Publications by authors named "Arielle Crespel"

65 Publications

Stimulus-Induced Rhythmic or Periodic Intermittent Discharges (SIRPIDs) in patients with triphasic waves and Creutzfeldt-Jakob disease.

Clin Neurophysiol 2021 Aug 20;132(8):1757-1769. Epub 2021 May 20.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Since the term Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs) was introduced into the vocabulary of electrophysiologists/neurologists, there has been an ongoing debate about its significance, as well as its correlation with outcomes. SIRPIDs are frequently seen in patients who are critically ill from various causes. The literature reflects the findings of triphasic morphology, with the generalized periodic discharge (GPD) classification in many patients with SIRPIDs: toxic/metabolic encephalopathies, septic, and hypoxemic/hypercapnic encephalopathies, but also sharp periodic complexes in Creutzfeldt-Jakob disease and advanced Alzheimer's disease. In these settings, GPDs disappear when patients fall asleep and reappear when patients spontaneously wake up, or are awoken by an external stimulus, or sometimes because of a respiratory event, with the possibility of the appearance of GPDs with a cyclic alternating pattern. SIRPIDs may be seen as a transitional pattern between sleep and waking states, corresponding to a postarousal/awakening phenomenon. As SIRPIDs are a transient phenomenon and can usually be recorded repeatedly with each stimulation, the word "Ictal" could be replaced by "Intermittent": Stimulus-Induced Rhythmic or Periodic Intermittent Discharges. However, considering that SIRPIDs may be "potentially ictal" or on an "ictal-interictal continuum" in some situations, the "plus" modifier may be added: SIRPIDs-plus.
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http://dx.doi.org/10.1016/j.clinph.2021.05.002DOI Listing
August 2021

Lateralized Periodic Discharges: Which patterns are interictal, ictal, or peri-ictal?

Clin Neurophysiol 2021 Jul 27;132(7):1593-1603. Epub 2021 Apr 27.

Epilepsy and EEG Unit, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.

There is an ongoing debate if Lateralized Periodic Discharges (LPDs) represent an interictal pattern reflecting non-specific but irritative brain injury, or conversely, is an ictal pattern. The challenge is: how to correctly manage these patients? Between this apparent dichotomous distinction, there is a pattern lying along the interictal-ictal continuum (IIC) that we may call "peri-ictal". Peri-ictal means that LPDs are temporally associated with epileptic seizures (although not necessarily in the same recording). Their recognition should lead to careful EEG monitoring and longer periods of video-EEG to detect seizure activity (clinical and/or subclinical seizures). In order to distinguish which kind of LPDs should be considered as representing interictal/irritative brain injury versus ictal/peri-ictal LPDs, a set of criteria, with both clinical/neuroimaging and EEG, is proposed. Among them, the dichotomy LPDs-proper versus LPDs-plus should be retained. Spiky or sharp LPDs followed by associated slow after-waves or periods of flattening giving rise to a triphasic morphology should be included in the definition of LPDs-plus. We propose defining a particular subtype of LPDs-plus that we call "LPDs-max". The LPDs-max pattern corresponds to an ictal pattern, and therefore, a focal non-convulsive status epilepticus, sometimes associated with subtle motor signs and epileptic seizures. LPDs-max include periodic polyspike-wave activity and/or focal burst-suppression-like patterns. LPDs-max have a posterior predominance over the temporo-parieto-occipital regions and are refractory to antiseizure drugs. Interpretations of EEGs in critically ill patients require a global clinical approach, not limited to the EEG patterns. The clinical context and results of neuroimaging play key roles.
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http://dx.doi.org/10.1016/j.clinph.2021.04.003DOI Listing
July 2021

Benign EEG variants in the sleep-wake cycle: A prospective observational study using the 10-20 system and additional electrodes.

Neurophysiol Clin 2021 Jun 16;51(3):233-242. Epub 2021 Apr 16.

Gui de Chauliac Hospital, Epilepsy Unit, Montpellier, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Recherche sur les Comportements et Mouvements Anormaux, Montpellier, France. Electronic address:

Objectives: To study the prevalence of benign EEG variants (BEVs) in the sleep-wake cycle among 1163 consecutive patients.

Methods: Prospective, observational EEG study using the 10-20 system with systematically two additional anterior-temporal electrodes. Depending on clinical indications, other electrodes were added. REM sleep identification was based on its characteristic EEG grapho-elements and rapid eye movements, clearly detectable with the additional anterior-temporal and fronto-polar electrodes due to eye proximity. The video-EEG monitoring duration was between 24hours and eight days.

Results: We identified 710 patients (61%) with BEVs. Positive occipital sharp transients of sleep (POSTs) were observed in 36.4% of participants, mu rhythm in 22.4%, lambda waves in 16.7%, wicket spikes (WS) in 15%, 14- and 6-Hz positive bursts in 8.3%, benign sporadic sleep spikes (BSSS) in 3.3%, rhythmic mid-temporal theta burst of drowsiness (RMTD) in 2.15%, midline theta rhythm in 2.1% and six-Hz spike and wave (SW) bursts in 0.1%. WS and RMTD were present during wakefulness, NREM (14.1%, 1.3%, respectively) and REM sleep (3.3%, 1.1%, respectively). Mu rhythm was also observed during NREM (1.5%) and REM sleep (7.7%). Fourteen- and 6-Hz positive bursts were present during NREM (4.5%) and REM sleep (6.5%). BSSS and six-Hz SW bursts were only observed during NREM sleep.

Conclusions: The prevalence of BEVs is much higher than current estimates. POSTs and WS can no longer be considered as unusual patterns but physiological patterns of NREM sleep. RMTD and mu rhythm may be observed during NREM and REM sleep.
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http://dx.doi.org/10.1016/j.neucli.2021.03.006DOI Listing
June 2021

Epilepsy with eyelid myoclonias (Jeavons syndrome): An electro-clinical study of 40 patients from childhood to adulthood.

Seizure 2021 Apr 26;87:30-38. Epub 2021 Feb 26.

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France; Research Unit (URCMA: Unité de Recherche sur les Comportements et Mouvements Anormaux), INSERM, U661, Montpellier, F-34000, France. Electronic address:

Purpose: To describe the typical and atypical clinical and electroencephalographic (EEG) features of 40 patients with Jeavons syndrome (JS).

Method: Retrospective analysis from two French tertiary centers.

Results: Forty patients were enrolled (31 females and 9 males; sex ratio F/M = 3.44; mean age at epilepsy onset: 6.2 ± 3.4 years [range: 1-15 years]). A positive family history of generalized genetic epilepsy was reported by 13 patients (32.5 %). Eyelid myoclonias with or without absence were the seizure onset in 29 patients (72.5 %), and generalized tonic-clonic seizures in 11 (27.5 %). Over the course of the disease, all had absences. Intellectual disability and psychiatric disorders were reported in 14 (35 %) and 18 patients (45 %), respectively. Focal EEG abnormalities were observed in 65 % of patients, with a posterior (57.7 %) or anterior (30 %) distribution. Generalized EEG discharges were identified in 37 patients (92.5 %). Epileptiform abnormalities were activated during NREM sleep and increased upon awakening. Response to intermittent light stimulation (ILS) was observed in 34 patients (85 %), with an unusual pattern of epileptiform abnormalities at the same frequency of the flashes in 20 patients. Patients with all seizure types were more likely to have this response (p = 0.017).

Conclusion: JS is a lifelong genetic epileptic syndrome with onset in childhood, female preponderance, and a positive family history of epilepsy in one-third of the cases. Focal EEG abnormalities are frequent. Response to ILS appears different from other photosensitive syndromes, with an unusual pattern of photo-induced abnormal synchronization. Intellectual disability and psychiatric disorders are not rare.
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http://dx.doi.org/10.1016/j.seizure.2021.02.028DOI Listing
April 2021

Failure to recognize muscular artifacts on the EEG may cause a wrong diagnosis of myoclonic status epilepticus.

Epilepsy Behav Rep 2020 5;14:100362. Epub 2020 Apr 5.

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France.

•Quetiapine may cause myoclonus.•Usually, no muscular artifact on the midline EEG electrodes•The EEG pattern of myoclonic jerks is rather polyspike-waves and not only polyspikes.•Failure to recognize muscular artifacts may cause a wrong diagnosis of polyspikes.
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http://dx.doi.org/10.1016/j.ebr.2020.100362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782929PMC
April 2020

Spikes/spike-waves time-locked to the flash frequency during intermittent light stimulation in Jeavons syndrome.

Clin Neurophysiol 2020 10 6;131(10):2479-2481. Epub 2020 Aug 6.

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France; Research Unit (URCMA: Unité de Recherche sur les Comportements et Mouvements Anormaux), INSERM, U661, Montpellier F-34000, France.

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http://dx.doi.org/10.1016/j.clinph.2020.07.012DOI Listing
October 2020

How to carry out and interpret EEG recordings in COVID-19 patients in ICU?

Clin Neurophysiol 2020 08 13;131(8):2023-2031. Epub 2020 May 13.

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

There are questions and challenges regarding neurologic complications in COVID-19 patients. EEG is a safe and efficient tool for the evaluation of brain function, even in the context of COVID-19. However, EEG technologists should not be put in danger if obtaining an EEG does not significantly advance diagnosis or change management in the patient. Not every neurologic problem stems from a primary brain injury: confusion, impaired consciousness that evolves to stupor and coma, and headaches are frequent in hypercapnic/hypoxic encephalopathies. In patients with chronic pulmonary disorders, acute symptomatic seizures have been reported in acute respiratory failure in 6%. The clinician should be aware of the various EEG patterns in hypercapnic/hypoxic and anoxic (post-cardiac arrest syndrome) encephalopathies as well as encephalitides. In this emerging pandemic of infectious disease, reduced EEG montages using single-use subdermal EEG needle electrodes may be used in comatose patients. A full 10-20 EEG complement of electrodes with an ECG derivation remains the standard. Under COVID-19 conditions, an expedited study that adequately screens for generalized status epilepticus, most types of regional status epilepticus, encephalopathy or sleep may serve for most clinical questions, using simplified montages may limit the risk of infection to EEG technologists. We recommend noting whether the patient is undergoing or has been placed prone, as well as noting the body and head position during the EEG recording (supine versus prone) to avoid overinterpretation of respiratory, head movement, electrode, muscle or other artifacts. There is slight elevation of intracranial pressure in the prone position. In non-comatose patients, the hyperventilation procedure should be avoided. At present, non-specific EEG findings and abnormalities should not be considered as being specific for COVID-19 related encephalopathy.
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http://dx.doi.org/10.1016/j.clinph.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217782PMC
August 2020

Open-label, uncontrolled retrospective study of perampanel in adults with Lennox-Gastaut syndrome.

Seizure 2020 Feb 16;75:66-69. Epub 2019 Dec 16.

Centre Saint Paul-H. Gastaut, Marseille, France.

Purpose: Perampanel (PER) was added to the anticonvulsant regimen of 71 patients with Lennox-Gastaut Syndrome (LGS) to evaluate its efficacy against seizures and its tolerability.

Method: We evaluated at 3-month intervals 62 with pure LGS and 9 with LGS-like epileptic encephalopathy (28 females, 43 males, mean age 40.1 ± 11.5 yrs, median 38, range 20-71) in whom PER was introduced by 2 mg steps at 2- to 4-week intervals up to 6 mg/day, with possible dose reduction or increases after that. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed.

Results: Mean PER exposure was 538.9 days ± 425 (median 429), with 44 patients (62 %) on PER at last follow-up. About 2/3 of patients were responders, including 35.2 % that had a ≥75 % decrease in their seizures. Among these 16.9 % had a ≥90 % decrease. No improvement was seen in 14 patients; 5 had a less than 50 % response, and 6 had seizure aggravation. Therefore, 25 (35.2 %) were considered non-responders. Half of the patients developed at least one side-effect. Significant negative changes in behavior were noted in 1/3 of the cases, including irritability (8.5 %) and aggressivity (7 %). Contrastingly, 4 patients reported positive behavioral and psychological well-being side-effects.

Conclusions: This retrospective, open-label study provides evidence that PER may significantly help in LGS. PER should be tried in LGS patients who are not satisfactorily controlled. Its use may be limited in some patients due to behavioral side-effects occurring, particularly at doses ≥ 6 mg/d.
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http://dx.doi.org/10.1016/j.seizure.2019.12.012DOI Listing
February 2020

Treatment of Juvenile Myoclonic Epilepsy in Patients of Child-Bearing Potential.

CNS Drugs 2019 03;33(3):195-208

Epilepsy Unit, Hôpital Gui de Chauliac, 80 Avenue Fliche, 34295, Montpellier Cedex 05, France.

Juvenile myoclonic epilepsy (JME) is both a frequent and a very characteristic epileptic syndrome with female preponderance. Treatment of JME in women of childbearing potential must consider multiple factors such as desire for pregnancy, use of contraception, seizure control and previously used antiepileptic drugs (AEDs). Approximately 85% of cases are well controlled with valproate, which remains the reference AED in JME but is nowadays considered unsafe for the expecting mother and her fetus. The prescription of valproate is now severely restricted in women of childbearing potential but may still be considered, at the lowest possible dose and when pregnancies can be reliably planned, with temporary alternatives to valproate prescribed before fertilization. Alternatives have emerged, especially lamotrigine and levetiracetam, but also topiramate, zonisamide, and recently perampanel, but none of these AEDs can be considered fully safe in the context of pregnancy. In special settings, benzodiazepines and barbiturates may be useful. In some cases, combination therapy, especially lamotrigine and levetiracetam, may be useful or even required. However, lamotrigine may have the potential to aggravate JME, with promyoclonic effects. Carbamazepine, oxcarbazepine and phenytoin must be avoided. Valproate, levetiracetam, zonisamide, topiramate if the daily dose is ≤ 200 mg and perampanel if the daily dose is ≤ 10 mg do not affect combined hormonal contraception. Lamotrigine ≥ 300 mg/day has been shown to decrease levonorgestrel levels by 20% but does not compromise combined hormonal contraception. Patients with JME taking oral contraceptive should be counselled on the fact that the estrogenic component can reduce concentrations of lamotrigine by over 50%, putting patients at risk of increased seizures. Pregnancy is a therapeutic challenge, and the risk/benefit ratio for the mother and fetus must be considered when choosing the appropriate drug. Lamotrigine (< 325 mg daily in the European Registry of Antiepileptic Drugs in Pregnancy) and levetiracetam seem to be comparatively safer in pregnancy than other AEDs, especially topiramate and valproate. Plasma concentration of lamotrigine and levetiracetam decreases significantly during pregnancy, and dosage adjustments may be necessary. With persisting generalized tonic-clonic seizures, the combination of lamotrigine and levetiracetam offer the chance of seizure control and lesser risks of major congenital malformations. The risk of malformation increases when valproate or topiramate are included in the drug combination. In one study, the relative risk of autism and autism spectrum disorders (ASD) in children born to women with epilepsy (WWE) treated with valproate were, respectively, 5.2 for autism and 2.9 for ASD versus 2.12 for autism and 1.6 for ASD in WWE not treated with valproate. More studies are needed to assess the risk of autism with AEDs other than valproate. The current knowledge is that the risk appears to be double that in the general population. In patients with JME, valproate remains an essential and life-changing agent. The consequences of a lifetime of poorly controlled epilepsy need to be balanced against the teratogenic risks of valproate during limited times in a woman's life. The management of JME in WWE should include lifestyle interventions, with avoidance of sleep deprivation, and planned pregnancy.
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http://dx.doi.org/10.1007/s40263-018-00602-2DOI Listing
March 2019

Hypoxemia following generalized convulsive seizures: Risk factors and effect of oxygen therapy.

Neurology 2019 01 19;92(3):e183-e193. Epub 2018 Dec 19.

From the Department of Functional Neurology and Epileptology (S.R., B.M.A., V.A.), Hospices Civils de Lyon and University of Lyon; Lyon's Neuroscience Research Center (S.R., B.M.A., V.A., L.B., P.R.), INSERM U1028/CNRS UMR 5292, France; Hospital of Clinics of Ribeirão Preto (V.A.), University of São Paulo, Brazil; Department of Neurology (J.C., L.V.), University Hospital of Toulouse; Neurology Department (L.M.), University Hospital of Nancy; Clinical Neurophysiology and Epileptology Department (F.B.), Timone Hospital, Marseille; Department of Clinical Neurophysiology (P.D.), Lille University Medical Center, EA 1046, University of Lille2; Department of Neurology (E.H.), University Hospital of Strasbourg; Department of Neurology (V.M.), Hôpital Pellegrin, Bordeaux; Epilepsy Unit, Department of Neurosurgery (F.C.), Centre Hospitalier Sainte-Anne, University Paris Descartes; La Teppe Epilepsy Center (D.T.), Tain l'Hermitage,; Epilepsy Unit (A.C.), Montpellier; Department of Neurology (A.B.), University Hospital of Rennes; Epileptology Unit (V.N.), Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière and Brain and Spine Institute (ICM; INSERM UMRS1127, CNRS UMR7225, UPMC University Paris 06); Department of Neurology (P.K.), Grenoble-Alpes University Hospital, GIN, INSERM U1216, and Grenoble Alpes University; Department of Clinical Neurophysiology (B.D.T.), INSERM U930, University Hospital of Tours; Department of Neurology (P.T.), University Hospital of Nice; Department of Neurology (S.R.), University Hospital of Clermont-Ferrand, France; Department of Clinical Neurosciences (S.R., P.R.), Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland; and Epilepsy Institute (E.H., L.B., P.R.), Lyon, France.

Objective: To analyze the factors that determine the occurrence or severity of postictal hypoxemia in the immediate aftermath of a generalized convulsive seizure (GCS).

Methods: We reviewed the video-EEG recordings of 1,006 patients with drug-resistant focal epilepsy included in the REPOMSE study to identify those with ≥1 GCS and pulse oximetry (SpO) measurement. Factors determining recovery of SpO ≥ 90% were investigated using Cox proportional hazards models. Association between SpO nadir and person- or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures.

Results: A total of 107 GCS in 73 patients were analyzed. A transient hypoxemia was observed in 92 GCS (86%). Rate of GCS with SpO <70% dropped from 40% to 21% when oxygen was administered early ( = 0.046). Early recovery of SpO ≥90% was associated with early administration of oxygen ( = 0.004), absence of postictal generalized EEG suppression (PGES) ( = 0.014), and extratemporal lobe epilepsy ( = 0.001). Lack of early administration of O ( = 0.003), occurrence of PGES ( = 0.018), and occurrence of ictal hypoxemia during the focal phase ( = 0.022) were associated with lower SpO nadir.

Conclusion: Postictal hypoxemia was observed in the immediate aftermath of nearly all GCS but administration of oxygen had a strong preventive effect. Severity of postictal hypoxemia was greater in temporal lobe epilepsy and when hypoxemia was already observed before the onset of secondary GCS.
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http://dx.doi.org/10.1212/WNL.0000000000006777DOI Listing
January 2019

Myoclonus epilepsy and ataxia due to KCNC1 mutation: Analysis of 20 cases and K channel properties.

Ann Neurol 2017 May;81(5):677-689

Department of Neurology and Epileptology, Epilepsy Center Hamburg-Alsterdorf, Hamburg, Germany.

Objective: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever.

Methods: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant K 3.1 channels.

Results: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type K 3.1, increasing channel availability.

Interpretation: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type K 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.
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http://dx.doi.org/10.1002/ana.24929DOI Listing
May 2017

Perampanel in 12 patients with Unverricht-Lundborg disease.

Epilepsia 2017 04 6;58(4):543-547. Epub 2017 Feb 6.

Centre Saint Paul-H. Gastaut, Marseille, France.

Objective: Perampanel (PER) was used in 12 patients with Unverricht-Lundborg disease (ULD) to evaluate its efficacy against myoclonus and seizures.

Methods: We treated 11 patients with EPM1 mutations (6 F, 5 M, aged 13-62 years) and a 43-year-old man with de novo KCNC1 mutation. PER was introduced by 2 mg steps at 2-4 week intervals until 6 mg/day, with a possible dose reduction or dose increase.

Results: Ten patients had a clear clinical response of myoclonus, and five were able to reduce concomitant therapy. Improvement was noted sometimes as soon as with 2 mg/day. Epileptic seizures stopped on PER in the six patients who still had experienced generalized tonic-clonic or myoclonic seizures (100%). Some abatement of efficacy on myoclonus was seen in two patients who still retained some benefit. Weight gain was reported in six patients (50%). Psychological and behavioral side-effects were observed in six patients (50%) and led to withdrawal of PER in three cases and dose reduction in three, with abatement of the problems.

Significance: This study provides evidence that for ULD patients, PER may show marked efficacy even in severe cases, particularly against myoclonus, but also against seizures. PER should thus be tried in ULD patients whose seizures are not satisfactorily controlled. Its use is limited because of psychological and behavioral side effects, with higher doses of approximately 6 mg/day or greater likely risk factors.
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http://dx.doi.org/10.1111/epi.13662DOI Listing
April 2017

Efficacy of naloxone in reducing postictal central respiratory dysfunction in patients with epilepsy: study protocol for a double-blind, randomized, placebo-controlled trial.

Trials 2016 11 3;17(1):529. Epub 2016 Nov 3.

Epilepsy Institute (IDEE), Lyon, France.

Background: Generalized tonic-clonic seizures (GTCSs) are the main risk factor for sudden unexpected death in epilepsy (SUDEP). Experimental and clinical data strongly suggest that the majority of SUDEP results from a postictal respiratory dysfunction progressing to terminal apnea. Postictal apnea could partly derive from a seizure-induced massive release of endogenous opioids. The main objective of this study is to evaluate the efficacy of an opioid antagonist, naloxone, administered in the immediate aftermath of a GTCS, in reducing the severity of the postictal central respiratory dysfunction.

Methods/design: The Efficacy of Naloxone in Reducing Postictal Central Respiratory Dysfunction in Patients with Epilepsy (ENALEPSY) study is a multicenter, double-blind, randomized, placebo-controlled trial conducted in patients with drug-resistant focal epilepsy who are undergoing long-term video-electroencephalogram (EEG) monitoring (LTM) in an epilepsy monitoring unit (EMU). We plan to randomize 166 patients (1:1) to receive intravenous naloxone (0.4 mg) or placebo in the immediate aftermath of a GTCS. Because inclusion in the study needs to take place prior to the occurrence of the GTCS, and because such occurrence is observed in about one-fourth of patients undergoing LTM, we plan to include a maximum of 700 patients upon admission in the EMU. The primary endpoint will be the proportion of patients whose oxygen saturation is <90 % between 1 and 3 min after the end of a GTCS. Secondary outcomes will include the following: the proportion of patients who show postictal apnea, the occurrence and duration of postictal generalized EEG suppression, the total duration of the postictal coma, postictal pain, and the number of patients who have a second GTCS within 120 min after the intravenous injection.

Discussion: The demonstration of naloxone's efficacy on the severity of postictal hypoxemia will have two primary consequences. First, naloxone would be the first and only therapeutic approach that could be delivered immediately to reverse postictal apnea. Second, demonstration that an opioid antagonist can effectively reduce postictal apnea would pave the way for an assessment of a preventive therapy for SUDEP targeting the same pathophysiological pathway using oral administration of naltrexone.

Trial Registration: ClinicalTrials.gov identifier: NCT02332447 . Registered on 5 January 2015.
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http://dx.doi.org/10.1186/s13063-016-1653-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5094038PMC
November 2016

Cost-effectiveness analysis of epilepsy surgery in a controlled cohort of adult patients with intractable partial epilepsy: A 5-year follow-up study.

Epilepsia 2016 Oct 5;57(10):1669-1679. Epub 2016 Sep 5.

Department of Functional Neurology and Epileptology and the Institute of Epilepsies, Hospices Civils de Lyon, Lyon, France.

Objective: Despite its well-known effectiveness, the cost-effectiveness of epilepsy surgery has never been demonstrated in France. We compared cost-effectiveness between resective surgery and medical therapy in a controlled cohort of adult patients with partial intractable epilepsy.

Methods: A prospective cohort of adult patients with surgically remediable and medically intractable partial epilepsy was followed over 5 years in the 15 French centers. Effectiveness was defined as 1 year without a seizure, based on the International League Against Epilepsy (ILAE) classification. Clinical outcomes and direct costs were compared between surgical and medical groups. Long-term direct costs and effectiveness were extrapolated over the patients' lifetimes with a Monte-Carlo simulation using a Markov model, and an incremental cost-effectiveness ratio (ICER) was computed. Indirect costs were also evaluated.

Results: Among the 289 enrolled surgery candidates, 207 were operable-119 in the surgical group and 88 in the medical group-65 were not operable and not analyzed here, 7 were finally not eligible, and 10 were not followed. The proportion of patients completely seizure-free during the last 12 months (ILAE class 1) was 69.0% in the operated group and 12.3% in the medical group during the second year (p < 0.001), and it was respectively 76.8% and 21% during the fifth year (p < 0.001). Direct costs became significantly lower in the surgical group the third year after surgery, as a result of less antiepileptic drug use. The value of the discounted ICER was 10,406 (95% confidence interval [CI] 10,182-10,634) at 2 years and 2,630 (CI 95% 2,549-2,713) at 5 years. Surgery became cost-effective between 9 and 10 years after surgery, and even earlier if indirect costs were taken into account as well.

Significance: Our study suggests that in addition to being safe and effective, resective surgery of epilepsy is cost-effective in the medium term. It should therefore be considered earlier in the development of epilepsy.
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http://dx.doi.org/10.1111/epi.13492DOI Listing
October 2016

Unverricht-Lundborg disease.

Epileptic Disord 2016 Sep;18(S2):28-37

Department of Pharmacology, University of Tartu, Tartu, Estonia.

We first review the clinical presentation and current therapeutic approaches available for treating Unverricht-Lundborg disease (ULD), a progressive myoclonus epilepsy. Next, we describe the identification of disease causing mutations in the gene encoding cystatin B (CSTB). A Cstb-deficient mouse model, which recapitulates the key features of ULD including myoclonic seizures, ataxia, and neuronal loss, was generated to shed light on the mechanisms contributing to disease pathophysiology. Studies with this model have elucidated the diverse biological roles for Cstb from functioning as a protease inhibitor, to regulating glial activation, oxidative stress, serotonergic neurotransmission, and hyperexcitability. These findings set the stage for future studies that may open avenues to improved therapeutic approaches.
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http://dx.doi.org/10.1684/epd.2016.0841DOI Listing
September 2016

Is there a difference between various presentations of valproate for cognitive outcome after in utero exposure?

Epilepsia 2016 Mar;57(3):523-4

Epilepsy Unit, Gui de Chauliac Hospital, Montpellier, France.

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http://dx.doi.org/10.1111/epi.13301DOI Listing
March 2016

Risk factors of postictal generalized EEG suppression in generalized convulsive seizures.

Neurology 2015 Nov 2;85(18):1598-603. Epub 2015 Sep 2.

From the Department of Functional Neurology and Epileptology (V.A., B.M., S.R.) and the Institute of Epilepsies (E.H., P.R., S.R.), Hospices Civils de Lyon and Lyon 1 University; Lyon's Neuroscience Research Center (V.A., B.M., P.R., S.R.), INSERM U1028/CNRS UMR 5292, Lyon, France; the Hospital of Clinics of Ribeirão Preto (V.A.), University of São Paulo, Brazil; the Department of Neurology (L.V., M.D.), University Hospital of Toulouse; the Neurology Department (L.M., J.J.), University Hospital of Nancy; the Clinical Neurophysiology and Epileptology Department (F.B.), Timone Hospital, Marseille; the Department of Clinical Neurophysiology (W.S.), Lille University Medical Center, EA 1046, University of Lille2; the Department of Neurology (E.H.), University Hospital of Strasbourg; the Department of Neurology (C.M.), Hôpital Pellegrin, Bordeaux; the Epilepsy Unit (F.C.), Department of Neurosurgery, Centre Hospitalier Sainte-Anne; University Paris Descartes; La Teppe Epilepsy Center (J.P.), Tain l'Hermitage; the Epilepsy Unit (A.C.), Montpellier; the Department of Neurology (A.N.), University Hospital of Rennes; the Epileptology Unit (V.N.), Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière and Brain and Spine Institute (ICM; INSERM UMRS1127, CNRS UMR7225, UPMC University Paris 06), Paris; the Department of Neurology (P.K.), Michallon Hospital, GIN, INSERM U836, UJF, Grenoble Alpes University, Grenoble; the Department of Clinical Neurophysiology (B.D.T.), INSERM U930, University Hospital of Tours; the Department of Neurology (P.T.), University Hospital of Nice; the Department of Neurology (S.R.), University Hospital of Clermont-Ferrand, France; and the Department of Clinical Neurosciences (P.R.), Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland.

Objective: To identify the clinical determinants of occurrence of postictal generalized EEG suppression (PGES) after generalized convulsive seizures (GCS).

Methods: We reviewed the video-EEG recordings of 417 patients included in the REPO2MSE study, a multicenter prospective cohort study of patients with drug-resistant focal epilepsy. According to ictal semiology, we classified GCS into 3 types: tonic-clonic GCS with bilateral and symmetric tonic arm extension (type 1), clonic GCS without tonic arm extension or flexion (type 2), and GCS with unilateral or asymmetric tonic arm extension or flexion (type 3). Association between PGES and person-specific or seizure-specific variables was analyzed after correction for individual effects and the varying number of seizures.

Results: A total of 99 GCS in 69 patients were included. Occurrence of PGES was independently associated with GCS type (p < 0.001) and lack of early administration of oxygen (p < 0.001). Odds ratio (OR) for GCS type 1 in comparison with GCS type 2 was 66.0 (95% confidence interval [CI 5.4-801.6]). In GCS type 1, risk of PGES was significantly increased when the seizure occurred during sleep (OR 5.0, 95% CI 1.2-20.9) and when oxygen was not administered early (OR 13.4, 95% CI 3.2-55.9).

Conclusion: The risk of PGES dramatically varied as a function of GCS semiologic characteristics. Whatever the type of GCS, occurrence of PGES was prevented by early administration of oxygen.
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http://dx.doi.org/10.1212/WNL.0000000000001949DOI Listing
November 2015

Can emotional stress trigger the onset of epilepsy?

Epilepsy Behav 2015 Jul 28;48:15-20. Epub 2015 May 28.

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France; Research Unit (URCMA: Unité de Recherche sur les Comportements et Mouvements Anormaux), INSERM U661, Montpellier, France.

Objective: The aim of this study was to investigate the potential role of an acute adverse stress as "trigger" for the onset of epilepsy.

Methods: Among 4618 consecutive patients, twenty-two reported a major life event within three months before the onset of epilepsy.

Results: All patients had focal epilepsy except one with idiopathic generalized epilepsy. The temporal lobe was involved in 90% of patients with focal epilepsy. More precisely, 13 patients (62% of patients with focal epilepsy) had medial temporal lobe epilepsy (MTLE), two had lateral temporal lobe epilepsy, four had temporoparietooccipital junction epilepsy, and two patients had central lobe epilepsy. The mean age and the median age at onset of epilepsy for patients with MTLE were both 38 years (range: 9.5-65 years). Ten patients had right and three had left MTLE. Among patients with focal epilepsy, MRI was abnormal in 7 (33%) with hippocampal sclerosis in four, periventricular nodular heterotopia in two, and complex cortical dysgenesis in one. The mean age at onset of epilepsy for patients with brain lesions was 26 years (range: 9.5-49). Twelve patients (54%) reported a death as a triggering factor for the onset of their epilepsy. Seven patients (32%) reported that a relationship of trust had been broken. Three patients (14%) had been subjects of violence. No patient reported sexual abuse as a triggering factor.

Conclusion: This study provides evidence that some patients (5/1000 patients) began their seizures in the wake of significant life events. The average age at onset of epilepsy is quite late, around age 30, even in the presence of brain lesions. These patients are emotionally and affectively more prone to have consequences of a stressful life event. The recognition and management of such situations may bring significant relief with improvement of the control of epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2015.05.010DOI Listing
July 2015

Galanin pathogenic mutations in temporal lobe epilepsy.

Hum Mol Genet 2015 Jun 17;24(11):3082-91. Epub 2015 Feb 17.

Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva (iGE3), Geneva, Switzerland.

Temporal lobe epilepsy (TLE) is a common epilepsy syndrome with a complex etiology. Despite evidence for the participation of genetic factors, the genetic basis of TLE remains largely unknown. A role for the galanin neuropeptide in the regulation of epileptic seizures has been established in animal models more than two decades ago. However, until now there was no report of pathogenic mutations in GAL, the galanin-encoding gene, and therefore its role in human epilepsy was not established. Here, we studied a family with a pair of monozygotic twins affected by TLE and two unaffected siblings born to healthy parents. Exome sequencing revealed that both twins carried a novel de novo mutation (p.A39E) in the GAL gene. Functional analysis revealed that the p.A39E mutant showed antagonistic activity against galanin receptor 1 (GalR1)-mediated response, and decreased binding affinity and reduced agonist properties for GalR2. These findings suggest that the p.A39E mutant could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to TLE. In a cohort of 582 cases, we did not observe any pathogenic mutations indicating that mutations in GAL are a rare cause of TLE. The identification of a novel de novo mutation in a biologically-relevant candidate gene, coupled with functional evidence that the mutant protein disrupts galanin signaling, strongly supports GAL as the causal gene for the TLE in this family. Given the availability of galanin agonists which inhibit seizures, our findings could potentially have direct implications for the development of anti-epileptic treatment.
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http://dx.doi.org/10.1093/hmg/ddv060DOI Listing
June 2015

Mixed myoclonic-absence status epilepticus in juvenile myoclonic epilepsy.

Epileptic Disord 2015 Mar;17(1):95-6

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier Research Unit URCMA (Unité de recherche sur les comportements et mouvements anormaux), INSERM, U661, Montpellier, France.

Myoclonic status epilepticus or mixed absence-myoclonic status is uncommon in juvenile myoclonic epilepsy (JME), often precipitated by sleep deprivation, withdrawal of medication, or inadequate antiepileptic drugs (Thomas et al., 2006; Crespel et al., 2013). Such episodes respond well to benzodiazepines or valproate (Crespel et al., 2013). We present the video-EEG of a 24-year-old woman with JME and bipolar disorder. She had a confusional state five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor with subtle myoclonus of the face and the arms. The EEG showed absence status (figures 1, 2), which stopped after IV injection of clonazepam (1 mg) (figure 3). Consciousness returned to normal [Published with video sequence and figures (1)].
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http://dx.doi.org/10.1684/epd.2014.0719DOI Listing
March 2015

A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy.

Nat Genet 2015 Jan 17;47(1):39-46. Epub 2014 Nov 17.

Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Progressive myoclonus epilepsies (PMEs) are a group of rare, inherited disorders manifesting with action myoclonus, tonic-clonic seizures and ataxia. We sequenced the exomes of 84 unrelated individuals with PME of unknown cause and molecularly solved 26 cases (31%). Remarkably, a recurrent de novo mutation, c.959G>A (p.Arg320His), in KCNC1 was identified as a new major cause for PME. Eleven unrelated exome-sequenced (13%) and two affected individuals in a secondary cohort (7%) had this mutation. KCNC1 encodes KV3.1, a subunit of the KV3 voltage-gated potassium ion channels, which are major determinants of high-frequency neuronal firing. Functional analysis of the Arg320His mutant channel showed a dominant-negative loss-of-function effect. Ten cases had pathogenic mutations in known PME-associated genes (NEU1, NHLRC1, AFG3L2, EPM2A, CLN6 and SERPINI1). Identification of mutations in PRNP, SACS and TBC1D24 expand their phenotypic spectra to PME. These findings provide insights into the molecular genetic basis of PME and show the role of de novo mutations in this disease entity.
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http://dx.doi.org/10.1038/ng.3144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281260PMC
January 2015

Zonisamide for refractory juvenile absence epilepsy.

Epilepsy Res 2014 Sep 14;108(7):1263-6. Epub 2014 May 14.

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France. Electronic address:

Purpose: To examine the clinical effect of zonisamide (ZNS) in patients with drug-resistant juvenile absence epilepsy (JAE).

Methods: Between 2006 and 2010, 13 JAE patients were successively treated with add-on ZNS. Safety and efficacy were assessed according to the patient and caregiver reports at visits every 3 months. Response rate was defined as a 50% or greater reduction in seizure frequency.

Results: Mean age was 42 years. No patient had been seizure free for a period ≥12 months before ZNS. The mean follow-up was 34 months. The mean dosage of ZNS was 388 mg. ZNS was effective for absence seizures (AS) in all patients (more than 50% AS reduction). Four patients reached seizure reduction on 550-600 mg/day. Three (23%) had a reduction in AS frequency >75% and five (38.5%) between 50% and 75%. Seizure freedom was achieved in five patients (38.5%) (three patients with AS only and two with AS plus generalized tonic-clonic seizures (GTCS)). Before ZNS, four patients had AS evolving to absence status. After ZNS, three of them were in the seizure-free group, the later never experienced this type of complication. Among seven patients with AS plus GTCS, two of them did not report any improvement in the frequency of GTCS (29%).

Conclusion: This observational post-marketing study confirms the broad-spectrum activity of ZNS that includes GTCS, myoclonic seizures and now AS. This study provides evidence that add-on ZNS is efficient and well tolerated in adult patients with refractory JAE, even at high doses.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.04.010DOI Listing
September 2014

Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study.

Lancet Neurol 2013 Oct 4;12(10):966-77. Epub 2013 Sep 4.

Hospices Civils de Lyon and CRNL, INSERM U1028, CNRS 5292, Lyon, France. Electronic address:

Background: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide.

Methods: Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available.

Findings: 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10,000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal.

Interpretation: SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time.

Funding: Commission of European Affairs of the International League Against Epilepsy.
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http://dx.doi.org/10.1016/S1474-4422(13)70214-XDOI Listing
October 2013

Consensus on diagnosis and management of JME: From founder's observations to current trends.

Epilepsy Behav 2013 Jul;28 Suppl 1:S87-90

University of Rome Sapienza II, Rome, Italy.

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?
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http://dx.doi.org/10.1016/j.yebeh.2012.11.051DOI Listing
July 2013

Management of juvenile myoclonic epilepsy.

Epilepsy Behav 2013 Jul;28 Suppl 1:S81-6

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France; Research Unit "Movement Disorders" (URMA), Department of Neurobiology, Institute of Functional Genomics, Montpellier, France.

Juvenile myoclonic epilepsy (JME) is a common form of epilepsy and a fairly lifelong disorder that may significantly lower a patient's expectations and potential for a full life. Luckily, it is also a highly treatable disorder, and up to 85% of patients with JME will enjoy satisfactory seizure control. Among anticonvulsants, valproate still stands out as the most efficacious drug, but may be poorly tolerated by some, and is considered unsafe for the fetuses of pregnant women. Alternatives have emerged in recent years, especially levetiracetam, but also topiramate, zonisamide or lamotrigine. In some cases, combination therapy may be useful or even required. One should not forget the potential aggravation induced not only by some commonly used anticonvulsants, especially carbamazepine and oxcarbazepine, but also, in some patients, by lamotrigine. In special settings, older drugs like benzodiazepines and barbiturates may be useful. But the management of JME should also include intervention in lifestyle, with strict avoidance of sleep deprivation and the management of copathologies, including the cognitive and psychiatric problems that are often encountered. With adequate management, there will only remain a small proportion of patients with uncontrolled epilepsy and all of its related problems. Juvenile myoclonic epilepsy is a condition in which the clinician has a fair chance of significantly helping the patient with medication and counseling.
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http://dx.doi.org/10.1016/j.yebeh.2013.01.001DOI Listing
July 2013

Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy.

J Biol Chem 2012 Dec 26;287(51):42900-9. Epub 2012 Oct 26.

Department of Neuroscience, Albert Einstein College of Medicine,Bronx, New York 10461,USA.

Carboxypeptidase A6 (CPA6) is a member of the A/B subfamily of M14 metallocarboxypeptidases that is expressed in brain and many other tissues during development. Recently, two mutations in human CPA6 were associated with febrile seizures and/or temporal lobe epilepsy. In this study we screened for additional CPA6 mutations in patients with febrile seizures and focal epilepsy, which encompasses the temporal lobe epilepsy subtype. Mutations found from this analysis as well as CPA6 mutations reported in databases of single nucleotide polymorphisms were further screened by analysis of the modeled proCPA6 protein structure and the functional role of the mutated amino acid. The point mutations predicted to affect activity and/or protein folding were tested by expression of the mutant in HEK293 cells and analysis of the resulting CPA6 protein. Common polymorphisms in CPA6 were also included in this analysis. Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix. The mutants with reduced extracellular CPA6 protein levels showed normal levels of 50-kDa proCPA6 in the cell, and this could be converted into 37-kDa CPA6 by trypsin, suggesting that protein folding was not greatly affected by the mutations. Interestingly, three of the mutations that reduced extracellular CPA6 protein levels were found in patients with epilepsy. Taken together, these results provide further evidence for the involvement of CPA6 mutations in human epilepsy and reveal additional rare mutations that inactivate CPA6 and could, therefore, also be associated with epileptic phenotypes.
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http://dx.doi.org/10.1074/jbc.M112.414094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522286PMC
December 2012

IgG leakage may contribute to neuronal dysfunction in drug-refractory epilepsies with blood-brain barrier disruption.

J Neuropathol Exp Neurol 2012 Sep;71(9):826-38

From the CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.

Focal epilepsies are often associated with blood-brain barrier disruption. In 4 entorhinal cortex tissue samples and 13 hippocampal samples from patients with pharmacoresistent temporal lobe epilepsy, we observed immunoglobulin G (IgG) leakage in the parenchyma and IgG-positive neurons that had evidence of neurodegeneration, such as shrinkage and eosinophilia. These findings were not present in samples from 12 nonepileptic control subjects. To complement these findings, we used a rat in vivo model that mimics the development of limbic epilepsy with blood-brain barrier disruption. During epileptogenesis, IgG leakage and neuronal IgG uptake increased concomitantly with the occurrence of seizures. Immunoglobulin G accumulation in neurons was selective, particularly for interneurons and pyramidal neurons. Immunohistochemistry and electron microscopy showed that IgG uptake in the rat neurons was associated with eosinophilia, shrinkage, and ultrastructural degenerative changes. Moreover, IgG-positive neurons lost their NeuN immunohistochemical staining. Together, these observations suggest that IgG leakage is related to neuronal impairment and may be a pathogenic mechanism in epileptogenesis and chronic epilepsy.
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http://dx.doi.org/10.1097/NEN.0b013e31826809a6DOI Listing
September 2012

Dramatic weight loss with rufinamide.

Epilepsia 2013 Jan 10;54(1):e5-8. Epub 2012 Jul 10.

Department of Neurology, Gui de Chauliac Hospital, Montpellier, France.

Rufinamide (RUF) is a novel antiepileptic drug considered as second-line therapy in the treatment of Lennox-Gastaut syndrome. Treatment-emergent adverse events (AEs) have consisted mainly of drowsiness, irritability, vomiting, and loss of appetite. RUF is considered as a "weight-neutral" drug. We found clinically significant weight loss in 7 of 15 consecutive adult patients (47%; 3 male, 4 female, aged 18-31 years) treated with RUF as add-on therapy (800-2,400 mg/day: 23.5-57.1 mg/kg/day). The body mass index (BMI) decreased by 7.3-18.7%. Two patients were obese class I before RUF. Five patients (71%) were underweight before RUF (mild in one case, moderate in two cases, and severe in two cases). Four of these patients stopped RUF because of this adverse effect. RUF was recommenced in two patients using a lower and slower dosing strategy; one patient showed improvement in seizure control and no weight loss but RUF was re-stopped in the second patient because of continued weight loss. Despite of weight loss, RUF was continued in two other patients because it reduced seizure activity. We primarily related weight loss to reduced food intake, that is, loss of appetite and nausea, although in two patients no obvious loss of appetite was reported. RUF can cause clinically significant weight loss in adult patients, even at low dose. This AE can affect patients who are already underweight. There is a possibility that lower starting doses and slower escalation might minimize weight loss, but further information is required to determine whether this is the case.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03579.xDOI Listing
January 2013

Sleep before and after temporal lobe epilepsy surgery.

Seizure 2012 May 12;21(4):260-5. Epub 2012 Feb 12.

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France.

Purpose: Patients with epilepsy often complain of non-restorative sleep. This is the consequence of the acute effect of seizures and the chronic effect of epilepsy responsible for disrupting sleep architecture. Other factors such as antiepileptic drugs (AEDs), also play a role in the alteration of sleep organization. The aim of this study was to evaluate the specific effect of seizures and interictal epileptiform abnormalities (IEAs) on sleep, in particular to see whether reducing seizure frequency by epilepsy surgery might improve sleep organization in these patients.

Methods: Eleven patients with refractory mesial temporal lobe epilepsy, who underwent surgical treatment and who were seizure free at the follow-up, were included in the study. Treatment with AEDs was not significantly modified before the second year of follow-up. Patients were evaluated before surgery, at 1-year and 2-year follow-up visits with a videoEEG monitoring (24h/24). At each follow-up visit, interictal epileptiform abnormalities and sleep macrostructure parameters were assessed.

Results: All patients showed a reduction of their IEAs. At 1-year follow-up, total sleep time and REM sleep increased significantly (p=0.032 and p=0.006, respectively). At 2-year follow-up, an important increase of REM sleep was observed (p=0.028). Most significant variations were noted 1 year after surgery. No significant variations were observed between the first and the second year after surgery.

Conclusions: Surgical treatment of temporal lobe epilepsy may improve sleep macrostructure by reducing the number of seizures and of IEAs. These results indirectly confirm the role of epilepsy in disrupting sleep organization chronically.
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http://dx.doi.org/10.1016/j.seizure.2012.01.007DOI Listing
May 2012
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