The International Restless Legs Syndrome Study Group published consensus guidelines on rodent models of RLS.

By Jane Kollmer

The diagnosis of restless legs syndrome (RLS) is based on the subjective report of symptoms by a patient. But when studying RLS, many researchers use subjects that cannot report their symptoms or what alleviates them—that is because they use rodent models of RLS.

So the translation of RLS symptoms from humans to rodents becomes complicated, wrote International Restless Legs Syndrome Study Group (IRLSSG) members Aaro Salminen, PhD, of Munich, Germany, Mauro Manconi, MD, PhD, of Lugano, Switzerland, and Alessandro Silvani, MD, PhD, of Bologna, Italy, in an email to Sleep Review. The three were members of an IRLSSG task force that aimed to “create a consensus between RLS clinicians and basic researchers on which surrogate measures to use in rodent models to demonstrate RLS-like behavior,” they say. “Such consensus did not exist prior to this task force, resulting in a fragmentation of the research field.”

Their consensus guidelines were recently published in the journal Movement Disorders.

“We hope that the guidelines will provide a reference document to researchers working in the field of RLS animal models, as well as for new researchers entering the field,” say Salminen, Manconi, and Silvani. “Using this guideline in planning new experiments will make the data produced by different groups and different laboratories easier to compare and to replicate by others.”

Sleep physician Marie Nguyen Dibra, MD, who was not involved in the task force, says, “I agree that guidelines are needed when evaluating RLS symptoms in an animal model. Since many RLS symptoms are subjective, there needs to be a more standardized way of assessing RLS using objective measures when working with animals.”

Why Rodent Models Are Important for RLS Research

In the clinical setting, the symptoms of RLS respond well to low doses of dopamine agonists. But for some patients, their symptoms come back, they experience serious adverse effects, or the treatment stops working over time. In some cases, the patient’s symptoms worsen on long-term treatment with the drugs. These challenges in clinical practice highlight the urgent need for new treatments and prevention tactics in RLS.

Answers may become clearer with a systematic preclinical research program that is able to identify novel druggable targets and move drug candidates through to clinical testing quickly. Animal models are useful for studying the mechanisms of RLS and facilitating efficient platforms for evaluating new therapeutics. Rodent models, in particular, are frequently used due to the cost effectiveness of laboratory mice and rats and also because their genetics and neuroanatomy are already well understood.

But variations in the way these studies of animal models of RLS are conducted from lab to lab has historically made it difficult to compare study results and assess the model’s validity externally.

“Animal models are essential for the testing of pathophysiological hypotheses and preclinical testing of novel treatments,” says John Winkelman, MD, PhD, chief of the sleep disorders clinical research program at Massachusetts General Hospital and one of two supervisors who reviewed the methods and outcome measures produced by the IRLSSG task force. “This work provides an expert consensus on key aspects of translational research in RLS needed to develop a standardized preclinical framework to model this human disease in animals.”

[RELATED: Are Dopamine Agonists Doing More Harm Than Good for Restless Legs Syndrome Patients?]

Arriving at Consensus

The task force followed the Delphi method to achieve a transparent and clear consensus with a validated methodology. “The Delphi method is a structured communication technique that deploys a controlled feedback process, with the aim to let the experts’ opinions converge to a consensus on a specific theme,” say Salminen, Manconi, and Silvani. “Each expert sends her/his contribution in a written and anonymous form to a moderator, thus avoiding pitfalls and biases of direct confrontations. The questionnaire rounds can be repeated as many times as necessary to achieve a general consensus.”

Members of the task force first gathered the most important clinical features of RLS.

After agreeing on which human behaviors and phenotypes are appropriate proxies for RLS, the team generated and prioritized a consensus set of methods and outcome measures intent on capturing these features in humans without the input of verbal communication. These were, in turn, translated into corresponding methods and outcome measures for research on laboratory rats and mice and used to generate the final recommendations.

The task force recommended activity-based techniques in addition to gold standard video polysomnography approaches to assess sleep disturbances and periodic limb movements, which are objective features that typically occur with RLS. Data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the principal defining feature of RLS.

Additionally, the task force recommended specific pharmacological interventions or induction of iron deficiency to improve or worsen the RLS-like behavior in rodents.

One limitation of the recommendations made by the task force is the lack of abundant rodent data available relating to most of the phenotypes that were assessed. Due to this limitation, the task force refrained from recommending cutoff values for any outcome measures and instead only indicated the expected direction of change (endpoint) in an RLS animal model compared to unaffected controls.

And although the guidelines present a number of methods that are considered suitable for animal model translation of human RLS features, the task force did not rank any one method above another. The choice of method should be dictated by the individual experimental design, they wrote.

“We expect that the future attempts in developing animal models of RLS will include the essential outcome measures suggested by the task force. This should provide all necessary information to interpret results and compare them with those of other research groups,” say Salminen, Manconi, and Silvani. “The ultimate aim of our guidelines is to facilitate preclinical research in the RLS field and to attract new groups of researchers to the study of sleep-related movement disorders.”

Neurologist and chief medical officer of Nox Health, Jeffrey Durmer, MD, PhD, who was not involved in the task force, thinks the newly published paper is a “great step for scientists to have these guidelines and will help them add to the RLS literature.

“By standardizing animal models, these guidelines offer a better route to discovery and reduce animal use because new studies can build off of studies that have already been done. The most innovative research happens when a field of research becomes broader and enables bench-to-bedside collaboration.

“The consensus guidelines are meaningful because this is the first time there are standards built around the concept of having consistent animal models from lab to lab.”

The same IRLSSG task force is also working on guidelines for construct validity of RLS animal models. The two papers will complement one another and together act as a comprehensive roadmap to the creation and testing of novel RLS animal models. As with any set of guidelines, updates will need to be made as sufficient additional clinical and experimental data become available.

“Once both guidelines are published, we hope to see new research published in the field of RLS animal models at a higher rate than before, ultimately accelerating the understanding of the pathophysiology of RLS and the development of novel and more effective treatments for this afflicting disorder,” the authors say.

Jane Kollmer is co-owner of Ch/At Communications, which provides writing and editing services to clients in the healthcare and travel industries. 


Salminen AV, Silvani A, Allen RP, et al. Consensus guidelines on rodent models of restless legs syndrome. Mov Disord. 2021 Mar;36(3):558-69.

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