Table 1
Summary of studies examining vitamin D levels and restless legs syndrome.
| VITAMIN D LEVELS IN PEOPLE WITH RLS | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| AUTHOR YEAR | STUDY TYPE | POPULATION | CRITERIA FOR VITAMIN D DEFICIENCY | GROUPS | DIAGNOSTIC/ELIGIBILITY CRITERIA FOR RLS | RLS DIAGNOSIS METHOD | SAMPLE SIZE | N (%) VITAMIN D DEFICIENT | VITAMIN D LEVELS (NG/ML) | NOTES |
| Wali 2018 [8] | Case-Control | Healthy Adults | <50 nmol/L (<20 ng/mL) | All RLS | 2014 IRLSSG [116] | Study-specific questionnaire for diagnostic criteria and associated mimics [116] along with neurological examination of lower limbs | 78 | 59 (75.6%) | 12.7 ± 7.0 | Secondary analysis controlled for comorbid/clinical conditions |
| Primary RLS | 50 | 37 (74.0%) | Not reported | |||||||
| Secondary RLS | 28 | 6 (21.4%) | Not reported | |||||||
| Controls | Age- and sex-matched at frequency of 2:1 control:RLS ratio | 123 | 52 (42.3%) | 26.1 ± 9.9 | ||||||
| Jiménez-Jiménez 2021 [16] | Case-Control | Healthy Adults | N/A | RLS | 2014 IRLSSG [116] | Clinical interview in most participants; excluded secondary causes of RLS; excluded conditions: liver, kidney, thyroid and parathyroid diseases, and obesity | 285 | N/A | 21.9 ± 9.7 | Excluded participants with known vitamin D deficiency |
| Controls | Age- and sex-matched | 325 | N/A | 18.6 ± 9.8 | ||||||
| Liu 2021 [15] | Case-Control | Healthy Adults | <50 nmol/L (<20 ng/mL) | All RLS | 2014 IRLSSG [116] | Physician interview; excluded secondary causes of RLS, other sleep disorders, diseases that affect vitamin D levels, people taking medications that affect vitamin D levels or drugs that alleviate RLS, and pregnant/lactating women | 57 | 46 (81%) | 16.1 ± 5.4 | |
| Mild-Moderate RLS | 36 | Not reported | 17.3 ± 5.4 | |||||||
| Severe RLS | 21 | Not reported | 14.0 ± 4.9 | |||||||
| Controls | Age- and sex-matched | 57 | 1 (2%) | 27.0 ± 5.0 | ||||||
| Balaban 2012 [17] | Case-Control | Healthy Adults | N/A | RLS Females | 1995 IRLSSG [117] | Clinical interview; no comorbidities and normal neurological examination; excluded known causes of secondary RLS, a familial history of RLS, or any medical conditions that would affect the assessment of RLS | 28 | Not reported | 7.3 ± 4.6 | |
| RLS Males | 8 | Not reported | 11.4 ± 6.2 | |||||||
| Control Females | Age- and sex-matched | 27 | Not reported | 12.3 ± 5.3 | ||||||
| Control Males | 11 | Not reported | 13.0 ± 5.4 | |||||||
| Almeneessier 2020a [19] | Case-Control | Pregnant Women | Normal: Insufficient: | Pregnant RLS | 2014 IRLSSG [116] | Clinical interview by trained medical students; excluded conditions that could mimic RLS | 223 | 47 (21.0%) | Not reported | |
| Pregnant Control | N/A | N/A | 519 | 66 (12.7%) | Not reported | |||||
| Miyazaki 2023 [20] | Case-Control | Pregnant Women | <10 ng/mL and <20 ng/mL | Pregnant RLS | ICSD 3rd [118] | Clinical Phone Interview with Japanese version of CH-RLSq13 [119] | 35 | LC-MS/MS <10: 12 (34.3%) LC-MS/MS <20: 33 (94.3%) | LC-MS/MS: 11.4 (7.0) | Serum 25(OH)D levels reported as median (IQR) Two different methods of quantifying levels: LC-MS/MS and CLEIA |
| CLEIA <10: 24 (68.6%) CLEIA <20: 25 (100%) | CLEIA: 7.2 (6.1) | |||||||||
| Pregnant Controls | N/A | N/A | 168 | LC-MS/MS <10: 24 (14.3%) LC-MS/MS <20: 129 (76.8%) | LC-MS/MS: 15.4 (8.1) | |||||
| CLEIA <10: 25 (50.6%) CLEIA <20: 158 (94.0%) | CLEIA: 9.8 (6.3) | |||||||||
| Almeneessier 2020b [21] | Case-Control | Non-pregnant Women | < 25 nmol/L | Non-pregnant RLS | 2014 IRLSSG [116] | Clinical interview by trained professionals; excluded comorbid conditions that could mimic RLS and other sleep disorders | 271 | 173 (63.8%) | Not reported | |
| Non-pregnant Control | N/A | N/A | 865 | 390 (45.1%) | Not reported | |||||
| Bener 2019 [22] | Case-Control | Type II Diabetes Mellitus (T2DM) | Deficient: <20 ng/mL Insufficient: 20-29 ng/mL Sufficient: >30 ng/mL | T2DM RLS | Not reported | Not reported | 199 | Deficient: 122 (61.3%) Insufficient: 43 (21.6%) Sufficient: 34 (17.1%) | 7.7 ± 3.6 | |
| T2DM No RLS | N/A | N/A | 672 | Deficient: 289 (43.0%) Insufficient: 214 (31.8%) Sufficient: 169 (25.1%) | 8.7 ± 3.8 | |||||
| Evans 2018 [25] | Case-Control | Healthy Pediatric (3-12 years) | Deficient: <10 ng/mL Insufficient: 11-30 ng/mL Normal: 31-75 ng/mL | RLS | “Yes” to relief from movement | Leg pain questionnaire [120] | 12 | Deficient: 5 (41.7%) Insufficient: 4 (33.3%) Normal: 3 (25.0%) | 15.3 (5.3–61.8) | Vitamin D levels presented as median (minimum-maximum) |
| GP | “Yes” to questions 1-5 | 28 | Deficient: 4 (14.3%) Insufficient: 20 (71.4%) Normal: 4 (14.3%) | 19.7 (4.2–59.3) | ||||||
| GP+RLS | “Yes” to questions 1-5 and 9 | 37 | Deficient: 10 (27.0%) Insufficient: 24 (64.9%) Normal: 3 (8.1%) | 12.8 (4.5–60.7) | ||||||
| Controls | Age- and gender-matched | 13 | Deficient: 4 (30.8%) Insufficient: 7 (53.8%) Normal: 2 (15.4%) | 15.6 (7.9–61.8) | ||||||
| Işıkay 2018 [27] | Case-Control | Pediatrics (11–18 years) with Celiac Disease | N/A | Celiac RLS | IRLSSG criteria (version not specified) | Questionnaire – questions/methods otherwise not specified | 8 | N/A | 9.9 ± 4.7 | “No patient previously diagnosed with RLS was included in or excluded from the study” RLS severity was negatively associated with serum vitamin D levels |
| Celiac no RLS | 218 | N/A | 12.5 ± 11.7 | |||||||
| RLS IN PEOPLE WITH VITAMIN D DEFICIENCY | ||||||||||
| AUTHOR YEAR | STUDY TYPE | POPULATION | VITAMIN D STATUS | GROUPS | DIAGNOSTIC/ELIGIBILITY CRITERIA FOR RLS | RLS DIAGNOSIS METHOD | SAMPLE SIZE (N) | N (%) RLS | VITAMIN D LEVELS (NG/ML) | NOTES |
| Çakır 2015 [28] | Case-Control | Healthy Adults | <20 ng/mL | VDD | 2003 IRLSSG 4 criteria [29] | Survey (method not specified); excluded diabetes, vitamin B12 deficiency, chronic renal failure, anemia, and use of any medications that could mimic RLS | 57 | 30 (52.6%) | N/A | |
| >20 ng/mL | Controls | 45 | 17 (37.7%) | N/A | ||||||
| Oran 2014 [10] | Case-Control | Healthy Adults | <20 ng/mL | VDD | 2003 IRLSSG 4 criteria [29] | Neurologist Evaluation; excluded abnormal levels of ferritin or with a known condition to cause secondary RLS and people with a family history of RLS (among others) | 119 | 60 (50.4%) | 11.2 ± 4.7 | |
| >20 ng/mL | Controls | 36 | 6 (16.7%) | 34.2 ± 10.0 | ||||||
| Olama 2013 [23] | Case-Control | Premenopausal women with primary fibromyalgia syndrome (PFMS) | ≤20 ng/mL | PFMS VDD | 2003 IRLSSG 4 criteria [29] | Clinical evaluation; Jenkins’ Sleep Questionnaire [121]; excluded inflammatory rheumatic disease, known osteoporosis, treated with antiresorptive drugs, renal disease, hepatic disease, malabsorption disorder, anticonvulsant therapy, malignancy and pregnancy | 28 | 16 (57.1%) | Not reported | |
| >20 ng/mL | PFMS Controls | 22 | 6 (27.3%) | Not reported | ||||||
[i] Note: RLS restless legs syndrome; IRLSSG International Restless Legs Syndrome Study Group; N/A not applicable; ICSD International Classification of Sleep Disorders; CH-RLSq13 Cambridge-Hopkins Restless Legs Syndrome Short Form Diagnostic Questionnaire; LC-MS/MS liquid chromatography–tandem mass spectrometry; CLEIA chemiluminescent enzyme immunoassay; IQR interquartile range; T2DM type II diabetes mellitus; GP growing pains; VDD vitamin D deficiency; PFMS primary fibromyalgia syndrome.
Table 2
Summary of studies examining the effect of vitamin D supplementation on symptoms of Restless Legs Syndrome.
| FIRST AUTHOR, YEAR (CITATION) | POPULATION | STUDY TYPE | SAMPLE SIZE | DOSAGE | DURATION | CONTROL CONDITION | OUTCOME |
|---|---|---|---|---|---|---|---|
| Wali, 2019 [32] | RLS with normal vitamin D levels | Randomized Double-blind Placebo-controlled Trial | 35 (17 vitamin D group; 18 placebo group) 22 completed study (12 vitamin D; 10 placebo) | 50,000 IU orally weekly | 12 weeks | Placebo (orally) | No significant change in RLS severity from baseline (IRLS = 14.6) to follow up (IRLS = 14.5) in the vitamin D group (p = 0.540) |
| Buratti, 2017 [33] | Turner syndrome and RLS with vitamin D deficiency | Case Study | 1 | Not Specified | 6 months | N/A | Normal vitamin D levels achieved and complete recovery in RLS symptoms after 6 months |
| Wali, 2015 [34] | Primary RLS with vitamin D deficiency | Longitudinal Study | 12 | 28,000 IU oral dose/week or 200,000 IU intramuscular injection/month with 400 IU daily maintenance dose | Continued until vitamin D levels corrected (range: 3 to 8 months) | N/A | RLS severity improved from baseline (IRLS = 26) to when the vitamin D levels were corrected (IRLS = 10; p = 0.002) |
| Tutunca, 2019 [35] | Idiopathic RLS with vitamin D deficiency | Longitudinal Study | 21 (19 included in analyses) | 50,000 IU/week | 2 months | N/A | Vitamin D levels increased (13.2 to 42.8 ng/mL) and RLS severity improved (IRLS = 24.9 to IRLS = 21.1; p < 0.001). |
[i] Note: RLS restless legs syndrome; IU international units; IRLS International Restless Legs Syndrome Severity Score.
Figure 1
Hypothetical influences on the interaction between vitamin D and restless legs syndrome.