Sulthiame add-on treatment in children with epileptic encephalopathy with status epilepticus: an efficacy analysis in etiologic subgroups.

PURPOSE: Sulthiame (STM) has been recommended as an effective antiepileptic drug (AED) in children with epileptic encephalopathy with status epilepticus in sleep (ESES). The aim of this study is to evaluate the efficacy of STM add-on treatment in children with pattern of ESES with respect to the etiologic subgroup. METHODS: Twenty-nine children with ESES pattern with three different etiologic subgroups (epileptic syndromes: 14, structural/infectious: 9, unknown: 6) who were given STM as add-on treatment were included into the study. The efficacy of STM was evaluated in terms of seizure control, electroencephalography (EEG) findings, need of the new AEDs after add-on STM, and behavioral and cognitive improvement. RESULTS: The range of the follow-up duration after add-on STM treatment was between 5 and 51 months. At the end of 1 year of STM treatment, the most successful electrophysiologic improvement was identified in the well-defined epileptic syndrome group; epileptic syndrome, 71.4% (10/14); structural/infectious, 33.3% (3/9); and unknown, 0% (0/6). Patients who had complete response or persistent ESES pattern at the 3rd month were still in the same condition at the 6th and 12th months. However, the ESES pattern reappeared in 35.2% of the patients who had partial electrophysiological improvement at the 3rd month. In the epilepsy syndrome group, eight out of ten patients who had either complete or partial EEG response after 1 year of STM treatment displayed behavioral and cognitive improvement. CONCLUSION: Sulthiame might be a valid add-on treatment of ESES especially in children with epilepsy syndromes.

The utility of whole exome sequencing for identification of the molecular etiology in autosomal recessive developmental and epileptic encephalopathies.

AIM: Developmental and epileptic encephalopathies (DEEs) are a group of devastating disorders caused by epileptic activity, resulting in deterioration in developmental, cognitive, and motor functions. The number of genes identified as being responsible for DEEs has been increasing rapidly. However, despite a comprehensive molecular analysis, a molecular diagnosis can only be established in 50% of cases. The aim of this project is to use whole exome sequencing (WES) to determine the molecular etiology of DEEs in undiagnosed patients with a pedigree suggestive of an autosomal recessive single gene disease. METHODS: Three DEE families, having either consanguineous parents of an affected individual and/or having more than one affected offspring, were enrolled in the project. Prior to this project, the families had been evaluated using a next-generation sequencing panel including 16 DEE genes in a previous study; however, no molecular diagnosis could be established. In five cases from the three selected DEEs families in our study, the genetic etiology was investigated using WES. RESULTS: All patients in the study group had infantile onset epileptic seizures; however, semiologies varied. All patients presented with severe developmental delay. WES revealed biallelic disease causing mutations in DENDD5A, GRN, and TBCD genes in family 1, family 2, and family 3, respectively. In each family, the identified variants associated with the disease were segregated. Reverse phenotyping supported the molecular analysis. CONCLUSION: This study provided a valuable contribution to the genotype-phenotype relationship by determining rare epilepsy syndromes in undiagnosed patients previously. WES is a useful diagnostic alternative, particularly in consanguineous families.

A rare cause of ischemic stroke in childhood: spontaneous long segment intracranial dissection.

Craniocervical arterial dissection is an important cause of arterial ischemic stroke in children. Recognition of dissections is of particular importance both in determining the risk of recurrence and in bringing about different treatment alternatives. We report a 10-year-old girl who presented with acute ischemic stroke due to spontaneous long segment dissection involving the parasellar internal carotid artery up to the distal M1 portion of the middle cerebral artery. Three-dimensional digital subtraction angiography with flat panel detector revealed the presence of major vessels originating from both true and false lumens and had a critical role in the treatment decision of the case.

WWOX-associated encephalopathies: identification of the phenotypic spectrum and the resulting genotype-phenotype correlation.

Epileptic encephalopathies are a group of disorders in which epileptiform abnormalities cause progressive deterioration in cerebral function. Genetic causes have been described in several of the epileptic encephalopathies, and many previously unknown genes have been identified. WW domain-containing oxidoreductase (WWOX) has recently been implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy. With whole-exome sequencing, we identified a homozygous WWOX missense mutation, p.Leu239Arg, in a girl from a consanguineous family with psychomotor developmental delay, acquired microcephaly, and epileptic seizures. WWOX-related epileptic encephalopathy is a rare condition but it should be considered in cases having early epileptic spasms and parental consanguinity.

A treatable cause of myelopathy and vision loss mimicking neuromyelitis optica spectrum disorder: late-onset biotinidase deficiency.

Biotinidase deficiency is characterized by severe neurological manifestations as hypotonia, lethargy, ataxia, hearing loss, seizures and developmental retardation in its classical form. Late-onset biotinidase deficiency presents distinctly from the classical form such as limb weakness and vision problems. A 14-year-old boy presented with progressive vision loss and upper limb weakness. The patient was initiated steroid therapy with a preliminary diagnosis of neuromyelitis optica spectrum disorder due to the craniospinal imaging findings demonstrating optic nerve, brainstem and longitudinally extensive spinal cord involvement. Although the patient exhibited partial clinical improvement after pulse steroid therapy, craniocervical imaging performed one month after the initiation of steroid therapy did not show any regression. The CSF IgG index was <0.8 (normal: <0.8), oligoclonal band and aquaporin-4 antibodies were negative. Metabolic investigations revealed a low biotinidase enzyme activity 8% (0.58 nmoL/min/mL; normal range: 4.4 to 12). Genetic testing showed c.98-104delinsTCC and p.V457 M mutations in biotinidase (BTD) gene. At the third month of biotin replacement therapy, control craniospinal MRI demonstrated a complete regression of the lesions. The muscle strength of the case returned to normal. His visual acuity was 7/10 in the left eye and 9/10 in the right. The late-onset form of the biotinidase deficiency should be kept in mind in all patients with myelopathy with or without vision loss, particularly in those with inadequate response to steroid therapy. The family screening is important to identify asymptomatic individuals and timely treatment.

Whole-exome sequencing identifies recessive WDR62 mutations in severe brain malformations.

The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers. An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development. Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis. Here we demonstrate the use of whole-exome sequencing to overcome these obstacles by identifying recessive mutations in WD repeat domain 62 (WDR62) as the cause of a wide spectrum of severe cerebral cortical malformations including microcephaly, pachygyria with cortical thickening as well as hypoplasia of the corpus callosum. Some patients with mutations in WDR62 had evidence of additional abnormalities including lissencephaly, schizencephaly, polymicrogyria and, in one instance, cerebellar hypoplasia, all traits traditionally regarded as distinct entities. In mice and humans, WDR62 transcripts and protein are enriched in neural progenitors within the ventricular and subventricular zones. Expression of WDR62 in the neocortex is transient, spanning the period of embryonic neurogenesis. Unlike other known microcephaly genes, WDR62 does not apparently associate with centrosomes and is predominantly nuclear in localization. These findings unify previously disparate aspects of cerebral cortical development and highlight the use of whole-exome sequencing to identify disease loci in settings in which traditional methods have proved challenging.

Ictal urinary urge: localization and lateralization value in a pediatric case.

BACKGROUND: Ictal urinary urge is a rare autonomic symptom usually lateralizing to the non-dominant hemisphere and localizing to the temporal lobe. CASE REPORT: A 12-year-old boy was referred with desire to void and contraction of the left arm. The history of the case revealed tickling and an unpleasant rising feeling in the stomach and sense of fear lasting for 1 year. He had been evaluated and treated several times with the diagnosis of gastroesophageal reflux and cystitis. His cranial MRI displayed an intra-axial mass formation on the right temporal lobe. Pathological findings were consistent with a low-grade glial mass. CONCLUSION: Ictal urinary urge has a considerable value both for localization and lateralization of seizures.

The Utility of Genetic Testing in Infantile Epileptic Spasms Syndrome: A Step-Based Approach in the Next-Generation Sequencing Era.

BACKGROUND: To evaluate the utility of genetic testing for etiology-specific diagnosis (ESD) in infantile epileptic spasms syndrome (IESS) with a step-based diagnostic approach in the next-generation sequencing (NGS) era. METHODS: The study cohort consisted of 314 patients with IESS, followed by the Pediatric Neurology Division of Ege University Hospital between 2005 and 2021. The ESD was evaluated using a step-based approach: step I (clinical phenomenology), step II (neuroimaging), step III (metabolic screening), and step IV (genetic testing). The diagnostic utility of genetic testing was evaluated to compare the early-NGS period (2005 to 2013, n = 183) and the NGS era (2014 to 2021, n = 131). RESULTS: An ESD was established in 221 of 314 (70.4%) infants with IESS: structural, 40.8%; genetic, 17.2%; metabolic, 8.3%; immune-infectious, 4.1%. The diagnostic yield of genetic testing increased from 8.9% to 41.7% in the cohort during the four follow-up periods. The rate of unknown etiology decreased from 34.9% to 22.1% during the follow-up periods. The genetic ESD was established as 27.4% with genetic testing in the NGS era. The genetic testing in the NGS era increased dramatically in subgroups with unknown and structural etiologies. The diagnostic yields of the epilepsy panels increased from 7.6% to 19.2%. However, the diagnostic yield of whole exome sequencing remained at similar levels during the early-NGS period at 54.5% and in the NGS era at 59%. CONCLUSIONS: The more genetic ESD (27.4%) was defined for IESS in the NGS era with the implication of precision therapy (37.7%).

Diagnostic tools of early brain disturbances in an asymptomatic neonate with maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare inherited metabolic disorder resulting from the defective activity of branched-chain 2-ketoacid dehydrogenase complex. Routine screening of newborn with tandem mass spectroscopy on the third day of life may detect elevated branched-chain amino acids in blood before the appearance of encephalopathic symptoms in MSUD cases. If undiagnosed by such a routine screening test, patients often present with encephalopathy and seizures. Clinical neurologic examination is supplemented by electroencephalography and imaging. Here, we report abnormal amplitude-integrated electroencephalography, electroencephalography, magnetic resonance imaging, and magnetic resonance imaging spectroscopy findings in a neurologically asymptomatic male newborn who was diagnosed with MSUD at the third week of life. These neurologic disturbances disappeared at the fourth month of life with appropriate special diet. Therefore, even in already asymptomatic cases, early neurologic deterioration of brain metabolism and structure can be detected with these early laboratory findings, indicating the importance of early diagnosis and management. Patients may also benefit from these investigations during the follow-up period.

Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.

BACKGROUND: The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background. METHODS: Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue. RESULTS: Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7. DISCUSSION: These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.

Changing views of cerebral palsy over 35 years: the experience of a center.

In this study, it was aimed to evaluate the demographic and clinical characteristics of cerebral palsy (CP) cases over a 35-year period. Findings of 442 patients with CP followed from 1995 to 2006 (Group 2) were compared with 208 patients with CP followed between 1972 and 1994 (Group 1) in the same pediatric neurology division. Ratios of both prematurity (38% vs. 17.7%) and very low birth weight (VLBW) infants (13.8% vs. 1.5%) significantly increased in Group 2. There was also a four-fold increase in cesarean delivery in Group 2 (42.3% vs. 9.6%). A significant increase in the rate of early diagnosis during the first year was also found in this group (56.9% vs. 39.4%). The rate of spastic diparesis cases has significantly increased (33.7% vs. 7.7%), while the rate of spastic tetraparesis cases has significantly decreased (63.5% vs. 37.3%). It was seen that preventable risk factors continue today.

Cerebral folate transporter deficiency: a potentially treatable neurometabolic disorder.

Cerebral folate deficiency (CFD) syndrome is a rare treatable neurometabolic disorder with low levels of the active form of folaten in cerebrospinal fluid (CSF) arising from different causes such as FOLR1 gene mutations or autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus. It is characterized by late infantile onset refractory seizures, ataxia, movement disorder, and unexplained global developmental delay. Here, we report a patient diagnosed with autistic spectrum disorder, followed by refractory myoclonic-atonic seizures, ataxia, and loss of motor skills over time. A homozygous missense (c.665A > G) mutation in FOLR1 gene and extremely low CSF 5-methyltetrahydrofolate level led to the diagnosis of CFD. Although she was initiated on combined oral and intravenous high doses of folinic acid treatment at 6 years of age, mild improvement was achieved in terms of epileptic seizures and motor skills. It is important that CFD should be kept in mind in cases with refractory myoclonic-atonic seizure and folinic acid treatment should be started as soon as possible.

What are the predominant predictors of seizure relapse following discontinuation of anti-seizure medication in epileptic children?

OBJECTIVE: The aim of the study was to identify the predominant predictors of seizure relapse following discontinuation of ASM in epileptic children. METHODS: The study cohort consisted of 403 epileptic children who had a withdrawal process of ASM (monotherapy: 344; dual therapy or polytherapy: 59) after at least a 2-year seizure-free period. Patients were categorized if they had a well-defined epileptic syndrome. Epileptic children with ongoing ketogenic diet, vagal nerve stimulation, or surgery were excluded from the cohort due to the additional withdrawal process related to other therapy modalities. RESULTS: The cohort's seizure relapse rate was 12.7% (51/403). The highest rates of seizure relapse were defined for genetic etiology at 25% and structural etiology at 14.9%. An epilepsy syndrome was defined in 183 of 403 children (45.4%). There was no difference in the seizure relapse rate between the subgroups of well-defined epileptic syndromes; 13.8% for self-limited focal epileptic syndromes, 11.7% for developmental and epileptic encephalopathies, and 7.1% for generalized epileptic syndromes. Five predictors were defined as the most powerful predictors of seizure relapse in univariate analysis: age at epilepsy diagnosis >2 years (hazard ratio [HR]: 1.480; 95% confidence interval [CI]: 1.134-1.933), defined etiology (HR: 1.304; 95% CI: 1.003-1.696), focal seizure (HR: 1.499; 95% CI: 1.209-1.859), ≤3 months duration of the withdrawal process (HR: 1.654; 95% CI: 1.322-2.070), and a history of neonatal encephalopathy with or without seizures (HR: 3.140; 95% CI: 2.393-4.122). In multivariate analysis, the main predictor of seizure relapse was a history of neonatal encephalopathy with or without seizures (HR: 2.823; 95% CI: 2.067-3.854). SIGNIFICANCE: The duration of seizure freedom before discontinuation of ASM was not a predominant risk factor for seizure relapse: 2-3 years versus >3 years. The predictive values of five predictors of seizure relapse rate should be evaluated for patients with different epilepsy subgroups.

Sleep problems in adolescents with epilepsy and their caregivers: associations with behavioural difficulties.

BACKGROUND: The aim of this study was to investigate the frequency of sleep problems in adolescents with epilepsy and their caregivers. We also examined the behavioural difficulties in adolescents with epilepsy and compared these behaviors with healthy controls. METHODS: This observational case-control study included 37 adolescents with epilepsy and their caregivers, and 43 healthy age-matched adolescents and their caregivers. The Children`s Sleep Habits Questionnaire (CSHQ), DSM-5 Level 2 Sleep Disorders Scale for Children, and Strengths & Difficulties Questionnaire (SDQ) were used to evaluate sleep habits, sleep problems, and behavioural difficulties in adolescents. The DSM-5 sleep disorder scale for adults was used to evaluate the caregivers` sleep problems. RESULTS: Adolescents with epilepsy had higher sleep problem scores such as daytime sleepiness and overall sleep problems compared with healthy controls. The psychopathological symptoms such as conduct problems, hyperactivity/inattention, and total behavior were also more frequent in adolescents with epilepsy. There was a nonsignificant increase in DSM-5 sleep disturbance score in caregivers of adolescents with epilepsy. Sleep onset delay had a significant negative correlation with total behavioral difficulties (r = -0.44, p < 0.01), and emotional problems (r = -0.47, p < 0.05) in adolescents with epilepsy. Sleep duration was negatively correlated with conduct problems (r = -0.33, p < 0.05), but positively correlated with prosocial score (r = 0.46, p < 0.01) in adolescents with epilepsy. Night waking was positively correlated with total behavioral difficulties (r = 0.35, p < 0.05) and hyperactivity score (r = 0.38, p < 0.05) in adolescents with epilepsy. CONCLUSIONS: Adolescents with epilepsy have more frequent sleep disturbances and maladaptive behaviors such as hyperactivity/inattention, and conduct problems compared with healthy controls, and their caregivers are more vulnerable to sleep problems. Moreover, we also demonstrated a strong association between sleep disturbances and behavioral problems in adolescents with epilepsy.

Assessment of Prognostic Factors and Validity of Scoring Models in Childhood Autoimmune Encephalitis.

OBJECTIVE: The aim of this study is to evaluate the prognostic factors in a single-center pediatric cohort with autoimmune encephalitis. MATERIALS AND METHODS: The study group consisted of 23 pediatric autoimmune encephalitis patients (seropositive autoimmune encephalitis: 15, seronegative autoimmune encephalitis: 8). Five group prognostic parameters were evaluated: clinical manifestations, elect roenc ephal ograp hy features, magnetic resonance imaging characteristics, biomarkers, and treatment modalities. Three scoring models were applied: the Antibody Prevalence in Epilepsy and Response to Immunotherapy in Epilepsy for predicting autoimmune-related epilepsy in the whole cohort and the anti-N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status score for overall outcome in patients with anti-N-methyl-d-aspartate receptor encephalitis. RESULTS: The initial clinical spectrum of the disease was similar in the seronegative and seropositive groups. Almost half of the patients (48%) recovered without any complications with first-line immunotherapy. The patients with movement disorders in the acute phase of the disease needed more likely second-line immunotherapy (P = .039). The presence of status epilepticus at admission was significantly associated with adverse outcomes and the development of autoimmune-related epilepsy (P = .019). Autoimmune-related epilepsy was defined in an equal proportion of patients (91.5%) with 2 immune epilepsy scores (Antibody Prevalence in Epilepsy and Response to Immunotherapy in Epilepsy). The N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status score and the modified Rankin score assessed for the first-year prognosis were strongly correlated among the patients with anti-N-methyl-d-aspartate receptor encephalitis (P = .03, Spearmen's rho = 0.751). CONCLUSIONS: The presence of status epilepticus was the most important prognostic factor in the patients with the adverse outcome. The studied scoring models (Anti-N-methyl-d-aspartate receptor Encephalitis 1-Year Functional Status, Antibody Prevalence in Epilepsy, and Response to Immunotherapy in Epilepsy) have also been proven to be applicable to the pediatric age group for predicting overall outcome and autoimmune-related epilepsy.

Diagnostic tools of metabolic and structural brain disturbances in neonatal non-ketotic hyperglycinemia.

Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive disorder of glycine metabolism. We report a newborn case of NKH and discuss the effects of this rare disease on brain metabolism and structure together with amplitude-integrated electroencephalography, cranial magnetic resonance and magnetic resonance spectroscopy findings which are very rarely reported together so far.

Melatonin Versus Chloral Hydrate for Sleep Electroencephalography Recording in Children: A Comparative Study Using Bispectral Index Monitoring Scores and Electroencephalographic Sleep Stages.

PURPOSE: To compare the effects of chloral hydrate and melatonin on sleep EEG recordings in children by using standard EEG sleep stages and the bispectral index scores (BIS). METHODS: A total of 86 children were randomly assigned to two groups: (1) melatonin group (n = 43) and (2) chloral hydrate group (n = 43). BIS monitoring scores and sleep EEGs were recorded simultaneously. The effect of two drugs on sleep EEG recording was evaluated with sleep stages of EEG and BIS. RESULTS: There was no statistically significant difference between the groups with regard to time to sleep onset and the need for a second drug ( P = 0.432; P = 1.000). Eight patients (18.6%) in chloral hydrate group reported side effects while there were no reported side effects in the melatonin group ( P = 0.006). Mean BIS values during EEG recordings were similar in both groups (59.72 ± 18.69 minutes and 66.17 ± 18.44 minutes, respectively, P = 1.000). The average time to achieve N2 sleep was 32.38 minutes in the chloral hydrate group and 43.25 minutes in the melatonin group ( P < 0.001). Both "time spent in wakefulness" and "N1 sleep" were found to be significantly higher in the melatonin group ( P < 0.001 and P = 0.005). BIS scores higher than 75 were found to be suggestive for wakefulness; 75 to 66 for N1, 65 to 46 for N2, and values lower than 46 were found to be indicative for N3 sleep with a good strength of agreement in weighted Kappa analysis (95% confidence interval; weighted Kappa = 0.67). CONCLUSIONS: Melatonin is reliable and at least as effective as chloral hydrate for sleep EEG acquisition in children.

Video/EEG recording of myoclonic absences in GLUT1 deficiency syndrome with a hot-spot R126C mutation in the SLC2A1 gene.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is an inborn error of brain energy metabolism characterized by impaired glucose transport into the brain. A classic phenotype comprising epilepsy, mental retardation, an often paroxysmal disorder, and several subtypes has been described. Although typical absences are frequent in GLUT1DS, myoclonic absence seizures are rarely reported. Here we describe a novel Turkish patient with a hot-spot mutation (R126C) in the SLC2A1 gene who presented with unusual myoclonic absence epilepsy and paroxysmal shivering. The case is discussed in view of eight other cases carrying the R126C mutation.

A rare cause of recurrent stroke in childhood: left atrial rhabdomyosarcoma.

UNLABELLED: We present a case of recurrent stroke secondary to cardiac rhabdomyosarcoma. The detected prothrombotic mutations at the first attack had seemed to be the main cause, but the echocardiography performed at the recurrence revealed the actual underlying cause of stroke. CONCLUSION: The aetiological investigation into childhood stroke should absolutely include echocardiography regardless of the presence of other risk factors.