Restless Legs Syndrome: A Unique Case and Essentials of Diagnosis and Treatment

Abstract

Restless legs syndrome (RLS) is a common, poorly understood movement disorder that can cause significant sleep disruption. RLS is characterized by uncomfortable sensations deep in the legs, relieved only by voluntary movement. Differential diagnosis includes peripheral neuropathy, leg cramps, and akathesia. Although RLS is familial in 50% of cases, secondary etiologies can be medically important, such as iron deficiency anemia and renal failure. We report a rare case of RLS associated with hyperparathyroidism. To our knowledge, only 1 other case of hyperparathyroid-related RLS has been described.

Case Presentation

The patient is a 40-year-old right-handed woman with a 30-year history of symptoms of restless legs syndrome (RLS), and a history of RLS in her mother. Until 2000, she had been able to control her symptoms with exercise and a combination of vitamin supplements. In 2000, she experienced an acute exacerbation of RLS symptoms, with severe insomnia. Laboratory evaluation revealed elevated calcium level. Subsequent workup revealed a parathyroid adenoma, and removal of her left inferior parathyroid relieved RLS symptoms to baseline level.

The patient experienced mild RLS symptoms until 2002, when she underwent an L4-5 decompression laminectomy. About 2 weeks after surgery, her RLS symptoms worsened; and were further exacerbated in late 2003 when she was involved in a motor vehicle accident. She was the restrained passenger in a vehicle that was sideswiped and ran into a pole, with airbag deployment. She suffered no head injury, or loss of consciousness.

The patient was prescribed a variety of agents for RLS, including dopamine agonists, benzodiazepines, and gabapentin. She obtained complete relief with tramadol 50 mg nightly. However, tolerance to the medication developed, and she began to increase the dose of tramadol on her own, obtaining medication from Internet pharmacies and other nonstandard means, and at one point taking up to 500 mg of tramadol daily.

Ongoing calcuria and a suspicious technetium-99m sestamibi parathyroid scan led to the diagnosis of a second parathyroid adenoma in the superior left thyroid region. Excision led to significant improvement in RLS symptoms.

Discussion and Review of the Literature

RLS is a movement disorder characterized by uncomfortable, distressing sensations deep inside the limbs especially at rest and at bedtime.[1] Up to 15% of the general population experience RLS symptoms; it impairs sleep and can significantly affect quality of life.[2]

Etiology and Pathogenesis

Although the underlying cause of RLS is unknown, the disorder is thought to be related to abnormalities in the body's use and storage of iron, which in turn may contribute to dopaminergic dysfunction.[3,4] Iron is an essential cofactor in the production of dopamine in the central nervous system. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) evidence suggests that reduced dopamine D2 receptor binding and nigrostriatal presynaptic dopaminergic hypofunction may contribute to the syndrome.[5]

In our case patient, hypercalcemia may have exacerbated the patient's RLS. The mechanism is unclear. Elevated levels of serum calcium have been associated with RLS in hemodialysis patients[6] and lung transplant recipients.[7] Of interest, exposure to calcium antagonists also has been associated with RLS in hemodialysis patients.[8]

RLS is familial in about 50% of cases.[1] Genetic linkage has been demonstrated at chromosome 12q as well as other loci.[9] RLS may also be idiopathic or be associated with iron deficiency, pregnancy, or advanced renal disease.[1] Prevalence of RLS increases with age and is greater in women than men.[10] Several medications have been reported to cause or worsen RLS, including antidepressants, antihistaminics, and dopamine receptor blockers. Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may also worsen RLS.[2]

Clinical Presentation

RLS is characterized by a deep, ill-defined discomfort or dysesthesia in the legs that arises during prolonged rest or when the patient is drowsy and trying to fall asleep, especially at night.[11] Patients describe the sensation in various ways including creeping, crawling, gnawing, itching, pulling, or even boring pain. Sensations occur in the muscles or bones of the legs and occasionally in the arms. Patients often report symptoms when traveling in a car or plane for prolonged periods. These sensations are relieved by moving the legs or walking. Because the symptoms occur predominately at night and interrupt sleep, RLS patients complain of daytime drowsiness leading to impairments at work and in social life. Patients with RLS can also have significant depression and anxiety.

Two different clinical subtypes of RLS have been identified, early and late onset. Persons whose RLS symptoms start at an earlier age (younger than 45 years) are more likely to have a family history of RLS and tend to have more slowly progressive symptoms compared with individuals with late-onset disease.[12]

Children may describe sensations differently than adults, but as with adults, symptoms are more common at rest or at night and improve with movement. Children may become fidgety when sitting and may be mistakenly diagnosed as having attention-deficit/hyperactivity disorder (ADHD). Nighttime symptoms may be confused with growing pains or insomnia.

Diagnosis

Standardized criteria have been formulated by the International Restless Legs Syndrome Study Group (IRLSSG).[1]

Essential diagnostic criteria for RLS include (1) urge to move the legs, (2) worse during rest or inactivity; (3) relieved by activity such as walking, and (4) worse in the evening or night.

Supportive clinical features of RLS include (1) family history of RLS, (2) response to dopaminergic therapy, and (3) periodic limb movements during wakefulness or sleep.

The RLS Epidemiology, Symptoms and Treatment (REST) study[3,4] revealed that, of a large population of patients seeking medical help, only 6.2% received a diagnosis of RLS. Symptoms more often were attributed to medical conditions such as back pain, arthritis, or peripheral neuropathy. Investigators ascribed the low diagnosis rate of RLS to lack of physician familiarity with RLS.

Differential Diagnosis

Periodic leg movements in sleep. Approximately 85% of patients with RLS will also have periodic leg movements in sleep (PLMS); and improvement in RLS symptoms translates to a decline in PLMS.[13] However, PLMS is a disorder distinct from RLS, and is also associated with narcolepsy, Parkinson's disease, and chronic sleep apnea. PLMS consists of involuntary, brief, rhythmic jerks of the legs. The movements last roughly 0.5 to 5 seconds and occur every 20 to 40 seconds. They may result in multiple arousals and may disrupt sleep. Two small clinical trials of patients with RLS with PLMS reported elevations in systolic and diastolic blood pressure and heart rate.[14,15] This indicates autonomic activation, which may confer long-term cardiovascular consequences. This finding has to be evaluated further in larger trials.

Whereas RLS symptoms are subjective, sensory, uncomfortable, and distressing to the patient, patients are typically unaware of PLMS. Generally these movements are reported by a bed partner or demonstrated in a sleep study.

Peripheral neuropathy. Because RLS can present with paresthesia and dysesthesia, it is often mistaken for peripheral neuropathy. Patients with neuropathy are more likely to have symptoms in their toes, whereas RLS patients will report discomfort in their legs and calves.[16] Although neuropathic symptoms may be more bothersome at night, they tend not to be relieved by movement. RLS and neuropathy may coexist; and the incidence of RLS may be increased in patients with peripheral neuropathy.[17]

Leg cramps. As with symptoms of RLS, leg cramps often occur at night, however, they are usually localized to specific muscle groups, accompanied by muscle hardening or knotting, and not easily relieved by walking.

Arterial insufficiency. In contrast to symptoms of RLS, symptoms of arterial insufficiency are generally not worse at night and often increase with exercise such as walking, and improve with rest.

Drug-induced akathisia. Drug-related akathesia is usually associated with a history of receiving a dopamine receptor blocking agent, and typically includes spontaneous movement of the whole body.

Venous insufficiency. Venous insufficiency is usually accompanied by swollen legs and marked by changes in skin color.

Painful legs and moving toes. Painful legs and moving toes is a rare syndrome usually associated with peripheral nerve injury or disease. It consists of severe pain, typically in the legs, associated with involuntary, slow, writhing movements of the toes. The syndrome is distinct from RLS in that the painful sensations have no diurnal variation and are unrelieved by activity; the movements are involuntary.

Restless-like syndrome. This recently described syndrome fulfills criteria for RLS but lacks PLMS and does not respond to dopaminergic agents. Patients with restless-like syndrome tend to have more severe symptoms, be younger, and are more likely to suffer from psychiatric comorbidities.[18]

Confirmation of Diagnosis

The diagnosis of RLS is based on the criteria established by the IRLSSG and described above. Physical and neurologic examination in patients with primary RLS are generally normal. Patients with secondary RLS may demonstrate evidence of peripheral neuropathy or radiculopathy. Iron deficiency and end-stage renal disease are common causes of secondary RLS and thus should also be investigated to confirm the diagnosis and guide treatment. Polysomnography has no role in confirming a diagnosis of RLS. However, it can confirm related disorders such as PLMS, or rule out other sleep disorders. Electromyography/nerve conduction studies are indicated in the setting of an abnormal sensory or motor examination, or symptoms suspicious for peripheral neuropathy such as burning pain in the soles of the feet.

Treatment of Restless Legs Syndrome

Address the underlying causes. Successful treatment of RLS relies on a thorough search for the etiology of the symptoms. Exclude or treat any possible secondary causes of RLS, including iron deficiency, which may itself be a marker for serious systemic disease such as gastrointestinal malignancy. Other common secondary causes include renal disease, neuropathy, and myelopathy.

Hyperparathyroidism, as described in the case report, is a rare cause of secondary RLS; to our knowledge, this is the second reported case.[19] As the case also illustrates, it is important to search for secondary causes, even in the setting of a positive family history, especially if there has been any significant worsening of symptoms.

Identify and discontinue exacerbating agents. A variety of medications can cause or worsen RLS, including tricyclic antidepressants, selective serotonin reuptake inhibitors, sedating antihistamines including diphenhydramine, dopamine receptor-blocking neuroleptics, and anti-emetics including metoclopramide. Alcohol, caffeine, and nicotine may also exacerbate symptoms.

Explore nonpharmacologic options. Good sleep hygiene includes regular bedtimes and wake times, and reserving the bedroom for sleep and sex only. Moderate, regular exercise may improve symptoms. Relaxation techniques such as hot baths, leg vibration, massage, and biofeedback may also be helpful.[2]

Pharmacologic treatment. Decision to pursue pharmacologic treatment depends on symptom severity and frequency, as well as the impact of symptoms on sleep and quality of life. Patients with occasional or intermittent symptoms may benefit from a variety of agents, including levodopa, zolpidem, gabapentin, or tramadol. However, for patients with frequent or daily symptoms, dopamine agonists such as pramipexole or ropinirole are the treatment of choice. Patients with severe RLS refractory to dopamine agonists may require combination therapy.

Medications for Restless Legs Syndrome

Dopaminergic agents. Levodopa (a dopamine precursor, coadministered with carbidopa or benserazide) is the best-studied treatment for RLS. It is inexpensive and has a fast onset of action (∼20 minutes). Levodopa is most appropriate for treatment of occasional, bothersome RLS symptoms rather than for daily use because of a common treatment complication termed “augmentation,” in which RLS severity increases over time. Signs of augmentation include onset of symptoms earlier in the day, shorter latency to symptoms at rest, and spread of symptoms to the arms and trunk. In severe cases of augmentation, RLS symptoms can persist throughout the day and despite physical activity.[20] Augmentation is common, occurring in over 70% of patients treated with levodopa.[21]

More appropriate for long-term treatment are the dopamine agonists ropinirole and pramipexole, which have recently been approved by the US Food and Drug Administration (FDA) for treatment of RLS. Dopamine agonists are associated with a lower risk of augmentation relative to levodopa (< 30% in most series).[22] Note that the onset of action is ∼90–120 minutes, so the medication must be taken earlier in the evening than levodopa, before RLS symptoms appear.

In general, dopamine agonists are generally very well-tolerated treatments that provide excellent and sometimes dramatic, relief from RLS symptoms.[22] Side effects include nausea, orthostatic hypotension, and hallucinations. Note that in this population, dopamine agonists can cause impulse control disorders such as compulsive gambling and hypersexuality, with a prevalence as high as 7%.[23]

Gabapentin is a gaba-ergic agent that may be especially helpful in hemodialysis patients or if RLS symptoms are perceived as painful.[24] One trial found that gabapentin 300–1200 mg was as effective as ropinirole 0.25–1.50 mg in reducing PLMS and RLS symptoms.[25] Initiate therapy at 100 mg at bedtime in elderly patients. Doses of up to 1800 mg per day may be needed for efficacy.[26] Pregabalin showed some efficacy in a small, open-label trial of RLS patients with and without neuropathic pain; the mean effective dose was 300 mg at bedtime.[27]

Second-line agents. Benzodiazepines or benzodiazepine receptor agonists: clonazepam (0.5–2 mg) improves sleep efficiency and subjective sleep quality,[28–30] but may cause a “hangover effect” the next morning. Tolerance may occur in daily use. Shorter-acting agents such as zolpidem (5–10 mg) may be helpful for patients who have difficulty falling asleep; but RLS symptoms may fragment sleep later on in the night. Zolpidem controlled-release formulations may improve sleep fragmentation, although this has yet to be studied.

In an open-label study, tramadol 50–150 mg at bedtime significantly improved RLS symptoms in 10 of 12 patients, with a favorable side-effect profile.[31] Oxycodone 15 mg was effective in reducing unpleasant leg sensations, motor restlessness, and daytime sleepiness in a double-blind crossover randomized trial.[32] However, a double-blind study comparing propoxyphene to levodopa and placebo noted better sleep and alertness with levodopa. Potential adverse effects include nausea and constipation. Dependency and addiction, as illustrated in the case report, are fortunately uncommon in this population.[33]

For patients with serum ferritin < 20 mcg/L or iron saturation < 16%, most experts recommend oral iron supplementation, ferrous sulfate 325 mg 3 or 4 times daily, co-administered with vitamin C 100 mg, given on an empty stomach. Because most patients with severe RLS have serum ferritin < 50 mcg/L,[34] oral iron replacement has been recommended for these patients as well. Although iron supplementation is anecdotally curative in cases of iron deficiency,[35,36] its role in therapy is otherwise unclear. Oral ferrous sulfate 325 mg twice daily was found not to be effective in treatment of RLS.[37] An open-label study of intravenous iron dextran 1000 mg improved symptom severity, sleep time, and PLMS in 7 of 10 patients; 3 patients had no response, and 1 patient suffered an acute allergic reaction.[38] RLS symptoms returned on average 6 months after the initial infusion; supplemental infusions of 450 mg iron dextran (iron reinfusion allowed only if the patient's serum ferritin < 300 mcg/L) controlled symptoms over a 2-year period.[39] A double-blind, placebo-controlled trial of patients with end-stage renal disease and RLS demonstrated that high-dose iron dextran was superior to placebo at 2 weeks, but not at 4 weeks.[40] More recently, a double-blind, placebo-controlled trial of IV iron sucrose was stopped prematurely due to a lack of significant clinical benefit, despite a significant increase in cerebrospinal fluid ferritin.[41] The safety and efficacy of intravenous iron supplementation remains unclear, and awaits further controlled trials.

Injected botulinum toxin type A was found to be effective in a small, open-label study,[42] and is currently being investigated in a placebo-controlled, double-blind trial. Anecdotally, patients have reported that sequential compression devices worn for prophylaxis against deep venous thrombosis are helpful for RLS; a controlled trial is underway. XP13512 is a gabapentin prodrug currently in clinical trials for RLS.

Special Populations

Pregnant patients. The frequency of RLS increases during pregnancy, especially in the third trimester. Pregnant patients may have folate and iron deficiency, which can be treated. No medication is completely safe in pregnancy, but some opioids may be tried with relative safety. Use of these drugs may be restricted for severe cases and delayed until the third trimester, but warrants consideration, because the sleep disruption of RLS may itself cause complications of prematurity and difficult delivery.[43] In most cases of pregnancy, new-onset RLS will resolve soon after delivery.[44]

Children. Studies in children are quite rare but most patients respond to nonpharmacologic treatment and only few require pharmacologic treatment. Initial treatment approaches include good sleep hygiene and caffeine restriction. Dopaminergic drugs have been shown to improve RLS symptoms in children.[45] In cases of associated ADHD, the dopaminergics may benefit ADHD symptoms as well.[45]

Patients with secondary RLS. Secondary RLS requires managing the underlying condition, discontinuing medications that may worsen symptoms, and correcting iron deficiency. Antidepressants, especially serotonin reuptake blockers, may also aggravate RLS. The best antidepressants for patients with RLS are agents such as bupropion that stimulate dopamine release. Dialysis does not improve RLS in patients with uremia, but transplantation does.[46]

Conclusion

RLS is an underrecognized and undertreated illness, relatively easily diagnosed in the office. It can have a significant effect on quality of life, and should be suspected in any patient with leg discomfort in the evening or at night. Prevalence increases with age but some experience the onset in childhood. The primary complaint is often related to sleep disturbance. Physical examination is generally normal except in patients with RLS secondary to renal disease or iron deficiency and pregnancy. Laboratory tests should include evaluation of anemia, iron stores, and medications that may worsen symptoms. Dopaminergic agents, especially the dopamine agonists, are generally very effective first-line agents. Second-line agents include gabapentin, opioids, and clonazepam.