Common, Underdiagnosed, Yet Highly Treatable: RLS

The neurologists and researchers most involved with RLS have been busy publishing an increasing number of reviews and research papers to inform other neurologists and primary care physicians (PCPs) about the syndrome and its features, diagnosis, and treatment.

"It's very common, it's very distressing, and easily quite treatable, so we like to get the word out," said Richard P. Allen, PhD, assistant professor, Department of Neurology, Johns Hopkins University School of Medicine, and research associate at the Johns Hopkins Center for Restless Legs Syndrome. Allen is coauthor of an article appearing in the June issue of Archives of Internal Medicine¹ that reported the frequency rate for RLS symptoms occurring at least once a week was 7.2% among 15,391 people who returned completed questionnaires as part of a population-based study of RLS in the United States and 5 European countries. The total number of people reporting moderate to severe RLS symptoms was 416, or 2.7%. However, of those 416 patients, 337 wrote that they had discussed their symptoms with PCPs, who diagnosed RLS in only 21--or 6.2%.

In perspective, RLS is a relatively new neurologic syndrome. It is generally considered to be a sleep disorder expressed most in the drowsy state that precedes sleep onset and is characterized by a powerful urge to move, usually associated with efforts to relieve uncomfortable sensations in the legs. The pathophysiology is poorly defined, but researchers believe it may be related to improper processing of dopamine and inadequate presence of iron in the brain. About half the cases are familial, according to a number of sources. The rest are associated with various other conditions or disorders, or with pregnancy. Generally, it affects women more than men and symptoms progress with age.

"Most patients with restless legs present because they can't sleep at night," said Michael J. Thorpy, MD, associate professor of neurology at Albert Einstein College of Medicine and director of the Sleep-Wake Disorders Center at Montefiore Medical Center in the Bronx, NY. Because PCPs are usually the first to see these patients, "the first thing to do is to increase their awareness of it. The second thing is to get them asking the right questions. We believe the primary care docs can treat this. It's a clinical diagnosis; you don't need any special expertise. The drugs that are being used [are] mainly dopamine agonists. With their increased awareness of the fact that these drugs can be used safely, and simply, they can initiate and maintain treatment."

PREVALENCE AND INCREASING RESEARCH

Estimates of the prevalance of RLS have ranged from 3% to 9%² and 3% to 15%³ of the general Western population. A paper published in 2003 in the Archives of Internal Medicine,⁴ also coauthored by Allen, reported that as many as 24% of patients from a rural primary care practice in Idaho had all symptoms of RLS during a 1-year period. This is the same percentage of patients that reported having RLS symptoms in the 2005Sleep in America Poll conducted by the National Sleep Foundation (www. sleepfoundation.org/_content/ hottopics/2005_summary_of_findings.pdf).

If you extrapolated these percentages to the 2000 census figure of 281.4 million total US population, that could mean that 7.6 million people in the United States alone could have RLS symptoms that are severe enough to require medical treatment, and an additional 59.9 million could have milder symptoms, which may or may not require treatment. In comparison, an estimated 4 million Americans have Alzheimer disease, according to the Alzheimer's Disease Education and Referral Center, and 2.7 million Americans have epilepsy, according to the Epilepsy Foundation.

Swedish neurologist Karl-Axel Ekbom⁵ first described RLS in a 1945 paper. Published research papers and reviews began to increase in the 1980s. According to a search in PubMed, 16 papers were published in 1985, compared with 4 in 1980, and 27 were published in 1986. The number rose to 69 in 1999 and to 172 in 2004. During the first 7 months of 2005, 72 papers were published.

Arthur S. Walters, MD, who coauthored many of these papers beginning in 1986,^6-7 is an internationally recognized RLS expert and director of the Center for Sleep Disorders Treatment, Research and Education at the New Jersey Neuroscience Institute, JFK Medical Center, in Edison. He attributes the growth in research to the development of the RLS Foundation (www.rls.org), incorporated in 1992; the publication in 1995 of a refined definition of the clinical features of RLS⁸; and the publication in 2003 of a revised version⁹ of the article on clinical features of RLS after an NIH conference on RLS that was held in 2002.

During those years, the International Restless Legs Syndrome Study Group (IRLSSG) developed a rating scale¹⁰ that served as a standard instrument to more easily diagnose RLS. "This really was important, because previously the only objective measurement we had of the RLS symptoms was a sleep study, and an overnight sleep study is very expensive--at least $1500, and it's time-consuming," said Walters. "To really do large-volume research, where you're seeing 300 to 400 patients in a study, you really need to have a quick instrument that actually gets to the core features of the condition."

Also contributing to the growth in research, pharmaceutical companies have been using the IRLSSG rating scale to conduct large studies to develop drugs, Walters added. The NIH also has increased its funding of RLS research over the years. "The more money you have circulating, the more people you have applying for money and the more people you have interested in investigating the area," Walters explained. The actual development of medications to treat RLS symptoms also has contributed to the growth in research, added Thorpy.

DIAGNOSIS OF RLS

Those 1995 and 2003 papers have provided physicians with essential criteria for reaching an RLS diagnosis. The 4 primary features of RLS are:

• A compelling urge to move the legs, and possibly also the arms. It is usually--but not always--associated with unpleasant sensations in the legs.

• The urge or unpleasant sensation begins or worsens during rest or sitting.

• The urge or unpleasant sensation is relieved partially or totally by moving the legs.

• The urge or unpleasant sensation is worse at night or only occurs at night.

Corresponding to the above criteria, the questions to ask patients who complain about sleep problems, according to Thorpy, are:

• Is there any discomfort in the legs when you lie down at night?

• Is the discomfort relieved by moving the legs?

• Is the discomfort made worse by rest or inactivity?

• Does the discomfort occur more often at night than during the day?

A general chemistry screen would be helpful in determining the diagnosis also, Thorpy said, especially as it relates to serum ferritin levels. If a screen shows levels below 50 µg/L, it's an indication that could prompt treatment with iron supplements.

A differential diagnosis is critical^2,3 because RLS can coexist or be confused with other neurologic disorders, including attention deficit hyperactivity disorder (ADHD),^11,12 periodic limb movements disorder (PLMD),¹³ and Parkinson disease (PD).^14-16 Furthermore, in some cases the traditional diagnosis of "growing pains" may instead be RLS.¹⁷

In ADHD, symptoms of restlessness can manifest during the day, rather than at night, and appear as lack of attentiveness or hyperactivity. "It's very difficult to separate out that symptom," said Mary L. Wagner, MS, PharmD, associate professor in the Department of Pharmacy Practice and Administration, Rutgers, The State University of New Jersey, in Piscataway. "Any person with insomnia is going to have possible attentional problems during the day due to sleep deprivation. Also, in kids, the restlessness of RLS may be confused with hyperactivity of ADHD." Added Allen of Hopkins, you have to do a differential diagnosis to determine whether the problem is ADHD, ADHD with RLS, or RLS.

In a study published last December in Annals of Neurology,¹⁸ Mayo Clinic researchers concluded that, for 32 patients with childhood-onset RLS, 24 (72%) had serum ferritin levels below 50 µg/L and 23 had a strong family connection to RLS. Suresh Kotagal, MD, professor of neurology at Mayo Clinic College of Medicine, Rochester, MN, said he has noticed that about a third of the children he sees for ADHD, which accounts for the childhood onset, also have underlying RLS symptoms. "There are also some short but important case reports of children with ADHD and RLS that [show that] as you treat RLS, the daytime symptoms of inattentiveness, hyperactivity, and oppositional behavior seem to settle down."

RLS and PLMD are 2 distinct disorders and the diagnosis often is confused, said Frank Skidmore, MD, assistant professor of neurology at the University of Florida College of Medicine and director of the Malcolm Randall VA Medical Center Movement Disorders Clinic. For PLMD, "typically, people do not come in complaining that they have restless legs that keep them up at night. Typically, their partner comes in and complains that so and so is kicking all night."

Anecdotally, Emile R. Mohler, 3rd, MD, director of vascular medicine at the University of Pennsylvania Health System in Philadelphia, said he has associated RLS with peripheral artery disease (PAD). "I see it commonly in my practice. I think patients with PAD for whatever reason have irritable muscle, and that causes cramping at night" that is usually consistent with RLS, he said. Most of his patients are aged 70 years or older or are aged 50 years or older and have a history of diabetes and smoking. "I usually have to prompt them and ask them about their symptoms. I ask them if relief comes from laying the leg over the side of the bed or pushing against the edge of the bed with the foot," he explained. The latter points to RLS and the former points to critical limb ischemia, he added.

TREATMENT AND MANAGEMENT

Neurologists and PCPs have plenty of guidance in the literature on how to manage RLS symptoms and treat RLS patients. Numerous studies have been published on treatments that include dopamine agonists, anticonvulsants, opioids, and combination therapies. Last year, a treatment algorithm¹⁹ for RLS was publishedin Mayo Clinic Proceedings that recommends medications and nonpharmacologic therapies for the different levels of RLS. The American Academy of Sleep Medicine also has provided guidance.^20,21

Generally, dopamine agonists are first-line treatments for patients who have RLS that is severe enough to require treatment. Gabapentin (Neurontin, Pfizer) can be an alternative, as well as low-potency opioids. For patients whose condition is refractory to initial treatment with a dopamine agonist, alternatives can include a different dopamine agonist, gabapentin, a benzodiazepine, or an opioid. Levodopa also has been used.¹⁸ Dopaminergic agents amantadine and selegiline could also be effective RLS and PLMD treatments.^20,21

RLS patients got a boost earlier this year with the FDA's approval of ropinirole (Requip, GlaxoSmithKline) as the first drug specifically labeled for the treatment of moderate to severe RLS. Researchers found in several clinical trials ropinirole, a dopamine agonist that also is used to treat PD, to be effective for treatment of RLS.^22-26

Other dopamine agonists that are being used, but are not yet approved for the labeling for RLS, include pramipexole (Mirapex, Boehringer Ingelheim/Pfizer)²⁷ and cabergoline (Dostinex, Pfizer).²⁸ In addition, pergolide (Permax, Eli Lilly),²⁹ an alkaloid that has agonist activity, has been effective in large trials but has been associated with rare but significant cardiac complications that have not been found to occur with either ropinirole or pramipexole.

Nonpharmacologic treatment has to be tailored with drug therapy. "The typical treatment that we provide has to be combined with sleep hygiene recommendations, lifestyle alterations, and avoidance of specific substances," said Alon Y. Avidan, MD, MPH, assistant professor of neurology and director of the Sleep Disorders Clinic at the University of Michigan Health System. Those recommendations include avoiding heavy exercise regimens too close to bedtime and refraining from the use of substances such as alcohol, caffeine, and nicotine, which can exacerbate RLS symptoms, he said.

RLS AND PD

Special considerations need to be taken into account when managing RLS in patients who also have PD, said Skidmore, a Parkinson expert. "It's not uncommon that the 2 go together," he explained. "Restless legs can occur first, and then several years later, Parkinson's disease develops." He said he doesn't think RLS causes PD, or vice versa; they are more like "fellow travelers, as opposed to one causing the other."

"Many of these folks in Parkinson's disease are already on Requip or Mirapex, or other dopaminergic medications," Skidmore said. "For restless legs, we have to go to the next step and look for something else to treat them with because obviously the typical dopamine-related medications are not doing the trick for them." For those patients, he said, he might try gabapentin or clonazepam.

In a study published last year in Neurology,³⁰ some results surprised the principal author. "Subthalamic stimulation [STN] is helpful for the motor features in PD, just like levodopa, so you would think it would help with RLS," said Rajeev Kumar, MD, in private practice as a neurologist in Houston, TX, and director of the Movement Disorders Center at the Texas Nerve and Paralysis Institute. Instead, 11 of 195 patients who underwent STN deep brain stimulation were diagnosed postoperatively with RLS. STN probably did not cause RLS; rather, symptoms of RLS probably were masked by PD medications, Kumar said. When levodopa was reduced postoperatively in these patients, the RLS became manifest.

WHERE TO GO FROM HERE

A general consensus is that the next big area of RLS research should be its pathophysiology. "Understanding the iron metabolism issue is going to be very helpful," said Allen of Johns Hopkins. "If we can sort out the genetic issue and the iron metabolism issue, we might be able to anticipate environmental factors. That might be enough to blunt occurrence of this disorder or protect people from having it."

Walters at New Jersey Neuroscience Institute said he will be looking into possible immunologic and blood pressure connections. "RLS sometimes remits for months at a time, then it will come back," he said; that suggests an immunologic mechanism, which opens up a new area of research. Also, he said he will be studying blood pressure elevation after kicking movements of PLMD in patients who have RLS by examining MRI scans of the brains of these patients.

Skidmore said that learning more about RLS could also mean learning more about PD. "We're getting a good handle on things that are actually working for [RLS], and we're getting that information before we have a clear appreciation for the actual nuts and bolts of what's going on in the brain. If we had a better understanding of restless legs syndrome and the causes, we might be able to look deeper and see if other things are going on in the brain, such as things that might lead to Parkinson's disease--that's a big black box right now." *

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