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Prodromal muscle cramps predict rapid motor functional decline in amyotrophic lateral sclerosis
  1. Kazumoto Shibuya,
  2. Sonoko Misawa,
  3. Yukari Sekiguchi,
  4. Minako Beppu,
  5. Hiroshi Amino,
  6. Tomoki Suichi,
  7. Yo-ichi Suzuki,
  8. Atsuko Tsuneyama,
  9. Satoshi Kuwabara
  1. Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
  1. Correspondence to Dr Satoshi Kuwabara, Department of Neurology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; kuwabara-s{at}

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Muscle cramps are a common and annoying symptom in patients with amyotrophic lateral sclerosis (ALS). A previous study reported that 95% of patients with ALS experience muscle cramps during the disease course.1 Up to 20% of patients have severe and frequent (more than once/day) cramps, and sleeping is disturbed in 50%.

The origin of muscle cramps is uncertain, but distal motor axons potentially contribute to ectopic burst activity and thereby muscle cramps. Nerve excitability measurements have disclosed hyperexcitable state of motor nerve in patients with ALS.2 Hyperexcitability leads to fasciculations and muscle cramps, and potentially enhances motor neuron death, via glutamate-induced excitotoxicity and increased oxidative stress and metabolic demand.

In line with this view, patients with ALS with hyperexcitable motor nerve, measured by nerve excitability measurements, have shorter survival.2 The relationship between muscle cramps and ALS progression has not been elucidated. The aim of this study was to reveal characteristics of muscle cramps and their relationship with disease progression.

Materials and methods


Forty-three consecutive patients with sporadic ALS (29 men), who fulfilled the Awaji diagnostic criteria for definite or probable ALS, with sporadic ALS (29 men) were included in this study. They were evaluated according to ALS Functional Rating Scale-Revised (ALSFRS-R) at first visit.3 Initial weakness, including bulbar palsy, was defined as disease onset. Disease onset occurred in the bulbar region in 8eight patients and limbs in the remaining 35. Their age ranged from 41 to 82 years (mean, 65 years). The mean duration between disease onset and first visit was 12 months.

At first visit, patients were interviewed on experiences of muscle cramps, including the frequency, site and extent of disability, prospectively. Disability was scored from 0 (none) to 3 (severe), according to the published cramp disability score.4 None of the patients had obvious dementia. Similar symptoms, such as pain, spasticity, myoclonus and clonus, were carefully excluded. We defined muscle cramps, which occurred more than twice per month or involved upper limbs or trunk, as pathological.4

Statistical analysis

All statistical analyses were performed by one of the authors (KS) using SPSS V.24 software. To evaluate the factors which affect ALS progression rate, univariate and multiple regression analyses were performed. ALS progression rate, ΔALSFRS-R, was calculated as previously reported: ‘48- ALSFRS-R score at first visit/time between disease onset and first visit in months’.3 To perform regression analyses, patients were divided into two groups according to gender, age at onset, site of onset or cramp experience. Cut-off value in age at onset was set as the average of this cohort. Data are presented as mean (SD). In regression analyses, β>0.2 was judged as correlated.


Of the 43 patients, 26 (60%) had experienced pathological muscle cramps before first visit. The mean frequency was 24.7 (SD, 56.8) cramps/month. Of the 26 patients, 13 had cramps 15.1 (21.0) months prior to initial weakness, and cramps disappeared before initial weakness in two patients. Muscle cramps vanished before first visit in 11 patients. Cramps were reported in lower limbs in 22 patients, upper limbs in 6 patients and trunk or neck in 2 patients. Their grades were 3 (severe) in 5 patients, 2 (moderate) in 15 patients and 1 (mild) in 6 patients.

Univariate regression analyses revealed influence factors for ΔALSFRS-R, with age at onset (over the average; the mean ΔALSFRS-R 1.4 (1.4), under the average; 0.7 (1.0), p=0.11), gender (male; 1.0 (1.1), female 1.1 (1.5), p=0.83), site of onset (bulbar; 1.9 (1.7), limb; 0.9 (1.2), p=0.10), experience of cramp (presence; 1.3 (1.5), absence; 0.6 (0.4), p=0.042) and cramp before initial weakness (presence; 1.8 (1.8), absence; 0.7 (0.6), p=0.048) (table 1). A multiple regression analysis disclosed that cramps before initial weakness are significantly related to ΔALSFRS-R (β=0.43, p=0.0075), but experience of cramps was not associated with ΔALSFRS-R.

Table 1

Factors which affect ALS functional decline speed


Our results show that approximately 60% of the patients with ALS have experienced pathological muscle cramps before first visit. Of those, 50% patients underwent prodromal muscle cramps. Frequent cramps substantially disturbed daily activities in 50% of them, but cramp frequencies were variable. Prodromal muscle cramps were independently related to rapid functional decline.

Patients with prodromal muscle cramps had rapid functional decline on ALSFRS-R. The rapid decline suggests rapid disease progression and poor prognosis.3 Prodromal muscle cramps are probably derived from hyperexcitable motor nerve, or potentially from motoneuronal cell body, which is exposed to glutamate-induced excitotoxicity, and may result in rapid cell death and disease progression. Prominent prodromal muscle cramps may be associated with rapid motor neuron death.

Fewer patients in this cohort experienced muscle cramps than those of previous study.1 The previous study examined cramps during the disease course and included ‘pathological’ cramps and ‘ordinary’ cramps. Cramps also occur in healthy subjects mainly in elderly subjects, but the extent of it is milder than those of ALS. The discrepancy may result from differences of those conditions and definitions. The rate of disturbance in daily activities and sites of cramp were almost similar to those of the previous study.

This study has several limitations. First, we did not perform nerve excitability testing, and therefore, the direct correlation between nerve excitabilities and cramps was not assessed. Second, cramp history was subjective data, and might suffer recall bias. Finally, the number of patients in this study was relatively small.

Recent clinical trials of sodium channel blockers for ALS showed reduced muscle cramps and fasciculations.5 However, so far, ion channel blockers have not disclosed the efficacy to prevent motor decline in ALS. Further studies are needed to elucidate the direct relationship of abnormal muscle cramps and motor neuronal death in patients with ALS.


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  • Contributors KS and SK designed the study. KS, SM, YS, MB, HA, TS, YS and AT collected clinical data. KS and SK drafted the manuscript. KS performed statistical analyses. SK supervised the study.

  • Funding KS, SM, YS and SK receive research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. SK receives Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval This study was approved by the Ethics Committee of Chiba University School of Medicine.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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