Mary O'Regan

Abnormalities in cardiac and respiratory function observed during seizures in childhood.

The aim of this study was to observe any changes in cardiac and respiratory function that occur during seizures. Thirty‐seven children (20 males, 17 females; median age 7y 6mo, range 1y 6mo to 15y 6mo) were studied. We recorded electroencephalograms, respiratory rate, heart rate, electrocardiograms, blood pressure, oxygen saturation, heart rate variability (time domain analysis), and cardiac vagal tone. A respiratory pause was defined as an interruption in respiration lasting more than 3s but less than 15s. Apnoea was defined as absence of respiration for more than 15s. Tachypnoea was defined as a 10% increase in respiratory rate from the pre‐ictal baseline. Bradypnoea was defined as a 10% decrease in respiratory rate from the pre‐ictal baseline. Significant hypoxia was defined as a saturation of less than 85%. A significant change in heart rate was taken as a 10% increase or decrease below the baseline rate. Data were obtained from 101 seizures: 40 focal seizures, 21 generalized seizures, and 40 absences. Focal seizures were frequently associated with significant respiratory abnormalities, tachypnoea in 56%, apnoea in 30%, frequent respiratory pauses in 70%, and significant hypoxaemia in 40%. The changes seen in respiratory rate were statistically significant. Changes in cardiac parameters, an increase or decrease in heart rate, were observed in only 26% of focal seizures and 48% of generalized seizures. We conclude that seizure activity can disrupt normal physiological regulation and control of respiratory and cardiac activity.

Epileptic aphasia: a consequence of regional hypometabolic encephalopathy?

A series of 25 children, 13 females and 12 males, who had an acquired communication disorder together with epilepsy, but did not fulfil the strict criteria of the Landau‐Kleffner syndrome, was studied. All children had a clinical neurological evaluation, speech and language assessment, an awake and sleep EEG, cranial MRI, SPET scan, and audiometry. Clinical seizures were most often polymorphic in type (17 of 25). Atypical absences were the commonest individual seizure type occurring in 15 cases. All patients had an unequivocal epileptiform EEG. Normal sleep phenomena were only observed in 10 cases, enhancement of epileptiform activity in sleep was seen in 16. Cranial MRI was abnormal in six and normal in 19 cases. The SPET scans were abnormal in 22 of 25 children. The language deficits were classified neurologically as receptive aphasia, 24 of 25; expressive aphasia, 20 of 25; nominal aphasia, eight of 25; articulator dyspraxia, 10 of 25; and auditory agnosia, nine of 25. It is hypothesized that the loss of communication skills is due to an encephalopathy secondary to the persistent epileptic discharge and manifests as a hypometabolic area on the SPET scan.

IS ACTH A KEY TO UNDERSTANDING ANTICONVULSANT ACTION

Adrenocorticotrophin hormone (ACTH) has been used as an anticonvulsant for many years. In this paper, the use of ACTH in 23 children with intractable epilepsies is described. It was found that ACTH worked most effectively when the EEG showed benzodiazepine sensitivity. A mechanism of action of ACTH is proposed.

Genome-wide Polygenic Burden of Rare Deleterious Variants in Sudden Unexpected Death in Epilepsy.

Sudden unexpected death in epilepsy (SUDEP) represents the most severe degree of the spectrum of epilepsy severity and is the commonest cause of epilepsy-related premature mortality. The precise pathophysiology and the genetic architecture of SUDEP remain elusive. Aiming to elucidate the genetic basis of SUDEP, we analysed rare, protein-changing variants from whole-exome sequences of 18 people who died of SUDEP, 87 living people with epilepsy and 1479 non-epilepsy disease controls. Association analysis revealed a significantly increased genome-wide polygenic burden per individual in the SUDEP cohort when compared to epilepsy (P = 5.7 × 10− 3) and non-epilepsy disease controls (P = 1.2 × 10− 3). The polygenic burden was driven both by the number of variants per individual, and over-representation of variants likely to be deleterious in the SUDEP cohort. As determined by this study, more than a thousand genes contribute to the observed polygenic burden within the framework of this study. Subsequent gene-based association analysis revealed five possible candidate genes significantly associated with SUDEP or epilepsy, but no one single gene emerges as common to the SUDEP cases. Our findings provide further evidence for a genetic susceptibility to SUDEP, and suggest an extensive polygenic contribution to SUDEP causation. Thus, an overall increased burden of deleterious variants in a highly polygenic background might be important in rendering a given individual more susceptible to SUDEP. Our findings suggest that exome sequencing in people with epilepsy might eventually contribute to generating SUDEP risk estimates, promoting stratified medicine in epilepsy, with the eventual aim of reducing an individual patients risk of SUDEP.

Electro-clinical phenotypes of chromosome disorders associated with epilepsy in the absence of dysmorphism.

Chromosome imbalances are associated with epilepsy but electro-clinical phenotypes are lacking for all but the best-known syndromes. Scanty information is contained in older case reports published in genetics journals that describe children with severe patterns of malformation and dysmorphism. From a larger series of children with chromosome abnormalities and epilepsy, we identified 10 patients with associated dysmorphism without malformation. Electro-clinical features are described for each patient. We found that these patients are at greater risk of delayed diagnosis, particularly when there are no learning difficulties at the onset of epilepsy, as in ring chromosome 20 syndrome. Chromosome studies should be ordered on all children with learning difficulties and epilepsy, and on children with atypical non-lesional epilepsy, even in the absence of learning difficulties or dysmorphism.

Early Neurodevelopmental Profiles and Family Impact in Newly Diagnosed Epilepsy: Findings from a 3-year Prospective Cohort

proliferative disorders (PTLDs); primary CNS lymphoma (PCNSL). Disclosures: Gandhi, M: Consultant Advisory Role: Celgene, Merck Sharpe & Dohme, Janssen-Cilag, Gilead, Bristol Myers Squibb; Honoraria: Amgen, Janssen-Cilag, Gilead, Roche, Merck Sharpe & Dohme, Takeda; Research Funding: Celgene, Bristol Myers Squibb, JanssenCilag, Gilead; Other Remuneration: Roche. Tobin, J: Honoraria: Amgen, Janssen – conference attendance 2017. Trappe, R: Consultant Advisory Role: Abbvie, Atara; Research Funding: Hoffmann-La Roche; Other Remuneration: Travel support from Celgene, Janssen, Gildead, Abbvie. Blyth, E: Consultant Advisory Role: Abbvie, MSD, Novartis. Wight, J: Honoraria: Janssen, Alexion. Keane, C: Consultant Advisory Role: Celgene, Gilead, MSD; Other Remuneration: Roche (Conference Travel).

Aetiology, Treatment and Outcome of Electrical Status Epilepticus in Sleep

Background: Congenital muscular dystrophies (CMD) are subdivided into forms with severe structural brain involvement (Fukuyama CMD, Muscle-Eye-Brain Disease, WalkerWarburg syndrome) and those without (merosin deficient CMD; Ullrich CMD; CMD with rigidity of the spine; MDClB and MDClC). The three forms with structural brain involvement are secondary to mutations in glycosyltransferases and have in common a marked secondary deficiency of a-dystroglycan, a likely substrate for these enzymes. MDClC is also due to mutations in a glycosyltransferase (fukutin-relatedprotein gene, FKRP) and by a secondary a-dystroglycan deficiency but CNS involvement has never been observed. Objectives: In order to establish i fFKRP gene mutations can also involve the brain, we studied this gene in three families with severe brain involvement. Method: We studied three unrelated patients who had, in addition to a pattern of muscle involvement identical to MDClC, severe learning disability and structural brain involvement. This was characterized by cerebellar cysts in two patients, and by cerebellar cysts, Dandy Walker variant, and pachygyria in a third patient, who in addition had high myopia and bilateral ablatio retinae. Results: Analysis of theFKRP gene demonstrated in each case novel homozygous mutations (C663A leading to Ser22 lArg and C98lA, leading to Pro315Thr in the 2 patients with cerebellar cysts; and T919A leading to T)~307Asp in the 3rd patient). Muscle biopsy studies showed severe dystrophic findings along with a profound depletion of a-dystroglycan. Conclusions: Mutations within the FKRP gene can result in not only MDC 1C but also in variants with associated learning disability, cerebellar cysts, pachygyria and myopia, therefore resembling MEB disease. This adds structural brain defects to the already wide spectrum of abnormalities caused by FKRP mutations. The constant finding of a severe depletion of a-dystroglycan expression reinforces the view that FKRP is involved in the processing of a-dystroglycan.