A case of epilepsy with myoclonic atonic seizures caused by SLC6A1 gene mutation due to balanced chromosomal translocation

IntroductionEpilepsy with myoclonic atonic seizures (EMAtS) was previously thought to occur in normally developing children. We report a female case of EMAtS and mild developmental delay before onset. Importantly, a de novo balanced chromosomal translocation was recognized in the patient.Case presentationThe patient was a 4-year-old girl. Mild developmental delay was observed during infancy. At the age of one and a half years, she developed atonic seizures once a month. At 4 years of age, her seizures increased to more than 10 times per hour. An ictal electroencephalogram (EEG) showed a 3–4-Hz spike-and-wave complex, which was consistent with atonic and myoclonic seizures of the trunk, eyelids, and lips. Therefore, EMAtS was diagnosed based on the symptoms and EEG findings. After administration of valproic acid (VPA), the epileptic seizures disappeared immediately. At the age of 5 years and 2 months, the seizures recurred but disappeared again when the dose of VPA was increased. Subsequently, no recurrence was observed until 6 years and 3 months of age on VPA and lamotrigine. Chromosome analysis of the patient disclosed 46,XX,t(3;11)(p25;q13.1)dn. Long-read sequencing of the the patient’s genomic DNA revealed that the 3p25.3 translocation breakpoint disrupted the intron 7 of the SLC6A1 gene.ConclusionThe SLC6A1 disruption by chromosome translocation well explains the clinical features of this patient. Long-read sequencing is a powerful technique to determine genomic abnormality at the nucleotide level for disease-associated chromosomal abnormality.     

Epileptic spasms in paediatric post‐traumatic epilepsy at a tertiary referral centre

Aim. To recognize epileptic spasms (ES) as a seizure type after traumatic brain injury (TBI), accidental or non‐accidental, in infants and children. In the process, we aim to gain some insight into the mechanisms of epileptogenesis in ES. Methods. A retrospective electronic chart review was performed at the Children's Hospital of Michigan from 2002 to 2012. Electronic charts of 321 patients were reviewed for evidence of post‐traumatic epilepsy. Various clinical variables were collected including age at TBI, mechanism of trauma, severity of brain injury, electroencephalography/neuroimaging data, and seizure semiology. Results. Six (12.8%) of the 47 patients diagnosed with post‐traumatic epilepsy (PTE) had ES. Epileptic spasms occurred between two months to two years after TBI. All patients with ES had multiple irritative zones, manifesting as multifocal epileptiform discharges, unilateral or bilateral. Cognitive delay and epileptic encephalopathy were seen in all six patients, five of whom were free of spasms after treatment with vigabatrin or adrenocorticotropic hormone. Conclusion. The risk of PTE is 47/321(14.6%) and the specific risk of ES after TBI is 6/321 (1.8%). The risk of ES appears to be high if the age at which severe TBI occurred was during infancy. Non‐accidental head trauma is a risk factor of epileptic spasms. While posttraumatic epilepsy (not ES) may start 10 years after the head injury, ES starts within two years, according to our small cohort. The pathophysiology of ES is unknown, however, our data support a combination of previously proposed models in which the primary dysfunction is a focal or diffuse cortical abnormality, coupled with its abnormal interaction with the subcortical structures and brainstem at a critical maturation stage.     

Epilepsy with myoclonic atonic seizures and chronic cerebellar symptoms associated with antibodies against glutamate receptors N2B and D2 in serum and cerebrospinal fluid

A 3‐year‐old boy with normal development presented with acute cerebellitis at one year and 10 months of age. His truncal ataxia resolved without treatment. He experienced a relapse of truncal ataxia and atonic seizures at 2 years and one month of age. Five months later, he experienced myoclonic atonic seizures. By 3 years of age, the truncal ataxia had become severe, and the frequency of myoclonic atonic seizures increased. Compared to controls, we found higher levels of anti‐C‐terminal GluN2B and anti‐N terminal GluD2 antibodies in the serum, and anti‐N terminal GluN2B and anti‐C terminal GluD2 antibodies in the cerebrospinal fluid (CSF). A cell‐based assay revealed the presence of anti‐NMDA‐type glutamate receptor antibody in the serum, but absence in the CSF. Ictal EEG of myoclonic atonic seizures showed generalized spike and wave complexes. The patient was diagnosed with myoclonic atonic epilepsy. Adrenocorticotrophic hormone therapy resolved the truncal ataxia and myoclonic atonic seizures, along with the decreased serum anti‐C‐terminal GluN2B and anti‐N‐terminal GluD2 antibodies, and CSF anti‐N‐terminal GluN2B and anti‐C‐terminal anti‐GluD2 antibodies. Our results suggest that the anti‐GluN2B and anti‐GluD2 antibodies may be associated with myoclonic atonic epileptic seizures and chronic cerebellitis.     

Infantile spasms combined with partial seizures: electroclinical study of eleven cases

We studied 11 infants (7 males) with combined infantile spasms (IS) and partial seizures. The age of onset of the spasms ranged from 6 days to 9 months. All of the children had neurological or CT/MRI abnormalities, and five also had a family history of epilepsy. The clinical and polygraphic patterns of the clusters of spasms combined with partial seizures were analysed. Ten infants were followed-up for a mean period of 3 years, 4 months (range 1 year 10 months to 4 years 11 months). At the last check-up, the seizures were controlled in 2 patients; the others continued to have spasms and/or partial seizures. All of the patients developed mild to severe pshychomotor retardation. This condition defines a subgroup of infants presenting with IS, which is distinct from West syndrome.

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Sommario Abbiamo studiato 11 bambini (7 maschi) che avevano spasmi infantili nello stesso episodio critico. L'età all'inizio degli spasmi variava da 6 giorni a 9 mesi. Tutti i bambini presentavano anormalità neurologiche o neuroradiologiche, e 5 avevano anche una familiarità epilettica. Abbiamo analizzato gli aspetti clinici e poligrafici dei cluster di spasmi associati a crisi parziali. Dieci di questi bambini vennero seguiti per un periodo medio di 3 anni e 4 mesi. All'ultima visita, le crisi hanno avuto sucessivamente un ritardo psicomotorio da lieve a grave. Questa condizione definisce un sottogruppo particolare, tra i bambini che presentano spasmi infantili, diverso dalla sindrome di West.

     

Doose syndrome (myoclonic–astatic epilepsy): 40 years of progress

Doose syndrome, otherwise traditionally known as myoclonic–astatic epilepsy, was first described as a unique epilepsy syndrome by Dr Hermann Doose in 1970. In 1989, the International League Against Epilepsy classified it formally as a symptomatic generalized epilepsy, and 20 years later it was renamed ‘epilepsy with myoclonic–atonic seizures’. In this review, we discuss the components of this unique disorder including its incidence, clinical features, and electroencephalographic findings. Recent evidence has suggested possible genetic links to the GEFS+ (generalized epilepsy with febrile seizures plus) family, and, additionally, some children with structural brain lesions can mimic the Doose syndrome phenotype. Treatment strategies such as corticosteroids, ethosuximide, and valproate have been described as only partially effective, but newer anticonvulsants, such as levetiracetam and zonisamide, may provide additional seizure control. The most effective treatment reported to date appears to be the ketogenic diet. Prognosis is quite varied in this disorder; however, many children can have a remarkably normal neurodevelopmental outcome.     

Epileptic spasms preceded by partial seizures with a close temporal association

PURPOSE: To investigate the distinctive features of patients with West syndrome who had partial seizures followed by epileptic spasms (PS-ES). METHODS: We examined 45 patients with West syndrome whose epileptic spasms were recorded with simultaneous video-electroencephalography (EEG) monitoring between 1982 and 1996. We investigated the patients who had PS-ES and compared the PS-ES patients with the 37 patients without PS-ES. RESULTS: Of the 45 patients who had epileptic spasms in clusters (ES) and hypsarrhythmia on the interictal EEG, eight (17%) had ES preceded by partial seizures (PS) with a close temporal association. Seven of these eight were female patients. The underlying disorders were tuberous sclerosis (one patient), Aicardi syndrome (one), nonketotic hyperglycinemia (one), and focal cortical dysplasia (one). The etiology was unknown in the remaining four patients, but was suspected to be of prenatal origin in three. Three types of seizure sequence were identified: PS followed several seconds later by ES (two patients), alternating PS and ES starting with PS (three), and PS gradually replaced by ES with overlapping of the two (three). PS-ES disappeared or was replaced by other types of seizures in 1-34 months. Six patients could not walk, and all patients could not speak any sentences at age 3 years. CONCLUSIONS: Compared with patients without PS-ES, those with PS-ES more often had organic brain lesions of prenatal origin, other types of seizures before the onset of ES, asymmetric hypsarrhythmia on the EEG, and poor psychomotor outcome.     

Mixed myoclonic‐absence status epilepticus in juvenile myoclonic epilepsy

Myoclonic status epilepticus or mixed absence‐myoclonic status is uncommon in juvenile myoclonic epilepsy (JME), often precipitated by sleep deprivation, withdrawal of medication, or inadequate antiepileptic drugs (Thomas et al., 2006 ; Crespel et al., 2013 ). Such episodes respond well to benzodiazepines or valproate (Crespel et al., 2013 ). We present the video‐EEG of a 24‐year‐old woman with JME and bipolar disorder. She had a confusional state five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor with subtle myoclonus of the face and the arms. The EEG showed absence status (figures 1, 2), which stopped after IV injection of clonazepam (1 mg) (figure 3). Consciousness returned to normal [Published with video sequence and figures 1 ].     

Rolandic epilepsy: an uncommon presentation with leg motor seizures

Rolandic epilepsy (RE) is the most common and one of the most benign epileptic syndromes of childhood. It is typically characterized by sleep-related orofacial seizures, of brief duration, of variable frequency, in otherwise healthy children. Electroencephalography (EEG) shows typical centrotemporal spike and spike-and-wave complexes, often bilateral and asynchronous, activated by sleep. Therapy is often unnecessary and seizures spontaneously end at puberty. Apart from typical orofacial localization, arm or more diffuse clonic jerks are frequently described by parents. More rare and probably underestimated are sensorimotor seizure localized to one leg. When such seizures represent the only type of seizures in RE, the exact recognition of this benign epileptic syndrome appears difficult, leading to unnecessary investigation and therapy. We describe six children, among 230 with RE, who presented leg sensorimotor seizures as the mainly type of ictal manifestations.     

Focal epileptic spasms, involving one leg, manifesting during the clinical course of west syndrome (WS)

OBJECTIVES: Epileptic spasms (ES) in West syndrome (WS) are classified as being of the generalized seizure type. However, evidence of a focal neocortical origin has been proposed based mainly on surgical WS series. We report herein two infants with WS, whose ES subsequently evolved into focal ES of the right lower extremity. METHODS: Medical records, electroencephalographic and neuroimaging findings were retrospectively analyzed. RESULTS: A 2 year-old Japanese girl developed ES at 3 months of age. Focal ES of the right leg manifested one month after successful ACTH therapy performed at 6 months of age. Brief jerking of the right leg, every few seconds, occurred immediately after awakening. A 7 month-old girl with symptomatic WS had developed focal seizures with postural signs at 2 months of age. The seizures gradually diminished and had been replaced by ES by 3 months of age. ES gradually evolved into focal ES of the right leg. A video-polygraphic study demonstrated the ES with marked predominance in the right leg corresponding to a left sided predominant paroxysmal biphasic slow wave complex. Brain MRI revealed no abnormal findings although interictal EEG demonstrated left centro-parieto-temporal localized spike foci. CONCLUSIONS: The focal ES of one lower limb, following treatment of ES in these two infants with WS, suggests the origin of the ES in the first case to be a neocortical focus involving the primary motor cortex representing the lower limb while that in the second case involves more widespread neocortical area with predominance in the same motor cortex as the first case.     

Psychogenic non‐epileptic seizures

Psychogenic non‐epileptic seizures (PNES) are diagnosed in at least 10–40% of the patients seen for long‐term monitoring of epilepsy, and it is no surprise that patients with PNES are often treated for epilepsy. Given the substantial economic costs and mental health burden of misdiagnosis, it is imperative to establish early identification, correct diagnosis, and effective treatment of PNES in order to provide the greatest opportunity for remission of events, improved psychological functioning, and social‐vocational outcome. This article outlines an informed, practical approach to diagnosing this common condition and provides a summary of factors, based on medical history and semiology, that may suggest PNES. We discuss also the issues of communicating the diagnosis to the patient and making treatment recommendations which should ideally be coordinated using a multi‐disciplinary team approach, involving the disciplines of neurology, psychiatry, psychology, social work, and nursing.     

Self‐induction seizures in sunflower epilepsy: a video‐EEG report

Seizures triggered by visual stimuli are the most common type of reflex seizure. Self‐induced seizures produced by stimulation of natural light are rare and self‐induction is a mode of seizure precipitation employed by either intellectually disabled or healthy photosensitive individuals. Absences and myoclonic jerks are the most common seizure types in self‐induction. We report on a girl with normal intelligence who self‐induced seizures by waving her outspread fingers in front of a bright light. This situation is called sunflower epilepsy. [Published with video sequences]     

Adjunctive rufinamide in Lennox‐Gastaut syndrome: a long‐term,open‐label extension study

Kluger G, Glauser T, Krauss G, Seeruthun R, Perdomo C, Arroyo S. Adjunctive rufinamide in Lennox‐Gastaut syndrome: a long‐term, open‐label extension study.
Acta Neurol Scand: 122: 202–208.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objective – This open‐label extension evaluated the long‐term efficacy and tolerability of rufinamide in patients with Lennox‐Gastaut syndrome (LGS) who had previously completed a 12‐week double‐blind study. Materials and methods – In total, 124 patients (aged 4–37 years), receiving 1–3 concomitant antiepileptic drugs, were treated with rufinamide ～25–60 mg/kg/day. Efficacy was assessed by seizure frequency; tolerability by adverse events (AEs) and laboratory tests. Results – Overall, patients were treated with rufinamide for a median (range) of 432 (10–1149) days. Reductions in seizure frequency were observed throughout the study; during the last 12 months of treatment, 41.0% and 47.9% of patients had ≥50% reduction in total and tonic–atonic seizure frequency, respectively. The most common AEs were vomiting (30.6%) and pyrexia (25.8%). Conclusions – In this open‐label extension, rufinamide appeared to be an effective long‐term adjunctive therapy for the treatment of LGS‐associated seizures in children and young adults.     

Dravet syndrome: Early electroclinical findings and long‐term outcome in adolescents and adults

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age. Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy.