Correlates of night-time and exercise-associated lower limb cramps in healthy adults.

INTRODUCTION/AIMS: We explored correlates of night-time and exercise-associated lower limb cramps in participants of the 1000 Norms Project. METHODS: A volunteer community sample of healthy people aged ≥18 y underwent assessment of motor function and physical performance, and were questioned about muscle cramps in the previous 3 mo. RESULTS: Of 491 (221 female) participants age 18-101 y (mean: 59.12; SD: 18.03), about 1 in 3 experienced night-time lower limb cramps, and about 1 in 4 experienced exercise-associated lower limb cramps. For night-cramps, a one unit increase in Beighton score (greater whole-body flexibility) was associated with a 31% reduced odds of cramps (odds ratio [OR] = 0.69, 95% confidence interval [CI]:0.45, 0.99) and passing all three lesser-toe strength tests was associated with 50% reduced odds of cramps (OR = 0.50, 95% CI: 0.32, 0.78). For exercise-associated cramps, participants in the fourth (lowest arch) quartile of Foot Posture Index were 2.1 times (95% CI: 1.11, 3.95) more likely to experience cramps than participants in the first (highest arch) quartile. Odds of experiencing both types of cramps versus no cramps were lower with passing all three lesser-toe strength tests (OR = 0.40, 95% CI: 0.19, 0.85) and better performance in the six-minute walk test (OR = 0.997, 95% CI: 0.996, 0.998). DISCUSSION: People who experienced both exercise-associated and night-time cramps were less functional. The association between night-time cramps with less whole-body flexibility and reduced lesser-toe flexor strength should be explored to determine causation. Planovalgus (low-arched) foot type was independently associated with exercise-associated cramps. The effectiveness of foot orthoses for secondary prevention of exercise-associated cramps in people with low-arched feet should be explored.

H-reflex and M-wave responses after voluntary and electrically evoked muscle cramping.

PURPOSE: Despite the widespread occurrence of muscle cramps, their underlying neurophysiological mechanisms remain unknown. To better understand the etiology of muscle cramps, this study investigated acute effects of muscle cramping induced by maximal voluntary isometric contractions (MVIC) and neuromuscular electrical stimulation (NMES) on the amplitude of Hoffmann reflexes (H-reflex) and compound muscle action potentials (M-wave). METHODS: Healthy men (n = 14) and women (n = 3) participated in two identical sessions separated by 7 days. Calf muscle cramping was induced by performing MVIC of the plantar flexors in a prone position followed by 2.5-s NMES over the plantar flexors with increasing frequency and intensity. H-reflexes and M-waves evoked by tibial nerve stimulation in gastrocnemius medialis (GM) and soleus were recorded at baseline, and after MVIC-induced cramps and the NMES protocol. RESULTS: Six participants cramped after MVIC, and H-reflex amplitude decreased in GM and soleus in Session 1 (- 33 ± 32%, - 34 ± 33%, p = 0.031) with a similar trend in Session 2 (5 cramped, p = 0.063), whereas the maximum M-wave was unchanged. After NMES, 11 (Session 1) and 9 (Session 2) participants cramped. H-reflex and M-wave recruitment curves shifted to the left in both sessions and muscles after NMES independent of cramping (p ≤ 0.001). CONCLUSION: Changes in H-reflexes after a muscle cramp induced by MVIC and NMES were inconsistent. While MVIC-induced muscle cramps reduced H-reflex amplitude, muscle stretch to end cramping was a potential contributing factor. By contrast, NMES may potentiate H-reflexes and obscure cramp-related changes. Thus, the challenge for future studies is to separate the neural consequences of cramping from methodology-based effects.

[The cramp-fasciculation-syndrome (CFS)]. / Das Myalgie-Faszikulations-Krampus-Syndrom (MFKS).

The present review focuses on the cramp-fasciculation syndrome, a benign disorder which is regarded as a hyperexcitability syndrome of the peripheral nervous system. The article presents clinical features, pathophysiology, differential diagnosis, therapy and a case report to illustrate the cramp-fasciculation-syndrome.

Muscular cramp: causes and management.

Muscular cramp is a common symptom in healthy people, especially among the elderly and in young people after vigorous or peak exercise. It is prominent in a number of benign neurological syndromes. It is a particular feature of chronic neurogenic disorders, especially amyotrophic lateral sclerosis. A literature review was undertaken to understand the diverse clinical associations of cramp and its neurophysiological basis, taking into account recent developments in membrane physiology and modulation of motor neuronal excitability. Many aspects of cramping remain incompletely understood and require further study. Current treatment options are correspondingly limited.

Clinical Heterogeneity in Patients with Glutamate Decarboxylase Antibody.

OBJECTIVE: To explore the diversity and clinical features of anti-glutamate decarboxylase (GAD) antibody-associated neurological diseases. METHODS: Clinical data of a series of 5 patients positive for anti-GAD antibodies were retrospectively analyzed. RESULTS: All 5 patients were female, with a median age of 41.5 years (range 19-60 years). Their neurological symptoms included stiff-person syndrome (SPS), encephalitis, myelitis, cramp, visual loss, and paresthesia. Three patients (60%) were diagnosed with tumors, 2 cases of thymic tumor and 1 of breast cancer. On immunohistochemistry for tumor pathology, expression of GAD65 was found only in 1 patient. Four patients (80%) had abnormal brain MRI findings. All patients received immunotherapy and improved significantly after treatment, but 4 (80%) then experienced a relapse. CONCLUSIONS: Neurological manifestations in anti-GAD-positive patients are diverse and include SPS, encephalitis, myelitis, cramp, visual loss, and paresthesia.

Metformin's impact on statin-associated muscle symptoms: An analysis of ACCORD study data and research materials from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center.

Statins are widely prescribed, yet statin muscle pain limits their use, leading to increased cardiovascular risk. No validated therapy for statin muscle pain exists. The goal of the study was to assess whether metformin was associated with reduced muscle pain. A secondary analysis of data from the ACCORD trial was performed. An ACCORD sub-study assessed patients for muscle cramps and leg/calve pain while walking, typical non-severe statin muscle pain symptoms. We compared muscle pain between patients using a statin (n = 445) or both a statin and metformin (n = 869) at baseline. Overall patient characteristics were balanced between groups. Unadjusted analysis showed fewer reports of muscle cramps (35%) and leg/calve pain while walking (40%) with statins and metformin compared to statin only (muscle cramps, 42%; leg/calve pain while walking, 47%). Multivariable regression demonstrated a 22% odds reduction for muscle cramps (P = 0.049) and a 29% odds reduction for leg/calve pain while walking (P = 0.01). Metformin appears to reduce the risk of non-severe statin muscle pain and additional research is needed to confirm the findings and assess metformin's impact on statin adherence and related cardiovascular outcomes.

Referred cramping phantom hand pain elicited in the face and eliminated by peripheral nerve block.

Phantom limb pain is a restricting condition for a substantial number of amputees with quite different characteristics of pain. Here, we report on a forearm amputee with constant phantom pain in the hand, in whom we could regularly elicit the rare phenomenon of referred cramping phantom pain by touching the face. To clarify the underlying mechanisms, we followed the cramp during the course of an axillary blockade of the brachial plexus. During the blockade, both phantom pain and the referred cramp were abolished, while a referred sensation of "being touched at the phantom" persisted. Furthermore, to identify the cortical substrate, we elicited the cramp during functional magnetic imaging. Imaging revealed that referred cramping phantom limb pain was associated with brain activation of the hand representation in the primary sensorimotor cortex. The results support the hypothesis that referred cramping phantom limb pain in this case is associated with a substantial brain activation in the hand area of the deafferented sensorimotor cortex. However, this alone is not sufficient to elicit referred cramping phantom limb pain. Peripheral inputs, both, from the arm nerves affected by the amputation and from the skin in the face at which the referred cramp is evoked, are a precondition for referred cramping phantom limb pain to occur, at least in this case.

Cramp Training Induces a Long-Lasting Increase of the Cramp Threshold Frequency in Healthy Subjects.

OBJECTIVE: A low cramp threshold frequency (CTF) is associated with an increased cramp susceptibility. Recent data indicate that the CTF can be substantially increased by a cramp training consisting of electrically induced muscle cramps (EIMCs). This study investigated if four cramp training sessions induce sustained effects on the CTF. METHODS: In ten healthy male subjects, EIMCs were induced in the gastrocnemius medialis of one leg (intervention leg, IL) twice a week, while the opposite leg served as control leg (CL). The stimulation protocol consisted of three sets of six bipolar rectangular wave pulsed currents (5 sec on, 10 sec off) at 30 Hz above the individual CTF. RESULTS: After four cramp training sessions (2 weeks) the CTF differed (p < 0.001) from pre-values in the IL (pre: 19.2 ± 1.4 Hz post 29.8 ± 8.0 Hz) but not in the CL (pre: 18.2 ± 1.5 Hz post 19.6 ± 2.8 Hz; p > 0.05). Thereafter, the CTF remained elevated in the IL for 22 days (22 days post: 22.2 ± 3.2 Hz; p < 0.05) when compared to pre and was significantly (p < 0.05) higher than that of the CL 5, 10, and 14 days after the intervention. CONCLUSION: The applied cramp training induced a long-term CTF increase of 14 days.

Prodromal spinocerebellar ataxia type 2: Prospects for early interventions and ethical challenges.

The characterization of prodromal stages in neurodegenerative disorders is becoming increasingly important because of the need for early neuroprotective therapies. Research during the past 3 decades in spinocerebellar ataxia type 2 has revealed a large body of evidence suggesting that many disease features precede the manifest cerebellar syndrome, which delineates the prodromal stage of this disorder. This stage is defined by clinical, imaging, and functional criteria, which are supported by early molecular events demonstrated in animal models. Knowledge regarding prodromal spinocerebellar ataxia type 2 provides insight into the mechanisms underlying neurodegeneration from the early stages, which enables the design of promising disease-modifying clinical trials through the identification of the optimum moment to begin the therapies, the appropriate selection of individuals, and the identification of sensitive outcome measures. The management of patients in prodromal spinocerebellar ataxia type 2 may raise ethical dilemmas related to predictive diagnosis and early interventions, which impose new challenges to clinical and therapeutic research. © 2017 International Parkinson and Movement Disorder Society.

Muscle cramp susceptibility increases following a volitionally induced muscle cramp.

INTRODUCTION: Muscle cramping may increase peripheral nervous system excitability. It is unknown if, and how long, cramp susceptibility is affected by previous cramping. We tested whether volitionally induced muscle cramps (VIMCs) lowered cramp threshold frequency (TFc ) and how long TFc was affected post-VIMC. METHODS: Fifteen cramp-prone participants volitionally induced a flexor hallucis brevis (FHB) cramp on 4 separate days. FHB TFc was measured before VIMC (i.e., baseline) and 5, 30, and 60 min post-VIMC. VIMC electromyography (EMG) amplitude, VIMC duration, and perceived VIMC intensity were measured to ensure consistency of VIMC between days. RESULTS: VIMC EMG amplitude, duration, and perceived intensity were similar between days (P > 0.05). VIMC lowered TFc ; baseline TFc (18 ± 6 Hz) was higher than 5-min (14 ± 6 Hz), 30-min (14 ± 5 Hz), and 60-min TFc (14 ± 5 Hz; P < 0.05). DISCUSSION: Acute VIMCs increase cramp susceptibility. Clinicians should apply treatments for at least 60 min postcramp to decrease the probability of cramp recurrence. Muscle Nerve 56: E95-E99, 2017.

Effects of TRPV1 and TRPA1 activators on the cramp threshold frequency: a randomized, double-blind placebo-controlled trial.

PURPOSE: Previous data indicate that a strong sensory input from orally administered TRPV1 and TRPA1 activators alleviates muscle cramps in foot muscles by reducing the α-motor neuron hyperexcitability. We investigated if TRP activators increase the cramp threshold frequency of the medial gastrocnemius. METHODS: We randomly assigned 22 healthy male participants to an intervention (IG) and a control group (CG). While participants of the IG ingested a mixture of TRPV1 and TRPA1 activators, the CG received a placebo. We tested the cramp threshold frequency (CTF), the cramp intensity (EMG activity), and the perceived pain of electrically induced muscle cramps before (pre), and 15 min, 4, 8, and 24 h after either treatment. We further measured the maximal isometric force of knee extensors at pre, 4, and 24 h to assess potential side-effects on the force output. RESULTS: When we included all measurement time points, no group-by-time interaction was observed for the CTF. However, when only pre and 15 min values were incorporated, a significant interaction, with a slightly greater CTF increase in IG (3.1 ± 1.5) compared to the CG (2.0 ± 1.5), was observed. No significant group by time interaction was found for the cramp intensity, the perceived pain, and the maximal isometric force. CONCLUSION: Our data indicate that orally administered TRPV1 and TRPA1 activators exert a small short-term effect on the CTF, but not on the other parameters tested. Future studies need to investigate whether such small CTF increments are sufficient to prevent exercise-associated muscle cramps.

HANAC Syndrome Col4a1 Mutation Causes Neonate Glomerular Hyperpermeability and Adult Glomerulocystic Kidney Disease.

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.

Disorders of motor neurons manifested by hyperactivity.

Neuronal and/or axonal hyperactivity and hyperexcitability is an important feature of motor neuron diseases. It results clinically in cramps and fasciculations. It is not specific to motor neuron diseases, and can occur in healthy subjects, as well as in various pathologies of the peripheral nervous system, including nerve hyperexcitability syndromes. Hyperexcitability plays an important and debated role in the pathophysiology of motor neuron diseases, especially in amyotrophic lateral sclerosis (ALS). The mechanisms causing hyperexcitability are not yet clearly identified. While most studies favor a distal axonal origin site of fasciculations, some of the fasciculations could be of cortical origin. The consequences of hyperexcitability are also discussed, whether it is rather protective or deleterious in the disease course. Fasciculations are depicted both clinically and using electromyogram, and more recently the interest of ultrasound has been highlighted. The importance of fasciculation potentials in the diagnosis of ALS led to changes in electrophysiological criteria at Awaji consensus conference. The contribution of these modifications to ALS diagnosis has been the subject of several studies. In clinical practice, it is necessary to distinguish fasciculations potentials of motor neuron disease from benign fasciculations. In most studies of fasciculation potentials in ALS, the presence of complex fasciculation potentials appears to be relevant for the diagnosis and the prognosis of the disease.

Natural history of muscle cramps in amyotrophic lateral sclerosis.

INTRODUCTION: Muscle cramping is a common symptom in amyotrophic lateral sclerosis (ALS) that lacks efficacious treatment. The natural history of this symptom is unknown, which hampers efforts to design optimal clinical trials. METHODS: We surveyed early stage ALS patients about their experience with cramps each month by phone for up to 21 months. RESULTS: Cramps developed in 95% of patients over the course of their disease. The number of cramps experienced by an individual varied widely from month-to-month and trended lower after the first year of illness (P = 0.26). Those with limb-onset and age >60 years had more cramps than bulbar-onset (P < 0.0001) and younger patients (P < 0.0001). CONCLUSIONS: The high variability of the number of cramps experienced suggests that clinical trials will need to use crossover designs or large numbers of participants, even when the treatment effect is substantial.

Increased HCN channel driven inward rectification in benign cramp fasciculation syndrome.

Muscle cramps are a common complaint associated with sudden painful involuntary contractions of a muscle. The mechanisms responsible for muscle cramps are still not clear. Axonal excitability and multi-unit electromyography studies were performed in 20 patients suffering from benign cramp fasciculation syndrome, not currently on medication. The measures of axonal excitability suggested greater inward rectification, indicative of an increase in Ih. Mathematical modelling suggested that the data were best explained by depolarization of the voltage dependence of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Parameters associated with polarization of resting membrane potential were not changed. These findings suggest that a role for HCN channels may become apparent during the rhythmic discharge associated with a voluntary contraction. Consistent with this view, patients had higher motor unit discharge rates than healthy controls during maximal voluntary effort.

[Seronegative celiac disease: A case report].

The paper describes a rare case of celiac disease in the absence of serum anti-tissue transglutaminase (anti-tTG) antibodies. A 51-year-old patient has been suffering from diarrheas for 20 years. He has lost 15 kg gradually; weakness progressed; muscle cramps, leg edemas, and signs of dynamic pseudoobstruction appeared. Morphological examination revealed small intestinal mucosal (SIM) villous atrophy (Marsh IIIC stage). IgA anti-tTG and IgG anti-tTG antibodies were 0.086 and 0.178, respectively. The patient was prescribed a gluten-free diet, water electrolyte solutions to correct metabolic disturbances, and prednisolone. During a control examination after 6 months, the patient had no complaints and gained 22 kg, and the SIM villus height was increased. The specific feature of the case is specific negative serological tests for celiac disease.

Prospective study of muscle cramps in Charcot-Marie-tooth disease.

INTRODUCTION: This study aims to assess the frequency, location, severity, duration, and fluctuation over time of muscle cramps in Charcot-Marie-Tooth disease (CMT). METHODS: Inherited Neuropathies Consortium Contact Registry participants recorded the occurrence and characteristics of muscle cramps using an 11-question survey administered 3 times over 8 weeks. RESULTS: A total of 110 adult patients with CMT completed the survey. Weekly cramp frequency was 9.3 (SD 12.3), and 23% had daily muscle cramps. Twenty-two percent reported a significant impact on quality of life. Over 8 weeks, the daily frequency and severity of muscle cramps did not change significantly. CONCLUSIONS: Patients with CMT have muscle cramps that vary little over an 8-week period, and they may interfere with quality of life. These data may be useful in the planning of clinical trials of agents to treat adults with CMT-associated muscle cramps.

Electrically induced muscle cramps induce hypertrophy of calf muscles in healthy adults.

OBJECTIVES: Skeletal muscles usually cramp at short lengths, where the tension that can be exerted by muscle fibers is low. Since high tension is an important anabolic stimulus, it is questionable if cramps can induce hypertrophy and strength gains. In the present study we investigated if electrically induced cramps (EIMCs) can elicit these adaptations. METHODS: 15 healthy male adults were randomly assigned to an intervention (IG; n=10) and a control group (CG; n=5). The cramp protocol (CP) applied twice a week to one leg of the IG, consisted of 3x6 EIMCs, of 5 s each. Calf muscles of the opposite leg were stimulated equally, but were hindered from cramping by fixating the ankle at 0° plantar flexion (nCP). RESULTS: After six weeks, the cross sectional area of the triceps surae was similarly increased in both the CP (+9.0±3.4%) and the nCP (+6.8±3.7%). By contrast, force of maximal voluntary contractions, measured at 0° and 30° plantar flexion, increased significantly only in nCP (0°: +8.5±8.8%; 30°: 11.7±13.7%). CONCLUSION: The present data indicate that muscle cramps can induce hypertrophy in calf muscles, though lacking high tension as an important anabolic stimulus.