Cover image for Vol. 57 Issue 9

Edited By: Astrid Nehlig, PhD, Michael Sperling, MD. and Gary W. Mathern, MD.

Impact Factor: 4.706

ISI Journal Citation Reports © Ranking: 2015: 25/192 (Clinical Neurology)

Online ISSN: 1528-1167

Editors' Choice Articles: Free Access

May 2014 articles from the Editors

Antiepileptic drug use in seven electronic health record databases in Europe: A methodological comparison
Mark C. H. de Groot, Markus Schuerch, Frank de Vries, Ulrik Hesse, Belén Oliva, et al.

Up to 1.1% of the European population is estimated to use antiepileptic drugs (AEDs). The annual prevalence of AED prescribing apparently differs among European countries probably from different type of data sources and time periods. This study measured prevalence of AED prescribing across health care data databases in Spain, Denmark, the Netherlands, the UK, and Germany between 2001 and 2009. Analyses were stratified by sex, age, and AED and standardized to the European 2008 reference population. Results showed that prevalence of any AED varied from 88 (Netherlands) to 144 per 10,000 (Spain and Denmark) in 2001. In all databases prevalence increased linearly from 6% in Denmark to 15% in Spain each year since 2001. The increase was attributed to an increase in new, recently marketed AEDs while prevalence of older AEDs hardly changed. AED use increased with age for both females and males up to ages of 80-89 years-old and tended to be higher in females than in males from age 40 to 70. Using a standardized methodology showed consistent trends across databases and countries over time. Differences in age and sex distribution explained only part of the variation between countries. Thus remaining variation in AED use was attributed to other differences in national health care systems.

Effects of an Inpatient Rehabilitation Program after Temporal Lobe Epilepsy Surgery and other Factors on Employment two Years after Epilepsy Surgery
Rupprecht Thorbecke, Theodor W. May, Steffi Koch-Stoecker, Alois Ebner, Christian G. Bien and Ulrich Specht

Multiple studies reported on the positive effects of temporal lobe resection on seizure control and quality of life. The employment outcome, though, is more heterogeneous. The effects of postsurgical rehabilitation programs on employment status two years after temporal lobe epilepsy surgery were evaluated in 232 adult patients who had a three week inpatient rehabilitation program immediately after surgery (“Rehab group”) compared with 119 patients who had surgery before such a rehabilitation program existed. In the Rehab group, 139 (59.9%) subjects attended the rehabilitation program. Preoperatively, both groups did not differ in variables relevant for employment, including employment rate. Two years after surgery, the rate of unemployment had decreased in the Rehab group from 38.4% to 27.6% (p<0.001), and slightly increased in the control group (37.8% to 42.0%; n.s.), resulting in a difference of 14.4% in favor of the Rehab group (p=0.008). General unemployment rates during the two observation periods were similar. Besides the offer of rehabilitation support (“Rehab group”) and preoperative employment, seizure outcome, diagnosis of a personality disorder preoperatively, and age at surgery were shown as negative predictors for employment post-surgery in multivariate regression analysis. These data show that a three week inpatient rehabilitation program after temporal lobe epilepsy surgery seems to improve employment status two years after surgery.

April 2014 articles from the Editors

ILAE Official Report--A practical clinical definition of epilepsy
Robert S. Fisher, Carlos Acevedo, Alexis Arzimanoglou, Alicia Bogacz, J. Helen Cross, et al.

The 2005 International League Against Epilepsy (ILAE) defined Epilepsy as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. This definition was practically applied as having two unprovoked seizures more than 24 hours apart. While useful the conceptual definition ran into problems when being applied in the clinical setting.As a consequence, the ILAE commissioned a Task Force to revisit this issue and formulate an operational definition of epilepsy. The results of that work are published in this issue of Epilepsia where epilepsy is defined as:

1. At least two unprovoked (or reflex) seizures occurring more than 24 hours apart;
2. One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years;
3. Diagnosis of an epilepsy syndrome.

The task force further defined that Epilepsy is considered to be resolved for individuals who either had an age-dependent epilepsy syndrome but are now past the applicable age without seizures or those who have remained seizure-free for the last 10 years and off anti-seizure medicines for at least the last 5 years.

The new definition is a much needed advance for those that treat patients with epilepsy, but should still be considered a ‘work in progress’.Some of the recommendations of the task force were made on expert consensus rather than. Those issues are addressed in the Commentaries related to the task force report, and in addition we are asking for the public’s input on some of the assumptions.

Please go to http://surveys.verticalresponse.com/a/show/1539433/ea840f4206/0 and complete a poll related to the new definition of seizures and epilepsy.

March 2014 articles from the Editors

Emergency management of febrile status epilepticus: Results of the FEBSTAT study
Syndi Seinfeld, Shlomo Shinnar, Shumei Sun, Dale C. Hesdorffer, Xiaoyan Deng, Ruth C. Shinnar, Kathryn O’Hara, Douglas R. Nordli Jr., L. Matthew Frank, William Gallentine, Solomon L. Moshé, John M. Pellock and the FEBSTAT study team (2014)

Febrile status epilepticus (FSE) is often a child’s first seizure and families are rarely educated about emergency treatment. In this study, 199 subjects, age 1 month to 6 years, were recruited from 2002 to 2010 as part of a prospective, multicenter study of consequences of FSE. 179 children received at least one antiepileptic drug (AED) to terminate FSE and more than one AED was required in 140 patients (70%).  Mean seizure duration was 81 minutes for subjects given medication prior to ED and 95 minutes for those who did not. Median time from the first dose of AED to end of seizure was 38 minutes. Initial dose of lorazepam or diazepam was suboptimal in 32 of 166 patients (19%). Median seizure duration for respiratory support group was 83 vs 58 minutes for nonrespiratory vs respiratory support group. Reducing time from seizure onset to AED initiation reduced significantly seizure duration. It appears that FSE rarely stops spontaneously, is fairly resistant to medications and even with treatment persists for a significant period of time.  Earlier onset of treatment results in shorter total seizure duration. Thus a standard pre-hospital treatment protocol should be used nationwide and education of EMS responders is necessary.

Two year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS system pivotal trial
Christianne N. Heck, David King-Stephens, Andrew D. Massey, Dileep Nair, Barbara C. Jobst, Gregory L. Barkley, Vicenta Salanova, Andrew J. Cole, Michael C. Smith, Ryder P. Gwinn, Christopher Skidmore, Paul C. Van Ness, Gregory K. Bergey, Yong D. Park, Ian Miller, Eric Geller, Paul A. Rutecki, Richard Zimmerman, David C. Spencer, Alica Goldman, Jonathan C. Edwards, James W. Leiphart, Robert E. Wharen, James Fessler, Nathan B. Fountain, Gregory A. Worrell, Robert E. Gross, Stephan Eisenschenk, Robert B. Duckrow, Lawrence J. Hirsch, Cormac O'Donovan, Felice T. Sun, Tracy A. Courtney, Cairn G. Seale and Martha Morrell (2014)

The objective of this randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS® System) was to demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy in adults with medically intractable partial onset seizures arising from one or two seizure foci. 1 month post-implantation subjects with medically intractable partial onset seizures from one or two foci were randomized 1:1 to active or sham stimulation. After the fifth post-implant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of post-implantation follow-up. The study showed that at the end of the blinded period seizures decreased by 38% vs 17% in the active vs sham stimulation group. The median percent reduction in seizures in the OLP progressively improved, reaching 44% at 1 year and 53% at 2 years. The serious adverse event rate related to implantation of a medical device was not different between active and sham stimulation. There were no adverse effects on neuropsychological function or mood. Thus, stimulation to the seizure focus reduced the frequency of partial onset seizures acutely, improved seizure reduction over time, was well tolerated and acceptably safe. This study demonstrates that the RNS System provides an additional treatment option for patients with medically intractable partial onset seizures.

February 2014 articles from the Editors

Evaluation of Kilifi Epilepsy Education Programme (KEEP): A randomised controlled trial
Fredrick Ibinda, Caroline K. Mbuba, Symon M. Kariuki, Eddie Chengo, Anthony K. Ngugi, Rachael Odhiambo, Brett Lowe, Greg Fegan, Julie A. Carter Charles R. Newton (2014)

The epilepsy treatment gap is largest in resource-poor countries. This randomized control trial evaluated the efficacy of a one-day health education program in a rural area in Kenya. The primary outcome was adherence to anti-epileptic drugs (AEDs) as measured by blood drug levels, and the secondary outcomes were seizure frequency and Kilifi Epilepsy Beliefs and Attitudes Scores (KEBAS). The study comprised 738 persons with epilepsy (PWE) that were randomized to the intervention (education) or non-intervention group. Data were collected at baseline and one year after the education intervention; 581 PWE were assessed at both time points. At the end of the study, 105 PWE from the intervention group and 86 from the non-intervention groups gave blood samples which were assayed for the most common AEDs (phenobarbital, phenytoin, carbamazepine). Both experimental groups adhered to AEDs based on detectable drug levels and self-report. The beliefs about traditional causes of epilepsy, cultural treatment and negative stereotypes were reduced in the intervention compared with the non-intervention group. There was no difference in seizure frequency between both groups. In both groups, improved therapeutic adherence was positively associated with positive change in beliefs about risks of epilepsy and the absence of non-traditional religious beliefs. Positive changes in KEBAS were associated with having tertiary education as compared with none. This study shows that health education improves knowledge about epilepsy but a single contact does not improve adherence which might need sustained education.

A potassium leak channel silences hyperactive neurons and ameliorates status epilepticus
Deblina Dey, Veit-Simon Eckle, Iuliia Vitko, Kyle A. Sullivan, Zofia M. Lasiecka, Bettina Winckler, Ruth L. Stornetta, John M. Williamson, Jaideep Kapur and Edward Perez-Reyes (2014)

TREK-1 (KCNK2) is a two-pore domain K+ channel highly expressed in the nervous system where it modulates neuronal excitability. The resting activity of TREK-1 channels drive the membrane potential closer to the K+ equilibrium potential (-80 mV), and hyperpolarize neurons. The authors developed a constitutively active K+mutant leak channel (TREK-M) to validate its ability to silence hyperactive neurons. They found that TREK-M inhibited neuronal firing by hyperpolarizing the resting membrane potential and decreasing input resistance in hippocampal neurons in culture. Adeno-associated virus (AAV) delivery of TREK-M to animals before lithium-pilocarpine SE initiation decreased the duration of SE by 50% and reduced neuronal death in areas targeted by the AAV injection (hippocampus and entorhinal cortex). These findings demonstrate that TREK-M can silence hyperexcitable neurons and opens the possibility for alternative gene therapy treatment of SE and for studies of AAV-TREK-M's effect on spontaneous seizures.

January 2014 articles from the Editors

The Editors selected three studies this month that evaluate the efficacy, safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Combined, the three studies show the efficacy and tolerance of 20-150 mg/day BRV as adjunctive therapy in adult patients with difficult to control mostly focal epilepsy.

Study 1: EPI-00353-2013: Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a Phase III, double-blind, randomized, placebo-controlled, flexible dose trial
Patrick Kwan, Eugen Trinka, Wim Van Paesschen, Ivan Rektor, Martin E Johnson, Sarah Lu (2013)

This Phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT00504881) was performed in 480 adult (16–70 years) patients with uncontrolled focal (n=431) or generalized (n=49) epilepsy. Ninety percent of patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events. The most frequent adverse effects were headache, somnolence, and dizziness. The incidence of psychiatric adverse effects reached about 12% with BRV and PBO. In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group over PBO was 7.3% (p=0.125). In patients with generalized seizures, the number of seizure days/week decreased from 1.42 at baseline to 0.63 in BRV-treated patients, and from 1.47 at baseline to 1.26 in PBO-treated patients. Thus, adjunctive BRV given at individualized tailored doses (20–150 mg/day) was well tolerated in adults with uncontrolled epilepsy.

Study 2: EPI-00528-2013: Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: a Phase III randomized, double-blind, placebo-controlled trial
Victor Biton, Samuel F Berkovic, Bassel Abou-Khalil, Michael R Sperling, Martin E Johnson, Sarah Lu(2013)

This study evaluated the efficacy, safety/ tolerability of adjunctive BRV in adults with uncontrolled focal seizures. It was a prospective, multicenter, randomized, double-blind, placebo controlled, parallel-group, fixed-dose trial (N01253; NCT00464269) on adults (16−70 years) with well-characterized focal epilepsy not fully controlled despite treatment with 1 or 2 AEDs. Patients experiencing ≥8 focal-onset seizures, secondarily generalized or not, were randomized to receive twice-daily placebo (PBO) or BRV (5, 20, or 50 mg/day) or placebo (PBO) without titration. A total of 361/396 completed the study. Percent reduction in focal-onset seizure frequency/week and /28 days over PBO reached 12.8% and 22.0%, respectively for BRV 50 mg/day but was not significant at lower doses. In the BRV 50 mg/day group, the ≥50% responder rate reached 32.7% vs. 16.7% for PBO (p=0.008). Adverse events reported by ≥5% patients were somnolence, dizziness, fatigue, influenza, insomnia, nasopharyngitis, vomiting, diarrhea, urinary tract infection, and nausea. Thus, in uncontrolled focal-onset seizures adjunctive BRV at a daily dose of 50 mg was associated with significant reductions in seizure frequency and was generally well tolerated.

Study 3: EPI-00536-2013: Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: results from a double-blind, randomized, placebo-controlled trial
Philippe Ryvlin, Konrad J Werhahn, Barbara Blaszczyk, Martin E Johnson, and Sarah Lu(2013)

This double-blind, randomized, placebo-controlled trial conducted across Europe and India (N01252; NCT00490035) evaluated the efficacy and safety/tolerability of BRV (20, 50, and 100 mg/day) compared with placebo (PBO) in patients aged 16–70 years with uncontrolled focal seizures with/without secondary generalization, despite treatment with 1–2 AEDs. Eligible patients had ≥2 focal seizures/month for 3 months prior to screening and ≥8 focal seizures during the 8-week prospective baseline. Overall, 367/398 patients completed the study and 345/398 patients continued into long-term follow up studies. Percent reduction over PBO in baseline-adjusted focal seizure frequency/week was 6.8%, 6.5%, and 11.7% (p=0.037) for BRV 20, 50 and 100 mg/day, respectively. Median percent reduction from baseline in focal seizure frequency/week was about 30.0% for all BRV dosages compared with 17.0% for PBO. Responder rates (≥50%) were 27.3% at BRV 20 and 50 mg/day, and 36.0% (p=0.023) for BRV 100 mg/day, compared with 20.0% for PBO. Complete seizure freedom was reported by 2/99, 0/99 and 4/100 patients on BRV 20, 50, and 100 mg/day, respectively, compared with 0/100 on PBO. The incidence of adverse effects was higher for BRV (56-63.0%) than PBO (53.0%). The most frequently reported adverse effects in the BRV groups were headache, somnolence, dizziness, and fatigue. In this study of adjunctive BRV (20–100 mg/day) in adults with uncontrolled focal seizures, the dose of 100 mg/day BRV was well-tolerated and effective in reducing baseline-adjusted focal seizure frequency/week and ≥50% responder rate over PBO.

December 2013 articles from Editor-in-Chief Astrid Nehlig

Conceptual distinctions between reflex and non-reflex precipitated seizures in the epilepsies: a systematic review of definitions employed in the research literature
Josephine L. Illingworth and Howard Ring(2013)

In this review, the authors addressed how reflex and non-reflex epilepsies with seizure precipitants are defined and how these concepts are differentiated from one another in practice. In this systematic literature review, definitions of reflex seizures, reflex epilepsies, and precipitation in a non-reflex context were extracted from 161 published definitions extracted from 122 research papers. It appeared that there was very little consistency within definitions and authors used their own definitions even when ILAE definitions were available. This review should help in extending the distinction between reflex and non-reflex epilepsies and allowing progress in ongoing research in this area.

Resting state networks in temporal lobe epilepsy
Mauro Cataldi, Massimo Avoli and Etienne de Villers-Sidani (2013)

The study of brain networks involved in epileptic activity in TLE has traditionally been limited to the hippocampus, limbic structures, and thalamus. A new level of complexity was recently added by evidence that TLE also alters the activity of brain-wide neural networks involved in the control of higher order brain functions, not traditionally linked to epilepsy. In this review, the authors detail the present knowledge on "resting state networks", and concentrate on the default mode network, the attention network, and reward/emotion network. The data reviewed showed important differences in the activity of the major resting state networks in patients with TLE when compared to normal subjects and importantly, these differences were present interictally. The studies indicate that the dysfuction of resting state network could have a role in the genesis of the cognitive and psychiatric comorbidities associated with TLE. Furthermore, these new imaging techniques could represent an opportunity to investigate the origins of and possible better treatments for the disabling cognitive and psychiatric manifestations of TLE.

November 2013 articles from Editor-in-Chief Astrid Nehlig

Prevention of bone loss and vertebral fractures in patients with chronic epilepsy - Antiepileptic drug and osteoporosis prevention trial (ADOPT).
Antonio A. Lazzari, Philip M. Dussault, Manisha Thakore-James, David Gagnon, Errol Baker, Samuel A. Davis and Antoun M. Houranieh (2013)

Osteoporotic fractures is a major health problem associated with the chronic use of AEDs, and is related to reduction of serum levels of vitamin D. In this study, the authors evaluated whether use of a bisphosphonate (risedronate) in addition to calcium and vitamin D in male veteran patients with epilepsy chronically taking AEDs can prevent the loss of bone mineral density (BMD). This was a randomized prospective placebo controlled study, double blinded involving 80 male veterans over two years. BMD significantly improved compared to baseline scans in 70% of the participants, with significantly more at the lumbar spine in the risedronate group than in the placebo group. The authors draw the attention of caregivers to the positive and preventive action of a concurrent supplementation by calcium and vitamin D associated with the chronic use of some AEDs. The addition of a biphosphonate like risedronate improves even more BMD in these patients. Moreover, the use of risedronate plus calcium and vitamin D appeared to prevent the incidence of new vertebral and nonvertebral fractures in this cohort.

Minimum requirements for the diagnosis of psychogenic nonepileptic seizures: A staged approach. A report from the International League Against Epilepsy Nonepileptic Seizures Task Force.
W. Curt LaFrance Jr., Gus A. Baker, Rod Duncan, Laura H. Goldstein and Markus Reuber (2013)

The ILAE has identified psychogenic nonepileptic seizures (PNES) as one of the 10 key neuropsychiatric issues associated with epilepsy. The misdiagnosis of PNES leads to inappropriate treatment of presumed epilepsy, with significant risk of iatrogenic injury, morbidity and cost to patients and to the health care system. An international consensus group of clinician-researchers in epilepsy, neurology, neuropsychology, and neuropsychiatry collaborated with the aim of developing clearguidance on standards for the diagnosis of PNES. This was necessary as video electroencephalogram (EEG) is not available world-wide for every patient. Therefore, the group delineated a staged approach to PNES diagnosis. Using a consensus review of the literature, it evaluated key diagnostic approaches. These included: history, EEG, ambulatory EEG, video EEG/monitoring, neurophysiologic, neurohumoral, neuroimaging, neuropsychological testing, hypnosis, and conversation analysis. Levels of diagnostic certainty were developed including possible, probable, clinically established and documented diagnosis, and based on the availability of history, witnessed event and investigations including video EEG (vEEG). The aim and hope of this report is to provide greater clarity about the process and certainty of the diagnosis ofPNES, with the intent to improve the care for people with epilepsy and nonepileptic seizures.

October 2013 articles from Editor-in-Chief Astrid Nehlig

Microstructural integrity of early- versus late-myelinating white matter tracts in medial temporal lobe epilepsy.
Lee CY, Tabesh A, Benitez A, Helpern JA, Jensen JH, Bonilha L (2013)

In patients with medial temporal lobe epilepsy (MTLE), structural brain damage involves both gray matter (GM) and white matter (WM). Structural abnormalities in MTLE extend beyond the hippocampus, particularly to extrahippocampal and extratemporal limbic regions. This suggests the existence of a pathologic network mechanism evolving from the seizure-onset zone and extending into areas of seizure propagation. In addition, the chronology of myelination during brain development has been recently proposed as an important determinant of WM vulnerability to neurologic diseases. Using diffusional kurtosis imaging scans, the authors explored in 25 patients with MTLE and 36 matched healthy controls the respective vulnerability of late- versus early myelinating WM tracts. It appeared that late-myelinating tracts exhibited a larger decrease in mean, axial, and radial kurtosis compared with early-myelinating tracts. Moreover, the change in radial kurtosis was more pronounced in late-myelinating tracts ipsilateral to the side of seizure onset. These data demonstrate that late-myelinating WM tracts are more sensitive to MTLE-related microstructural damage compared with early-myelinating WM tracts, suggesting that the chronology of myelination may be a factor involved in microstructural damage caused by seizures. These data also raise the possibility that mechanisms leading to WM damage in epilepsy may be the result of a complex interaction between ontogenesis, seizure excitotoxicity and the proximity of the WM pathways to the networks underlying seizure onset.

Seizure predisposition after perinatal hypoxia: Effects of subsequent age and of an epilepsy predisposing gene mutation.
Leonard AS, Hyder SN, Kolls BJ, Arehart E, W Ng KC, Veerapandiyan A, Mikati MA (2013)

Neonatal hypoxia increases the risk for onset of epilepsy later in life. Despite important insights gained from rodent models, mechanisms that could underlie changes in long-term consequences of hypoxia are still not fully understood. In this study on a mouse model, the authors investigated two distinct factors: (1) the impact of developmental age at the occurrence of perinatal hypoxia and (2) the consequences of the insult coupled to the presence of a seizure predisposing mutation. The highest susceptibility to hypoxia-induced seizures (4% O2 over 45 min) in mouse pups was found to occur between PD2 (postnatal day 2) and PD8 with the highest susceptibility recorded at PD6, age at which the reminder of the studies was performed. Seizure susceptibilities to flurothyl-induced seizures during a single exposure and to flurothyl kindling were determined from PD7 to adulthood. A parallel work was performed on heterozygous mice with deletion of one copy of the Kcn1a gene. This gene codes for Kv1.1 voltage-gated potassium channels that modulate action potential generation. The Kcn1a gene predisposes to seizures in humans, its heterozygous mutations predispose to flurothyl-induced seizures in mice and Kv1.1 channels have a role in the processes that follow hypoxia in the developing brain. Hypoxia performed at PD6 in wild-type mice shortened seizure latency in response to single flurothyl exposure only at PD50, not at PD7 or PD28. In addition, perinatal hypoxia at PD6 enhanced the rate of development of flurothyl kindling performed at PD28-38, but not at PD7-17. Kcn1a heterozygous mice subjected to hypoxia at PD6 were more susceptible to flurothyl-induced seizures at PD50 compared to normoxia heterozygous littermates, and to wild-type hypoxia and normoxia mice. In addition, these heterozygous mice exposed to hypoxia at PD6 were the only group in which spontaneous seizures were detected during long-term monitoring. In this mouse model of mild perinatal hypoxia, increased susceptibility to flurothyl-induced seizures and kindling appears after a latent period. The data demonstrate also that a mutation in a susceptibility gene can exacerbate the long-term consequences of hypoxic injury. These findings support the concept that epilepsy predisposing gene mutations could account for at least part of the heterogeneous clinical outcomes after perinatal hypoxia.

September 2013 articles from Editor-in-Chief Philip A. Schwartzkroin

High-dose rapamycin blocks mossy fiber sprouting but not seizures in a mouse model of temporal lobe epilepsy.
Heng K, Haney MM, Buckmaster PS (2013)

The role of granule cell axon (mossy fiber) sprouting in temporal lobe epileptogenesis is unclear and controversial. Rapamycin suppresses mossy fiber sprouting, but its reported effects on seizure frequency are mixed. The authors used high-dose rapamycin (10mg/kg/day) to block mossy fiber sprouting in pilocarpine-treated mice, and then measured the effect on seizure frequency (video monitoring) starting 1 month after status epilepticus, for 1 month. A subset of mice was prepared for anatomical analysis, and mossy fiber sprouting was measured. Extensive mossy fiber sprouting developed in mice that experienced status epilepticus and were treated with vehicle. In rapamycin-treated mice, mossy fiber sprouting was blocked almost to the level of naïve controls. Seizure frequency was similar in vehicle- and rapamycin-treated mice. These findings lead to two important conclusions: First, contrary to common hypothesis, mossy fiber sprouting does not seem to be necessary for epileptogenesis in the mouse pilocarpine model. Second, rapamycin does not have anti-seizure or anti-epileptogenic effects in this model. While these results are important in our understanding of epileptogenesis, the authors appropriately caution that a general conclusion will require an analysis of rapamycin effects in other models.

Hypothermia for pediatric refractory status epilepticus.
Guilliams K, Rosen M, Buttram S, Zempel J, Pineda J, Miller B, Shoykhet M (2013)

Refractory status epilepticus (RSE) is a life-threatening emergency, demonstrating (by definition) significant pharmacoresistance. The authors describe five cases of pediatric RSE treated with mild hypothermia (32-35°C) at two tertiary-care pediatric hospitals between 2009-2012. Retrospective chart review indicated that hypothermia reduced seizure burden during and after treatment in all cases. Prior to initiation of hypothermia, four children received pentobarbital infusions to treat RSE, but relapsed after pentobarbital discontinuation. No child relapsed after treatment with hypothermia. This is the largest pediatric case series reporting treatment of RSE with mild hypothermia, and suggests that even mild hypothermia can decrease seizure burden and may prevent RSE relapse. However, the sample number remains small, and a larger-scale analysis is needed.

August 2013 articles from Editor-in-Chief Simon Shorvon

Epilepsy informatics and an ontology-driven infrastructure for large database research and patient care in epilepsy.
Sahoo SS, Zhang G-Q, Lhatoo SD (2013)

See also Commentaries (in Gray Matters) from P. Bergin and J. Buchhalter (pp.1507-1511).

This review by Sahoo and colleagues is most interesting and adds significantly to the current debate about ‘classification’ in epilepsy. Ontology, as defined in this article in rather obtuse jargon, is ‘the formal representation of knowledge in a given domain that allows both human users and machines to consistently and accurately interpret terms’. The authors make the case for a new approach to the data underpinning classification. As they write in their summary: ‘The epilepsy community increasingly recognizes the need for a modern classification system that can also be closely integrated with effective informatics tools. In the United States, the 2010 reports by the President’s Council of Advisors on Science and Technology (PCAST) identified informatics as a critical resource to improve quality of patient care, drive clinical research, and reduce the cost of healthcare. An effective informatics infrastructure for epilepsy, which is underpinned by a formal knowledge model, can leverage ever increasing amounts of multi-modal data to improve, (a) clinical decision support, (b) access to information for patients and their families, (c) easier data sharing, and (d) accelerate secondary use of clinical data. Modelling the recommendations of the International League Against Epilepsy (ILAE) classification system in the form of an epilepsy domain ontology is essential for consistent use of terminology in a variety of applications, including Electronic Health Records.’ The review introduces the data management issues in epilepsy, and the benefits of an ontology-driven informatics infrastructure. This significant contribution is further discussed in two commentaries in the Gray Matters section of this August issue. In my view, this novel way of looking at classification is very important. It is possible that future generations will wonder why such an approach was not previously taken, and view our informal efforts at classification with a mixture of amusement and disbelief. In the Commentaries, Bergin supports the idea wholeheartedly, points to the difficulties in producing the epilepsy ontology, but remains cautiously optimistic that it will eventually be successful. Buchhalter is also enthusiastic, but recognizes the difficulties. He points to the need to understand the basic concepts of clinical bioinformatics (semantic heterogeneity), and suggests a consortium approach. He points out that a significant challenge will be the requirement for individuals in the epilepsy community to give up a little autonomy in their use of preferred terms and concepts. This project would require a sea change in attitude, but is certainly one worth detailed consideration.

July 2013 articles from Editor-in-Chief Philip A. Schwartzkroin

Structural correlates of impaired working memory in hippocampal sclerosis.
Winston GP, Stretton J, Sidhu MK, Symms MR, Thompson PJ, Duncan JS (2013)

Recent evidence suggests that working memory is compromised in temporal lobe epilepsy (TLE). Functional MRI (fMRI) studies demonstrate working memory involves a bilateral fronto-parietal network, the activation of which is disrupted by hippocampal sclerosis (HS). However, the structural correlates of disrupted working memory in HS have not been explored. Using 3T structural MRI, the authors studied 54 individuals with medically refractory TLE and unilateral HS (29 left) and 28 healthy controls. In assessment of working memory, individuals with left or right HS performed less well than healthy controls. fMRI demonstrated a bilateral fronto-parietal network during the working memory task, with reduced activation of the right parietal lobe in TLE/HS patients. Working memory performance correlated with the gray matter volume of both frontal lobes and white matter integrity within the fronto-parietal network and contralateral temporal lobe. These data provide further evidence that working memory is disrupted in HS, and demonstrate impaired integrity of both grey and white matter in functionally relevant areas. The authors suggest that these gray and white matter deficits form the structural basis of the impairment of working memory, indicating widespread and functionally significant structural changes in patients with apparently isolated HS.

Lacosamide treatment following status epilepticus attenuates neuronal cell loss and alterations in hippocampal neurogenesis in a rat electrical status epilepticus model.
Licko T, Seeger N, Zellinger C, Russmann V, Matagne A, Potschka H (2013)

The putative preventive or disease-modifying effects of drugs may affect epileptogenesis, intrinsic severity and co-morbidities. In this study, the authors assessed the impact of a relatively new AES, lacosamide, on the development of epilepsy and associated cellular alterations. The effect of lacosamide was evaluated in an electrical rat status epilepticus (SE) model; the impact of lacosamide on the development of spontaneous seizures (based on continuous video-/EEG-monitoring), as well as on neuronal cell loss and alterations in hippocampal neurogenesis, were assessed. Neither low- nor high-dose lacosamide affected the development of spontaneous seizures. A dose-dependent neuroprotective effect of lacosamide with significant reduction of neuronal cell loss was observed in the hippocampal CA1 region, as well as in the piriform cortex. In addition, lacosamide attenuated the impact of SE on the rate of hippocampal cell neurogenesis. Interestingly, although lacosamide reduced SE-associated cellular alterations, these data do not support an anti-epileptogenic effect of lacosamide. Thus, the relationship between major cellular effects of this AED and disease-modifying effects of treatment remain to be determined.

Can structural or functional changes following traumatic brain injury in the rat predict the epileptic outcome?
Shultz SR, Cardamone L, Liu YR, Hogan RE, Maccotta L, Wright DK, Zheng P, Koe A, Gregoire M-C, Williams JP, Hicks RJ, Jones NC, Myers DE, O’Brien TJ, Bouilleret V (2013)

June 2013 articles from Editor-in-Chief Philip A. Schwartzkroin

Early developments outcomes in children following convulsive status epilepticus: A longitudinal Study.
Martinos MM, Yoong M, Patil S, Chong WK, Mardari R, Chin RFM, Neville BGR, de Haan M, Scott RC (2013)

Convulsive status epilepticus (CSE) is the most common pediatric neurological emergency and is often associated with unfavorable neurodevelopmental outcomes. In this study, the authors followed the early developmental trajectory of children following CSE in order to better understand the emergence of adverse long-term outcomes. Fifty-four children were prospectively recruited (ages between 1 and 42 months) who had at least one episode of CSE, and were studied at a mean of 38 days following convulsive status epilepticus. Twenty-seven children had prolonged febrile seizures (PFS) and 27 had non-febrile convulsive status epilepticus. Children with non-febrile CSE had a worse developmental outcome than children with PFS (p<0.002), despite there being no differences in seizure characteristics. In contrast to expectations, the PFS group had a worse developmental outcome than healthy controls (p=0.002). There were no significant differences in performance from baseline to one-year follow-up for the 70.4% of children who provided data, and seizure characteristics were not shown to be significant predictors of performance. Given the absence of a change in performance from baseline to follow-up, and the lack of a relationship between seizure characteristics and developmental outcomes, the authors suggest that pre-morbid abilities may be overshadowing any direct effects of CSE itself on outcome.

What predicts enduring intractability in children who appear medically intractable in the first 2 years after diagnosis?
Wirrell EC, Wong-Kisiel LC-L, Mandrekar J, Nickels, KC (2013)

In a population-based retrospectivestudy, 381 children with newly-diagnosed epilepsy were followed for >36 months. Seventy five (19.7%) had early medical intractability (“apparent” medical intractability in the first 2 years). After a median follow-up of 11.7 years, 49% remained intractable. On multivariable analysis, preditors of early medical intractability were neuroimaging abnormality (p=0.0004), abnormal neurological examination at diagnosis (p=0.015) and mode of onset [association was significant for focal vs generalized onset (p0.0001) but not unknown vs generalized onset (p=0.065)]. The only factor predicting for enduring intractability was neuroimaging abnormality (p=0.0006). While a significant minority of children with early medical intractability ultimately achieved seizure control without surgery, those with an abnormal imaging study did poorly. For this subgroup, early surgical intervention is strongly advised to limit co-morbidities of ongoing, intractable seizures. Conversely, a cautious approach is suggested for those with normal imaging, as most will remit with time.

Psychiatric symptoms in children prior to epilepsy surgery differ according to suspected seizure focus.
Salpekar JA, Berl MM, Havens K, Cushner-Weinstein S, Conry JA, Pearl PL, Yaun AL, Gaillard WD (2013)

Children and adolescents with epilepsy have an overrepresentation of psychiatric illness. The goal of this study was to assess psychiatric symptoms in children with medically refractory epilepsy and ascertain whether symptoms were associated with specific localization. Case records were reviewed for 40 children with medically refractory epilepsy at the time of their referral for presurgical evaluation. The majority of the sample had psychiatric diagnoses and behavior problems, well beyond the level reported in chronic epilepsy populations. Additionally, children with temporal lobe seizure foci had more behavioral problem categories rated in the clinically significant range (as identified by parents), and also were more likely to have clinical diagnoses of depression. These results suggest that routine psychiatric evaluation prior to epilepsy surgery may be very important for pediatric patients with medically refractory epilepsy. Psychiatric illness, particularly depression, may be especially prominent for those with temporal lobe seizure foci.

May 2013 articles from Editor-in-Chief Simon A. Shorvon

SCN1A testing for epilepsy: Application in clinical practice.
Hirose S, Scheffer IE, Marini C, Jonghe P, Andermann E, Goldman AM, Kauffman M, Tan NCK, Lowenstein DH, Sisodiya SM, Ottman R, Berkovic SF for the Genetics Commission of the ILAE (2013)

This report is a useful reference guide for genetic testing of SCN1A in practice. SCN1A ισ τηε γενε ενχοδινγ τηε a1 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 epilespy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. The authors make 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, hemi-clonic 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 of 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 neurological deficits apparent at birth or structural abnormalities of the brain.

The authors also note the following cautions in interpreting test results:

(1) Mutational testing of SCN1A involves both conventional DNS 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 electro-clinical 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, promoter or regulatory regions; hence, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype.

(4) Importantly, 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.

Examining factors related to accelerated long-term forgetting in epilepsy using ambulatory EEG monitoring.
Fitzgerald Z, Thayer Z, Mohamed A, Miller LA (2013)

Accelerated forgetting is an interesting phenomenon which may well explain the often-noted discrepancy between a patient's complaint of memory loss and the apparent normality of conventional memory testing when memory is tested at relatively short intervals (e.g., 30 min). Such patients may show substantial loss over longer delay periods (e.g., days or weeks) when compared to healthy control subjects. This pattern of accelerated "long-term forgetting" (ALF) impacts on the patients' everyday lives, yet goes undetected by standard neuropsychological memory tests. Its pathophysiological basis is poorly understood.

By testing memory over a period of concurrent ambulatory EEG, the current study aimed to investigate possible factors contributing to ALF. Thirty-nine patients diagnosed with epilepsy or probable epilepsy underwent 5 days of continuous ambulatory electroencephalography (EEG): Eighteen had normal EEGs, 10 had focal epileptic discharges, 5 had generalized epileptic discharges, and 6 had one or more seizures. Fifteen matched healthy control subjects also participated, but did not undergo EEG. Subjects were taught 13-item word and design lists to criterion, and recall was tested at 30 minutes, 24 hours and 4 days. Subjects also completed questionnaires pertaining to everyday memory and mood.

This group analyses (excluding patients who experienced seizures during monitoring) indicated that patients who experienced generalized discharges during the 24hr to 4 day delay intervals showed higher rates of forgetting for nonverbal information. Those with focal discharges showed ALF between 30 minutes and 4 days for verbal information, while those with normal EEGs over the 4 days recording had no evidence of ALF. Surprisingly, mood and epilepsy variables (such as duration of disease or number of anticonvulsant medications) showed no significant correlation with ALF. Self-report of everyday memory functioning was related to recall at longer delays, but not at 30 minutes.

The findings indicated that ALF in epilepsy is associated with subclinical discharges rather than AEDs, mood or sleep disturbance. Measures of longer-term recall can reveal correlations with subjective everyday memory complaints that are not evident when recall is only tested at a standard (30 minutes) delay interval. This study is a useful contribution to this fascinating topic.

A systematic review of meta-analysis of the role of ABCC2 variants on drug response in patients with epilepsy.
Grover S, Kukreti R (2013)

There is a lot of nonsensical discussion about 'drug resistance' - as if this phenomenon is likely to be due to a single mechanism. In this study, the authors performed a meta-analysis of published studies on the commonly reported genetic variants of ABCC2 as associated with drug response in patients with epilepsy (PWE). In their search of electronic databases, the authors found a total of eight reports, which included 1294 good responders and 1529 poor responders. Of all the commonly reported variants that included c.-24C>T or rs717620, c.1249G>A or rs2273697 (V4171) and c.3972C>T or rs3740066 (l1324l), they observed an overall significant association of high promoter variant c.-24C>T with drug response (TT+CT vs. CC: OR dom=1.38 (1.11-1.71), Pdom=0.004, 12=3%; CT vs. CC: OR co-dom=1.28 (1.02-1.61), Pco-dom=0.03, 12=0%; T vs. C: OR all=1.34 (1.11-1.61), Pall=0.002, 12=35%). However, all the associations were lost after testing for multiple corrections.

Although the authors concluded that the results of their meta-analysis indirectly suggested a possible role of the ABCC2 transporter, the associations were not significant. The authors suggest that further studies are warranted in different ethnic groups to investigate the effects of the ABCC2 haplotypic variants, with stratified analysis on the basis of different phonotypic covariates. I wonder, however, if such analyses will really yield significant new insights.

April 2013 articles from Editor-in-Chief Philip A. Schwartzkroin

Altered sleep regulation in a mouse model of SCN1A-derived Genetic Epilepsy with Febrile Seizures Plus (GEFS+).
Papale LA, Makinson CD, Ehlen JC, Tufik S, Decker MJ, Paul KN, Escayg A (2013)

Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, a role for SCN1A in the regulation of sleep architecture has not been directly examined. Using a mouse model of GEFS+, the authors tested the hypothesis that SCN1A contributes to the regulation of sleep architecture - and therefore that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. They showed, immunohistochemically, expression of Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. In a detailed analysis of sleep and wake electroencephalographic (EEG) patterns (during 48 continuous hours) in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants), they found increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts. These results establish a direct role for SCN1A in the regulation of sleep. The use of this animal model to address this issue offers an excellent example of how animal models can be used to address clinically important questions.

Ethosuximide reduces epileptogenesis and behavioural comorbidity in the GAERS model of genetic generalised epilepsy.
Dezsi G, Ozturk E, Stanic D, Powell KL, Blumenfeld H, O'Brien TJ, Jones NC (2013)

Ethosuximide (ESX) is a drug of choice for the symptomatic treatment of absence seizures. Chronic treatment with ESX has previously been reported to have disease-modifying anti-epileptogenic activity in the WAG/Rij rat model of genetic generalized epilepsy with absence seizures. In the current study, the authors examined whether chronic treatment with ESX in a different model - the GAERS - also has anti-epileptogenic effects and results in mitigation of behavioral comorbidity. ESX treatment significantly reduced seizures in GAERS during treatment (3-22 weeks of age), and this effect was maintained during a 12 week post-treatment period. Further, the anxiety-like behaviors present in GAERS were reduced by this ESX treatment. These results confirm that early, chronic ESX treatment has disease-modifying effects in genetic models of generalized epilepsy, a result that may have important implications for clinical treatment. The study also suggests that the cellular mechanism for these effects involves epigenetic modifications.

March 2013 articles from Editor-in-Chief Simon D. Shorvon

The epileptic aura in literature: Aesthetic and philosophical dimensions. An essay.
Wolf P (2013)

This most interesting and original paper by Peter Wolf looks at the way an 'aura' has been depicted in literature. As the author points out, literary treatments of epilepsy provide insights which are different from medical texts because they are given from a different perspective. They present the impressions that seizures make on uninitiated observers. And as they reflect societal views, these literary treatments are an important part of the cultural history of epilepsy. Accounts of auras add the dimension of subjective seizure experiences or patients' reactions to these experiences. Wolf cites 34 different authors and fifty literary works. The paper is illustrated with Botticelli and Duchamps, and includes illustrations of a self-induced and spontaneous seizure. This paper is well worth reading by anyone interested in the broader cultural aspects of epilepsy.

Genetic testing in benign familial epilepsies of the first year of life: Clinical and diagnostic significance.
Zara F, Specchio N, Striano P, Robbiano A, Gennaro E, Paravidino R, Vanni N, Beccaria F, Capovilla G, Bianchi A, Caffi L, Cardilli V, Darra F, Dalla Bernardina B, Fusco L, Gaggero R, Giordano L, Guerrini R, Incorpora G, Mastrangelo M, Spaccini L, Laverda AM, Vecchi M, Vanadia F, Veggiotti P, Viri M, Occhi G, Budetta M, Taglilatela M, Coviello DA, Vigevano F, Minetti C (2013)

More down to earth is this really excellent research paper by Zara and colleagues, whose genetic work is consistently innovative and exciting and who have made many contributions of practical importance to the field. The purpose of this paper is to dissect the genetics of benign familial epilepsies of the first year of life, and to assess the extent of the genetic overlapping between benign familial neonatal seizures (BFNS), benign familial neonatal-infantile seizures (BFNIS), and benign familial infantile seizures (BFIS). In multiplex families, SCN2A, KCNQ2, KCNQ3, PPRT2 point mutations were analyzed by direct sequencing of amplified genomic DNA. Genomic deletions involving KCNQ2 and KCNQ3 were analyzed by multiple-dependent probe amplification method. A total of 46 families, including 165 affected members, were collected. Eight families were classified as BFNS, nine as BFNIS and 29 as BFIS. Genetic analysis led to the identificaion of forty-one mutations, 14 affecting KCNQ2, 1 KCNQ3, 5 SCN2A and 21 PRRT2. The detection rate of mutations in the entire cohort was 89%. In BFNS, mutations specifically involve KCNQ2. In BFNIS, two genes are involved: KCNQ2 (6 families) and SCN2A (2 families). BFIS families are most genetically heterogeneous, with all 4 genes involved, with about 70% of them carrying a PRRT2 mutation. The data indicate an important role of K-channel genes beyond the typical neonatal epilepsies. The identification of a novel SCN2A mutation in a family with infantile seizures with onset between 6 and 8 months provides further confirmation that this gene is not specifically associated to BFNIS but is also involved in families with a delayed age of onset. The data indicate that PRRT2 mutations are clustered in families with BFIS. Paroxysmal kinesigenic dyskinesia emerges as a distinctive, although uncommon feature of PRRT2 families. The authors show that the age of onset of seizures is significantly correlated to underlying genetics, as about 90% of the typical BFNS families are linked to KCNQ2 compared to only 3% of the BFIS families, for which PRRT2 represents the major gene.March 2013 articles from Editor-in-Chief Simon D. ShorvonThe epileptic aura in literature: Aesthetic and philosophical dimensions. An essay Wolf P (2013)This most interesting and original paper by Peter Wolf looks at the way an 'aura' has been depicted in literature. As the author points out, literary treatments of epilepsy provide insights which are different from medical texts because they are given from a different perspective. They present the impressions that seizures make on uninitiated observers. And as they reflect societal views, these literary treatments are an important part of the cultural history of epilepsy. Accounts of auras add the dimension of subjective seizure experiences or patients' reactions to these experiences. Wolf cites 34 different authors and fifty literary works. The paper is illustrated with Botticelli and Duchamps, and includes illustrations of a self-induced and spontaneous seizure. This paper is well worth reading by anyone interested in the broader cultural aspects of epilepsy.

Cardiac injury in refractory status epilepticus.
Hocker S, Prasad A, Rabinstein AA (2013)

My final selection this month is an excellent paper, by Hocker and her colleagues, that describes the range of cardiac injury in 35 patients with refractory status epilepticus (RSE). Twenty-two of 35 patients demonstrated markers of cardiac injury. In the twenty-three patients who had troponin levels determined at onset of SE, 9 were abnormal. ECG findings at onset of SE included: ST elevation (11.4%), ST depression (5.7%), new T wave inversion (37.1%), and non-specific ST changes (37.1%). Cardiac arrhythmias included: ventricular tachycardia/fibrillation (11.4%), atrioventricular block (2.9%), atrial fibrillation/flutter (20.0%), sinus bradycardia (48.6%), and sinus tachycardia (65.7%). Intervention was required for cardiac arrhythmias in 42.9%. QTc was prolonged in 22.9% of patients. One patient met criteria for non-ST elevation myocardial infarction (NSTEMI). Three of 14 patients evaluated with an echocardiogram during SE demonstration reversible systolic dysfunction. In-hospital mortality was 34.3%. The authors conclude that cardiac injury is common in RSE and may be under-recognized. The types of disturbances seen may require specific treatment and are often reversible. Status epilepticus is a dangerous and life-threatening condition, and this paper provides more insight into the diverse nature of the difficulties that face patients with this condition and their physicians. Although the study focuses on a selected group, the observations are of general importance, indicating that patients in status epilepticus should be carefully monitored for cardiac changes.

February 2013 articles from Editor-in-Chief Phil Schwartzkroin

Research implications of the Institute of Medicine Report, Epilepsy Across the Spectrum: Promoting Health and Understanding.
Hesdorffer DC, Beck V, Begley CE, Bishop ML, Cushner-Weinstein S, Holmes GL, Shafer PO, Sirven JI, Austin JK (2013)

In March 2012, the Institute of Medicine (IOM) released the report, Epilepsy across the Spectrum: Promoting Health and Understanding. This report has resulted in dramatically increased public awareness of the public health dimensions of the epilepsies.For this article in Epilepsia, the authors were asked to expand upon the research priorities from each of the major chapter themes in the IOM report: epidemiological surveillance in epilepsy; interventions for people with epilepsy and depression; identification/screening for learning impairments in children with epilepsy; effective innovative teaching strategies; identification of risk factors and interventions that increase employment and improve quality of life; information needs of people with epilepsy and their families, associated with epilepsy-related risks, specifically SUDEP; and trends in knowledge, awareness, attitudes, and beliefs about epilepsy over time and in specific population subgroups. The goal of this paper is to spell out some of the research implications of the IOM report, and provide a roadmap for future investigations.mRNA blood expression patterns in new onset idiopathic pediatric epilepsy. Greiner HM, Horn PS, Holland K, Collins J, Hershey AD, Glauser TA (2013)There is growing evidence that blood mRNA expression patterns may provide useful biomarkers for various forms of epilepsy. In the current study, investigators used this approach to determine if a biologically meaningful mRNA expression pattern is detectable in whole blood of pediatric subjects with new onset and untreated epilepsy. They determined the differential expression patterns between epilepsy subjects (n=37) with generalized onset or partial onset seizures compared to healthy controls (n=28). 575 genes were differentially expressed; the generalized seizure subgroup versus control (GvC) gene list and the partial seizure subgroup versus control (PvC) gene list were different (p 0.05).Tissue expression analysis identified almost half of the genes in GvC and PvC as brain based. Functional group analysis identified several biologically relevant pathways, including mitochondria and lymphocyte activation (in the GvC list) and apoptosis, inflammatory defense and cell motion pathways (in the PvC list). This analysis found many similar pathways to those identified in brain studies examining lesional intractable epilepsy, and provides promise that blood-based mRNA analysis can be developed as a useful clinical tool.

Ripple classification helps to localize the seizure-onset zone in neocortical epilepsy.
Wang S, Wang IZ, Bulacio JC, Mosher JC, Gonzalez-Martinez J, Alexopoulos AV, Najm IM, So NK (2013)

Mutations in the voltage-gated sodium channel SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition to seizures, patients with SCN1A mutations often experience sleep abnormalities, suggesting that SCN1A may also play a role in the neuronal pathways involved in the regulation of sleep. However, a role for SCN1A in the regulation of sleep architecture has not been directly examined. Using a mouse model of GEFS+, the authors tested the hypothesis that SCN1A contributes to the regulation of sleep architecture - and therefore that SCN1A dysfunction contributes to the sleep abnormalities observed in patients with SCN1A mutations. They showed, immunohistochemically, expression of Scn1a in regions of the mouse brain that are known to be involved in seizure generation and sleep regulation. In a detailed analysis of sleep and wake electroencephalographic (EEG) patterns (during 48 continuous hours) in a knock-in mouse line that expresses the human SCN1A GEFS+ mutation R1648H (RH mutants), they found increased wakefulness and reduced non-rapid eye movement (NREM) and rapid eye movement (REM) sleep amounts. These results establish a direct role for SCN1A in the regulation of sleep. The use of this animal model to address this issue offers an excellent example of how animal models can be used to address clinically important questions.

Fast ripples are reported to be highly localizing to the epileptogenic or seizure onset zone (SOZ) but may not be readily found in neocortical epilepsy, while ripples are insufficiently localizing. These investigators classified interictal neocortical ripples by associated characteristics, to identify a subtype that may help to localize the SOZ in neocortical epilepsy. They studied 35 epileptic patients with neocortical epilepsy by stereotactic EEG (SEEG) or subdural grid electrodes, and classified neocortical ripples were as type I when superimposed on epileptiform discharges such as paroxysmal fast spike or sharp wave, and as type II when independent of epileptiform discharges.

Type I ripples were detected in 14 cases almost exclusively in the SOZ or primary propagation area and marked the SOZ with higher specificity than interictal spikes. In contrast, type II ripples were not correlated with the SOZ. These results that interictal ripple classification may be used as a sensitive marker of the SOZ in neocortical epilepsy.

Evidence for a shared genetic susceptibility to migraine and epilepsy.
Winawer MR, Connors R, and the EPGP Investigators (2013)

Although epilepsy and migraine are known to co-occur within individuals, the contribution of a shared genetic susceptibility to this comorbidity remains unclear. The authors investigated the hypothesis of shared genetic effects on migraine and epilepsy. Using the Epilepsy Phenome/Genome Project (EPGP) cohort, they studied prevalence of a history of migraine in 730 EPGP participants aged ≥12 years with non-acquired focal epilepsy (NAFE) or generalized epilepsy (GE) from 501 families containing ≥2 individuals with epilepsy of unknown cause.

Information on migraine without aura (MO) and migraine with aura (MA) was collected using an instrument validated for individuals ≥12 years. Prevalence of a history of MA (but not MO-only) was significantly increased in enrolled participants with ≥2 additional affected first degree relatives. These findings support the hypothesis of a shared genetic susceptibility to epilepsy and MA.

January 2013 articles from Editor-in-Chief Simon D. Shorvon

Safety and tolerability of adjunctive lacosamide IV loading dose in lacosamide-naïve patients with partial onset seizures.
Nathan B. Fountain NB, Krauss G, Isojarvi J, Dilley D, Doty P, Rudd GD (2013)

This issue of Epilepsia includes a number of studies of lacosamide, a relatively new antiepileptic. These papers comprise the editors’ choices for this month, for they all throw light upon this medication. This first study looks at the safety and tolerability of rapidly initiating adjunctive lacosamide via a single IV loading dose, followed by twice-daily oral lacosamide in lacosamide-naïve adults with partial-onset seizures.

The paper describes an open-label, multicenter trial, using intravenous lacosamide at a loading dose of 200 mg, 300 mg, or 400 mg, and followed 12 hours later by initiation of oral dosing consisting of one-half of the loading dose administered twice daily for 6.5 days. A total of 100 patients were enrolled, 25 in each cohort.

The authors found that IV loading doses of 200 mg and 300 mg lacosamide administered over 15 minutes followed by oral lacosamide were well tolerated in lacosamide-naïve patients. The 400 mg loading dose was less well tolerated due to a higher frequency of dose-related TEAEs. These results support the feasibility of rapid initiation of adjunctive lacosamide treatment. Although not licensed in status epilepticus, this study does provide some data for the initiation of this drug in status epilepticus.

The adverse event profile of lacosamide: A systematic review and meta-analysis of randomized controlled trials.
Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti A (2013)

Lacosamide is a relatively new drug which has been the subject of at least ten randomized controlled trials in various indications. The authors of this paper aggregate the side-effect data from these RCTs – three in pharmacoresistant epilepsy, four in neuropathic pain, one in migraine, one in fibromyalgia, and one in knee osteoarthritis; the total number of patients included was 3148.

No serious adverse events were found to be significantly associated with lacosamide therapy. Eleven adverse effects were noted, and the number increased with increasing dose. The most common adverse effects were dizziness, vertigo, ataxia, balance disorder, diplopia, fatigue, nausea, vomiting, and tremor.

The authors concluded that a range of AEs suggestive of vestibulocerebellar dysfunction is significantly associated with lacosamide treatment and their incidence increases with increasing doses. This is a useful study, and the inclusion of non-epilepsy trials is helpful to the reader of Epilepsia who may be unfamiliar with these studies.

Rapid loading of intravenous lacosamide: Efficacy and practicability during presurgical video-EEG monitoring.
Li W, Stefan H, Matzen J, Rampp S, Heinze H-J, Schmitt FC (2013)

This study investigated immediate efficacy and safety of intravenous application of de-novo lacosamide (LCM) as add-on therapy in patients with pharmacoresistant focal epilepsy. During pre-surgical video-EEG-monitoring, seventeen adult inpatients received LCM infusion (200mg every 12 hours for 2-3 days) followed by oral formulation with the same regime. In the acute phase, i.v.-initiation of LCM was well tolerated, with few mild or moderate adverse events (3/17, 17.6%).

A significant reduction of seizure frequency in the treatment phase, as compared to mean seizure frequency in the 2-day baseline phase, was achieved (p0.05 for the first treatment day, and p0.005 for the second treatment day). 61.5% of the patients were seizure-free on the first treatment day, and 84.6% on the second treatment day. After one month, the 50%-responder-rate was 46.6%; after the three month period, 42.8%. The authors concluded that the rapid i.v. initiation of de novo LCM is safe and rapidly effective.

December 2012 articles from Editor-in-Chief Simon D. Shorvon

Epilepsy in Rett syndrome, CDKL5- and FOXG1-gene-related encephalopathies.
Guerrini R, Parrini E (2012)

This paper presents a superb review of the current knowledge about epilepsy and Rett Syndrome. Rett syndrome is an X-linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3years is unlikely, and onset after age 20 is rare.

Diagnosis of Rett syndrome is based on key clinical elements that identify "typical" Rett syndrome but also "variant" or "atypical" forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50-70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations.

The progressive parting of CDKL5- and FOXG1-gene-related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization.

The prognosis of idiopathic generalized epilepsy.
Seneviratne U, Cook M, D’Souza W (2012)

This paper presents an interesting review of the prognosis of idiopathic generalized epilepsy (IGE), providing an overview about what is known and what is not known. Most studies show a good prognosis in comparison with other epilepsy syndromes. Studies looking at the long-term outcome of different IGE syndromes are relatively scant. Childhood absence epilepsy appears to have a higher rate of remission compared to juvenile absence epilepsy.

In absence epilepsies, development of myoclonus and generalized tonic-clonic seizures predicts lower likelihood of remission. Although most patients with juvenile myoclonic epilepsy (JME) achieve remission on antiepileptic drug therapy, 20% appear to remain in remission without treatment. Data on the prognosis of other IGE syndromes are scarce. There are contradictory findings reported on the value of electroencephalography as a predictor of prognosis. Comparisons are made difficult by study heterogeneity, particularly in methodology and diagnostic criteria.

Emil Theodor Kocher-Valve surgery for epilepsy.
Surbeck W, Stienen MN, Hildebrandt G (2012)
Epilepsia 53:2099-2103 [doi: 10.1111/j.1528-1167.2012.03663.x; published online September 11, 2012]

This interesting historical paper concerns the Noel Prize winner Emil Theodor Kocher (1841-1917). He won the Prize for his work on thyroid disease, but he was also interested in epilepsy surgery - having learned about epielpsy from his close friend Victor Horsley.

This paper reviews his little-known work on elevated intracranial pressure and valve surgery for recurrent general convulsions - unusual and a cul-de-sac, but nevertheless instructive.

November 2012 articles from Editor-in-Chief Phil Schwartzkroin

Altered theta coupling between medial entorhinal cortex and dentate gyrus in temporal lobe epilepsy.
Froriep UP, Kumar A, Cosandier-Rimélé D, et al. (2012)

Temporal lobe epilepsy is often accompanied by neuron loss and rewiring in the hippocampus. The authors tested the hypothesis that the interaction of sub-networks of the entorhinal-hippocampal loop should show significant signatures of these pathological changes. Toward that end, they recorded local field potentials in entorhinal cortex (EC) and dentate gyrus (DG) in freely behaving kainate-injected mice, examined these animals histologically, and applied computational modeling.

They found that in healthy mice, theta band activity was synchronized between EC and DG. In contrast, in epileptic mice, theta activity in the EC was delayed with respect to the DG. A computational neural mass model suggested that hippocampal cell loss leads to imbalanced coupling across sub-networks, introducing the observed shift in theta synchronization. This finding is particularly interesting in light of recent evidence that suggests that desynchronization of regional theta band activity is associated with impaired cognitive/behavioral performance.

Tissue plasminogen activator does not alter development of acquired epilepsy: Evidence from mice and humans.
Tan M-L, Ng A, Pandher PS, Sashindranath M, et al. (2012)

The expression of tissue plasminogen activator (t-PA) is enhanced after seizures. t-PA is a proven therapy for acute ischemic stroke, is associated with neuronal activity and synaptic plasticity, and is involved in seizure propagation throughout the brain. The authors therefore examined the possibility that usage of t-PA to treat stroke may have important implications for the development of post-stroke epilepsy.

Mice deficient in t-PA (t-PA -/-) or mice transgenically modified to overexpress neuronal t-PA (T4) underwent amygdala kindling, and seizure threshold and rates of kindling were compared to these measures in wildtype mice. T4 mice were more seizure prone than wildtype mice, exhibiting lower seizure thresholds (p=0.002); however, there were no significant differences observed in the rate of kindling development when comparing either T4 mice or t-PA -/- mice to wildtype controls.

In a parallel clinical study, the authors recruited acute ischemic stroke patients who either received intravenous t-PA treatment on admission to hospital (n=177; cases) or did not (n=158; controls), and assessed the incidence of early and late onset seizures and epilepsy in these patients. The authors found no significant differences between the proportion of post-stroke patients experiencing early or late seizures, or developing epilepsy, between t-PA-treated cases and controls.

These findings suggest that overexpression of endogenous t-PA may lower seizure threshold but does not appear to influence epileptogenesis. Importantly, therapeutic administration of t-PA in humans did not influence the development of acquired post-stroke epilepsy.

October 2012 articles from Editor-in-Chief Simon D. Shorvon

Intracranial EEG in predicting surgical outcome in frontal lobe epilepsy.
Holtkamp M, Sharan A, Sperling MR (2012)

This is the first paper of a trio on frontal lobe epilepsy surgery. In this report, 25 patients operated upon with frontal lobe epilepsy were reviewed. In terms of outcome, 15 patients (60%) were seizure-free (Engel class I) and 10 patients (40%) continued to have seizures (two were class II, three were class III, and five were class IV).

The EEG characteristics associated with lack of seizure freedom included: the presence of interictal epileptiform discharges in scalp recordings, widespread discharges on intracranial ictal recordings, and spread to structures beyond the frontal lobe. The authors conclude that widespread epileptogenicity, as indicated by rapid onset of spread of ictal activity, is the likely reason for lack of seizure freedom following frontal resective surgery. One curious and unexplained finding was the fact that left frontal surgery had a worse outcome than right frontal surgery; possibly this finding was due to the limitations in the size of left-sided resection due to proximity to the speech area.

Outcome of frontal lobe epilepsy surgery.
Lazow SP, Thadani VM, Gilbert KL, Morse RP, et al. (2012)

There are a number of studies of outcome in frontal lobe epilepsy, most pointing often to a rather dismal result. In this paper, a retrospective survey of 58 patients who had had resective frontal lobe surgery for epilepsy was undertaken, with a mean follow-up period of 79 months (range 12–208 months).

Thirty-three (57%) patients with resective surgery had an Engel class I outcome, and 78% an Engel class I or II result. The mean time to first seizure after surgery was 33.3 months (range 0–208). Only 14 patients (24%) were completely seizure-free without auras (Engel IA) throughout the entire follow-up period. In addition, 32% of patients made gains in employment and 52% were able to reduce use of antiepileptic drugs, although only 9% discontinued antiepileptic drugs. Some patients became depressed but there was no correlation between pre-operative and post-operative depression.

Other cognitive effects were not sought. Small retrospective series are not an ideal way of assessing outcome, but despite the limitations of this method, these results were considered promising. Surprisingly to this writer, neither the presence of an MRI lesion nor of abnormal pathology correlated with outcome (31% were MRI-negative).

Memory in frontal lobe epilepsy: An fMRI study.
Centeno M, Vollmar C, O’Muircheartaigh J, et al. (2012)

The third article in this frontal lobe surgery trio is concerned with the functional anatomy of memory in frontal lobe epilepsy. 32 patients were compared with 18 controls; the patients were found to recruit more widely-distributed areas, as measured by fMRI, than the controls. The authors suggest that that reflect an effective compensatory mechanism for maintaining memory function - a rather speculative conclusion.

As the authors also mention, memory is a highly complex cognitive function and cannot be assigned to a circumscribed structure in the brain. One therefore wonders if fMRI is really a helpful method of assessing memory, which is in any case always going to be a widely-distributed cerebral function. The effects of attention and concentration, which may be influenced by frontal lobe surgery, also complicate this analysis.

September 2012 articles from Editor-in-Chief Phil Schwartzkroin

Predictors and course of medically intractable epilepsy in young children presenting before 36 months of age: A retrospective, population-based study.
Wirrell E, Wong-Kisiel L, Mandrekar J, Nickels K (2012)

The investigators carried out a retrospective study on 127 children with newly-diagnosed epilepsy prior to 36 months of age, to identify predictors of medical intractability – and to assess the impact of intractability on long-term mortality and intellectual function.

They found that about a third of these children became medically intractable; predictors included early age at diagnosis, developmental delay at time of diagnosis, neuroimaging abnormality, and focal EEG slowing. When intractability was observed, it was seen relatively early in most children. As might be expected, intractability was associated with higher mortality and poorer intellectual outcome.

This study indicates that intractability is rather common in early-diagnosed epilepsy, and that it may have significant medical and behavioral consequences. Importantly, intractability can often be recognized at an early age. These results emphasize the need for novel antiepileptic treatments that can be provided early in development.

Developmental outcomes of childhood-onset temporal lobe epilepsy: A community-based study.
Wilson SJ, Micallef S, Henderson A, Rayner G, Wrennall JA, Spooner C, Harvey AS (2012)

This investigation entailed a prospective longitudinal study of childhood-onset temporal lobe epilepsy, to assess age-specific developmental tasks. Fifty-four individuals (age range 12-29 years, and age of TLE-onset 0.2-15 years) were assessed. About half the children progressed normally, about a third achieved some developmental tasks, and the rest achieved few tasks.

Membership in these three groups could be predicted by chronicity of seizures and cognitive functioning, with the discrimination between the latter two groups also predicted by having surgically remediable epilepsy and gender. These results show that a significant proportion of childhood-onset TLE patients show negative developmental consequences.

Predictors may help to provide appropriate treatment and counseling. Effective control of seizure activity may significantly influence these developmental results, although it remains unclear to what extent the underlying biology (independent of seizure activity) determines these developmental outcomes.

August 2012 articles from Editor-in-Chief Simon D. Shorvon

Dilemmas in the interpretation of diagnostic accuracy studies on presurgical workup for epilepsy surgery.
Burch J, Marson A, Beyer F, Soares M, Hinde S, Wieshmann U, Woolacott N (2012)
[doi: 10.1111/j.1528-1167.2012.03534.x; published online June 12, 2012 ]

This important paper points out that the data available in interpreting studies in this field have serious limitations. These limitations are relevant to a proper evaluation of the clinical utility of diagnostic modalities used to identify the epileptogenic zone in patients being worked up for epilepsy surgery.

The poor level of evidence is of great concern, and it is extraordinary how little proper assessment there has been – especially considering the high costs of evaluation and the risks of the therapy. This paper suggests alternative methods of data collection that concentrate on the impact of tests on the decision-making process, therapeutic management decisions, and patient outcomes. As such, this paper is required reading by all those assessing the available technologies.

Predictors for long-term seizure outcome in juvenile myoclonic epilepsy: 25-63 years of follow-up.
Geithner J, Schneider F, Wang Z, Berneiser J, Herzer R, Kessler C, Runge U (2012)
[doi: 10.1111/j.1528-1167.2012.03526.x; published online June 12, 2012 ]

It has been known for sometime that although many juvenile myoclonic epilepsy (JME) patients do well, there is a group of less fortunate persons with a poorer outcome. This timely, if somewhat small, study examines the very long-term outcome in patients with this condition.

Two thirds of the patients were in prolonged remission, and about 20% were able to discontinue therapy. Adverse factors for seizure control or discontinuation of medication were the occurrence of tonic-clonic seizures preceded by myoclonus, long duration of active epilepsy, the need for polytherapy, and the occurrence of photosensitivity. The authors emphasize the very important message that juvenile myoclonic epilepsy is a heterogeneous condition. The reliable identification of JME patients who are not going to do well would be useful in clinical practice, and this paper provides clinicians with initial information on this topic.

July 2012 articles from Editor-in-Chief Phil Schwartzkroin

Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE.
Jupp B, Williams J, Binns D, Hicks RJ, Cardamone L, Jones N, Rees S, O’Brien TJ (2012)
[doi: 10.1111/j.1528-1167.2012.03525.x; published online June 12, 2012 ]

Temporal hypometabolism on fluorodeoxyglucose positron emission tomography (FDG-PET) is a common finding in patients with drug resistant temporal lobe epilepsy (TLE). It is unclear whether the hypometabolism reflects a primary epileptogenic process or occurs later - as a result of limbic atrophy or of chronic seizures. This study in a rat model was designed to investigate the relationship between seizure onset, limbic atrophy, histological changes and hypometabolism.

The authors applied serial in-vivo imaging with FDG-PET and volumetric magnetic resonance (MR) in rats in which status epilepticus (SE) was induced by kainate injection, and correlated the imaging data with histological measures of cell loss. They demonstrated hippocampal hypometabolism on FDG-PET 24 hours following SE. In contrast, atrophy of limbic structures became evident from 7 days post-SE, progressing markedly on serial MRI over subsequent weeks. Interestingly, no relationship was observed between the severity of MR-detected atrophy or CA1 pyramidal cell loss and the degree of the hypometabolism on FDG-PET. These findings show that hypometabolism occurs early in the processes of limbic epileptogenesis and is not merely a consequence of pyramidal cell loss or the progressive atrophy of limbic brain structures that follow.

The authors speculate that hypometabolism may reflect cellular mechanisms occurring early during epileptogenesis. As such, this imaging result may provide us with an early marker of the epileptogenic process.

Simultaneous BOLD fMRI and local field potential measurements during kainic acid-induced seizures.
Airaksinen AM, Hekmatyar SK, Jerome N, Niskanen J-P, Huttunen JK, Pitkänen A, Kauppinen RA, Gröhn OH (2012)
[doi: 10.1111/j.1528-1167.2012.03539.x; published online June 12, 2012 ]

In this study, the authors investigated how kainic acid-induced epileptiform activity is related to hemodynamic changes as seen with blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI). Epileptiform activity was induced with kainic acid (KA) and simultaneous fMRI (at 7 T) and deep electrode local field potential (LFP) recordings were performed.

Local field potentials and robust positive BOLD responses were seen bilaterally; however, some of the seizures detected in LFP recording did not cause detectable BOLD signal change. These data suggest that neuronal activity and BOLD response can become decoupled during recurrent kainic acid-induced seizures, a result which suggests caution in interpreting fMRI data obtained during prolonged epileptiform activity.

Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation.
van Vliet EA, Forte G, Holtman L, den Burger JCG, Sinjewel A, de Vries HE, Aronica E, Gorter JA (2012)
[doi: 10.1111/j.1528-1167.2012.03513.x; published online May 21, 2012 ]

Previous studies have shown that inhibition of the mammalian target of rapamycin (mTOR) pathway with rapamycin prevents epileptogenesis after pharmacologically induced status epilepticus (SE) in rat models for temporal lobe epilepsy. Since rapamycin is also known for its immunosuppressant properties, it is possible that this effect may be due to suppression of brain inflammation, a process that has been suggested to play a major role in the development and progression of epilepsy.

To test this hypothesis, the authors treated rats with rapamycin (or vehicle) after the induction of status epilepticus (SE) evoked by electrical stimulation of the angular bundle. Video-electroencephalograpy was used to monitor the occurrence of seizures, and neuronal death, synaptic reorganization, and microglia and astrocyte activation were assessed by immunohistological staining. Rapamycin treatment did not alter SE severity and duration, but did prevent (or greatly reduce) seizure development during the 6 week treatment (compared to vehicle-treated rats which showed a progressive increase of seizures starting 1 week after SE). Cell loss and sprouting that normally occur after SE were visible but significantly reduced in rapamycin-treated rats. However, various microglial markers were dramatically upregulated after SE, and were not significantly different between rapamycin and control groups.

Thus, mTOR inhibition led to strong reduction of seizure development even in the presence of microglia activation, suggesting that rapamycin’s effects on seizure development are not due to a control of inflammation. This result provides important information about the mechanisms of action of rapamycin, and provide new insight into an exciting new antiepileptogenic treatment.

June 2012 articles from Editor-in-Chief Simon D. Shorvon

Pharmacokinetics and drug interactions of eslicarbazepine acetate.
Bialer M, Soares-da-Silva P (2012)
[doi: 10.1111/j.1528-1167.2012.03519.x; published online March 21, 2012 ]

Eslicarbazepine is a newly-developed and licensed antiepileptic drug. It has many similarities to oxcarbazepine, but their pharmacokinetic properties differ in important ways. Meir Bialer is an authority in the area of AED pharmacokinetics, and this review constitutes an important contribution to the literature on this new antiepileptic agent – required reading for all prescribers wanting to know more about the compound.

Music and epilepsy: A critical review.
Maguire MJ (2012)
[doi: 10.1111/j.1528-1167.2012.03523.x; published online March 21, 2012]

Ever since the classic papers by Critchley - ‘Musicogenic epilepsy’ (1937), and his magnus opus ‘Music and the Brain’ (1977) - there has been a continuing specialist interest in this topic. In the current review, the author considers musical processing, mechanisms of musicogenic epilepsy, musical ictal phenomena, effects on musical appreciation of epilepsy surgery and antiepileptic drug therapies, and also musical therapies.

This interesting and informative paper reviews what is known, and importantly also what is not known, in a fascinating area of brain science. This refreshing new look at this subject is commended to all.

May 2012 articles from Editor-in-Chief Phil Schwartzkroin

The system epilepsies: A pathophysiological hypothesis.
Avanzini G, Manganotti P, Meletti S, et al.
[doi: 10.1111/j.1528-1167.2012.03462.x; published online April 25, 2012 ]

The authors propose that some types of epilepsies - “system epilepsies” (SystE) - reflect the pathological expression of an identifiable neural system, made up of brain areas the integrated activities of which subserve normal physiological functions. As such, SystE lead to functional results that cannot be obtained by pathological activity within the individual elements alone.

The phenomenology associated with a given SystE is determined by a contextual involvement of the contributing structures, and therefore predictable according to the functional specialization of the involved system. The SystE hypothesis further postulates that the “enduring propensity to generate seizures” of some epilepsies is due to the specific susceptibility of a system as a whole, although it may be possible to identify some trigger areas within the system. The persistent susceptibility of the seizure-generating system is assumed to exist also in the interictal period.

The authors offer a number of examples of this provocative hypothesis, with absence epilepsy and juvenile myoclonic epilepsy providing the prototypes, and such developmental phenomena as West syndrome (with infantile spasms and hypsarrhythmia) described as potentially system epilepsies. It remains to be seen whether this hypothesis actually provides a productive new way of thinking about and investigating seizure types (and epilepsy syndromes), and whether this approach will result in new therapeutic perspectives.

Spatiotemporal neuronal correlates of seizure generation in focal epilepsy.
Bower M, Stead M, Meyer FB, et al.
[doi: 10.1111/j.1528-1167.2012.03417.x; published online February 21, 2012]

Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathological brain. Despite a number studies focusing on single-neuron activity in patients with epilepsy, no study has examined long–term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure onset zone. In this study, microelectrode arrays were used to record action potentials from neurons in mesial temporal structures (often including contralateral mesial temporal structures) in seven patients with mesial temporal lobe epilepsy.

Surprisingly, only about 8% of microelectrode sites showed increased neuronal firing rates prior to seizure onset, and only about a third of microelectrodes showed any seizure-related activity changes; the majority of microelectrodes (including some located within the seizure onset zone) showed no change throughout the seizure. Furthermore, changes in firing rate prior to and at seizure onset were observed on microelectrodes located outside the seizure onset zone and even in contralateral mesial temporal lobe.

These early changes varied from seizure to seizure, demonstrating the heterogeneity of ensemble activity underlying the generation of focal seizures. Increased neuronal synchrony was primarily observed only following seizure onset. These results challenge our current thinking about neuronal contributions to seizures. The data indicate that cellular contributions to seizure initiation and sustained ictal discharge in mesial temporal lobe epilepsy involve a small subset of the neurons within and outside the seizure onset zone. Further, the “epileptic ensemble” or “network” responsible for seizure generation appears to be quite complex and heterogeneous. This study indicates the need for a new conceptual understanding of seizure mechanisms, and perhaps for new therapeutic approaches that target neuronal activities outside the clinical seizure onset zone.

April 2012 articles from Editor-in-Chief Simon D. Shorvon

The urinary safety profile and secondary renal effects of retigabine (ezogabine): A first-in- class antiepileptic drug that targets KCNQ (Kv7) potassium channels.
Brickel N, Gandhi P, VanLandingham K, Hammond J, DeRossett S (2012)
Epilepsia 53:606-612. [doi: 10.1111/j.1528-1167.2012.03441.x; published online March 16, 2012]

Retigabine (or ezogabine as it is known as in the US) is a new antiepileptic drug recently licensed in Europe and the USA. It is a potassium channel opener, enhancing the effects of KCNQ2/3 activity in the brain. It also has a pharmacological effect on urinary smooth bladder muscle, and so carries a risk of urinary side-effects, particularly urinary retention and urinary hesitation. Consequently, there has been much interest in the adverse event (AE) profile of RTG/EZG and the potential risk of effects on the urinary system.

This excellent and definitive review, from the medical team of GlaxoSmithCline and Valeant Pharmaceuticals, summarizes the urinary safety profile, based on data from the 813 patients in the pivotal controlled trials and the 1365 patients in the phase 2/3 clinical development program. The potential for secondary renal effects is also discussed. Effects on the urinary system are unusual for an antiepileptic drug, and reflect the unique mode of action of retigabine.

Onset of intractability and its course over time: The Dutch study of epilepsy in childhood.
Geerts A, Brouwer O, Stroink H, van Donselaar C, Peters B, Peeters E, Arts WF (2012)
Epilepsia 53:741-751. [doi: 10.1111/j.1528-1167.2012.03429.x; published online March 14, 2012]

The view has grown up, partly fuelled by what many consider a recent ill-conceived definition of drug-resistant epilepsy, that intractability can be reliably defined by the early response (or lack thereof) to medication. In this study of 413 people with childhood onset epilepsy who were followed for a mean of 15 years, the authors found a large and unpredictable variation in time of onset, course, and duration of ‘intractability’.

They concluded that this variation represented the natural course of epilepsy rather than any effect of medication. The paper is an interesting contribution to this long-running debate, on a topic which has been written about for at least 150 years. Despite this long history, there remains fierce disagreement over how to define intractability and how to predict it.

The topic is important as many patients are distressed by the erroneous view that a failure to respond to initial therapy will mean inevitable chronic epilepsy. This study shows the complexity of patterns of epilepsy, and concludes wisely that a solid and all-encompassing definition of intractability remains to be established.

March 2012 articles from Editor-in-Chief Phil Schwartzkroin

The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy.
Gunthorpe MJ, Large CH, Sankar R

The pharmacological profile of retigabine (RTG [international nonproprietary name]; ezogabine [United States adopted name]), is different from all currently approved antiepileptic drugs (AEDs). Its primary mechanism of action (MoA) as a positive allosteric modulator of KCNQ2–5 (Kv7.2–7.5) ion channels defines RTG/EZG as the first neuronal potassium (K+) channel opener for the treatment of epilepsy. KCNQ2–5 channels are predominantly expressed in neurons and are important determinants of cellular excitability, as indicated by the occurrence of human genetic mutations in KCNQ channels that underlie inheritable disorders, including (in the case of KCNQ2/3) the syndrome of benign familial neonatal convulsions. KCNQ channels contribute a continual hyperpolarizing influence that stabilizes cellular excitability.

The MoA of RTG/EZG increases the number of KCNQ channels that are open at rest and also primes the cell to retort to membrane depolarization or increased neuronal excitability with a larger, more rapid, and more prolonged response. In this way, RTG/EZG amplifies this natural inhibitory force in the brain. This action to restore physiological levels of neuronal activity is thought to underlie the efficacy of RTG/EZG as an anticonvulsant in a broad spectrum of preclinical seizure models and in placebo-controlled trials in patients with partial epilepsy. In this article, the authors consider the pharmacological characteristics of RTG/EZG at the receptor, cellular, and network levels, as a means of understanding the novel and efficacious MoA of this potential new AED as defined in both preclinical and clinical research.

The spectrum of anticonvulsant efficacy of retigabine (ezogabine) in animal models: Implications for clinical use.
Large CH, Sokal DM, Nehlig A, Gunthorpe MJ, Sankar R, Crean CS, VanLandingham KE, White HS

Retigabine (RTG [international nonproprietary name]; ezogabine [EZG; United States adopted name]) is a first-in-class antiepileptic drug (AED) that reduces neuronal excitability by enhancing the activity of KCNQ (Kv7) potassium (K+) channels. RTG/EZG has recently been approved by the European Medicines Agency and the US Food and Drug Administration as adjunctive therapy in adults with partial-onset seizures. This review discusses the activity that RTG/EZG has demonstrated across a broad spectrum of in vitro/in vivo animal models of seizures, the compound’s ability to resist and block the occurrence of seizures induced by a range of stimuli across different regions of the brain, and side-effects of RTG/EZG in these animal models.

The synergistic and additive activity of RTG/EZG with other AEDs supports its potential use in therapeutic combinations for different seizure types. The distinct mechanism of action of RTG/EZG from those of currently available AEDs, along with its broad preclinical activity, underscores the key role of KCNQ (Kv7) K+ channels in neuronal excitability, and further supports the potential efficacy of this unique molecule in the treatment of epilepsy.

February 2012 articles from Editor-in-Chief Simon D. Shorvon

Unifying the Definitions of SUDEP.
Nashef L, So, EL, Ryvlin P, Tomson T

Sudden unexpected death in epilepsy (SUDEP) is a category of deaths in people with epilepsy occurring in the absence of a known structural cause of death and is most likely heterogeneous with regard to mechanisms and circumstances. SUDEP is particularly difficult to investigate in research studies for several reasons, including its relatively low incidence, its unpredictable occurrence often in unwitnessed settings, and its low rate of complete autopsy examinations. In this paper, the authors describe scenarios that demonstrate the basis for various SUDEP categories, and propose a unified SUDEP definition and classification to resolve current ambiguities and to retrieve cases that would not have been further studied if the previous definitions were used.

The electroencephalogram of idiopathic generalized epilepsy.
Seneviratne U, Cook M, D’Souza W

Idiopathic generalized epilepsy (IGE) is classified into several sub-syndromes based on clinical and electroencephalographic (EEG) features. The electrographic signature of IGE is bisynchronous, symmetric and generalized spike-wave complex - although focal, irregular and so called ‘fragments’ of discharges are not uncommon. Other characteristic EEG features include polyspikes, polyspike-wave discharges, occipital intermittent rhythmic delta activity and photoparoxysmal response. Both human and animal data suggest involvement of the thalamus and the cortex in the generation of spike-wave discharges in IGE. Circadian variations of generalized epileptiform discharges are well described which can be useful in diagnostic confirmation. Activation procedures such as hyperventilation, intermittent photic stimulation, eye closure and fixation-off are useful techniques to increase the yield of both interictal and ictal EEG abnormalities. Variations of electrographic abnormalities are evident between different electroclinical syndromes. The EEG is also affected by certain external as well as internal factors, which should be borne in mind when interpreting the EEG in IGE.

Mortality after temporal lobe epilepsy (TLE) surgery.
Seymour N, Granbichler CA, Polkey CE, Nashef L

This study reports mortality, after a longer interval, in a cohort (306 patients) with drug-resistant epilepsy treated by temporal lobe surgery between 1975 and 1995. Deaths occurring after December 1st 1997 and until 1st December 2009 were evaluated. In 3569 person-years (py) of follow-up, 19 deaths occurred. In this cohort, the risk for premature death in patients undergoing TLE surgery decreased over time but remained above the standard population. Men suffered a slightly higher risk than women, as did right-sided resections in mesial temporal sclerosis. Though lower, the risk of SUDEP remained.

January 2012 articles from Editor-in-Chief Phil Schwartzkroin

Overexpression of ADK in human astrocytic tumors and peritumoral tissue is related to tumor-associated epilepsy
de Groot M, Iyer A, Zurolo E, Anink J, Heimans JJ, Boison D, Reijneveld JC, Aronica E
Adenosine kinase (ADK), a largely astrocyte-based metabolic enzyme, regulates adenosine homeostasis in the brain. Overexpression of ADK decreases extracellular adenosine and consequently leads to seizures. Using immunohistochemistry and western blot, we examined ADK expression and cellular distribution in surgically removed tumor tissue and peritumoral cortex of patients with glial and glioneuronal tumors. ADK immunoreactivity was significantly stronger in tumor and peritumoral tissue compared to normal white matter and normal cortex (from autopsy controls). Further, there was a significantly higher expression of ADK in the peritumoral infiltrated tissue of patients with epilepsy than in patients without epilepsy. These results suggest a dysregulation of ADK in astrocytic brain tumors, and are consistent with a role of this enzyme in tumor-associated epilepsy.

Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis
Chuang Y-C, Chuang H-Y, Lin T-K, Chang C-C, Lu C-H, Chang W-N, Chen S-D, Tan T-Y, Huang C-R, Chan SHH
Long-term therapy with antiepileptic drugs (AEDs) has been associated with metabolic consequences that lead to an increase in risk of atherosclerosis in patients with epilepsy. We compared the long-term effects of monotherapy using different categories of AEDs on markers of vascular risk and the atherosclerotic process. Patients who were under long-term monotherapy with carbamazepine (CBZ), phenytoin (PHT) or valproic acid (VPA) exhibited altered circulatory markers of vascular risk that may contribute to the acceleration of the atherosclerotic process, which is significantly associated the duration of AED monotherapy. No significant alterations in the markers of vascular risk were observed in patients who received long-term lamotrigine (LTG) monotherapy. This information offers guidance in the choice of drug in patients with epilepsy who require long-term AED therapy, particularly in aged and high-risk individuals.

A once-per-day drug-in-food protocol for prolonged administration of antiepileptic drugs in animal models
Ali A, Dua Y, Constance JE, Franklin MR, Dudek FE
Convenient and effective methods for administering potential antiepileptic drugs (AEDs) chronically should facilitate many experiments in animal models of chronic epilepsy with spontaneous recurrent seizures. This proof-of-principle study aimed to optimize a once-per-day, drug-in-food protocol by testing the effect of carbamazepine (CBZ) on the frequency of convulsive seizures in rats with kainate-induced epilepsy. Food pellets with CBZ (30, 100 or 300 mg/kg/day) were provided once per day in three 2-week trials. With this daily feeding protocol, CBZ significantly reduced the frequency of spontaneous convulsive seizures in a dose-dependent manner. The effect of CBZ was consistent across days and throughout each day of the trials. This AED-in-food protocol is simple, efficient, inexpensive, reliable and non-invasive; it allows easier long-term drug administration and is less stressful and more humane than other methods of AED administration.

December 2011 articles from Editor-in-Chief Simon Shorvon

The new ILAE report on terminology and concepts for organization of epileptic seizures: A clinician’s critical view and contribution.
Chrysostomos P. Panayiotopoulos.
Volume 52, Issue 12, pages 2155–2160, December 2011

This Invited Commentary is an important and interesting contribution to the ongoing robust debate about the proposed revisions to the ILAE classifications of seizures and syndromes.  This paper focuses on the classification of seizures, and takes a largely critical view of the new ILAE Commission recommendations.

Validation of FDG-PET/MRI co-registration in non-lesional refractory childhood epilepsy.
Rubí S, Setoain X, Donaire A, Bargalló N, Sanmartí F, Carreño M, Rumià J, Calvo A, Aparicio J, Campistol J, Pons F.
Volume 52, Issue 12, pages 2216–2224, December 2011

The purpose of this paper was to validate the use of FDG-PET/MRI co-registration for epileptogenic zone detection in children with MRI non-lesional refractory epilepsy, and also to assess the ability of this technique to guide a second interpretation of the MRI studies.  Thirty-one children with refractory epilepsy whose MRIs were non-lesional were prospectively included. The authors found that both FDG-PET and FDG-PET/MRI detected hypometabolism in 67.8% of patients, with good concordance on a subject basis and on the cerebral region involved (Kappa statistic=0.83 and 0.79, respectively). Hypometabolism detected by single PET, as well as by PET/MRI fusion images, was located in the same hemisphere as indicated by electroclinical data in 58% of patients, and at the same place in 39% of cases. Although the study was based on a small number of patients and in a selected group, the findings are interesting. The authors concluded that PET/MRI co-registration was as least as accurate as PET alone in detecting the epileptogenic zone in pediatric non-lesional patients. They also suggest (somewhat inconclusively) that these findings can help with a re-evaluation of “non-lesional” diagnoses based solely on MRI.

Initiation of epileptiform activity in a rat model of periventricular nodular heterotopia
Volume 52, Issue 12, pages 2304–2314, December 2011

In a rat model in which injection of methylazoxymethanol (MAM) into pregnant rat dams produces offspring with periventricular nodular heterotopia (PNH)-like brain abnormalities, electrophysiological methods were used to examine the activity of the MAM-induced PNH relative to activity in the neighboring hippocampus and overlying neocortex.  Recordings were obtained simultaneously from these three structures in slice preparations from MAM-exposed rats and in intact animals.  Bath application or systemic injection of bicuculline was used to induce epileptiform activity. The authors found thatin the in vitro slice, epileptiform discharges were generally initiated in hippocampus. In some cases, independent PNH discharge occurred, but the PNH never “led” discharges in hippocampus or neocortex. Intracellular recordings from PNH neurons confirmed that these cells received synaptic drive from both hippocampus and neocortex, and sent axonal projections to these structures – consistent with anatomical observations on biocytin-injected PNH cells. In intact animal preparations, bicuculline injection resulted in epileptiform discharge in all experiments, with a period of ictal-like electrographic activity typically initiated within 2-3 minutes after drug injection.  In almost all animals, the onset of ictus was seen synchronously across PNH, hippocampal, and neocortical electrodes; in a few cases, the PNH electrode (histologically confirmed) did not participate, but in no case was activity initiated in the PNH electrode.  Interictal discharge was also synchronized across all three electrodes; again, the PNH never “led” the other two electrodes, and typically followed (onset several milliseconds after hippocampal/neocortical discharge onset). These important findings do not support the hypothesis, often made, that the PNH lesion is the primary epileptogenic site since the PNH does not initiate or lead epileptiform activity that subsequently propagates to other brain regions.