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Restless Legs Syndrome: Pathophysiology and the Role of Iron and Folate

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Restless Legs Syndrome: Pathophysiology and the Role of Iron and Folate Alternative Medicine Review Volume 12, Number 2 2007 Review Article Restless Legs Syndrome: Pathophysiology and the Role of Iron and Folate Lyn Patrick, ND A study of 23,052 primary care patients evalu- ated for RLS revealed that nine percent had weekly symptoms of RLS. Although the majority of those di- agnosed (88%) had primary complaints of insomnia, Abstract only 13 percent had actually received a prior diagnosis of RLS.2 Of those who had received a prior diagnosis, Restless Legs Syndrome (RLS) is a common movement disorder the majority had been prescribed therapies known to characterized by a circadian variation in symptoms involving be ineffective in RLS. Misdiagnoses included varicose an urge to move the limbs, usually the legs. Pregnant women, veins, other venous disorders, depression, myalgia, back patients with end-stage renal disease or iron-deficiency anemia, or spinal injury, and diabetic neuropathy. and children with attention deficit hyperactivity disorder (AD/ HD) have a significantly higher prevalence of RLS. The classic Diagnostic Criteria presentation includes the onset or worsening of symptoms when RLS is classified as either familial (primary at rest and the circadian pattern of exacerbation of symptoms RLS), with a clear genetic component, or acquired (sec- at night. These symptoms reflect a circadian fluctuation of ondary RLS). Primary RLS occurs in approximately 50 dopamine in the substantia nigra. Patients with RLS have lower percent of first-degree relatives of those with RLS and is levels of dopamine in the substantia nigra and respond to iron believed to be related to an inherited defect in dopamine administration. Iron, as a cofactor in dopamine production, plays metabolism.11 Acquired RLS involves altered iron me- a central role in the etiology of RLS. Folic acid administration tabolism and occurs in a variety of patient populations, has also been shown to alleviate the symptoms of RLS and including pregnant women, patients with end-stage re- 12 may play a role in the treatment of primary (familial) RLS. nal disease, and individuals with iron deficiency. (Altern Med Rev 2007;12(2):101-112) The diagnosis of RLS consists of four essential clinical criteria based solely on symptoms (Table 1).13 A compelling urge to move the limbs occurs on resting or Introduction lying down and discomfort is alleviated by movement of Restless Legs Syndrome (RLS) is a neurologi- a body part (usually the legs) or the entire body. RLS is cal movement disorder that is common, under-diag- also characterized by involuntary or spontaneous move- nosed, under-treated, and has a poorly understood eti- 1 ment, such as floor pacing, tossing and turning in bed, ology. Due to a lack of awareness among primary care and rubbing the legs to relieve sensations – described providers, both misdiagnosis and mistreatment of RLS appear to be common.2 Studies in North America and Northern Europe confirm RLS is a common disorder Lyn Patrick, ND – Bastyr University graduate 1984; Private practice, Durango, with a prevalence of 5-25 percent in the general popu- CO, specializing in Environmental Medicine and chronic hepatitis C; Faculty of lation.3-8 It is twice as prevalent in women,9 and more the postgraduate Certification Course in Environmental Medicine, Southwest College of Naturopathic Medicine; Contributing Editor, Alternative Medicine common in the elderly, with 10-20 percent over age 65 Review; Physician-member of the Hepatitis C Ambassadors Team. experiencing significant symptomology.10 Correspondence address: 117 CR 250 Suite A, Durango, CO 81301. Email: [email protected] Page 101 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007 Alternative Medicine Review Volume 12, Number 2 2007 Restless Legs Syndrome as “creeping, crawling, itching, burning, sear- Table 1. Essential Clinical Criteria for Diagnosis of RLS ing, tugging, drawing, aching, like an electric current.”1 The symp- 1. A sensation of an urge to move the limbs (commonly legs) – usually toms have a circadian associated with paresthesia pattern – always im- proved when at rest in 2. Onset or worsening of symptoms when at rest – not associated with the morning and worse any specific body position. when at rest in the eve- 13 ning. 3. Relief of symptoms with movement; complete relief immediately or shortly after initiating movement. Differential Diagnosis 4. Marked circadian variation in degree or occurrence of symptoms; Several other worse in the evening, improved in the morning regardless of quality disorders resemble RLS or quantity of sleep. and are differentiated by symptom descrip- tion, laboratory testing, and other appropri- ate diagnostic workup (Table 2).14 Neuropathies and (fasting), thyroid hormone, vitamin B6, and vitamin radiculopathies can be ruled in or out by electrophysi- B12.15 Abnormalities of any of these would help rule ological assessment and testing blood levels of glucose out RLS. Table 2. Differential Diagnosis – to Differentiate from RLS Peripheral Neuropathy No circadian changes No periodic leg movements in sleep Nerve conduction abnormal No improvement with movement Akathisia No circadian pattern No paresthesia Improvement from dopamine blockers Peripheral Vascular Disease Worse with movement, better with rest Vascular and skin changes seen on exam Nocturnal Leg Cramps Unilateral, focal, sudden severe onset Painful Legs and Moving Toes No urge to move, no worsening at rest or improvement with movement No circadian changes Page 102 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007 Alternative Medicine Review Volume 12, Number 2 2007 Review Article results in sleep impairment equal to or greater than any other sleep disorder. In one polysomnographic study of Table 3. Populations At-Risk for Restless 26 RLS patients, sleep efficiency was decreased by 50 Legs Syndrome percent, leaving 30 percent of patients with less than 3.5 full hours of sleep nightly.12 With the exception of Pregnancy mania, severe RLS results in the greatest level of sleep deprivation of any sleep disorder.12 End-stage renal disease on hemodialysis Given recent findings that show 30-40 percent of those with chronic insomnia may also have clinical Primary family history of RLS depression, this level of sleep deprivation may be related to the significantly higher incidence of anxiety and de- Iron deficiency anemia pression in RLS patients compared to the general pop- ulation.18 Patients presenting in a sleep disorder clinic with either RLS or periodic leg movement disorder Frequent blood donations (PLMD) had a greater than 50 percent chance of hav- ing some form of depression.20 The negative impact of Gastric surgery RLS on quality of life has been shown to be equal to or greater than chronic obstructive pulmonary disease or Pediatric AD/HD myocardial infarction.12 At-Risk Populations for RLS Pregnancy, end-stage renal disease, certain RLS: A Cause of Serious Sleep medications, and iron deficiency are associated with a 15 Impairment significantly higher incidence of RLS (Table 3). RLS is a form of sleep disorder that includes periodic limb movements in sleep (PLMS), a condition Pregnancy where involuntary motor movements of the limbs occur During pregnancy the incidence of iron defi- during the sleep cycle and lead to a shift in sleep stage ciency is significant; less than optimal iron intake can 21 and repeated awakenings.12 PLMS can also occur in occur in 90 percent of pregnant American women. conditions such as narcolepsy, Parkinson’s disease, and Research estimates 11-27 percent of pregnant women other disorders related to impairments in dopamine experience RLS at some point during pregnancy, most 22-24 production.16 PLMS is more prevalent as age increases commonly in the third trimester. RLS is the most – up to 30 percent of individuals over age 50 experience common movement disorder in pregnancy and gener- 25 PLMS secondary to a disease state or medication side ally remits with delivery. effect.17 The etiology of RLS in pregnancy is related Approximately 20 percent of those with RLS to iron and folate insufficiency. During normal preg- do not have involuntary motor movements during sleep nancy, the requirements for both nutrients increase (it is not necessary for a diagnosis). However, the condi- significantly – iron requirement increases 3- to 4-fold 22 tion results in severe sleep disruption for the majority and folate requirement increases 8- to 10-fold. Defi- of RLS patients and has been recognized as a cause of ciencies of either nutrient have been found in pregnant sleep impairment in 5-10 percent of the U.S. popula- women with RLS, and the resolution of RLS appears tion.18 Because PLMS leads to multiple awakenings to correlate with normalization of folate and iron levels 26 at night, RLS is considered the fourth-leading cause postpartum. The prevalence of RLS in women receiv- of insomnia. Sleep impairment, although usually not ing folate supplementation throughout pregnancy was voluntarily disclosed without direct questioning, is the significantly lower compared to the prevalence in wom- main complaint described by those with RLS.19 RLS en with no folate supplementation (9% versus 80%, respectively).27 Page 103 Copyright © 2007 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission. Alternative Medicine Review Volume 12, Number 2 June 2007 Alternative Medicine Review Volume 12, Number 2 2007 Restless Legs Syndrome In a prospective trial of pregnant wom- en with RLS and matched pregnant controls, he- Figure 1. Changes in Serum Folate from Preconception moglobin and serum folate, iron, ferritin (storage until One-month Postpartum iron), and vitamin B12 were monitored precon- 26 ception and once each trimester. Although no 18 serum folate measurements fell below the normal range of 4-20 ng/mL, folate levels were signifi- 16 cantly lower in the RLS group (Figure 1) prior to 14 conception and during the ensuing nine months.
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