Sarah E. Buerki

Incidence and Outcomes of Symptomatic Neonatal Arterial Ischemic Stroke

BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. METHODS: This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. RESULTS: One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11–17) per 100 000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. CONCLUSIONS: NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.

Neuroimaging in childhood arterial ischaemic stroke: evaluation of imaging modalities and aetiologies

Aim  The aim of this study was to describe neuroimaging patterns associated with arterial ischaemic stroke (AIS) in childhood and to differentiate them according to stroke aetiology.

Retrospective evaluation of low long-term efficacy of antiepileptic drugs and ketogenic diet in 39 patients with CDKL5-related epilepsy

OBJECTIVE Mutations in the CDKL5 gene cause an early-onset epileptic encephalopathy. To date, little is known about effective antiepileptic treatment in this disorder. METHOD Accordingly, the aim of this retrospective study was to explore the role of different antiepileptic drugs (AEDs) and the ketogenic diet (KD) in the treatment of this rare genetic disorder. We evaluated the efficacy in 39 patients with CDKL5 mutations at 3, 6 and 12 months after the introduction of each treatment. One patient was lost to follow-up after 6 and 12 months. RESULTS The responder rate (>50% reduction in seizure frequency) to at least one AED or KD was 69% (27/39) after 3 months, 45% (17/38) after 6 months and 24% (9/38) after 12 months. The highest rate of seizure reduction after 3 months was reported for FBM (3/3), VGB (8/25), CLB (4/17), VPA (7/34), steroids (5/26), LTG (5/23) and ZNS (2/11). Twelve patients (31%) experienced a seizure aggravation to at least one AED. Most patients showed some but only initial response to various AEDs with different modes of actions. SIGNIFICANCE Considering both age-related and spontaneous fluctuation in seizure frequency and the unknown impact of many AEDs or KD on cognition, our data may help defining realistic treatment goals and avoiding overtreatment in patients with CDKL5 mutations. There is a strong need to develop new treatment strategies for patients with this rare mutation.

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.

De novo FGF12 mutation in 2 patients with neonatal-onset epilepsy.

Objective: We describe 2 additional patients with early-onset epilepsy with a de novo FGF12 mutation. Methods: Whole-exome sequencing was performed in 2 unrelated patients with early-onset epilepsy and their unaffected parents. Genetic variants were assessed by comparative trio analysis. Clinical evolution, EEG, and neuroimaging are described. The phenotype and response to treatment was reviewed and compared to affected siblings in the original report. Results: We identified the same FGF12 de novo mutation reported previously (c.G155A, p.R52H) in 2 additional patients with early-onset epilepsy. Similar to the original brothers described, both presented with tonic seizures in the first month of life. In the first patient, seizures responded to sodium channel blockers and her development was normal at 11 months. Patient 2 is a 15-year-old girl with treatment-resistant focal epilepsy, moderate intellectual disability, and autism. Carbamazepine (sodium channel blocker) was tried later in her course but not continued due to an allergic reaction. Conclusions: The identification of a recurrent de novo mutation in 2 additional unrelated probands with early-onset epilepsy supports the role of FGF12 p.R52H in disease pathogenesis. Affected carriers presented with similar early clinical phenotypes; however, this report expands the phenotype associated with this mutation which contrasts with the progressive course and early mortality of the siblings in the original report.

Coexistent childhood renovascular and cerebrovascular disease

Paroxysmal dyskinesias constitute a group of episode movement disorders that have been historically classified based on precipitant, duration, and family history. Careful description of phenotypes has shown that classification based on precipitant is the most powerful for predicting features and clinical course. The three major groups are: (1) kinesigenic – triggered by sudden movement; (2) exertional – triggered by sustained exertion; (3) non-kinesigenic – no discrete trigger but with attacks often following ingestion of ethanol or caffeine, or after sleep deprivation. All three forms can exist as primary disorders or may be secondary to specific brain lesions. The primary forms typically begin in childhood and are not associated with neurologic abnormalities between episodes. Several causative genes have been described, but the major gene responsible for paroxysmal kinesigenic dyskinesia (PKD) has been elusive until recently. Silveira-Moriyama et al. describe the clinical features of children with PKD and PRRT2 gene mutations. Since discovery of the association between PRRT2 mutations and PKD, there has been substantial progress in further defining the phenotypic spectrum of these mutations. Mutations in the PRRT2 gene may cause PKD, infantile convulsions, or familial hemiplegic migraine. PRRT2 mutations may also cause episodic ataxia or febrile seizures. In addition to contributions toward better understanding of the disorder and its prognosis, the findings of SilvieraMoriyama et al. raise important conceptual questions about the pathophysiology of paroxysmal disorders. Early reports of paroxysmal dyskinesias raised the question of whether they might be a form of epilepsy, yet surface electroencephalography is normal during attacks. By convention, seizures are viewed as cortical phenomena due to the paroxysmal discharge of neurons. However, it is reasonable to hypothesize that paroxysmal dyskinesias are due to paroxysmal discharge of subcortical neurons. Supporting this notion is the exquisite clinical response of PKD to low doses of anticonvulsant medications such as carbamazepine or phenytoin. Can some forms of hemiplegic migraine also result from paroxysmal neuronal discharge? Or can PRRT2 mutations lead to paroxysmal of neuronal depression? Further study of neuronal function in the setting of PRRT2 mutations is likely to shed light on the pathophysiology of many paroxysmal disorders including seizures, migraine, paroxysmal movement disorders, and paroxysmal ataxia.

A.01 Targeted analysis of whole exome sequencing and genotype-phenotype correlation in epileptic encephalopathies

SE Buerki (Vancouver) EB Toyota (Vancouver) I Guella (Vancouver) M McKenzie (Vancouver) D Evans (Vancouver) S Adam (Vancouver) MI van Allen (Vancouver) C Boelman (Vancouver) G Horvath (Vancouver) CD Van Karnebeek (Vancouver) P Eydoux (Vancouver) L Huh (Vancouver) A Datta (Vancouver) KA Selby (Vancouver) A Michoulas (Vancouver) TN Nelson (Vancouver) MJ Farrer (Vancouver) MB Demos (Vancouver)* MB Connolly (Vancouver)*

MG-127 Diagnostic accuracy of chromosome microarray in children with epilepsy and neurological abnormalities of unknown aetiology

Background Chromosome MicroArray-based genomic copy-number analysis (CMA) has an important role in the discovery of both novel and recurrent epilepsy-associated copy number variants (CNVs) in patients with epilepsy. In case of an additional neuro-developmental disorder the diagnostic accuracy may be as high as 15%. Objectives The purpose of this study is to describe the results of performed CMA on 706 children with unexplained epilepsy associated with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies (‘epilepsy plus’). Design/method Retrospective chart review on clinical and genetic aspects of CNVs identified in 706 patients with ‘epilepsy plus’, seen at the Vancouver BC Children’s Hospital from 2009 to 2014. All patients had CMA performed using Affymetrix Genome-Wide Human SNP Array 6.0 or CytoScanHD®. Results Abnormal CMA results were identified in 191 out of 706 children with ‘epilepsy plus’. 122/706 (17.3%) patients had variants of unknown significance (VUS), and 80/706 (11.3%) patients had pathogenic CNVs. This group included 19 patients that had CNVs in genomic “hotspots” predisposing to epilepsy, including 1q21.1 (n = 1), 15q11.2 (n = 2), 15q13.3 (n = 4), 15q11-q13 (n = 3), 16p11.2 (n = 1046), and 16p13.11 (n = 3). Among other known microdeletion/microduplication syndromes (n = 20) was 22q13.3 deletion (Phelan-McDermid Syndrome) (n = 4). One of the four 22q13.3 deletion patients had treatment resistant epilepsy and a small deletion (47kb) of the SHANK3 gene. Conclusions CMA revealed pathogenic CNVs in epilepsy “hotspots”, and known microdeletion syndromes like Phelan-McDermid syndrome in 11.3% of children with ‘epilepsy plus’. Examination of CNVs also plays an important role in the identification of possible epilepsy genes i.g. SHANK3 mutations in patients with 22q13.3 deletions.

The importance of cerebral magnetic resonance imaging in evaluation of neonatal seizures

Complex environmental factors feed into eventual outcomes following ABI. Future research using the methodologies demonstrated by Kelly et al. should, in my opinion, focus on these variables, creating research projects exploring the effects of focused interventions on this broader environmental process. It is likely that this approach will yield optimal outcomes for the child and his or her family.