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Table of Contents    
Year : 2018  |  Volume : 66  |  Issue : 4  |  Page : 1028-1030

Restless legs syndrome: A continuing search for better diagnostic criteria

Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi, India

Date of Web Publication18-Jul-2018

Correspondence Address:
Dr. Sanjay Pandey
Department of Neurology, Academic Block, Room Number 507, Department of Neurology, Govind Ballabh Pant Postgraduate Institute of Medical Education and Research, New Delhi - 110 002
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.236993

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How to cite this article:
Tater P, Pandey S. Restless legs syndrome: A continuing search for better diagnostic criteria. Neurol India 2018;66:1028-30

How to cite this URL:
Tater P, Pandey S. Restless legs syndrome: A continuing search for better diagnostic criteria. Neurol India [serial online] 2018 [cited 2023 Mar 23];66:1028-30. Available from: https://www.neurologyindia.com/text.asp?2018/66/4/1028/236993

Restless legs syndrome (RLS), also known as Willis Ekbom's syndrome, is a neurological disorder characterized by sensorimotor abnormality leading to an irresistible urge to move the limbs due to abnormal unpleasant sensations involving the limbs.[1],[2],[3],[4] The prevalence of this disorder ranges from 3 to 10%, with a higher rate of occurrence in females and in older aged patients.[5] RLS can either be primary wherein there is no apparent cause identified, or secondary due to iron deficiency anemia, pregnancy or chronic kidney disease. It is seen most commonly in the third trimester of pregnancy and usually resolves in a month's time following delivery.[4] Other disease associations include cardiovascular disease, obesity, diabetes, rheumatological disorders, peripheral neuropathy, radiculopathy, Parkinson's disease, multiple sclerosis,  Charcot-Marie-Tooth disease More Details, and spinal cord lesions but the associations of these diseases are not well established.[6] Secondary RLS should be suspected when the age of onset is more than 45 years.[7] Usually, early onset RLS is idiopathic or has a genetic association (as an autosomal dominant entity) if a positive family history is present.[8] There can be various RLS mimics like leg position discomfort, neuroleptics induced akathisia, leg injury, arthritis, leg cramps or nerve damage.[9]

RLS is seen to hamper sleep hygiene of the patients and is also associated with periodic limb movements during sleep in almost 88% of the patients. Despite this, the presence of periodic limb movements during sleep is not an essential criterion for diagnosing RLS. The disease affects the quality of life in terms of its adverse action on effective work output and it also has an adverse effect on the cardiovascular profile.[10]

Various pathophysiological mechanisms have been implicated in the occurrence of RLS.[11] These include genetics variants, abnormal iron metabolism, dopaminergic dysfunction, and the involvement of the central opiate system.[12] It is believed that as iron is a cofactor for tyrosine hydroxylase, the rate limiting enzyme involved in the synthesis of dopamine, its abnormal metabolism leads to a decreased production of dopamine, thereby leading to symptoms of RLS. Iron is stored in the endothelial cells at the level of the blood brain barrier and is required for various other metabolic reactions in the central nervous system. A11 dopaminergic cells near the hypothalamus in the midbrain seem to be the major source of dopamine to the spinal cord. These cells have a role to play in generating RLS features with the associated circadian rhythm.[12]

Functional studies have shown bilateral brainstem and cerebellar activation with contralateral thalamic activation suggesting their involvement in RLS. Also, the medial thalamus is a part of the limbic system and regulates the dopaminergic release.[12]

It was observed that in an iron deficient state, there was loss of dopaminergic cells in the substantia nigra. Another proposed mechanism is the involvement of the central opioid system, which is thought to be protective for this dopaminergic pathway.[12]

Various genes have been found using genome wide studies within the intronic or intergenetic regions of MEIS1 (2p), LBXCOR1/MAP2K5 (15q), BTBD9 (6p), neuronal nitric oxide synthase (NOS1) [12q] and protein tyrosine phosphatase receptor type delta (9p) genes. A family history of as high as 40 to 60% has been found in patients with RLS, reiterating the genetic basis of the disorder.[11]

The International Restless Legs Syndrome Study Group (IRLSSG) first laid down the clinical criterion for this disorder in 1995.[13] They gave some essential criteria, which included an urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs; the presence of unpleasant sensations or the urge to move, beginning or worsening during periods of rest or inactivity such as lying or sitting, with relief in these sensations partly or totally by movements such as walking, bending, stretching, etc., at least for as long as the activity continues. There is worsening of these symptoms in the evening or at night much more than during the day, or the manifestations may only occur in the evening or night.

These criteria were further edited in May 2002 and finally reviewed by the International Restless Legs Syndrome Study Group (IRLSSG) and published in 2003 with modifications.[14] The major changes included addition of another essential criterion, the differential diagnosis, to improve specificity by requiring that RLS symptoms not be confused with similar symptoms from other conditions. There was also addition of a specifier to delineate clinically significant RLS, and the addition of course specifiers to classify RLS as chronic-persistent or intermittent, and the merging of the paediatric with the adult diagnostic criteria.[15]

Thus, the diagnosis of this disorder is mainly on clinical grounds and all the four essential criteria must be met with to label the disease as RLS.[14] Though, the disease is primarily described as affecting the legs predominantly, 48% of the patients can have upper limb involvement as well.[5]

The sensitivity and specificity of the criteria given by IRLSSG were validated later in a few studies. Hening et al., stated that the specificity of the proposed criteria was only 84%.[9] Popat RA et al., reported a sensitivity and specificity for the standard questionnaire of 86% and 45% respectively; for the expanded questionnaire, however, the specificity increased to 73% and the sensitivity dropped to 81%.[16] The Hindi translation of the Cambridge-Hopkins diagnostic questionnaire for RLS (CHRLSq) stated the sensitivity of the criteria as being equal to 83.3%. The sensitivity dropped to 72.2%, and the specificity increased to 86.7% if the subjects did not control the response for item 6 in the questionnaire, which was related to relief with movement of the limb.[17] The above facts highlight the aspect that there is a need to revise the criteria so that maximum number of false positive patients are excluded and the true positive ones are not missed out.

There are a few studies from our country that have stated that the prevalence of RLS ranges from 2.1% to 2.9%.[18],[19] Comparing this prevalence with that reported in the worldwide population, it is apparent that the recognition of RLS in our country is under-reported probably due to the decreased sensitisation of clinicians to the entity, and also due to the stringent requirement of the essential inclusion criteria for its diagnosis, which are probably difficult to apply considering the different genetic make up, sociocultural practices, and linguistic variabilities in our population. This aspect has been dealt with in the study published in this issue by Garima et al., wherein the standard RLS questionnaire was modified to include specific questions pertaining to our social and cultural practices and was applied on 155 patients.[20] This led to an increase in the sensitivity (100%), specificity (44%), positive predictive value (79%), and negative predictive value (100%) in diagnosing RLS. The questionnaire has 10 parts, wherein part three has all the four standard essential criteria for RLS, part four comprises of supportive features, and part five includes relieving manoeuvres for RLS pertaining to sociocultural aspects. A positive response for RLS was considered when at least 2 of the essential diagnostic criteria (part 3 of the questionnaire) along with at least 3 supportive features (part 4) and at least 2 relieving manoeuvres (part 5) were present. They found that in part five of their questionnaire, maximum positive response (80%) was present for the question “Is there relief with massaging?”. Another important observation made by them was that the response to the third question in the essential criteria led to missing out on “true positive” cases of RLS by almost a margin of 20%, thus highlighting the need to have a scale which is region and language specific to improve the diagnostic yield of RLS.[20]

The RLS6 is one of the widely used rating scales for RLS. It has six items which look at daytime sleepiness, the patient's satisfaction with sleep, and the severity of RLS at the time of falling asleep, during the night, during the day while sitting or during recumbency, and during the day when active.[21]

Diagnosing RLS seems to be one part of the story, while effectively treating RLS remains its another part. The various treatment options available are based on the pathological deficits and include iron therapy, dopamine agonists, levodopa, opioid analgesics, anti-epileptics (alpha-2-delta ligands) and benzodiazepines (clonazepam).[1]

The first line therapy is decided based on the associated symptomatology. If the patients have concomitant depression or periodic limb movements, the first choice would be dopamine agonists. They are started in a low dose and gradually escalated to avoid the phenomena of augmentation. If the patient has concomitant pain syndrome, neuropathy, anxiety disorder, impulse control disorder and/or sleep disturbances with insomnia, then the preferred first line therapy is alpha -2 delta ligands (gabapentin, pregabalin).[1] Gabapentin enacarbil has also been found to be efficacious in recent trials. Usually patients who are refractory to the above two therapies or have existing contraindication, are treated with opioid therapy. The treatment of the underlying iron deficiency may be carried out utilizing either the oral or intravenous route. The efficacy of oral iron therapy is doubtful whereas intravenous iron therapy has been found to be extremely efficacious in the treatment of RLS. Other supportive measures found to be effective include vitamin E/C and pneumatic pumps. An exercise regime for patients with RLS in renal failure was also found to be efficacious, according to the recent studies.[22]

To conclude, RLS is a clinical disorder without any specific biological marker, which affects the sleep hygiene, quality of life and compromises the working hours of the patient. The current diagnostic criteria have several limitations and there is an urgent need to have better diagnostic tools for appropriate identification of the cases suffering from RLS in order to institute an early and effective treatment.

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