In the group with myoclonic seizures, 50% responder, 75% responder and seizure freedom rates were reported as 74.3% (101/ 136), 60.3% (82/136) and 57.4% (78/136), respectively, with a follow-up duration of 6-12 months. However, in one post-hoc analysis of data from patients with IGE, the efficacy of PER as treatment for myoclonic seizures during the double-blind phase showed no significant difference compared to placebo. The efficacy of PER for symptomatic myoclonus was reported in a total of 119 patients. Four studies (n=88 patients) reported the efficacy of PER as a decrease in myoclonus score/scale. In the remaining 31 patients, symptomatic myoclonus resolved in three patients, decreased in 21 patients and seven patients showed no improvement. We also analysed the number of patients who were already on levetiracetam (LEV) or valproic acid (VPA) at the time of PER initiation; these data were available for 153 patients. Of these, 56.8% were on LEV and 75.1% were on VPA when PER was initiated. This systematic review suggests that PER maybe effective as treatment for drug-resistant myoclonic seizures and symptomatic myoclonus. It may also be effective in patients who have already failed to respond to LEV and VPA. These findings are preliminary yet encouraging. This study has several limitations, particularly given the scarcity of high-quality randomized controlled trials and marked heterogeneity regarding the type and results of the studies. Hence, the findings of this review should be viewed with considerable reservation.