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.

Early and effective treatment of KCNQ2 encephalopathy.

OBJECTIVES: To describe the antiepileptic drug (AED) treatment of patients with early infantile epileptic encephalopathy due to KCNQ2 mutations during the neonatal phase and the first year of life. METHODS: We identified 15 patients and reviewed the electroclinical, neuroimaging, and AED treatment data. RESULTS: Seizure onset was between 1 and 4 days of age with daily tonic asymmetric, focal and clonic seizures in nine patients and status epilepticus in the remaining six. Electroencephalography (EEG) showed multifocal epileptiform abnormalities in nine patients and a burst-suppression pattern in six. All patients were trialed with adequate daily doses of several AEDs before they reached seizure freedom. Six patients (40%) achieved seizure control within 2 weeks of carbamazepine (CBZ) administration and five (33%) were seizure-free with phenytoin (PHT). The last four patients (27%) were successfully treated with topiramate (TPM) (two patients), levetiracetam (LEV) (one), and a combination of LEV with TPM (one). Most patients reached seizure freedom within the first year of life and remained seizure-free thereafter. Twelve patients had moderate-to-severe developmental delay at follow-up. However, the two patients whose seizures ceased within a few days of onset showed only mild cognitive impairment. SIGNIFICANCE: Our findings suggest that drugs acting on sodium channels including CBZ and PHT should be considered as first-line treatment in patients with KCNQ2 encephalopathy. Voltage-gated sodium and potassium channels co-localize at the neuronal membrane. Therefore, the efficacy of drugs acting as sodium-channel blockers could be linked to their modulating effect on both channels. The type of KCNQ2 mutation might influence AED response as well as developmental outcome. Early recognition of KCNQ2 encephalopathy followed by the most appropriate and effective treatment may be important for reducing the neurodevelopmental impairment associated with this disorder.

Lidocaine treatment in refractory status epilepticus resulting from febrile infection-related epilepsy syndrome: a case report and follow-up.

We report the management of refractory status epilepticus (SE) by using continuous intravenous infusions of lidocaine in a previously healthy 15-year-old girl with a "catastrophic encephalopathy" in whom a diagnosis of febrile infection-related epilepsy syndrome was supposed. One week after a banal pharyngitis and fever, the patient presented confusion and intractable clusters of seizures. Although she underwent multiple examinations investigating all possible etiologies (intracranial infection, autoimmune disease, or toxic and metabolic illness), all results were negative except a feeble positivity to Mycoplasma pneumoniae serum antibodies. SE was initially treated with benzodiazepine followed by administration of barbiturates and subsequent induction of coma because of refractory SE; different antiepileptic drugs (AEDs) were given at different times in a period of 6 weeks but clinical and electroencephalographic improvements were achieved only after continuous infusion of lidocaine. When she recovered from SE, the patient developed severe psychomotor and cognitive impairment associated with cerebral atrophy. Treatment with lidocaine or other alternative drugs in cases of prolonged SE should be taken into account as soon as it becomes clear that the clinical condition is refractory to common AEDs included in available guidelines for SE treatment, to improve the bad outcome of this severe condition, at least limiting the negative effects of prolonged high metabolic demand due to continuous epileptiform activity and/or the possible negative effects of prolonged burst-suppression coma.

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.

Transient nonverbal learning disorder in a child suffering from Familial Hemiplegic Migraine.

OBJECTIVE: To study the link between nonverbal learning disorder and right cerebral hemisphere dysfunction due to migraine attack in a case of Familial Hemiplegic Migraine. BACKGROUND: Familial Hemiplegic Migraine can cause neuropsychological deficits besides the motor ones. The nonverbal learning disorder is thought to be caused by a right hemisphere dysfunction. METHODS: We describe a child with Familial Hemiplegic Migraine type 2 who showed a transient neuropsychological impairment featuring a nonverbal learning disorder during and after a Hemiplegic migraine attack. RESULTS: Clinical and neuropsychological data showed a nonverbal learning disorder. A mutation in the ATP1A2 gene on chromosome 1q23 was found. Symptoms of nonverbal learning disorder outlasted the left hemiparesis. Two months later he showed a full recovery. Neurophysiological and neuroradiological evaluations were congruent with clinical course and with right hemisphere involvement. CONCLUSION: The link between nonverbal learning disorder and right cerebral hemisphere dysfunction due to migraine attack is confirmed. Familial Hemiplegic Migraine can cause transient complex neuropsychological syndromes that can be overlooked if not appropriately investigated.

Unusual segmental narrowing of spinal cord responsible for child paraparesis.

We describe a 7-year-old girl with spastic paraparesis. Her clinical condition was due to a unusual segmental thoracic narrowing of spinal cord. We show the imaging of her spinal cord, we compare her condition with the few similar cases from the literature and we try to suppose an aetiology.

Poor repertoire General Movements predict some aspects of development outcome at 2 years in very preterm infants.

BACKGROUND: Observation of the quality of endogenously generated "General Movements" has been proved to be a reliable and sensitive tool in the assessment of fragile neonates. The absence of fidgety movements at 2-4 months post-term is highly predictive of Cerebral Palsy. On the contrary, the presence of a poor repertoire pattern during the writhing period is not reliable in predicting motor or neurobehavioral disorders at any stage of development. AIM: To examine if the presence of a PR pattern at 1 month post-term was associated with lower neurodevelopmental quotients at 2 years. STUDY DESIGN: General Movements evaluation at 1 and 3 months and the Griffiths Scales of Mental Development at 2 years were administered to a sample of very preterm infants. Infants were divided into two groups: poor repertoire pattern group and normal pattern group. Student's t Test and Chi squared test and ANOVA were used to compare neonatal variables and results between the two groups. SUBJECTS: 79 very preterm infants (birthweight≤1500 g or gestational age≤32 weeks), born January 2003 to December 2006 who had a follow-up at 2 years. OUTCOME MEASURE: Griffiths developmental quotient at 2 years. RESULTS: The Poor Repertoire group had lower Gestational Age, lower Birth Weight, lower Apgar scores at birth and lower Developmental Quotient at 2 years. Eye and Hand Coordination (subscale D) was the domain mostly responsible for such a difference. Quality of fidgety movements (normal or abnormal fidgety) at 3 months did not show any correlation with outcome measures at 2 years. CONCLUSION: The presence of a PR pattern at 1 month post-term seems to predict lower neurodevelopmental scores at 2 years especially in the domain of eye and hand coordination. Longer follow-up is necessary in order to ascertain if such difference will continue to persist at older ages.