Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs.

PURPOSE: To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD). METHODS: This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy. RESULTS: Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations. CONCLUSION: PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Reactive Disruption of the Hippocampal Neurogenic Niche After Induction of Seizures by Injection of Kainic Acid in the Amygdala.

Adult neurogenesis persists in the adult hippocampus due to the presence of multipotent neural stem cells (NSCs). Hippocampal neurogenesis is involved in a range of cognitive functions and is tightly regulated by neuronal activity. NSCs respond promptly to physiological and pathological stimuli altering their neurogenic and gliogenic potential. In a mouse model of mesial temporal lobe epilepsy (MTLE), seizures triggered by the intrahippocampal injection of the glutamate receptor agonist kainic acid (KA) induce NSCs to convert into reactive NSCs (React-NSCs) which stop producing new neurons and ultimately generate reactive astrocytes thus contributing to the development of hippocampal sclerosis and abolishing neurogenesis. We herein show how seizures triggered by the injection of KA in the amygdala, an alternative model of MTLE which allows parallel experimental manipulation in the dentate gyrus, also trigger the induction of React-NSCs and provoke the disruption of the neurogenic niche resulting in impaired neurogenesis. These results highlight the sensitivity of NSCs to the surrounding neuronal circuit activity and demonstrate that the induction of React-NSCs and the disruption of the neurogenic niche are not due to the direct effect of KA in the hippocampus. These results also suggest that neurogenesis might be lost in the hippocampus of patients with MTLE. Indeed we provide results from human MTLE samples absence of cell proliferation, of neural stem cell-like cells and of neurogenesis.

Intravenous lacosamide (LCM) in status epilepticus (SE): Weight-adjusted dose and efficacy.

BACKGROUND: Some studies suggest higher efficacy of lacosamide (LCM) in status epilepticus (SE) with higher loading doses; however, this weight-adjusted dose has not been evaluated. OBJECTIVE: The objective was to evaluate the relationship between loading weight-adjusted dose and efficacy of LCM in SE. METHODS: A group of patients with SE treated with LCM from Spanish hospitals was examined retrospectively. Demographic data, type of SE, etiology, response rate, last antiepileptic drug (AED) used, treatment line in which LCM was used, total loading dose, and weight-adjusted dose were collected. RESULTS: One hundred sixty-five cases of SE were collected; 87 (52.7%) patients had nonconvulsive SE. Mean age was 64.2 ±â€¯17.2 and 60.6% (n = 100) were men. Regarding etiology, SE was considered as acute symptomatic in 85 (51.5%), remote symptomatic in 51 (30.9%), progressive symptomatic in 10 (6.1%), and cryptogenic in 19 (11.5%). Lacosamide was used as the third drug in 46.1%, and as a second option in 28%. In 115 patients, clonazepam had been used as the first option, and no benzodiazepines had been administered in the remaining 50. The median loading dose was 400 mg (100-600 mg), and the weight-adjusted dose was 5 mg/kg (3-6 mg/kg). The response rate was 63.3%, and 55.1% responded within the first 12 h. Efficacy was significantly higher in patients who had taken benzodiazepines at LCM loading doses >5.3 mg/kg (p = 0.006). This relationship was maintained independent of using other concomitant AEDs. However, if benzodiazepines were not taken, this relationship was not found. CONCLUSIONS: In adults with benzodiazepine-resistant SE, the response rate to LCM was higher, with weight-adjusted doses above 5.3 mg/kg.

Cardiovascular autonomic and hemodynamic responses to vagus nerve stimulation in drug-resistant epilepsy.

PURPOSE: Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treating patients with drug-resistant epilepsy. The impact of VNS on cardiovascular autonomic function remains to be fully understood. We determined changes in cardiovascular sympathetic and parasympathetic, and hemodynamic function in association with VNS in patients with drug-resistant focal epilepsy. METHOD: Longitudinal (n=15) evaluation of beat-to-beat blood pressure (BP) and heart rate variability (HRV), baroreflex sensibility, and hemodynamic function performed before VNS implantation, 6-months after implantation, and a mean of 12-months after implantation; and cross-sectional study (n=14) of BP and HR variability and baroreflex sensitivity during VNS on and VNS off. RESULTS: In the longitudinal study, no differences were observed between the baseline, the 6-month visit, and the final visit in markers of parasympathetic cardiovagal tone or baroreflex sensitivity. Systolic and diastolic BP upon 5-min of head-up tilt increased significantly after VNS implantation (Systolic BP: -16.69±5.65mmHg at baseline, 2.86±16.54mmHg at 6-month, 12.25±12.95mmHg at final visit, p=0.01; diastolic BP: -14.84±24.72mmHg at baseline, 0.86±16.97mmHg at 6-month, and 17±12.76mmHg at final visit, p=0.001). CONCLUSION: VNS does not seem to produce alterations in parasympathetic cardiovagal tone, regardless of the laterality of the stimulus. We observed a slight increase in sympathetic cardiovascular modulations. These changes had no significant hemodynamic implications. These findings contribute to the understanding of potential mechanisms of action of VNS.

Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

[This corrects the article DOI: 10.1371/journal.pbio.1002466.].

Correction: Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

[This corrects the article DOI: 10.1371/journal.pbio.1002466.].

Neuronal Hyperactivity Disturbs ATP Microgradients, Impairs Microglial Motility, and Reduces Phagocytic Receptor Expression Triggering Apoptosis/Microglial Phagocytosis Uncoupling.

Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.

Laforin and malin deletions in mice produce similar neurologic impairments.

Lafora disease is a progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin or in the EPM2B gene encoding malin. It is characterized by the presence of polyglucosan intracellular inclusion bodies (Lafora bodies) in brain and other tissues. Targeted disruption of Epm2a or Epm2b genes in mice produced widespread neuronal degeneration and accumulation of Lafora bodies in neuronal and nonneuronal tissues. Here we analyzed the neurologic alterations produced by disruption of the laforin gene in Epm2a mice and compared them to those in malin-deficient mice. Both Epm2a and Epm2b mice showed altered motor activity, impaired motor coordination, abnormal hind limb clasping, and episodic memory deficits. Epm2a mice also had tonic-clonic seizures, whereas both Epm2a and Epm2b mice had spontaneous single spikes, spike-wave, polyspikes, and polyspike-wave complexes with correlated myoclonic jerks. Neurologic alterations observed in the mutants were comparable and correlated with the accumulation of abundant Lafora bodies in the cerebral cortex, the hippocampus, the basal ganglia, the cerebellum, and the brainstem, suggesting that these inclusions could cause cognitive and behavioral deterioration. Thus, both Epm2a and Epm2b mice exhibit many pathologic aspects seen in patients with Lafora disease and may be valuable for the study of this disorder.

Efficacy and tolerability of zonisamide in idiopathic generalized epilepsy.

OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of zonisamide (ZNS) for the treatment of idiopathic generalized epilepsies (IGEs). METHODS: Thirteen patients with different types of IGEs who were treated with ZNS between the years 2006 and 2008 were identified. Efficacy and tolerability were assessed at months 6 and 12 post-treatment. Response was defined as a 50% or greater reduction in seizure frequency. RESULTS: Twelve patients (92.3%) continued with ZNS at month 6, and 11 (84.6%) at month 12. Mean daily dose was 319 mg (range 100-500 mg/d). Response was achieved at month 6 in eight of the 12 patients that continued with ZNS (66.6%), of which 7 were seizure-free (58.3%). At month 12, eight of the 11 patients that continued with ZNS were responders (72.7%) and 6 were seizure-free (63.6%). For different types of seizures, better responses were observed for absences and generalized tonic-clonic seizures. Four out of 13 patients (30.7%) experienced adverse events and in two (15.3%), these led to withdrawal. CONCLUSION: In this retrospective study, ZNS showed efficacy and tolerability for the treatment of different types of IGEs. Limitations include a small sample size and a relatively short period of follow-up. Our results are promising and justify the need for prospective controlled trials in IGE.