Oral and Topical Treatment of Painful Diabetic Polyneuropathy: Practice Guideline Update Summary

ObjectiveTo update the 2011 American Academy of Neurology (AAN) guideline on the treatment of painful diabetic neuropathy (PDN) with a focus on topical and oral medications and medical class effects.MethodsThe authors systematically searched the literature from January 2008 to April 2020 using a structured review process to classify the evidence and develop practice recommendations using the AAN 2017 Clinical Practice Guideline Process Manual.ResultsGabapentinoids (standardized mean difference [SMD] 0.44; 95% confidence interval [CI], 0.21–0.67), serotonin-norepinephrine reuptake inhibitors (SNRIs) (SMD 0.47; 95% CI, 0.34–0.60), sodium channel blockers (SMD 0.56; 95% CI, 0.25–0.87), and SNRI/opioid dual mechanism agents (SMD 0.62; 95% CI, 0.38–0.86) all have comparable effect sizes just above or just below our cutoff for a medium effect size (SMD 0.5). Tricyclic antidepressants (TCAs) (SMD 0.95; 95% CI, 0.15–1.8) have a large effect size, but this result is tempered by a low confidence in the estimate.Recommendations SummaryClinicians should assess patients with diabetes for PDN (Level B) and those with PDN for concurrent mood and sleep disorders (Level B). In patients with PDN, clinicians should offer TCAs, SNRIs, gabapentinoids, and/or sodium channel blockers to reduce pain (Level B) and consider factors other than efficacy (Level B). Clinicians should offer patients a trial of medication from a different effective class when they do not achieve meaningful improvement or experience significant adverse effects with the initial therapeutic class (Level B) and not use opioids for the treatment of PDN (Level B).

Therapeutic Potential of Sodium Channel Blockers as a Targeted Therapy Approach in KCNA1-Associated Episodic Ataxia and a Comprehensive Review of the Literature

Introduction: Among genetic paroxysmal movement disorders, variants in ion channel coding genes constitute a major subgroup. Loss-of-function (LOF) variants in KCNA1, the gene coding for KV1.1 channels, are associated with episodic ataxia type 1 (EA1), characterized by seconds to minutes-lasting attacks including gait incoordination, limb ataxia, truncal instability, dysarthria, nystagmus, tremor, and occasionally seizures, but also persistent neuromuscular symptoms like myokymia or neuromyotonia. Standard treatment has not yet been developed, and different treatment efforts need to be systematically evaluated.Objective and Methods: Personalized therapeutic regimens tailored to disease-causing pathophysiological mechanisms may offer the specificity required to overcome limitations in therapy. Toward this aim, we (i) reviewed all available clinical reports on treatment response and functional consequences of KCNA1 variants causing EA1, (ii) examined the potential effects on neuronal excitability of all variants using a single compartment conductance-based model and set out to assess the potential of two sodium channel blockers (SCBs: carbamazepine and riluzole) to restore the identified underlying pathophysiological effects of KV1.1 channels, and (iii) provide a comprehensive review of the literature considering all types of episodic ataxia.Results: Reviewing the treatment efforts of EA1 patients revealed moderate response to acetazolamide and exhibited the strength of SCBs, especially carbamazepine, in the treatment of EA1 patients. Biophysical dysfunction of KV1.1 channels is typically based on depolarizing shifts of steady-state activation, leading to an LOF of KCNA1 variant channels. Our model predicts a lowered rheobase and an increase of the firing rate on a neuronal level. The estimated concentration dependent effects of carbamazepine and riluzole could partially restore the altered gating properties of dysfunctional variant channels.Conclusion: These data strengthen the potential of SCBs to contribute to functional compensation of dysfunctional KV1.1 channels. We propose riluzole as a new drug repurposing candidate and highlight the role of personalized approaches to develop standard care for EA1 patients. These results could have implications for clinical practice in future and highlight the need for the development of individualized and targeted therapies for episodic ataxia and genetic paroxysmal disorders in general.

Pharmacodynamic sodium channel blockers-induced seizure aggravation in patients with newly diagnosed focal epilepsy

Pharmacodynamic aggravation (PA) is an unpredictable increase in the frequency, the severity of existing seizures, and/or development of new seizure types despite rational (adequate for seizure type and epilepsy form) antiepileptic drug (AED) prescription. Many mechanisms and predictors of its development are still poorly understood.Objective: to analyze PA of seizures in patients with newly diagnosed focal epilepsy receiving monotherapy with sodium channel blockers with epileptiform activity index (EAI) assessment.Patients and methods. We enrolled 201 patients with newly diagnosed focal epilepsy aged 16—81 years. In twelve months, patients had five follow-up visits. At each visit, treatment tolerability and efficacy were assessed, taking into account changes in the type, severity, and frequency of seizures. Additionally, at each visit, video-electroencephalographic monitoring was performed with EAI assessment. PA of seizures occurred in patients on oxcarbazepine, carbamazepine, and lacosamide therapy.Results and discussion. Five patients with PA of seizures had increased total EAI and EAI before sleep at the second follow-up visit after sodium channel blockers prescription. Electroencephalographic correlates of PA occurred earlier than clinical manifestations. In patients with PA, the absolute increase in EAI was minimal in patients receiving oxcarbazepine, and lacosamide therapy was associated with a minimal relative increase in EAI. At the end of the follow-up, total EAI decreased by 54—80% relative to its initial value in all five patients. The difference in the total index during the first and last visits was statistically significant.Conclusion. Due to the low level of knowledge about PA of seizures, it seems necessary to consider its possibility in all cases of increased frequency, aggravation, or change in the type of seizures after the AED treatment initiation or an increase in its dose. It is also possible to use changes in total EAI and EAI before sleep as an early objective marker of PA in adults with focal epilepsy.

Sodium channel blockers in the management of long QT syndrome: a system review and meta-analysis

Background: β-blockers are first-line therapy in patients with long QT syndrome (LQTS). However, β-blockers had genotype dependent efficacy (LQT1>LQT2>LQT3). Sodium channel blockers have been recommended as add-on therapy for LQT3 patients. However, the effect of sodium channel blockers in all LQT patients remains unknown. Methods: We conducted a systematic electronic search of PubMed, Embase and the Cochrane Library. Fixed effects model was used to assess the effect of sodium channel blockers on QTc, cardiac events (CEs), and the proportion of QTc≥500 ms and QTc≤460 ms in LQTS patients. Results: Pooled analysis of 14 studies with 213 LQTS patients showed that sodium channel blockers significantly shortened QTc by nearly 50 ms (MD -49.43, 95%CI -57.80 to -41.05, P<0.001), reduced the incidence of CEs (OR 0.12, 95%CI 0.04 to 0.32, P<0.001) and the proportion of QTc≥500 ms (OR 0.15, 95%CI 0.09 to 0.26, P<0.001), and increased the proportion of QTc≤460 ms (OR 18.00, 95%CI 7.49 to 43.26, P<0.001). Sodium channel blockers significantly shortened QTc both in LQT3 and non-LQT3 patients, while the QTc shortening effect in LQT3 was superior to that in non-LQT3 (57.39 ms vs. 36.61 ms). Mexiletine, flecainide, and ranolazine all significantly shortened QTc, and the QTc shortening effect by mexiletine was the best (60.70 ms vs. 49.08 ms vs. 50.10 ms). Conclusions: sodium channel blockers can be useful both in LQT3 and non-LQT3 patients. Mexiletine, flecainide and ranolazine significantly shortened QTc in LQTS patients, and the QTc shortening effect by mexiletine was the best.