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The relationship between disease symptoms and restless legs syndrome in adult attention-deficit hyperactivity disorder without iron deficiency
Middle East Current Psychiatry volume 29, Article number: 59 (2022)
This study aimed to investigate the frequency of restless legs syndrome (RLS) and the affecting factors in the attention-deficit hyperactivity disorder (ADHD) group without iron deficiency. Drug-naive ADHD patients were included in the study. Patients without iron deficiency filled out the adult ADHD Self Reporting Scale, the Wender Utah Rating Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory. Scale scores were compared in ADHD patients with and without RLS. Univariate and multivariate binary logistic regression analyses were used to determine the risk factors associated with RLS.
A total of 120 ADHD patients participated in the study; 53 were predominantly inattentive ADHD patients (ADHD-I), and 67 were ADHD combined type (ADHD-C). RLS incidence was found to be 31.6%. ADHD symptoms, anxiety, and depression were found to be significantly more severe in patients with ADHD accompanying RLS. Also, anxiety and the presence of ADHD predicted RLS.
The presence of ADHD and accompanying anxiety was effective on RLS, regardless of iron deficiency. RLS is a comorbidity that frequently accompanies ADHD, and its diagnosis and treatment should not be ignored. This is the first study to investigate the frequency of RLS and accompanying factors by excluding iron deficiency in the ADHD group.
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that begins in childhood or adolescence and can extend into adulthood, characterized by signs of inattention, increased mobility, and impulsivity . Its frequency in school-age children is determined to be between 5 and 8%. A total of 60–85% of the cases diagnosed in childhood continue to meet the diagnostic criteria in adolescence. The prevalence of ADHD in adults is estimated to be around 2–4% [2, 3]. This disease often causes impairment in social and interpersonal relationships, emotion regulation, and academic functionality . Genetic and neuroimaging studies show that ADHD has a biological origin. The neurotransmitter most associated with ADHD symptoms is dopamine .
ADHD often occurs with sleep disorders such as restless legs syndrome (RLS), sleep apnea, and insomnia . RLS is a neurological sensorimotor disorder characterized by an irresistible inner urge to move the legs and by sensory discomfort in the lower legs . Previous studies have shown that there is a relationship between RLS and ADHD, which are neuropsychiatric disorders, whose etiology has not been elucidated yet. Several theories have been proposed on this issue. The dopaminergic system caused by iron deficiency in the central nervous system is thought to play a role in the pathophysiology of RLS, as in ADHD . Iron is a cofactor for tyrosine hydroxylase that is needed to convert tyrosine into levodopa, a precursor to dopamine. Dopaminergic medication is used in the treatment of both ADHD and RLS. Treatment of both diseases through the dopaminergic system may indicate a similar underlying etiological cause. Furthermore, it is well known that disorders that cause sleep problems can lead to or contribute to behavioral problems related to mood and inattention . Therefore, it is possible that RLS may cause ADHD or ADHD-like symptoms. Moreover, a case-control study showed that a high proportion of children with ADHD suffered from a periodic limb movement disorder (10.2%), while no children in the control group suffered from such a disorder . Studies have reported that RLS patients are more likely to experience impaired cognitive function and psychosocial distress, including problems with social activities, family life, and professional life, due to fatigue after sleep interruptions, as with ADHD . While RLS can be seen alone, it can also occur with certain diseases such as peripheral polyneuropathy, diabetes mellitus, kidney failure, Parkinson’s disease, or with the use of certain drugs such as antiepileptics, antidepressants, and dopamine agonists. Also, like RLS, ADHD has been associated with other neuropsychiatric disorders such as depression and migraine [11, 12].
In our study, we excluded the iron deficiency confounding factor, which significantly affects RLS. The aim of the study is to compare the prevalence of RLS in the newly diagnosed drug-naive ADHD group and to evaluate its relationship with ADHD subtypes without iron deficiency.
The study was carried out in the Hitit University Erol Olçok Training and Research Hospital, Department of Psychiatry. This prospective study was approved by the Hitit University Clinical Research Ethics Committee.
The study sample consisted of 120 drug-naive adult ADHD individuals. The criteria to be included in the study were being over 18 years of age, under 65 years of age, and literate, agreeing to participate in the study, and meeting the criteria for adult ADHD diagnosis for the patient group. In the patient group, those with other disorders that could cause secondary restless leg syndrome, such as iron deficiency, anemia, kidney dysfunction, diabetes mellitus, multiple sclerosis, rheumatological diseases, hypertension, any metabolic disease, epilepsy, stroke, and malignant diseases, were excluded from the study. In order to exclude iron deficiency and anemia, we included those with a ferritin level of 30 ng/mL and above, a hemoglobin value of 12 g/dl and above in women, and 13 g/dl and above in men, according to complete blood count values. Also, the study excluded those with psychotic disorder/mood disorder with psychotic characteristics, mental retardation, alcohol, and substance use disorder, and those using antipsychotic drugs and stimulants.
After the subjects who met the inclusion criteria were informed about the research, those who accepted to participate in the study signed the Informed Volunteer Consent Form. Then, a diagnostic interview for attention-deficit/hyperactivity disorder (DIVA) was applied to the patient group by the researcher in the study. The age of onset of the disease and the number of symptoms were determined according to the DSM-5 diagnostic criteria. ADHD subgroups were determined according to DIVA. Adult ADHD patients were divided into two as predominantly inattentive ADHD type (ADHD-I) and the combined type, in which hyperactivity, impulsivity, and attention deficiency co-exist (ADHD-C). Other psychiatric disorders were screened through the DSM-5 Structured Clinical Interview (SCID-5) in the patient group. The cases were diagnosed by the researcher-physician through a clinical interview. The adult ADHD groups completed a sociodemographic data form, the Wender Utah Rating Scale (WURS, the short form with 25 items), the Adult ADHD Self-Report Scale Symptom Checklist (ASRS), the Beck Depression Inventory (BDI), and the Beck Anxiety Inventory (BAI). Then, RLS diagnostic criteria were questioned for each patient. The RLS severity scale was used for patients meeting the RLS diagnostic criteria.
The sociodemographic data form
The sociodemographic data form, prepared by the researchers, questioned the demographic details and alcohol and substance use by the participants.
Structured Clinical Diagnostic Interview (SCID-5)
SCID is a semi-structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders — Fifth Edition (DSM-5) diagnoses developed by First 2015 . Turkish validity and reliability studies were conducted by Elbir et al. .
Diagnostic interview for ADHD in adults (DIVA)
The DIVA is a semi-structured diagnostic interview based on the DSM-IV diagnostic criteria for adult ADHD . It was translated to the Turkish language by Mukaddes et al. . It consists of three parts, each of which is applied to childhood and adulthood: (1) criteria for attention deficit (A), (2) criteria for hyperactivity/impulsivity (HI), and (3) dysfunction caused by symptoms. For diagnosis, there should be at least two of the functional areas and at least moderate impairment. For the A and HI symptom groups, the criteria in childhood and adulthood are collected separately. If a sufficient number of criteria are met, ADHD is diagnosed, and the predominant clinical picture in the last 6 months is stated.
Adult ADHD Self-Report Scale (ASRS)
The ASRS was developed by the World Health Organization (WHO) to screen adults for ADHD symptoms. The scale consisting of eighteen items is scored between 1 and 4 Likert type . It has two subscales, as attention deficit and hyperactivity/impulsiveness. The validity and reliability of the ASRS in the Turkish language were determined by Doğan et al. .
Wender Utah Rating Scale-25 (WURS)
This scale developed by Ward and Wender  evaluates the presence and severity of childhood ADHD symptoms in adults. The Turkish validity and reliability study was conducted by Öncü et al. . The WURS is a 5-point Likert type self-report scale consisting of 25 items. Each item is scored between 0 and 4, and the cutoff score of the scale is 36. When the cutoff point is 36 and above, sensitivity was 82.5%, and specificity was 90.8% .
Beck Depression Inventory (BDI)
The BDI is a self-evaluation scale of 21 questions, which was developed to measure somatic, emotional, cognitive, motivational, and psychomotor symptoms observed in depression and the level and change in severity of depressive symptoms . Validity and reliability studies have been made on the Turkish form of the scale . The scoring of each item is from 0 to 3 points, and a total score is obtained.
Beck Anxiety Inventory (BAI)
The BAI is a self-evaluation scale of 21 questions each one scored from 0 to 3, which was developed by Beck et al. . Adaptation to Turkish was made by Ulusoy et al. . It is used to determine the level of anxiety and distribution and severity of symptoms. High total points indicate a high level of anxiety.
Assessment of RLS
The diagnosis of RLS is mainly based on clinical history. The 2012 revised International Restless Legs Syndrome Study Group diagnostic criteria (2012 revised IRLSSG diagnostic criteria) were used by the interviewer for the diagnosis of RLS . Five diagnostic criteria focused on the characteristic features of RLS. Patients who meet all criteria are diagnosed with RLS. These are as follows:
The need to move the legs due to or with uncomfortable or unpleasant sensations in the legs
The need for movement or uncomfortable sensations begin or worsen at rest.
The need for movement or uncomfortable sensations are partially or totally relieved by movements such as walking or stretching.
The need for movement or uncomfortable sensations worsen during the day, in the evening, or at night or occur only in the evening or at night.
The features listed above cannot be considered solely in relation to primary symptoms or other medical or behavioral conditions (e.g., myalgia, venous stasis, leg edema, leg cramps, habitual foot shaking) .
Evaluation of RLS severity
This scale is used to numerically determine the most disturbing symptom and the severity of the disease in RLS. Developed by the International HBS Working Group in 2003, disease severity scale is considered the gold standard. It consists of 10 questions, each graded from 0 to 4. While the first 5 questions are about the severity of the symptoms, the last 5 questions are about the effects of RLS on activities of daily living or quality of life. The score obtained in total reflects the severity of the disease. The maximum score is 40, with 1–10 as mild, 11–20 as moderate, 21–30 as severe, and 31–40 as very severe disease .
Statistical analyses were performed using SPSS (Version 22.0, SPSS Inc., Chicago, IL, USA, Hitit University Licensed) package program. Descriptive statistics were presented as mean ± standard deviation and median (min-max) and categorical data as number and percentage (%) in accordance with the data distribution. The distribution of normality was analyzed using Kolmogorov-Smirnov and Shapiro-Wilk tests. In comparing the means of two independent samples for continuous variables, the T-test was used for normally distributed data, and the Mann-Whitney U-test was used for non-normally distributed data. In proportion comparisons between categorical variables, the chi-square (chi-square) test or the Fisher’s exact test was used depending on the sample size of the cells in the crosstab. Relationships between numerical variables were analyzed with the Spearman correlation coefficient for non-normally distributed data. Univariate and multivariate binary logistic regression analyses were used to determine the risk factors associated with RLS. Odds ratio (OR) and their 95% CIs calculated for each parameter were found to be statistically significant in logistic regression analysis. Statistical significance was evaluated at p < 0.05.
In the study, there were a total of 120 patients with ADHD, 53 of whom were predominantly inattentive ADHD patients, and 67 were the combined type ADHD patients. There was not a statistically significant age difference between the ADHD groups (p = 0.162). Gender, marital status, education level, psychiatric disorders comorbidity, WURS, BDI, and BAI scale scores were statistically similar between the ADHD groups (p = 0.336, p = 1000, p = 0.070, p = 0.853, p = 0.089, p = 0.324, p = 0.106). It was determined that 35 (29.1%) of 120 patients with ADHD had another psychiatric disorder, whose symptoms were not included in the exclusion criteria according to SCID-5. The comorbidities were classified as follows: 16 cases of depression, four cases of specific phobia (SP), two cases of generalized anxiety disorder (GAD), five cases of unspecified anxiety disorder, two cases of obsessive-compulsive disorder (OCD), four cases of panic disorder (PD), and two cases of post-traumatic stress disorder (PTSD). RLS and ASRS were statistically significantly different between the ADHD groups (p = 0.002, p < 0.001). RLS accompanied 31.6% of ADHD cases; 23.7% of the patients with restless legs were in the ADHD-I group and 76.3% in the ADHD-C group (Table 1).
Comparisons of demographic characteristics, ADHD subgroups, comorbidity of depression and/or anxiety disorder, ASRS, WURS, BDI, and BAI scale scores between the ADHD patients with and without RLS are presented in Table 2. Age, gender, marital status, education level, and comorbidity were statistically similar among those with RLS (p = 0.648, p = 0.804, p = 0.499, p = 0.154, p = 0.091). However, ADHD subgroups, ASRS, WURS, BDI, and BAI scale scores showed statistically significant differences in ADHD patients with RLS compared to those without RLS (p = 0.002, p = 0.001, p < 0.001, p = 0.001, p < 0.001; Table 1).
The relationship between RLS severity and ASRS, WURS, BAI, and BDI in the ADHD group is presented in Table 3. A weakly positive statistically significant correlation was found between the severity of RLS and WURS (p = 0.047, Table 3, Fig. 1).
Univariate and multivariate binary logistic regression analyses were performed to determine the effective risk factors and odds rates in the presence of RLS, and the results are presented in Table 4. The variables of ADHD, ASRS, WURS, BDI, and BAI (p = 0.003, p = 0.001, p = 0.001, p = 0.002, p < 0.001; Table 4), which were statistically significant in the univariate model, were included in the multivariate model. In the univariate model, non-statistically significant gender, marital status, education level, comorbidity, and age (p = 0.804, p = 0.324, p = 0.156, p = 0.094, p = 0.516) were not included in the multivariate model. The variables ASRS (p = 0.481), WURS (p = 0.254), and BDI (p = 0.841), which were significant in the univariate model but were not significant in the multivariate model, were also not included in the final model. The latest model established with ADHD and BAI, which was significant in the multivariate model, is presented in Table 4.
According to the results of the multivariate model, the possibility of having RLS was 3.191 (CI: 1.260–8.084) times higher in the ADHD-C group than in the ADHD-I group (p = 0.014). Increasing the anxiety scale (BAI) score by 1 unit increased the likelihood of RLS by 1.084 (CI: 1.041–1.129) times (p < 0.001).
In this study, the frequency of RLS and the factors affecting the presence of RLS in ADHD groups were investigated in detail, excluding the causes related to iron metabolism. We found the prevalence of RLS to be 31.6% in the group consisting of 120 drug-naive ADHD patients. Also, 43.3% of RLS cases were in the ADHD-C group, and 17.7% were in the ADHD-I group. Although there was no difference between the ADHD-C group and the ADHD-I group in terms of demographic data, the frequency of RLS and the ASRS scale scores was found to be significantly higher in the ADHD-C group. Consistent with the literature, the frequency of RLS was found to be high , and it was found to be statistically significantly higher in the ADHD-C group. This suggested that RLS may be seen more frequently in patients with ADHD-C than with ADHD-I, due to the fact that sleep problems are more common  or RLS symptoms may overlap with hyperactivity and impulsivity.
The WURS scores measuring the severity of ADHD symptoms in childhood and the ASRS scores measuring the severity of symptoms in adulthood were found to be significantly higher in ADHD patients with RLS. There was a positive correlation between RLS severity and the severity of ADHD symptoms in childhood. In the literature, a significant positive correlation was found between ADHD symptom severity and RLS severity . RLS symptom severity was found to be more closely related to childhood ADHD symptoms than to adult ADHD symptoms in our study.
While there was no difference between ADHD subgroups in terms of diagnosis of major depression and anxiety disorders or BAI and BDI scales measuring anxiety and depression symptom severity, anxiety and depression symptoms were found to be statistically significantly higher in ADHD patients with RLS. While there was no difference in the co-diagnosis of anxiety disorder and/or depression in ADHD cases accompanied by RLS, depression and anxiety symptoms were found to be significantly higher, suggesting that RLS is affected by internal symptoms such as depression, anxiety, and ADHD’s own attention-deficit and hyperactivity symptoms. In a group of 103 Turkish adults with RLS obtained from a population sample of 3234, depression and anxiety symptoms were significantly higher in the RLS group than in the control (p 0.001 for both variables) . Moreover, according to the multivariate model regression analysis, diagnosis of ADHD-C type and anxiety symptoms were found to be significantly higher among the factors affecting RLS in our study. The fact that anxiety is more prominent than depression makes us think that anxiety may be a factor reflecting the subjective experience of the dysphoric feeling of restless legs. So far, in the literature, the effect of anxiety, which is a common internalizing symptom that accompanies ADHD, on RLS has not been addressed in RLS-related studies conducted in the ADHD group. Based on the results of our study, frequent accompaniment of internalizing symptoms such as anxiety can be cited as one of the reasons for the high probability of RLS in the ADHD group. However, whether RLS increases anxiety and ADHD symptoms, or ADHD and accompanying anxiety symptoms increase RLS, the cause-and-effect relationship cannot be determined exactly. It is seen that cause-and-effect studies are needed in this regard.
In the literature, the etiology of RLS in the ADHD group is mostly evaluated over iron metabolism . We excluded confounding causes of iron deficiency and anemia in our study. So, we investigated factors other than iron affecting RLS in the ADHD group. Apart from iron deficiency, we found that the frequency of RLS was still high in the ADHD group. This can be interpreted as either that psychiatric comorbidities often accompany ADHD (one of these diseases is RLS) or that ADHD symptoms are a facilitating factor in diagnosing RLS. Our study differs from other studies in that it concludes that the core symptoms of ADHD and internalizing symptom anxiety significantly affect RLS.
The limitations of our study are having an observational cross-sectional design, using self-report screening scales, and having the comorbidities of depression and anxiety disorders. Longitudinal studies that determine the cause-and-effect relationship can be more explanatory. Although it is possible that studies conducted with the non-comorbid ADHD group may lead to different results, this makes our study more realistic because the general ADHD population often has internalizing symptoms. We did not research other sleep-related disorders in our study. On the other hand, the relatively large sample size, the use of strict exclusion criteria to eliminate confounding factors, the evaluation of the diagnosis of ADHD based on a detailed clinical interview with DIVA, and the inclusion of drug-naive patients are the strengths of our study.
We showed that ADHD often accompanied RLS even without iron deficiency. We found that the core symptoms of ADHD and accompanying anxiety were effective on RLS as the reason for this. This situation reveals that we should not ignore RLS when looking for comorbidities in ADHD patients. It is thought that there is a need for studies that need to clarify the cause-and-effect relationships in the etiology of ADHD and RLS.
Availability of data and materials
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Kiraz, S., Çipil, A. & Ergün, N. The relationship between disease symptoms and restless legs syndrome in adult attention-deficit hyperactivity disorder without iron deficiency. Middle East Curr Psychiatry 29, 59 (2022). https://doi.org/10.1186/s43045-022-00226-9
- Attention-deficit hyperactivity disorder
- Restless legs syndrome
- Iron deficiency