Two-year efficacy of lacosamide as adjunctive therapy for generalized tonic-clonic seizures in patients with juvenile myoclonic epilepsy.

OBJECTIVE: To report the long-term efficacy of adjunctive lacosamide therapy in patients with juvenile myoclonic epilepsy whose generalized tonic-clonic seizures were significantly reduced by treatment. METHODS: A retrospective study was conducted in patients who visited the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital and the Department of Pediatrics, National Hospital Organization Nagasaki Medical Center. Among patients who had been diagnosed with juvenile myoclonic epilepsy, those who received lacosamide as adjunctive therapy for refractory generalized tonic-clonic seizures for at least 2 years from January 2017 to December 2022, and who achieved seizure freedom or >50% seizure reduction in tonic-clonic seizures were included. The medical records and neurophysiological data of the patients were reviewed retrospectively. RESULTS: Four patients met the inclusion criteria. The mean age at the onset of epilepsy was 11.3 years (range 10-12), and the mean age of starting lacosamide was 17.5 years (range 16-21). All patients received two or more antiseizure medications prior to lacosamide. Three of four patients had seizure freedom for more than 2 years, and the one remaining patient had >50% seizure reduction for more than one year. Only one patient had recurrent myoclonic seizures after starting lacosamide. The mean lacosamide dose at the last visit was 425 mg/day (range 300-600). CONCLUSION: Adjunctive lacosamide therapy might be a treatment option for juvenile myoclonic epilepsy with generalized tonic-clonic seizures, which are not responsive to standard antiseizure medications.

The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus.

HCN1 is one of four genes encoding hyperpolarization-activated cyclic nucleotide-gated channels. The phenotypic spectrum associated with HCN1 variants ranges from neonatal developmental and epileptic encephalopathy to idiopathic generalized epilepsy. We report a Japanese patient with repetitive focal seizures and super-refractory status epilepticus since early infancy caused by a de novo HCN1 variant, NM_021072.4, c.1195T>C, p.(Ser399Pro). This variant might have a dominant-negative effect on channel function, leading to severe epileptic encephalopathy.

Clinical and electroencephalographic findings prior to the onset of juvenile myoclonic epilepsy: A case series.

The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded. We retrospectively reviewed the medical records and neurophysiological data of the patients. Four patients met the inclusion criteria. One patient was diagnosed with febrile seizures during childhood, and the remaining three had transitioned to juvenile myoclonic epilepsy from other epileptic disorders, such as self-limited epilepsy with autonomic seizures, genetic epilepsy with febrile seizure plus, or nonspecific genetic generalized epilepsy. All patients exhibited generalized spike-wave discharges or photoparoxysmal responses for >2 years before the onset of juvenile myoclonic epilepsy. The four patients had transitioned to juvenile myoclonic epilepsy from other epileptological preconditions. Patients with juvenile myoclonic epilepsy may show generalized electroencephalographic abnormality many years prior to the onset of symptoms. Generalized spike-waves on the electroencephalogram during the course of any type of epilepsy or febrile seizure may be a risk factor for developing juvenile myoclonic epilepsy.

Recurrence rates and risk factors for seizure recurrence following antiseizure medication withdrawal in adolescent patients with genetic generalized epilepsy.

OBJECTIVE: This study aimed to identify the recurrence rate of genetic generalized epilepsy (GGE) and risk factors for recurrence after antiseizure medication (ASM) withdrawal in adolescent patients. METHODS: We retrospectively reviewed medical records of patients with GGE who were included in the registry at the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital from 2000 through 2020. The eligibility criteria were as follows: onset of epileptic seizures at <15 years of age, treatment with an ASM, and attempted treatment withdrawal at 10-19 years of age. The rates of seizure recurrence after drug withdrawal were evaluated. Moreover, several variables were evaluated as predictors of recurrence. RESULTS: In total, 77 patients with GGE (21, 13, and 43 patients with juvenile myoclonic epilepsy [JME], juvenile absence epilepsy [JAE], and epilepsy with generalized tonic-clonic seizures alone [EGTCSA], respectively) were included in this study. Recurrence was detected in 68% of patients with GGE (86%, 31%, and 70% of patients with JME, JAE, and EGTCSA, respectively). Recurrence rates for patients who developed epilepsy at ≥13 years of age, those who started dose reduction at ≥16 years of age, those who exhibited a seizure-free period of <36 months before withdrawal, and those who chose to discontinue treatment at their own discretion were significantly higher than those for their counterparts. Multivariate analysis revealed that initiation of dose reduction at ≥16 years of age was associated with increased recurrence risk. Meanwhile, a diagnosis of JAE was associated with decreased recurrence risk. All patients with JAE were treated with valproic acid. SIGNIFICANCE: Antiseizure medication withdrawal at ≥16 years of age and a diagnosis other than JAE may be independent risk factors for seizure recurrence after drug withdrawal in adolescent patients.

Polymicrogyria with calcification in Pallister-Killian syndrome detected by microarray analysis.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures. RESULTS: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age. Neuroimaging revealed unilateral polymicrogyria with spot calcifications, which predominantly affected the right perisylvian region. Chromosome G-banding showed the karyotype 46,XY, however, array-based comparative genomic hybridization analysis showed mosaic duplication of chromosome 12p, in which CCND2, which encodes cyclin D2 and is a downstream mediator of PI3K-AKT pathway, is located. Supernumerary chromosome of 12p was detected in 58% of buccal mucosa cells by the interphase fluorescence in situ hybridization analysis using chromosome 12 centromere-specific D12Z3 probe. The diagnosis of PKS was made based on distinctive clinical features of our patient and the results of cytogenetic analyses. CONCLUSION: This report is, to our knowledge, the first case of a patient with PKS who clearly demonstrates polymicrogyria colocalized with calcifications, as shown by CT scans and MRI, and suggests that a patient with PKS could show structural brain anomalies with calcification. We assume that somatic mosaicism of tetrasomy could cause asymmetrical polymicrogyria in our patient, and speculate that increased dosages of CCND2 at chromosome 12p might be involved in the abnormal neuronal migration in PKS.

The association of epileptic focus estimated by magnetoencephalography with cognitive function in non-lesional epilepsy with continuous spikes and waves during slow wave sleep (ECSWS) children.

OBJECTIVE: Epilepsy with continuous spikes and waves during slow sleep (ECSWS) is associated with cognitive deficits. The underlying mechanism is thought to relate to disturbance of functions of the foci by the persistent epileptic activity. However, the relationship between epileptic foci and cognitive deficits remains largely unknown, except for in Landau-Kleffner syndrome. The aim of this study was to evaluate the relationship of epileptic foci estimated from magnetoencephalography (MEG) with cognitive functions at the period of diagnosis in non-lesional ECSWS children, excluding those with Landau-Kleffner syndrome. METHODS: MEG data and the Wechsler intelligence scale for children-III scores at ECSWS diagnosis, and medical records, were reviewed. Multiple regression analysis was performed to examine the relationship of parameters of MEG spike dipole clusters, including anatomical location or laterality, with the Wechsler intelligence scale for children-III scores at ECSWS diagnosis. RESULTS: Sixteen patients were included, all of whom were right-handed. Epilepsy onset (first unprovoked seizure) ranged from 31 to 110 months (mean, 68.5). The age at ECSWS diagnosis ranged from 72 to 156 months (mean, 108.9). The dipole clusters were estimated on the right Rolandic area (RA) in 4 patients (25%), right supramarginal gyrus (SMG) in 3 (19%), left RA in 2 (13%), left SMG in 2 (13%), bilateral RA in 3 (19%), multiple anatomical locations in 2 (13%). The age at epilepsy onset had the strongest prognostic effect, and full-scale intelligence quotient was relatively less-affected if the cluster was found on the SMG (ß = 14.7, p = 0.031). Cases with only a right side cluster exhibited reduced impairment of perceptual organization compared with those with only a left side cluster or bilateral clusters (ß = 17.48, p = 0.02). In 12 patients, long-term intellectual prognosis was evaluated, and was associated with intellectual level at the period of ECSWS diagnosis. CONCLUSION: In non-lesional ECSWS, the relationship between epileptic focus and cognitive deficits differs from that observed in adults. Rather, it is similar to epilepsies associated with congenital or early infantile brain insults, in that the left epileptic foci in right-handed patients were associated with lower non-verbal functions. Future studies are required to determine the role of plasticity of the immature brain in driving these differences.

Predicting factors of plural hospitalization with pneumonia in low-birthweight infants.

BACKGROUND: Children with a history of low birthweight (LBW) are often hospitalized with plural episodes of pneumonia after discharge from the neonatal intensive care unit. The aim of this study was to clarify the multiple factors predisposing them to developing three or more hospitalizations with pneumonia and whether the factors are related to their own prematurity. We also aimed to determine a predictable numerical formula for three or more episodes. METHODS: Fourteen patients with two hospitalizations with pneumonia were grouped into group A. Fourteen patients with at least three episodes during the same investigation period were grouped into group B. The quantification theory type III was employed to investigate the similarities among the items and the gravity of each attribution in the two groups. To evaluate the items of discrimination of both groups, six items were analyzed by the quantification theory type II. RESULTS: The dominant order of items contributing to the grouping was as follows: methicillin-resistant staphylococcus aureus detection (partial correlation coefficient = 0.5284), asthmatic attack (partial correlation coefficient = 0.4138), severe motor and intellectual disability, Haemophilus influenzae, accompanying diseases and chronic lung disease. A predicting numerical formula was attained from these results. The success rate of discrimination was 85.7%. The six items seemed to be related to the patients' own prematurity. CONCLUSIONS: The authors emphasize that plural hospitalizations with pneumonia in the patients with LBW might be caused by the combined influence of six clinical factors as well as their own prematurity.