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14. Safety and efficacy of prolonged mitoxantrone therapy
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Society Proceedings / Clinical Neurophysiology 122 (2011) e1–e7
tive apneas had a stronger impact than central ones on brain tissue oxygenation of the normal hemisphere ( 1.17 ± 0.52% versus 0.44 ± 0.22% per second, p = 0.003). Conclusions: During the acute phase of stroke SDB repetitively induces major cerebral oxygen desaturations on the normal hemisphere and has a more profound effect during obstructive (versus central) apneas. These new findings may reflect the asymmetry of brain metabolism and neurovascular coupling with potential clinical significance for stroke pathophysiology and recovery. doi:10.1016/j.clinph.2010.10.018
13. Primary vs secondary bilateral synchrony – Insights using simultaneous EEG/fMRI—O. Scheidegger 1, K. Jann 2, T. König 2, K. Meyer 3, R. Wiest 1, M. Hauf 1 (1 Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern, Switzerland, 2 Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, Bern, Switzerland, 3 Bethesda, Epilepsy Center, Tschugg, Switzerland) Introduction: Prevailing bilateral synchronous discharges on scalp electroencephalogram (EEG) do not allow a differentiation between primary generalized seizures and secondary bilateral synchrony in focal epilepsies. Here, we show how a comprehensive analysis of interictal simultaneous EEG/fMRI can help to differentiate primary from secondary bilateral synchrony. Methods: Simultaneous EEG/fMRI recordings were performed in one patient suffering from idiopathic generalized epilepsy (IGE) and in one patient suffering from lesional frontal lobe epilepsy (FLE) due to a developmental venous anomaly (DVA). Both patients showed bilateral synchronous discharges on scalp EEG. An independent component analysis (ICA) factor coding for time varying interictal epileptic discharges (IED) was convolved with a hemodynamic response function to predict the blood oxygen level dependent (BOLD) signal. Voxel-wise correlations between the ICA-based predictor and the BOLD signal were computed. The temporal pattern of the BOLD correlates was analysed by shifting the convoluted predictor in intervals of 1 s from 10 s before to 10 s after the IED. Results: Both patients showed widespread bilateral negative BOLD correlates in the association cortices of the frontal and parietal lobes beginning before and ending after the IED (duration: 12 s in IGE, 4 s in FLE). Additionally, the patient with IGE showed positive BOLD correlates 10 s prior to IED in the brainstem, evolving to a bilateral thalamic response from 8 to 0 s prior to the IED, whereas positive BOLD correlates were delineated in the cortex drained by the DVA 4 s prior to IED until 1 s after IED in the patient with FLE. Conclusions: A pattern of brain activity that is temporally linked to brief interictal epileptic activity has been depicted in two patients with bilateral synchronous discharges. As a common pathway of propagation of epileptic activity, widespread cortical deflection resembling a default mode network evolves along physiological brain networks. Corresponding to the pathophysiologic concept of centrocephalic crosstalk in the patient with IGE, a thalamo-reticular network has been observed, whereas a focal onset of brain activity emerging from the delineated lesion was depicted in the patient with lesional FLE. This study was supported in part by Grant 33CM30-124089 Imaging large scale networks in epilepsy from the Swiss National Science Foundation. doi:10.1016/j.clinph.2010.10.019
14. Safety and efficacy of prolonged mitoxantrone therapy—C. Zecca, C. Limoni, C.L. Bassetti, C. Gobbi (Ospedale Civico Lugano, Lugano, Switzerland) Introduction: Mitoxantrone (MTX), a DNA-topoisomerase II inhibitor, is an effective first line drug for patients with malignant form of MS and a second line treatment for patients with worsening relapsing remitting MS (RRMS) or secondary progressive MS (SPMS) unresponsive to interferon beta or glatirameracetate therapy. Unfortunately, its long term employment is limited by potentially severe side effects, both dose-related and unrelated. Therefore, the vast majority of the studies supporting MTX employment in clinical practice are related to 6 months to maximal 2 year protocols of treatment. The aim of this study is to evaluate safety and efficacy of prolonged (over 2 years) MTX regimens. Methods: Data source is the MS-registry of Ospedale Civico Lugano; all consecutive patients with worsening relapsing-remitting (RR)-MS or secondary progressive (SP)-MS treated with MTX for a minimum of 36 months since 1999–2009 were included. Patients were treated and followed according to the hospital internal guideline for MTX employment. Safety, tolerability and clinical/radialogical measures were evaluated. Data were compared by Wilcoxon signed rank test, One sample Wilcoxon signed rank test and One sample binomial test when applicable. Results: Twelve among 254 (4 RR, 8 SP) patients were treated with MTX for at least 36 months (median treatment duration 49.5 months) and followed for a median period of 69.5 months. Patients received a mean cumulative dose/m2 body surface of 121.8 ± 14.31. No major cardiac, oncologic nor internistic side effects were reported. After 3 years on treatment (OT) we observed no mean EDSS progression (0 ± 0.8, p = 0.861 NS). Annual relapse rate (ARR) OT was significantly lower than ARR before MTX initiation (1.41 ± 1.3 and 0.57 ± 0.57, respectively; p = 0.043). Mean number of Gd enhancing lesions was not significantly decreased after 3 years (1.56 ± 2.3 at BL and 0.1 ± 0.3 after 3 years OT, p = 0.13 NS); there was no significant increase in T2 lesion number after 3 years OT (mean number of new T2 lesions 1 ± 1.3, p = 0.13 NS). Conclusion: This retrospective study suggests that MTX is effective, well tolerated and safe in MS patients also for a treatment duration over 2 years. Based on this study low/delayed MTX regimens can be considered for patients without any other therapeutic options. doi:10.1016/j.clinph.2010.10.020
15. Spike triggered reaction-time-EEG, an assessment tool for driving ability?—H.E. Krestel, C. Liechti, A. von Allmen, A. Mosbacher, J. Mathis (Inselspital, Bern, Switzerland) Introduction: Epileptic seizures at the steering wheel are a rare but critical cause of traffic accidents. Interictal epileptic activity (IEA) can cause transitory cognitive impairment, as assessed in neuropsychological tests [1]. Its impact on driving has not been extensively tested [2,3], although guidelines often require an EEG compatible with the ability to drive. We set out to analyze the impact of IEA on reaction time in a pilot study with the perspective to establish an easy to handle tool in the routine EEG, allowing a validated judgement on the ability to drive. Methods: So far, nine patients in the age of 18–70 years were included. Four had absences, three idiopathic epilepsy with tonic clonic seizures, two unclassified epilepsy with generalized seizures. They all showed intermittent generalized IEA. Spike detection software (VIASYS) recognized IEA and triggered either a single light flash or an obstacle in the Javamodified Steer Clear Test (Healthdyne) (go signals). In the pilot experiments, he or she was instructed to press a button as rapidly
Society Proceedings / Clinical Neurophysiology 122 (2011) e1–e7
tive apneas had a stronger impact than central ones on brain tissue oxygenation of the normal hemisphere ( 1.17 ± 0.52% versus 0.44 ± 0.22% per second, p = 0.003). Conclusions: During the acute phase of stroke SDB repetitively induces major cerebral oxygen desaturations on the normal hemisphere and has a more profound effect during obstructive (versus central) apneas. These new findings may reflect the asymmetry of brain metabolism and neurovascular coupling with potential clinical significance for stroke pathophysiology and recovery. doi:10.1016/j.clinph.2010.10.018
13. Primary vs secondary bilateral synchrony – Insights using simultaneous EEG/fMRI—O. Scheidegger 1, K. Jann 2, T. König 2, K. Meyer 3, R. Wiest 1, M. Hauf 1 (1 Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern, Switzerland, 2 Department of Psychiatric Neurophysiology, University Hospital of Psychiatry, Bern, Switzerland, 3 Bethesda, Epilepsy Center, Tschugg, Switzerland) Introduction: Prevailing bilateral synchronous discharges on scalp electroencephalogram (EEG) do not allow a differentiation between primary generalized seizures and secondary bilateral synchrony in focal epilepsies. Here, we show how a comprehensive analysis of interictal simultaneous EEG/fMRI can help to differentiate primary from secondary bilateral synchrony. Methods: Simultaneous EEG/fMRI recordings were performed in one patient suffering from idiopathic generalized epilepsy (IGE) and in one patient suffering from lesional frontal lobe epilepsy (FLE) due to a developmental venous anomaly (DVA). Both patients showed bilateral synchronous discharges on scalp EEG. An independent component analysis (ICA) factor coding for time varying interictal epileptic discharges (IED) was convolved with a hemodynamic response function to predict the blood oxygen level dependent (BOLD) signal. Voxel-wise correlations between the ICA-based predictor and the BOLD signal were computed. The temporal pattern of the BOLD correlates was analysed by shifting the convoluted predictor in intervals of 1 s from 10 s before to 10 s after the IED. Results: Both patients showed widespread bilateral negative BOLD correlates in the association cortices of the frontal and parietal lobes beginning before and ending after the IED (duration: 12 s in IGE, 4 s in FLE). Additionally, the patient with IGE showed positive BOLD correlates 10 s prior to IED in the brainstem, evolving to a bilateral thalamic response from 8 to 0 s prior to the IED, whereas positive BOLD correlates were delineated in the cortex drained by the DVA 4 s prior to IED until 1 s after IED in the patient with FLE. Conclusions: A pattern of brain activity that is temporally linked to brief interictal epileptic activity has been depicted in two patients with bilateral synchronous discharges. As a common pathway of propagation of epileptic activity, widespread cortical deflection resembling a default mode network evolves along physiological brain networks. Corresponding to the pathophysiologic concept of centrocephalic crosstalk in the patient with IGE, a thalamo-reticular network has been observed, whereas a focal onset of brain activity emerging from the delineated lesion was depicted in the patient with lesional FLE. This study was supported in part by Grant 33CM30-124089 Imaging large scale networks in epilepsy from the Swiss National Science Foundation. doi:10.1016/j.clinph.2010.10.019
14. Safety and efficacy of prolonged mitoxantrone therapy—C. Zecca, C. Limoni, C.L. Bassetti, C. Gobbi (Ospedale Civico Lugano, Lugano, Switzerland) Introduction: Mitoxantrone (MTX), a DNA-topoisomerase II inhibitor, is an effective first line drug for patients with malignant form of MS and a second line treatment for patients with worsening relapsing remitting MS (RRMS) or secondary progressive MS (SPMS) unresponsive to interferon beta or glatirameracetate therapy. Unfortunately, its long term employment is limited by potentially severe side effects, both dose-related and unrelated. Therefore, the vast majority of the studies supporting MTX employment in clinical practice are related to 6 months to maximal 2 year protocols of treatment. The aim of this study is to evaluate safety and efficacy of prolonged (over 2 years) MTX regimens. Methods: Data source is the MS-registry of Ospedale Civico Lugano; all consecutive patients with worsening relapsing-remitting (RR)-MS or secondary progressive (SP)-MS treated with MTX for a minimum of 36 months since 1999–2009 were included. Patients were treated and followed according to the hospital internal guideline for MTX employment. Safety, tolerability and clinical/radialogical measures were evaluated. Data were compared by Wilcoxon signed rank test, One sample Wilcoxon signed rank test and One sample binomial test when applicable. Results: Twelve among 254 (4 RR, 8 SP) patients were treated with MTX for at least 36 months (median treatment duration 49.5 months) and followed for a median period of 69.5 months. Patients received a mean cumulative dose/m2 body surface of 121.8 ± 14.31. No major cardiac, oncologic nor internistic side effects were reported. After 3 years on treatment (OT) we observed no mean EDSS progression (0 ± 0.8, p = 0.861 NS). Annual relapse rate (ARR) OT was significantly lower than ARR before MTX initiation (1.41 ± 1.3 and 0.57 ± 0.57, respectively; p = 0.043). Mean number of Gd enhancing lesions was not significantly decreased after 3 years (1.56 ± 2.3 at BL and 0.1 ± 0.3 after 3 years OT, p = 0.13 NS); there was no significant increase in T2 lesion number after 3 years OT (mean number of new T2 lesions 1 ± 1.3, p = 0.13 NS). Conclusion: This retrospective study suggests that MTX is effective, well tolerated and safe in MS patients also for a treatment duration over 2 years. Based on this study low/delayed MTX regimens can be considered for patients without any other therapeutic options. doi:10.1016/j.clinph.2010.10.020
15. Spike triggered reaction-time-EEG, an assessment tool for driving ability?—H.E. Krestel, C. Liechti, A. von Allmen, A. Mosbacher, J. Mathis (Inselspital, Bern, Switzerland) Introduction: Epileptic seizures at the steering wheel are a rare but critical cause of traffic accidents. Interictal epileptic activity (IEA) can cause transitory cognitive impairment, as assessed in neuropsychological tests [1]. Its impact on driving has not been extensively tested [2,3], although guidelines often require an EEG compatible with the ability to drive. We set out to analyze the impact of IEA on reaction time in a pilot study with the perspective to establish an easy to handle tool in the routine EEG, allowing a validated judgement on the ability to drive. Methods: So far, nine patients in the age of 18–70 years were included. Four had absences, three idiopathic epilepsy with tonic clonic seizures, two unclassified epilepsy with generalized seizures. They all showed intermittent generalized IEA. Spike detection software (VIASYS) recognized IEA and triggered either a single light flash or an obstacle in the Javamodified Steer Clear Test (Healthdyne) (go signals). In the pilot experiments, he or she was instructed to press a button as rapidly