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nodding spasm [keywords]
- A potential effect of ganaxolone in an animal model of infantile spasms. [JOURNAL ARTICLE]
- Epilepsy Res 2014 Sep 2.
Infantile spasms (IS), a devastating epileptic encephalopathy of infancy, involve various etiologies associated with an unknown underlying common pathophysiology. The efficacy of adrenocorticotropic hormone (ACTH) as an IS therapy suggests a role for steroid hormones in treating IS. This study used an animal model of IS to test the efficacy of ganaxolone, a synthetic neurosteroid, promoting tonic GABAA inhibition.The model of cryptogenic IS used in this study involved prenatal priming of rats with betamethasone (0.4mg/kg i.p. at 08:30 and 18:30) on gestational day 15. To test the acute effects of ganaxolone, rats were pretreated with ganaxolone (10, 25, or 50mg/kg i.p.) or vehicle (β-cyclodextrin, i.p.) 30min prior to N-methyl-d-aspartate (NMDA)-induced spasms at postnatal day 15 (P15). To mimic human conditions, another group of rats was randomly divided and repeatedly treated with ganaxolone (20mg/kg at 9:00 and 18:00 from P13-15) or vehicle after experiencing NMDA-triggered spasms at P12. Additional spasms were triggered on P13 and P15. We determined latency to the onset of spasms and the total number of spasms per 90-min observation period after the trigger at P15. On P19 and P21, behavioral tests were performed in rats with randomized repeated treatments.The 25mg/kg and 50mg/kg doses of ganaxolone significantly delayed the onset of spasms compared with the controls, and significantly decreased the number of spasms or suppressed their incidence. Ganaxolone had significant side effects in terms of sedation: all animals with the 50mg/kg dose were sleeping during the test. Randomized ganaxolone treatment for 3 days also significantly delayed the onset and decreased the number of spasms triggered by NMDA on P15, and decreased exploratory behavior after multiple NMDA triggered spasms.Ganaxolone significantly suppresses the development of spasms in the rat model of cryptogenic IS. This synthetic neurosteroid active in an animal model of IS might contribute to the current armamentarium to treat human IS.
- Epilepsy in Menkes disease: An electroclinical long-term study of 28 patients. [JOURNAL ARTICLE]
- Epilepsy Res 2014 Aug 30.
Epilepsy is a frequent and severe feature of Menkes disease (MD) but only few studies described the long-term evolution of these children. We report a series of 28 epileptic MD patients, with clinical characteristics, EEG abnormalities, brain malformations and long-term outcome.EEG, clinical characteristics and neuroimaging features in 28 MD patients were analyzed at the onset of epilepsy and after long-term follow-up (at least 4 years). We subdivided the patients into two groups: Group 1, 16 patients who received a subcutaneous copper-histidine treatment, and Group 2 including 12 patients who did not get any therapies.The large majority of our patients presented at the onset of epilepsy focal seizures (FS) and infantile spasms (IS). Five patients had recurrent status epilepticus (SE). During the follow-up, patients showed multiple seizure types: 6 patients had generalized tonic clonic seizures (GCT), 6 patients presented IS, 10 children had FS, 11 had myoclonic jerks and 3 had SE. Therapy with various antiepileptic drugs had poor efficacy, except in three patients who showed seizure disappearance with consequent discontinuation of antiepileptic therapy. There was no difference of neurological outcome among the two groups analyzed.Epilepsy in MD is a difficult to treat problem. At the onset, the most frequent type of seizures are FC and IS; in the next months, other kinds of seizures can appear. Many children are drug resistant. Institution of replacement therapy with copper-histidine seems to be not beneficial for epilepsy.
- Mutant GABAA receptor subunits in genetic (idiopathic) epilepsy. [Journal Article]
- Prog Brain Res 2014.:55-85.
The γ-aminobutyric acid receptor type A (GABAA receptor) is a ligand-gated chloride channel that mediates major inhibitory functions in the central nervous system. GABAA receptors function mainly as pentamers containing α, β, and either γ or δ subunits. A number of antiepileptic drugs have agonistic effects on GABAA receptors. Hence, dysfunctions of GABAA receptors have been postulated to play important roles in the etiology of epilepsy. In fact, mutations or genetic variations of the genes encoding the α1, α6, β2, β3, γ2, or δ subunits (GABRA1, GABRA6, GABRB2, GABRB3, GABRG2, and GABRD, respectively) have been associated with human epilepsy, both with and without febrile seizures. Epilepsy resulting from mutations is commonly one of following, genetic (idiopathic) generalized epilepsy (e.g., juvenile myoclonic epilepsy), childhood absence epilepsy, genetic epilepsy with febrile seizures, or Dravet syndrome. Recently, mutations of GABRA1, GABRB2, and GABRB3 were associated with infantile spasms and Lennox-Gastaut syndrome. These mutations compromise hyperpolarization through GABAA receptors, which is believed to cause seizures. Interestingly, most of the insufficiencies are not caused by receptor gating abnormalities, but by complex mechanisms, including endoplasmic reticulum (ER)-associated degradation, nonsense-mediated mRNA decay, intracellular trafficking defects, and ER stress. Thus, GABAA receptor subunit mutations are now thought to participate in the pathomechanisms of epilepsy, and an improved understanding of these mutations should facilitate our understanding of epilepsy and the development of new therapies.
- Efficacy and Tolerability of Methylprednisolone Pulse Therapy in Childhood Epilepsies Other Than Infantile Spasms. [JOURNAL ARTICLE]
- Neuropediatrics 2014 Sep 3.
This retrospective study included 54 children with epilepsy. The treatment consisted of four pulses with single doses of 20 mg/kg/d methylprednisolone (MPR), administered every week on 3 consecutive days. After this initial phase, the intervals between the pulses were increased based on individual factors. MPR pulses were administered exclusively orally in 39 patients and 7.8% of all pulses were applied intravenously. After four pulses, 30 of 54 (56%) patients were responders, according to several clinical and electroencephalography criteria. A response was obtained in 12 of 20 (60%) cases with genetic, 7 of 17 (41%) with structural metabolic, and 11 of 17 (65%) with unknown etiology. Responder rates were 11 of 15 (73%) in patients with continuous spike-waves in slow sleep (CSWS) or Landau-Kleffner syndrome, 2 of 6 in patients with myoclonic astatic epilepsy or Lennox-Gastaut syndrome, and 17 of 31 (55%) in patients with unclassified epilepsies. A response was not correlated with any epilepsy-related clinical factor. The patients received a median of eight MPR pulses (range, 1-52), and the median duration of the therapy was 11 weeks. The response was maintained in 19 of 30 (63%) patients, and 3 of 24 (13%) without initial response became seizure-free (total responder rate at the end of the therapy 22/54 [41%]). The majority of patients experienced adverse effects that were typically mild and transient.
- Unilateral Eye Blinking Arising From the Ictal Ipsilateral Occipital Area. [JOURNAL ARTICLE]
- Clin EEG Neurosci 2014 Sep 1.
We report on an 18-month-old boy with unilateral left eye blinking as a single ictal manifestation without facial twitching. The clinical onset of this phenomenon was first recorded (as an occasional event) at age 3 months, and it was overlooked. By age 6 months, the child's blinking increased to almost daily occurrence in clusters: during blinking the infant showed intact awareness and occasional jerks in the upper limbs and right leg. A video-electroencephalography (video-EEG) documented clinical correlation with a focal pattern arising from the left occipital region, and brain magnetic resonance imaging (MRI) revealed severe brain damage, consisting in poroencephalic hollows and increased spaces in the convexities involving a large area of the left cerebral hemisphere. The boy was prescribed sodium valproate (30 mg/kg/d), resulting in drastic reduction of his clinical seizures. Follow-up to his current age documented good general status, with persistent partial right hemilateral seizures. The blinking progressively disappeared, and is no longer recorded. The pathogenic hypotheses of the unilateral ictal blinking include involvement of the ipsilateral cerebral hemisphere and/or the cerebellar pathways. Review of previous reports of unilateral eye blinking, arising from the ictal ipsilateral brain, revealed that different damaged regions may give rise to blinking ictal phenomena, likely via the trigeminal fibres innervating the subdural intracranial structures and the pial vessels in the ipsilateral affected brain. The eye blinking in the present child represents a further example of an ictal phenomenon, which is predictive of the damaged brain region.
- Practice Experience in the Treatment of Infantile Spasms at a Tertiary Care Center. [JOURNAL ARTICLE]
- Pediatr Neurol 2014 Jul 22.
The current treatment guidelines for treatment of infantile spasms is ambiguous regarding individuals with known etiology and is backed by limited evidence. Recently published survey data reveal diverse treatment variation for infantile spasms. We conducted a retrospective medical record review to better understand the clinical variables which affect treatment selection for new-onset infantile spasms.We systematically extracted demographic data and treatment response of children with new onset infantile spasms over a 3-year period at a single institution. Treatment was divided into three groups: vigabatrin, hormone treatment, and other therapies.Our final cohort had 65 patients; 74% had a known etiology. Sixty-two percent were initially treated with vigabatrin. Other therapies were used more often in known etiology than in unknown etiology as initial treatment (40% vs 6%; P = 0.002). Treatment response at 3 months was not statistically different between unknown etiology and known etiology groups (71% vs 46%; P = 0.08). Overall, initial treatment choice was effective in 35% (23 of 65). Eighty-six percent (37 of 42) who failed the initial medication had subsequent medication trials within 3 months.Etiology was strongly associated with initial treatment choice. The variation in treatment choice at our center reflects the limited evidence derived from well-designed clinical trials.
- Population Pharmacokinetics Analysis of Vigabatrin in Adults and Children with Epilepsy and Children with Infantile Spasms. [JOURNAL ARTICLE]
- Clin Pharmacokinet 2014 Aug 30.
Vigabatrin is an inhibitor of γ-aminobutyric acid transaminase. The purpose of these analyses was to develop a population pharmacokinetics model to characterize the vigabatrin concentration-time profile for adults and children with refractory complex partial seizures (rCPS) and for children with infantile spasms (IS); to identify covariates that affect its disposition, and to enable predictions of systemic vigabatrin exposure for patients 1-12 months of age.Vigabatrin pharmacokinetic data from six randomized controlled clinical trials and one open-label study were analyzed using nonlinear mixed-effects modeling. Data collected from 349 adults with rCPS and 119 pediatric patients with rCPS or IS were used in the analyses.A two-compartment model with first-order elimination and transit-compartment absorption consisting of five transit compartments adequately described the vigabatrin concentration-time data for these adult and pediatric patient populations. An exponential error model was used to estimate inter-individual variability for the transit-rate constant (k tr) (24.2 %), elimination rate constant (k) (14.7 %) and apparent central volume of distribution (V c/F) (18 %). For the study of children with IS, inter-occasion variability was estimated for k tr (58.1 %) and relative bioavailability (F) (26.9 %). Covariate analysis indicated that age, creatinine clearance (CLCR), and body weight were important predictors of vigabatrin pharmacokinetic parameters. Vigabatrin apparent clearance increased with increasing CLCR, consistent with renal excretion (primary pathway of vigabatrin elimination). Rate of vigabatrin absorption was dependent on age. The rate was slower in younger patients, which resulted in a smaller predicted maximum concentration and longer predicted time to maximum concentrations. Vigabatrin V c/F, apparent inter-compartmental clearance between the central and peripheral compartment, and apparent peripheral volume of distribution were increased with greater patient body weights. Sex did not contribute significantly to vigabatrin pharmacokinetic variability.The model adequately described vigabatrin pharmacokinetic and enabled predictions of systemic exposures in pediatric patients 1-12 months of age.
- Early neurodevelopmental screening in tuberous sclerosis complex: a potential window of opportunity. [Journal Article]
- Pediatr Neurol 2014 Sep; 51(3):398-402.
Infants born with tuberous sclerosis complex, a genetic condition resulting from a mutation in TSC1 or TSC2, are at increased risk for intellectual disability and/or autism. Features of epilepsy, neuropathology, genetics, as well as timing and type of mechanism-based medications have been proposed as risk factors. Neurodevelopmental outcomes have been reported among these studies; however, few include data about the individuals' early neurodevelopmental profile, a factor that may contribute significantly to these outcomes. Further, there is no clinical standard for the neurodevelopmental assessment of these infants. The paucity of data regarding the natural history of neurodevelopment in infants with tuberous sclerosis complex and the lack of a gold standard for neurodevelopmental evaluation present a significant challenge for clinicians and researchers.During the first year of life, we tracked the onset of infantile spasms, the type and timing of antiepileptic treatments, and the associated response of two age-matched infants with tuberous sclerosis complex. We also employed Capute Scales as a part of a structured neurodevelopmental evaluation to characterize and compare their neurodevelopmental profiles.Infant 1 developed infantile spasms with confirmed hypsarrhythmia at 4 months of age. Treatment with vigabatrin was initiated within 24 hours with near immediate cessation of seizures and no further seizures to date. Expressive language delay was detected at 12 months and treated with speech and/or language therapy. Infant 2 developed complex partial seizures at 1 month. Treatment included levetiracetam, oxcarbazepine, and the ketogenic diet. Vigabatrin was initiated on detection of hypsarrhythmia after 4 months. Intractable epilepsy persists to date. Global developmental delay was evident by 8 months and treated with physical, occupational, and speech and/or language therapy.Many risk factors have been associated with intellectual disability and/or autism in individuals with tuberous sclerosis complex; however, few data are available regarding practical clinical tools for early identification. In our case series, inclusion of the Capute Scales as a part of routine medical care led to the identification of developmental delays in the first 12 months of life and selection of targeted neurodevelopmental interventions. Development of a risk-based assessment using this approach will be the focus of future studies as it may provide a potential window of opportunity for both research and clinical purposes. In research, it may serve as an objective outcome measure. Clinically, this type of assessment has potential for informing clinical treatment decisions and serving as a prognostic indicator of long-term cognitive and psychiatric outcomes.
- Hereditary neurometabolic causes of infantile spasms in 80 children presenting to a tertiary care center. [Journal Article]
- Pediatr Neurol 2014 Sep; 51(3):390-7.
Infantile spasms are a devastating infantile epileptic syndrome with multiple etiologies. Hereditary neurometabolic disorders are rarely recognized causes of infantile spasms. The aim of this study was to identify hereditary neurometabolic disorders when they were the cause of infantile spasms in patients presenting to a tertiary care center in Saudi Arabia.We conducted a retrospective review of children presenting to the Pediatric Department of King Abdulaziz Medical City in Riyadh, Saudi Arabia over a 15-year interval.Eighty patients with infantile spasms were identified. A hereditary neurometabolic disorder was diagnosed in 10 patients (12.5%). Of these patients, two had a Leigh-like disorder and one patient had each of the following diagnoses: ethylmalonic aciduria, nonketotic hyperglycinemia, hyperinsulinemic hypoglycemia, leukodystrophy, short-chain acyl-coenzyme A dehydrogenase deficiency, molybdenum cofactor deficiency, primary carnitine deficiency, and neonatal hypoglycemia due to panhypopituitarism. This article is the first to report the association of the last three conditions with infantile spasms. Compared with the other etiologies, the hereditary neurometabolic disorder group had a strong history of similar disease in the same family (P = 0.002), and most of the patients were born of consanguineous parents (P = 0.021). In addition, a typical hypsarrhythmia pattern was more common in the hereditary neurometabolic disorder group (P = 0.003). Furthermore, this group had a poor response to therapy (P = 0.04). Otherwise, there were no significant differences regarding the type of spasms, neuroimaging or outcome; however, there was a trend toward poorer outcomes and death in the hereditary neurometabolic disorder group.Hereditary neurometabolic disorders are relatively common causes of infantile spasms in this subpopulation of Saudi patients. An early diagnosis via proper metabolic and genetic testing has significant implications for applying specific treatments and for facilitating proper family counseling.
- Efficacy of long term weekly ACTH therapy for intractable epilepsy. [JOURNAL ARTICLE]
- Brain Dev 2014 Aug 19.
Background: Adrenocorticotropic hormone (ACTH) therapy is the first-line therapy for infantile spasms, and is effective for many other intractable epilepsies. While spasms may respond to ACTH for weeks, a substantial proportion of patients develop recurrent seizures over a yearly period. To maintain efficacy, we treated two children with intractable epilepsy with weekly ACTH therapy for 1year and described the changes in clinical seizures, electroencephalograms, developmental assessments and side effects. Subjects and methods: A girl with infantile spasms due to lissencephaly and a boy with atypical absence seizures were studied. In both cases, seizures were frequent and resistant to antiepileptic drugs; electroencephalograms showed continuous epileptiform activities, and the patients' development was delayed and stagnant prior to ACTH treatment. The initial ACTH therapy (daily 0.015mg/kg for 2weeks, 0.015mg/kg every 2days for 1week, 0.0075mg/kg every 2days for 1week), was transiently effective in both cases. The second-round ACTH therapy consisted of the initial ACTH therapy protocol followed by weekly ACTH injections (0.015mg/kg or 0.0075mg/kg) for 1year. Both cases were followed for at least 1year after therapy. Results: In both patients, clinical seizures were completely controlled during and 1year after the second-round AHCH therapy. Continuous epileptiform discharges disappeared, while intermittent interictal epileptiform discharges remained. Both patients showed some developmental gains after achieving seizure control. No serious side effects were recorded. Conclusion: Further studies are warranted to determine if a long-term weekly ACTH is a safe and effective treatment for intractable epilepsy.