Perspectives: Life and Work of Dr. Stanley Fahn
Aug. 01, 2022
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Sleep-related leg cramps are a sleep-related movement disorder whereby painful contractions of the calf or foot muscles arise during time in bed and may interrupt sleep, and they may be associated with muscle cramps during daytime wakefulness. Sleep-related leg cramps are encountered at all ages, but they are especially prevalent among the elderly. They may result from a variety of pathologies, metabolic muscle and nerve disorders, electrolyte disturbances, vascular diseases, neurologic disorders such as Parkinson disease, and toxic and drug side effects. Sleep-related leg cramps may sometimes mimic and need to be differentiated from other sleep-related movement disorders, especially the manifestations of restless legs syndrome.
• Sleep-related leg cramps represent a common sleep-related movement disorder characterized by painful contractions of the muscles of the lower limbs during sleep.
• This disorder can be either idiopathic or secondary to metabolic, vascular, or neurologic diseases or medications.
• Diagnosis is clinical and requires exclusion of secondary forms; polysomnography may be helpful to rule out other conditions.
• Treatment comprises nonpharmacological and pharmacological therapies.
According to the American Academy of Sleep Medicine International Classification of Sleep Disorders, sleep-related leg cramps, previously classified within the parasomnias and precisely as a wake-sleep transition disorder, fall within the category of the sleep-related movement disorders (03). Within this category, sleep-related leg cramps are grouped together with restless legs syndrome, periodic limb movement disorder, sleep-related bruxism, sleep-related rhythmic movement disorder, benign sleep myoclonus of infancy, propriospinal myoclonus at sleep onset, and sleep-related movement disorder either unspecified, due to drug or substance, or to a medical condition. Sleep-related movement disorders are conditions that are primarily characterized by relatively simple, usually stereotyped movements that disturb sleep or by other sleep-related monophasic movement disorders such as sleep-related leg cramps. Leg cramps may be sleep related when they occur solely or predominantly during sleep and idiopathic when they remain unassociated with any other disturbance. On the other hand, sleep-related leg cramps may be secondary to several systemic or focal pathologic conditions.
Sleep-related leg cramps are characterized by sudden and intense involuntary painful contractions of the muscles or muscle groups of the lower limbs, in particular those of the posterior compartment of the leg and foot; the triceps surae is the muscle group most frequently affected. The forceful contraction of these muscles is accompanied by immediate intense pain that awakens the patient and interrupts sleep. During the calf cramp, the muscles involved are firm and tender, and feet and toes are held in extreme plantar flexion. Cramps are usually unilateral and last from several seconds to minutes (1.7 minutes as a mean) (52); the cramps may remit spontaneously and are followed by a residual tenderness for up to half an hour. Patients quickly learn to lengthen the cramping muscle (by forcible dorsal flexion of the foot), and this maneuver is usually enough to stop the cramping. Sometimes, however, patients are forced to jump out of bed and stand or walk in order to get rid of the cramps. Nocturnal leg cramps may be accompanied, particularly when secondary to systemic illnesses, by muscle cramps during wakefulness. The frequency of muscle cramps vary considerably from less than yearly to multiple episodes every night, but they intensify with older age (77).
Idiopathic sleep-related leg cramps are usually benign. When secondary, the prognosis of the cramps is that of the underlying systemic disorder. Idiopathic sleep-related leg cramps may remit spontaneously over time; however, they may also represent a longstanding complaint, especially in the elderly wherein 20% of patients report them for over 10 years (01). Patients, who had already used drugs to treat their cramps in the past, have a higher number of cramps per day (77).
According to a cross sectional study by Hawke and colleagues, sleep-related leg cramps were shown to be associated with impaired quality of life mediated through sleep disturbances (33). Besides low quality of sleep, nocturnal leg cramps were reported in association with daytime sleepiness (27). In contradiction to these results, an observational study has not confirmed the link between intensity of nocturnal cramps and poor sleep quality (78).
A 41-year-old woman had a family history positive for nocturnal leg cramps in her 69-year-old father and 3 paternal aunts. Her 67-year-old mother had thyroid disease. As a child, the patient underwent 3 operations for strabismus of her left eye; she developed hypothyroidism at 37 years of age, which was well controlled with thyroxine, 100 mg per day. At 36 years of age, she noticed painful cramping sensations arising suddenly in thoracic and abdominal muscles, followed by local tenderness. Within a year these cramping sensations quickly spread to involve the lower limbs, especially during the evening and at night when she was lying in bed trying to fall asleep. During the cramps, which especially involved the calves and feet, the muscles felt firm and tender.
Neurologic examination disclosed sporadic fasciculations in calf and foot muscles. Serum and urine electrolytes, creatinine phosphokinase, and thyroid and parathyroid hormones were normal. EMG documented fasciculation potentials in the abductor hallucis and gastrocnemius muscles without denervation. Motor and sensory conduction velocities were all normal, and no pathologic EMG activity could be induced by hyperventilation or ischemia. Forceful prolonged voluntary plantar flexion of the toes and short-lasting tetanic stimulation (10 Hz for 1 second) of the tibial nerve at the ankle readily evoked cramping in the abductor hallucis, which was relieved by stretching of the big toe. Polysomnographic recordings disclosed cramps in the plantar flexor muscles (more evident on the right), which lasted 18 to 25 seconds and slowly resolved by extension of foot and toes. Sleep structure was normal.
Administration of vitamin D, calcium, magnesium, gabapentin, and benzodiazepines was unsuccessful. The patient obtained partial relief with carbamazepine, 600 mg per day.
Sleep-related leg cramps may be either idiopathic or related to other diseases or drugs; however, no significant differences in clinical presentation due to a specific etiology have been evidenced.
Sleep-related leg cramps occur rarely in children, when they remain, for the most part, idiopathic. No systemic illnesses are typically present. Metabolic and hormonal disorders such as muscle glycogenoses, hypothyroidism and hypoparathyroidism, diabetes mellitus, and fluid and electrolyte disturbances (hypocalcemia, hypomagnesemia, hyponatremia, and uremia) are associated with cramps that may occur predominantly or exclusively during sleep. Such conditions as low levels of minerals, extracellular fluid volume depletion, and sedentary activity have been noted as potential contributing factors in elderly patients (62; 02; 77). In addition, the use of medications such as diuretics and long-acting beta2 agonists may be related to leg cramps (26). Spasticity and rigidity, peripheral neuropathy, and vascular insufficiency of the lower limbs represent conditions with an increased prevalence of sleep-related leg cramps. A study of 1788 patients with liver cirrhosis revealed a 51.8% prevalence of sleep-related leg cramps, thus placing emphasis on assessing for this bothersome symptom in hepatic disease (40).
Cramps are contractions of muscles brought about by sustained recruitment of one muscle’s motor units. EMG studies show that cramping is attended by a contraction of a slowly moving fraction of muscle fibers with extremely short potentials and unlike maximal voluntary contraction (70). Explicative hypotheses implicate an abnormal excitability of the muscular membrane or of the terminal motor axon at the muscle entry point (motor point). Although some studies hypothesized a central origin of muscle cramps, due to an abnormal CNS drive acting on the lower motor neuron or increased fusal and decreased Golgi tendon organ activity, causing changes in presynaptic input and spinal motor neuron excitation (74), the peripheral theory remains more convincing (58; 67). Lower limb muscle weakness is suggestive of being a risk factor for the development of nocturnal leg cramps in the elderly, which was seen in a case-controlled study where the authors concluded that age-related modifications in type II muscular fibers may expose to higher risk of nocturnal cramps (33). Also, muscle and tendon shortening are suspected to take part in the increasing the risk of occurrence of nocturnal leg cramps according the “squatting theory” (82; 17). Lower limb muscle weakness as seen in a case-controlled study was suggestive of being a risk factor for the development of nocturnal leg cramps in the elderly (33). Repetitive stimulation of homonymous afferents and magnetic stimulation of the nerve trunk induce muscle cramps, whereas cutaneous stimulation and antidromic Renshaw cell activation are effective in curtailing the cramp (05). After discharge activity is typically found following M and F waves in patients with muscle cramps, suggesting impaired motor neuron excitability. Foot and leg muscles have different cramp susceptibility (59), and various frequencies of electrical stimulation trigger different sized cramps (60).
Sleep-related leg cramps may be observed throughout sleep stages 1, 2, and 3 NREM as well as REM sleep; therefore, they cannot be attributed to physiologic changes during any specific sleep state.
Sleep-related leg cramps may have a genetic basis. Familial nocturnal cramping of the legs associated with myoclonic jerks and leading to painful awakenings has been observed to recur in a 3-generation family, transmitted in an autosomal dominant fashion (41). Muscle cramps both during sleep and wakefulness were associated with electromyographic findings suggestive of polyneuropathy with an autosomal dominant transmission in a Japanese family (13) and to neuropathic involvement in an Italian family (56).
Sleep-related leg cramps may be encountered at all ages. Epidemiologic studies in children demonstrated that nocturnal leg cramps have an overall incidence of 7.3%; the incidence increased at 12 years of age, peaking between 16 and 18 years. Nocturnal leg cramps were, however, absent in children younger than 8 years of age. Seventy-three percent of the children had cramps only during sleep; the remainder also had cramps during wakefulness. Leg cramps were unilateral in nearly 99% of cases, occurring 1 to 4 times per year in the majority of children, and each episode lasted 1.7 minutes as a mean, leaving a residual tenderness for about half an hour (52).
Sleep-related leg cramps also are frequent among the general population. The incidence and prevalence increases with age (62; 24). In a general population survey conducted in 1987 in Sao Paulo, Brazil, leg cramps were reported by 2.6% of 1000 representative adult residents, especially females (males to females ratio 1:1.8), but increased to 5.8% in a later survey conducted in 1995 in the same population (64). No association was found between gender and prevalence of sleep-related leg cramps (Naylor and Young 1994; 53). In a survey of veteran outpatients, 56% reported nocturnal leg cramps. In this population, leg symptoms were often associated with hypertension, renal disease, hypokalemia, and vascular disease affecting the legs, heart, and brain. In another survey of male veterans, cardiovascular disease and peripheral neurologic defects were significantly higher in patients with nocturnal leg cramps; there was no relation with use of diuretic, beta-agonist, or calcium channel antagonist drugs (31; 02; 53). In 365 elderly patients over 65 years of age, leg cramps were found in 50%. Cramps were more prevalent at night in 62% of patients and remained a longstanding complaint, being present for over 10 years in 20% of cases. Again, an association with peripheral vascular disease and arthritis was found (01). In a cross-sectional study of 516 subjects over the age of 60 years in France, prevalence of nocturnal leg cramps was 46% (53).
Nocturnal leg cramps have been associated with several other physiologic and pathologic conditions (43):
• Pregnancy: 30% to 81% of pregnant women experience nocturnal cramps, especially after the 25th week of pregnancy (36; 35). In this patient population, nocturnal leg cramps have been reported to occur together with restless legs syndrome (85).
• Venous insufficiency and varicose veins of the lower limbs.
• Root disease of the lower limbs and “vespers’ curse,” a condition in which lumbar radiculopathy and spinal stenosis combine to cause nocturnal calf cramps, fasciculations, night pain, and paresthesias (57).
• Liver cirrhosis
• Diabetes mellitus (in which patients with leg symptoms are usually younger and have earlier onset of diabetes).
• Parkinson disease (06)
• Tropical ataxic neuropathy and tropical spastic paraparesis due to human T-cell lymphotropic virus type 2
• Myokymia-cramp-fasciculation syndrome
• Myofascial pain syndrome of the gastrocnemius muscle (66)
• Myotonia and late-onset lipid storage myopathy
• Electrolyte disturbances (especially hypokalemia and hypocalcemia) and sweat loss during sports, even though the evidence for the electrolyte disturbances actually causing the muscle cramps is controversial (75).
• Thyroid dysfunction
• Metabolic syndrome (54)
• Maintenance hemodialysis
• Gitelman syndrome, a hereditary renal disorder with hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria (22; 50).
• Satoyoshi syndrome, characterized by progressive intermittent muscle spasms, alopecia, diarrhea, amenorrhea, and bony deformities (12).
• Machado-Joseph disease (44; 16).
• Anti-MAG neuropathy (68).
Sleep-related leg cramps are also known to complicate treatment with the following products: diuretics, beta2 agonists used as bronchodilators, statins (24), vincristine (where they signal early neurotoxicity), sodium oxybate used for narcolepsy (09), donepezil (72), oxcarbazepine for epilepsy (48), cholinesterase inhibitors, and hemodialysis for uremia. Statins, which are inhibitors of 3-OH-3 methylglutaryl coenzyme A reductase, used in lowering cholesterol blood levels, have been associated with persistent myalgias and muscle cramps with or without creatine kinase elevation, and even with rhabdomyolysis and muscle weakness. Cerivastatin seems the most implicated statin, but impaired hepatic and renal function, hypothyroidism, diabetes, and other concomitant medications seem to contribute to statin toxicity. Muscle pains and weakness may affect up to 5% of the patients using these drugs. The mechanisms of such statin-induced myopathy are still discussed; regulatory proteins involved in myocyte maintenance have been implicated (83). The pathophysiology of statin-induced myopathy and muscle symptoms is complex and involves mitochondrial dysfunction, disruption in calcium homeostasis, antibodies to HMG-CoA reductase, and other less well-defined mechanisms (69). Sleep-related leg cramps are also more common in patients with other sleep disturbances such as bruxism and sleep paralysis (63).
The positive effect of prophylactic stretching before sleep on nocturnal cramps is under debate and actual evidence is conflicting (23; 67). Sleep-related leg cramps may respond favorably to devices aimed at avoiding plantar flexion of the feet or toes (67). Because sedentary lifestyle was reported to be strongly associated with sleep-related leg cramps in elderly, promotion of physical activity is recommended expecting to prevent the disorder (17). Also, Pycnogenol has been reported to prevent the occurrence of cramps in athletes and patients with diabetic microangiopathy (86).
Sleep-related leg cramps need to be differentiated from other motor disturbances that may occur during sleep: periodic limb movements in sleep and restless legs syndrome, sleep starts or sudden bodily jerks during sleep, painful legs and moving toes, the syndrome of excessive fragmentary myoclonus during sleep, and the myokymia-cramp-fasciculation syndrome. However, the clinical features of nocturnal leg cramps are distinctive, and polysomnography is rarely necessary. Nocturnal leg cramps can be confused with restless legs syndrome, especially because patients with nocturnal leg cramps may satisfy the diagnostic criteria for restless legs syndrome (34). Muscle cramps, indeed, have been found to account for about 15% of the differential diagnosis cases with restless legs syndrome (61). However, the lack of response to dopaminergic treatment as well as the lack of the typical circadian profile represents helpful differentiating features (20).
The diagnostic criteria for the sleep-related leg cramps put forth by the American Academy of Sleep Medicine are the following (03):
(A) A painful sensation in the leg or foot is associated with sudden, involuntary muscle hardness or tightness, indicating a strong muscle contraction.
(B) The painful muscle contractions occur during the time in bed, although they may arise from either wakefulness or sleep.
(C) The pain is relieved by forceful stretching of the affected muscles, thus, releasing the contraction.
The diagnostic workup of nocturnal leg cramps should aim to:
(1) Detect the presence of cramps in the leg muscles during sleep. This task is best performed by polysomnography, which may disclose increased EMG activity of various durations over the muscles of the posterior compartment of the leg.
(2) Ascertain the underlying pathogenic condition in the case of cramps secondary to systemic or focal illnesses. Thus, neurologic visit, investigations for neuromuscular or peripheral vascular disease, thyroid function, and fluid and electrolyte disturbances are warranted.
(3) Exclude other conditions that may represent muscle leg cramps mimics, such as restless legs syndrome.
Nonpharmacological therapy consists of stretching techniques, physical therapy, and regular physical activity.
Passive pre-sleep stretching techniques of the affected muscles, in particular forcible dorsal flexion of the toes and feet, are repeatedly reported to be potentially effective in reducing the frequency and intensity of the cramps (15; Daniell et al 2012; 30; 32; 29). However, contradictory results, limited evidence, and biases of currently available studies limit the use of stretching techniques as treatment for leg muscle cramps (08; 23; 17). The strength of nonpharmacological therapy is the lack of side effects in contrast to most pharmacological treatment options; therefore, the stretching techniques offer a useful treatment alternative despite inconclusive evidence (29).
Regular physical activity is recommended, particularly in elderly adults because sedentary lifestyle was found to be strongly associated with nocturnal cramps in the group of individuals over 60 years (17).
Physical therapy measures for the patients with chronic nocturnal leg cramps have not been adequately studied so far. A case report of a single patient who received therapy focusing on muscle strengthening, joint mobility, soft tissue extensibility, and biomechanical influences during purposeful movement demonstrated improvements in pain and cramp duration, but the subject was still hesitant to perform certain tasks, possibly due to the lack of biopsychosocial interventions in the treatment plan (04).
Pharmacological treatment consists of withdrawal of offending drugs and treatment of the underlying causes. When this is effective and in mild cases, pharmacologic treatment may not be warranted. If sleep-related leg cramps severely disrupt quality of sleep and of life, drug treatment may be initiated.
Quinine sulphate. Quinine sulphate given orally at variable dosages (200 to 325 mg) before bedtime is significantly effective in reducing frequency (although seemingly not the severity or duration) of individual cramps as borne out by several randomized, double-blind, placebo-controlled studies and meta-analysis of efficacy (14; 55; 19; 87; 18). In elderly people, quinine reduced the number of nights with cramps by an average of 27.4% compared to placebo. A trial of 4 to 6 weeks of treatment with quinine has been recommended (11). Quinine has also been reported to be more effective when combined with theophylline in a single preparation. Quinine seems to act by decreasing the excitability of the motor end plate, thereby reducing the contractility of muscle fibers. Nevertheless, 200 mg of quinine at bedtime was ineffective in a double-blind, randomized, crossover trial (80). Quinine is significantly more effective than vitamin E; the latter at a dosage of 800 U at bedtime was shown to be ineffective compared to placebo in reducing leg cramps (14). Supplementation with vitamins E and C, however, was found significantly effective in the treatment of muscle cramps during hemodialysis (45; 28).
Quinine should be used cautiously and at the lowest dosage possible, especially in elderly people and in those with renal failure. Quinine should be avoided altogether during pregnancy and in liver disease. Quinine use is associated with increased side effects such as tinnitus, potentially fatal thrombocytopenia and hypersensitivity reactions, cutaneous photosensitivity and vasculitis, cortical renal necrosis (51), and granulomatous hepatitis. Quinine overdose, accidental or by self-poisoning, causes confusion, seizures, coma, and severe visual deficits, especially in older women, and may lead to death (10; 84). Therefore, a careful balance of the therapeutic gains and possible side effects of quinine should be made; in the elderly especially, treatment should be started with low incremental dosages and closely monitored by the attending physician. Use of tonic water or bitter lemon (commercial beverages containing quinine) for the purpose of curtailing nocturnal leg cramps should be discouraged (10). In conclusion, the use of quinine to treat legs cramps, especially in the elderly, is controversial, in particular considering the modest effect and the possible rare but serious adverse events (38; 67).
Other pharmacological treatments reported as effective are:
• Verapamil hydrochloride 120 mg orally at bedtime
• Rutosides given for nocturnal leg cramps associated with chronic venous insufficiency (65)
• Gabapentin, which at 600 mg/day proved effective in a case of myokymia-cramp syndrome and gave a nearly total reduction of cramps after 3 months of therapy in 30 patients with longstanding muscle cramps (79)
• The evidence of an effect of magnesium (oral or intravenous) in leg cramps prophylaxis in adults is insufficient or conflicting (88; 24; 67); however, there is weak evidence of a possible positive effect on pregnant women (76). Moreover, a randomized controlled trial demonstrated no effect on intravenous magnesium on leg cramps in a geriatric population (25). A randomized controlled trial comparing magnesium oxide to placebo demonstrated that magnesium was not superior to placebo in the treatment of nocturnal leg cramps (71).
• Oral zinc sulphate (49) and branched-chain amino acid supplements (73) improved muscle cramps in cirrhotic patients.
• Sleep-related leg cramps in patients with Parkinson disease respond to treatment with chronic release levodopa formulations (06).
• In a group of 24 patients with nocturnal calf cramps, lidocaine injection at the gastrocnemius trigger point gave a significant reduction in all aspects of cramps (46), with an outcome better than quinine 300 mg orally (66). The block of the medial branch of the deep peroneal nerve by using lidocaine has been reported as having a positive effect in patients experiencing nocturnal leg cramps following lumbar spine surgery (39).
• Likewise, botulinum injection into calf muscles significantly lowered patients’ cramping scores with a clinical benefit lasting about 3 months (07). Even axillary botulinum A injection was reported as effective in reducing muscle cramps associated with severe axillary sweating (21).
• Other reports concern the use of diltiazem, a calcium channel antagonist, low-dose aspirin, and jackyakamcho-tang (shaoyaogancao-tang), a Chinese herbal preparation (42), for nocturnal leg cramps, l-carnitine, extracts of peony and licorice roots (37) and vitamin E (28) for muscle cramps associated with hemodialysis.
Sleep-related leg cramps are usually worse or may actually appear during pregnancy (36). Thirty to eighty-one percent of pregnant women may be affected with leg cramps (36; 35). Quinine treatment for sleep-related leg cramps should not be used in pregnant women, but magnesium administration has been reported as safe. Indeed, a systematic review with meta-analysis (76) and Cochrane review found best evidence for magnesium in the treatment of leg cramps in pregnancy, whereas vitamins and calcium or sodium chloride treatments showed no efficacy over placebo (89). Other treatments include vitamins B supplementation (81) and habitual plant-based diets. The latter, owing to a higher dietary magnesium intake, result in improved magnesium status and reduce the frequency of calf cramps during the third trimester of pregnancy (47).
Jiri Nepozitek MD PhD
Dr. Nepozitek of Charles University and General University Hospital in Prague has no relevant financial relationships to disclose.See Profile
Federica Provini MD
Dr. Provini of the University of Bologna and IRCCS Institute of Neurological Sciences of Bologna received speakers' fees from Italfarmaco and Pfizer.See Profile
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