Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity.

BACKGROUND: The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive. METHODS: Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis. RESULTS: 4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure. CONCLUSIONS: Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses.

Refractory Convulsive Status Epilepticus Provoked by Intoxication with Dalfampridine in a Patient with Multiple Sclerosis and Depression Disorder: A Case Report and Literature Review.

PURPOSE: Dalfampridine (DFP) is used to improve motor functions in patients with multiple sclerosis (MS). Overdose of DFP can occur for a variety of reasons and can lead to a state of epilepsy. CASE REPORT: A 24-year-old woman with MS was admitted to hospital with severe sweating and delirium after attempting suicide by overdosing on DFP. At the time of hospitalization, she developed a tonic-clonic seizure that did not respond to immediate intravenous (IV) diazepam injection, followed by intravenous sodium valproate. Therefore, according to the hospital protocol of the neurology department, the patient was intubated and IV infusion of midazolam was started, Due to the persistence of seizures, sodium thiopental began and the patient was admitted to the intensive care unit (ICU). In the ICU, she received an infusion of sodium thiopental and intravenous sodium valproate, monitored by a daily electroencephalogram (EEG). The patient was discharged after four days due to her stable medical condition. CONCLUSION: Epilepsy in case of overuse of DFP should be considered as a life-threatening side effect and timely treatment should be done to prevent damage to the nervous system.

Aging-associated susceptibility to stress-induced ventricular arrhythmogenesis is attenuated by tetrodotoxin.

Aging is associated with increased prevalence of life-threatening ventricular arrhythmias, but mechanisms underlying higher susceptibility to arrhythmogenesis and means to prevent such arrhythmias under stress are not fully defined. We aimed to define differences in aging-associated susceptibility to ventricular fibrillation (VF) induction between young and aged hearts. VF induction was attempted in isolated perfused hearts of young (6-month) and aged (24-month-old) male Fischer-344 rats by rapid pacing before and following isoproterenol (1 µM) or global ischemia and reperfusion (I/R) injury with or without pretreatment with low-dose tetrodotoxin, a late sodium current blocker. At baseline, VF could not be induced; however, the susceptibility to inducible VF after isoproterenol and spontaneous VF following I/R was 6-fold and 3-fold higher, respectively, in old hearts (P < 0.05). Old animals had longer epicardial monophasic action potential at 90% repolarization (APD90; P < 0.05) and displayed a loss of isoproterenol-induced shortening of APD90 present in the young. In isolated ventricular cardiomyocytes from older but not younger animals, 4-aminopyridine prolonged APD and induced early afterdepolarizations (EADs) and triggered activity with isoproterenol. Low-dose tetrodotoxin (0.5 µM) significantly shortened APD without altering action potential upstroke and prevented 4-aminopyridine-mediated APD prolongation, EADs, and triggered activity. Tetrodotoxin pretreatment prevented VF induction by pacing in isoproterenol-challenged hearts. Vulnerability to VF following I/R or catecholamine challenge is significantly increased in old hearts that display reduced repolarization reserve and increased propensity to EADs, triggered activity, and ventricular arrhythmogenesis that can be suppressed by low-dose tetrodotoxin, suggesting a role of slow sodium current in promoting arrhythmogenesis with aging.

[The effect of fampridine on gait in people with Multiple sclerosis (MS)].

INTRODUCTION: Fampridine is a drug for people with Multiple Sclerosis (MS). It is a broad-spectrum voltage-dependent potassium channel blocker that enhances synaptic transmission. The drug has been shown to be able to enhance conduction in demyelinated axons, thereby leading to improved gait in patients with MS. The purpose of this study was to examine the effect of fampridine on gait function in people with MS in the end of a 2 weeks trial drug period and to observe how many patients continued drug therapy. MATERIAL AND METHODS: Data from 41 individuals with MS was collected retrospectively for this study. Measurements were administered by physiotherapists and the results from the Timed 25-Foot Walk (T25FW) and 12-item Multiple Sclerosis Walking Scale (MSWS-12) were obtained from medical records from The National University Hospital of Iceland. RESULTS: The results showed a significant difference in walking speed before and at the end of trial period (p<0.0001). The average improvement in walking speed was 22%. Results also demonstrated a significant difference in MSWS-12 scores before and at the end of treatment (p<0.0001). The average improvement in MSWS-12 was 11.4 points. Eighteen individuals (43.9%) continued treatment after the trial period. CONCLUSION: Fampridine can have a positive effect on impaired gait function in people with MS and can be an important adjunct to treatment.

De novo convulsive status epilepticus in patients with multiple sclerosis treated with dalfampridine.

BACKGROUND: Dalfampridine extended release (DAL) is a broad-spectrum voltage-gated potassium channel blocker that is indicated in multiple sclerosis to improve the nerve conduction of demyelinated axons. Seizures are a known side effect of DAL, which is contraindicated in patients with a history of epilepsy. OBJECTIVE: Three cases of multiple sclerosis (MS) with de novo convulsive status epilepticus (CSE) probably related to dalfampridine administration are described. METHODS: No patients had a history of seizures or renal impairment. Biological tests were normal. A brain magnetic resonance imaging (MRI) showed diffuse cortical and subcortical atrophy without active inflammatory lesions. RESULTS: All three patients presented with CSE that was attributed to DAL and so was discontinued. CONCLUSION: These case reports illustrate that, aside from seizures, de novo CSE is a potential complication of MS patients treated with DAL.

Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine.

BACKGROUND: Multiple sclerosis (MS) is a debilitating disease that negatively impacts patients' lives. OBJECTIVE: ENABLE assessed the effect of long-term prolonged-release (PR) fampridine (dalfampridine extended release in the United States) treatment on patient-perceived health impact in patients with MS with walking impairment. METHODS: ENABLE was a 48-week, open-label, Phase 4 study of PR-fampridine 10 mg twice daily. Patients who showed any improvement in Timed 25-Foot Walk walking speed at weeks 2 and 4 and any improvement in 12-item MS Walking Scale score at week 4 remained on treatment. The primary endpoint was change from baseline in 36-Item Short-Form Health Survey (SF-36) physical component summary (PCS) score. RESULTS: At week 4, 707/901 (78.5%) patients met the criteria to remain on treatment. Patients on treatment demonstrated significant and clinically meaningful improvements in SF-36 PCS scores from baseline (mean change (95% confidence interval)) to week 12 (4.30 (3.83, 4.78); p < 0.0001), week 24 (3.75 (3.23, 4.27); p < 0.0001), week 36 (3.46 (2.95, 3.97); p < 0.0001), and week 48 (3.24 (2.72, 3.77); p < 0.0001). Significant improvements from baseline were also demonstrated in secondary health measures in patients on treatment. CONCLUSION: PR-fampridine improved patient-perceived physical and psychological health impact of MS measured in a real-life setting.

Analysis of connexin expression during seizures induced by 4-aminopyridine in the rat hippocampus.

BACKGROUND: In epilepsy, seizures are generated by abnormal synchronous activity in neurons. In the rat hippocampus (HIP), epileptiform activity has been found to be associated with gap junctions (GJs). GJs are formed by the combination of two hemichannels, each composed of six connexins. At low doses, the convulsive drug 4-aminopyridine (4-AP) produces epileptiform activity without affecting glutamate levels; therefore, GJs could participate in its effect. Based on this argument, in this study, the expression of Cx 32, Cx 36 and Cx 43 protein and mRNA in the HIP of rats treated with 4-AP was evaluated. The evaluation of connexins was carried out by chemifluorescent immunoassay, semiquantitative RT-PCR and immunofluorescence to detect the amount and distribution of connexins and of cellular markers in the HIP and dentate gyrus (DG) of animals treated with NaCl and 4-AP in the right entorhinal cortex. In these animals, convulsive behavior and EEG signals were analyzed. RESULTS: The animals treated with 4-AP showed convulsive behavior and epileptiform activity 60 min after the administration. A significant increase in the protein expression of Cx 32, Cx 36 and Cx 43 was found in the HIP contralateral and ipsilateral to the site of 4-AP administration. A trend toward an increase in the mRNA of Cx 32 and Cx 43 was also found. An increase in the cellular density of Cx 32 and Cx 43 was found in the right HIP and DG, and an increase in the cellular density of oligodendrocytes in the DG and a decrease in the number of cells marked with NeuN were observed in the left HIP. CONCLUSIONS: Cx 32 and Cx 43 associated with oligodendrocytes and astrocytes had an important role in the first stages of seizures induced by 4-AP, whereas Cx36 localized to neurons could be associated with later stages. Additionally, these results contribute to our understanding of the role of connexins in acute seizures and allow us to direct our efforts to other new anticonvulsant strategies for seizure treatment.

Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers.

OBJECTIVE: 3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers. MATERIALS AND METHODS: In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires. RESULTS: After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (Cmax) were 8.09 ± 4.47 ng/mL and 35.8 ± 15.7 ng/mL, respectively (mean ± standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 ± 213 ng x min/mL and 2,097 ± 936 ng x min/mL (mean ± SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP. CONCLUSION: This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.

Novel predictive approaches for drug-induced convulsions in non-human primates using machine learning and heart rate variability analysis.

Drug-induced convulsions are a major challenge to drug development because of the lack of reliable biomarkers. Using machine learning, our previous research indicated the potential use of an index derived from heart rate variability (HRV) analysis in non-human primates as a biomarker for convulsions induced by GABAA receptor antagonists. The present study aimed to explore the application of this methodology to other convulsants and evaluate its specificity by testing non-convulsants that affect the autonomic nervous system. Telemetry-implanted males were administered various convulsants (4-aminopyridine, bupropion, kainic acid, and ranolazine) at different doses. Electrocardiogram data gathered during the pre-dose period were employed as training data, and the convulsive potential was evaluated using HRV and multivariate statistical process control. Our findings show that the Q-statistic-derived convulsive index for 4-aminopyridine increased at doses lower than that of the convulsive dose. Increases were also observed for kainic acid and ranolazine at convulsive doses, whereas bupropion did not change the index up to the highest dose (1/3 of the convulsive dose). When the same analysis was applied to non-convulsants (atropine, atenolol, and clonidine), an increase in the index was noted. Thus, the index elevation appeared to correlate with or even predict alterations in autonomic nerve activity indices, implying that this method might be regarded as a sensitive index to fluctuations within the autonomic nervous system. Despite potential false positives, this methodology offers valuable insights into predicting drug-induced convulsions when the pharmacological profile is used to carefully choose a compound.

A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus--effects on slowphase eye velocity, postural stability, locomotion and symptoms.

OBJECTIVE: The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires. METHODS: Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration. RESULTS: SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p<0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p<0.05). Patients improved in the 'get-up-and-go test' with 4-AP (p<0.001; post hoc: 5 mg: p=0.025; 10 mg: p<0.001). Tandem-walk time (both p<0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p<0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects. CONCLUSIONS: 4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.

Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome.

PURPOSE: Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV 1.1 sodium channel α subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced γ-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS. METHODS: We have studied heterozygous NaV 1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures. KEY FINDINGS: In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase. SIGNIFICANCE: We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches.

Pediatric cyanide poisoning by fire smoke inhalation: a European expert consensus. Toxicology Surveillance System of the Intoxications Working Group of the Spanish Society of Paediatric Emergencies.

Most fire-related deaths are attributable to smoke inhalation rather than burns. The inhalation of fire smoke, which contains not only carbon monoxide but also a complex mixture of gases, seems to be the major cause of morbidity and mortality in fire victims, mainly in enclosed spaces. Cyanide gas exposure is quite common during smoke inhalation, and cyanide is present in the blood of fire victims in most cases and may play an important role in death by smoke inhalation. Cyanide poisoning may, however, be difficult to diagnose and treat. In these children, hydrogen cyanide seems to be a major source of concern, and the rapid administration of the antidote, hydroxocobalamin, may be critical for these children.European experts recently met to formulate an algorithm for prehospital and hospital management of adult patients with acute cyanide poisoning. Subsequently, a group of European pediatric experts met to evaluate and adopt that algorithm for use in the pediatric population.

Comparison of 10-mg doses of 4-aminopyridine and 3,4-diaminopyridine for the treatment of downbeat nystagmus.

OBJECTIVE: Animal experiments have demonstrated that aminopyridines increase Purkinje cell excitability, and in clinical studies, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) improved downbeat nystagmus. In this double-blind, prospective, crossover study, the effects of equivalent doses of 4-AP and 3,4-DAP on the slow-phase velocity (SPV) of downbeat nystagmus were compared. METHODS: Eight patients with downbeat nystagmus due to different etiologies (cerebellar degeneration [n = 1], bilateral vestibulopathy [n = 1], bilateral vestibulopathy and cerebellar degeneration [n = 1], Arnold-Chiari I malformation and cerebellar ataxia [n = 1], cryptogenic cerebellar ataxia [n = 4]) were included. They were randomly assigned to receiving a single capsule of 10 mg of 3,4-DAP or 4-AP followed by 6 days with no medication. One week later, the treatment was switched, that is, 1 single capsule (10 mg) of the other agent. Recordings with 3-dimensional video-oculography were performed before and 45 and 90 minutes after drug administration. RESULTS: Both medications had a significant effect throughout time (pre vs post 45 vs post 90) (F() = 8.876; P < 0.01). Following the administration of 3,4-DAP, mean slow velocity decreased from -5.68°/s (pre) to -3.29°/s (post 45) to -2.96°/s (post 90) (pre vs post 45/post 90 P < 0.01). In 4-AP, the mean SPV decreased from -6.04°/s (pre) to -1.58°/s (post 45) to -1.21°/s (post 90) (pre vs post 45/post 90 P < 0.00001). Both after 45 and after 90, the mean SPVs were significantly lower for 4-AP than for 3,4-DAP (P < 0.05). None of the patients reported serious side effects. CONCLUSION: Based on these results, 10-mg doses of 4-AP lead to a more pronounced decrease of the SPV of downbeat nystagmus than do equivalent doses of 3,4-DAP.

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.

BACKGROUND: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. METHODS: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. FINDINGS: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. INTERPRETATION: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.

[4-Aminopyridine (Fampridine). A new attempt for the symptomatic treatment of multiple sclerosis]. / 4-Aminopyridin (Fampridin). Ein neuer Ansatz zur symptomatischen Therapie der Multiplen Sklerose.

Mobility limitation is a frequent clinical symptom of multiple sclerosis (MS) that poses a therapeutic challenge. For years results of animal experiments and clinical experience have indicated that the potassium channel blocker 4-aminopyridine improves axonal excitatory circuits and thus muscular strength in demyelinating diseases. A recently conducted randomized, placebo-controlled, multicenter phase 3 clinical trial in MS patients was able to show that an oral sustained-release formulation of 4-aminopyridine (Fampridine-SR) represents a suitable agent for treatment of walking disability in MS patients.This overview presents the study data and discusses the value of 4-aminopyridine for the symptomatic treatment of MS as a neurofunctional modifier of this disabling disease.

[Efficacy and safety of Kinezia (fampridine) in the complex therapy of multiple sclerosis]. / Effektivnost' i bezopasnost' preparata Kinezia (fampridin) v kompleksnoi terapii rasseyannogo skleroza.

OBJECTIVE: To analyze the efficacy and safety of fampridine** (Valenta Pharm, Russia) in the complex therapy of multiple sclerosis (MS). MATERIAL AND METHODS: One hundred and twenty-six patients with MS were double blind randomized to receive fampridine (n=60) or placebo (n=66). Fampridine was administered in prolonged-release form (film-coated tablets, 10 mg) at a dose of 10 mg (1 tablet) 2 times a day, for 24 weeks. The placebo group was treated in the same way. From the 12th week, all patients in the placebo group were transferred to therapy with fampridine, 10 mg 2 times a day, for another 12 weeks. Concomitant standard therapy for MS was allowed in both groups (concomitant disease-modifying medications and other treatment). The primary outcome in the study was the proportion of patients with reduced t25fw test time (determining walking speed on a 25-foot path) on at least two out of three visits compared to baseline. The mean change in Multiple Sclerosis Functional Composite (MSFC) scores from baseline was assessed at visits 4-7 (8-24 weeks). RESULTS: The proportion of patients with reduced t25fw test time compared to the baseline level was 31.7% in the fampridine group, which is higher than in the placebo group - 3.0% (p<0.001). The overall result of the Multiple Sclerosis Functional Composite (MSFC) reflected a gradual improvement in the patient's condition during treatment period. The dynamics of MSFC result relative to the baseline level significantly differed (p<0.05) between the fampridine and placebo groups in favor of the fampridine group during all treatment periods. In the fampridine group, adverse events (AE) associated with disorders of the nervous system were more common: headache, dizziness, and coordination disorders. CONCLUSIONS: Fampridine improves walking performance in MS patients. The Russian product fampridine has demonstrated a favorable safety profile.

Electrophysiological and behavioral properties of 4-aminopyridine-induced epileptic activity in mice.

4-aminopyridine (4-AP) is a widely used drug that induces seizure activity in rodents, especially in rats, although there is no consensus in the literature on the dose to be used in mice. The aim of the present study was to investigate the effect of the intraperitoneal administration of 4-AP in two doses (4 and 10 mg/kg) in vivo. EEG, movement, and video recordings were made simultaneously in male B6 mice to specify the details of the seizures and to determine whether there is a suitable non-lethal dose for seizure induction and for further molecular studies. Seizure behavior in mice differs from that seen in rats, with no characteristic stages of epileptic seizures, but with spiking and seizure activity. Seizure activity, although produced at both doses without being lethal, induced different changes of the EEG pattern. Smaller dose induced a lower amplitude seizure activity, decreased spiking activity and later onset of seizures, while higher dose induced a much more intense brain seizure activity and severe trembling. It is concluded that the intraperitoneal administration of 4-AP at a dose of 10 mg/kg induces explicit seizure activity in mice which is repeatable and can be suitable for further molecular research.

Efficacy and safety of fampridine for walking disability in multiple sclerosis.

Fampridine is the only drug approved for the treatment of walking impairment in multiple sclerosis. Around a third of the patients on treatment obtained an improvement in walking speed during the development phase. The effects are clinically significant, appear soon after the start of the treatment and are long-lasting, but disappear soon after the drug is withdrawn. In the real-world setting, the number of patients with a significant response to the treatment seems to be higher (around 70%). The tolerance is good, with mild to moderate, and transient adverse events. The most commonly reported are insomnia, headache, fatigue, back pain, dizziness, nausea and balance disorders. The main contraindications are a history of seizures, renal impairment and concomitant treatment with OCT2 inhibitors.

The effect of fampridine on the risk of seizure in patients with multiple sclerosis.

BACKGROUND: Fampridine was first approved by the US Food and Drug Administration (FDA) to improve walking in multiple sclerosis (MS) patients, which was demonstrated by an increase in their walking speed. Nevertheless, the medication has been reported to possess an epileptogenic effect since it blocks the voltage-gated potassium channels in neural fibers. Several studies have indicated that the risk of seizure among fampridine consumers is not substantially higher than that in the general MS population, however. The objective of this study is to describe 97 MS patients for whom fampridine was prescribed and to assess the incidence of post-medication seizures. METHODS: This cohort study included 97 MS patients with gait problems who referred to the Isfahan Clinic of MS from August 2017 to September 2019. The exclusion criteria were a previous or family history of seizure or a history of renal impairment. Fampridine was prescribed for all the patients at a dose of 10 mg twice daily (12 hours apart). RESULTS: three patients (with an approximate incidence rate of 0.015 per 100 patient-years) presented with generalized tonic-clonic seizures, 7, 9, and 14 months after initiating fampridine consumption. The radiological findings revealed significant cortical and subcortical lesions in the three patients. Further, two of them consumed baclofen or fingolimod simultaneously with fampridine. CONCLUSION: The reported incidence rate is relatively higher than that in the general MS population. The extensive (sub) cortical lesions and the concomitant medications probably have an important role in the epileptogenesis, regardless of fampridine. However, the potential pro-convulsant properties of fampridine should not be overlooked.