Michael C. Smith

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.

A physical map of the mouse genome

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human–mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.

Magnetoencephalographic patterns of epileptiform activity in children with regressive autism spectrum disorders

Background. One-third of children diagnosed with autism spectrum disorders (ASDs) are reported to have had normal early development followed by an autistic regression between the ages of 2 and 3 years. This clinical profile partly parallels that seen in Landau-Kleffner syndrome (LKS), an acquired language disorder (aphasia) believed to be caused by epileptiform activity. Given the additional observation that one-third of autistic children experience one or more seizures by adolescence, epileptiform activity may play a causal role in some cases of autism. Objective. To compare and contrast patterns of epileptiform activity in children with autistic regressions versus classic LKS to determine if there is neurobiological overlap between these conditions. It was hypothesized that many children with regressive ASDs would show epileptiform activity in a multifocal pattern that includes the same brain regions implicated in LKS. Design. Magnetoencephalography (MEG), a noninvasive method for identifying zones of abnormal brain electrophysiology, was used to evaluate patterns of epileptiform activity during stage III sleep in 6 children with classic LKS and 50 children with regressive ASDs with onset between 20 and 36 months of age (16 with autism and 34 with pervasive developmental disorder–not otherwise specified). Whereas 5 of the 6 children with LKS had been previously diagnosed with complex-partial seizures, a clinical seizure disorder had been diagnosed for only 15 of the 50 ASD children. However, all the children in this study had been reported to occasionally demonstrate unusual behaviors (eg, rapid blinking, holding of the hands to the ears, unprovoked crying episodes, and/or brief staring spells) which, if exhibited by a normal child, might be interpreted as indicative of a subclinical epileptiform condition. MEG data were compared with simultaneously recorded electroencephalography (EEG) data, and with data from previous 1-hour and/or 24-hour clinical EEG, when available. Multiple-dipole, spatiotemporal modeling was used to identify sites of origin and propagation for epileptiform transients. Results. The MEG of all children with LKS showed primary or secondary epileptiform involvement of the left intra/perisylvian region, with all but 1 child showing additional involvement of the right sylvian region. In all cases of LKS, independent epileptiform activity beyond the sylvian region was absent, although propagation of activity to frontal or parietal regions was seen occasionally. MEG identified epileptiform activity in 41 of the 50 (82%) children with ASDs. In contrast, simultaneous EEG revealed epileptiform activity in only 68%. When epileptiform activity was present in the ASDs, the same intra/perisylvian regions seen to be epileptiform in LKS were active in 85% of the cases. Whereas primary activity outside of the sylvian regions was not seen for any of the children with LKS, 75% of the ASD children with epileptiform activity demonstrated additional nonsylvian zones of independent epileptiform activity. Despite the multifocal nature of the epileptiform activity in the ASDs, neurosurgical intervention aimed at control has lead to a reduction of autistic features and improvement in language skills in 12 of 18 cases. Conclusions. This study demonstrates that there is a subset of children with ASDs who demonstrate clinically relevant epileptiform activity during slow-wave sleep, and that this activity may be present even in the absence of a clinical seizure disorder. MEG showed significantly greater sensitivity to this epileptiform activity than simultaneous EEG, 1-hour clinical EEG, and 24-hour clinical EEG. The multifocal epileptiform pattern identified by MEG in the ASDs typically includes the same perisylvian brain regions identified as abnormal in LKS. When epileptiform activity is present in the ASDs, therapeutic strategies (antiepileptic drugs, steroids, and even neurosurgery) aimed at its control can lead to a significant improvement in language and autistic features. autism, pervasive developmental disorder–not otherwise specified, epilepsy, magnetoencephalography, Landau-Kleffner syndrome.

Two‐year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.

Neurologic complications of critical medical illnesses

ObjectivesTo identify the neurologic complications of critical medical illnesses, and to assess their effect on mortality rates and on medical ICU and hospital lengths of stay. DesignProspective clinical evaluation of all medical ICU admissions for 2 yrs. SettingA 14-bed, general medical intensive and coronary care unit in a large university hospital. PatientsPatients (n = 1,850) admitted to the hospital, of whom 92 were admitted for primarily neurologic problems. Of the remaining 1,758 patients, 217 (12.3%) experienced a neurologic complication. InterventionsNone. Measurements and Main ResultsPatients developing a neurologic complication while in the medical ICU demonstrated an increased risk of inhospital mortality when compared with patients who did not suffer such problems (45.7% vs. 26.6%; p < .00001). Patients with neurologic complications experienced 2.5-fold longer medical ICU stay times (p < .001) and almost two-fold longer hospital stay times (p < .001). Metabolic encephalopathy, seizures, hypoxic-ischemic encephalopathy, and stroke were the most common complications. Sepsis was the most frequent cause of encephalopathy, and cerebrovascular lesions were the most common cause of seizures. Formal neurologic consulttions were requested in only 36% of the patients. ConclusionsNeurologic complications associated with increased mortality rates longer medical ICU and hospital lengths of st These conditions are probably underrecognis at present. ICUs have the potential to serve environments for neurologic teaching and search. (Crit Care Med 1993; 21:98–103)

Long-term treatment with responsive brain stimulation in adults with refractory partial seizures.

Objective: The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures. Methods: All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy. Results: The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%). Conclusions: The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures. Classification of evidence: This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

Epileptic encephalopathy of late childhood: Landau-Kleffner syndrome and the syndrome of continuous spikes and waves during slow-wave sleep.

Landau-Kleffner syndrome (LKS) and the syndrome of continuous spikes and waves during slow wave sleep (CSWS) are two points on the spectrum of functional childhood epileptic encephalopathies. They are characterized by a severe paroxysmal EEG disturbance that may permanently alter the critical synaptogenesis by strengthening synaptic contacts that should have been naturally “pruned.” The much more common benign epilepsy with centrotemporal spikes is also related to LKS and CSWS by a common pathophysiology. Although prognosis in LKS and CSWS for seizure control is good, cognitive function declines and permanent neuropsychologic dysfunction is seen in many cases. This permanent damage is most evident in those patients who had early-onset EEG abnormality and a prolonged active phase of continuous spike-and-wave discharges during sleep. If the active phase of paroxysmal activity persists for over 2 to 3 years, even successful treatment does not resolve neuropsychologic sequelae. In LKS, the paroxysmal activity permanently affects the posterior temporal area and results in auditory agnosia and language deficits; in CSWS, the frontal lobes are more involved and other cognitive disturbances predominate. Aggressive treatment should include high-dose antiepileptic drugs, corticosteroids, and surgery in specific cases

Extended-release formulations: simplifying strategies in the management of antiepileptic drug therapy

Advances in our understanding, diagnosis, and treatment of seizure disorders have transformed the management of epilepsy. As the number of antiepileptic drugs and their formulations increase, so do the expectations of therapy. Once limited to attaining complete control of seizures, epilepsy management now strives to enable patients to lead lifestyles consistent with their own capabilities. Extended-release antiepileptic drug formulations can help achieve the primary treatment goals for many patients with epilepsy: preventing occurrence of seizures and preventing or reducing side effects. The dosing flexibility and consistency of serum levels (without marked peak-to-trough fluctuations) conferred by extended-release formulations help achieve these goals. These same attributes of extended-release formulations may also improve compliance, quality of life, and patient satisfaction with treatment.

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.

Multiple Subpial Transection in Patients with Extratemporal Epilepsy

Summary: Multiple subpial transection (MST) was developed to permit the treatment of partial epilepsies that reside in or encroach on eloquent cortex (language and sensorimotor cortex). It was conceived after the discoveries of the columnar organization of neocortex and that expression and spread of seizures utilize the transverse fiber network. Although the technique is simple in principle, it takes a skilled and practiced hand to avoid damage to the neocortical columns and vascular supply. The efficacy in controlling seizures with MST in extra‐temporal epilepsy is similar to that of resective surgery. Activities of daily living are not adversely impacted by MST. MST is a viable alternative to resection in extratemporal epilepsy.