Patricia K. Crumrine

De novo mutations in epileptic encephalopathies

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders.

Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

BACKGROUND Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. METHODS We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. FINDINGS We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7-3·2, p=9·1 × 10-8; familial non-acquired focal epilepsy 3·6, 2·7-4·9, p=1·1 × 10-17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10-8) that were lower than expected from a random sampling of genes. INTERPRETATION We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. FUNDING National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Management of seizures in Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is an epilepsy syndrome that begins in childhood (between 1 and 8 years of age), worsens during latency and persists frequently into adulthood, is refractory to antiepileptic medications, and results in cognitive decline and behavioral problems in affected individuals. Seizure types consist primarily of axial tonic, atonic, and atypical absence; nocturnal tonic seizures are the most common seizure pattern in this population, but often are not one of the initial seizure patterns. Some patients also have myoclonic seizures; this seizure pattern is less frequent than the three preceding types. Although there are some cases that are cryptogenic, most are symptomatic, arising during prenatal and perinatal periods from intrauterine infections, and vascular insults to the brain. Examples of causes of Lennox-Gastaut syndrome include migrational abnormalities of the brain, late effects of CNS infections, certain genetic disorders such as tuberous sclerosis, and inherited metabolic disorders. The difficulty early in the course of Lennox-Gastaut syndrome is distinguishing this diagnosis from severe myoclonic epilepsy of infancy (Dravet syndrome) or from myoclonic-astatic epilepsy (Doose syndrome), as the seizure patterns in these three syndromes may overlap at the onset. EEG is a helpful diagnostic tool in the diagnosis of Lennox-Gastaut syndrome, usually demonstrating high voltage, bifrontal 1.5–2.5 Hz spike and wave complexes interictally, and attenuation with paroxysmal fast activity (10–13 Hz) during the ictal phase.Treatment options for Lennox-Gastaut syndrome have been less than optimal. In recent years, several drugs have been tested and approved for the treatment of this syndrome; these include felbamate, lamotrigine, topiramate, and rufinamide. The long-term outcome does not appear to be any better with the newer antiepileptic drugs than when using earlier prescribed antiepileptic drugs or polytherapy. Treatment options other than antiepileptic drugs include a ketogenic diet, vagus nerve stimulation, and corpus callosotomy. Long-term outcome of these patients relative to seizure control and cognition is poor. Most develop moderate intellectual disability within a few years of onset of the syndrome. Many develop behavioral problems with inattention, hyperactivity, and aggression.

Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy

Infantile spasms (IS) and Lennox–Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome‐predicted CNVs by array‐based methods is still required due to false‐positive rates of prediction algorithms. Our exome‐based results are consistent with recent array‐based studies in similar cohorts and highlight novel candidate genes for IS and LGS. Ann Neurol 2015;78:323–328

Trends in American Board of Psychiatry and Neurology specialties and neurologic subspecialties

Objective: To review the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) specialties and neurologic subspecialties and discuss the implications of those trends for subspecialty viability. Methods: Data on numbers of residency and fellowship programs and graduates and ABPN certification candidates and diplomates were drawn from several sources, including ABPN records, Web sites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of the Journal of the American Medical Association. Results: About four-fifths of neurology graduates pursue fellowship training. While most recent neurology and child neurology graduates attempt to become certified by the ABPN, many clinical neurophysiologists elect not to do so. There appears to have been little interest in establishing fellowships in neurodevelopmental disabilities. The pass rate for fellowship graduates is equivalent to that for the “grandfathers” in clinical neurophysiology. Lower percentages of clinical neurophysiologists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high. Conclusion: The initial enthusiastic interest in training and certification in some of the ABPN neurologic subspecialties appears to have slowed, and the long-term viability of those subspecialties will depend upon the answers to a number of complicated social, economic, and political questions in the new health care era.

Antiepileptic Drug Selection in Pediatric Epilepsy

This review article presents information concerning treatment options for various pediatric epilepsy syndromes. The decisions made in the selection of antiepileptic drugs are determined by a number of variables that include, but are exclusive of, risk of seizure recurrence, patient age, epilepsy syndrome, known drug reactions, and prognosis of the epilepsy syndrome. The review discusses issues pertinent to antiepileptic drug selection including simple pharmacokinetic principles, antiepileptic drug formulations, and information concerning clinical studies using some of the antiepileptic drugs. Information is provided concerning the issues of seizure recurrence. Suggested paradigms for antiepileptic drug selection for partial seizures are provided. A table of antiepileptic drug costs is provided for assistance in prescribing and advising families. Psychosocial issues pertinent to the treatment of children are discussed. (J Child Neurol 2002;17:2S2—2S8).

Childhood oligodendrogliomas presenting with seizures and low‐density lesions on computed tomography

Three children with cerebral oligodendrogliomas causing partial complex or generalized seizures presented with completely normal neurologic examinations. CT showed low-density, nonenhancing surface lesions. Although these CT features are usually associated with infarcts or cysts, neoplasm was suspected because of irregularity of the margins and erosion of the adjacent inner table of the skull. Oligodendrogliomas often enlarge slowly and may cause seizures years before they produce focal neurologic signs. CT of all children with seizures not responsive to anticonvulsant medication and focal clinical or EEG abnormalities will hasten diagnosis of slowly growing intracranial mass lesions.

The Ketogenic Diet: The Need for a Multidisciplinary Approach

FOR APPROXIMATELY 80% of patients with epilepsy, available pharmacologic treatment results in the desired control of seizures with tolerable adverse effects.1 However, for patients with epilepsy refractory to drug therapy, other therapies such as surgery,1 the ketogenic diet,2-4 and the vagus nerve stimulator may be selected as therapeutic options. Therapies that have been used, but not tested using scientific paradigms, include intravenous immune globulin2 and the ketogenic diet. Of these, the most controversial therapy has been the ketogenic diet, which has been both advocated and criticized since first reported by Wilder in 1921; it is now described by Tallian et al. in their comprehensive review. There have been no controlled trials of this therapy3: there is a study under way at one medical center. The efficacy of the ketogenic diet is founded in case series4 and in the testimonials of patients, families, and physicians who have recorded sometimes dramatic and remarkable patient progress. Potential benefits include reduction and eventual elimination of antiepileptic medications and subjective improvement in alertness and behavior.3 Without scientifically rigorous trials, no firm conclusions can be made regarding efficacy of the ketogenic diet in comparison with other treatment modalities. The diet has been most beneficial in young children older than 1 year of age, particularly those with “mixed” seizure types, myoclonic seizures, or atonic/akinetic seizures.3 However, any patient with inadequate seizure control despite multidrug combinations of usual or investigational agents may be treated.3 When high-dose antiepileptic drug combinations produce intolerable toxicity, including central nervous system effects limiting social, intellectual, and other neurologic development and/or adversely impacting the quality of life of children, the ketogenic diet may be considered. The ketogenic diet may also be helpful for children who are unlikely to benefit from or are unwilling to undergo surgical modalities for improved seizure control. Although the ketogenic diet may be considered for selected adolescents and adults, concerns regarding efficacy and noncompliance generally preclude its use.3 At this time, the ketogenic diet would rarely be instituted as a “first-line” treatment strategy, no matter how attractive the concept of avoiding antiepileptic agents, in most newly diagnosed patients. There are, however, exceptions to this, as the ketogenic diet may be considered for initial treatment of patients with mitochondrial disorders associated with seizures. How many patients are using the ketogenic diet for management of epilepsy? The numbers in any geographic area are likely to be small; for example, more than 50 children have been followed at the Children’s Hospital of Pittsburgh. Patient numbers have fluctuated over years of use, a reflection of national media interest, scientific publications and presentations by prominent physician advocates, parent focus groups, and now, the availability of on-line computer information through Internet technology. As the medical care of these patients is often focused in tertiary healthcare institutions, pediatric pharmacy specialists in these environments may be initially involved in patient-specific care at the time the diet is initiated. As Tallian et al. highlight, there are important issues of pharmaceutical care that may complement the therapeutic benefit of the ketogenic diet and that may be well-addressed by pharmacists. We advocate a multidisciplinary approach when patients are treated with the ketogenic diet. The importance of the neurologist in overseeing this novel therapy is obvious. The Ketogenic Diet: The Need for a Multidisciplinary Approach

Building a Division of Child Neurology: A Tribute to Michael J. Painter, MD

In this era of changing priorities, regulations, and resources, it is useful to look both back and forward at the building of a division of child neurology in the context of the emergence of child neurology as a nationally and internationally recognized distinct subspecialty of both pediatrics and neurology. Both Pittsburgh and national colleagues of Dr Michael J. Painter were fortunate to have such a glimpse at a Festschrift held in his honor in January 2002 and, more recently, at the October 2002 meeting of Professors of Child Neurology, where he presented his view of “Building a Child Neurology Division the Old-Fashioned Way.” The narrative that follows draws heavily from both of these events and from insights gained from Dr Painters long and broad experience in the establishment and nurturing of both the specialty of child neurology and many of its current practitioners. (J Child Neurol 2003; 18:127—130).

Electroencephalographic Changes in Pediatric Patients following Metrizamide Cisternography

Serial electroencephalograms were obtained over a 24-hour period in 15 children from 3 months to 17 years following metrizamide CT cisternography. Persistent EEG abnormalities were noted in 8 children, 5 of whom were older than 2 years. Bifrontal slowing was a frequent change in the children older than 2 years.