Mary B. Connolly

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self‐limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

Pyridoxine dependent epilepsy and antiquitin deficiency Clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up

Antiquitin (ATQ) deficiency is the main cause of pyridoxine dependent epilepsy characterized by early onset epileptic encephalopathy responsive to large dosages of pyridoxine. Despite seizure control most patients have intellectual disability. Folinic acid responsive seizures (FARS) are genetically identical to ATQ deficiency. ATQ functions as an aldehyde dehydrogenase (ALDH7A1) in the lysine degradation pathway. Its deficiency results in accumulation of α-aminoadipic semialdehyde (AASA), piperideine-6-carboxylate (P6C) and pipecolic acid, which serve as diagnostic markers in urine, plasma, and CSF. To interrupt seizures a dose of 100 mg of pyridoxine-HCl is given intravenously, or orally/enterally with 30 mg/kg/day. First administration may result in respiratory arrest in responders, and thus treatment should be performed with support of respiratory management. To make sure that late and masked response is not missed, treatment with oral/enteral pyridoxine should be continued until ATQ deficiency is excluded by negative biochemical or genetic testing. Long-term treatment dosages vary between 15 and 30 mg/kg/day in infants or up to 200 mg/day in neonates, and 500 mg/day in adults. Oral or enteral pyridoxal phosphate (PLP), up to 30 mg/kg/day can be given alternatively. Prenatal treatment with maternal pyridoxine supplementation possibly improves outcome. PDE is an organic aciduria caused by a deficiency in the catabolic breakdown of lysine. A lysine restricted diet might address the potential toxicity of accumulating αAASA, P6C and pipecolic acid. A multicenter study on long term outcomes is needed to document potential benefits of this additional treatment. The differential diagnosis of pyridoxine or PLP responsive seizure disorders includes PLP-responsive epileptic encephalopathy due to PNPO deficiency, neonatal/infantile hypophosphatasia (TNSALP deficiency), familial hyperphosphatasia (PIGV deficiency), as well as yet unidentified conditions and nutritional vitamin B6 deficiency. Commencing treatment with PLP will not delay treatment in patients with pyridox(am)ine phosphate oxidase (PNPO) deficiency who are responsive to PLP only.

ADHD, neurological correlates and health-related quality of life in severe pediatric epilepsy.

Summary:  Purpose: ADHD is reported as a frequent comorbidity in pediatric epilepsy. We aimed to clarify the prevalence of ADHD, its neurological correlates and the role of ADHD in health‐related quality of life (HRQOL) in children with severe epilepsy.

Hemispheric Surgery in Children with Refractory Epilepsy: Seizure Outcome, Complications, and Adaptive Function

Summary:  Purpose: To describe seizure control, complications, adaptive function and language skills following hemispheric surgery for epilepsy.

Exome Sequencing and the Management of Neurometabolic Disorders

BACKGROUND Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. METHODS To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patients clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. RESULTS We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%). CONCLUSIONS Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Childrens Hospital Foundation and others.).

Electroclinical features of absence seizures in childhood absence epilepsy

Objective: To accurately define the electroclinical features of absence seizures in children with newly diagnosed, untreated childhood absence epilepsy (CAE). Methods: The authors searched an EEG database for absence seizures in normal children with new onset untreated absence epilepsy. Seventy consecutive children were classified into IGE syndromes. The clinical and EEG features of the seizures in the children with CAE were analyzed using video-EEG recordings. Results: The authors analyzed 339 absence seizures in 47 children with CAE. The average seizure duration was 9.4 seconds and clinical features consisted of arrest of activity, loss of awareness, staring, and 3-Hz eyelid movements, but there was individual variation. Ictal EEG predominantly showed regular 3-Hz generalized spike and wave (GSW) with one or two spikes per wave; however, disorganization of discharges was common and three or more spikes per wave occurred rarely. Postictal slowing was frequent. Interictal abnormalities included fragments of GSW, posterior bilateral delta activity, and focal discharges. Although all 47 children met the current criteria for CAE, only 5 fulfilled the recently proposed criteria for CAE. Conclusion: The heterogeneous nature of each clinical and EEG feature of untreated absence seizures is of critical importance when determining criteria for childhood absence epilepsy.

Recommendations for HLA‐B*15:02 and HLA‐A*31:01 genetic testing to reduce the risk of carbamazepine‐induced hypersensitivity reactions

To systematically review evidence on genetic risk factors for carbamazepine (CBZ)–induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA‐B*15:02 and HLA‐A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ‐induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA‐B*15:02 or HLA‐A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?

Surgical outcome in tuberous sclerosis complex: a multicenter survey.

Summary:  Multicenter, retrospective analysis of 70 subjects with TSC following surgery for relief of epilepsy revealed significant associations between younger age at seizure onset, present/prior history of infantile spasms, interictal focality (bilateral versus unilateral), and absence of residual postoperative predominant tuber, and poorer postoperative outcome (p < 0.01). Ictal multifocality, mental retardation, and discordant EEG and MRI data showed a negative trend toward outcome, but were not significant.

Lysine restricted diet for pyridoxine-dependent epilepsy: First evidence and future trials

OBJECTIVE To evaluate the efficacy and safety of dietary lysine restriction as an adjunct to pyridoxine therapy on biochemical parameters, seizure control, and developmental/cognitive outcomes in children with pyridoxine-dependent epilepsy (PDE) caused by antiquitin (ATQ) deficiency. METHODS In this observational study, seven children with confirmed ATQ deficiency were started on dietary lysine restriction with regular nutritional monitoring. Biochemical outcomes were evaluated using pipecolic acid and α-aminoadipic semialdehyde (AASA) levels in body fluids; developmental/cognitive outcomes were evaluated using age-appropriate tests and parental observations. RESULTS Lysine restriction was well tolerated with good compliance; no adverse events were reported. Reduction in biomarker levels (measurement of the last value before and first value after initiation of dietary lysine restriction) ranged from 20 to 67% for plasma pipecolic acid, 13 to 72% for urinary AASA, 45% for plasma AASA and 42% for plasma P6C. For the 1 patient in whom data were available and who showed clinical deterioration upon interruption of diet, cerebrospinal fluid levels decreased by 87.2% for pipecolic acid and 81.7% for AASA. Improvement in age-appropriate skills was observed in 4 out of 5 patients showing pre-diet delays, and seizure control was maintained or improved in 6 out 7 children. CONCLUSIONS This observational study provides Level 4 evidence that lysine restriction is well tolerated with significant decrease of potentially neurotoxic biomarkers in different body compartments, and with the potential to improve developmental outcomes in children with PDE caused by ATQ deficiency. To generate a strong level of evidence before this potentially burdensome dietary therapy becomes the mainstay treatment, we have established: an international PDE consortium to conduct future studies with an all-inclusive integrated study design; a website containing up-to-date information on PDE; a methodological toolbox; and an online registry to facilitate the participation of interested physicians, scientists, and families in PDE research.

Surgical Resection for Intractable Epilepsy in “Double Cortex” Syndrome Yields Inadequate Results

PURPOSE To analyze the results of surgical treatment of intractable epilepsy in patients with subcortical band heterotopia, or double cortex syndrome, a diffuse neuronal migration disorder. METHODS We studied eight patients (five women) with double cortex syndrome and intractable epilepsy. All had a comprehensive presurgical evaluation including prolonged video-EEG recordings and magnetic resonance imaging (MRI). RESULTS All patients had partial seizures, with secondary generalization in six of them. Neurologic examination was normal in all. Three were of normal intelligence, and five were mildly retarded. Six patients underwent invasive EEG recordings, three of them with subdural grids and three with stereotactic implanted depth electrodes (SEEG). Although EEG recordings showed multilobar epileptic abnormalities in most patients, regional or focal seizure onset was recorded in all. MRI showed bilateral subcortical band heterotopia, asymmetric in thickness in three. An additional area of cortical thickening in the left frontal lobe was found in one patient. Surgical procedures included multiple subpial transections in two patients, frontal lesionectomy in one, temporal lobectomy with amygdalohippocampectomy in five, and an additional anterior callosotomy in one. Five patients had no significant improvement, two had some improvement, and one was greatly improved. CONCLUSION Our results do not support focal surgical removal of epileptogenic tissue in patients with double cortex syndrome, even in the presence of a relatively localized epileptogenic area.