A randomized, double-blind, placebo-controlled, multicenter study assessing the efficacy of magnesium oxide monohydrate in the treatment of nocturnal leg cramps.

BACKGROUND: Magnesium supplements are widely used for prophylaxis and treatment of nocturnal leg cramps (NLC). However, there is little evidence in support of their effectiveness. The main impediment stems from the lack of assessments of cellular absorption. In the current study, we tested the efficacy and safety of a magnesium supplement - magnesium oxide monohydrate (MOMH), for which increased cellular absorption rates were demonstrated in an ex-vivo setting. METHODS: A randomized, double-blind, placebo-controlled multicenter study was conducted in hospitals and outpatient clinics in Ukraine, from February to August 2018. Eligible subjects received a capsule with MOMH 226 mg or placebo, once daily, at bedtime, for a 60-day period. The assessed parameters included frequency and duration of NLC episodes, quality of sleep, NLC-induced pain and quality of life sub-scores. The Fisher's Exact Test for comparison of groups by categorical variables was used. The Student's test or Mann-Whitney test were used for between-group comparison at different timepoints. ANCOVA followed by contrast analysis was used for comparison of groups at the end of the study. RESULTS: 175 (81%) out of 216 initially screened subjects completed the study. The number of NLC episodes has significantly decreased by the end of the study period as compared to baseline in both groups (p < 0.001 for both). There was a significant between-group difference in the magnitude of reduction in NLC episodes (p = 0.01), indicating a higher decrease in the MOMH group as compared to the placebo group (- 3.4 vs - 2.6, respectively). In addition, MOMH treatment resulted in a greater reduction in NLC duration (p < 0.007) and greater improvement in sleep quality (p < 0.001) as compared to placebo. CONCLUSIONS: MOMH was shown to be effective in the treatment of NLC as well as safe and well-tolerated. TRIAL REGISTRATION: NCT03807219 , retrospectively registered on January 16, 2019.

Sleep-Related Rhythmic Movements and Sleep Terrors: A Possible Common Neurophysiological Background in a Preschool Boy.

None: We report the case of a 3-year-old boy with a history of frequent and injurious sleep-related rhythmic movements and sleep terrors. We documented six episodes of body rocking and head banging via video polysomnography. No epileptic seizures were observed. In addition to the association between a sleep movement disorder and a disorder of arousal, our case shows that sleep-related rhythmic movements can arise not only during relaxed wakefulness or during a stable sleep stage, but also during a less clearly defined sleep stage during which it is difficult to further subtype non-rapid eye movement sleep. On the contrary, the portion of sleep without rhythmic movement episodes were clearly depicted with their physiological features. These findings might be of relevance for understanding the pathophysiology of both sleep-related rhythmic movements and sleep terrors and emphasize the importance to assess sleep using polysomnography, especially when episodes are frequent and injurious. The neurophysiological information obtained from this assessment might be helpful and guide an eventual treatment option.

[Tolerability, compliance, quality of life, and clinical outcome during treatment with quinine sulfate in patients with nocturnal calf cramps. A multicenter non-interventional study (NIS) in adults]. / Chininsulfat in der Therapie nächtlicher Wadenkrämpfe: Verträglichkeit, Compliance, Lebensqualität und Einfluss auf Symptome : Eine multizentrische nichtinterventionelle Studie (NIS) bei Erwachsenen.

BACKGROUND: Frequent and painful nocturnal leg cramps (NLC) require an effective therapy to improve quality of life and sleep performance in patients. METHOD: In a multicenter, prospective, non-interventional study (NIS) data on the effectiveness, tolerability and safety of quinine sulfate were collected in daily medical management in adult patients with frequent and painful nocturnal leg cramps. RESULTS: In total 596 patients were included into the study. Of these, 568 patients finished the study as planned (95.3%). Number, duration and pain intensity of NLC were reduced in the majority of patients after 2 weeks of therapy with quinine sulfate 200 mg OD. Physicians rated global assessment of treatment effect as "good" and "very good" in 535 patients (92.4%) which was concurrent with the patients' rating ("good" and "very good" by 534 patients = 92.2%), based on the full analysis set of 579 patients. Furthermore, quality of life and sleep were improved. Adverse drug reactions were reported in 35/592 patients (5.9%). Severe adverse events were not observed. The total incidence of therapy-associated adverse effects was comparable in the subgroup of patients with concomitant ß-blocker therapy (149/592 patients, 25.2%; totally 10%, subgroup 10.1%). Efficacy and tolerability of quinine sulfate were evaluated as "very good" or "good" by the majority of physicians and patients. CONCLUSIONS: The present NIS confirms effectiveness and tolerability of the therapy with quinine sulfate in daily clinical routine for adult patients with frequent and painful nocturnal leg cramps.

Effect of Magnesium Oxide Supplementation on Nocturnal Leg Cramps: A Randomized Clinical Trial.

Importance: Magnesium supplements are widely marketed for prophylaxis of nocturnal leg cramps (NLC) despite no evidence of significant benefit. Objective: To determine whether magnesium oxide is better than placebo for NLC prophylaxis. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled clinical trial of 2 weeks eligibility screening followed by 4 weeks of treatment was conducted in northern Israel, from February to October 2013. An intention-to-treat data analysis was performed from March 22, 2014, to April 17, 2016. We used a volunteer sample of community-dwelling individuals experiencing NLC, 21 years or older, with 4 or more documented episodes of NLC during 2 weeks of screening. Interventions: Capsules containing either magnesium oxide or a similar-looking placebo to be taken orally, once daily at bedtime for a period of 4 weeks. Main Outcomes and Measures: The primary outcome was the difference in the mean number of NLC per week between the screening and treatment phases. Secondary outcomes included severity and duration of NLC, quality of life, and quality of sleep. Results: Of the 166 volunteers, 72 (43%) were excluded, of whom 15 declined to participate and 57 did not meet the inclusion criteria. Of the 94 individuals (39% male; mean [SD] age, 64.9 [11.1] years) randomly assigned to magnesium oxide (48) or placebo (46), 6 did not complete the study protocol (3 in each group). Mean (SD) change of NLC was -3.41 (4.05) (from 7.84 [5.68] to 4.44 [5.66]) and -3.03 (4.53) (from 8.51 [5.20] to 5.48 [4.93]) per week in the magnesium oxide and placebo groups, respectively, a difference between groups of 0.38 (0.48) NLC per week (P = .67 in an intention-to-treat analysis). There were no between-group differences in the severity and duration of NLC, quality of life, or quality of sleep. Conclusions and Relevance: Oral magnesium oxide was not superior to placebo for older adults experiencing NLC. The decrease in the mean number of NLC per week, from the screening to the treatment phase in both groups, is probably a placebo effect that may explain the wide use of magnesium for NLC. Trial Registration: clinicaltrials.gov Identifier: NCT01709968.

Botulinum Toxin Treatment for Nocturnal Calf Cramps in Patients With Lumbar Spinal Stenosis: A Randomized Clinical Trial.

OBJECTIVES: To evaluate the clinical effectiveness of botulinum toxin (BTX) injection into the gastrocnemius muscles in patients with lumbar spinal stenosis (LSS) who have frequent nocturnal calf cramps (NCCs). DESIGN: Prospective, randomized clinical trial. SETTING: Outpatient department for interventional pain management. PARTICIPANTS: Patients (N=50) with LSS who have NCCs at least once per week were enrolled. INTERVENTION: Patients were randomly allocated to receive either conservative treatments plus gabapentin (group GPN) or BTX injection (group BTX). MAIN OUTCOME MEASURES: We assessed back/leg pain intensity, the frequency and severity of NCCs, insomnia severity, and functional disability at baseline and after 2 weeks, 1 month, and 3 months. Additionally, Patient Global Impression of Change was assessed. RESULTS: Forty-five patients completed all assessments (group GPN, n=21; group BTX, n=24). Compared with group GPN, leg pain intensity, cramp frequency, and cramp severity were significantly decreased in group BTX at all follow-up visits (all, P<.01). Also, insomnia significantly improved in group BTX at the 2-week (P=.018) and 1-month follow-up (P=.037). Functional disability significantly improved in group BTX at 2 weeks' follow-up (P=.041). At the 3-month follow-up, patients in group BTX reported a higher impression of improvement for NCC symptoms than did those in group GPN (P<.001). A mean dose of 642.8mg of gabapentin was given daily in group GPN, but 7 patients (33.3%) reported systemic side effects. There were no serious complications related to BTX use. CONCLUSIONS: BTX treatment appears to be effective and safe for NCCs in symptomatic LSS patients receiving conservative care.

Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2.

Autism spectrum disorders (ASDs) are a group of devastating neurodevelopmental syndromes that affect up to 1 in 68 children. Despite advances in the identification of ASD risk genes, the mechanisms underlying ASDs remain unknown. Homozygous loss-of-function mutations in Contactin Associated Protein-like 2 (CNTNAP2) are strongly linked to ASDs. Here we investigate the function of Cntnap2 and undertake pharmacological screens to identify phenotypic suppressors. We find that zebrafish cntnap2 mutants display GABAergic deficits, particularly in the forebrain, and sensitivity to drug-induced seizures. High-throughput behavioral profiling identifies nighttime hyperactivity in cntnap2 mutants, while pharmacological testing reveals dysregulation of GABAergic and glutamatergic systems. Finally, we find that estrogen receptor agonists elicit a behavioral fingerprint anti-correlative to that of cntnap2 mutants and show that the phytoestrogen biochanin A specifically reverses the mutant behavioral phenotype. These results identify estrogenic compounds as phenotypic suppressors and illuminate novel pharmacological pathways with relevance to autism.

Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (aswpd), delayed sleep-wake phase disorder (dswpd), non-24-hour sleep-wake rhythm disorder (n24swd), and irregular sleep-wake rhythm disorder (iswrd): an update for 2015

A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed.

Seasonal effects on the occurrence of nocturnal leg cramps: a prospective cohort study.

BACKGROUND: It has been anecdotally reported that nocturnal leg cramps in pregnant women are worse in summer. We analyzed population-level data to determine whether the symptom burden of nocturnal leg cramps is seasonal in the general population. METHODS: We examined time-series data for 2 independent measures of the symptom burden of leg cramps: (a) new quinine prescriptions (reflecting new or escalating treatment of leg cramps) from December 2001 to October 2007 among adults aged 50 years and older, which were obtained from linked health care databases that contain the prescribing information for the 4.2 million residents of British Columbia, Canada; and (b) the Internet search volume from February 2004 to March 2012 for the term "leg cramps" (reflecting public interest), which we obtained from Google Trends data and geographically limited to the United States and Australia. We assessed seasonality by determining how well a least-squares sinusoidal model predicted variability in the outcomes. RESULTS: New quinine prescriptions and Internet searches related to leg cramps were both seasonal, with highs in mid-summer and lows in mid-winter, and a peak-to-peak variability that was about two-thirds of the mean. Seasonality accounted for 88% of the observed monthly variability in new quinine prescriptions (p < 0.001) and 70% of the observed variability in Internet searches related to leg cramps (p < 0.001). INTERPRETATION: New quinine prescriptions and Internet searches related to leg cramps were seasonal and roughly doubled between the winter lows and summer highs. Why a disorder of peripheral motor neurons displays such strong seasonality warrants exploration.

Effect of magnesium therapy on nocturnal leg cramps: a systematic review of randomized controlled trials with meta-analysis using simulations.

BACKGROUND AND OBJECTIVE: Nocturnal leg cramps (NLC) are common in primary care and may cause severe pain and sleep disturbance. We systematically reviewed the effectiveness of magnesium in treating NLC and the side-effect profile of magnesium compared to placebo. METHODS: We searched Medline, Embase, Cochrane Library, ClinicalTrials.gov, the International Standard Randomised Controlled Trial Number and the International Clinical Trials Registry Platform registries until August 2012. All randomized controlled trials (RCTs) comparing magnesium therapy for NLC in adults with any other comparator were eligible. Two investigators independently selected, extracted data from and rated the risk of bias of relevant studies. To compensate for the heterogeneity in outcome measures, simulations were used to summarize the data. RESULTS: Seven RCTs were included in the review (n = 361), all comparing magnesium to placebo. Three of these trials included only pregnant women. The difference in the median number of leg cramps per week between the placebo and the intervention groups was 0.345 (quantile 2.5%: -0.133, quantile 97.5%: 0.875). This difference was 0.807 (quantile 2.5%: 0.015, quantile 97.5%: 1.207) in the three studies involving only pregnant women and 0.362 (quantile 2.5%: -0.386, quantile 97.5%: 1.148) in the others. Overall gastrointestinal side effects were slightly more common with magnesium therapy than with placebo. The strength of this evidence was weak, mainly due to small study sizes and short follow-up. CONCLUSIONS: Magnesium therapy does not appear to be effective in the treatment of NLC in the general population, but may have a small effect in pregnant women. Further research using better designed RCTs is necessary.