• Repetitive physical activity of lower extremities

While an exact cause of muscle spasm (or cramping) remains unclear, common episodes of muscle spasm frequently occur with repetitive activity or stress of the LE at any time during exercise when the muscle is tired or fatigued [1]. It is suggested that during physical activity, individuals are predisposed to acute water loss leading to hypovolemia (e.g., acute fluid and electrolyte imbalance) and dehydration (i.e., loss of water or not getting enough water) thereby increasing one’s risk of developing muscle spasm [10]. Interestingly, the mechanisms behind various types of muscle cramps involved in different types of physical activity is not known.  As explained by Maughan et al.,⁵ the highly localized cramp in the calf that afflicts a soccer play late in the game in very different from the whole-body cramps described by American football players and tennis players, which are different from the cramp that afflicts small muscles used in repetitive exercise such as the hand in writers or typists (Table 1).

Table 1: Common causes/risk factors of muscle spasm.

1. Repetitive physical activity on a muscle or muscle group
2. Hypovolemia or acute extracellular volume depletion/fluid imbalance
3. Electrolyte imbalance
4. Dehydration
5. Medications
6. Serious underlying medical conditions (Table 3)

• Acute Fluid Loss and electrolyte imbalance

The problem of hypovolemia

Maintaining a specific fluid balance of electrolytes is called euvolemia and is essential for cells to work normally [11]. Hypovolemia, in contrast, is a process in which too much water and sodium (salt) is depleted in the human body leading to an electrolyte imbalance [12]. Symptoms of hypovolemia may include fatigue, thirst, muscle cramps, dry mouth, changes in skin tone (loss of elasticity), dizziness when standing (orthostatic vertigo) and urinating less than usual [13]. Severe hypovolemia may cause abdominal pain, chest pain and confusion [13] (Table 2). Loss of fluid through vomiting, diarrhea or heavy sweating can lead to electrolyte imbalance due to hypovolemia. 

The problem of dehydration

Dehydration refers to loss of water only or not getting enough water to maintain the body’s balance of sodium [12]. Any medical condition that causes diuresis (or a person to perspire or urinate more than usual) can lead to hypovolemia and dehydration [16]. Hemodialysis, diarrhea and diuretic therapy (substance used to promote excretion of water) can lead to volume depletion and dehydration [17]. Similarly, not drinking enough water to make up for normal amounts of water lost normally can lead to dehydration.

Table 2: Symptoms of hypovolemia.

1. Fatigue
2. Thirst
3. Muscle cramps
4. Dry mouth
5. Loss of skin tone or elasticity
6. Orthostatic vertigo
7. Decreased urination
8. Abdominal pain
9. Chest pain
10. Confusion

Medications

There are many medications that are known to have an association with muscle spasm. These may include diuretics, beta-blockers, cholesterol-lowering statins, bronchodilators, neuroleptics, tolcapone, nifedipine, terbutaline, albuterol, isotretinoin, zolpidem [1]. Others known to be related to nocturnal muscle spasm include long-acting beta agonists (LABA), diuretics (thiazide/potassium sparing diuretics), loop diuretics and cholesterol-lowering statins [1].

• Underlying medical conditions associated with muscle spasm (Table 3)
• Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive neuromuscular and degenerative disorder that causes muscle weakness, disability and eventual death [18]. The clinical hallmark of ALS is the combination of upper and lower motor neuron signs and symptoms [18]. Common symptoms in this condition include muscle weakness (reduced muscle strength), atrophy (wasting of muscle cells) and fasiculations (involuntary visible muscle twitching) [18,19]. Muscle cramps in ALS are a common manifestation of loss of lower motor neurons [19].
• Congestive heart failure (CHF) is a cardiac condition in which the heart pump inefficiently contracts or pumps blood in its effort to provide a normal supply within the body. Consequently, because heart failure results in poor blood flow, inadequate circulation and impaired oxygenation, muscle cramps can occur in the lower extremities [20]. Leg cramps that persist despite inactivity or that are frequently present with ambulation or exercise can be an early sign of heart failure.²¹ Currently, the role of altered skeletal muscles during CHF and the influence of intracellular changes of metabolism in the myocardium remains the subject of ongoing investigation [20].  
• Hepatic (liver) cirrhosis represents a late stage of progressive liver fibrosis characterized by scarring and the formation of regenerative nodules [22]. In advanced stages, cirrhosis is generally considered to be irreversible. In earlier stages, specific treatments aimed at the underlying cause of liver disease may improve or even reverse cirrhosis [22]. It is estimated that up to 88% of patients with hepatic cirrhosis experience painful muscle cramps resulting in sleep deprivation and impaired quality of life. Muscle cramps in liver disease generally affect the hands, legs and feet but may also affect the neck, back and sides [23]. The etiology of muscle cramps in patients with liver disease is still largely unknown.²⁴ Management is often based on poor evidence with varying degrees of success in controlling the frequency and severity of muscle cramps in this group [24].  
• Lumbar spinal stenosis (LSS) is an anatomic condition that results in narrowing of the intraspinal (central) canal, lateral recess, and/or neural foramen [8]. As a major clinical problem, LSS is commonly seen in individuals over 60 years old [25]. This spinal disorder may cause compression of the spinal nerves leading to neurophysiologic dysfunction, degeneration and reduced blood flow in nerve roots [26]. Commonly associated symptoms in LSS include intermittent claudication, pain, numbness and decreased sensation. The most common symptom of spinal stenosis, however, is cramping or aching in the calves [27]. As this spine condition advances, it becomes increasingly difficult for individuals to stand and walk due to the intensity of the resulting leg pain (and muscle spasm). At this time, there is limited information available in the medical literature on the relationship between muscle spasm and LSS, and there is a scarcity of research available on the impact of nonsurgical or surgical interventions on leg cramps in patients with LSS [25].
•  

Table 3:  Serious underlying medical conditions associated with muscle spasm.

• Motor neuron disorder: Amyotrophic lateral sclerosis (ALS)/Lou Gehrig’s disease
• Cardiac disorder: Congestive heart failure (CHF)
• Metabolic disorder: Hepatic cirrhosis
• Musculoskeletal disorder: Lumbar spinal stenosis (LSS)

Nocturnal Muscle Cramps (NMC)

NMC and other sleep-related leg cramps are a common lower extremity condition that produces significant pain leading to disruption of sleep (Table 10).  The differential diagnosis of nighttime leg discomfort includes, (a) restless leg syndrome, (b) periodic limb movements and (c) muscle cramps associated with pregnancy (2^nd and 3^rd trimester).^{38, 39} In addition, (d) various medications have been associated with nighttime muscle cramps (Table 4).

NMC are common and frequently go unreported to clinicians thereby contributing to the anecdotal nature [28]. Symptoms result from involuntary muscle contractions, which are sudden in onset, usually affect the calf or foot [1]. Conditions related to leg symptoms with nocturnal muscle cramps include, (a) hypertension (HTN), (b) peripheral vascular disease (PVD), (c) coronary artery disease (CAD), (d) cerebrovascular disease (CVD), (e) kidney disease and (f) hypokalemia [30]. In particular, nerve root compression and PVD are believed to be predisposing factors for nocturnal leg cramps [31]. Frequently observed in patients with peripheral neuropathy (damage to nerves connecting the brain and spinal cord to the rest of the body), there is prevalence of nocturnal leg cramps (NLC) associated with lumbar spine stenosis (LSS) and severity of symptoms [26] (Table 5).

Table 4: Differential diagnosis of nighttime leg discomfort

1. Restless leg syndrome
2. Periodic limp movements
3. Muscle spasm/cramps associated with pregnancy
4. Medication-related muscle spasm

Table 5: Common causes of nocturnal muscle cramps

1. Underlying serious medical conditions
2. Peripheral neuropathy
3. Lumbar spine stenosis
4. Hypertension
5. Peripheral vascular disease
6. Coronary artery disease
7. Cerebrovascular disease
8. Kidney disease
9. Hypokalemia

Table 6: Medications associated with increased risk of nocturnal muscle cramps

1. Long-acting beta agonists (LABA)
2. Diuretics (thiazide/potassium sparing diuretics)
3. Loop diuretics
4. Cholesterol-lowering statins

 

Associated risk factors for nocturnal muscle spasm
Risk factors and conditions are anecdotal and may be coincidental given high prevalence of the symptoms, particularly in those with medical comorbidities [1] (Tables 7-9) Thus, the majority of patients with leg cramps have no definitively known underlying cause.  Clinical features of nocturnal muscle spasm are identified in Table 10.

Activities that are associated with repetitive lower extremity stress of the muscles of the lower extremities are associated with increased risk of nocturnal muscle cramps [1]. Examples include prolonged sitting, positioning that place prolonged pressure on the leg and walking or running on concrete floors [1].

Medications associated with increased risk of nocturnal muscle cramps include long-acting beta agonists (LABA), diuretics (thiazide/potassium sparing diuretics, loop diuretics and statins [32] (Table 6). Statin-associated side effects (SASE) are rare in clinical trials making a causal relationship with statins unclear [33]. They are important, however, because the muscle cramps associated with statins may trigger dose reduction, change in medication dose or discontinuation altogether of these life-saving agents [33].

Table 7: General risk factors associated with muscle spasm

1. Repetitive activities that stress muscles of lower extremities
2. Medications
3. Secondary nocturnal cramps
4. Exercise associated muscle cramps
5. Radiculopathy
6. Cardiac disease
7. Other medical conditions (Table 9)

Table 8: Secondary nocturnal cramps

1. Sleep disorders (e.g., restless leg syndrome, periodic limb movements of sleep, obstructive sleep apnea)
2. Peripheral vascular disease (PVD)
3. Fluid imbalance
4. Pregnancy
5. Metabolic disorders (diabetes type II, hypoglycemia, hypocalcemia, alcoholism, hypothyroidism)
6. Neurologic disorders (motor neuron disorders and polyneuropathy)

Table 9: Other medical conditions associated with muscle spasm

1. Anemia
2. Raynaud phenomenon
3. Opioid withdrawal
4. Nonalcoholic liver cirrhosis
5. History of bariatric surgery

Prevalence of Muscle Spasm
The prevalence of muscle spasm in the adult healthy population is 50-60% [37]. There are no differences between male or females except in pregnant women (usually in 2^nd trimester, but also in 3^rd trimester) [38,39], the incidence is about 30-50% [37,38]. The frequency of cramps increases with age [38]. There is a higher prevalence of muscle cramping in the elderly population and in endurance athletes [37,38,40]. In endurance athletes the incidence of muscle cramps appears to be associated with high intensity and prolonged duration [37,41]. About 40% of the participants of the studies on muscle cramps had cramp episodes more than three times per week, with an average duration of 9 minutes [37].

Patients with type II diabetes mellitus (DM) appear to have a higher age-adjusted prevalence of muscle spasm than individuals without DM II [42]. One epidemiological study showed that the age-adjusted prevalence of cramps was higher in patients with type II diabetes (65.2 vs. 45.5%; P = 0.009) but not type 1 diabetes (61.2 vs. 45.5%; P = 0.13) compared with healthy volunteers [42]. Patients with lower motor neuron disease, neuropathies and metabolic disorders increase the likelihood of muscle cramps [43]. Over 70% of patients with chronic liver disease report painful muscle cramps and a causal relationship (opposed to a simple association) has been described [43].

In the general population, NMC are present in 40 percent of individuals over age 50, increase in frequency with age and some report no sex preference [30,37], while others relate that woman
are more likely to experience NMC than men [37]. NMC are associated with sleep disturbance and overall poor health [30].

Pathogenesis of Muscle Spasm
The origin of the mechanism of muscle spasm remains the subject of debate [36]. Described in the literature, muscle spasm or cramps are, however, believed to originate from spontaneous ectopic activity in the terminal motor axon (nerve terminals) [33,34]. leading to muscle pain caused by ischemia [35]. Muscle ischemia leads to a drop in pH and the release of pain-producing substances such as bradykinin, ATP and H⁺ leading to persistent, involuntary muscle contraction [35].

Electromyography during cramping event reveals variable high-frequency discharge of motor units at several sites, recruited either simultaneously or sequentially [33] with evidence that abnormal discharges come from both central and peripheral motor neurons [36]. According to Huang et al., evidence of peripheral origin includes variable EMG morphology of fasiculations, the fact that cramps can be induced by repetitive peripheral nerve stimulation and high-frequency discharge rates (: 150 Hz) [36].

Table 10:  Clinical features of nocturnal leg cramps [1]

The following characteristics generally describe the clinical features of nocturnal leg cramps:

1. Symptoms of sudden muscle tightness are usually painful and most commonly occur in the calf, foot or thigh. Calf cramping may induce extreme plantar flexion of the foot and toes.
2. Duration of symptoms typically last from seconds to many minutes and are relieved by forceful stretching of the affected muscles. The average duration of nocturnal muscle cramps is nine minutes.
3. Timing of nocturnal muscle cramps typically occur while in bed; patients may be awake or asleep. Most individuals have these cramps only at night (73 percent) but can also occur during the day and night (20 percent of patients) and only during the daytime (7 percent).
4. Residual soreness may linger following the resolution of the acute cramp. Persistent soreness typically lasts for several hours. However, discomfort for up to 48 to 72 hours following resolution of the muscle cramp has been described. Nocturnal cramps affecting the thigh are more commonly associated with prolonged soreness than cramps affecting the calf and foot.
5. Frequency of nocturnal muscle cramps can occur three times a week in about 40 percent of individuals experiencing them, and 5-10 percent of individuals report nightly cramping.
6. Sleep disturbance is associated with nocturnal muscle cramps leading patients to complain of insomnia. Daytime fatigue is sometimes reported.
7. Seasonal variation is described in patients with nocturnal muscle cramps with higher prevalence in winter and summer. This variation is suggested by an analysis of the frequencies of new quinine prescriptions and internet searches related to leg cramps (both of which are doubled in winter compared to summer).