Alica Goldman

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.

Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death

Mice engineered to carry a human mutation that causes heart problems also have epilepsy, suggesting a cause of SUDEP, sudden unexplained death in epilepsy. Patients with epilepsy face an extra frightening burden. Occasionally, otherwise healthy individuals with this disease die unexpectedly for no apparent cause. The incidence of sudden death is ~10% for epilepsy patients—a risk far greater than that faced by a non-epileptic person. Sudden unexplained death in epilepsy (SUDEP) frequently follows a seizure, and patients who experience many seizures have a greater risk of SUDEP. But the causes of SUDEP remain a mystery. Now, Goldman et al. shed new light on how defective potassium channels contribute to this syndrome. Various causes of SUDEP have been proposed—some that produce irreversible cardiac dysfunction and some that produce respiratory distress. One suggested cause invokes the common dependence of the heart and brain on electrical activity for proper functioning. When ion channels—the membrane proteins that control electrical activity—go awry (by gene mutation or a drug), the brain becomes uncontrollably excited, producing a seizure, during which the regular beating of the heart is disrupted and can cease altogether. Both people and a mouse model display mutations in the KCNQ1 gene—which encodes a potassium channel in the heart—that give rise to heartbeat abnormalities and a higher risk for sometimes fatal arrhythmias. Goldman et al. studied KCNQ1-mutant mice and found that this same potassium channel that causes problems in the heart is also present in neurons in the brain and is in particularly high abundance in regions that are susceptible to epilepsy. A closer look at the brains of these mice disclosed that their electrical discharges display abnormalities characteristic of epilepsy and that these aberrations often occur at the same time as abnormal heartbeats. Continuous video surveillance of these mice revealed that many also experienced overt seizures. In one instance, a mouse with the mutant ion channel suffered increasingly frequent seizures accompanied by irregular abnormal cardiac activity and ultimately went into cardiac arrest, a mouse version of SUDEP. Taken together, these results reinforce hints in the literature that SUDEP may result from common excitability defects in the brain and heart. Cardiac abnormalities that resemble those in the mutant mice can be caused in humans by mutations in ~10 genes. The ability to screen epilepsy patients for these mutations would allow those who are at risk for cardiac-induced sudden death to take preventive measures. Sudden unexplained death is a catastrophic complication of human idiopathic epilepsy, causing up to 18% of patient deaths. A molecular mechanism and an identified therapy have remained elusive. Here, we find that epilepsy occurs in mouse lines bearing dominant human LQT1 mutations for the most common form of cardiac long QT syndrome, which causes syncopy and sudden death. KCNQ1 encodes the cardiac KvLQT1 delayed rectifier channel, which has not been previously found in the brain. We have shown that, in these mice, this channel is found in forebrain neuronal networks and brainstem nuclei, regions in which a defect in the ability of neurons to repolarize after an action potential, as would be caused by this mutation, can produce seizures and dysregulate autonomic control of the heart. That long QT syndrome mutations in KCNQ1 cause epilepsy reveals the dual arrhythmogenic potential of an ion channelopathy coexpressed in heart and brain and motivates a search for genetic diagnostic strategies to improve risk prediction and prevention of early mortality in persons with seizure disorders of unknown origin.

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.

SCN1A testing for epilepsy: Application in clinical practice

This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage‐gated sodium channels (protein name: Nav1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.

High‐resolution molecular genomic autopsy reveals complex sudden unexpected death in epilepsy risk profile

Advanced variant detection in genes underlying risk of sudden unexpected death in epilepsy (SUDEP) can uncover extensive epistatic complexity and improve diagnostic accuracy of epilepsy‐related mortality. However, the sensitivity and clinical utility of diagnostic panels based solely on established cardiac arrhythmia genes in the molecular autopsy of SUDEP is unknown. We applied the established clinical diagnostic panels, followed by sequencing and a high density copy number variant (CNV) detection array of an additional 253 related ion channel subunit genes to analyze the overall genomic variation in a SUDEP of the 3‐year‐old proband with severe myoclonic epilepsy of infancy (SMEI). We uncovered complex combinations of single nucleotide polymorphisms and CNVs in genes expressed in both neurocardiac and respiratory control pathways, including SCN1A, KCNA1, RYR3, and HTR2C. Our findings demonstrate the importance of comprehensive high‐resolution variant analysis in the assessment of personally relevant SUDEP risk. In this case, the combination of de novo single nucleotide polymorphisms (SNPs) and CNVs in the SCN1A and KCNA1 genes, respectively, is suspected to be the principal risk factor for both epilepsy and premature death. However, consideration of the overall biologically relevant variant complexity with its extensive functional epistatic interactions reveals potential personal risk more accurately.

Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography

Patients with suspected mesial temporal lobe (MTL) epilepsy typically undergo inpatient video–electroencephalography (EEG) monitoring with scalp and/or intracranial electrodes for 1 to 2 weeks to localize and lateralize the seizure focus or foci. Chronic ambulatory electrocorticography (ECoG) in patients with MTL epilepsy may provide additional information about seizure lateralization. This analysis describes data obtained from chronic ambulatory ECoG in patients with suspected bilateral MTL epilepsy in order to assess the time required to determine the seizure lateralization and whether this information could influence treatment decisions.

Silent hippocampal seizures and spikes identified by foramen ovale electrodes in Alzheimer's disease

We directly assessed mesial temporal activity using intracranial foramen ovale electrodes in two patients with Alzheimers disease (AD) without a history or EEG evidence of seizures. We detected clinically silent hippocampal seizures and epileptiform spikes during sleep, a period when these abnormalities were most likely to interfere with memory consolidation. The findings in these index cases support a model in which early development of occult hippocampal hyperexcitability may contribute to the pathogenesis of AD.

Sudden unexpected death in epilepsy genetics: Molecular diagnostics and prevention

Epidemiologic studies clearly document the public health burden of sudden unexpected death in epilepsy (SUDEP). Clinical and experimental studies have uncovered dynamic cardiorespiratory dysfunction, both interictally and at the time of sudden death due to epilepsy. Genetic analyses in humans and in model systems have facilitated our current molecular understanding of SUDEP. Many discoveries have been informed by progress in the field of sudden cardiac death and sudden infant death syndrome. It is becoming apparent that SUDEP genomic complexity parallels that of sudden cardiac death, and that there is a pauci1ty of analytically useful postmortem material. Because many challenges remain, future progress in SUDEP research, molecular diagnostics, and prevention rests in international, collaborative, and transdisciplinary dialogue in human and experimental translational research of sudden death.

Novel brain expression of ClC-1 chloride channels and enrichment of CLCN1 variants in epilepsy

Objective: To explore the potential contribution of genetic variation in voltage-gated chloride channels to epilepsy, we analyzed CLCN family (CLCN1-7) gene variant profiles in individuals with complex idiopathic epilepsy syndromes and determined the expression of these channels in human and murine brain. Methods: We used parallel exomic sequencing of 237 ion channel subunit genes to screen individuals with a clinical diagnosis of idiopathic epilepsy and evaluate the distribution of missense variants in CLCN genes in cases and controls. We examined regional expression of CLCN1 in human and mouse brain using reverse transcriptase PCR, in situ hybridization, and Western immunoblotting. Results: We found that in 152 individuals with sporadic epilepsy of unknown origin, 96.7% had at least one missense variant in the CLCN genes compared with 28.2% of 139 controls. Nonsynonymous single nucleotide polymorphisms in the “skeletal” chloride channel gene CLCN1 and in CLCN2, a putative human epilepsy gene, were detected in threefold excess in cases relative to controls. Among these, we report a novel de novo CLCN1 truncation mutation in a patient with pharmacoresistant generalized seizures and a dystonic writers cramp without evidence of variants in other channel genes linked to epilepsy. Molecular localization revealed the unexpectedly widespread presence of CLCN1 mRNA transcripts and the ClC-1 subunit protein in human and murine brain, previously believed absent in neurons. Conclusions: Our findings support a possible comorbid contribution of the “skeletal” chloride channel ClC-1 to the regulation of brain excitability and the need for further elucidation of the roles of CLCN genes in neuronal network excitability disorders.

Mechanisms of sudden unexplained death in epilepsy.

PURPOSE OF REVIEW Human and experimental research has identified cardioautonomic and respiratory dysfunction as a frequent accompaniment in human and animal model events of sudden unexpected death in epilepsy (SUDEP). This review aims to provide an overview of the scientific evidence behind the currently accepted risk factors and working hypotheses regarding SUDEP pathophysiology. RECENT FINDINGS Epidemiological analysis of public health burden of SUDEP has shown that it rates second only to stroke in the years of potential life lost. Clinical and experimental studies uncovered the dynamic cardiorespiratory dysfunction interictally and imminently to SUDEP, and model systems have facilitated discoveries in SUDEP mechanistic understanding and application of pilot therapeutic interventions. Pilot molecular profiling of human SUDEP has uncovered complex genomic structure in the candidate gene network. SUMMARY Extensive clinical and experimental work has established a rationale for the conceptual thinking about SUDEP mechanisms. The application of the global molecular profiling will be invaluable in unraveling the individually unique genomic complexities and interactions that underlie the physiological signature of each patient. At the same time, sophisticated model systems will be critical in the iterative translation of human genetics, physiology, pharmacological interventions, and in testing preventive interventions.