Risk factors and clinical features associated with basal ganglia manganese deposition in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: T1-hyperintensity of the basal ganglia (BG) due to manganese deposition is a known radiologic finding in patients with hereditary hemorrhagic telangiectasia (HHT), but risk factors and associated clinical manifestations are unclear. This study conducted a quantitative analysis of the association of T1-hyperintensity in HHT patients with specific risk factors, signs, and symptoms. METHODS: Patients seen at our center between 2005 and 2020 with a definitive diagnosis of HHT who had an available non-contrast T1-weighted brain MRI were included. Hyperintensity was evaluated using oval regions of interest measurements. The BG: thalamus intensity ratio was used to quantitatively evaluate T1-hyperintensity. Patient laboratory values and clinical findings were collected from electronic medical records. Hyperintensity was analyzed for its association with laboratory values, and clinical findings. Variables were analyzed through regression analysis. RESULTS: A total of 239 patients were included in this study. On 1.5 T scanners, values that were significant on multivariable regression analysis were age (p < .001), hepatic AVMs (p < .001), iron deficiency anemia (p = .0021), and cirrhosis (p = .016). On 3 T scanners, values that were significant on multivariable analysis were hepatic AVMs (p = .0024) and cirrhosis (p = .0056). On 3 T scanners, hyperintensity was significantly associated with tremor (OR = 1.17, p = .033), restless leg syndrome (OR = 1.22, p = .0086), and memory problems (OR = 1.17, p = .046). CONCLUSIONS: BG hyperintensity due to manganese deposition is significantly associated with hepatic risk factors on 1.5 T and 3 T scanners and iron deficiency anemia on 1.5 T scanners. On 3 T scanners, T1-hyperintensity is associated with neuropsychiatric signs and symptoms, such as tremor, restless leg syndrome, and memory problems.

Mitochondrial Ferritin: Its Role in Physiological and Pathological Conditions.

In 2001, a new type of human ferritin was identified by searching for homologous sequences to H-ferritin in the human genome. After the demonstration that this ferritin is located specifically in the mitochondrion, it was called mitochondrial ferritin. Studies on the properties of this new type of ferritin have been limited by its very high homology with the cytosolic H-ferritin, which is expressed at higher levels in cells. This great similarity made it difficult to obtain specific antibodies against the mitochondrial ferritin devoid of cross-reactivity with cytosolic ferritin. Thus, the knowledge of the physiological role of mitochondrial ferritin is still incomplete despite 20 years of research. In this review, we summarize the literature on mitochondrial ferritin expression regulation and its physical and biochemical properties, with particular attention paid to the differences with cytosolic ferritin and its role in physiological condition. Until now, there has been no evidence that the alteration of the mitochondrial ferritin gene is causative of any disorder; however, the identified association of the mitochondrial ferritin with some disorders is discussed.

White matter tract-specific alterations in patients with primary restless legs syndrome.

Prior diffusion tensor imaging (DTI) studies have investigated white matter (WM) changes in patients with primary restless legs syndrome (RLS), but the results were inconsistent. Here, we proposed using tract-specific statistical analysis (TSSA) to find alterations in specific WM tracts to clarify the pathophysiological mechanisms of RLS. We enrolled 30 patients with RLS and 31 age- and sex- matched controls who underwent brain magnetic resonance imaging, neuropsychological tests, and polysomnography. Fractional anisotropy (FA) maps obtained from whole-brain diffusion tensor imaging and TSSA were used to localize WM changes in patients with RLS. Subsequently, a comparison of FA values for each tract between patients and controls was performed. The associations between FA values and clinical, polysomnographic, and neuropsychological parameters in RLS patients were assessed. RLS patients demonstrated decreased FA values in the left corticospinal tract (CST) and cingulum, and in the right anterior thalamic radiation (ATR) and inferior fronto-occipital fasciculus (IFO). Patients' attention/executive function and visual memory scores positively correlated with FA values in the right ATR, and anxiety levels negatively correlated with FA values in the right IFO. Additionally, the number of periodic leg movements and movement arousal index were negatively correlated with FA values in the left CST. The TSSA method identified previously unknown tract-specific alterations in patients with RLS and significant associations with distinct clinical manifestations of RLS.

The urge to move: From restless legs syndrome to impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs) in Parkinson's disease (PD) are defined as a failure to resist an "urge" to behave in a way that may be debilitating for oneself or others. The suggested immobilization test (SIT) has been developed to assess the "urge" to move and support the diagnosis of restless legs syndrome (RLS) in the general population and in PD. A clinical association between RLS and ICDs has been shown in PD and in the general population. We hypothesized that there could be a semiological overlap between RLS and ICDs, and conducted SIT in PD patients with and without ICDs. Fifty PD patients with (n = 17) and without (n = 33) current ICDs were included. SIT, videopolysomnography, demographical treatment, and motor, psycho-behavioural and sleep characteristics, including RLS, were recorded. PD patients with ICDs reported increased subjective discomfort during SIT (SD-SIT) compared to those without ICDs (p = .024). Multivariable analysis confirmed ICDs as an independent factor associated with increased SD-SIT in PD, regardless of the presence of RLS, PD severity and dopamine agonist treatment dose. The discomfort measured by SIT might not only reflect the "urge" to move in RLS but also the ICDs in PD, suggesting that ICDs and RLS in PD could share a common phenomenology.

Restless in the mouse cage-A new genetic model for restless legs syndrome: An Editorial Highlight for "Deficiency of Meis1, a transcriptional regulator, in mice and worms:Neurochemical and behavioral characterizations with implications in the restless legs syndrome" on page 522.

Restless legs syndrome (RLS) is a movement disorder that is characterized by an uncomfortable sensation in the legs, and the urge to move the legs. Meis1 has previously identified as a risk gene for RLS. This Editorial highlights the study by Lyu and colleagues who developed a novel genetic mouse model heterozygous for Meis1 expression in neurons of the central nervous system. Using behavioral tests, the authors established hyperactivity of the mice, reminiscent of symptoms found in RLS patients. In addition, the authors took a closer look at the iron, dopaminergic, and cholinergic system of these mice.

Gray matter alterations in restless legs syndrome: A coordinate-based meta-analysis.

BACKGROUND: Voxel-based morphometry (VBM) is an objective structural magnetic resonance imaging (MRI) technique which allows researchers to investigate group-level differences in regional gray matter (GM) volume or density over the whole brain. In the last decade, VBM studies in restless leg syndrome (RLS) have exhibited inconsistent and conflicting findings. METHODS: Studies will be identified through a computerized literature search of the following databases: PubMed, Web of Science, and Embase until October 1, 2018 and updated on March 1, 2020. This protocol will be performed in accordance with the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P). In addition, we will follow the recent guidelines and recommendations for coordinate-based meta-analysis (CBMA). This CBMA will be performed with the seed-based d mapping with permutation of subject images (SDM-PSI) software. RESULTS: This CBMA will offer the latest evidence of GM alterations in RLS. CONCLUSIONS: To our knowledge, this will be the first CBMA that pooled VBM findings in RLS. This quantitative evidence of GM alterations will characterize brain morphometry of RLS. PROSPERO REGISTRATION NUMBER: CRD42018117014.

Statistical shape analysis of corpus callosum in restless leg syndrome.

OBJECTIVES: In this study we aimed to investigate corpus callosum shape differences between restless leg syndrome patients and healthy controls, and to determine whether disease severity and duration are indicators for corpus callosum deformation in RLS patients. METHODS: This study was conducted using the magnetic resonance imaging scans of 33 restless leg syndrome patients and 33 control subjects. Landmarks were marked on the digital images and callosal landmark coordinate data were used to assess shape difference by performing Generalized Procrustes analysis. The shape deformation from controls to the patients was evaluated performing the Thin Plate Spline approach. RESULTS: There was a statistically significant shape difference between the groups. Highest deformation was determined at the posterior midbody of the corpus callosum. Growth curve analyses showed that with the increase in disease duration and severity, the CC size decreased. DISCUSSION: The present study demonstrated callosal shape differences in restless leg syndrome using a landmark-based geometric morphometric approach, considering the topographic distribution of corpus callosum for the first time.

Peculiar lifespan changes of periodic leg movements during sleep in restless legs syndrome.

The objective of this observational cohort study was to analyse the age-related changes of periodic leg movements during sleep using the newest international scoring rules, to expand past analyses, including patients in the paediatric age range, and also to analyse the changes of short-interval and isolated leg movements during sleep throughout the lifespan. One hundred and sixty-five patients (84 women) with restless legs syndrome were recruited in the following age groups: 16 preschoolers (≤5 years of age), 29 school-age children (6-12 years), 19 adolescents (13-17 years), 17 young adults (19-40 years), 47 adults (41-60 years) and 37 seniors (>60 years). Total, periodic, short-interval and isolated leg movements during sleep and periodicity indexes were obtained by polysomnography. The total index showed (quartic polynomial interpolation) a decrease before 10 years, followed by a steady increase up to 30 years, a relatively stable period until 60 years, and a final increase up to 80 years. This course was almost entirely due to changes in periodic movements. Isolated movements did not change significantly and short-interval movements showed only an increase in seniors. Our study indicates that, in restless legs syndrome, the total index shows a peculiar and unique course throughout the lifespan, mainly due to periodic movements. These age-related changes may mirror developmental changes in network complexity known to occur in dopaminergic circuits. These data further confirm the need to better assess the periodicity of leg movements in sleep during the human development period, in order to obtain clinically useful information.

Comparative efficacy and acceptability of treatments for restless legs syndrome in end-stage renal disease: a systematic review and network meta-analysis.

BACKGROUND: Restless legs syndrome (RLS) is common in end-stage renal disease (ESRD) patients and impairs health and quality of life significantly. However, the optimal treatment of RLS in ESRD patients is uncertain and less studied compared with idiopathic RLS patients. METHODS: We conducted a systematic review and network meta-analysis to compare the efficacy and acceptability of treatments for RLS in ESRD patients. Randomized controlled trials (RCTs) by February 2019 in the PubMed, Cochrane Library, Embase and ClinicalTrials.gov were reviewed. RLS severity reduction was treated as treatment efficacy, and adverse events were treated as acceptable. Both outcomes were appraised using a random effects model expressed as standardized mean differences and odds ratios with 95% confidence intervals (CIs), respectively, and were ranked using surface under the cumulative ranking curve (SUCRA) probabilities to obtain a hierarchy of interventions. RESULTS: A total of 12 RCTs were included, comprising 9 interventions and 498 participants. All the interventions significantly improved RLS severity without critical side effects compared with placebo. Gabapentin achieved the greatest decrease of RLS severity [standardized mean difference (SMD) = 1.95, 95% CI 0.81-3.09 (SUCRA: 79.3%)], despite its frequent adverse events [SMD = 0.18, 95% CI 0.02-1.50 (19.9%)]. The combination therapy of exercise plus dopamine agonist had better efficacy [SMD = 1.60, 95% CI 0.08-3.12 (59.8%)] and acceptability [SMD = 1.41, 95% CI 0.01-142.53 (63.9%)] compared with that of vitamin C plus vitamin E [SMD = 1.50, 95% CI 0.47-2.54 (56.6%); SMD = 0.32, 95% CI 0.04-2.86 (32.5%)]. CONCLUSIONS: This network meta-analysis supports that gabapentin is the most effective treatment for RLS in ESRD patients. Exercise plus dopamine agonist is a favorable combination therapy concerning side effects. Future large RCTs with long-term treatment outcomes are necessary.

Evaluation of restless leg syndrome symptoms in patients with lumbosacral canal stenosis comparison with normal population.

Introduction: Restless leg syndrome (RLS) is a neurological disorder that causes an irresistible urge to move the legs often associated with an unpleasant sensation. Due to some common presentations between RLS and lumbosacral spinal stenosis, the purpose of this study was to evaluate the symptoms of RLS in the presence of spinal stenosis at the same time as normal populations.Materials and methods: This cross-sectional study examined 45 patients with lumbosacral spinal canal stenosis and 45 normal individuals without a specific disease. Patients aged 50-70 years were included in the study. All the statistical analyses were carried out using SPSS 21.0 software and p < 0.05 was considered statistically significant.Results: 19 subjects (42.22%) in the patient group and eight in the normal group (17.8%) suffered from restless leg syndrome. Multiple linear regression analysis revealed that patients with lumbosacral canal stenosis had almost five score less than others in RLS scale.Conclusion: RLS symptoms were more prominent in lumbosacral canal stenosis patients compared to the normal group. The awareness of its symptoms can help reduce misdiagnosis.

Blood pressure profile and endothelial function in restless legs syndrome.

Restless legs syndrome (RLS) is frequently comorbid with hypertension and cardiovascular diseases; however this relationship and underlying mechanisms remain controversial. After clinical evaluation, 84 drug-free patients with primary RLS (53 women; mean age 55.1 ± 12.3 years) and 76 controls (47 women; mean age 52.2 ± 15.3 years) underwent 24-hour ambulatory blood pressure (BP) and polysomnographic monitoring, and peripheral arterial tonometry to assess endothelial function for 61 patients and 69 controls. Hypertension was diagnosed in 11.9% of patients with RLS based on office measurement, and in 46.4% on the 24 h recording, with nighttime hypertension, two times more frequent than daytime hypertension. Periodic limb movement during sleep (PLMS), markers of sleep fragmentation, and systolic and mean BP non-dipping profile were more frequent among patients. BP non-dipping status was associated with older age, later RLS onset and diagnosis, RLS severity and higher sleep fragmentation. The mean 24-hour, daytime and nighttime BP values, the frequency of hypertension and the endothelial function were comparable between groups. However, both systolic and diastolic BP trajectories over a 24-hour period differed between groups. In conclusion, patients with RLS exhibit a 24-hour BP deregulation with increased frequency of systolic non-dipping profiles that could worsen the risk for CVD morbidity and mortality.

Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients' sera in a mouse model of restless legs syndrome.

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Hemodialysis patients also exhibit higher rates of RLS compared with the healthy population. However, little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. Here we evaluated sleep and leg muscle activity of Btbd9 mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. At baseline, the amount of rapid eye movement (REM) sleep was decreased and leg muscle activity during non-REM (NREM) sleep was increased in MT mice compared to wild-type (WT) mice. Wake-promoting effects of rotigotine were attenuated by injection of serum from RLS patients in both WT and MT mice. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity. Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS.

Restless legs syndrome in patients on hemodialysis: Polysomnography findings.

INTRODUCTION: Restless legs syndrome (RLS) is a highly prevalent sleep movement disorder usually accompanied by periodic limb movements of sleep (PLMS). The incidence of RLS and PLMS in patients with end-stage renal disease (ESRD) on dialysis is much higher. Clinically, RLS and PLMS can co-occur. We hypothesized that patients with ESRD on dialysis would have a distinct presentation of RLS, with a higher prevalence of PLMS. METHODS: We examined clinical, demographic, biochemical, and polysomnographic characteristics of RLS in patients on dialysis matched to control subjects with normal renal function based on age, sex, body mass index, and frequency of apneas and hypopneas per hour of sleep, defined by the apnea and hypopnea index (AHI), in a proportion of 3:1. Patients with ESRD were on hemodialysis three times per week. Polysomnography was performed overnight in the sleep laboratory. FINDINGS: Patients on dialysis compared to control subjects had a lower amount of N3 sleep (77.6 ± 39.9 minutes vs. 94.8 ± 33.7 minutes, p = 0.037) and REM sleep (55.6 ± 27.5 minutes vs. 74.1 ± 28.4 minutes, p = 0.006), regardless of the presence of RLS. Among the patients on dialysis, those with RLS had higher PLMS. In the control group, patients with RLS had a lower ferritin level, which was not observed in the dialysis group. There was a significant interaction between PLMS and ESRD (p = 0.001), with a higher prevalence of PLMS in patients with ESRD on dialysis in a model adjusted for AHI, sex, arousals, and age. Factors that were associated with PLMS were RLS (p = 0.003), ESRD (p = 0.0001), and AHI (p = 0.041), with an adjusted R2 of 0.321. CONCLUSION: RLS in patients with ESRD on dialysis is independently associated with PLMS, regardless of the severity of sleep apnea, arousals, and age.

[Restless legs syndrome in ischemic stroke patients: clinical features and significance].

OBJECTIVE: To investigate the clinical features and implication of restless legs syndrome (RLS) in ischemic stroke patients. METHODS: A total of 199 ischemic stroke patients were enrolled and assessed by polysomnography (PSG). RLS was identified according to criteria of International Restless Legs Syndrome Study Group. Epworth Sleepiness Scale (ESS), Mini-mental State Examination (MMSE) and Patient Health Questionnaire (PHQ-9) were used to evaluate the sleep quality, cognitive function and post-stroke depression, respectively. The National Institute of Health Stroke Scale (NIHSS) was used to evaluate the neurological function 3 months after stroke onset. Gender-and age-matched non-ischemic stroke patients with RLS (primary PLS) were selected as controls. RESULTS: Twenty-two cases of RLS were identified among 199 ischemic stroke patients (11.1%). Generalized linear model and logistic regression showed that low serum ferritin level (ß=-133.3 mg/L, 95%CI:-200.4--0.1, P<0.01), subcortical infarction (OR=4.05, 95%CI:1.15-14.18, P<0.05) and female (OR=2.54, 95%CI:1.04-6.23, P<0.05) were identified as the risk factors of RLS in ischemic stroke patients. Compared with ischemic stroke patients without RLS, ESS increased by 4.37 (95%CI:2.33-6.41, P<0.01), PHQ-9 increased by 2.17 (95%CI:0.39--3.94, P<0.05), and reduced NIHSS from the baseline deceased by 0.97 (95%CI:-1.79--0.15, P<0.05) in ischemic stroke patients with RLS. In addition, the incidence of moderate-severe depression increased (OR=4.27, 95%CI:1.40-13.10, P<0.05) in ischemic stroke patients with RLS. The index of periodic leg movements of sleep (PLMS) with arousal in ischemic stroke patients with RLS was significantly higher than that in patients with primary RLS (ß=12.85, 95%CI:2.04-23.67, P<0.05). CONCLUSIONS: RLS is common in ischemic stroke patients and has adverse influences on patients.

Advancing synthetic therapies for the treatment of restless legs syndrome.

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

Caenorhabditis elegans and its applicability to studies on restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological disorder in the United States. This disorder is characterized by an irresistible urge to move the legs, although the symptoms vary in a wide range. The pathobiology of RLS has been linked to iron (Fe) deficiency and dopaminergic (DAergic) dysfunction. Several genetic factors have been reported to increase the risk of RLS. Caenorhabditis elegans (C. elegans) is a well-established animal model with a fully sequenced genome, which is highly conserved with mammals. Given the detailed knowledge of its genomic architecture, ease of genetic manipulation and conserved biosynthetic and metabolic pathways, as well as its small size, ease of maintenance, speedy generation time and large brood size, C. elegans provides numerous advantages in studying RLS-associated gene-environment interactions. Here we will review current knowledge about RLS symptoms, pathology and treatments, and discuss the application of C. elegans in RLS study, including the worm homologous genes and methods that could be performed to advance the pathophysiology RLS.

Patterns of gray matter alterations in migraine and restless legs syndrome.

Objectives: Migraine and restless legs syndrome (RLS) are often comorbid and share elements of pathology; however, their neuroanatomical underpinnings are poorly understood. This study aimed to identify patterns of gray matter volume (GMV) alteration specific to and common among patients with RLS, migraine, and comorbid migraine and RLS. Methods: High-resolution T1-weighted images were acquired from 116 subjects: 27 RLS patients, 22 migraine patients, 22 patients with comorbid migraine and RLS, and 45 healthy controls. Direct group comparisons and conjunction analysis were first used to localize the distinct and shared neural signatures of migraine and RLS. We also investigated whether the shared neural signature could be replicated in an additional comorbid migraine/RLS group. Results: Compared with healthy controls, migraine patients showed GMV changes in the lateral occipital cortex, cerebellum, frontal pole, and middle frontal gyrus (MFG), and RLS patients showed GMV changes in the thalamus, middle temporal gyrus, anterior cingulate cortex, insular cortex, and MFG. In migraine, compared with RLS, GMV differences were found in the precuneus, lateral occipital and occipital fusiform cortex, superior frontal and precentral gyri, and cerebellum. Conjunction analyses for these disorders showed altered GMV in the MFG, also found in patients with comorbid migraine and RLS. The GMV of the MFG also correlated with sleep quality in patients with comorbid migraine and RLS. Interpretation: Migraine and RLS are characterized by shared and distinctive neuroanatomical characteristics, with a specific role of the MFG. These findings may be related to shared pathophysiology of these two distinct disorders.

Clinical and radiological characteristics of restless legs syndrome following acute lacunar infarction.

BACKGROUND: Recent studies have suggested that cerebral ischemic infarction may contribute to the development of restless legs syndrome (RLS). This study analyzed the clinical and radiological profiles of RLS with onset after acute lacunar infarction. METHODS: In this retrospective study we enrolled 244 consecutive patients with acute lacunar infarction between January 2012 and June 2014. RLS was identified and evaluated based on the International RLS Rating Scale (IRLS-RS). Individual sleep quality was assessed using the Epworth Sleepiness Scale (ESS). Psychological state was also assessed using the Hamilton Depression Scale (HDS) and the Hamilton Anxiety Scale (HAS). RESULTS: The incidence of RLS in patients with lacunar infarction was 5.33%. Our participant group consisted of nine males and four females. Three patients had symptoms in bilateral limbs, and 10 patients had symptoms only contralateral to the cerebral infarction. The infarctions were localized to the pons, centrum semiovale, thalamus, putamen, medulla, and occipital lobe. Contralateral paralysis was found in 13 patients, and contralateral sensory deficit in seven patients. The average IRLS-RS, ESS, HDS, HAS scores were 19.07 ± 8.70, 4.69 ± 5.82, 4.38 ± 4.68, and 3.85 ± 4.76, respectively. Nine patients had diabetes mellitus. After administration of dopaminergic drugs, patients' RLS significantly improved. CONCLUSIONS: The incidence of RLS after acute lacunar infarction was 5.33%. Pons, centrum semiovale, and basal ganglia were the common locations of responsible lesions. Compared to idiopathic RLS, symptoms of RLS after acute lacunar infarction appeared more unilateral and more likely involved the arm. Moreover, diabetes mellitus may be a risk factor for RLS in stroke patients.

Attention-Deficit Hyperactivity and Obsessive-Compulsive Symptoms in Adult Patients With Primary Restless Legs Syndrome: Different Phenotypes of the Same Disease?

OBJECTIVES: To investigate the prevalence of attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) symptoms in adult patients with primary restless legs syndrome (RLS) and to determine the iron biological correlates of these comorbidities. PARTICIPANTS AND METHODS: We obtained demographic and clinical data from consecutive 105 outpatients with idiopathic RLS who answered validated questionnaires designed to assess the presence of ADHD and OCD symptoms. In these patients, iron blood parameters were routinely checked. RESULTS: Of the total sample, 42.86% of the patients with RLS showed symptoms reminiscent either of ADHD or OCD. Prevalence of ADHD and OCD symptoms was 27.62% and 7.62%, respectively. Compared to other groups, a significantly higher percentage of RLS patients with ADHD symptoms was on antidepressant (p = 0.012); and women with ADHD symptoms, either alone or combined with OCD symptoms, showed significant reduced ferritin concentrations compared to men with either isolated ADHD symptoms or with combined ADHD and OCD symptoms (p = 0.028 and p = 0.025, respectively). CONCLUSIONS: Our findings highlight the high prevalence of ADHD and OCD symptoms in adult patients with primary RLS and independently of serum iron stores decrease, except for women with ADHD symptoms either alone or in combination with OCD symptoms. This may suggest an overlapping neurobiological dopaminergic and serotoninergic dysfunction in ADHD, OCD, and RLS, and question the expression of different RLS phenotypes. The efficacy of dopamine agonists in these groups of patients should be questioned in future studies.

Neuroimaging Applications in Restless Legs Syndrome.

Neuroimaging studies provide information useful to understand the pathophysiology of restless legs syndrome. Molecular PET and SPECT imaging findings mainly supported dysfunction of dopaminergic pathways involving not only the nigrostriatal but also mesolimbic pathways. Magnetic resonance imaging (MRI) studies have used different techniques. Studies using iron-sensitive sequences supported the presence of a regionally variable low brain iron content, mainly at the level of substantia nigra and thalamus. The search for brain structural or microstructural abnormalities by voxel-based morphometry, diffusion tensor imaging or cortical thickness analysis has reported none or variable findings in restless legs syndrome patients, most of them in regions belonging to sensorimotor and limbic/nociceptive networks. Functional MRI studies have substantially demonstrated activation or connectivity changes in the same networks. Magnetic resonance spectroscopy studies showed metabolic changes in the thalamus, which is a hub of these networks. In summary, neuroimaging findings in restless legs syndrome support the presence of reduction of brain iron content, of dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and of abnormalities at level of limbic/nociceptive and sensorimotor networks.