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Altered GABAA receptor subunit expression at thalamocortical synapses in an animal model of absence epilepsy
Abstracts / Journal of the Neurological Sciences 333 (2013) e1–e64
e33
Abstract — WCN 2013 No: 1853 Topic: 1 — Epilepsy Treatment outcome in epilepsy caused by intracranial vascular malformations
The countryside in Africa is occupied by more than 80% of the population and significant progress are made by individuals, families and the community in the management of epilepsy. Several cross-sectional studies taking into account the qualitative aspects were conducted in several locations. These studies have focused on the general population, patients living with epilepsy, accompanying persons, traditional healers, health officials and notables. The knowledge and interpretation of epilepsy are wrong. Epilepsy is considered to be supernatural, scary, dishonourable, contagious, incurable disease, deadly whose cause may be witchcraft, heredity or the transgression of taboos and prohibitions. The consequences are failure to comply with the treatment and the resurgence of epileptic seizures. For example, Benin is a high prevalence area because the rate of epilepsy varies from 15 to 38.4% but the average national is valued at 8%. Preventive treatment through the respect of banned cultural as sexual abstinence, not fresh meat and okra, the prohibition of drinking alcohol consumption and respect for taboos. Epilepsy therapeutic route begins at a traditherapeute upon the occurrence of the first crisis. He will later consult a nurse who issued the phenobarbital, only often available antiepileptic. But while effective this modern treatment will be stopped due to lack of financial means. The implementation of the results and the recommendations of the various studies will help to positively change the habits and behaviour of populations.
G. Kiteva-Trenchevska. University Clinic of Neurology, Skopje, FYROM — The Former Yugoslav Republic of Macedonia
doi:10.1016/j.jns.2013.07.124
were receiving antiepileptic therapy in standard therapeutical doses. Drug-resistant epilepsy was defined as uncontrolled seizures over a year despite attempts to treat with three or more different AEDs. We managed to build family tree of every studied patient viewing relatives up to 4th level of kinship, which included 6659 people. According to genealogical research, 71 male probands had 192 relatives suffering with epilepsy and 50 female probands had 181 relatives with diagnoses of epilepsy at some point of their lives. Group with well-controlled epilepsy (group I) included 213 patients, while pharmacoresistant group (group II) was presented by 96 patients. Group I had 16.9% of probands whose relatives suffered with epilepsy, while group II had 88.5% of patients whose relatives were diagnosed with epilepsy (p b 0.001). In the group of patients with pharmacoresistant epilepsy the prevalence of relatives suffering with epilepsy at some point of life was nearly5 times higher than in non-resistant group. Family history of epilepsy can be important factor in predicting result of epilepsy pharmacotherapy. doi:10.1016/j.jns.2013.07.122
Intracranial vascular malformations may be asymptomatic but may also cause partial onset seizures (POS) and lesional epilepsy, intracranial bleeding and different neurological deficits. The aim is to evaluate the treatment outcome in epilepsy caused by intracranial vascular malformations. Eleven patients with (POS), females/males — 8/3, aged 15–50 years, were evaluated clinically, electrophysiologically and with MRI. Four patients had childhood seizure onset, five adolescence and two adulthood. Cerebral cavernous malformation (CCM) was found in four, cerebral arterio-venous malformations (AVM) in four and Sturge–Weber syndrome (SWS) in three. Two patients with SWS and one with AVM developed hemiparesis contralateral to the vascular malformation, additional two patients developed hemiparesis after surgery (one after AVM embolisation, one after CCM lesionectomy) improving gradually. Three of four patients with AVM underwent surgery, only one is seizure free with AED and one is only on pharmacological treatment with rare POS. Three of four patients with CCM underwent surgery, all are seizure free while still on AEDs, one of them after polytherapy with two AEDs. One patient with multiple CCM is on AEDs, with rare seizures during pregnancy with carbamazepine monotherapy when acetazolamide was withdrawn. Three patients with SWS are on AEDs without seizure control, but with rare seizures in two and frequent seizures in one, who developed hemiparesis and intellectual deterioration during the course of the disease from childhood to adulthood. AEDs, surgery or both should be used for intracranial vascular malformations treatment to prevent seizure reoccurrence, neurological and intellectual deficits thus improving the life quality. doi:10.1016/j.jns.2013.07.123
Abstract — WCN 2013 No: 1926 Topic: 1 — Epilepsy Epilepsy in African cultural approaches D.G. Avodé, C. Adjien. Neurology, CNHU-HKM, FSS/UAC, Cotonou, Benin
Abstract — WCN 2013 No: 1785 Topic: 1 — Epilepsy Altered GABAA receptor subunit expression at thalamocortical synapses in an animal model of absence epilepsy S. Seo, B. Leitch. Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand Absence epilepsy is a non-convulsive generalized form of epilepsy, characterized by spike-wave discharges, which predominantly affects children. It is accompanied by sudden impairment of consciousness and has an adverse impact on childhood learning. While disruption of the thalamocortical (TC) network is known to lead to generation of hypersynchronous intrathalamic oscillatory activity during absence seizures, the underlying cellular and molecular mechanisms remain largely unknown. Recent studies using human and animal models suggest region-specific changes in GABAA receptors (GABAAR) in the thalamus may underlie hypersynchronous oscillations in absence seizures. Therefore the aim of the current study was to investigate whether GABAAR α1 and β2 subunits mediating phasic inhibition at TC synapses are altered in the well-established stargazer mouse model of absence epilepsy. Postembedding electron microscopy-immunogold cytochemistry was used to analyze density of GABAAR subunits in epileptic stargazers compared to matched non-epileptic control littermates (n = 6, 200 synapses/subunit). In the epileptic mice, synaptic expression of both GABAAR α1 and β2 subunits was significantly increased by 54% (p b 0.01) and 49% (p b 0.01), respectively. These findings suggest upregulation of phasic GABAAR-mediated inhibition at TC synapses in the ventrobasal thalamus. Whether such changes occur pre- or post-seizure remains to be investigated. Enhanced phasic GABAAR inhibition may be one of many factors contributing to increased inhibition recently reported in TC neurons of other absence models. Currently available anti-epileptics are associated with varying degrees of adverse side effects and inefficacy, thus further
e34
Abstracts / Journal of the Neurological Sciences 333 (2013) e1–e64
studies to elucidate the mechanisms underlying hypersynchronous activity in absence seizures may highlight novel drug targets for absence epilepsy treatment. doi:10.1016/j.jns.2013.07.125
Abstract — WCN 2013 No: 1956 Topic: 1 — Epilepsy Neural autoantibodies and immunotherapy-responsive epilepsy: A prospective study R. Iorioa, G. Assenzab, G. Della Marcaa, G. Colicchioa, M. Tombinib, V. Damatoa, A. Benvengab, A. Evolia, D. Plantonea, A. Martia, C. Vollonoa, G. Frisulloa, A.P. Batocchia. aCatholic University, Roma, Italy; b Campus Bio-Medico University, Roma, Italy Background: Autoantibodies specific for neural antigens have been described in association with several encephalopathies which have seizures as a prominent feature. In these cases seizures are poorly controlled with conventional anti-epileptic drugs (AED). In contrast, a good response is often achieved with immunotherapies. Objectives: To evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to the immunotherapy. Materials and methods: Two groups of patients were included in the study: 29 patients with epilepsy and other neurological symptoms and/ or autoimmune diseases (group 1) and 30 patients with AED-resistant epilepsy (group 2). Forty-two age and sex-matched healthy subjects (HS) were included as controls. Patients' Serum and CSF, when available, were evaluated for the presence of neural autoantibodies by immunohistochemistry on frozen sections of mouse brain and by cellbased assays. GAD65-IgGs were tested by RIA. Results: Neural-specific autoantibodies were detected in 11/59 patients (19%) but not in healthy controls. In particular, neuralspecific IgGs were detected in two patients from group 1 (2/29, 7%) (anti-GAD65, 1; antibody specific for an unclassified intracellular antigen [AUIA], 1) and in nine patients from group 2 (9/29, 31%) (anti-LGI1, 2; anti-GAD65, 1; AUIA, 4; antibody specific for an unclassified synaptic antigen, 2). In four patients from group 2, immunotherapy resulted in N50% seizure reduction at three months. Conclusions: A significant percentage of patients with AED-resistant epilepsy harbor neural-specific autoantibodies and may respond to immunotherapy. doi:10.1016/j.jns.2013.07.126
Abstract — WCN 2013 No: 1948 Topic: 1 — Epilepsy Sustained release forms: Application to antiepileptic drugs in developing countries J. Josta,b, P.-M. Preuxa,b, M. Druet-Cabanaca,b, V. Ratsimbazafya,b. a INSERM UMR 1094, Tropical Neuroepidemiology, Limoges, France; b Univ Limoges, School of Medicine, Institute of Neuroepidemiology and Tropical Neurology, CNRS FR 3503 GEIST, Limoges, France Background: Epilepsy is a chronic neurological disease affecting more than 70 million people worldwide, among them nearly 90% in developing countries (DCs). There, primary healthcare is extremely limited, only four major antiepileptic drugs (AEDs) are used: phenobarbital, carbamazepine, sodium valproate and phenytoin. Furthermore, there is also a problem of accessibility, availability and quality of drugs.
Objective: The main hypothesis of the study was based on the fact that a “long” sustained release form that would reduce the number of drug's administrations would allow overcoming the problems of compliance and accessibility. Methods: A literature review of sustained release forms applicable to an AED was performed and the primary endpoint was duration of active ingredient release longer than 24 h. We also assessed the feasibility and acceptability in DCs. Results: Two AEDs were found not to be of conventional release: carbamazepine and sodium valproate. But they are not of sustained release. Several techniques were available including: esterification, transdermal devices, liposomes and polymeric devices preformed or in situ formed. In situ methods for the preparation of injectable biodegradable microparticles or implants for the controlled delivery seemed best suited to our objective. Furthermore, they seem to fulfill the requirements of feasibility and cost. Sodium valproate appeared to be the most suitable molecule by reducing its cost and its hepatotoxicity with a “long” sustained release form. Conclusion: This new approach to the treatment of epilepsy would solve many problems in the DCs. However, preclinical and clinical studies are required to obtain an approval. doi:10.1016/j.jns.2013.07.127
Abstract — WCN 2013 No: 1961 Topic: 1 — Epilepsy Preventive and treatment aspects of the post-traumatic epilepsy N. Kufterinaa, I. Grygorovaa, O. Gichkob. aNeurology, Kharkiv, Ukraine; b Kharkiv National Medical University, Kharkiv, Ukraine Background: Posttraumatic epilepsy is one of the serious consequences of traumatic brain injury (TBI). To achieve the timely prevention and control of paroxysms therapeutic measures should be directed to the correct selection of major antiepileptic drugs and dose titration to the initial therapy. Objective: To study the effectiveness of antiepileptic drugs in prevention and treatment of post-traumatic epilepsy. Material and methods: We examined 48 patients with different periods of TBI who were treated at the Emergency Unit Hospital. All patients were divided into 3 groups: I with acute TBI (18), II with intermediate period of TBI (15), III with distant period of TBI (15). The control group was 15 almost healthy individuals. Were used clinical, neurological, instrumental, laboratory, and statistical methods. Results: The patients of the first group received antiepileptic drugs with preventive aim after an epileptic seizure in anamnesis. The best results were obtained with lamotrigine (p b 0.05). Posttraumatic epilepsy patients in groups II and III revealed the following manifestations: generalized seizures (65.3%), focal seizures (24.2%), combined paroxysms (11.5%), paroxysmal activity on EEG with a predominance of polyphasic complexes (69.4%), spike-waves (63.1%), and sharp waves (78.3%). In these groups of patients was the most efficient use of combination therapy of valproate and lamotrigine (p b 0.05). Conclusions: Thus, our findings demonstrate the effectiveness of lamotrigine for the prevention of post-traumatic epilepsy. And high efficiency combined therapy using valproate and lamotrigine in the treatment of post-traumatic epilepsy. doi:10.1016/j.jns.2013.07.128
e33
Abstract — WCN 2013 No: 1853 Topic: 1 — Epilepsy Treatment outcome in epilepsy caused by intracranial vascular malformations
The countryside in Africa is occupied by more than 80% of the population and significant progress are made by individuals, families and the community in the management of epilepsy. Several cross-sectional studies taking into account the qualitative aspects were conducted in several locations. These studies have focused on the general population, patients living with epilepsy, accompanying persons, traditional healers, health officials and notables. The knowledge and interpretation of epilepsy are wrong. Epilepsy is considered to be supernatural, scary, dishonourable, contagious, incurable disease, deadly whose cause may be witchcraft, heredity or the transgression of taboos and prohibitions. The consequences are failure to comply with the treatment and the resurgence of epileptic seizures. For example, Benin is a high prevalence area because the rate of epilepsy varies from 15 to 38.4% but the average national is valued at 8%. Preventive treatment through the respect of banned cultural as sexual abstinence, not fresh meat and okra, the prohibition of drinking alcohol consumption and respect for taboos. Epilepsy therapeutic route begins at a traditherapeute upon the occurrence of the first crisis. He will later consult a nurse who issued the phenobarbital, only often available antiepileptic. But while effective this modern treatment will be stopped due to lack of financial means. The implementation of the results and the recommendations of the various studies will help to positively change the habits and behaviour of populations.
G. Kiteva-Trenchevska. University Clinic of Neurology, Skopje, FYROM — The Former Yugoslav Republic of Macedonia
doi:10.1016/j.jns.2013.07.124
were receiving antiepileptic therapy in standard therapeutical doses. Drug-resistant epilepsy was defined as uncontrolled seizures over a year despite attempts to treat with three or more different AEDs. We managed to build family tree of every studied patient viewing relatives up to 4th level of kinship, which included 6659 people. According to genealogical research, 71 male probands had 192 relatives suffering with epilepsy and 50 female probands had 181 relatives with diagnoses of epilepsy at some point of their lives. Group with well-controlled epilepsy (group I) included 213 patients, while pharmacoresistant group (group II) was presented by 96 patients. Group I had 16.9% of probands whose relatives suffered with epilepsy, while group II had 88.5% of patients whose relatives were diagnosed with epilepsy (p b 0.001). In the group of patients with pharmacoresistant epilepsy the prevalence of relatives suffering with epilepsy at some point of life was nearly5 times higher than in non-resistant group. Family history of epilepsy can be important factor in predicting result of epilepsy pharmacotherapy. doi:10.1016/j.jns.2013.07.122
Intracranial vascular malformations may be asymptomatic but may also cause partial onset seizures (POS) and lesional epilepsy, intracranial bleeding and different neurological deficits. The aim is to evaluate the treatment outcome in epilepsy caused by intracranial vascular malformations. Eleven patients with (POS), females/males — 8/3, aged 15–50 years, were evaluated clinically, electrophysiologically and with MRI. Four patients had childhood seizure onset, five adolescence and two adulthood. Cerebral cavernous malformation (CCM) was found in four, cerebral arterio-venous malformations (AVM) in four and Sturge–Weber syndrome (SWS) in three. Two patients with SWS and one with AVM developed hemiparesis contralateral to the vascular malformation, additional two patients developed hemiparesis after surgery (one after AVM embolisation, one after CCM lesionectomy) improving gradually. Three of four patients with AVM underwent surgery, only one is seizure free with AED and one is only on pharmacological treatment with rare POS. Three of four patients with CCM underwent surgery, all are seizure free while still on AEDs, one of them after polytherapy with two AEDs. One patient with multiple CCM is on AEDs, with rare seizures during pregnancy with carbamazepine monotherapy when acetazolamide was withdrawn. Three patients with SWS are on AEDs without seizure control, but with rare seizures in two and frequent seizures in one, who developed hemiparesis and intellectual deterioration during the course of the disease from childhood to adulthood. AEDs, surgery or both should be used for intracranial vascular malformations treatment to prevent seizure reoccurrence, neurological and intellectual deficits thus improving the life quality. doi:10.1016/j.jns.2013.07.123
Abstract — WCN 2013 No: 1926 Topic: 1 — Epilepsy Epilepsy in African cultural approaches D.G. Avodé, C. Adjien. Neurology, CNHU-HKM, FSS/UAC, Cotonou, Benin
Abstract — WCN 2013 No: 1785 Topic: 1 — Epilepsy Altered GABAA receptor subunit expression at thalamocortical synapses in an animal model of absence epilepsy S. Seo, B. Leitch. Department of Anatomy, Brain Health Research Centre, University of Otago, Dunedin, New Zealand Absence epilepsy is a non-convulsive generalized form of epilepsy, characterized by spike-wave discharges, which predominantly affects children. It is accompanied by sudden impairment of consciousness and has an adverse impact on childhood learning. While disruption of the thalamocortical (TC) network is known to lead to generation of hypersynchronous intrathalamic oscillatory activity during absence seizures, the underlying cellular and molecular mechanisms remain largely unknown. Recent studies using human and animal models suggest region-specific changes in GABAA receptors (GABAAR) in the thalamus may underlie hypersynchronous oscillations in absence seizures. Therefore the aim of the current study was to investigate whether GABAAR α1 and β2 subunits mediating phasic inhibition at TC synapses are altered in the well-established stargazer mouse model of absence epilepsy. Postembedding electron microscopy-immunogold cytochemistry was used to analyze density of GABAAR subunits in epileptic stargazers compared to matched non-epileptic control littermates (n = 6, 200 synapses/subunit). In the epileptic mice, synaptic expression of both GABAAR α1 and β2 subunits was significantly increased by 54% (p b 0.01) and 49% (p b 0.01), respectively. These findings suggest upregulation of phasic GABAAR-mediated inhibition at TC synapses in the ventrobasal thalamus. Whether such changes occur pre- or post-seizure remains to be investigated. Enhanced phasic GABAAR inhibition may be one of many factors contributing to increased inhibition recently reported in TC neurons of other absence models. Currently available anti-epileptics are associated with varying degrees of adverse side effects and inefficacy, thus further
e34
Abstracts / Journal of the Neurological Sciences 333 (2013) e1–e64
studies to elucidate the mechanisms underlying hypersynchronous activity in absence seizures may highlight novel drug targets for absence epilepsy treatment. doi:10.1016/j.jns.2013.07.125
Abstract — WCN 2013 No: 1956 Topic: 1 — Epilepsy Neural autoantibodies and immunotherapy-responsive epilepsy: A prospective study R. Iorioa, G. Assenzab, G. Della Marcaa, G. Colicchioa, M. Tombinib, V. Damatoa, A. Benvengab, A. Evolia, D. Plantonea, A. Martia, C. Vollonoa, G. Frisulloa, A.P. Batocchia. aCatholic University, Roma, Italy; b Campus Bio-Medico University, Roma, Italy Background: Autoantibodies specific for neural antigens have been described in association with several encephalopathies which have seizures as a prominent feature. In these cases seizures are poorly controlled with conventional anti-epileptic drugs (AED). In contrast, a good response is often achieved with immunotherapies. Objectives: To evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to the immunotherapy. Materials and methods: Two groups of patients were included in the study: 29 patients with epilepsy and other neurological symptoms and/ or autoimmune diseases (group 1) and 30 patients with AED-resistant epilepsy (group 2). Forty-two age and sex-matched healthy subjects (HS) were included as controls. Patients' Serum and CSF, when available, were evaluated for the presence of neural autoantibodies by immunohistochemistry on frozen sections of mouse brain and by cellbased assays. GAD65-IgGs were tested by RIA. Results: Neural-specific autoantibodies were detected in 11/59 patients (19%) but not in healthy controls. In particular, neuralspecific IgGs were detected in two patients from group 1 (2/29, 7%) (anti-GAD65, 1; antibody specific for an unclassified intracellular antigen [AUIA], 1) and in nine patients from group 2 (9/29, 31%) (anti-LGI1, 2; anti-GAD65, 1; AUIA, 4; antibody specific for an unclassified synaptic antigen, 2). In four patients from group 2, immunotherapy resulted in N50% seizure reduction at three months. Conclusions: A significant percentage of patients with AED-resistant epilepsy harbor neural-specific autoantibodies and may respond to immunotherapy. doi:10.1016/j.jns.2013.07.126
Abstract — WCN 2013 No: 1948 Topic: 1 — Epilepsy Sustained release forms: Application to antiepileptic drugs in developing countries J. Josta,b, P.-M. Preuxa,b, M. Druet-Cabanaca,b, V. Ratsimbazafya,b. a INSERM UMR 1094, Tropical Neuroepidemiology, Limoges, France; b Univ Limoges, School of Medicine, Institute of Neuroepidemiology and Tropical Neurology, CNRS FR 3503 GEIST, Limoges, France Background: Epilepsy is a chronic neurological disease affecting more than 70 million people worldwide, among them nearly 90% in developing countries (DCs). There, primary healthcare is extremely limited, only four major antiepileptic drugs (AEDs) are used: phenobarbital, carbamazepine, sodium valproate and phenytoin. Furthermore, there is also a problem of accessibility, availability and quality of drugs.
Objective: The main hypothesis of the study was based on the fact that a “long” sustained release form that would reduce the number of drug's administrations would allow overcoming the problems of compliance and accessibility. Methods: A literature review of sustained release forms applicable to an AED was performed and the primary endpoint was duration of active ingredient release longer than 24 h. We also assessed the feasibility and acceptability in DCs. Results: Two AEDs were found not to be of conventional release: carbamazepine and sodium valproate. But they are not of sustained release. Several techniques were available including: esterification, transdermal devices, liposomes and polymeric devices preformed or in situ formed. In situ methods for the preparation of injectable biodegradable microparticles or implants for the controlled delivery seemed best suited to our objective. Furthermore, they seem to fulfill the requirements of feasibility and cost. Sodium valproate appeared to be the most suitable molecule by reducing its cost and its hepatotoxicity with a “long” sustained release form. Conclusion: This new approach to the treatment of epilepsy would solve many problems in the DCs. However, preclinical and clinical studies are required to obtain an approval. doi:10.1016/j.jns.2013.07.127
Abstract — WCN 2013 No: 1961 Topic: 1 — Epilepsy Preventive and treatment aspects of the post-traumatic epilepsy N. Kufterinaa, I. Grygorovaa, O. Gichkob. aNeurology, Kharkiv, Ukraine; b Kharkiv National Medical University, Kharkiv, Ukraine Background: Posttraumatic epilepsy is one of the serious consequences of traumatic brain injury (TBI). To achieve the timely prevention and control of paroxysms therapeutic measures should be directed to the correct selection of major antiepileptic drugs and dose titration to the initial therapy. Objective: To study the effectiveness of antiepileptic drugs in prevention and treatment of post-traumatic epilepsy. Material and methods: We examined 48 patients with different periods of TBI who were treated at the Emergency Unit Hospital. All patients were divided into 3 groups: I with acute TBI (18), II with intermediate period of TBI (15), III with distant period of TBI (15). The control group was 15 almost healthy individuals. Were used clinical, neurological, instrumental, laboratory, and statistical methods. Results: The patients of the first group received antiepileptic drugs with preventive aim after an epileptic seizure in anamnesis. The best results were obtained with lamotrigine (p b 0.05). Posttraumatic epilepsy patients in groups II and III revealed the following manifestations: generalized seizures (65.3%), focal seizures (24.2%), combined paroxysms (11.5%), paroxysmal activity on EEG with a predominance of polyphasic complexes (69.4%), spike-waves (63.1%), and sharp waves (78.3%). In these groups of patients was the most efficient use of combination therapy of valproate and lamotrigine (p b 0.05). Conclusions: Thus, our findings demonstrate the effectiveness of lamotrigine for the prevention of post-traumatic epilepsy. And high efficiency combined therapy using valproate and lamotrigine in the treatment of post-traumatic epilepsy. doi:10.1016/j.jns.2013.07.128