Stefan Spinty

Migrating partial seizures of infancy: expansion of the electroclinical, radiological and pathological disease spectrum

Migrating partial seizures of infancy, also known as epilepsy of infancy with migrating focal seizures, is a rare early infantile epileptic encephalopathy with poor prognosis, presenting with focal seizures in the first year of life. A national surveillance study was undertaken in conjunction with the British Paediatric Neurology Surveillance Unit to further define the clinical, pathological and molecular genetic features of this disorder. Fourteen children with migrating partial seizures of infancy were reported during the 2 year study period (estimated prevalence 0.11 per 100,000 children). The study has revealed that migrating partial seizures of infancy is associated with an expanded spectrum of clinical features (including severe gut dysmotility and a movement disorder) and electrographic features including hypsarrhythmia (associated with infantile spasms) and burst suppression. We also report novel brain imaging findings including delayed myelination with white matter hyperintensity on brain magnetic resonance imaging in one-third of the cohort, and decreased N-acetyl aspartate on magnetic resonance spectroscopy. Putaminal atrophy (on both magnetic resonance imaging and at post-mortem) was evident in one patient. Additional neuropathological findings included bilateral hippocampal gliosis and neuronal loss in two patients who had post-mortem examinations. Within this cohort, we identified two patients with mutations in the newly discovered KCNT1 gene. Comparative genomic hybridization array, SCN1A testing and genetic testing for other currently known early infantile epileptic encephalopathy genes (including PLCB1 and SLC25A22) was non-informative for the rest of the cohort.

Safety, Tolerability, and Pharmacokinetics of SMT C1100, a 2-Arylbenzoxazole Utrophin Modulator, following Single- and Multiple-Dose Administration to Pediatric Patients with Duchenne Muscular Dystrophy

Purpose SMT C1100 is a utrophin modulator being evaluated as a treatment for Duchenne muscular dystrophy (DMD). This study, the first in pediatric DMD patients, reports the safety, tolerability and PK parameters of single and multiple doses of SMT C1100, as well as analyze potential biomarkers of muscle damage. Methods This multicenter, Phase 1 study enrolled 12 patients, divided equally into three groups (A–C). Group A were given 50 mg/kg on Days 1 and 11, and 50 mg/kg bid on Days 2 to 10. Group B and C received 100 mg/kg on Days 1 and 11; Group B and Group C were given 100 mg/kg bid and 100 mg/kg tid, respectively, on Days 2 to 10. A safety review was performed on all patients following the single dose and there was at least 2 weeks between each dose escalation, for safety and PK review. Adverse events (AEs) were monitored throughout the study. Results Most patients experienced mild AEs and there were no serious AEs. Two patients required analgesia for pain (headache, ear pain and toothache). One patient experienced moderate psychiatric AEs (abnormal behaviour and mood swings). Plasma concentrations of SMT C1100 at Days 1 and 11 indicated a high degree of patient variability regardless of dose. Unexpectedly the SMT C1100 levels were significantly lower than similar doses administered to healthy volunteers in an earlier clinical study. In general, individual baseline changes of creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase levels fell with SMT C1100 dosing. Conclusions SMT C1100 was well tolerated in pediatric DMD patients. Trial Registration ClinicalTrials.gov NCT02383511

An investigation into the relationship between vigabatrin, movement disorders, and brain magnetic resonance imaging abnormalities in children with infantile spasms

We aimed to investigate the relationship between movement disorders, changes on brain magnetic resonance imaging (MRI), and vigabatrin therapy in children with infantile spasms.

Developing standardized corticosteroid treatment for Duchenne muscular dystrophy

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

Phenytoin dosing and serum concentrations in paediatric patients requiring 20 mg/kg intravenous loading

Introduction Phenytoin has complex pharmacokinetics. The intravenous loading dose of phenytoin for children in status epilepticus has recently been increased from 18 to 20 mg/kg. There are no data on the clinical effectiveness and safety of this new dose. Methods The use of intravenous loading doses of phenytoin was audited over 27 months to evaluate the pharmacokinetic, clinical and toxic effects of the new dose in clinical practice. Serum phenytoin concentrations were compared with dose (weight-adjusted) and time. Results Serum phenytoin concentrations were measured on 48 occasions from 41 children (39 retrospective and 9 prospective), of which 24 were within 60–180 (median 105) minutes following completion of infusion of the loading dose. Use of estimated weights meant patients received between 15.5 and 27.5 mg/kg (78% to 138% expected dose). Supra-therapeutic serum concentrations >20 µg/mL were present in 5/24 (20.1%) (after doses based on actual weight in three and estimated weight in two patients). Three adverse effects consistent with phenytoin toxicity were noted in children with supra-therapeutic concentrations. Two errors in dose prescriptions were found. Conclusions The majority of serum phenytoin concentrations were in the therapeutic range. Estimating weight in children for the 20 mg/kg intravenous loading dose of phenytoin is often clinically necessary but inaccurate, resulting in up to 138% of the expected and recommended dose in this cohort.

Clinical reasoning: a case of acute onset bilateral ptosis in a young child.

A 5-year-old boy presented with acute onset bilateral ptosis. An initial unilateral ptosis had evolved over the preceding 3 days, following a resolved pyrexial upper respiratory tract illness (URI) treated with oral penicillin. His mother reported that recently he was unable to walk half a mile to school, but had no difficulty with stairs. There was no history of ocular pain, vomiting, headaches, weight loss, dysphagia, constipation, or urinary disturbance. The ptosis was reported not to fluctuate, with no reported tearing, photophobia, or visual disturbance. His prior development was normal, and there was no family history of relevant neuromuscular or autoimmune disorders. On examination he was alert and apyrexial, without rash or lymphadenopathy. His systemic examination was unremarkable aside from enlarged noninflamed tonsils. He had bilateral ptosis obscuring the visual axis: marginal reflex distances were −3 mm and −2 mm on the left and right, respectively. There was no conjunctival injection or tearing. Pupil sizes were 4 mm, equal, and reacted briskly to light and accommodation without relative afferent pupillary defect. Fundus examination was normal. There was full range and no fatigability of extraocular movements. Cover test findings were equivocal: a subtle left esophoria at near, and small (8 D) esotropia with horizontal diplopia at distance. Forced eye closure was normal without eyelid myotonia. Other cranial nerve examination was normal including facial sensation, bulbar strength, and gag reflex. He had normal muscle bulk, tone, and active muscle …

The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy

Objective With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids. Methods Through the NorthStar Network, standardised clinical data including the NorthStar Ambulatory Assessment score (NSAA) on 513 ambulant UK boys with DMD were analysed from 2004 to 2012. For the analysis of the genetic subpopulation, we also included data from 172 Italian boys with DMD. NSAA raw scores were converted into linear scores. Results On the linearised NSAA, we observed an average decline of 8 units/year (4 units on raw NSAA analysis) after age 7. The median age at loss of ambulation (LOA) was 13 years (95% CI 12.1 to 13.5); 2 years prior to LOA, the estimated mean linearised NSAA score was 42/100 (13/34 raw scale). Starting glucocorticoids between 3 and 5 years conferred an additional gain in motor function of 3 units/year (1.3 raw units) up to age 7. When analysing the effect of genotype in the UK and Italian cumulative cohorts, individuals with deletions amenable to exons 44 and 46 skipping declined at a slower rate over 2 years (9 units (4 raw units), p<0.001), while 53 and 51 skippable deletions showed a faster decline of 14 (4.5; p<0.001) and 5 linearised units (2.4 NSAA units; p=0.02), respectively. Conclusions Our study provides a novel insight on the current natural history of DMD, which will be instrumental for the design of future clinical trials.