YEAR IN REVIEW EPILEPSY IN 2013
Progress across the spectrum of epilepsy research Frances E. Jensen
Over the past year, we have witnessed major advances in several areas of epilepsy research, including genetics and disease mechanisms, neurodevelopmental effects of antiepileptic drugs, and new therapeutic approaches based on closed-loop neurostimulator systems. The findings have important implications both for clinical practice and for future research. Jensen, F. E. Nat. Rev. Neurol. 10, 63–64 (2014); published online 14 January 2014; doi:10.1038/nrneurol.2013.277
malformations of cortical development, tumours, toxic–metabolic status epilepticus, autoimmune syndrome, and genetic causes. Most idiopathic generalized epilepsies are thought to have a genetic component, and linkage studies, genome-wide association studies, and animal model and transgenic studies have yielded well over 100 epilepsy-associated genes. Most epilepsies occur in the absence of a notable family history and, to address the contribution of de novo mutations, a research consortium named the Epilepsy Genotype Phenotype Project and its follow-on group Epi4K2 were formed to carry out detailed phenotyping and next-generation sequen cing in pairs of first-degree relatives and probands, as well as in biological parents without epilepsy. In the first study from the consortium,2 de novo mutations were screened in patients with two classic epileptic encephalopathies: infantile spasms and Lennox–Gastaut syndrome. The researchers sequenced the exomes of 264 probands and their parents, and confirmed 329 de novo mutations. Four patients had mutations in GABRB3, and ALG13 exhibited the same de novo mutation in two patients. Mutations in both genes showed clear statistical evidence of association with epileptic encephalopathy. Other genes with de novo mutations in the cohort included CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L, as well as specific gene sets that included genes regulated by the fragile X protein. This novel approach suggests that a substantial proportion of epileptic encephalopathy cases have a genetic basis, and many different mutations are likely to account for this
NATURE REVIEWS | NEUROLOGY
broad class of epilepsies. The level of scientific accuracy could be attributed to the size of the team, which included experts in paediatric neurology, molecular genetics, engineering, information technology, and public health policy. Another large-scale project addressed the causes of SUDEP, via a consortium aptly named MORTEMUS (MORTality in Epilepsy Monitoring Unit Study). 3 Recent studies have revealed that SUDEP accounts for four out of every 1,000 deaths in patients with uncontrolled epilepsy, representing a 12% cumulative risk over 40 years for patients with uncontrolled childhood-onset epilepsy. 4 The mechanisms underlying SUDEP are poorly understood, but basic research suggests potential decreases in brainstem systems
Mopic | Dreamstime.com
2013 has been a remarkable year for publications in the clinical, translational and basic science realms of the epilepsy field. Clinical advances were reported from large-scale, population-based genomic studies, research into mechanisms of sudden unexplained death in epilepsy (SUDEP), and investigations of the effects of in utero exposure to commonly used antiepileptic drugs (AEDs). The concept of a closed-loop neurostimulator system has become a reality—in November 2013, the FDA approved the first implantable neurostimulator that detects seizure onset and delivers electrical stimulation to terminate a seizure, and researchers are now moving forward with more elegant approaches involving optogenetics. These advances follow on from an important landmark in 2012: the publication of the Institute of Medicine (IOM) Report on Epilepsy.1 This report represents the first comprehensive effort by public, private and patient organizations to assess the burden of this disease. Importantly, an initial reanalysis of existing data in prepar ation for this IOM report revealed that one in 26 people will experience epilepsy at some point in their lifetime. Epilepsy can be a chronic disease, and almost 30% of people with epilepsy do not achieve full seizure control on currently available medications. Beyond the seizures, about half of all patients with chronic epilepsy exhibit cognitive or psychiatric disorders. Current medical treatment options do not ‘cure’ epilepsy; they only suppress the seizures. Surgery can have disease-modifying effects, but its invasive nature limits widespread use. Epilepsy has many aetiologies, including trauma, perinatal hypoxia–ischaemia,
VOLUME 10 | FEBRUARY 2014 | 63 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ The Epi4K Consortium identified a plethora of de novo mutations that are associated with epileptic encephalopathies2 ■■ The MORTEMUS report demonstrated a role for early postictal centrally mediated cardiorespiratory dysfunction in sudden unexpected death in epilepsy3 ■■ The NEAD study found that in utero exposure to valproate, but not lamotrigine, phenytoin or carbamazepine, has dose-dependent effects on cognition6 ■■ Optogenetics can be used to target either excitation or inhibition in a cell-specific manner, paving the way for circuitspecific nonpharmacological therapy in epilepsy9,10
controlling sensitivity to hypoxaemia– hypercapnia, and central control of cardiac rhythm.5 These hypotheses have had little clinical support, however, as the diagnosis was often made postmortem. The MORTEMUS report describes, with astonishing accuracy, retrospective monitoring data obtained in real time while patients with refractory epilepsy succumbed to SUDEP during routine monitoring for presurgical assessment.3 Many of these patients were intentionally being withdrawn from their AEDs to elucidate the location of their epileptic focus. In view of the rarity of SUDEP, MORTEMUS obtained recordings of SUDEP and near-SUDEP events from epilepsy monitoring units from all over the world. The investigators identified a pattern of events leading up to death following secondary generalized tonic–clonic seizures, with initially rapid breathing followed within a few minutes by transient or terminal combined cardiorespiratory dysfunction. For the first time, these clinical data suggest early postictal centrally mediated cardiorespiratory dysfunction. The study also identified factors that were associa ted with avoidance of SUDEP, including video-EEG monitoring, roundthe-clock supervision, pulse oximetry, and electrocardiographic monitoring. Epilepsy in pregnancy is always a therapeutic challenge, and previous studies have described many dysmorph isms related to specific AEDs, but little is known about effects on cognition. NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) is the largest prospective investigation of the cognitive effects of fetal AED exposure to date.6 The study 64 | FEBRUARY 2014 | VOLUME 10
followed 305 pregnancies, and evaluated IQ at 6 years of age, as well as other cognitive variables, adjusted for maternal IQ, AED type, standardized dose, gestational birth age, and use of peric onceptional folate. Dose-dependent effects on IQ, verbal and nonverbal ability, memory, and executive function were observed for valproate but not for lamotrigine, phenytoin or carba mazepine. Animal studies have shown that exposure of the perinatal brain to certain AEDs, including valproate, results in an increase in constitutive apoptosis, and alters synaptic and growth factor gene expression.7 Taken together, these results point to a compelling need for more translational research in this area. In November 2013, the FDA approved the first implantable responsive neurostimulator connected to depth or subdural leads placed in cortical seizure foci.8 The neurostimulator continually senses electro corticographic activity, and is programmed by the physician to detect patient-specific abnormal electrocorticographic activity and then provide stimulation to abort seizure activity. This approach could provide an alternative to surgery for some patients with medically refractory epilepsy. While this device is an important technological breakthrough, there are obvious limitations, including nonspecific effects of electrical stimulation. To address these limitations, researchers are taking an exciting new direction; namely, the application of optogenetics to the problem of focal epilepsy. Paz et al. 9 used optogenetic stimulation of the thalamus to suppress seizure activity in a rat model of seizures due to cortical stroke with secondary thalamic damage. The thalamic damage consisted of decreased ascending inhibitory output to the cortex, owing to reduced excitability and excitation in the inhibitory reticular thalamic neurons. Hence, the intrathalamic network was hyperexcitable, generating epileptiform oscillations and thalamocortical epilepsy in injured animals. The group used a closed-loop system to detect seizures and trigger optogenetic stimulation to the affected thalamic area. In response to the poststroke seizures, yellow light was delivered intracranially, via a fibre-optic cable, to cells expressing the inhibitory opsin NpHR, which in turn aborted the seizures. Another important aspect of this study was that optogenetics was used to map circuitry, revealing that subcortical
structures such as the thalamus critically regulate the cortex. In another recent study,10 a similar ondemand approach was used in a rodent model of temporal lobe epilepsy. In this case, targeting was accomplished via the excitatory opsin ChR2 in parvalbuminexpressing inhibitory interneurons in the hippocampus. Taken together, these studies show that optogenetics can be used to target either excitation or inhib ition in a cell-s pecific manner, possibly avoiding some of the nonspecific effects of electrical stimulation, and paving the way for c ircuit-specific nonpharmacological therapy in epilepsy. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 3rd Floor Gates Building, Philadelphia, PA 19104‑4283, USA. [email protected] Competing interests The author declares no competing interests. 1.
Institute of Medicine. Epilepsy across the spectrum: promoting health and understanding. The National Academies Press, Washington, DC [online], http://books.nap.edu/ openbook.php?record_id=13379 (2012). 2. Epi4K Consortium & Epilepsy Phenome/ Genome Project. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). 3. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 12, 966–977 (2013). 4. Sillanpää, M. & Shinnar, S. Long-term mortality in childhood-onset epilepsy. N. Engl. J. Med. 363, 2522–2529 (2010). 5. Sowers, L. P., Massey, C. A., Gehlbach, B. K., Granner, M. A. & Richerson, G. B. Sudden unexpected death in epilepsy: fatal post-ictal respiratory and arousal mechanisms. Respir. Physiol. Neurobiol. 189, 315–323 (2013). 6. Meador, K. J. et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 12, 244–252 (2013). 7. Turski, C. A. & Ikonomidou, C. Neuropathological sequelae of developmental exposure to antiepileptic and anesthetic drugs. Front. Neurol. 3, 120 (eCollection 2012). 8. Morrell, M. J. & RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011). 9. Paz, J. T. et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat. Neurosci. 16, 64–70 (2013). 10. Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat. Commun. 4, 1376 (2013).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
Progress across the spectrum of epilepsy research Frances E. Jensen
Over the past year, we have witnessed major advances in several areas of epilepsy research, including genetics and disease mechanisms, neurodevelopmental effects of antiepileptic drugs, and new therapeutic approaches based on closed-loop neurostimulator systems. The findings have important implications both for clinical practice and for future research. Jensen, F. E. Nat. Rev. Neurol. 10, 63–64 (2014); published online 14 January 2014; doi:10.1038/nrneurol.2013.277
malformations of cortical development, tumours, toxic–metabolic status epilepticus, autoimmune syndrome, and genetic causes. Most idiopathic generalized epilepsies are thought to have a genetic component, and linkage studies, genome-wide association studies, and animal model and transgenic studies have yielded well over 100 epilepsy-associated genes. Most epilepsies occur in the absence of a notable family history and, to address the contribution of de novo mutations, a research consortium named the Epilepsy Genotype Phenotype Project and its follow-on group Epi4K2 were formed to carry out detailed phenotyping and next-generation sequen cing in pairs of first-degree relatives and probands, as well as in biological parents without epilepsy. In the first study from the consortium,2 de novo mutations were screened in patients with two classic epileptic encephalopathies: infantile spasms and Lennox–Gastaut syndrome. The researchers sequenced the exomes of 264 probands and their parents, and confirmed 329 de novo mutations. Four patients had mutations in GABRB3, and ALG13 exhibited the same de novo mutation in two patients. Mutations in both genes showed clear statistical evidence of association with epileptic encephalopathy. Other genes with de novo mutations in the cohort included CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L, as well as specific gene sets that included genes regulated by the fragile X protein. This novel approach suggests that a substantial proportion of epileptic encephalopathy cases have a genetic basis, and many different mutations are likely to account for this
NATURE REVIEWS | NEUROLOGY
broad class of epilepsies. The level of scientific accuracy could be attributed to the size of the team, which included experts in paediatric neurology, molecular genetics, engineering, information technology, and public health policy. Another large-scale project addressed the causes of SUDEP, via a consortium aptly named MORTEMUS (MORTality in Epilepsy Monitoring Unit Study). 3 Recent studies have revealed that SUDEP accounts for four out of every 1,000 deaths in patients with uncontrolled epilepsy, representing a 12% cumulative risk over 40 years for patients with uncontrolled childhood-onset epilepsy. 4 The mechanisms underlying SUDEP are poorly understood, but basic research suggests potential decreases in brainstem systems
Mopic | Dreamstime.com
2013 has been a remarkable year for publications in the clinical, translational and basic science realms of the epilepsy field. Clinical advances were reported from large-scale, population-based genomic studies, research into mechanisms of sudden unexplained death in epilepsy (SUDEP), and investigations of the effects of in utero exposure to commonly used antiepileptic drugs (AEDs). The concept of a closed-loop neurostimulator system has become a reality—in November 2013, the FDA approved the first implantable neurostimulator that detects seizure onset and delivers electrical stimulation to terminate a seizure, and researchers are now moving forward with more elegant approaches involving optogenetics. These advances follow on from an important landmark in 2012: the publication of the Institute of Medicine (IOM) Report on Epilepsy.1 This report represents the first comprehensive effort by public, private and patient organizations to assess the burden of this disease. Importantly, an initial reanalysis of existing data in prepar ation for this IOM report revealed that one in 26 people will experience epilepsy at some point in their lifetime. Epilepsy can be a chronic disease, and almost 30% of people with epilepsy do not achieve full seizure control on currently available medications. Beyond the seizures, about half of all patients with chronic epilepsy exhibit cognitive or psychiatric disorders. Current medical treatment options do not ‘cure’ epilepsy; they only suppress the seizures. Surgery can have disease-modifying effects, but its invasive nature limits widespread use. Epilepsy has many aetiologies, including trauma, perinatal hypoxia–ischaemia,
VOLUME 10 | FEBRUARY 2014 | 63 © 2014 Macmillan Publishers Limited. All rights reserved
YEAR IN REVIEW Key advances ■■ The Epi4K Consortium identified a plethora of de novo mutations that are associated with epileptic encephalopathies2 ■■ The MORTEMUS report demonstrated a role for early postictal centrally mediated cardiorespiratory dysfunction in sudden unexpected death in epilepsy3 ■■ The NEAD study found that in utero exposure to valproate, but not lamotrigine, phenytoin or carbamazepine, has dose-dependent effects on cognition6 ■■ Optogenetics can be used to target either excitation or inhibition in a cell-specific manner, paving the way for circuitspecific nonpharmacological therapy in epilepsy9,10
controlling sensitivity to hypoxaemia– hypercapnia, and central control of cardiac rhythm.5 These hypotheses have had little clinical support, however, as the diagnosis was often made postmortem. The MORTEMUS report describes, with astonishing accuracy, retrospective monitoring data obtained in real time while patients with refractory epilepsy succumbed to SUDEP during routine monitoring for presurgical assessment.3 Many of these patients were intentionally being withdrawn from their AEDs to elucidate the location of their epileptic focus. In view of the rarity of SUDEP, MORTEMUS obtained recordings of SUDEP and near-SUDEP events from epilepsy monitoring units from all over the world. The investigators identified a pattern of events leading up to death following secondary generalized tonic–clonic seizures, with initially rapid breathing followed within a few minutes by transient or terminal combined cardiorespiratory dysfunction. For the first time, these clinical data suggest early postictal centrally mediated cardiorespiratory dysfunction. The study also identified factors that were associa ted with avoidance of SUDEP, including video-EEG monitoring, roundthe-clock supervision, pulse oximetry, and electrocardiographic monitoring. Epilepsy in pregnancy is always a therapeutic challenge, and previous studies have described many dysmorph isms related to specific AEDs, but little is known about effects on cognition. NEAD (Neurodevelopmental Effects of Antiepileptic Drugs) is the largest prospective investigation of the cognitive effects of fetal AED exposure to date.6 The study 64 | FEBRUARY 2014 | VOLUME 10
followed 305 pregnancies, and evaluated IQ at 6 years of age, as well as other cognitive variables, adjusted for maternal IQ, AED type, standardized dose, gestational birth age, and use of peric onceptional folate. Dose-dependent effects on IQ, verbal and nonverbal ability, memory, and executive function were observed for valproate but not for lamotrigine, phenytoin or carba mazepine. Animal studies have shown that exposure of the perinatal brain to certain AEDs, including valproate, results in an increase in constitutive apoptosis, and alters synaptic and growth factor gene expression.7 Taken together, these results point to a compelling need for more translational research in this area. In November 2013, the FDA approved the first implantable responsive neurostimulator connected to depth or subdural leads placed in cortical seizure foci.8 The neurostimulator continually senses electro corticographic activity, and is programmed by the physician to detect patient-specific abnormal electrocorticographic activity and then provide stimulation to abort seizure activity. This approach could provide an alternative to surgery for some patients with medically refractory epilepsy. While this device is an important technological breakthrough, there are obvious limitations, including nonspecific effects of electrical stimulation. To address these limitations, researchers are taking an exciting new direction; namely, the application of optogenetics to the problem of focal epilepsy. Paz et al. 9 used optogenetic stimulation of the thalamus to suppress seizure activity in a rat model of seizures due to cortical stroke with secondary thalamic damage. The thalamic damage consisted of decreased ascending inhibitory output to the cortex, owing to reduced excitability and excitation in the inhibitory reticular thalamic neurons. Hence, the intrathalamic network was hyperexcitable, generating epileptiform oscillations and thalamocortical epilepsy in injured animals. The group used a closed-loop system to detect seizures and trigger optogenetic stimulation to the affected thalamic area. In response to the poststroke seizures, yellow light was delivered intracranially, via a fibre-optic cable, to cells expressing the inhibitory opsin NpHR, which in turn aborted the seizures. Another important aspect of this study was that optogenetics was used to map circuitry, revealing that subcortical
structures such as the thalamus critically regulate the cortex. In another recent study,10 a similar ondemand approach was used in a rodent model of temporal lobe epilepsy. In this case, targeting was accomplished via the excitatory opsin ChR2 in parvalbuminexpressing inhibitory interneurons in the hippocampus. Taken together, these studies show that optogenetics can be used to target either excitation or inhib ition in a cell-s pecific manner, possibly avoiding some of the nonspecific effects of electrical stimulation, and paving the way for c ircuit-specific nonpharmacological therapy in epilepsy. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 3rd Floor Gates Building, Philadelphia, PA 19104‑4283, USA. [email protected] Competing interests The author declares no competing interests. 1.
Institute of Medicine. Epilepsy across the spectrum: promoting health and understanding. The National Academies Press, Washington, DC [online], http://books.nap.edu/ openbook.php?record_id=13379 (2012). 2. Epi4K Consortium & Epilepsy Phenome/ Genome Project. De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). 3. Ryvlin, P. et al. Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol. 12, 966–977 (2013). 4. Sillanpää, M. & Shinnar, S. Long-term mortality in childhood-onset epilepsy. N. Engl. J. Med. 363, 2522–2529 (2010). 5. Sowers, L. P., Massey, C. A., Gehlbach, B. K., Granner, M. A. & Richerson, G. B. Sudden unexpected death in epilepsy: fatal post-ictal respiratory and arousal mechanisms. Respir. Physiol. Neurobiol. 189, 315–323 (2013). 6. Meador, K. J. et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 12, 244–252 (2013). 7. Turski, C. A. & Ikonomidou, C. Neuropathological sequelae of developmental exposure to antiepileptic and anesthetic drugs. Front. Neurol. 3, 120 (eCollection 2012). 8. Morrell, M. J. & RNS System in Epilepsy Study Group. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011). 9. Paz, J. T. et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat. Neurosci. 16, 64–70 (2013). 10. Krook-Magnuson, E., Armstrong, C., Oijala, M. & Soltesz, I. On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat. Commun. 4, 1376 (2013).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
![[Progress in treatment of epilepsy].](/assets/img/hold.png)
