GAA-FGF14 disease: defining its frequency, molecular basis, and 4-aminopyridine response in a large downbeat nystagmus cohort.

BACKGROUND: GAA-FGF14 disease/spinocerebellar ataxia 27B is a recently described neurodegenerative disease caused by (GAA)≥250 expansions in the fibroblast growth factor 14 (FGF14) gene, but its phenotypic spectrum, pathogenic threshold, and evidence-based treatability remain to be established. We report on the frequency of FGF14 (GAA)≥250 and (GAA)200-249 expansions in a large cohort of patients with idiopathic downbeat nystagmus (DBN) and their response to 4-aminopyridine. METHODS: Retrospective cohort study of 170 patients with idiopathic DBN, comprising in-depth phenotyping and assessment of 4-aminopyridine treatment response, including re-analysis of placebo-controlled video-oculography treatment response data from a previous randomised double-blind 4-aminopyridine trial. FINDINGS: Frequency of FGF14 (GAA)≥250 expansions was 48% (82/170) in patients with idiopathic DBN. Additional cerebellar ocular motor signs were observed in 100% (82/82) and cerebellar ataxia in 43% (35/82) of patients carrying an FGF14 (GAA)≥250 expansion. FGF14 (GAA)200-249 alleles were enriched in patients with DBN (12%; 20/170) compared to controls (0.87%; 19/2191; OR, 15.20; 95% CI, 7.52-30.80; p < 0.0001). The phenotype of patients carrying a (GAA)200-249 allele closely mirrored that of patients carrying a (GAA)≥250 allele. Patients carrying a (GAA)≥250 or a (GAA)200-249 allele had a significantly greater clinician-reported (80%, 33/41 vs 31%, 5/16; RR, 2.58; 95% CI, 1.23-5.41; Fisher's exact test, p = 0.0011) and self-reported (59%, 32/54 vs 11%, 2/19; RR, 5.63; 95% CI, 1.49-21.27; Fisher's exact test, p = 0.00033) response to 4-aminopyridine treatment compared to patients carrying a (GAA)<200 allele. Placebo-controlled video-oculography data, available for four patients carrying an FGF14 (GAA)≥250 expansion, showed a significant decrease in slow phase velocity of DBN with 4-aminopyridine, but not placebo. INTERPRETATION: This study confirms that FGF14 GAA expansions are a frequent cause of DBN syndromes. It provides preliminary evidence that (GAA)200-249 alleles might be pathogenic. Finally, it provides large real-world and preliminary piloting placebo-controlled evidence for the efficacy of 4-aminopyridine in GAA-FGF14 disease. FUNDING: This work was supported by the Clinician Scientist program "PRECISE.net" funded by the Else Kröner-Fresenius-Stiftung (to CW, AT, and MSy), the grant 779257 "Solve-RD" from the European's Union Horizon 2020 research and innovation program (to MSy), and the grant 01EO 1401 by the German Federal Ministry of Education and Research (BMBF) (to MSt). This work was also supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) N° 441409627, as part of the PROSPAX consortium under the frame of EJP RD, the European Joint Programme on Rare Diseases, under the EJP RD COFUND-EJP N° 825575 (to MSy, BB and-as associated partner-SZ), the NIH National Institute of Neurological Disorders and Stroke (grant 2R01NS072248-11A1 to SZ), the Fondation Groupe Monaco (to BB), and the Montreal General Hospital Foundation (grant PT79418 to BB). The Care4Rare Canada Consortium is funded in part by Genome Canada and the Ontario Genomics Institute (OGI-147 to KMB), the Canadian Institutes of Health Research (CIHR GP1-155867 to KMB), Ontario Research Foundation, Genome Quebec, and the Children's Hospital of Eastern Ontario Foundation. The funders had no role in the conduct of this study.

Performance Measures and Plasma Biomarker Levels in Patients with Multiple Sclerosis after 14 Days of Fampridine Treatment: An Explorative Study.

Peripheral cytokine levels may serve as biomarkers for treatment response and disease monitoring in patients with multiple sclerosis (pwMS). The objectives were to assess changes in plasma biomarkers in PwMS after 14 days of fampridine treatment and to explore correlations between changes in performance measures and plasma biomarkers. We included 27 PwMS, 14 women and 13 men, aged 52.0 ± 11.6 years, with a disease duration of 17 ± 8.5 years, and an Expanded Disability Status Scale of 6 [IQR 5.0/6.5]. Gait and hand function were assessed using performance tests completed prior to fampridine and after 14 days of treatment. Venous blood was obtained, and chemiluminescence analysis conducted to assess plasma cytokines and neurodegenerative markers. All performance measures demonstrated improvements. Biomarkers showed decreased tumor necrosis factor (TNF) receptor-2 levels. Associations were found between change scores in (i) Six Spot Step Test and Interleukin (IL)-2, IL-8, and IL-17 levels; (ii) timed 25-foot walk and interferon-γ, IL-2, IL-8, TNF-α, and neurofilament light levels, and (iii) 12-Item Multiple Sclerosis Walking Scale and IL-17 levels. The associations may reflect increased MS-related inflammatory activity rather than a fampridine-induced response or that a higher level of inflammation induces a better response to fampridine.

Measuring and predicting the effect of remyelinating therapy in multiple sclerosis: a randomised controlled trial protocol (RESTORE).

INTRODUCTION: Remyelination failure hampers symptomatic recovery in multiple sclerosis (MS), underlining the importance of developing remyelinating therapies. Optic neuritis is currently the most established method of measuring remyelination in MS trials. Complementary more generalisable methods of measuring remyelination are required to confirm treatment efficacy. Measuring internuclear ophthalmoplegia (INO) with infrared oculography provides such a method. Moreover, this method can be expanded with a test for selecting likely treatment responders by using fampridine. The aim of this trial is to investigate the (long-term) remyelinating effects of clemastine fumarate in patients with MS and INO and to evaluate if treatment response can be predicted using fampridine. METHODS AND ANALYSIS: RESTORE is a single-centre double-blind randomised placebo-controlled trial of clemastine fumarate versus placebo. Prior to clemastine treatment improvement in oculographic features of INO after a single 10 mg dose of fampridine is measured in all participants and used to predict the treatment response to clemastine. Eighty individuals with MS and INO will be 1:1 randomised to 4 mg of clemastine fumarate two times a day for 6 months or equivalent placebo. Our primary outcome is improvement in the Versional Dysconjugacy Index-area under the curve, measured by infrared oculography after 6 months of treatment. Participants are assessed for persistent treatment effects 6, 18 and 30 months after end of treatment. Secondary outcome measures include other oculography parameters including double-step saccades, retinal imaging, visual acuities, physical disability, cognition and patient-reported outcomes. ETHICS AND DISSEMINATION: Clemastine is a registered and very well-established drug with well-known safety and side effects. The protocol was approved by the medical ethical committee of the Amsterdam UMC, location VUMC and the Dutch Central Committee on Research Involving Human Subject. Written informed consent is obtained from all participants. The results will be published in peer-reviewed medical scientific journals. TRIAL REGISTRATION NUMBER: EudraCT: 2021-003677-66, ClinicalTrials.gov: NCT05338450.

Dalfampridine as a promising agent in the management of hereditary spastic paraplegia: A triple-blinded, randomized, placebo-controlled pilot trial.

Limited but encouraging results support the use of dalfampridine in patients with hereditary spastic paraplegia (HSP). Our aim was to investigate the effects of dalfampridine on walking speed, muscle length, spasticity, functional strength, and functional mobility in patients with HSP. In this triple-blinded, randomized, placebo-controlled pilot trial, four patients with HSP received dalfampridine (10 mg twice daily) in addition to physiotherapy (twice a week), and four patients received placebo in addition to physiotherapy for eight weeks. The group allocation was masked from the assessor, treating physiotherapists, and patients. The primary outcome was the Timed 25-foot Walk Test (T25FWT) at the end of the eight-week treatment. The secondary outcome measures were functional mobility, functional muscle strength, muscle length, and spasticity. The improvement in the T25FWT values was significantly higher in the experimental group than in the control group (p < 0.05). All patients in the experimental group exceeded the proposed minimally important clinical difference for T25FWT. The degrees of improvement in most muscle length and spasticity assessments and functional muscle strength were also higher in the experimental group (p < 0.05). No significant difference was observed between the groups regarding functional mobility (p > 0.05). No adverse events or side effects were noted. This pilot trial yields encouraging evidence that the combination of dalfampridine and physiotherapy may enhance muscle parameters and improve walking speed in patients with HSP. However, further research involving larger sample sizes and more comprehensive assessments is needed to validate these results and establish the clinical benefits of this treatment approach. Trial registration ID: NCT05613114 (https://clinicaltrials.gov/), retrospectively registered on November 14, 2022.

Synthesis and Biological Study of 4-Aminopyridine-Peptide Derivatives Designed for the Treatment of Neurodegenerative Disorders.

BACKGROUND: Alzheimer's disease (AD) and Multiple sclerosis (MS) lead to neurodegenerative processes negatively affecting millions of people worldwide. Their treatment is still difficult and practically incomplete. One of the most commonly used drugs against these neurodegenerative diseases is 4-aminopyridine. However, its use is confined by the high toxicity. OBJECTIVES: The aim of this work is to obtain new peptide derivatives of 4-aminopyridine with decreased toxicity compared to 4-aminopyridine. METHODS: Synthesis was conducted in solution using a consecutive condensation approach. The new derivatives were characterized by melting points, NMR, and Mass spectra. Important ADME (absorption, distribution, metabolism, and excretion) properties have been studied in silico using ACD/Percepta v.2020.2.0 software. Acute toxicity was determined in mice according to a Standard protocol. All new derivatives were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (NEURO 2A) tumor cell lines via a standard MTT-based colorimetric method. ß-secretase inhibitory activity was determined by applying the fluorescent method. RESULTS: New derivatives of 4-aminopyridine containing analogues of the ß-secretase inhibitory peptide (Boc-Val-Asn-Leu-Ala-OH) were obtained. The in vivo toxicity of the tested compounds was found to be as high as 1500 mg/kg. Cell toxicity screening against tumor cell lines of different origins showed negligible growth-inhibitory effects of all investigated 4-aminopyridine analogues. CONCLUSION: Synthesis of new peptide derivatives of 4-aminopyridine is reported. Acute toxicity studies revealed a ca. 150 times lower toxicity of the new compounds as compared to 4-aminopyridine that may be ascribed to their peptide fragment.

Fampridine for gait imbalance in patients with multiple sclerosis (MS): a systematic review and meta-analysis.

BACKGROUND: Gait imbalance is one of the frequent complications in subjects with multiple sclerosis (MS). Fampridine (4-aminopyridine) is a potassium-channel blocker that is administered for gait imbalance in MS. Different studies showed the effects of fampridine on gait status based on various tests in subjects with MS. Some showed significant improvement after treatment, and others did not. So, we designed this systematic review, and meta-analysis to estimate the pooled effects of fampridine on gait status in patients with MS. METHODS: The main goal is the evaluation of times of different gait test pre and post fampridine treatment. Two independent expert researchers conducted a systematic and comprehensive search in PubMed, Scopus, EMBASE, Web of Science, and Google Scholar and also gray literature, including references of the references and conference abstracts. The search was done on September 16, 2022. Before-after studies trials reporting scores of the walking tests. We extracted data regarding the total number of participants, first author, publication year, country of origin, mean age, Expanded Disability Status Scale (EDSS), and the results of walking tests. RESULTS: The literature search revealed 1963 studies; after deleting duplicates, 1098 studies remained. Seventy-seven full texts were evaluated. Finally, 18 studies were included for meta-analysis, while most of them were not placebo-controlled trials. The most frequent country of origin was Germany, and the mean age and EDSS ranged between 44 and 56 years and 4 and 6, respectively. The studies were published between 2013 and 2019. The pooled standardized mean difference (SMD) (after-before) of the MS Walking Scale (MSWS-12) was - 1.97 (95%CI: - 1.7, - 1.03) (I2 = 93.1%, P < 0.001). The pooled SMD (after-before) of the six-minute walk test (6MWT) was 0.49 (95%CI: 0.22, - 0.76) (I2 = 0%, P = 0.7). The pooled SMD (after-before) of T Timed 25-Foot Walk (T25FW) was - 0.99(95%CI: - 1.52, - 0.47) (I2 = 97.5%, P < 0.001). CONCLUSION: This systematic review and meta-analysis show that fampridine improves gait imbalance in patients with MS.

KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine.

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage-gated K+ channel subunit KV 1.1. So far, loss-of-function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain-of-function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4-aminopyridine. Clinical use of 4-aminopyridine was associated with reduced seizure burden, enabled simplification of co-medication and prevented rehospitalization.

Effects of 4-Aminopyridine on Combined Nerve and Muscle Injury and Bone Loss.

PURPOSE: Musculoskeletal injuries are common, and peripheral nerve injury (PNI) causes significant muscle and bone loss within weeks. After PNI, 4-aminopyridine (4-AP) improves functional recovery and muscle atrophy. However, it is unknown whether 4-AP has any effect on isolated traumatic muscle injury and PNI-induced bone loss. METHODS: A standardized crush injury was performed on the sciatic nerve and muscles in mice, and the mice were assigned to receive normal saline or 4-AP treatment daily for 21 days. The postinjury motor and sensory function recovery was assessed, injured muscles were processed for histomorphometry, and the tibial bone was scanned for bone density. RESULTS: 4-Aminopyridine significantly accelerated the postinjury motor and sensory function recovery, improved muscle histomorphometry, increased muscle satellite cell numbers, and shifted muscle fiber types after combined nerve and muscle injury. Importantly, the 4-AP treatment significantly reduced PNI-induced bone loss. In contrast, in the case of isolated muscle injury, 4-AP had no effect on functional recovery and bone density, but it improved muscle-specific histomorphometry to a limited extent. CONCLUSIONS: These findings demonstrate the potential beneficial effects of 4-AP on the recovery of muscle morphology and bone density after combined muscle and nerve injury. CLINICAL RELEVANCE: Nerve injuries frequently involve muscle and result in rapid muscle and bone atrophy. In this scenario, 4-AP, in addition to accelerating nerve functional recovery, might work as an adjunctive agent to improve the recovery of injured muscle and attenuate PNI-induced bone loss.

Current advances in the pharmacological prevention and management of cognitive dysfunction in multiple sclerosis.

INTRODUCTION: Cognitive impairment (CI) is a core feature of Multiple Sclerosis (MS), being detectable in up to 65% of subjects. Treatment of CI can be considered of paramount importance. However, no standardized strategies are available to date to define the best treatment approach, especially for the pharmacological management. AREAS COVERED: In this narrative review, the authors outline the latest advances in pharmacological management of CI in MS, including Disease Modifying Treatments (DMTs) which indirectly may or may not influence CI and symptomatic drugs. Selected publications were restricted to those written in English, reporting on an adult relapsing-remitting MS or progressive MS sample, assessing the effects of (at least) 1 DMT or treatment in a longitudinal design, reporting data on (at least) one standardized cognitive test performed at baseline and follow-up, and published between January 2018 and May 2022. EXPERT OPINION: Recent data can be considered encouraging and inspiring for future studies. Overall, there is preliminary evidence of a beneficial effect of DMTs on cognition, particularly for high-efficacy DMTs. As for symptomatic treatments, dalfampridine appears to be the only medication with robust evidence of a positive effect on cognition. However, the definition of clinically meaningful change/improvement in cognitive functions remains an unmet need. Future studies should assess the role of other patient-related factors that can be associated with a better cognitive response to treatments and investigate the possible positive effect of multimodal interventions on cognition.

Fampridine in multiple sclerosis patients with acute phase of cervical transverse myelitis: a double-blind, randomized placebo-controlled trial.

BACKGROUND: Fampridine is a potassium channel blocker drug used to improve walking ability in patients with multiple sclerosis (MS). We evaluated the effect of fampridine in patients with MS in the acute phase of transverse myelitis. METHODS: In a randomized, placebo-controlled trial, 30 patients who had their first episode of cervical myelitis with quadriparesis presentation, with the final diagnosis of MS, were randomly divided into two equal groups. The intervention group received intravenous methylprednisolone (IVMP) for 7 days plus fampridine. The placebo group received IVMP for 7 days plus placebo. To compare the treatment results, we compared the Barthel index (BI) scores of the groups at the start of the trial and the 21st day after the start of treatment. RESULTS: There was no significant difference in baseline characteristics between the intervention and placebo groups in terms of mean age, sex, and mean admission BI (p > 0.05). Mean (SD) admission BI in placebo and intervention groups was 27.20 (7.341) and 27.87(5.78), respectively (p = 0.784). The measured mean (SD) BI after treatment was 48.73 (15.54) in the placebo and 64.93 (11.81) in the intervention group (p = 0.003) after 3 weeks. CONCLUSION: Using fampridine plus IVMP in the acute phase of transverse myelitis in MS patients improved the disease's symptoms and increased the daily activity ability of patients.

Eficácia e segurança da Fampridina comparada com placebo no tratamento de disfunções motoras em adultos portadores de esclerose múltipla: revisão rápida de evidências / Effectiveness and safety of Fampridine compared with placebo in the treatment of motor dysfunctions in adults with multiple sclerosis: quick evidence review

Tecnologia: Fampridina Indicação: Tratamento de disfunções motoras em pacientes portado-res de esclerose múltipla. Pergunta: A Fampridina é eficaz e segurança para o tratamento de disfunções motoras em adultos portadores de esclerose múltipla comparada ao placebo? Méto-dos: Levantamento bibliográfico foi realizado na base de dados PUBMED, seguindo estratégias de buscas predefinidas. Foi feita avaliação da qualidade metodológica das revisões sistemáticas com a ferramenta AMSTAR-2 (Assessing the Methodological Quality of Systematic Reviews Version 2). Resultados: Foram selecionados três estudos que atenderam aos critérios de inclu-são. Conclusão: A fampridina foi eficaz e segura para tratar disfunções motoras em dosagens específicas. Conforme os resultados dos estudos analisados, a fampridina pode melhora de modo significativo e contínuo a capacidade de deambular dos portadores EM. Além disso, pode ser eficaz para tratar habilidades manuais e cognitiva

Technology: Fampridine. Indication: Treatment of motor disorders in patients with multiple sclerosis. Question: Is Fampridine effective and safe for the treatment of multiple sclerosis in adults with functional limitations compared to placebo? Methods: A bibliographic survey was carried out in the PUBMED database, following predefined search strategies. The methodological quality of systematic reviews was evaluated using the Assessing the Methodological Quality of Systematic Reviews Version 2 tool. Results: Three studies that met the inclusion criteria were selected. Conclusion: Fampridine was effective and safe to treat motor disorders at specific dosages. According to the results of the analyzed studies, fampridine can significantly and continuously improve the ability to walk in MS patients. Also, it can be effective for treating manual and cognitive skills

Cost-effectiveness analysis of prolonged-release fampridine to treat walking disability of multiple sclerosis in China.

Objectives: This study evaluates the cost-effectiveness of adding prolonged-release (PR)-fampridine to best supportive care (BSC) versus BSC alone in adult multiple sclerosis patients with walking disability in China. Materials & methods: A hybrid decision tree and Markov model from both the societal and healthcare perspectives were constructed. Parameters were derived from clinical trials of PR-fampridine, published sources and clinical expert interviews. Results: Over a 10-year time horizon, adding PR-fampridine to BSC led to 0.15 quality-adjusted life year (QALY) gain and lower costs, with incremental cost-effectiveness ratios of -238,806 Chinese Yuan/QALY and -113,488 Chinese Yuan/QALY from the societal and healthcare perspectives, respectively. Conclusion: Compared with BSC alone, PR-fampridine plus BSC is considered an economically dominant strategy for the treatment of multiple sclerosis-related walking disability in China.

Evaluation of functional outcome measures after fampridine treatment in patients with multiple sclerosis - An interventional follow-up study.

OBJECTIVE: The purpose of this interventional study on participants with multiple sclerosis (MS) with walking disability was to evaluate changes in functional hand and walking measurements after fampridine treatment, after stratifying by the Expanded Disability Status Scale (EDSS). We furthermore wanted to investigate different functional measurements to evaluate their ability to detect responders to fampridine with a clinically relevant improvement. METHODS: Patients were recruited from the MS Clinic at Odense University Hospital and were classified into two disability groups based on their EDSS score (moderate EDSS (EDSSMod) 4.5-5.5 [n = 19] and severe EDSS (EDSSSev) 6.0-7.0 [n = 14]). At baseline (visit 1) they completed the Timed 25-Foot Walk (T25FW), 2-Minute Walk Test (2MWT), Nine Hold Peg Test (9HPT), 12-item Multiple Sclerosis Walking Scale (MSWS-12), and the Six Spot Step Test (SSST). Participants were given 10 mg twice daily fampridine for 14 days before retested (visit 2). For each measurement, cut-off values were used to define responders with a clinically relevant improvement to treatment. The measurements were evaluated separately and in combination. RESULTS: Of the 33 participants, 25 (75.8%) were identified as having a clinically relevant improvement (CRI). For all patients combined (EDSSAll), all five measurements showed significant functional improvement after treatment. For the individual measurements, the highest participant response rates after 14 days of fampridine treatment were seen on the MSWS-12 (57.6%) and 2MWT (42.4%). The 2MWT also showed the largest performance improvement (18.5%) from visit 1 to visit 2. For patients with severe disability (EDSSSev), no significant improvement was seen after fampridine treatment on the T25FW, and most of the responders to T25FW had moderate disability (EDSSMod, 71.5%). Conversely for the SSST, most responders were EDSSSev (83.3%). No participants had a clinically relevant improvement on the 9HPT. The combination of T25FW, SSST, and MSWS-12 was less sensitive in distinguishing responders from non-responders, whereas the combination of 2MWT and MSWS-12 identified the same responders and could better distinguish fampridine responders from non-responders. CONCLUSION: EDSS level did not influence the effect of fampridine treatment on functional hand and walking measures and the responsiveness of the measurements differed only a little between moderate and severe EDSS levels. The combination of self-reported walking capacity (MSWS-12) and walking endurance (2MWT) was better than T25FW, SSST, and MSWS-12 at detecting clinically meaningful improvement after fampridine treatment, which could prove useful in the clinical monitoring of walking disabilities in MS during fampridine treatment.

Acute axon damage and demyelination are mitigated by 4-aminopyridine (4-AP) therapy after experimental traumatic brain injury.

Damage to long axons in white matter tracts is a major pathology in closed head traumatic brain injury (TBI). Acute TBI treatments are needed that protect against axon damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our prior characterization of axon damage and demyelination after TBI led us to examine repurposing of 4-aminopyridine (4-AP), an FDA-approved inhibitor of voltage-gated potassium (Kv) channels. 4-AP is currently indicated to provide symptomatic relief for patients with chronic stage multiple sclerosis, which involves axon damage and demyelination. We tested clinically relevant dosage of 4-AP as an acute treatment for experimental TBI and found multiple benefits in corpus callosum axons. This randomized, controlled pre-clinical study focused on the first week after TBI, when axons are particularly vulnerable. 4-AP treatment initiated one day post-injury dramatically reduced axon damage detected by intra-axonal fluorescence accumulations in Thy1-YFP mice of both sexes. Detailed electron microscopy in C57BL/6 mice showed that 4-AP reduced pathological features of mitochondrial swelling, cytoskeletal disruption, and demyelination at 7 days post-injury. Furthermore, 4-AP improved the molecular organization of axon nodal regions by restoring disrupted paranode domains and reducing Kv1.2 channel dispersion. 4-AP treatment did not resolve deficits in action potential conduction across the corpus callosum, based on ex vivo electrophysiological recordings at 7 days post-TBI. Thus, this first study of 4-AP effects on axon damage in the acute period demonstrates a significant decrease in multiple pathological hallmarks of axon damage after experimental TBI.

The efficacy of combining topiramate and 4-aminopyridine to reduce relapses and interictal progression in two cases of episodic ataxia type 2.

BACKGROUND: Episodic ataxia type 2 is an autosomal dominant channelopathy, caused by genetic variants in the voltage-dependent calcium channel a-1 subunit (CACNA1A), which is characterized by intermittent episodes of vertigo and ataxia. A slow progression of cerebellar signs is commonly observed in the course of the disease. Treatment with the carbonic anhydrase inhibitor acetazolamide is recommended. METHODS: We report the cases of two patients with EA-2 and migraine, linked to a novel CACNA1A mutation associated with disabling ictal and interictal disease, which did not respond to acetazolamide. RESULTS: A 30-year-old woman and a 50-year-old man, who was a ski instructor, reported disabling episodes of rotatory vertigo and progressive interictal ataxia. In both cases, the disease progressed despite treatment with acetazolamide. The concomitant use of topiramate and 4-aminopyridine significantly reduced the frequency and severity of relapses and migraine and improved the interictal cerebellar progression in both cases. CONCLUSIONS: We propose combined applications of topiramate and 4-aminopyridine in refractory cases and those with poor tolerance to acetazolamide and also in those with frequent associated migraine. The effectiveness of this combination of drugs for treating intermittent ataxic episodes and interictal signs in EA-2 has not been previously reported.

Altering neuronal circuitry with 4-aminopyridine for visual improvement in Leber's hereditary optic neuropathy (LHON).

In this retrospective, interventional, longitudinal small case series, we looked at the visual effects of pharmacologic intervention with 4-aminopyridine (4-AP) in chronic Leber's Hereditary Optic Neuropathy (LHON) patients who are non-responders to idebenone. We illustrate, as examples, the visual progression of three LHON patients with 4-AP as add-on therapy to idebenone. Each patient had a different primary LHON mutation and was treated with idebenone within one year of onset. No response to idebenone at 300 mg orally three times a day ranged from less than one year to 2.5 years, and the addition of 4-AP at 10 mg orally two times a day ranged from 24 to 29 months. Outcome measures included best-corrected distance visual acuity, color vision, automated perimetry, the average retinal nerve fiber layer (RNFL) thickness, and the full-field photopic negative response (PhNR) amplitude. The 19-year-old man with the LHON mutation 11778A > G had no response to the addition of 4-AP to idebenone. The 27-year-old man with the LHON mutation 3460A > G experienced a significant response to 4-AP. Finally, the 40-year-old man with the LHON mutation 14484 T > C had a milder response. Although this case series was too small to demonstrate the efficacy of idebenone with add-on 4AP, it allowed us to consider a new hypothesis that neuronal activity generated from 4-AP can add more potential for visual recovery in LHON patients.

A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment.

BACKGROUND: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. OBJECTIVE: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. METHODS: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). RESULTS: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). CONCLUSION: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

A Novel KCNA2 Variant in a Patient with Non-Progressive Congenital Ataxia and Epilepsy: Functional Characterization and Sensitivity to 4-Aminopyridine.

Kv1.2 channels, encoded by the KCNA2 gene, are localized in the central and peripheral nervous system, where they regulate neuronal excitability. Recently, heterozygous mutations in KCNA2 have been associated with a spectrum of symptoms extending from epileptic encephalopathy, intellectual disability, and cerebellar ataxia. Patients are treated with a combination of antiepileptic drugs and 4-aminopyridine (4-AP) has been recently trialed in specific cases. We identified a novel variant in KCNA2, E236K, in a Serbian proband with non-progressive congenital ataxia and early onset epilepsy, treated with sodium valproate. To ascertain the pathogenicity of E236K mutation and to verify its sensitivity to 4-AP, we transfected HEK 293 cells with Kv1.2 WT or E236K cDNAs and recorded potassium currents through the whole-cell patch-clamp. In silico analysis supported the electrophysiological data. E236K channels showed voltage-dependent activation shifted towards negative potentials and slower kinetics of deactivation and activation compared with Kv1.2 WT. Heteromeric Kv1.2 WT+E236K channels, resembling the condition of the heterozygous patient, confirmed a mixed gain- and loss-of-function (GoF/LoF) biophysical phenotype. 4-AP inhibited both Kv1.2 and E236K channels with similar potency. Homology modeling studies of mutant channels suggested a reduced interaction between the residue K236 in the S2 segment and the gating charges at S4. Overall, the biophysical phenotype of E236K channels correlates with the mild end of the clinical spectrum reported in patients with GoF/LoF defects. The response to 4-AP corroborates existing evidence that KCNA2-disorders could benefit from variant-tailored therapeutic approaches, based on functional studies.

4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy.

Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)­encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment.