J Neurol (2014) 261:837–841 DOI 10.1007/s00415-014-7294-y
NEUROLOGICAL UPDATE
Recent advances in epilepsy Stjepana Kovac • Matthew C. Walker
Received: 19 February 2014 / Accepted: 20 February 2014 / Published online: 4 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract We have reviewed some of the important studies published within the last 18 months that have advanced our understanding of the epilepsies, their aetiology and treatment. Clinical studies have revealed new insights into old themes including seizure prediction, mortality in epilepsy, febrile seizures and the pathophysiology of focal cortical dysplasias. The rapid advances in genetics and particularly whole exome sequencing have had an impact on our understanding of epileptic encephalopathies, and the aetiology of hippocampal sclerosis. Experimental research techniques such as viral vector gene delivery, optogenetics and cell based transplantation techniques have set the framework for novel approaches to the treatment of pharmacoresistant epilepsy. These few examples are indicative of the great strides that have recently been made in epilepsy research. Keywords Epilepsy Epilepsy genetics SUDEP Optogenetic Viral vectors
Introduction The epilepsies are a collection of conditions that result not only in spontaneous seizures, but also other morbidities (in particular psychiatric disease and increased mortality). The relative contribution of both genetic and environmental factors to the aetiology of individual epilepsies are now being realised, and we are entering a new era in the treatment of neurological disease in which both stem cells and gene therapies have become realistic possibilities. Moreover, advances in technology have meant that reliable S. Kovac (&) M. C. Walker Institute of Neurology, University College London, London, UK e-mail: [email protected]
seizure prediction may be possible. Here, we present a few of the studies from the last 18 months that emphasise and illustrate these advances.
Epilepsy morbidities Mortality and psychiatric disease in epilepsy The increased mortality that is associated with epilepsy has long been recognised, and research advances into the nature and mechanisms of these deaths continue to be made. Two important studies in 2013 illustrate the importance of psychiatric comorbidities and their impact on mortality and also possible mechanisms underlying sudden unexpected death in epilepsy (SUDEP). A large retrospective population study compared death rates in 69,995 patients with epilepsy born between 1954 and 2009 in Sweden to general population controls and unaffected siblings [1]. There was an 11-fold increase in the odds of premature mortality in patients suffering from epilepsy when compared to the general population and their healthy siblings. Sixteen percent of these deaths in patients suffering from epilepsy were related to external causes and this made up the largest category of deaths that was not related to underlying disease process. These deaths included suicide and accidents. Psychiatric comorbidity was high in patients when compared to control (18 vs. 3.5 %) and, therefore, may explain this finding. This study also highlighted preventable causes of death in epilepsy such as safety precautions to prevent accidents, particularly non-vehicle accidents which were high among patients suffering from epilepsy when compared to controls. The other important priorities identified are psychiatric co-
123
838
morbidities such as depression and substance abuse, potentially contributing to high risk of suicide seen in patient suffering from epilepsy. Another key study, which has contributed to understanding mortality in epilepsy, was a multicentre study focussing on SUDEP in epilepsy monitoring units [2]. SUDEP has been recognized as a cause for mortality in epilepsy and several risk factors have been suggested to play a role. Uncontrolled generalized tonic–clonic seizures play a pivotal role, yet the mechanisms behind SUDEP are far from fully understood [3]. MORTEMUS was a muliticentre study pooling data from 147 epilepsy monitoring units over a period of two years to investigate the mechanisms of SUDEP. Twenty-nine cardiorespiratory events were reported during this period. Of these, 16 were classified as SUDEP, nine as near SUDEP and four deaths were recorded from other causes. The strength of this study was that for the first time a considerable number of SUDEPs were recorded in real time with video-EEG. The key finding was that SUDEP in the patients recorded was preceded by a generalized tonic–clonic seizure followed by a period of normal or increased heart rate and respiratory rate. After this, a pattern of central apnoea, bradycardia and transient asystole occurred, together with EEG depression. In a third of patients asystole was terminal, whereas in the other patients there was a brief period of recovery of cardiac function with abnormal respiratory function and subsequent apnoea finally leading to a second, terminal asystole. The study concludes that postictal neurovegetative breakdown after generalized tonic–clonic seizures is a major culprit for SUDEP. Moreover, extrapolating their data, there might be a window for early interventions. In their series, patient classified as near SUDEP had successful resuscitatation within 3 min after onset of apnoea. This study provides considerable insight into the pathophysiological mechanisms involved in SUDEP and corroborates previous findings highlighting that effective seizure control or control of generalized tonic–clonic seizures is the best strategy to prevent SUDEP.
Aetiology of the epilepsies The increasing role that genetic factors play in the aetiology of the epilepsies has become increasingly apparent but environmental factors, including infection, also play a critical role. Here, we review some of the genetic studies but also include two important studies of epilepsy epidemics. Epilepsy genetic New techniques such as whole exome sequencing have expedited and fuelled discoveries in genetics. With regards
123
J Neurol (2014) 261:837–841
to epilepsy, one exciting project was completed in 2013 by the Epi4 consortium. The consortium investigated 149 patients with infantile spasms and 115 patients with Lennox–Gastaut syndrome as two classic forms of epileptic encephalopathies. By exome sequencing of patients and their parents (trio analysis), this study found 329 de novo mutations. Some of those de novo mutations have been found in genes which have been previously linked to epilepsy/epileptic encephalopathy such as CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2. MTOR and NEDD4L. In addition the authors found mutations in two new genes, GABRB3 and ALG13, which have previously not been linked to epileptic encephalopathy [4]. GABRB3 mutations occurred in four patients and ALG13 in two. Mutations in GABRB3 and ALG have been previously associated with autism spectrum disorder with the new study broadening the phenotype of these mutations to include epileptic encephalopathy. The study found substantial interconnections between the genes found and autism and intellectual disability gene networks. Some of the genes with de novo mutations in their cohort have been identified in patients with intellectual disorders and autism spectrum disorder highlighting the phenotypic variablitity of these genes. There are two interesting aspects here. First, this study highlights the importance of whole exome sequencing rather than screening a restricted panel of genes in identifying mutations in patients suffering from epilepsy. Second, the network analysis performed highlights hubs of genes which underlie specific dysfunction such as seizures and autism spectrum disorder. It is possible that targeting the function of these genes is pivotal for major breakthroughs in therapeutic approaches. Febrile seizures Epileptic encephalopathies are devastating syndromes, which are distinct from the most frequent cause of drugresistant epilepsy—mesial temporal lobe epilepsy. However, some epileptic encephalopathies, such as epileptic encephalopathies due to SCN1A mutations (Dravet syndrome and GEFS plus spectrum epilepsies) share common features with mesial temporal lobe epilepsies. In both epilepsies, febrile seizures are often found in the past medical history raising the question whether they may share some genetic similarities. This has been addressed by a recent study which sheds light on the association of SCN1A, febrile seizures and temporal lobe epilepsy. Kasperaviciute and colleagues undertook a genome wide association study in 1,018 patients with mesial temporal lobe epilepsy and 7,552 controls [5]. Meta- analysis in these cases revealed a association for mesial temporal lobe epilepsy with hippocampal sclerosis and febrile seizures within an intron of the SCN1A gene. When looking at a
J Neurol (2014) 261:837–841
cohort of 172 individuals with febrile seizures who did not develop epilepsy on follow up, this association was not found. A related issue has been studied by the FEBSTAT study team, which investigated the link between febrile seizures and its association with hippocampal sclerosis [6]. In their study, 228 children with either febrile status epilepticus (FSE), defined as febrile seizures lasting 30 min or longer/ repetitive febrile seizures, or 38 children with simple febrile seizures were recruited prospectively. They obtained MRI scans both in the acute phase, i.e., after the febrile seizure/status epilepticus and in some children also after 12 months follow up. The first scan showed abnormalities suggestive of hippocampal sclerosis in *10 % (22/226 children) of patients from the FSE group; Interestingly, in two children, hippocampal sclerosis was observed in the first scan after FSE. In 14 of these 22 children with an abnormal scan, follow up imaging was available. Ten scans showed hippocampal abnormalities suggestive of hippocampal atrophy or hippocampal hypoplasia on follow up. With this carefully designed study, the authors provide a temporal evolution of hippocampal changes in patient suffering from FSE. Interestingly, these changes are only seen in a minority of patients suffering from FSE, but within this minority, changes often seem to progress to a definite hippocampal pathology suggesting that this is the cohort at risk, which may be targeted in future interventional trials. Together these two studies emphasise the complex interplay between genetic factors and environmental triggers. PRRT2 and LGI1 Another advance in 2013 in epilepsy genetics, has been the expansion of the phenotypic spectrum and the discovery of new mutations within PRRT2. PRRT2 itself has been discovered in 2012 as the gene underlying paroxysmal kinesigenic dyskinesia with infantile convulsions [7]. Although discovered in 2012, novel PRRT2 mutations in sporadic and familial Caucasian cases of PKD and ICCA have been added to the known ones recently [8]. There have been several reports highlighting that PRRT2 mutations are found in hemiplegic migraine [9, 10], migraine with aura [11] and also in torticollis [9]. These different phenotypic manifestations suggest that certain genetic mutations may affect pathways or networks of proteins which are the basis of different paroxysmal, movement disorders or migraine. The overlap of movement disorders and epilepsy has been supported by the discovery of leucine-rich glioma inactivated-1 (LGI1) related seizures. Seizures in patients suffering from encephalitis due to autoantibodies against LGI1, a component of the voltage-
839
gated potassium channel, have a characteristic semiology and involve the dystonic posturing of the face and arm. A recent case study has highlightes that these seizures involve both subcortical and cortical networks [12]. There are several lessons to learn from these new studies. First, there seems to be a recognition of the fact that mutations in the same gene can lead to different phenotypes possibly highlighting the diversity of the function of the gene. Second, this also highlights the need for functional studies in epilepsy and other neurological diseases. It is likely that those functional studies rather than identification of the underlying gene will translate to treatment. It is also likely that several genetic mutations are converging to give rise to the same functional deficit. HPV16 in focal cortical dysplasia Focal cortical dysplasias are common pathologies encountered in pharmacoresistant epilepsy. Within the umbrella term of malformations of cortical development, focal cortical dysplasias have been mainly classified according to morphological characteristics. The presence of balloon cells is a defining feature of focal cortical dysplasia type IIB (FCDIIB), yet further characteristerization of ballon cells and their function was warranted. Chen and colleagues, surprisingly, found HPV16 protein expression in 50 specimen of FCDIIB which was not found outside the malformation and in control tissue [13]. These findings have been replicated by another group providing corroborative support for a role of HPV in FCD Type IIB [14]. In addition they found a HPV16 in a small subset of FCDIIA. How these findings are interpreted and whether there is a causal link between FCDs and intrauterine HPV16 infection remains unclear.
Experimental milestones new translational targets New approaches to treat epilepsy are underway and perhaps the most exciting developments in experimental epilepsy have been studies involving viral vector based therapies, optogenetic tools and cell grafting techniques. Optogenetics emerged as a powerful tool to study and manipulate brain function. Light sensitive ion channels encoded by viral vectors, can have both inhibitory and excitatory properties and are activated by light of specific wavelength, hence, the term optogenetics. Paz and colleagues injected viral vectors coding for a light activated channel which hyperpolarizes the membrane upon illumination with light. After induction of stroke in rats using the photothrombotic stroke model, they showed that the thalamus is involved in modulating cortical excitability after cortical injury and that targeting the thalamus is successful
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840
in interrupting electrographic and behavioural seizures [15]. A similar inhibition of seizure activity was shown in a temporal lobe epilepsy model by Krook-Magnuson and colleagues. In their study, optogenetic inhibition of excitatory, or activation of inhibitory cells within the hippocampus aborted seizures [16]. These studies used similar approaches when compared to previous viral vector based therapies in vivo [17], except that the primary target here was the thalamus or hippocampus and not the neocortex. Whether these optogenetic viral vector based approaches are less likely to interrupt cortical function interictally, as the authors claim, remains to be determined. Another exciting study, with possibly translational impact, is a study published by Hunt and colleagues [18]. They implanted progenitor cells from embryonic mice into adult epileptic mice to treat seizures. The progenitor cells were derived from the medial ganglionic eminence (MGE), which is the major source of interneurons in embryonic development. Given that those cells from embryonic donor mice were tagged with GFP, Hunt and colleagues were able to track the fate of the cells in epileptic animals. They found that after bilateral injection of the embryonic MGE cells into the hippocampus of epileptic mice, those cells migrated up to 1.5 mm from the injection site, differentiated into neurons and reduced the occurrence of seizures and spatial learning difficulties in epileptic mice. Both, the viral vector based therapies and the cell based therapies have high translational potential. We hope that some of these studies will be translated to a clinical trial in patients with pharmacoresistant epilepsy, which is not amendable to surgical treatment. Seizure prediction Seizure prediction in epilepsy has been a longstanding goal. Its advantages are obvious, as patients could adjust their lifestyle according to likelihood of seizures occuring in a particular situation (the unpredictability of seizures has a major impact). More importantly, effective seizure prediction would allow therapies such as local drug application to be delivered in a timely manner perhaps preventing seizures alltogether. Several algorithms have been developed, yet clinical applicability remained unclear as there was no prospective study testing efficacy of seizure prediction algorithms. In 2013 a proof-of-concept study by Cook and colleagues investigated feasibility and performance of a seizure detection device and algorithm [19]. Fifteen Patients were implanted with intracranial electrode arrays used to collect intracranial electroencephalogram (iEEG). The device underwent a four months training phase in which the algorithm was trained to detect seizure likelihood based on the patient’s own EEG signature classifying low, moderate and high probability of seizure
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occurrence. In the following four months ‘‘advisory’’ period the algorithm efficiently predicted seizures better than would be expected by chance in nine patients. With regards to safety, there were 11 device-related events within four months of implantation. Two of those were serious and were migrations of the device in one patient and seroma in the other. At 12-month follow up, another two serious adverse events were noted, which in both patients required explantation of the device. In addition to providing safety and efficacy data on their seizure prediction device, the study presented by Cook and colleagues, for the first time collected intracranial data for a long period which could be compared to the patient’s seizure diary. They found a discrepancy between the seizure counts in the diary when compared to the seizure count from iEEG in six of 11 patients in whom iEEG was recorded continuously, i.e., who met the study criteria, with many seizures being not reported by the patients. Whereas the utility of a seizure detection device in clinical practice has not been sufficiently addressed by this pilot study, this study certainly contributed to further advancing the field of seizure prediction with the hope that follow up studies might build on the current, encouraging findings. In addition, it has corroborated some of the concerns with regards to reliability of seizure diaries warranting new research into automated seizure detection devices.
Conclusion There continue to be considerable advances in epilepsy research that will possibly translate into therapies to prevent epilepsy and its co-morbidities and to treat people with pharmacoresistant epilepsy. However, despite the size of the problem (over 50 million people with epilepsy worldwide of whom 30 % do not respond adequately to our present therapies), epilepsy research remains poorly funded, and there is a continued need for investment. Acknowledgments This work was supported by Epilepsy Research UK. This work was undertaken at UCLH/UCL, which receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres’ funding scheme.
References 1. Fazel S, Wolf A, La˚ngstro¨m N et al (2013) Premature mortality in epilepsy and the role of psychiatric comorbidity: a total population study. Lancet 382:1646–1654. doi:10.1016/S01406736(13)60899-5 2. Ryvlin P, Nashef L, Lhatoo SD et al (2013) Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 12:966–977. doi:10.1016/S1474-4422(13)70214-X
J Neurol (2014) 261:837–841 3. Tomson T (2000) Mortality in epilepsy. J Neurol 247:15–21 4. Allen AS, Epi4 K Consortium, Epilepsy Phenome/Genome Project et al (2013) De novo mutations in epileptic encephalopathies. Nature 501:217–221. doi:10.1038/nature12439 5. Kasperaviciute D, Catarino CB, Matarin M et al (2013) Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A. Brain 136:3140–3150. doi:10. 1093/brain/awt233 6. Lewis DV, Shinnar S, Hesdorffer DC et al (2013) Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol. doi:10.1002/ana.24081 7. Lee H-Y, Huang Y, Bruneau N et al (2012) Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 1:2–12. doi:10.1016/j.celrep.2011.11.001 8. Becker F, Schubert J, Striano P et al (2013) PRRT2-related disorders: further PKD and ICCA cases and review of the literature. J Neurol 260:1234–1244. doi:10.1007/s00415-012-6777-y 9. Dale RC, Gardiner A, Antony J, Houlden H (2012) Familial PRRT2 mutation with heterogeneous paroxysmal disorders including paroxysmal torticollis and hemiplegic migraine. Dev Med Child Neurol 54:958–960. doi:10.1111/j.1469-8749.2012. 04394.x 10. Gardiner AR, Bhatia KP, Stamelou M et al (2012) PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine. Neurology 79:2115–2121. doi:10.1212/ WNL.0b013e3182752c5a 11. Sheerin U-M, Stamelou M, Charlesworth G et al (2013) Migraine with aura as the predominant phenotype in a family with a PRRT2 mutation. J Neurol 260:656–660. doi:10.1007/s00415012-6747-4
841 12. Boesebeck F, Schwarz O, Dohmen B et al (2013) Faciobrachial dystonic seizures arise from cortico-subcortical abnormal brain areas. J Neurol 260:1684–1686. doi:10.1007/s00415-013-6946-7 13. Chen J, Tsai V, Parker WE et al (2012) Detection of human papillomavirus in human focal cortical dysplasia type IIB. Ann Neurol 72:881–892. doi:10.1002/ana.23795 14. Liu S, Lu L, Cheng X et al (2013) Viral infection and focal cortical dysplasia. Ann Neurol. doi:10.1002/ana.24037 15. Paz JT, Davidson TJ, Frechette ES et al (2013) Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat Neurosci 16:64–70. doi:10.1038/nn.3269 16. Krook-Magnuson E, Armstrong C, Oijala M, Soltesz I (2013) Ondemand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Nat Commun 4:1376. doi:10.1038/ncomms2376 17. Wykes RC, Heeroma JH, Mantoan L et al (2012) Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Sci Transl Med 4:161ra152. doi:10.1126/sci translmed.3004190 18. Hunt RF, Girskis KM, Rubenstein JL et al (2013) GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat Neurosci 16:692–697. doi:10.1038/nn.3392 19. Cook MJ, O’Brien TJ, Berkovic SF et al (2013) Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol 12:563–571. doi:10.1016/S14744422(13)70075-9
123
NEUROLOGICAL UPDATE
Recent advances in epilepsy Stjepana Kovac • Matthew C. Walker
Received: 19 February 2014 / Accepted: 20 February 2014 / Published online: 4 March 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract We have reviewed some of the important studies published within the last 18 months that have advanced our understanding of the epilepsies, their aetiology and treatment. Clinical studies have revealed new insights into old themes including seizure prediction, mortality in epilepsy, febrile seizures and the pathophysiology of focal cortical dysplasias. The rapid advances in genetics and particularly whole exome sequencing have had an impact on our understanding of epileptic encephalopathies, and the aetiology of hippocampal sclerosis. Experimental research techniques such as viral vector gene delivery, optogenetics and cell based transplantation techniques have set the framework for novel approaches to the treatment of pharmacoresistant epilepsy. These few examples are indicative of the great strides that have recently been made in epilepsy research. Keywords Epilepsy Epilepsy genetics SUDEP Optogenetic Viral vectors
Introduction The epilepsies are a collection of conditions that result not only in spontaneous seizures, but also other morbidities (in particular psychiatric disease and increased mortality). The relative contribution of both genetic and environmental factors to the aetiology of individual epilepsies are now being realised, and we are entering a new era in the treatment of neurological disease in which both stem cells and gene therapies have become realistic possibilities. Moreover, advances in technology have meant that reliable S. Kovac (&) M. C. Walker Institute of Neurology, University College London, London, UK e-mail: [email protected]
seizure prediction may be possible. Here, we present a few of the studies from the last 18 months that emphasise and illustrate these advances.
Epilepsy morbidities Mortality and psychiatric disease in epilepsy The increased mortality that is associated with epilepsy has long been recognised, and research advances into the nature and mechanisms of these deaths continue to be made. Two important studies in 2013 illustrate the importance of psychiatric comorbidities and their impact on mortality and also possible mechanisms underlying sudden unexpected death in epilepsy (SUDEP). A large retrospective population study compared death rates in 69,995 patients with epilepsy born between 1954 and 2009 in Sweden to general population controls and unaffected siblings [1]. There was an 11-fold increase in the odds of premature mortality in patients suffering from epilepsy when compared to the general population and their healthy siblings. Sixteen percent of these deaths in patients suffering from epilepsy were related to external causes and this made up the largest category of deaths that was not related to underlying disease process. These deaths included suicide and accidents. Psychiatric comorbidity was high in patients when compared to control (18 vs. 3.5 %) and, therefore, may explain this finding. This study also highlighted preventable causes of death in epilepsy such as safety precautions to prevent accidents, particularly non-vehicle accidents which were high among patients suffering from epilepsy when compared to controls. The other important priorities identified are psychiatric co-
123
838
morbidities such as depression and substance abuse, potentially contributing to high risk of suicide seen in patient suffering from epilepsy. Another key study, which has contributed to understanding mortality in epilepsy, was a multicentre study focussing on SUDEP in epilepsy monitoring units [2]. SUDEP has been recognized as a cause for mortality in epilepsy and several risk factors have been suggested to play a role. Uncontrolled generalized tonic–clonic seizures play a pivotal role, yet the mechanisms behind SUDEP are far from fully understood [3]. MORTEMUS was a muliticentre study pooling data from 147 epilepsy monitoring units over a period of two years to investigate the mechanisms of SUDEP. Twenty-nine cardiorespiratory events were reported during this period. Of these, 16 were classified as SUDEP, nine as near SUDEP and four deaths were recorded from other causes. The strength of this study was that for the first time a considerable number of SUDEPs were recorded in real time with video-EEG. The key finding was that SUDEP in the patients recorded was preceded by a generalized tonic–clonic seizure followed by a period of normal or increased heart rate and respiratory rate. After this, a pattern of central apnoea, bradycardia and transient asystole occurred, together with EEG depression. In a third of patients asystole was terminal, whereas in the other patients there was a brief period of recovery of cardiac function with abnormal respiratory function and subsequent apnoea finally leading to a second, terminal asystole. The study concludes that postictal neurovegetative breakdown after generalized tonic–clonic seizures is a major culprit for SUDEP. Moreover, extrapolating their data, there might be a window for early interventions. In their series, patient classified as near SUDEP had successful resuscitatation within 3 min after onset of apnoea. This study provides considerable insight into the pathophysiological mechanisms involved in SUDEP and corroborates previous findings highlighting that effective seizure control or control of generalized tonic–clonic seizures is the best strategy to prevent SUDEP.
Aetiology of the epilepsies The increasing role that genetic factors play in the aetiology of the epilepsies has become increasingly apparent but environmental factors, including infection, also play a critical role. Here, we review some of the genetic studies but also include two important studies of epilepsy epidemics. Epilepsy genetic New techniques such as whole exome sequencing have expedited and fuelled discoveries in genetics. With regards
123
J Neurol (2014) 261:837–841
to epilepsy, one exciting project was completed in 2013 by the Epi4 consortium. The consortium investigated 149 patients with infantile spasms and 115 patients with Lennox–Gastaut syndrome as two classic forms of epileptic encephalopathies. By exome sequencing of patients and their parents (trio analysis), this study found 329 de novo mutations. Some of those de novo mutations have been found in genes which have been previously linked to epilepsy/epileptic encephalopathy such as CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2. MTOR and NEDD4L. In addition the authors found mutations in two new genes, GABRB3 and ALG13, which have previously not been linked to epileptic encephalopathy [4]. GABRB3 mutations occurred in four patients and ALG13 in two. Mutations in GABRB3 and ALG have been previously associated with autism spectrum disorder with the new study broadening the phenotype of these mutations to include epileptic encephalopathy. The study found substantial interconnections between the genes found and autism and intellectual disability gene networks. Some of the genes with de novo mutations in their cohort have been identified in patients with intellectual disorders and autism spectrum disorder highlighting the phenotypic variablitity of these genes. There are two interesting aspects here. First, this study highlights the importance of whole exome sequencing rather than screening a restricted panel of genes in identifying mutations in patients suffering from epilepsy. Second, the network analysis performed highlights hubs of genes which underlie specific dysfunction such as seizures and autism spectrum disorder. It is possible that targeting the function of these genes is pivotal for major breakthroughs in therapeutic approaches. Febrile seizures Epileptic encephalopathies are devastating syndromes, which are distinct from the most frequent cause of drugresistant epilepsy—mesial temporal lobe epilepsy. However, some epileptic encephalopathies, such as epileptic encephalopathies due to SCN1A mutations (Dravet syndrome and GEFS plus spectrum epilepsies) share common features with mesial temporal lobe epilepsies. In both epilepsies, febrile seizures are often found in the past medical history raising the question whether they may share some genetic similarities. This has been addressed by a recent study which sheds light on the association of SCN1A, febrile seizures and temporal lobe epilepsy. Kasperaviciute and colleagues undertook a genome wide association study in 1,018 patients with mesial temporal lobe epilepsy and 7,552 controls [5]. Meta- analysis in these cases revealed a association for mesial temporal lobe epilepsy with hippocampal sclerosis and febrile seizures within an intron of the SCN1A gene. When looking at a
J Neurol (2014) 261:837–841
cohort of 172 individuals with febrile seizures who did not develop epilepsy on follow up, this association was not found. A related issue has been studied by the FEBSTAT study team, which investigated the link between febrile seizures and its association with hippocampal sclerosis [6]. In their study, 228 children with either febrile status epilepticus (FSE), defined as febrile seizures lasting 30 min or longer/ repetitive febrile seizures, or 38 children with simple febrile seizures were recruited prospectively. They obtained MRI scans both in the acute phase, i.e., after the febrile seizure/status epilepticus and in some children also after 12 months follow up. The first scan showed abnormalities suggestive of hippocampal sclerosis in *10 % (22/226 children) of patients from the FSE group; Interestingly, in two children, hippocampal sclerosis was observed in the first scan after FSE. In 14 of these 22 children with an abnormal scan, follow up imaging was available. Ten scans showed hippocampal abnormalities suggestive of hippocampal atrophy or hippocampal hypoplasia on follow up. With this carefully designed study, the authors provide a temporal evolution of hippocampal changes in patient suffering from FSE. Interestingly, these changes are only seen in a minority of patients suffering from FSE, but within this minority, changes often seem to progress to a definite hippocampal pathology suggesting that this is the cohort at risk, which may be targeted in future interventional trials. Together these two studies emphasise the complex interplay between genetic factors and environmental triggers. PRRT2 and LGI1 Another advance in 2013 in epilepsy genetics, has been the expansion of the phenotypic spectrum and the discovery of new mutations within PRRT2. PRRT2 itself has been discovered in 2012 as the gene underlying paroxysmal kinesigenic dyskinesia with infantile convulsions [7]. Although discovered in 2012, novel PRRT2 mutations in sporadic and familial Caucasian cases of PKD and ICCA have been added to the known ones recently [8]. There have been several reports highlighting that PRRT2 mutations are found in hemiplegic migraine [9, 10], migraine with aura [11] and also in torticollis [9]. These different phenotypic manifestations suggest that certain genetic mutations may affect pathways or networks of proteins which are the basis of different paroxysmal, movement disorders or migraine. The overlap of movement disorders and epilepsy has been supported by the discovery of leucine-rich glioma inactivated-1 (LGI1) related seizures. Seizures in patients suffering from encephalitis due to autoantibodies against LGI1, a component of the voltage-
839
gated potassium channel, have a characteristic semiology and involve the dystonic posturing of the face and arm. A recent case study has highlightes that these seizures involve both subcortical and cortical networks [12]. There are several lessons to learn from these new studies. First, there seems to be a recognition of the fact that mutations in the same gene can lead to different phenotypes possibly highlighting the diversity of the function of the gene. Second, this also highlights the need for functional studies in epilepsy and other neurological diseases. It is likely that those functional studies rather than identification of the underlying gene will translate to treatment. It is also likely that several genetic mutations are converging to give rise to the same functional deficit. HPV16 in focal cortical dysplasia Focal cortical dysplasias are common pathologies encountered in pharmacoresistant epilepsy. Within the umbrella term of malformations of cortical development, focal cortical dysplasias have been mainly classified according to morphological characteristics. The presence of balloon cells is a defining feature of focal cortical dysplasia type IIB (FCDIIB), yet further characteristerization of ballon cells and their function was warranted. Chen and colleagues, surprisingly, found HPV16 protein expression in 50 specimen of FCDIIB which was not found outside the malformation and in control tissue [13]. These findings have been replicated by another group providing corroborative support for a role of HPV in FCD Type IIB [14]. In addition they found a HPV16 in a small subset of FCDIIA. How these findings are interpreted and whether there is a causal link between FCDs and intrauterine HPV16 infection remains unclear.
Experimental milestones new translational targets New approaches to treat epilepsy are underway and perhaps the most exciting developments in experimental epilepsy have been studies involving viral vector based therapies, optogenetic tools and cell grafting techniques. Optogenetics emerged as a powerful tool to study and manipulate brain function. Light sensitive ion channels encoded by viral vectors, can have both inhibitory and excitatory properties and are activated by light of specific wavelength, hence, the term optogenetics. Paz and colleagues injected viral vectors coding for a light activated channel which hyperpolarizes the membrane upon illumination with light. After induction of stroke in rats using the photothrombotic stroke model, they showed that the thalamus is involved in modulating cortical excitability after cortical injury and that targeting the thalamus is successful
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in interrupting electrographic and behavioural seizures [15]. A similar inhibition of seizure activity was shown in a temporal lobe epilepsy model by Krook-Magnuson and colleagues. In their study, optogenetic inhibition of excitatory, or activation of inhibitory cells within the hippocampus aborted seizures [16]. These studies used similar approaches when compared to previous viral vector based therapies in vivo [17], except that the primary target here was the thalamus or hippocampus and not the neocortex. Whether these optogenetic viral vector based approaches are less likely to interrupt cortical function interictally, as the authors claim, remains to be determined. Another exciting study, with possibly translational impact, is a study published by Hunt and colleagues [18]. They implanted progenitor cells from embryonic mice into adult epileptic mice to treat seizures. The progenitor cells were derived from the medial ganglionic eminence (MGE), which is the major source of interneurons in embryonic development. Given that those cells from embryonic donor mice were tagged with GFP, Hunt and colleagues were able to track the fate of the cells in epileptic animals. They found that after bilateral injection of the embryonic MGE cells into the hippocampus of epileptic mice, those cells migrated up to 1.5 mm from the injection site, differentiated into neurons and reduced the occurrence of seizures and spatial learning difficulties in epileptic mice. Both, the viral vector based therapies and the cell based therapies have high translational potential. We hope that some of these studies will be translated to a clinical trial in patients with pharmacoresistant epilepsy, which is not amendable to surgical treatment. Seizure prediction Seizure prediction in epilepsy has been a longstanding goal. Its advantages are obvious, as patients could adjust their lifestyle according to likelihood of seizures occuring in a particular situation (the unpredictability of seizures has a major impact). More importantly, effective seizure prediction would allow therapies such as local drug application to be delivered in a timely manner perhaps preventing seizures alltogether. Several algorithms have been developed, yet clinical applicability remained unclear as there was no prospective study testing efficacy of seizure prediction algorithms. In 2013 a proof-of-concept study by Cook and colleagues investigated feasibility and performance of a seizure detection device and algorithm [19]. Fifteen Patients were implanted with intracranial electrode arrays used to collect intracranial electroencephalogram (iEEG). The device underwent a four months training phase in which the algorithm was trained to detect seizure likelihood based on the patient’s own EEG signature classifying low, moderate and high probability of seizure
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occurrence. In the following four months ‘‘advisory’’ period the algorithm efficiently predicted seizures better than would be expected by chance in nine patients. With regards to safety, there were 11 device-related events within four months of implantation. Two of those were serious and were migrations of the device in one patient and seroma in the other. At 12-month follow up, another two serious adverse events were noted, which in both patients required explantation of the device. In addition to providing safety and efficacy data on their seizure prediction device, the study presented by Cook and colleagues, for the first time collected intracranial data for a long period which could be compared to the patient’s seizure diary. They found a discrepancy between the seizure counts in the diary when compared to the seizure count from iEEG in six of 11 patients in whom iEEG was recorded continuously, i.e., who met the study criteria, with many seizures being not reported by the patients. Whereas the utility of a seizure detection device in clinical practice has not been sufficiently addressed by this pilot study, this study certainly contributed to further advancing the field of seizure prediction with the hope that follow up studies might build on the current, encouraging findings. In addition, it has corroborated some of the concerns with regards to reliability of seizure diaries warranting new research into automated seizure detection devices.
Conclusion There continue to be considerable advances in epilepsy research that will possibly translate into therapies to prevent epilepsy and its co-morbidities and to treat people with pharmacoresistant epilepsy. However, despite the size of the problem (over 50 million people with epilepsy worldwide of whom 30 % do not respond adequately to our present therapies), epilepsy research remains poorly funded, and there is a continued need for investment. Acknowledgments This work was supported by Epilepsy Research UK. This work was undertaken at UCLH/UCL, which receives a proportion of funding from the Department of Health’s NIHR Biomedical Research Centres’ funding scheme.
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