Sleep Disorders | Sleep Review
The International Restless Legs Syndrome Study Group published consensus guidelines on rodent models of the RLS.
By Jane Kollmer
The diagnosis of Restless Legs Syndrome (RLS) is based on a patient’s subjective description of symptoms. But when studying RLS, many researchers use subjects who are unable to report their symptoms or what relieves them – that’s because they are using rodent models of RLS.
Hence, the transmission of RLS symptoms from humans to rodents becomes complicated, wrote members of the International Restless Legs Syndrome Study Group (IRLSSG) Aaro Salminen, PhD, from Munich, Germany; Mauro Manconi, MD, PhD, from Lugano, Switzerland, and Alessandro Silvani. MD, PhD, from Bologna, Italy, in an email to Sleep Review. The three were members of an IRLSSG task force aimed at “building consensus among RLS clinics and basic researchers on what surrogates should be used in rodent models to demonstrate RLS-like behavior,” they say. “There was no such consensus before this task force, which led to a fragmentation of the research field.”
Their consensus guidelines were recently published in Movement Disorders magazine.
“We hope that the guidelines will provide a reference document for researchers working in the RLS animal model field as well as new researchers working in the field,” say Salminen, Manconi and Silvani. “Using this guideline when planning new experiments will make it easier to compare and replicate data generated by different groups and different laboratories by others.”
Sleep doctor Marie Nguyen Dibra, MD, who was not on the task force, says, “I agree that guidance is needed for assessing RLS symptoms in an animal model. Since many RLS symptoms are subjective, the RLS must be assessed in a more standardized way when working with animals using objective measured variables. “
Why rodent models are important to RLS research
In the clinical setting, RLS symptoms respond well to low doses of dopamine agonists. But some patients have symptoms return, severe side effects, or treatment stop working over time. In some cases, the patient’s symptoms worsen with long-term treatment with the drugs. These challenges in clinical practice highlight the urgent need for new treatments and prevention tactics in RLS.
The answers could become clearer with a systematic preclinical research program capable of identifying new drug targets and getting drug candidates to clinical trial quickly. Animal models are useful to study the mechanisms of RLS and to enable efficient platforms for the evaluation of new therapeutics. Rodent models, in particular, are already well understood due to the cost effectiveness of laboratory mice and rats, as well as their genetics and neuroanatomy.
But differences in the way these studies are conducted on animal models of RLS from laboratory to laboratory have made it difficult in the past to compare study results and externally assess the validity of the model.
“Animal models are essential for testing pathophysiological hypotheses and pre-clinical testing of novel treatments,” said John Winkelman, MD, PhD, director of clinical research program for sleep disorders at Massachusetts General Hospital and one of two supervisors who reviewed the methods and outcomes of the reviewed measures the IRLSSG Task Force. “This work provides expert consensus on key aspects of translational research in RLS that are 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 using a validated methodology. “The Delphi method is a structured communication technique that uses a controlled feedback process with the aim of bringing together the opinions of experts on a particular topic to form a consensus,” say Salminen, Manconi and Silvani. “Each expert sends his / her contribution in written and anonymous form to a moderator, thus avoiding the pitfalls and prejudices of direct confrontations. The questionnaire rounds can be repeated as often as required in order to achieve a general consensus. “
Task force members first gathered the main clinical features of RLS.
After the team agreed which human behaviors and phenotypes are appropriate proxies for RLS, the team created and prioritized a consensus set of methodologies and outcome measures aimed at capturing these traits in humans without the input of verbal communications. These in turn were translated into appropriate methods and result 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 for assessing sleep disorders and periodic limb movements, which are objective features typically found in RLS. The data derived from these methods were determined to be the preferred surrogate measures for the urge to move, the most important defining characteristic of RLS.
In addition, the working group recommended specific pharmacological interventions or the induction of iron deficiency in order to improve or worsen RLS-like behavior in rodents.
One caveat to the Task Force’s recommendations is the lack of abundant rodent data on most of the phenotypes studied. Due to this limitation, the task force did not recommend any cutoff values for any outcome measures and instead only stated 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 deemed appropriate for animal model translation of human RLS traits, the Task Force has put one method above the other. The choice of method should be dictated by the individual experimental design, they wrote.
“We expect that future attempts to develop animal models of RLS will include the key outcome measures proposed by the task force. This should provide all the information necessary to interpret results and compare them with those of other research groups, ”said Salminen, Manconi and Silvani. “The ultimate goal of our guidelines is to facilitate preclinical research in the RLS area and to attract new research groups to study sleep-related movement disorders.”
Nox Health neurologist and chief medical officer, Jeffrey Durmer, MD, PhD, who was not on the task force, believes the newly published paper is “a big step for scientists in having these guidelines and helping them to supplement the RLS literature “. .
“By standardizing animal models, these guidelines provide a better way to discover and reduce the use of animals because new studies can build on studies that have already been done. The most innovative research occurs when a research field becomes broader and enables collaboration between the laboratory and the hospital bed.
“The consensus guidelines make sense because this is the first time there have been standards based on the concept of having consistent animal models from laboratory to laboratory.”
The same IRLSSG working group is also working on guidelines for the construct validity of RLS animal models. The two papers will complement each other and together serve as a comprehensive roadmap for the creation and testing of novel RLS animal models. As with all guidelines, updates will need to be made as soon as sufficient additional clinical and experimental data become available.
“As soon as both guidelines are published, we hope that new research in the area of RLS animal models will be published more frequently than before, which will ultimately accelerate understanding of the pathophysiology of RLS and the development of new and more effective treatments for this debilitating condition.” say the authors.
Jane Kollmer is a 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. Movement disorder. March 2021; 36 (3): 558-69.
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