Early-onset Restless Legs Syndrome Research Articles

Incident mental health episodes after initiation of gabapentinoids vs. dopamine agonists for early-onset idiopathic restless legs syndrome

Limited long-term safety information exists for gabapentinoid treatment of idiopathic restless legs syndrome (RLS). We estimated incident mental health-related emergency department visits and hospitalizations with a primary mental health diagnosis (primary outcome) among early-onset idiopathic RLS patients following first-line treatment initiation and examined outcome risk with gabapentinoids compared with dopamine agonists (DAs). A retrospective cohort study was conducted using administrative claims data from 2012 to 2019. Adults with early-onset (18–44 years) idiopathic RLS initiating either gabapentinoids or DAs within 60 days of new diagnosis were followed up to two years. Incidence rates were calculated and a log-binomial regression model with propensity score weighting estimated relative risk of the outcome and of substance use disorders (SUDs) as a secondary analysis with gabapentinoids. Among a cohort of 6,672 patients, 4,986 (74.7%) initiated DAs and 1,686 (25.3%) gabapentinoids. Incidence of the primary outcome (49.8 [95% CI 40.8–69.3] per 1,000 person-years) and SUDs (49.5 [95% CI 40.6–59.9] per 1,000 person-years) were higher in the gabapentinoid group compared with the DA group. A statistically significant risk of mental health diagnoses with gabapentinoids was not detected, but SUD risk was significant after covariate adjustment. High-risk mental health comorbidities (i.e., SUDs) should be considered when initiating RLS treatments.

Pediatric Restless Legs Syndrome.

Early-onset restless legs syndrome has a relatively high prevalence in pediatrics, is highly familial, and is often preceded by a diagnosis of periodic limb movement disorder or childhood insomnia. Diagnostic criteria are derived but not equal to those of the adult syndrome and are adapted according to children's age and linguistic competence. Diagnosis requires parents or caregivers to participate; video-polysomnographic nocturnal recording, although not mandatory, may help confirm dubious cases. The syndrome severely impacts children's sleep and cognitive-behavioral abilities. Iron supplementation is currently the most used and viable therapeutic option.

Clinical features and subtypes of restless legs syndrome in Chinese population: a study of 359 patients

BackgroundThe clinical spectrum of restless legs syndrome (RLS) has not been described in a Chinese population. We aim to evaluate the detailed clinical profile in a cohort of unselected RLS patients in China. MethodsWe enrolled RLS patients continuously according to the diagnostic criteria. Laboratory examinations were performed to exclude mimics and notable comorbidities. ResultsA total of 359 patients with RLS were enrolled. RLS symptoms were mostly symmetrical (65.2%), and purely unilateral RLS was not common (5.6%); however, unilateral dominant RLS was relatively more common. Only 1.1% of RLS patients reported no unpleasant sensations in the legs. The largest proportion of RLS patients described their uncomfortable sensation as indescribable (43.5%) and reported soreness (40.4%). In all, 8.9% of RLS patients described their abnormal sensation as painful, and 34.5% of RLS patients reported their symptoms fluctuated with seasonal trends. This population had a higher likelihood of an RLS family history. RLS patients with summer exacerbation had a younger age at RLS onset and longer disease duration (p < 0.01). Iron deficiency without anemia was common in Chinese RLS patients. Early-onset RLS patients were more likely to have a positive family history (p < 0.01), more summer worsening of symptoms (p < 0.01) and more severely disturbed peripheral iron status (p < 0.01) when compared to late-onset RLS patients. ConclusionThe subjective description is somewhat different, with Chinese RLS patients reporting less pain and more soreness than patients from Western countries. Seasonal fluctuation and iron deficiency without anemia are frequently seen in Chinese RLS patients and predict some other features. Differentiating these various subtypes can facilitate optimal management.

55. Assessing the risk of restless legs syndrome in small fiber peripheral neuropathy

The pathophysiology of restless legs syndrome (RLS) isn’t completely understood. Small Fiber Neuropathy (SFN) patients may have RLS-like sensory symptoms. The aim of this study was to assess the prevalence and clinical features of RLS in patients with SFN, compared with Large Fibres Neuropathy (LFN) patients and healthy controls. All patients underwent nerve-conduction studies and electromyography, and a skin biopsy to confirm SFN. RLS was diagnosed according to international criteria. We compared: frequency of RLS, age of onset, severity as measured by IRLS, insomnia and diabetes comorbidity. We included 39 SFN patients, 37 LFN patients and 40 matched controls. Peripheral nerve-conduction velocities were normal in SFN patients and controls. SFN patients had a 25.60% prevalence of RLS, compared to 10.80% in LFN and 7.50% in controls. Age of onset was 42.91 years, versus 62.67 in LFN and 58.50 in controls. Mean IRLS was 15.6 versus 19.5 in LFN and 18.6 in controls. The occurrence of insomnia was similar between SFN and LFN (43.58% and 43.24%), but higher than in controls (20%). Biopsy-proven SFN patients had a higher risk for an early-onset RLS. They show a less severe RLS, but it can frequently cause insomnia.

T2 relaxometry using 3.0-tesla magnetic resonance imaging of the brain in early- and late-onset restless legs syndrome.

Background and PurposePrevious T2 relaxometry studies have provided evidence for regional brain iron deficiency in patients with restless legs syndrome (RLS). Measurement of the iron content in several brain regions, and in particular the substantia nigra (SN), in early- and late-onset RLS patients using T2 relaxometry have yielded inconsistent results. In this study the regional iron content was assessed in patients with early- and late-onset RLS using magnetic resonance imaging (MRI), and compared the results with those in controls.MethodsThirty-seven patients with idiopathic RLS (20 with early onset and 17 with late onset) and 40 control subjects were studied using a 3.0-tesla MRI with a gradient-echo sampling of free induction decay and echo pulse sequence. The regions of interest in the brain were measured independently by two trained analysts using software known as medical image processing, analysis, and visualization. The results were compared and a correlation analysis was conducted to investigate which brain areas were related to RLS clinical variables.ResultsThe iron index in the SN was significantly lower in patients with late-onset RLS than in controls (p=0.034), while in patients with early-onset RLS there was no significant difference. There was no significant correlation between the SN iron index of the late-onset RLS group and clinical variables such as disease severity.ConclusionsLate-onset RLS is associated with decreased iron content in the SN. This finding supports the hypothesis that regional brain iron deficiency plays a role in the pathophysiology of late-onset RLS.

Topography of sensory symptoms in patients with drug-naïve restless legs syndrome

ObjectivesWe aimed to describe the sensory topography of restless legs syndrome (RLS) sensory symptoms and to identify the relationship between topography and clinical variables. MethodsEighty adult patients with drug-naïve RLS who had symptoms for more than 1year were consecutively recruited. During face-to-face interviews using a structured paper and pencil questionnaire with all participants, we obtained clinical information and also marked the topography of RLS sensory symptoms on a specified body template, all of which were subsequently inputted into our in-house software. The RLS sensory topography patterns were classified according to localization, lateralization, and symmetry. We investigated if these sensory topography patterns differed according to various clinical variables. ResultsThe lower extremities only (LE) were the most common location (72.5%), and 76.3% of participants exhibited symmetric sensory topography. Late-onset RLS showed more asymmetric sensory distribution compared with early-onset RLS (P=.024). Patients whose sensory symptoms involved the lower extremities in addition to other body parts (LE-PLUS) showed more severe RLS compared with those involving the LE (P=.037). ConclusionRLS sensory symptoms typically were symmetrically located in the lower extremities. LE-PLUS or an asymmetric distribution more often occurred in patients with more severe RLS symptoms or late-onset RLS.

Investigation of Unmedicated Early Onset Restless Legs Syndrome by Voxel-Based Morphometry, T2 Relaxometry, and Functional MR Imaging during the Night-Time Hours

The pathophysiology of eRLS has not yet been elucidated. The purpose of the study was to assess, in patients with eRLS, the volume, iron content, and activation of the brain during night-time episodes of SLD and PLMs. Eleven right-handed unmedicated patients with eRLS (mean age, 55.3 ± 8.4 years; disease duration, 17.5 ± 14.05 years) and 11 matched control subjects were studied with a T1-weighted high-resolution 3D spoiled gradient-echo sequence used for VBM and a multisection spin-echo T2-weighted sequence used for T2 relaxometry. Additionally, a single-shot multisection gradient echo-planar sequence was used for fMRI. Brain activation was recorded during spontaneous SLD and PLMs. SPM software was used for analysis of the functional data. The patients showed no regional brain volume change, but T2 relaxometry revealed decreased T2 relaxation time in the right globus pallidus internal and the STN, indicating increased iron content. The patients were observed to activate the following areas: in the left hemisphere, the primary motor and somatosensory cortex, the thalamus, the pars opercularis, and the ventral anterior cingulum; and in the right hemisphere, the striatum, the inferior and superior parietal lobules, and the dorsolateral prefrontal cortex. Bilateral activation was observed in the cerebellum, the midbrain, and the pons. eRLS is associated with increased iron content of the globus pallidus internal and STN, suggesting dysfunction of the basal ganglia. Activation of the striatofrontolimbic area may represent the neurofunctional substrate mediating the repetitive compulsive movements seen in RLS.

Altered Iron Metabolism in Lymphocytes from Subjects with Restless Legs Syndrome

Studies using cerebrospinal fluid, magnetic resonance imaging, and autopsy tissue have implicated a primary role for brain iron insufficiency in restless legs syndrome (RLS). If the abnormalities of brain iron regulation reflect a basic disturbance of iron metabolism, then this might be expressed at least partially in some peripheral systems. Thus the study aim was to determine whether patients with RLS and control subjects show differences in lymphocyte iron regulator proteins. Fasting morning blood samples were used to obtain common serum measures of iron status and to determine lymphocyte iron management proteins. Twenty-four women with early-onset RLS and 25 control women without RLS symptoms were studied. RLS and control subjects were matched for age, hemoglobin, and serum iron profile. However, transferrin receptor (TfR) and DMT1 (divalent metal transporter 1 protein) levels in lymphocytes were significantly higher for RLS patients than for controls. No significant differences in ferritin subtypes or transferrin levels were found. No significant correlations were found between lymphocyte and serum indices of iron status. RLS lymphocytes showed an increase in ferroportin, implying increased cellular iron excretion, in the face of increased iron need (increased TfR and DMT1). In the absence of changes in H-ferritin, the findings indicate a balance between input and output with no net iron change but probable overall increase in iron turnover. The lack of any significant correlation between serum and lymphocyte iron indices indicates that iron management proteins from lymphocytes are at a minimum an alternative and independent marker of cellular iron metabolism.

Genetics of Early Onset Restless Legs Syndrome

Linkage analysis was performed in a four-generational German family with restless legs syndrome (RLS) affecting 15 of 37 family members, in a study at the University of Lubeck, Germany.

Age-at-onset in restless legs syndrome: A clinical and polysomnographic study

Objective To determine the distribution of age-at-onset in a large cohort of patients with restless legs syndrome (RLS) and to compare clinical and polysomnographic characteristics of patients with early and late age-at-onset of RLS. Methods Two hundred and fifty patients with RLS were studied. Information on age-at-onset, etiology, familial history and symptoms severity of RLS was obtained. Age-at-onset density functions were determined from bootstrap methods and kernel density estimators. Results Age-at-onset showed a significant bimodal distribution with a large peak occurring at 20 years of age and a smaller peak in the mid-40s. Early- and late-onset RLS could be separated with a cut-off at 36 years of age. Distributions of age-at-onset differed as a function of presence/absence of a familial history and etiology of RLS. Age-at-onset clearly differentiated patients with a primary RLS (early onset) from those with secondary RLS. Finally, early-onset RLS was associated with increased RLS severity with higher indices of periodic leg movements in sleep (PLMS) associated with microarousals and periodic leg movements during wakefulness (PLMW). Conclusions Early- and late-onset RLS could be distinguished depending on familial history and etiology of RLS. Our data suggest that different pathological processes are involved in these two groups, the early-onset group being highly genetically determined.

Undiagnosed individuals with first-degree relatives with restless legs syndrome have increased periodic limb movements

Background and purpose To evaluate periodic limb movements during sleep (PLMS) in first-degree relatives of both restless legs syndrome (RLS) patients and matched controls without RLS in order to analyze patterns of this motor sign of RLS. Patients and methods First-degree relatives of a consecutive case series of RLS patients and matched community controls without RLS were evaluated for diagnosis of primary RLS and for PLMS as determined by a leg activity meter. The data were analyzed to determine whether or not PLMS rates are higher than expected for RLS subjects in these families, who have mostly milder disease, and family members of early-onset RLS patients not themselves diagnosed with RLS. Results PLMS activity in family members was significantly higher for those diagnosed as RLS compared to those diagnosed as not-RLS. This difference was greater for older than younger subjects. In family members older than the median study age (52 years old) who were diagnosed as not-RLS, PLMS were significantly more frequent in those related to an early-onset RLS proband than in those related to either a control or late-onset RLS proband. Conclusions PLMS are elevated even in those with mild RLS and reveal an age-related worsening of the motor component of RLS. PLMS may represent an incomplete expression of RLS tendencies in families of patients with early-onset RLS, but this needs to be confirmed in future longitudinal studies. The increase in PLMS with age, reported in healthy controls, may in fact occur in part as a partial expression of familial or genetic factors associated with RLS.

Is ferroportin–hepcidin signaling altered in restless legs syndrome?

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.

MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome

ObjectiveCerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and autopsy studies have suggested that brain iron may be reduced in restless legs syndrome (RLS). Further analysis of the data also suggests that diminished brain iron may selectively be for early-onset RLS. This study was designed to replicate and extend our previous findings, specifically with regard to early-onset RLS. In this study our primary hypothesis was that substantia nigra (SN) iron index would be decreased in early-onset RLS compared to controls. MethodsThe iron concentration or ‘iron index’ in 10 brain regions was determined using MRI in 39 controls and in 22 early-onset and 19 late-onset RLS subjects. The Johns Hopkins RLS severity (JHRLSS) scale was used to define disease severity. ResultsThe mean iron index from the SN was significantly lower in the early-onset RLS compared to controls (t=2.5, P=0.016), while late-onset RLS and controls did not differ. There was a significant negative Spearman rank correlation between SN iron index and JHRLSS scale for the control-early-onset-RLS cohort (ρ=−0.32, P=0.016). ConclusionsThe current MRI results in combination with previous autopsy data support the role of low brain iron in the SN in at least those with early-onset RLS symptoms.

Ferritin Levels in the Cerebrospinal Fluid and Restless Legs Syndrome: Effects of Different Clinical Phenotypes

To determine whether patients with restless legs syndrome (RLS) and controls differ in regard to levels of ferritin and transferrin in the cerebrospinal fluid (CSF) when samples are collected at night, to determine whether patients with early-onset and late-onset RLS show a different outcome for CSF values, and to determine whether the CSF ferritin level correlates with disease severity. Collection of CSF and plasma; assessment of disease severity using objective (periodic limb movements) and subjective (Johns Hopkins Restless Legs Severity Scale) measures of severity. General Clinical Research Center. Thirty subjects with idiopathic RLS (15 early- and 15 late-onset RLS) and 22 age- and sex-matched controls. N/A. Nighttime CSF ferritin levels were lower in the total RLS group compared with controls. Further assessment found that the early-onset (less than 45 years of age) but not the late-onset (greater than or equal to 45 years of age) RLS group had significantly lower CSF ferritin levels compared with controls. There was a strong correlation between the age of symptom onset and CSF ferritin values (r = 0.64): the earlier the age, the lower the ferritin level. A regression analysis showed that both sex and RLS subtype had significant effects on the CSF ferritin level, with women with early-onset RLS having substantial lower values than men with late-onset RLS. A comparison between these nighttime CSF values and previously published daytime samples suggests that diurnal changes may have effects on the findings. This study is distinct in showing that the degree of the CSF-ferritin effect is best defined by the clinical phenotypes of sex and age of symptom onset and by the time of day that samples are collected.

CSF hypocretin-1 levels in restless legs syndrome.

CSF hypocretin-1 levels at 6 PM did not significantly differ between patients with restless legs syndrome (RLS) and control subjects as measured by direct radioimmunoassay and after acid extraction. The authors did not observe significant differences between early onset and late onset RLS. Hypocretin-1 levels did not correlate with RLS severity or polysomnographic measures. These results contrast with previous findings reporting significantly increased CSF hypocretin-1 in the late evening and mostly in early onset RLS.

Restless legs syndrome symptoms in primary care: a prevalence study.

There are relatively few studies on the prevalence of restless legs syndrome (RLS) in the general population, even fewer that used diagnostic questions covering all 4 essential diagnostic criteria defining the RLS symptom complex, and none that have reported on the 2 RLS phenotypes for patients seen by family physicians. To determine the prevalence of the symptom complex, diagnostic for RLS in a primary care patient population, a prospective population-based single-center study was performed. Every adult patient presenting for care in a small rural primary care practice with mostly white patients was surveyed for a 1-year period using a validated RLS diagnostic questionnaire. A total of 2099 patients completed the questionnaire. Analysis revealed that 24.0% of these patients were positive for all 4 of the essential symptoms used to make the diagnosis of RLS and 15.3% reported these symptoms at least weekly. In addition, the RLS symptom complex was reported significantly more often by women than men and, as a whole, patients reporting the RLS symptoms were significantly older than patients without symptoms. The prevalence of symptoms increased with age until about 60 years and then showed a steady decrease thereafter. Further, early-onset RLS was significantly more common in women than men. A high prevalence of RLS symptoms was observed in this primary care population. This finding supports the need for heightened awareness in both the medical community and general population regarding this disorder, which can often be effectively treated within the primary care practice.

Restless Legs Syndrome: A Clinical Study of 55 Patients

Background: Restless legs syndrome (RLS) is a common sleep disorder. In 1995, clinical criteria for the diagnosis of RLS were defined. Objective: To describe the clinical spectrum in a series of unselected RLS patients meeting the new diagnostic criteria. Methods: We prospectively assessed by questionnaire and clinical assessment the characteristics of 55 consecutive RLS patients (35 women, 20 men; mean age = 62 ± 16 years). Results: In 27% of the patients, RLS started before the age of 20 years (early-onset RLS). Sensory disturbances were painful in 56% of patients and felt in legs (98%), arms (35%), and ‘internally’ (45%). Motor disturbances included ‘dyskinesias while awake’ (36%). Insomnia (58%) was commoner than hypersomnia (24%). In 67% of the patients, no etiology of RLS was found (idiopathic RLS). Early-onset RLS was more commonly familial (p = 0.01) and associated with ‘growing pains’ (p = 0.005) than late-onset RLS. Patients with RLS and hypersomnia were younger (p = 0.01) and less commonly had painful sensations (p = 0.04) than patients with RLS and insomnia. Patients with idiopathic RLS were younger (p = 0.004), and less commonly had insomnia (p = 0.01) than patients with symptomatic RLS. Conclusions: RLS is a clinically pleomorphic syndrome, reflecting the contribution of multiple genetic and acquired factors in the pathogenesis of RLS.

Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset

Objective: RLS varies considerably in both frequency of occurrence in a family and in age of onset of symptoms. Patients whose RLS symptoms start before or at age 45 have many more affected relatives than those whose symptoms start later, suggesting etiological differences. When etiology differs, factors affecting severity may differ. This study compares the effects of current age and serum ferritin on RLS severity for early- and late-onset (over 45) RLS. Design and methods: RLS severity was evaluated using a validated clinical severity scale and sleep efficiency on a standard polysomnogram. Data from 26 consecutive RLS patients (14 early- and 12 late-onset) who met study criteria were analyzed. Results: Age-of-onset groups showed no significant differences in age, gender and RLS symptom severity. Regression analyses showed significant ( P<0.05) differences with RLS severity primarily affected by age for early-onset RLS and by serum ferritin for late-onset RLS. Conclusions: The age effect for early-onset RLS indicates a slowly progressive disorder. Thus early-onset RLS appears to occur commonly in families, slowly progress with age and have a limited relation to serum iron status. In contrast, late-onset RLS appears to occur less commonly in families, rapidly progress with age and have a strong relation to serum iron status. Age of symptom onset should be considered to better define the RLS phenotype in future studies.