Restless Legs Syndrome, the Pitfall: Hardly Diagnosed and Rarely Treated Neurological Disease

Review Article

Austin J Clin Neurol 2017; 4(5): 1118.

Restless Legs Syndrome, the Pitfall: Hardly Diagnosed and Rarely Treated Neurological Disease

Chavda Vishal K and Patel Snehal S*

Department of Neuropharmacology, Nirma University, India

*Corresponding author: Patel Snehal S, PG- 201 Pharmacology Research lab, Department of Pharmacology, Institute of Pharmacy, Near S G highway, Nirma University Ahmedabad-382481, India

Received: June 02, 2017; Accepted: July 04, 2017; Published: July 21, 2017


Restless legs syndrome is a chronic progressive sleep associated sensory motor disorder which develops within the neurological disorders like Parkinsonism, Neuropathy pain and possible dementia. The global prevalence of restless legs syndrome is increasing day by day and research studies have been reported the essential need for research in specific diagnosis and treatment of restless legs syndrome. Prevalence of Restless legs syndrome is more in Female and pregnant women than men in the almost whole world. In India and many other countries of Asia and throughout the world the term Restless legs syndrome (RLS) is still a questionnaire. It is reported many a time by the Physicians, Neurologists and Gynecologists as a mal-diagnosis of Restless legs syndrome in India and in others countries also. The exact pathophysiology of the RLS is still not clear, but some superficial assumptions regarding the progressions of disease and root of disease through the gene molecular concepts. Few Traditional Chinese medicine and allopathic medicine have been reported a successful treatment of RLS, but it is either symptomatic or depends on time management. Dopamine Agonist and opioids are possible symptomatic treatment for RLS, but no treatment is available if it has entered in a severe stage of RLS. Relations to the lower cerebral ferric and Dopamine levels are probably reported as the cause for Restlessness like, although genetic biomarkers have been developed for the diagnosis of the disease. The core treatment of the disease is still under discovery. Early diagnosis of the disease can make difference in the first line treatment.

Keywords: Restless leg syndrome; Parkinsonism; Neuropathy; Preeclampsia; Dopamine antagonist; Ferric ion; Pregnancy; Periodic limb movement disorder (PLMD)


Restless legs syndrome (RLS) which is also known as wills Ekbom Disease (WED), Wittmaack Ekbom disease is complicated hardly diagnosed neurological disease which vary with symptoms and degree of morbidity [1]. As per the guidelines of National Institute of Neurological Disorders and Stroke (NINDS), Restless Legs Syndrome is a medical condition characterized by unpleasant sensations in the legs, including burning, tugging, and tightening, and feels like insects crawling inside the legs. British anatomist and physician, Thomas Willis in the 17th century stated the first clinical description of RLS and later on in 1945 Swedish neurologist Ekbom, characterized the neuropathological syndrome more specifically. Now a days with more based on research data it is considered as more organic brain disease than systemic brain neurodegenerative disorder based on dysfunction of the neurotransmitter system of dopamine and iron signaling in brain with a unknown genetic mutation which modulate the metabolism of iron with different degree in brain and substantial space. RLS is a neurological sleep associated sensory motor cognitive disorder that makes urge to move legs continuously [2,3]. It makes difficult to get sleep due to uncomfortable urge of moving legs. Sleep is disturbed due to unknown pathology in brain including lowering the Grey and white matter, fluctuated iron levels in brain which affects the dopamine levels in SN [4]. The symptoms gets worsen most at night and individual can’t sleep well [5]. Most of the time it gets difficult to explain about the restless legs event happened at night. Due to this REM and NREM cycle is disturbed and hence it affects most of the normal physiology of brain. Individual feel day time weakness, Body ache, depression like behavior, Sleep during day, irritability, Swings of mood, Confusion like symptoms and if there are presence of any associated systemic disease like kidney disease, anemia, respiratory disease like arthritis, blood disorder or metabolic disorder, pregnancy, epilepsy then it get worsen a lot and affects at highest degree of quality of life [6-8]. Research in Restless legs syndrome has been approached many a times with animal models but there is no significant model developed which mimic the same exact mechanism involved in it. So that further targeted research to understand the exact reason of RLS should get focused. There are mainly two types of RLS are defined up till yet, one is at the early stage of life before 45 and second is after 45 years of age which is more worsen progressively. Early or Primary RLS is very complicated and difficult to diagnose [9]. Primary RLS affects total quality of life progressively with no identified cause and mal diagnosed as growing pain in children that is why it is categorized as idiopathic more often [10]. The RLS is a complex neurological sleep disorder which involves many physiological symptoms which confuses with other pathophysiology like Parkinsonism more often hence misdiagnosed and mal treated more often [6].


RLS is hardly diagnosed as silent symptoms or confusing symptoms with many neurological and vascular diseases. Hence prevalence of RLS is reported very less worldwide. More often the reported prevalence is not sure to be the exact figure as it remains undiagnosed in many countries globally [11]. The prevalence of RLS is reported in India is about 2-5% and other Asian countries. There were no surveys done in India to measure the prevalence of RLS as it is neglected diagnosis most of the time. Although, few clinical trials and research studies have shown 1.5-6.6% in Indian population. In India its ratio was found to be more in males than female according to one study made in hospital. Usually a higher prevalence is found in females than in males, and increasing in frequency with older age worldwide studies. According to American data RLS affects 2.5-15% of American population. In comparison to Caucasian to African countries it is found more prominent in Caucasian with higher ratio in females and children comparison to male. As per data suggests it has shown 3% prevalence of RLS in Middle Eastern population [12,13].

Prevalence based on clinical trials and research done on RLS

According to the National Sleep Foundation Report in 1998, about 1/4th pregnant females develop Restless legs Syndrome in their 3rd trimester and disappears within the first month after delivery in most cases [11]. Most of the studies has shown 2:1 ratio among females in comparison of men. RLS is the most common neglected diagnosis during pregnancy in anemic conditions. In Ancient Research Based Clinical Studies of RLS had shown RLS like symptoms in 500 women at 33-34 weeks’ gestation and 4 weeks after delivery. Observed prevalence of RLS in those females was 19.5% which is more likely attentive than any other disease in women. Severity of RLS was, observed only in seven women and after four weeks of delivery, only 3 of them had had RLS symptoms with severity and sleep disturbances. IRLSSG criteria to assess RLS in pregnant women were defined already as diagnostic guidelines. Based on that Criteria 2 studies were conducted to assure the RLS symptoms in Pregnant Females. The first study was conducted in Italy a with 606 women at the time of delivery and second study was conducted in Brazil upon 524 women. Symptoms were assessed as double blind study using the IRLSSG criteria of 1995 for RLS. In that conclusion of Italian Female Study, 26.6% was found to be having RLS like symptoms and 62.7% of these women had never experienced RLS symptoms before pregnancy [14]. Prevalence was decreased up to 13% in pregnant women followed months. Few months later i.e. of 6 months only 7 Italian Females had reported to be have RLS like symptoms. Another study which was conducted in 524 Brazilian Females using the IRLSSG criteria of 2003 had shown 13.5% of prevalence in RLS and 94.4% were found to be affected in the 2nd or 3rd trimester with RLS like Symptoms. In that study, prevalence of RLS like symptoms or RLS was found to be 5.3%, 14.7% 15.2% in the first, second and third trimester respectively. From the study it was concluded and observed that the total prevalence or RLS like symptoms are found to be increasing by the progression of trimester in females during their pregnancy [15]. The results indicated that women who are having had primary or idiopathic RLS or RLS like symptoms during their pregnancy had a 4-fold increased risk of developing chronic RLS by the progression of pregnancy and life. Many Clinical trial studies have shown that there is increased risk of RLS developing with progression of age. In controversy, few studies have also reported rapid progression up to 70 years of age and then decreased or fixed stage of progression of RLS. Idiopathic RLS have shown rapid progression of disease up to 30-40 years of age in few clinical studies [16].

The Indian perspective

RLS is a neglected diagnosis in India [17]. Due to absence of literature based on research done on RLS the exact prevalence is unknown. Mostly, the laboratory diagnosis leads to the iron deficiency and pain like symptoms in pregnant women. Due to non identical stage, RLS is a neglected diagnosis among Neurophysician and Gynecologists. Most of the time silent RLS or RLS like symptoms just treated with multivitamins and iron supplements [18]. The prevalence of RLS has been reported to be 1.5-6.6% in patients of medical renal disease as compared to the healthy humans. The Ratio of iron deficiency affected RLS is little higher than any other associated systemic disease. Females are more prone to RLS as compared to the males in Indian population in hospital based studies [19-21].


Etiology or Causes of RLS depends upon various factors affected and classified accordingly. RLS if happen before 45 year or early stage of life can be primary (idiopathic) and after 45 years of age with any systemic disease called as secondary RLS. Individuals associated with iron-deficiency or anemia like conditions including pregnancy, renal failure, and anemia are more prone to develop Restless legs syndrome or like symptoms (Figure 1A). George Albert, et al. suggested that 34% of people who have iron deficiency or blood disorders have higher chances to develop RLS [22]. It is observed in Clinical surveys that if there is an association of systemic diseases with restless legs syndrome like Celiac disease, Auto Immune disease, Parkinson’s disease, Thyroid disease and other illness like folate deficiency, magnesium deficiency, fibromyalgia, sleep apnea, uremia, diabetes, peripheral neuropathies, periodic limb movement disorder, vein disease can worsen the symptoms of RLS which affects the quality of life more significantly [23]. If there is a dopamine dysfunction associated with neurological disease like ADHD can more worsen the stage of Restless legs syndrome [24-27]. Genetic Research focused on Genes showed the association of RLS and 5 Genes: MEIS1, BTBD9, MAP2K5, SKOR1, and PTPRD. PTPRD has shown strong correlation with Restless legs syndrome. Chromosome 6p21.2 which shows the expression of gene BTBD9 has implicated association of Restless legs syndrome, Periodic limb movements. There are many loci found associated with restless legs syndrome but there is no exact role identified of that loci associated with pathology [6].