The connection between RLS and migraines

Restless legs syndrome affects an estimated 10% to 15% of the general population.1 However, there is a higher prevalence of RLS in people who suffer migraine headaches (migraineurs). For example, an Italian study2 found that 25.6% of patients in a group of migraineurs were affected by RLS; a German study3 found that 17.3% of migraineurs had RLS, while only 5.6% of non-migraineurs did. Most studies examining the association between RLS and migraines in people with both disorders have viewed them as two distinct disorders. In recent years, scientists have begun suspecting that the two disorders may actually have a shared pathophysiology.

Restless Legs Syndrome

A person with RLS has creepy, crawling uncomfortable sensations in the legs that occur in the late evening or just as the person is ready to go to bed. The sensations are most noted when the person is relaxed (eg, sitting quietly or lying down), and can be relieved only by moving the legs around, massaging them, walking around, rubbing them on bedsheets, etc. These actions, however, only temporarily relieve the uncomfortable sensations, and a person soon has to repeat them to get relief again. Repeated attempts to relieve the sensations can delay the onset of sleep. The sensations usually stop soon before the person goes to bed or just as a person is falling asleep. Some people who have migraines report insufficient sleep as a trigger for migraine headache.4 Insufficient sleep resulting from an RLS sufferer’s attempts to relieve the uncomfortable leg sensations could hypothetically play a role in migraine, although scientists have not examined this extensively.

Migraine

Migraine (from the Greek, hemikrania, meaning “half the head”) is a vascular headache. An attack is preceded by the sudden vasoconstriction of the cranial arteries, which may be associated with sensory symptoms (ie, an aura). An aura can involve visual changes such as seeing jagged lines, sparks, or spots, or blindness in half of the visual field in one or both eyes; speech disorders such as slurred speech; or changes in sensation such as numbness or tingling of the lips, face, or hands. Vasoconstriction is then followed by vasodilation. It is during the vasodilation stage that the pain occurs. The pain is typically described as throbbing and is usually felt on one side of the head. In addition to the pain, a person may vomit; have nausea; be extremely sensitive to light and sound; or, due to contraction of the scalp muscles, have a feeling of a tight band around the head or tender spots on the head and neck. For most migraineurs, the headache is not preceded by an aura.

In the past, migraine headaches were treated with drugs derived from ergotamine. These drugs are believed to work by binding to serotonin receptors located on intracranial blood vessels. This action constricts the vessels, which then relieves the migraine. However, side effects such as nausea can make taking these medications problematic. The vasoconstrictive effects of droperidol—a beta-adrenergic antagonist and dopamine antagonist—have been widely used to treat migraine and are less likely to cause nausea. Droperidol blocks the dopamine D2 receptor, which results in vasoconstriction and alleviation of the migraine. Because droperidol is a dopamine antagonist, a drawback of droperidol treatment is that it can result in akathisia, a type of motor restlessness in which there is a sensation of muscular quivering or an urge to move. 

The Link

In 2003, Silberstein5 and associates reported that 30% of their migraine patients reported severe akathisia after beginning treatment with droperidol. This finding suggested that RLS symptoms in patients with migraines were an adverse drug effect. However, that same year, Ehrenberg6 questioned whether droperidol-induced akathisia was in actuality restless leg syndrome that had been unmasked by the dopamine antagonist action of the drug. Ehrenberg further pointed out that most migraineurs are diagnosed while young (between 20 and 40 years of age), but most RLS sufferers are diagnosed at 45 years or later. This potentially means that many migraineurs who are not yet middle aged may have undiagnosed RLS.

Scientists have not yet determined the pathological link between migraine and RLS. Some factors that have been proposed are faulty iron metabolism in the central nervous system, impaired function of the A11 nucleus, genetics, and improper levels of melatonin. These factors may link the two disorders in the following ways.

Iron Metabolism in the Central Nervous System

The iron-containing D2 receptors are found in the basal ganglia, a collection of nuclei at the base of the brain. Low levels of iron may affect the function of this receptor and result in RLS since some basal ganglia play a role in movement. Some research7 indicates that the brain in migraineurs stores an increased amount of iron in the periaqueductal gray matter—part of a neuronal network that plays a role in migrainous pain. The increased iron level in the periaqueductal gray matter, which indicates impaired iron metabolism, may allow the improper transmission of signals to occur in the vessels surrounding the trigeminal nerve, which then can contribute to migrainous pain.

Impaired Function of the A11 Nucleus

The A11 nucleus is located in the hypothalamus. The hypothalamus, along with the periaqueductal gray matter, is part of the neuronal network that plays a role in migraines. The dopaminergic cells in the A11 nucleus provide axons to the spinal cord. Dysfunction or atrophy of neurons in the A11 nucleus is a suspected cause of RLS.7 In addition, animal studies indicate that lesioning the A11 nucleus can increase motor restlessness and can promote signaling in the trigeminovascular system, which may increase the perception of pain.1,8

Genetics

Gene mapping of several generations of two separate Italian families revealed a genetic marker, D14S288, that is located within region 21 on chromosome 14 and is present in people who have RLS9 and in people who have migraines without aura.10 Region 21 contains genes that encode for various proteins that play a role in neuronal development, maintenance, and survival. Alterations in some of these genes may subsequently play a role in RLS and migraine without aura; however, this has not been extensively investigated. 

Improper Levels of Melatonin

The neurotransmitter melatonin inhibits dopamine secretion in the central nervous system.7 The nocturnal increase in melatonin may therefore trigger the nocturnal onset of RLS symptoms in a person with this disorder. At proper levels, melatonin has an analgesic (ie, pain-relieving) effect. It may exert this effect by inhibiting the production of the enzyme nitric oxide synthase, which synthesizes nitric oxide (NO, a neurotransmitter that plays a role in pain perception). Some research11 indicates that, during an acute migraine attack, the level of melatonin falls below normal. This may allow nitric oxide synthase to produce increased amounts of NO, which then may result in migraine pain. 

Treating coexistent RLS and migraine presents a dilemma because of the opposing effects of dopamine antagonist drugs (eg, droperidol, prochlorperazine) used to relieve migraines and dopamine agonists (eg, pramipexole) used to relieve RLS symptoms. The use of drugs that do not interact with the dopaminergic system may be an alternative. For example, the drug gabapentin, which is typically used to treat epilepsy, has been used to relieve the pain of migraines and relieve symptoms of RLS.12 However, gabapentin as a treatment for RLS and for migraine is an off-label use of the drug and has not been extensively studied as a treatment for these disorders.

Future studies may determine whether treating coexistent RLS and migraine needs to take into account the type of migraine a person has. For now, scientists have noted a higher prevalence of RLS in people who have migraines without aura than in people who have migraines with aura. For example, d’Onofrio7 and colleagues in their clinical study compared the frequency of RLS among non-migraineurs and people who had migraines with aura, migraines without aura, and other types of headaches (episodic tension-type headache, episodic cluster headache). Among the people who had migraines, RLS affected only 4.5% of people who had migraines with aura, but 61.4% of people who had migraines without aura.

Rhode3 and colleagues found that 4.3% of their migraineurs with an aura had RLS, but 84.9% of the migraineurs without aura had RLS. This difference in the prevalence of RLS in migraineurs with and without aura may represent different pathophysiological processes and potentially require different treatment approaches.

A clearer understanding of the factors that result in the coexistence of RLS and migraines could potentially improve treatment in patients with both disorders. Although many questions remain, it may nevertheless be beneficial to assess patients who have migraines for RLS. This may help a person avoid using a drug therapy that may inadvertently exacerbate RLS symptoms or exacerbate migraines. SR

Regina Patrick, RPSGT, is a contributing writer for Sleep Review

REFERENCES

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