Gain of function SCN1A disease-causing variants: Expanding the phenotypic spectrum and functional studies guiding the choice of effective antiseizure medication.

OBJECTIVE: This study was undertaken to refine the spectrum of SCN1A epileptic disorders other than Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS+) and optimize antiseizure management by correlating phenotype-genotype relationship and functional consequences of SCN1A variants in a cohort of patients. METHODS: Sixteen probands carrying SCN1A pathogenic variants were ascertained via a national collaborative network. We also performed a literature review including individuals with SCN1A variants causing non-DS and non-GEFS+ phenotypes and compared the features of the two cohorts. Whole cell patch clamp experiments were performed for three representative SCN1A pathogenic variants. RESULTS: Nine of the 16 probands (56%) had de novo pathogenic variants causing developmental and epileptic encephalopathy (DEE) with seizure onset at a median age of 2 months and severe intellectual disability. Seven of the 16 probands (54%), five with inherited and two with de novo variants, manifested focal epilepsies with mild or no intellectual disability. Sodium channel blockers never worsened seizures, and 50% of patients experienced long periods of seizure freedom. We found 13 SCN1A missense variants; eight of them were novel and never reported. Functional studies of three representative variants showed a gain of channel function. The literature review led to the identification of 44 individuals with SCN1A variants and non-DS, non-GEFS+ phenotypes. The comparison with our cohort highlighted that DEE phenotypes are a common feature. SIGNIFICANCE: The boundaries of SCN1A disorders are wide and still expanding. In our cohort, >50% of patients manifested focal epilepsies, which are thus a frequent feature of SCN1A pathogenic variants beyond DS and GEFS+. SCN1A testing should therefore be included in the diagnostic workup of pediatric, familial and nonfamilial, focal epilepsies. Alternatively, non-DS/non-GEFS+ phenotypes might be associated with gain of channel function, and sodium channel blockers could control seizures by counteracting excessive channel function. Functional analysis evaluating the consequences of pathogenic SCN1A variants is thus relevant to tailor the appropriate antiseizure medication.

Acquired Demyelinating Syndromes of the Central Nervous System in Children: The Importance of Regular Follow-up in the First Year After Onset.

AIM: We reviewed the clinical features of a sample of pediatric acquired demyelinating syndromes with the purpose of determining the appropriate protocol for follow-up after the first episode. METHODS: A multicenter retrospective observational study was conducted on a cohort of 40 children diagnosed with a first episode of acquired demyelinating syndrome over the period 2012-2021. Patients were evaluated with clinical and neuroradiologic assessment after 3, 6, and 12 months, with a median follow-up of 4.0 years. RESULTS: At the first acquired demyelinating syndrome episode, 18 patients (45%) were diagnosed with acute disseminated encephalomyelitis, 18 (45%) with clinical isolated syndrome, and 4 (10%) with multiple sclerosis. By month 12, 12 patients (30%) had progressed from an initial diagnosis of acute disseminated encephalomyelitis (2) or clinical isolated syndrome (10) to multiple sclerosis. Of these, 6 had clinical relapse and 6 radiologic relapse only. The first relapse occurred after a median of 3 months. Among the patients who had evolved toward multiple sclerosis, there was a prevalence of females (P = .014), higher oligoclonal bands positivity (P = .009), and older median age (P < .001) as compared with those who had remained stable. INTERPRETATION: Both clinical and radiologic follow-up of children with acquired demyelinating syndromes is crucial, especially during the first year after acute onset, for early identification of multiple sclerosis and prompt initiation of disease-modifying treatment to delay axonal damage and to limit disability.

Evolution of the EEG in children with Rasmussen's syndrome.

PURPOSE: The early diagnosis of Rasmussen's syndrome (RS) is often difficult, with differentiation between RS and focal cortical dysplasia (FCD) at epilepsy onset problematic. This study reviewed electroencephalography (EEG) in the two conditions for early indicators of either pathology. METHODS: All children with either suspected RS or with unilateral FCD undergoing evaluation for epilepsy surgery between 1992 and 2005 were identified. Case notes and standard EEG recordings were reviewed. EEG findings were compared where available at <3, 3-6 months, and 3-5 years after seizure onset. KEY FINDINGS: Nineteen children with RS and 17 with FCD were ascertained. In EEG studies performed <3 months after seizure onset, 50% (5/10) of the RS group showed background abnormalities, with 80% of these (4/5) showing persistent high-amplitude delta activity over the affected hemisphere. This compared to 66% (6/9) of the FCD group with 17% (1/6) showing marked background asymmetry. By 3-6 months after seizure onset, independent interictal abnormalities over the nonaffected hemisphere were seen in 25% (2/8) of the RS group and by 3-5 years in 62% (5/8) compared to none in the FCD group at any time points measured. These independent contralateral interictal abnormalities were notably associated with a significant decline in cognitive skills over time. SIGNIFICANCE: No specific EEG changes at diagnosis of epilepsy were identified to help differentiate between RS and FCD. Emerging persistent delta activity over the affected hemisphere with contralateral normal background rhythms, followed in due course by independent interictal epileptiform abnormalities over the unaffected hemisphere may support the diagnosis of RS as the condition evolves, and highlight the risk of overall cognitive dysfunction.

Lafora disease: spectroscopy study correlated with neuropsychological findings.

PURPOSE: To evaluate the metabolic changes both in grey and white matter in Lafora disease using proton magnetic resonance spectroscopy and to determine the possible correlation with the pattern of cognitive impairment. METHODS: Five patients with Lafora disease and six healthy controls were included in the study. Patients underwent at the same time-point neuropsychological testing and 1[H]MRS, using PRESS sequences (TE=136 and 25 ms) positioned in the frontal and posterior cingulate gyrus cortexes and in the adjacent frontal and parietal white matter. RESULTS: Neuropsychological testing showed in all patients a prevalent involvement of performance abilities--with partial sparing of verbal competences--and of executive functions, suggesting a major involvement of frontal areas. Analysis of 1[H]MRS showed a statistically significant reduction in NAA/mI and NAA/Cr in grey matter of patients compared to controls, more significant in frontal regions. In white matter, a significant reduction of NAA/mI ratio was observed both in the frontal and parietal regions, associated with a reduction of the NAA/Cr only in the frontal white matter. NAA/mI was found to be the most statistically significant altered parameter in all regions studied and the only significantly altered ratio in strong correlation with all sets of neuropsychological parameters. CONCLUSIONS: Our study confirmed the predominant metabolic damage in the frontal cortex, also demonstrating NAA/mI ratio to be the most sensitive parameter to detect metabolic brain changes in Lafora disease; moreover, it evidenced frontal white matter spectroscopic changes. Both spectroscopy values and clinical features of cognitive impairment showed a prevalent frontal impairment.

Mutational scanning of potassium, sodium and chloride ion channels in malignant migrating partial seizures in infancy.

The mutational analysis of potassium (KCNQ2, KCNQ3), sodium (SCN1A, SCN2A), and chloride (CLCN2) ion channels was performed in three children with typical features of the recently described syndrome of migrating partial seizures in infancy. Mutational analysis was performed by PCR and automatic sequencing. The coding regions, including the exon-intron boundaries, were amplified in the patients using appropriate primers sets. No mutations associated to migrating partial seizures have been found. Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three patients. The same variation has been found in 38 out of 100 control alleles. The identification of the genetic basis of this new epileptic encephalopathy requires further studies that might be enforced by familial cases.

Early-onset occipital idiopathic epilepsy: a syndrome to be treated?

The purpose of this study was to evaluate prognostic factors in early-onset childhood epilepsy with occipital paroxysms. We studied retrospectively a population of 46 patients, which was divided into three groups according to seizure frequency group 1, patients experiencing a single seizure (3396); group 2, patients experiencing two to six seizures (48%); and group 3, patients experiencing more than six seizures (20%). The mean follow-up period was about 5 years in the three groups. At the end of the first 6 months of this retrospective follow-up, the average number of seizures was higher in group 3 (2.9 seizures) than in groups 2 and 1 (1.8 and 1 seizure, respectively). We suggest that low seizure frequency in the first 6 months of follow-up could have prognostic value. We propose that the introduction of anti-epilepsy drugs be delayed for 6 months following epilepsy onset and be subsequently limited to patients with frequent seizure recurrence.

Topiramate efficacy in an infant with partial seizures refractory to conventional antiepileptic drugs.

Many studies showed that Topiramate (TPM) may be a useful drug in a wide spectrum of childhood epilepsies. We report a 3-month-old female with stormy onset of secondarily generalized partial seizures. She showed a high seizure frequency and a progressive worsening electroencephalogram (EEG), despite standard antiepileptic drugs administration. TPM succeeded in controlling seizures, even after the other drugs were discontinued. This case suggests that TPM may represent a good choice for the treatment of partial seizures refractory to conventional drugs in infants.

Brain MRI findings in severe myoclonic epilepsy in infancy and genotype-phenotype correlations.

INTRODUCTION: To determine the occurrence of neuroradiological abnormalities and to perform genotype-phenotype correlations in severe myoclonic epilepsy of infancy (SMEI, Dravet syndrome). PATIENTS AND METHODS: Alpha-subunit type A of voltage-gated sodium channel (SCN1A) mutational screening was performed by denaturing high-performance liquid chromatography (DHPLC) and multiplex ligation probe amplification (MLPA). MRI inclusion criteria were: last examination obtained after the age of 4 years on 1.5-T systems; hippocampal cuts acquired perpendicular to the long axis of the hippocampus; qualitative assessment was performed on T(1)-weighted, T(2)-weighted, proton density, and 1-3 mm thick coronal FLAIR images. RESULTS: We collected 58 SMEI patients in whom last MRI was performed at or later than 4 years of age. SCN1A mutations occurred in 35 (60%) cases. Thirteen (22.4%) out of 58 patients showed abnormal MRIs. Eight patients showed cortical brain atrophy of which 3 associated to ventricles abnormalities, 1 to cerebellar atrophy, 1 to white matter hyperintensity; 3 patients had ventricles enlargement only; 1 patient showed hippocampal sclerosis (HS); 1 had focal cortical dysplasia. Genotype-phenotype analysis indicated that abnormal MRIs occurred more frequently in patients without SCN1A mutations (9/23; 39.1%) compared to those carrying SCN1A mutations (4/35; 11.4%) (p=0.02). CONCLUSION: Different brain abnormalities may occur in SMEI. Only one case with HS was observed; thus, our study does not support the association between prolonged febrile seizures and HS in SMEI. Abnormal MRIs were significantly more frequent in patients without SCN1A mutations. Prospective MRI studies will assess the etiological role of the changes observed in these patients.