Marcio Sotero de Menezes

Lamotrigine‐Induced Tic Disorder: Report of Five Pediatric Cases

Summary: Purpose: To describe the clinical spectrum of lamotrigine (LTG)‐induced tics (an uncommon side effect) in children.

Stiripentol in Dravet syndrome: results of a retrospective U.S. study.

To review the efficacy and tolerability of stiripentol in the treatment of U.S. children with Dravet syndrome.

Clinical and electrographic features of epileptic spasms persisting beyond the second year of life

Summary:  Purpose: Few reports detailing the electroclinical features of epileptic spasms persisting beyond infancy have been published. We sought to characterize this unique population further.

Alternating hemiplegia of childhood: Retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers’ questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

Dravet syndrome: patients with co-morbid SCN1A gene mutations and mitochondrial electron transport chain defects.

PURPOSE To review our cohort of patients with Dravet syndrome and determine if patients with SCN1A mutations can also express mitochondrial disease due to electron transport chain dysfunction. METHODS A retrospective chart review was used to describe clinical manifestations and retrieve biochemical testing, neuroimaging, gene sequencing, and electroencephalographic results of patients expressing both mitochondrial disease and Dravet syndrome. RESULTS Two children were found to have pathological mutations in the SCN1A gene and defects in mitochondrial electron transport chain complex activity. Both developed early febrile and medically intractable afebrile seizures with resulting neurocognitive decline. In the first patient, a muscle biopsy demonstrated complex IV dysfunction and in the second patient, complex III dysfunction. Patient 1 had more difficult to control seizures, and had features consistent with severe autism. Patient 2, who had earlier control and less severe seizures, did not have features of autism. Patient 1 had SCN1A missense mutation, c. 3734 G>A and patient 2 had a mutation, c. 3733 C>T, which produces a truncation mutation. CONCLUSION Our two patients underscore the need to rule out possible co-morbid mitochondrial disease and Dravet syndrome. The treatment of seizures for each is different, with valproic acid being first line treatment in Dravet syndrome and contraindicated in many mitochondrial diseases, due to possible induction of liver failure and death. Failure to pursue complete diagnostic evaluation might influence medication choice, possible seizure control, and developmental outcomes.

Temporal lobectomy in early childhood: the need for long-term follow-up.

We retrospectively identified 15 children ages 12 years and under with anticonvulsant resistant epilepsy who underwent a temporal lobectomy at Childrens Hospital, Boston, between 1978 and 1993. Our aim was to study the long-term seizure outcome. Data pertaining to preoperative evaluation, electroencephalography (EEG), neuroimaging, surgery, seizure outcome, and postoperative complications were reviewed. Only patients followed for more than 12 months were included. The average duration of follow-up was 57 months. At the last visit, 47% (7 of 15) of the children were seizure free or only had auras; another 33% (5 of 15) had > 90% reduction in seizure frequency. Three patients had < 90% seizure reduction. Four cases were initially seizure free but had subsequent recurrence between 11 and 28 months after the epilepsy surgery. Factors associated with a good outcome include exclusively focal EEG discharges or an imaging suggestive of a low-grade tumor; factors associated with a poor outcome include generalized EEG discharges and a normal magnetic resonance image. Temporal lobectomy is useful in the treatment of early childhood drug-resistant partial epilepsy, but long-term follow-up is necessary as late seizure recurrence may occur up to 28 months after surgery. (J Child Neurol 2001;16:585-590).

Persistence of Suppression-Bursts in a Patient With Ohtahara Syndrome

Early infantile epileptic encephalopathy, or Ohtahara syndrome, is characterized by tonic spasms and a suppression-burst pattern on the electroencephalography (EEG). The EEG demonstrates a suppression-burst pattern during waking and sleeping states that often evolves into hypsarrhythmia and followed later by a diffuse slow spike-wave pattern. In other patients, the EEG evolves into focal spike discharges or multiple independent spike foci. We report a 5-year-old girl with Ohtahara syndrome that persistently demonstrated tonic spasms and suppression-burst on multiple EEGs. Over her lifetime, neither hypsarrhythmia nor diffuse slow spike-wave pattern were seen. This suggests that in Ohtahara syndrome, a suppression-burst pattern can persist over a long period of time.

Research conference summary from the 2014 International Task Force on ATP1A3-Related Disorders

Objective: ATP1A3-related neurologic disorders encompass a broad range of phenotypes that extend well beyond initial phenotypic criteria associated with alternating hemiplegia of childhood (AHC) and rapid-onset dystonia parkinsonism. Methods: In 2014, the Alternating Hemiplegia of Childhood Foundation hosted a multidisciplinary workshop intended to address fundamental challenges surrounding the diagnosis and management of individuals with ATP1A3-related disorders. Results: Workshop attendees were charged with the following: (1) to achieve consensus on expanded diagnostic criteria to facilitate the identification of additional patients, intended to supplement existing syndrome-specific diagnostic paradigms; (2) to standardize definitions for the broad range of paroxysmal manifestations associated with AHC to disseminate to families; (3) to create clinical recommendations for common recurrent issues facing families and medical care providers; (4) to review data related to the death of individuals in the Alternating Hemiplegia of Childhood Foundation database to guide future efforts in identifying at-risk subjects and potential preventative measures; and (5) to identify critical gaps where we most need to focus national and international research efforts. Conclusions: This report summarizes recommendations of the workshop committee, highlighting the key phenotypic features to facilitate the diagnosis of possible ATP1A3 mutations, providing recommendations for genetic testing, and outlining initial acute management for common recurrent clinical conditions, including epilepsy.

[Paroxysmal non-epileptic events]

Objective: this publication aims at reviewing one of the most important problems faced by the pediatrician in the field of child neurology. The paroxistic non-epileptic events are also a frequent reason for pediatric neurology consultations and admission for diagnostic video-eletroencephalogram monitoring. Methods: literature review on the subject was perform on Medline, data was also collected from the main Pediatric Neurology Textbooks, which were found to be important and unique source of information on the subject. Results: many of entities discussed in this paper are very common in the pediatric population like syncope, breath-holding spells and the movement disorders associated with gastroesophageal reflux. Other syndromes are less frequent such as the pararoxymal dystonias and the Segawa Syndrome (dystonia with diurnal variation). Conclusions: the basic knowledge of these syndromes is very important since it may avoid unnecessary procedures and the wrongful diagnosis of epilepsy. Patients who are mistakenly diagnosed as epileptics are exposed to anti-convulsant medications, which are probably not going to be effective and may expose them to the risk of side effects.

Focal Seizures in Patients With SCN1A Mutations Response to Treatment

The SCN1A gene has been implicated in the etiology of various forms of epilepsy. New research has linked this gene to specific types of epilepsy, all of which present in infancy or early childhood. This study examines the time course and pathology of pediatric patients who have a mutation in the SCN1A gene in order to open a discussion regarding the key trends of this form of epilepsy as well as important clinical considerations in management for patients who present with symptoms relating to the SCN1A mutations. We retrospectively examined 20 patients who presented to the clinic with focal seizures, as well as were positive for an SCN1A genetic mutation. Despite the small sample size, we were able to find important trends in the time course of the disorder as well as important areas of clinical practice that must be taken into consideration for these patients.