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Keywords:

  • restless legs syndrome;
  • migraine;
  • prevalence

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Statement of Authorship
  7. References

Objective

While previous studies have investigated the prevalence of restless legs syndrome (RLS) in patients with migraine, we aimed to explore the prevalence and characteristics of migraine in adult patients diagnosed with RLS.

Backgrounds

The association of primary headaches, especially of migraine, with RLS has recently attracted much attention. Migraine prevalence was reported to be higher in patients with RLS than in the general population, and the role of dopamine was strengthened.

Methods

We evaluated 265 consecutive adult RLS patients (137 males and 128 females) followed up in a Sleep Disorders Unit and diagnosed according to criteria defined by the International Restless Legs Syndrome Study Group (IRLSSG). RLS characteristics, and the severity, were performed by using the IRLSSG severity scale. The diagnosis of headache subtypes was defined by the International Classification of Headache Disorders. Gender, age, age at RLS onset, duration of RLS, family history of RLS, family history of headache, presence of depression, any treatments given for RLS, and the change in headache following RLS treatment were questioned.

Results

The mean age of the study population was 50.4 ± 12.8 years, mean age at RLS onset was 41.6 ± 13.2 years, and mean disease duration was 8.40 ± 8.6 years. Of these, 163 patients had headache; 40 of them were diagnosed to have migraine-type headache (15.1%). The presence of migraine-type headache was 9.4% in males with RLS, and 21.1% in female RLS patients. In RLS patients with migraine, 67.5% were females, while 48.0% of RLS patients with other types of headache were females (P = .032), and only 41.2% of RLS patients without headache were females (P = .005). The severity of RLS was significantly higher in patients with migraine compared with those without headache (P < .001). The presence of depression, the family history of RLS, and headache were also higher in patients with migraine compared with RLS patients with other types of headache or those without headache. Thirty-six patients with headache reported partial or substantial benefit from RLS treatment.

Conclusions

Our results did not suggest higher rates of migraine-type headache in RLS patients when compared with population-based prevalence studies from Turkey. Alternatively, the severity of RLS was significantly higher in patients with migraine. Although the increase in these scores does not constitute a relationship etiopathogenetic, it suggests a correlation between the type cross-model nociceptive systems. Moreover, the family history of RLS was higher in patients with migraine. The prevalence of migraine in patients with RLS, however, waits to be better demonstrated.

Restless legs syndrome (RLS) is a common sleep-related movement disorder, characterized by unpleasant sensation in the legs, especially at rest and at bed time, which is relieved by voluntary movements.[2] The prevalence of RLS displays large differences across different populations, with rates ranging between 2% and 15% (approximately 5% in studies from Turkey).[3-7] RLS is more common in women than in men. The etiopathogenesis of RLS is mostly of idiopathic, although some secondary etiologies such as uremia, iron depletion, spinal disorders, rheumatoid arthritis, or polyneuropathy may also be present. Although the underlying pathophysiological mechanism of RLS has not yet reached a definite conclusion, functional abnormalities in the dopaminergic system and iron deficiency reflected by low serum ferritin levels are strongly suggested. RLS animal models where a dysfunction or atrophy of the dopaminergic A11 cell group was demonstrated in hypothalamus[8] explained the well response of RLS to dopaminergic drugs, as well as its circadian rhythm.

In recent years, the association of primary headaches, especially of migraine, with RLS has attracted much attention. Migraine is comorbid with a growing list of several medical, neurologic, psychiatric, and painful disorders. This comorbidity was interpreted as an association of 2 or more disorders occurring together, greater than chance alone.[10] Migraine prevalence rates were reported at 12% in a general population, while it was known to be more common in women (18%) than in men (6%).[9] Most previous studies have investigated the prevalence of RLS in patients with migraine and other types of primary headaches, and strengthened the role of dopamine in their pathogenesis.[11] In this study, we aimed to explore the prevalence and characteristics of migraine in adult patients diagnosed with RLS, the relationship between migraine and RLS characteristics, and to discuss possible pathophysiologic pathways in association of these disorders.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Statement of Authorship
  7. References

We evaluated 265 consecutive adult primary RLS patients diagnosed according to criteria defined by the International Restless Legs Syndrome Study Group (IRLSSG)[2] and followed up in our Sleep Disorders Unit between 2006 and 2011 at least once per year. We included patients only with a diagnosis of primary RLS, with the exclusion of any other causes of semptomatic RLS including uremia, diabetes, polyneuropathy, rheumatoid arthritis, and any other patients with abnormal findings on neurological examination or with accompanying neurological disorder. Physicians or a psychologist with a preformed questionnaire questioned all patients. RLS characteristics and the severity were performed by using the IRLSSG severity scale.[12] The presence and the characteristics of headache, if present, were documented in detail. The diagnosis of headache subtypes was defined by the International Classification of Headache Disorders (ICHD).[13] Although secondary types of headache were not included in this study, they were also questioned and grouped separately. The presence of depression was also evaluated in all patients and diagnosed on the basis of Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV TR criteria.[14] On the basis of these criteria, the questionnaire was filled in for each patient. Any patient with substance abuse, substance withdrawal, patients taking antipsychotics, or a history of overuse of opiate analgesics were not included into the study. The study was approved by local ethical committee.

Gender, age, disease duration of RLS and headache, past medical history, family history of RLS and headache, presence of depression, any treatments given for RLS and headache, and the change in headache following RLS treatment were questioned and analyzed separately in this 2 groups. The benefit from RLS treatment in terms of headache was interrogated during which no change in headache treatment was made; this question was excluded if there is any change in headache treatment while the patient is under RLS treatment.

Statistical analysis was performed by SPSS v 11.5 program for Windows (Statistical Package for Social Sciences, Chicago, IL, USA). Data were given in mean ± standard deviation or percentiles. Statistical analysis was performed by chi-square test for nominal variables, and by non-parametric Mann–Whitney U-test for ordinal variables. The threshold level for significance was set at a P value equal to or less than .05.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Statement of Authorship
  7. References

Out of 265 consecutive patients with RLS, 137 patients (51.7%) were males, and 128 patients (48.3%) were females. The mean age of the study population was 50.4 ± 12.8 years (ranging between 15 and 83 years). The mean age at RLS onset was 41.6 ± 13.2 (ranging between 6 and 75 years) years, and the mean disease duration was 8.40 ± 8.6 years. The mean scores of the IRLSSG scale was found as 19.7 ± 8.0 points (between 4 and 37 points). The family history of RLS was present in 162 patients (61.1%). Depression was detected in 83 of 265 patients (31.3%) with RLS.

RLS treatment was given to 154 patients (58.1%). Of these, 58 patients (37.7%) were on dopamine-3 receptor agonist drugs, 43 patients (27.9%) were on gabapentin or pregabalin treatment, and the remaining patients were on other treatments such as levodopa (3.2%), iron supplementation, or on irregular drug intake as needed. Remaining 111 patients were not given RLS treatment because of infrequent or mild symptomatology.

Questioning of headache according to ICHD-II classification revealed that 163 patients (61.5%) had headache. Of these, 40 patients were diagnosed to have migraine-type headache (40/265 patients, 15.1%). The presence of migraine-type headache in males with RLS was 9.4% (13/137 patients), while in female RLS patients, migraine was present in 21.1% (27/128 patients). The investigation of migraine subtypes revealed that only 5 patients (4 females and 1 male) had migraine with aura, while all others had migraine without aura. The other types of headache are given in Table 1. Seventy-five patients were on treatment for headache (75/163 patients, 46.0%). Only 11 of these patients (11/75 patients, 14.6%) had regular prophylactic treatments (including selective serotonin reuptake inhibitors and serotonin and noradrenalin reuptake inhibitors), while the remaining patients were on acute treatment in need (less than 4 times in a month) with non-steroidal anti-inflammatory agents (74.7%) and selective 5-hydroxy tryptophan agonists (4%).

Table 1. Types of Headache in Patients With RLS in Accordance With ICHD-II Classification
Headache TypesAll Patients (N = 265)
n%
  1. a

    Headaches secondary to obstructive sleep apnea, hypertension, cerebrovascular disease, and Arnold-Chiari malformation.

  2. ICHD = International Classification of Headache Disorders; RLS = restless legs syndrome.

Migraine-type headache4015.1
Tension-type headache6624.9
Secondary headachea3814.3
Undetermined197.1

The demographic and clinical data in RLS patients with or without migraine headache were analyzed (Table 2). In RLS patients with migraine, 67.5% were females while 48.0% of RLS patients with other types of headache were females (P = .032), and only 41.2% of RLS patients without headache were females (P = .005). The mean age and age at disease onset were higher in patients with migraine compared with the other 2 groups, but not significant. The mean scores of the IRLSSG scale were significantly higher in RLS patients with migraine when compared with those without headache (23.8 ± 7.5 vs 16.0 ± 6.5, P < .001). The presence of depression, family history of RLS, and headache were higher in patients with migraine compared with the other 2 groups, being statistically significant between RLS patients with migraine and those without headache (Table 2). The evaluation of change in headache following RLS treatment revealed that headache was resolved in 31 patients (35.2%); 9 of these patients had migraine. In addition, 5 patients (5.7%) had partial benefit from RLS treatment regardless of headache treatment, and 3 of them had migraine. A total of 12 patients with migraine (30%) had benefit (total or partial) from RLS treatment. The remaining 52 patients (59.1%) reported no change in their headache frequency and/or severity following RLS treatment. The change in headache parameters was not different among headache types and between early- or late-onset RLS patients. The analysis of drugs given for RLS revealed that dopamine-3 receptor agonists, gabapentin, or pregabalin were the more commonly used treatments in headache patients with partial or total benefit (38.9% and 41.7%, respectively) compared with those without any benefit (23.1% for each); this difference did not reach to a statistically significant level (P = .324).

Table 2. Comparison Clinical Data of RLS Patients With or Without Migraine
ParametersRLS Patients With Migraine n = 40RLS Patients With Other Types of Headache n = 123RLS Patients Without Headache n = 102P Value
  1. Bold P values indicate the statistical significance.

  2. a

    P values between RLS patients with migraine and other types of headache.

  3. b

    P values between RLS patients with migraine and those without headache.

  4. IRLSSG = International Restless Legs Syndrome Study Group; RLS = restless legs syndrome; SD = standard deviation.

Gender (M/F, %)32.5/67.552.0/48.058.8/41.2

.032a

.005b

Age (mean ± SD)53.6 ± 10.749.7 ± 12.650.5 ± 12.9

.195a

.310b

Age at disease onset (mean ± SD)45.6 ± 11.740.3 ± 13.841.8 ± 12.7

.065a

.156b

Early-onset vs late-onset RLS (%)42.5/57.556.9/43.151.0/49.0

.114a

.365b

IRLSSG scale points (mean ± SD)23.8 ± 7.521.0 ± 8.116.0 ± 6.5

.072a

<.001b

Depression (%)45.738.822.2

.466a

.008b

Family history of RLS (%)48.632.827.3

.089a

.024b

Family history of headache (%)56.442.319.6

.124a

<.001b

We divided our study population into 2 groups as (1) early-onset (<45 years old) and (2) late-onset (≥45 years old) RLS patients. In the first group with early onset, migraine was present in 8.6% of patients, while in the second group with late onset, 16.7% of patients were diagnosed to have migraine (P = .503). All other parameters analyzed in our study were also compared separately in RLS patients with early- or late-onset disease, but none of them showed statistically significant difference.

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Statement of Authorship
  7. References

In this study, we investigated the comorbidity of headache, particularly migraine, in 265 consecutive patients with RLS. Upon questioning for the occurrence of headache according to ICHD-II classification, we found that 163 patients (61.5%) had headache, and 40 patients of them were diagnosed to have migraine-type headache (15.1%), with higher prevalence in female RLS patients (21.1%). Female preponderance in RLS patients with migraine showed significant difference when compared with RLS patients with other types of headache or those without headache. The prevalence of migraine-type headache was reported to vary between 7% and 14% in many studies,[15-18] although higher rates of migraine were also reported in women in a recent study from Turkey.[19] Only 1 recent study, by Gupta et al[20] investigating 99 patients with RLS, showed that 22.8% of this particular group had migraine-type headache. Our results did not support higher rates of migraine-type headache in RLS patients when compared with population-based prevalence studies from Turkey. On the other hand, the mean scores of the IRLSSG scale was significantly higher in RLS patients with migraine when compared with those without headache. Moreover, the family history of RLS was also higher in patients with migraine. Age of RLS onset, however, was no different in migrainous or non-migrainous patients, or other RLS patients without headache. Our study showed no increase in the prevalence of migraine in the RLS group but an increase in intensity score on the IRLSSG scale. Although the increase in these scores does not constitute a relationship etiopathogenetic, it suggests a correlation between the type crossmodel nociceptive systems.

The association of migraine-type headache and RLS has recently attracted attention in the literature with several studies investigating the prevalence of RLS in migraine patients.[22] The first report regarding comorbidity of RLS and headache was published in 2003 by Young et al,[21] who found a higher prevalence of RLS in a cohort of 50 patients with headache. The authors proposed that RLS should be added to the list of comorbid disorders associated with migraine. Subsequently, Rhode et al[11] performed a case–control study in 411 migraine patients with sex- and age-matched control subjects, and demonstrated a significantly higher RLS frequency in migraine patients. The authors also observed that depression was more frequent but not significant in migraine patients with RLS, which was also shown in our study. An observational study by D'Onofrio et al[10] also showed significantly higher RLS frequency in headache patients. Another study investigating the frequency of RLS in different primary headache disorders and its impact and clinical correlates in 772 migraine patients revealed that the frequency of RLS was higher in patients with migraine and associated with a poorer sleep quality.[22]

There have been some hypotheses to explain this newly recognized comorbidity.[23] First, these 2 common disorders may coincidentally be observed becase of subject ascertainment. Another explanation could be the presence of shared environmental or genetic risk factors that ground for the co-occurrence of these 2 disorders. In addition, independent genetic or environmental risk factors could also provoke both conditions. The A11 dopaminergic nucleus of the dorsal-posterior hypothalamus has recently been shown to play a crucial role in the pathophysiology of RLS in animal models.[8] Animal studies have also shown that lesioning the A11 nucleus facilitates trigeminovascular nociception.[24] These findings together suggest a shared dopaminergic dysfunction in A11 nucleus as a neuroanatomical substrate linking migraine and RLS, which could explain higher RLS frequency in migraine-type headache patients. The prevalence of migraine in patients with RLS, however, waits to be better demonstrated.

Some limitations of our study should also be addressed. First of all, the study population is small, although we used strict inclusion criteria with a requirement of at least a 1-year follow-up duration, excluding any other secondary causes that might trigger or exacerbate RLS. This is because we aimed to document the effect of RLS treatment on headache symptomatology with the RLS severity scale, but we did not observe a significant change. Another limitation with our study is that it is a hospital-based study conducted in a tertiary center in Istanbul, Turkey, which might have resulted in a bias selection of severe and/or complicated cases, making it difficult to generalize the data and compare with community-based epidemiologic studies. Population-based studies with a larger sample size should therefore be performed to better investigate the etiopathogenetic association between RLS and migraine.

Statement of Authorship

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Statement of Authorship
  7. References

Category 1

  • (a)
    Conception and Design
    Derya Karadeniz, Baki Goksan
  • (b)
    Acquisition of Data
    Gokcen Gozubatik-Celik, Gulcin Benbir, Funda Tan
  • (c)
    Analysis and Interpretation of Data
    Gulcin Benbir, Derya Karadeniz, Baki Goksan

Category 2

  • (a)
    Drafting the Manuscript
    Gokcen Gozubatik-Celik, Gulcin Benbir
  • (b)
    Revising It for Intellectual Content
    Derya Karadeniz, Baki Goksan

Category 3

  • (a)
    Final Approval of the Completed Manuscript
    Gokcen Gozubatik-Celik

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Statement of Authorship
  7. References
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