Restless Legs Syndrome Foundation Blog

NIH releases the 2021 Sleep Research Plan

The Sleep Research and Sleep Disorders Research Advisory Board is congressionally mandated to develop the US Sleep Research Plan every five years. Established in 1993 by the US Congress, the National Center on Sleep Disorders Research (NCSDR) is part of the National Heart, Lung and Blood Institute (NHLBI), whose focus is to study the toll that sleep disorders and sleep loss have on productivity, longevity, illness, and mortality. The Sleep Disorders Research Advisory Board (SDRAB), which is an advisory board to the National Institutes of Health and National Sleep Center is responsible for writing the Sleep Research Plan.

RLS Foundation Board Member and SDRAB Member, Linda Secretan, was directly involved with writing the 2021 Sleep Research Plan. She helped to determine the plan’s key strategic goals and priorities.

The plan comprises five specific goals:

1. Sleep and Circadian Mechanisms Underlying Health and Disease
2. Risk Reduction and Treatment of Sleep and Circadian Disorders
3. Clinical Implementation of Sleep and Circadian Research
4. Sleep and Circadian Disruptions and Health Disparities
5. Foster the Development of a Strong and Diverse Workforce for Sleep and Circadian Research

These five goals provide opportunities for research in sleep and circadian rhythms but also encourage research into other areas of interest in the field of sleep. Secretan’s input helped shape the final plan, which includes nine critical opportunities that seek to expand research in the science of circadian and sleep research.

Sufficient sleep is an essential requirement for overall health and wellbeing, yet half of all US adults and three-quarters of teens report sleep deficiency – factors that impair sleep quality, sleep quality, and total sleep time. The 2021 Sleep Research Plan is a comprehensive document that highlights the importance of sleep and personal strategies to ensure restorative sleep. The plan also underscores the importance of sleep in overall health maintenance and disease prevention.

Sleep is an essential pillar to health maintenance just as diet and exercise. However, sleep is often the pillar given the least attention in health promotion activities. Yet, all three pillars need equal attention for optimum health and disease prevention.

The 2021 Sleep Research Plan will advance the science of sleep and circadian research leading to better patient outcomes for those living with sleep disorders.

A special note of thanks to the over 200 RLS community members who attended the Virtual Congressional Briefing on Tuesday, January 25, 2022, to announce the 2021 Sleep Research Plan.

Call for RLS Grant Proposals

The RLS Foundation, a 501(c)(3) nonprofit corporation, aspires to achieve universal awareness of the disease, to support identification of effective treatments, and to find the cure for the millions of men, women, and children who suffer from RLS.

The RLS Foundation calls for grant proposals of a 1 year-duration, with funding levels of up to $50,000 (including 8% for F&A costs), based on the number of funded applications. Additionally, grant applications may be supported for a total of 2 years, including a 1-time competitive renewal, for a total of up to $100,000 (including 8% for F&A costs). However, funding for the 2nd year will be contingent on progress reports that must be submitted 6 months and 12 months from the grant starting date, together with a funding request and an application for the 2nd year.

Spring 2022 Priorities

For this round of funding, the primary research priorities are:

• Neurobiological interaction: Elucidate the points of interaction between RLS-relevant neuro-transmitters and neuropathways and iron deficiency
• Therapeutic responsiveness: Elucidate genetic, epigenetic, biologic, phenotypic and other predictors of responders to pharmacologic and IV iron therapeutics; including predictors of augmentation;
• Clinical Practice: research based on innovations in patient care delivery including but not limited to population health programs, technology-enabled healthcare delivery (i.e.; telemedicine) and public health initiatives.

Requirements

• Eligibility: All institutions within the United States, Canada, and other countries where supervision of grant administration is possible are eligible.
• Human Subject Protection: Approval by the institution’s human investigation committee is necessary for all projects that involve human subjects.
• Recombinant DNA Research and Animal Welfare: The RLS Foundation has adopted the regulations pertaining to these areas, as established by the US Public Health Service.
• Multiple Awards: Individual investigators may receive a maximum of one RLSF grant award of any kind in a given year.

Application process

• Submission is a two-step process requiring both preapplication (letter of intent) due no later than March 4, 2022 and full application as indicated below.
• The application title and all information for the Principal Investigator (PI), Business Official(s), Performing Organization, and Contracting Organization must be consistent throughout the entire preapplication and full application submission process.
• If a joint submission by multiple PIs (Partnering PI Option): The Initiating PI must complete the preapplication submission process and submit the contact information for the partnering PI. The Partnering PI(s) will then be notified of the preapplication submission separately by email.
• Fund disbursement for successful applications will be contingent upon documentation of approved institutional review or animal user protocols, as appropriate.

Preapplication (Letter of Intent) Submission Components

The Letter of Intent (LOI) should consist of preproposal narrative with:

• Rationale: State the hypothesis and reasoning on which the proposed research project is based. Briefly describe how preliminary data, scientific rationale, and referenced literature support the research hypothesis. Clearly demonstrate that there is sufficient rationale for the project (Limit: 500 words).
• Focus Area: State the Research Priority that the proposed study seeks to address. Select one or more from the current research priority list.
• Specific Aims and Study Design: Clearly describe the type of research study being proposed. Concisely state the project’s objectives, specific aims, and ultimate endpoints. As applicable, briefly describe the proposed recruitment strategies and methods, how they will accomplish the project’s aims, as well as the outcome measures that will be used. (Limit: 500 words)
• Research Team: Provide a description of the research team that clearly demonstrates the appropriate background and experience to accomplish the proposed work. (Limit: 250 words)
• Impact and Relevance to RLS: Describe how the proposed work will impact healthcare and quality-of-life needs for patients and/or family members or beneficiaries living with RLS. (Limit: 250 words)

In addition, applicants should provide a reference list (one-page limit), list of abbreviations, acronyms, and symbols, and key personnel biographical sketches (NIH format).

Letter of intent to be submitted online here no later than March 4, 2022.

Applicants will be informed within 6 weeks of the deadline if their proposal will be invited for a full application.

Full Application Submission Components

If selected, the full online application consists of a cover page that must be signed by the university or organizational representative(s) and the principal investigator, an abstract with a clearly stated hypothesis, and the proposal that includes:

Project Narrative (no more than 5 pages), with background, hypothesis / objective, specific aim(s) and research strategy. Within the research strategy section, describe the study design, methods, models, and analyses in sufficient detail for assessment of the application. Explain how the research strategy will meet the project’s goals and milestones within the proposed period of performance. Address potential pitfalls and problem areas and present alternative methods and approaches. For studies performing prospective human subject recruitment or observation: Describe the population(s) of interest. Describe how data will be reported.

Budget and budget justification

Biographic sketches of each investigator (NIH format)

Disclosure of previous RLS Foundation support and other sources of funding.

Full Applications to be submitted online, link to be provided in LOI acceptance notification.

Award Process

Schedule: The RLS Foundation Scientific and Medical Advisory Board (SMAB) and external reviewers strives to review all applications in a timely manner. The goal is to provide the results to the LOI applicants within 2 months of the respective grant deadline and 4 months after submission of the full proposals.

Review: The SMAB will evaluate and rank the full proposals based on scientific merit. Overall impact, significance, approach, innovation (conceptual, technical) and individual criteria will be taken into account for funding consideration.

Award: The RLS Foundation Board of Directors will make final award decisions in accordance with available funds, based on the evaluation provided by the SMAB and other prioritization factors as determined by the Board of Directors.

Recipient Requirements: In order to receive an RLS Foundation research grant, the recipient must:

1. Within one month of the grant award, provide a photo of the grantee and a one-page article for publication in NightWalkers (the Foundation’s quarterly news magazine), describing in layman’s language the importance of the research to the RLS community and the recipient’s intention for future research.
2. Use the terminology restless legs syndrome in all grant-related publications and correspondence.
3. For 1-year awards, agree to submit a progress report after 6 months and 12 months from the starting date of the grant.
4. Acknowledge the RLS Foundation’s support in any published work or audiovisual productions resulting from research that the Foundation has supported. (Provide pdf copies of any reprints to the Executive Director of the RLS Foundation.)
5. Agree, if RLS Foundation funded research is commercialized or generates revenues, to devote a portion of the revenues to repaying the entire amount of the grant received, plus interest at the-prevailing prime rate, to the Foundation. Interest will be calculated semi-annually on the unpaid portion of the amount to be repaid.

Lastly, the intent of the RLS Foundation Research Grant Program is to provide seed monies to support researchers in their research endeavors and help them obtain the data to successfully request large scale funding elsewhere.

Thus, while an application may be also submitted to other organizations or agencies for funding, the applicant may not receive funding from the RLS Foundation, if any of those other projects are awarded or funded prior to the award being granted by the RLS Foundation.

The applicant will notify the RLS Foundation in writing of award funding for the same proposal from another organization and withdraw the application from consideration.

Costs Not Permitted

The following costs are not allowable under the RLS Foundation’s grant programs:

• New construction, alterations, or renovations of existing facilities
• Consultant fees, unless specified in the original grant application
• Travel costs

RLS Research Grant Program

The RLS Grant Program started in 1997 and has funded 48 grants totalling nearly $2 million. Funding is provided by generous individual donors. We thank all of the donors this month giving in memory of Robert H. (Bob) Waterman, Jr. who was responsible for spearheading the RLS Research Grant Program in 1997. Help us to continue to fund promising new RLS research.

Nighttime Agitation — Is It RLS?

By Kathy Richards, PhD, RN, FAAN; member of the RLS Foundation’s Scientific and Medical Advisory Board

For people in the dementia stage of Alzheimer’s disease (AD-D), the problem of nighttime agitation, defined as the presence or worsening of behaviors such as aggression or wandering in the afternoon or evening, is a management challenge for their caregivers. This problem often leads to more and more restrictive living environments for persons with AD-D, including placement in nursing homes. In addition to AD-D, nighttime agitation might be a manifestation of a common neurologic condition: restless legs syndrome (RLS). Symptoms of RLS match those of nighttime agitation – that is, not being able to remain still, and experiencing symptoms in the evening.

In a recent study published in the Journal of Post-Acute and Long-Term Care Medicine, the characteristics and behaviors of 76 older adults with AD-D, nighttime agitation, and newly diagnosed RLS were measured. RLS was diagnosed using the Behavioral Indicators Test – Restless Legs, a validated tool for diagnosis of RLS in persons with AD-D. The individuals in the study were unable to cognitively and verbally report their RLS symptoms. The older adults with AD-D were also observed for nighttime agitation behaviors. Assessment of iron status and sleep quality (using motion sensors) was conducted for these patients as well. The researchers found that fewer minutes of documented sleep and lower transferrin (iron) saturation were associated with more frequent behaviors of nighttime agitation. Over three-quarters of the patients with RLS and nighttime agitation had been prescribed medications that worsen RLS, such as antihistamines and serotonin reuptake inhibitors.

These findings support clinical consideration of nighttime agitation as a sign of RLS and highlight the need for further research to identify new management strategies. The findings also suggest that medical providers should take steps to identify and diagnose RLS; treat iron deficiency anemia if indicated by low transferrin saturation; and deprescribe medications that worsen RLS. The combination of these strategies will lead to a reduction in any RLS component of nighttime agitation in patients with AD-D. In addition, it is recommended that nursing homes change common practices that are likely to worsen RLS discomfort and nighttime agitation, such as restricting residents from evening walking and putting them to bed early.

Kathy Richards, PhD, RN, FAAN, is a research professor at The University of Texas at Austin, School of Nursing. As a UT Austin PhD graduate, Kathy has conducted sleep research in Alzheimer's disease for 20 years, and received over $25 million in NIH funding to support her research endeavors. Her recent project is the NightRest project and the Behavioral Indicators Test for Restless Legs Syndrome in older adults. In partnership with Christine Kovach, PhD, RN, FAAN, Richards received a $3.9 million five year grant from the National Institute on Aging to improve the treatment of nighttime agitation in those with Alzheimer's disease. They hypothesize that RLS may be a cause for nighttime agitation and sleep disturbance in these individuals. This study marks the very first time that a new diagnostic tool will be used in research on nighttime agitation.

The RLS community has lost a giant with the recent passing of Robert H. Waterman, Jr. His career as a management consultant and Senior Partner with McKinsey & Co. culminated with the publication of the first “blockbuster” book on sound management practices. In Search of Excellence, co-authored by Bob and his McKinsey partner, Tom Peters, rose to the top of the New York Times Best Seller List, and changed the way business leaders around the globe thought about their roles as heads of successful companies.

Like many individuals who have served on the Board of Directors of the RLS Foundation, Bob was afflicted by the disease - so much so that it disrupted his career as a Senior Partner at McKinsey and led him to a path as an independent management consultant with The Waterman Group. It also led him to more than two decades of leadership at the RLS Foundation.

Bob served as Chair of the Board of Directors for six years (1999-2005) and later as Chair Emeritus (2010-2019).

Bob brought his insights, along with his passion for excellence, to the RLS community. He was a strong proponent of strategic planning and led the strategic planning initiatives for the RLSF Board for many years. He believed in setting BHAGs — Big Hairy Audacious Goals — and in that vein articulated basic strategic goals that remain at the core of the Foundation’s work today: Improve Awareness; Develop Better Treatments; Find a Cure.

As a member of the Board during the organization's early years, he took it upon himself to establish the Research Grant Program. The program's purpose was to attract leading researchers from around the globe to apply for seed money grants to further develop a hypothesis for external funding at the National Institutes of Health or other organizations in the hopes of identifying durable treatments and a cure for RLS.

As the RLS Foundation approaches its 30th anniversary in 2022, the RLS community is thankful for Bob spearheading the Research Grant Program effort at this pivotal point in the organization's early years. Member support of this initiative has led to 48 grants totaling nearly $2 million in funding. In 2022, the Research Grant Program will celebrate its 25th anniversary. Bob's leadership and vision for the program has led to breakthrough discoveries in genetics, iron regulation, neurophysiology, and treatment.

Bob received the prestigious Ekbom Award in 2008 in recognition of his meritorious service to the RLS Foundation.

Memorial donations in his honor can be made to the Waterman Memorial Research Fund to support RLS research.

Support Group Leader and Secretary, RLS Foundation Board of Directors

I recently had the pleasure to sit down and chat with one of the extraordinary members of our Board of Directors, Linda Secretan. Since she became a Foundation member in 1997, she has served the RLS community in so many ways. From starting a support group in Idaho, to serving as the RLS Foundation’s representative on the Sleep Disorders Research Advisory Board of the National Institutes of Health, to her leadership roles on the Foundation’s Board of Directors, she seems to do it all with compassion and a smile. During her six years of service, Secretan has served as secretary of the Board and chair of the Governance and Nomination Committee, two roles critical to the effective functioning of the Foundation.

Linda’s lifelong struggle with RLS and her experience as an educator and life coach make her an invaluable member of the RLS Foundation’s Board of Directors.

Q: How did you get involved with the RLS Foundation’s Board?

A: I was a long-time member of the RLS Foundation and had just moved to Idaho, transitioned careers and had a lot more free time and flexibility. I spent a long time thinking about just the right volunteer commitment where I could best spend my time and resources. Then I realized that the RLS Foundation had been essential to my well-being for many years. I relied on the Foundation for information, encouragement and general support in dealing with my RLS. I noticed that there wasn’t a support group leader in Idaho, so I thought I would apply, and my application was accepted! A generous donor had given the Foundation a grant to create educational materials specifically for kids and adolescents. Since Karla Dzienkowski, executive director at the Foundation, knew of my background in education, she asked me to help out with that project, and I was delighted to volunteer my time and experience with education and RLS. Then I got a call from Karla and Jacci Bainbridge, former chair of the Board, to ask me if I would consider becoming a board member. I was thrilled to be asked. I obviously had to ask questions and think hard about it, but there was no way I could turn them down. It was such an amazing opportunity to grow closer to the organization, learn more and maybe offer more to an organization that had given me so much.

Q: How has joining the Board affected your RLS journey?

A: First of all, it is very exciting to be on the Board, because you tend to hear about things first. You understand what is happening with the Scientific and Medical Advisory Board; when any research reports are published, we are the first to know. The Board is kept updated on all of the advocacy efforts, and that gives me a lot of insight and hope. Being on the Board reminds me that no matter how my own symptoms wax and wane – as they do, no matter how many regimens that I try – there is always a group that has my back. The Board is not just a bunch of names on a piece of paper, but people who are really interested in investing in and improving the lives of people with RLS. Serving on the Board makes my RLS more bearable, brings me hope and keeps the mission front and center in my mind.

Q: How has your service as a support group leader helped you during your time on the Board?

A: I consider myself a patient advocate serving on the Board. My time as a support group leader is so beneficial to my board service, because I have the opportunity to talk to many RLS patients to understand their concerns and their difficulties. I am able to be their advocate in board discussions and decisions that affect the people we serve, our members.

Q: How has your experience as a life coach helped you on the Board?

A: Any good coach begins with the premise that clients are creative, resourceful and whole – always approaching things from an awareness of great humility and curiosity. I think that also makes a good board member. We must be curious and assume the people that we deal with are creative, resourceful and whole, except that they have this interesting but limiting disease. Knowing that we are all sound people, we can make a difference, we can change, and we can learn. Always be curious, because when you are curious you keep your mind open.

Q: You chair the Governance and Nomination Committee. What does that involve?

A: As the Governance Committee, we are guardians of the bylaws. We are charged with making sure that, as a Board, we are doing right by ourselves and adhering to our own principles and standards. The other part of this committee involves nomination. As the Nomination Committee, we are always looking for people who are interested in board service. It is our job to seek out members of the community, Foundation members or individuals with leadership qualities. It takes passionate people to do the work. We have the best executive director in the world, but ultimately the Board is responsible for making some important decisions. We must make decisions about how to spend and allocate the resources available.

Q: What do you look for in a board member?

A: People are surprised to know that not all of our board members actually have RLS. It is not required that you have RLS, but you must have knowledge about the disease and what it means to live with RLS. You need to be willing to commit your time and resources to this important cause. This is a working board. All board members are expected to attend each meeting. In ordinary times, we hold one face-to-face meeting a year and three to four meetings by phone or Zoom. Your financial commitment to the Foundation should be equal to or greater than any of your other charitable giving commitments. One of the key responsibilities for each board member is to thank our major donors, by either phone or letter. When a donor gives a substantial gift to the Foundation, it is important that they get recognition and sincere thanks from a board member. Often, we learn more about the concerns and interests of donors through thank-you calls. This knowledge helps us keep in touch with members and helps inform future board decisions.

Q: Are you currently looking for new board members? How do you find them?

A: We are always looking for new board members; our terms don’t last forever — which is a good thing. We want new people who have new ideas. Several of our current members attended the RLS Symposium held in La Jolla a couple of years ago. It was a great opportunity to meet new people in person with an interest in board service. Sometimes we look at people who have come to us for help, or who have become interested enough to become a donor, and we reach out to see if they may be interested in further service.

When I was considering what to spend my volunteer energy on, I realized that there are many causes that are dear to my heart. Racial justice and climate change are both important issues. I wanted to make a difference in the world, and not just for RLS. I was torn. But, here is the thing: If my RLS isn’t somewhat manageable, then I’m not able to do anything. My RLS wouldn’t be manageable without the support I receive from the Foundation. I wouldn’t know what to do, where to go, how to find information, how to manage my RLS. Once I put that into perspective, there was only one answer. I am only able to volunteer because of the support of this Foundation – the support of this Board – so I darn well better serve this Board and the Foundation, and that’s what made my decision.

Q: Do you have any advice for those who are considering the decision to join the Board?

A: Talk to us! Find out how we operate, find out how you might fit, ask questions. We are open to speaking with you. If we can provide the information that would tip the balance toward your becoming more involved, give us a call.

I’m in my 50’s and have been in corporate sales for over 30 years. My diagnosis of RLS should have come when I was five years old; however, back then, members of the medical community did not know nearly as much as they do today.

My path has been both different and similar to most people with chronic RLS – not an earth-shattering revelation. I can remember tapping my left leg during childhood to distract the unpleasant sensations that I would have throughout the day – not every day, but many days. It wasn’t until my early 30’s that RLS became an everyday, chronic experience. Before then, RLS would appear when I had been sitting for long periods, when I was experiencing stress or when I was over-caffeinating myself.

After college, I had to come to grips with RLS, as my career required me to be somewhere specific on a daily basis. I had to be “on” as best I could, since I considered myself an achiever and didn’t want to allow this RLS thing to hamper my career.

Although it didn’t happen as quickly as I would have liked, “it” did happen. The “it” being my acceptance of RLS. For some time, I resisted and sought ways to heal the RLS by myself. And by so doing, I dealt with the symptoms in a way that didn’t help me in the workplace. Being short on sleep and being angry about it was not a great strategy.

Through acceptance, I discovered some ideas that helped me to be at my best in the workplace:

• Optimized Workspace: My RLS sensations occur in my hamstrings. If I sit for too long, they will begin to appear. I am able to bend down on one knee and work on my computer. In the past, I have worked from a standing desk, which is a great idea for people with RLS. I’ve also arranged to walk outside of my office daily while making phone calls. When I have days where I don’t have to make phone calls, I will still take midafternoon walks. This not only provides a positive break for my RLS but also is excellent timing for digesting lunch from two hours before.
• An Earlier Bedtime: What is early? This is subjective, but 10:30 pm works for me. However, the more sleep I am able to get before midnight, the better my sleep and the more rested I feel. This technique is not original. Becoming a student of RLS, I learned from some of the top sleep specialists in the industry that there is something powerful that occurs when we get to sleep earlier rather than later. I will also add that making this a habit was not easy. Getting up early was the key. After a long period of adjustment, getting up early (even when I didn’t want to) created the sleepiness to help me form the habit of getting to bed early.
• Exercise: Wow, this is so key! It is one of the most important habits for a healthy lifestyle, but even more important for people with chronic conditions. Exercise creates endorphins in our bodies that help us feel good. This in turn helps us to be productive, improves our mood and helps us sleep.
• Deep Breathing/Meditation: This is a fantastic habit for anyone wanting to be successful and reach their potential in life. I wonder if I would even have developed this habit had I not had RLS. The good news for me is that I did discover this wonderful habit. It’s the gift that truly keeps on giving. I invest 15 to 30 minutes per day in quiet meditation. I take deep breaths during that time and focus on my breathing. That’s it; that’s what I do once or twice per day. I rarely miss a day. And when I am able to do it twice a day, my day is that much better. By better, I mean clearer of mind, relaxed in my body and my mind. The “restless” part of our RLS condition is not lost on me. I believe that we have things going on in our body for reasons. When they are problematic, like RLS, they often have a message within them. In my case, I was restless in all areas of my life. As I learned to invest time daily in quiet, while breathing deeply and focusing my mind on my breath, over time my thinking and feeling and actions in life took on more peaceful and productive patterns that have served me well.

I am forever grateful for the RLS Foundation. I have benefited more from learning about other people’s RLS experience through the Foundation than from any other available forum. Through the years, I have read NightWalkers and met people who work for, volunteer for or are simply members of the Foundation who have touched and bettered my life in ways I would never have imagined. More than anything else, I learned that I am not alone! Now that is a life lesson worth learning.

Understanding Augmentation and How to Recover from Dopamine Dependence

Dopaminergic medications had been the mainstay of first-line pharmacological treatment of RLS for many years, but they have significantly fallen out of favor in the past decade due to high rates of augmentation and, secondarily, impulse-control disorders. Clinical consensus guidelines no longer consider these agents to be first-line treatments, despite the abundance of research demonstrating significant efficacy in the short term (months to a few years). The high rates of augmentation, which is thought to be inevitable with long-term use, begs the question: “Should anyone take dopaminergic agents at all for this chronic, lifelong condition?”

Despite relegation of dopaminergics to second-line status in the more updated clinical guidelines since 2015, many RLS experts only use these medications now in rare circumstances. If these therapies are considered, they should be trialed only after the ineffectiveness or intolerable side effects of the other treatments available for RLS. After initiation for daily use, regular monitoring must be performed for early identification of the stages of effects on the dopaminergic system, including dependence, tolerance, mild augmentation and severe augmentation. Dopamine agonists may have initial side effects, including nausea, vomiting, headache, sleepiness and dizziness.

The most commonly used dopamine agonists are the short-acting pramipexole and ropinirole, and the long-acting transdermal rotigotine patch. Levodopa is reserved for intermittent RLS symptoms, due to extremely rapid onset of augmentation (weeks to months) when taken daily. Though no studies have investigated augmentation with intermittent use, three doses or fewer per week has been considered reasonable. Potential uses include evening dosing for occasional RLS symptoms, dosing prior to sedentary situations (e.g., plane flight, theater presentation), and dosing for patients in whom the diagnosis of RLS is in doubt.

Augmentation

Since dopamine agonists became a first-line treatment for RLS in the early 2000s, two decades of experience have demonstrated high rates of (possibly inevitable) augmentation with long-term use. Augmentation is a worsening of RLS with one or more of the following features: an advance of the typical time of day when symptoms begin, two or more hours earlier than before the start of treatment; a spread of restlessness from the legs to the arms or trunk; a shorter interval before symptoms start after inactivity (sitting or lying); progressive dosage escalation to produce the same effect; and even paradoxical triggering of RLS symptoms immediately after taking the medication.

Augmentation has led to the most dramatic paradigm shift in RLS management, as it causes the majority of refractory RLS cases. This phenomenon poses significant philosophical challenges to the clinician, as a potential worsening of the condition long term in most cases should prohibit the use in the short term, regardless of the significant short-term effectiveness. Because of the increasing prevalence of augmentation, the RLS Foundation’s Scientific and Medical Advisory Board published a guideline outlining the identification and treatment of augmentation. The presence of one or more of the following factors is known to increase the likelihood of augmentation: more frequent RLS symptoms before treatment, greater discomfort with RLS symptoms before treatment, co-morbid asthma, older age, longer treatment duration, lower serum ferritin levels, and greater baseline severity of RLS.

Four screening questions are recommended to identify augmentation:

1. Do RLS symptoms appear earlier than when the drug was first started?
2. Are higher doses of the drug now needed, or does the medication need to be taken earlier in the day, to control the RLS symptoms compared to the original effective dose?
3. Has the intensity of symptoms worsened since starting the medication?
4. Have symptoms spread to other parts of the body (e.g., arms, trunk, face) since starting the medication?

Augmentation is considered mild if all of the following are present: symptoms manifest predominantly as a temporal shift of symptoms to earlier in the day compared to before starting treatment; dopaminergic monotherapy is at a total daily dose at or below maximum recommended levels; symptoms cause only mild distress; and there has been no prior increase in total dose above that which was previously therapeutically effective. In cases of mild augmentation, there is more time to make adjustments to treatment regimen, but the symptoms do represent an early stage of dopaminergic system impairment and dependence. This will progress to more severe symptoms and advanced augmentation if no changes are made or dopamine medication dosage is simply increased.

Augmentation is considered severe if it does not fulfill the criteria for mild augmentation (e.g., the total agonist dose exceeds recommended levels or the symptoms cause more than mild distress) or does not respond to treatment of mild augmentation.

Treating Augmentation

Initially, it is important to identify and eliminate or treat factors that exacerbate RLS. These could include poor sleep hygiene or other untreated sleep disorders, ingestion of drugs/foods that worsen RLS symptoms, or low levels of ferritin or percent transferrin saturation. If the iron stores are low, then iron therapy (oral or intravenous) should be considered.

For mild augmentation, the dopamine agonist medication could be continued and the total dose maintained but given in divided doses, or the medication could be given earlier to precede the onset of RLS symptoms. If symptoms are not managed by splitting the dosage, then the addition of other therapies should be considered, such as iron infusion, alpha-2-delta ligand medications, and possibly opioid medications. Changing to a longer-acting dopaminergic agent such as transdermal rotigotine could be considered, but this will only delay the inevitable augmentation to future months or years. Rotigotine has lower rates of augmentation long term in studies but is thought to mask augmentation due to having a steady level of the drug in the system continuously without time off from the drug. If the second treatment added does not provide symptom relief, then augmentation should be considered severe. Even if augmentation is mild, long-term plans should be discussed for transition to other treatments before more severe augmentation develops. Tapering off the dopamine agonist, with or without a second-line agent added, should be considered long term, to initiate dopaminergic system withdrawal and reconstitution.

For severe augmentation, the goal over several weeks to months is to wean, slowly but completely, off all dopaminergic agents to enable withdrawal, recovery from dopaminergic dependence, and maximal reconstitution of the natural dopaminergic system to as close to previous baseline as possible. One method is to perform a slow wean of the dopaminergic agent, followed by a two-week drug holiday, and then the addition of an alternative agent if still requiring symptomatic treatment. Though this approach is ideal in terms of natural recovery and limiting medication side effects, it is often met with apprehension due to the severity of withdrawal symptoms. The addition of a second medication prior to reduction in the dopaminergic medication is more common. Therapies may include an IV iron infusion (more potent and rapid than oral iron), alpha-2-delta ligands, opioids and, rarely, benzodiazepines. The dopamine agonist weaning process can be highly variable among patients, depending on initial severity of symptoms and strength of dosage. Anecdotal evidence suggests that many patients can go through a mini-withdrawal and recovery process after each dosage decrease in four to seven days, but some may take a few weeks or require increases in the secondary agent if they do not improve. Recovery after complete discontinuation may be the greatest in the first two weeks, though some patients take much longer to recover significantly. Many may have slow improvement beyond the initial few weeks for months or years after discontinuation, though the natural history of dopamine agonist withdrawal and recovery has not been well studied yet.

Dose reduction must be managed by a healthcare provider, and each situation is different; however, there are some management guidelines. Ropinirole may be tapered by 0.25 to 0.5 mg per week as tolerated, pramipexole by 0.125 mg, and rotigotine by 1 mg. However, the initial decreases may be larger, particularly if the patient is on dosages beyond maximum recommended, with progressively smaller decreases as the patient approaches discontinuation. Symptoms of withdrawal are generally a temporary but possibly severe worsening of restless legs symptoms, including more severe breakthrough symptoms, symptoms during the night leading to insomnia, earlier onset of symptoms during daytime with possible spread to other anatomic regions, and even involuntary limb movements while awake. These symptoms generally improve over several days before the patient can begin the next step in the tapering process. If a second agent is used, it may need to be adjusted to balance effectiveness with side effects, to combat the withdrawal symptoms. Other symptoms during dopaminergic withdrawal may include high levels of anxiety, irritability, insomnia, excessive daytime sleepiness and depressed mood.

After at least two weeks from discontinuation, the patient should be reassessed to see if the new symptomatic agent can be gradually tapered as well, or a second medication added in the case of patients who tapered without additional drug treatment. Several weeks to months after complete withdrawal, recovery is frequently seen and further dosage reduction can be made, as the dosage of a second medication is generally higher in the withdrawal period than weeks to months after recovery, due to progressive reconstitution of the dopaminergic system.

Impulse Control Disorders

Impulse control disorders are another side effect of dopamine agonist therapy. Due to long-term effects on the dopaminergic system and behavioral pathways, dopamine agonists are associated with impulse control disorders (e.g., pathologic gambling, excessive shopping, hypersexuality) within nine months of treatment onset. Symptoms of impulse control disorders (and augmentation) should be screened regularly, regardless of duration of use. The consequences of unrecognized impulse control disorders can be devastating, including substantial financial loss, the threat of criminal prosecutions, substance abuse and social disruption. However, complete resolution of the pathologic tendencies is the general rule with discontinuation or dose decrease of the causative agent.

Education and Awareness

Decades of dopamine agonist use have revealed the risk of augmentation and impulse control disorders. Education of healthcare providers is the first step to raise awareness about RLS treatment guidelines and the adverse side effects of dopaminergic medications. Support for RLS research leading to the identification of new medications that address the chronic progressive nature of RLS and its treatment challenges are priorities for the RLS community.