Pathophysiology Of Restless Legs Syndrome Research Articles

Enhanced Hippocampal Long-Term Potentiation and Fear Memory in Btbd9 Mutant Mice

Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.

Cırcadıan changes ın cortıcal excıtabılıty ın restless legs syndrome

Various investigations have revealed a widespread and somewhat controversial pattern of cerebral, cerebellar and brainstem involvement in the pathophysiology of restless legs syndrome (RLS). However, several studies which investigated functional or structural aspects indicated cortical involvement in RLS. In this study, we aimed to analyze circadian changes of cortical excitability in idiopathic RLS patients by means of transcranial magnetic stimulation (TMS). Eleven idiopathic RLS patients and eight healthy age and sex matched subjects were investigated using single-pulse TMS and motor nerve conduction studies during early afternoon when there were no symptoms and late at night (22:00–23:00) when the symptoms reappeared. Central motor conduction time, latencies and amplitudes of scalp and cervical motor evoked potentials, resting and active motor thresholds, and cortical silent period were measured. Measured parameters were similar between RLS patients and healthy subjects during the daytime. At night, cortical silent periods tended to shorten, and motor thresholds tended to decrease in the RLS group, whereas in controls they tended to increase.At night, active motor-threshold measurements were significantly lower in the RLS group (28.5±6.2% vs 40.4±8.4%, p=0.006). Therefore, we propose that in patients with RLS, conduction along the motor corticospinal axons is normal, with the possible loss of subcortical inhibition at nighttime.

Racial differences in restless legs symptoms and serum ferritin in an incident dialysis patient cohort

Restless legs syndrome (RLS), a debilitating sleep disorder that is frequently reported by CKD patients on dialysis, may be more common in whites than in non-whites. Iron deficiency is associated with RLS, and serum ferritin is higher among African Americans compared to Caucasians in the general population. No prior studies have compared restless legs symptoms and serum ferritin levels of African-American and those of the Caucasian patients on dialysis. In a multicenter observational study that included in-person interviews and medical chart review, we studied 210 patients who had recently started renal dialysis. Predictors of restless legs symptoms were examined in a multivariable logistic regression model. African Americans had a reduced risk of restless legs complaint compared to Caucasian patients (OR, 0.44 [95% CI 0.21-0.93]; P=0.03). African-American patients were also less likely than Caucasian patients to have low serum ferritin values (<100 ng/ml), and among patients with serum ferritin≥100 ng/ml, the average serum ferritin of African-American patients was higher than that of Caucasian patients. Further study of racial and iron status relationships could advance the understanding of RLS pathophysiology, and RLS is an important patient outcome to monitor, as revised anemia and iron protocols are implemented in the clinical setting.

Prevalence of neuroleptic-induced restless legs syndrome in patients taking neuroleptic drugs

Dopamine deficiency or dopamine dysfunction has been implicated as one of the factors involved in the pathophysiology of restless legs syndrome (RLS). Our objective is to determine the prevalence of primary RLS in patients taking neuroleptic drugs. One hundred patients taking neuroleptic drugs and 100 healthy age- and sex-matched controls were interviewed with the Cambridge-Hopkins diagnostic questionnaire for RLS. Patients with malignancy, end-stage renal disease, neuropathy, history of spinal cord diseases, pregnancy and Parkinson's disease were excluded. Only one patient had symptoms consistent with RLS (1%), similar to one patient in the control group. She was a 40years old female with a diagnosis of depression. She started having RLS symptoms approximately four years after starting perphenazine. The symptoms persisted after the medications were discontinued but decreased in severity and frequency. Her serum ferritin level was 90.3ng/ml. The prevalence of primary RLS is low in patients attending the out-patient clinic who are taking neuroleptic drugs. Other factors apart from dopaminergic dysfunction are likely to be involved in the pathogenesis of RLS.

Epidemiologic study about restless legs syndrome and migraine

Restless legs syndrome (RLS) is a sensorimotor disorder with prevalence between 2.5% and 10% in white population. The pathophysiology of RLS involves a dysfunction of the dopaminergic neurotransmitter system. Migraine attacks may also be influenced by dopamine […] Epidemiologic study about restless legs syndrome and migraine (Abstract). Dissertation. Ribeirao Preto, 2010

Síndrome de piernas inquietas en pacientes con concentración de ferritina elevada y hierro normal

To document the association between restless legs syndrome (RLS) and high ferritin levels in five patients. The five patients were male, mean age: 59 years (range: 36-73 years). The patients were referred for RLS (two of them blood donors), in two cases associated with obstructive sleep apnea. Patients underwent a video-PSG recording. Serum iron and serum ferritin were determined. All patients fulfilled the clinical criteria for RLS: leg paresthesias associated with an urge to move, motor restless-ness, worsening of symptoms during the evening and night, and partial relief with activity, difficulty falling asleep, and presence of nocturnal awakenings due to RLS. Neurological examination, EEGs, EMGs and MRIs were normal. Video-PSGs recordings showed a disturbed and fragmented sleep with a reduction in total sleep time, low sleep efficiency, respiratory abnormalities with an apnea-hipopnea index > 10/h in two cases, and in all of them a periodic leg movements index > 5/h. The serum iron levels were within the normal range in all cases, whereas those in serum ferritin levels were high. To our knowledge the association of normal serum iron with high serum ferritin levels in patients diagnosed clinically and polygraphically as having RLS with periodic leg movements has not been described before. The notion of an involvement of a dopaminergic mechanism in the pathophysiology of RLS is supported by the decrease in the values of serum ferritin concentration observed in one patient during follow-up while being treated with dopaminergic agents.

Restless Legs Syndrome Presenting as an Acute Exacerbation of Multiple Sclerosis

Restless legs syndrome is common in patients with multiple sclerosis but has not been reported as occurring due to an acute, inflammatory, demyelinating attack. Restless legs syndrome is known to be related to low brain iron levels. Multiple sclerosis has been associated with the abnormal accumulation of iron in the chronic, progressive phase of axonal degeneration. Iron deficiency may play a role in demyelination. This suggests that restless legs syndrome may be caused by the inflammatory, demyelinating component of multiple sclerosis rather than axonal degeneration. The author presents a case of self-limited restless legs syndrome occurring as an acute attack of multiple sclerosis, supporting the notion that inflammatory demyelination is the underlying pathophysiology of restless legs syndrome in multiple sclerosis.

Restless legs syndrome in Friedreich ataxia: A polysomnographic study

Friedreich ataxia (FA) is the most common type of hereditary ataxia. Frataxin deficiency due to a GAA expansion in the first intron of chromosome 9 results in intramitochondrial iron accumulation. On the basis of the patients' complaints about sleep disturbance and pathophysiological considerations, we systematically assessed sleep history and polysomnography in FA. We included 16 consecutive FA patients (11 men, 5 women; mean age, 35.4 ± 11.1 years) with a mean disease duration of 16.5 ± 7.0 years. All patients underwent a standardized protocol including a detailed sleep history and polysomnographic recordings. Eight out of 16 patients were diagnosed with restless legs syndrome (RLS). In seven patients, RLS onset was after the onset of FA. Interestingly, FA patients with RLS had significantly lower serum ferritin levels than FA patients without RLS (76.3 ± 56.0 μg/L vs. 176.3 ± 100.7 μg/L; P = 0.043 after correction for sex and age). Moreover, periodic leg movements in wakefulness (PLMW) indices were significantly higher in FA patients with RLS than FA patients without RLS (FA with RLS, 118.1 ± 50.7; FA without RLS, 65.6 ± 44.2; P = 0.028). There was an inverse correlation between serum ferritin levels and PLMW indices obtained in all FA patients (rho -0.538, P = 0.039). RLS is common in FA. Its frequency in this primarily spinal ataxia appears consistent with the concept of dysfunctional spinal sensorimotor integration in the pathophysiology of RLS. The finding that RLS is more frequent in the context of lower serum ferritin levels in FA is interesting, but requires further investigation in larger patient samples.

Restless legs syndrome in Parkinson's disease: clinical characteristics and biochemical correlations

Restless legs syndrome (RLS) is a neurological disorder that responds to dopaminergic drugs, indicating a common pathophysiology with Parkinson's disease (PD). The prevalence of RLS was estimated in a group of PD patients and its clinical and biochemical characteristics were analysed. Forty-eight patients with PD were evaluated into two groups, with and without RLS. Clinical characteristics assessed in both groups were age, gender, duration of PD, Hoehn and Yahr, and Schwab and England scales. Laboratory variables such as hemoglobin, s-iron, s-ferritin and creatinine were obtained. The prevalence of RLS was 18.75%. No significant differences regarding clinical variables and biochemical parameters were observed. The high prevalence of RLS found in PD patients suggests the concept of a common etiological link and it seems that secondary causes did not play a central role in the pathophysiology of RLS in this group of parkinsonian patients.

Decision making in restless legs syndrome

The dopamine system is implicated in reward-based decision making with explicit information (decision making under risk) and implicit probabilities (decision making under ambiguity). Although the pathophysiology of restless legs syndrome (RLS) is not yet fully understood, the genetic factors, iron status, and dopaminergic system are thought to play a role. RLS provides an opportunity to test the dopaminergic hypothesis in a drug-free population and to characterize reward processing using decision-making paradigms. We investigated impulsivity, impulse control disorders, and decision making in 50 untreated patients with primary RLS compared with 60 sex- and age-matched normal controls using one night of polysomnography recording, a structured psychiatric interview, and questionnaires (RLS Severity Scale, Beck Depression Inventory, and Urgency Premeditation Perseverance Impulsive Behavior Scale). Subjects performed the Iowa Gambling Task to assess decision making under ambiguity and the Game of Dice Task to assess decision making under risk. Patients with RLS showed selective changes in decision making on the Iowa Gambling Task and normal decision making on the Game of Dice Task compared with controls. Patients with RLS had greater depressive symptoms than controls, but no difference was found in impulsivity, impulse control disorders, or addictive behaviors. Clinical and polysomnographic variables were unrelated to decision-making performance. Results indicate reduced decision-making performance under ambiguity in drug-free patients with RLS. From a clinical perspective, when using dopaminergic medication to treat RLS, patients with abnormal baseline behaviors should be closely monitored.

Restless legs syndrome in chronic inflammatory demyelinating polyneuropathy

The prevalence of restless legs syndrome (RLS) is unknown in chronic inflammatory demyelinating polyneuropathy (CIDP). We prospectively studied 28 patients with CIDP. Prevalence of RLS in CIDP was ascertained by face-to-face interview using validated criteria and compared with that in 28 age- and gender-matched controls. Eleven (39.3%) CIDP patients were diagnosed with RLS, compared with 2 (7.1%) controls (P < 0.01). A significant correlation was ascertained between presence of RLS and lower limb weakness, functional disability, and summated compound muscle action potential (CMAP). The prevalence of RLS in CIDP was significantly higher than in controls in our study population, approaching 40%. Screening for RLS in CIDP patients may be appropriate, particularly in those with weakness, disability, and motor axonal loss in the lower limbs. Our findings may otherwise suggest the existence of peripheral components to the pathophysiology of RLS in patients with CIDP.

Restless legs syndrome in hemodialysis patients: association with depression and quality of life

The prevalence of restless legs syndrome (RLS) ranging from 6.6% to 83% has been reported in different case series. The pathophysiology of RLS in uremia is still unclear. The aim of this study was to assess the frequency of RLS in the hemodialysis patients and to explore depression and associated detrimental impact on quality of life. The diagnosis of RLS was made using the criteria of the International Restless Legs Study Group. The polyneuropathy was diagnosed according to clinical signs and symptoms. Each subject completed three questionnaires: Beck Depression Inventory, Short Form-36 Quality of Life Scale, and the Epworth Sleepiness Scale (ESS). Biochemical parameters including hemoglobin, serum ferritin, and Kt/V index were collected. The data of the patients with and without RLS or clinical polyneuropathy (PNP) were compared. There were 41 male and 40 female patients. RLS, PNP, and high ESS scores were seen in 12%, 47%, and 7% of hemodialysis patients, respectively. Beck depression inventory scores were high in patients with RLS when compared to those without (28.9 ± 9, p = 0.007). General health score in the RLS patients, physical functioning score in the PNP patients were significantly lower (GH, 20.7; p = 0.036; PF, 10.5; p < 0.005). We did not observe any association between hemoglobin, ferritin levels, and Kt/V index in the RLS patients. However, Kt/V index in the PNP patients were low. The frequency of RLS in hemodialysis patients was lower than that reported from similar studies in other countries. The presence of RLS and PNP in hemodialyzed patients negatively affects quality of life, and RLS contributes to occurrence of depression.

Restless legs syndrome: pathophysiology, clinical presentation and management

Restless legs syndrome (RLS) is a somatosensory network disorder that is clinically diagnosed according to four main criteria: an urge to move the legs, usually associated with unpleasant leg sensations; induction or exacerbation of symptoms by rest; symptom relief on activity; and diurnal fluctuations in symptoms with worsening in the evening and at night. Genetic variants in four chromosomal regions have been identified that increase the risk of RLS. In addition, various different lesions, ranging from peripheral neuropathies to spinal cord lesions or alterations of brain metabolism, are implicated in RLS. In most cases, sleep disorders with frequent sleep fragmentation and characteristic periodic limb movements during sleep can be identified during a polysomnographic recording. The first-line drugs for RLS are dopaminergic agents, which are effective in low to moderate doses. Alternative or additional treatments include opioids and anticonvulsants. Augmentation-paradoxical worsening of symptoms by dopaminergic treatment-is the main problem encountered in difficult-to-treat patients. Iron deficiency must be identified and treated by supplementation, both to improve RLS symptoms and to potentially lower the risk of augmentation. Here, we review the latest studies pertaining to the pathophysiology, clinical presentation and management of RLS.

Physiopathologie du syndrome des jambes sans repos

Restless legs syndrome (RLS) could be the consequence of sensorimotor dysfunction. Dopaminergic treatment has been successful in RLS, suggesting dopaminergic abnormalities. The specific pathophysiology of idiopathic RLS is not well known but recent studies have raised the hypothesis of diencephalospinal pathway dysfunction. This pathway includes spinal, subcortical and cortical structures. In idiopathic RLS, an implication of A11 neurons has been evoked, but further studies are needed to confirm this hypothesis. Brain iron is reduced in RLS. This decrease plays a major role in RLS occurrence. Genetic analyses are necessary to better understand the pathophysiological mechanisms of RLS.

Altered eyeblink reflex conditioning in restless legs syndrome patients

Background Restless legs syndrome (RLS) is characterized by abnormal leg sensations and an uncontrollable urge to move the lower extremities during rest periods. Evidence suggests that reflex tasks that involve sensory–motor integration may be altered in RLS patients. This led us to determine if RLS patients show alterations in a sensory–motor reflex conditioning task called differential eyeblink conditioning. Methods RLS subjects were washed out of treatment medication for 7 days prior to testing. Subjects (20 RLS and 19 Control) received 120 discrimination conditioning trials consisting of 60 CS+ trials (i.e., an auditory stimulus paired with the airpuff-US separated by a silent 900 ms trace interval) and 60 CS− trials (i.e., a different auditory stimulus that was NOT paired with the US). Results Control subjects showed normal differential responding to the CS+ and CS−, but the RLS patients showed little or no differential responding. A post-test questionnaire provides evidence that symptomatic interference was not responsible for the eyeblink conditioning deficits in the RLS subjects, and further suggests that neurophysiological factors were responsible for these deficits. Conclusions Together these results suggest that deficits in eyeblink conditioning are related to the pathophysiology of RLS. The eyeblink conditioning test may also be useful for supporting a clinical diagnosis or treatment strategy for RLS.

Restless legs syndrome

Restless legs syndrome (RLS) is a common neurological sensory-motor disorder that is characterized by intense restlessness and unpleasant creeping sensations deep inside the lower legs. Symptoms appear when the legs are at rest and are worst in the evening and at night. They force patients to keep moving their legs, and often to get out of bed and wander about. Periodic limb movements (PLMS) are also common during sleep amongst those suffering from RLS, and sleep efficiency is severely reduced. There are idiopathic as well as symptomatic forms of RLS, the latter being associated with e.g. pregnancy, iron deficiency and chronic renal failure. A family history of RLS is very common and pedigrees in these cases suggest an autosomal-dominant transmission with high penetrance. Genetic investigations have been performed in order to identify genes associated with RLS. Several loci have been found (on chromosomes 12q, 14q, 9p, 2q, 20p and 16p). Pathophysiology of RLS remains incompletely understood. However, advanced brain imaging studies and positive results of dopaminergic treatment suggest that RLS may be generated by dopamine dysfunction locally within the central nervous system. At present, there is a wide range of treatment options including levodopa, dopamine agonists, opioids, benzodiazepines, antiepileptic drugs and iron supplements.

Changes of cortical excitability after dopaminergic treatment in restless legs syndrome

Objective Dopaminergic pathways are most likely involved in the pathophysiology of restless legs syndrome (RLS). In previous investigations, an alteration of cortical excitability was suggested to be related to a dopaminergic dysfunction in RLS. The purpose of our study was to compare practice-dependent plasticity in RLS patients before and after a month of dopaminergic treatment. Methods Single-pulse transcranial magnetic stimulation (TMS) was used to define motor evoked potential (MEP) amplitude, motor threshold, and silent period (SP) as well. Subjects performed three exercise blocks (bimanual motor task). MEP amplitude, registered immediately after each exercise block and after a rest period, was compared to baseline. The time course of intra-cortical inhibition was tested using paired-pulse TMS at short inter-stimulus intervals. For the single-pulse TMS procedures, we enrolled 12 patients affected by primary RLS and 12 normal subjects. For the paired-pulse TMS procedures, only six patients underwent the examination. RLS patients underwent the examination in both pre- and post-dopaminergic treatment conditions. Results In RLS patients MEP amplitude increased after the rest period only in the post-treatment condition, showing a delayed facilitation. After exercise, MEP amplitude increased, but not enough to be significant, showing a positive trend but not a clear-cut post-exercise facilitation. In the pre-treatment condition instead, MEP amplitude did not change either after rest period or after exercise. RLS patients showed a marked increase of the central motor inhibition, assessed by using paired-pulse TMS at short inter-stimulus intervals after pramipexole treatment. On the contrary, the duration of the SP did not change compared to the pre-treatment condition. Conclusions In RLS patients after dopaminergic treatment, the main finding was the changing of MEP amplitude after rest following a motor task. Since dopaminergic treatment can reverse delayed facilitation in RLS, we hypothesized that cortical plasticity related to dopaminergic systems may play a crucial role in RLS pathophysiology.

Bilateral restless legs affecting a phantom limb, treated with dopamine agonists

Background: Restless legs syndrome (RLS) is a common condition characterised by unpleasant sensations deep inside the legs, which usually occurs at rest and especially at night. These sensations are accompanied...

Crohnʼs Disease Is Associated with Restless Legs Syndrome

Purpose: Extraintestinal manifestations of Crohn's disease (CD) rarely include the central nervous system (CNS). Restless legs syndrome (RLS) is a CNS disorder that is either idiopathic or secondary to a number of diseases. RLS is the strong urge to move the legs often with discomfort, occurs in 10% of the population, and causes poor sleep and reduced quality of life. The aim of this study was to determine if CD was associated with RLS since both are associated with iron deficiency. Inflammation and bacterial overgrowth are also associated with RLS and occur commonly in pts with CD. Methods: All consecutive CD outpatients (F-151, M-121; mean age 43.8 yrs) were prospectively surveyed by gastroenterologists at Specialists in Gastroenterology, a community GI practice (N = 135), Weill Cornell Medical Center (N = 71), Washington University School of Medicine (N = 54), and Johns Hopkins School of Medicine (N = 12). No patients were excluded or refused the survey. All four international criteria were required to be positive for RLS: 1) urge to move legs often with discomfort, 2) worse at rest, 3) worsening at night, and 4) relief with activity. Incidence (having RLS at any point in time), prevalence (having RLS at time of survey), clinical characteristics, RLS risk factors, and potential qualitative relationship to GI symptoms were queried. One IRB limited the RLS frequency question to prevalence and did not allow RLS risk factor questions (54 of 272 surveys). Results: RLS incidence was 42.7% (93/218). Prevalence of RLS was 30.2% (82/272; CI 29.9–30.3%) vs. 8.7% (17/194; CI 8.6–8.8%) of spouses (P < 0.0001; odds ratio = 4.5; CI 2.54–7.87%). In 91.8% pts, RLS started during or after onset of diagnosis of CD. Among 72 RLS (+) pts, 44.5% stated there was correlation of qualitative RLS symptom improvement with overall CD symptom improvement. RLS (+) pts and RLS (−) CD pts had: mean age of 46.8 vs. 42.6 yrs, small intestine involvement in 77.9% vs. 66.7%, colon involvement in 39.7% vs. 63.2%, and prior iron deficiency anemia in 49.3% vs. 33.1%. There was no difference between the CD groups with respect to: gender ratio, current iron deficiency (4.6%), RLS family history (12%), or the rare prevalence of concomitant RLS disorders. Conclusion: RLS occurs frequently in CD and appears to be a new extraintestinal manifestation. Factors other than iron deficiency play a role in RLS pathophysiology in CD. The potential relationship of RLS with CD activity needs further investigation. Determination of the effect of RLS on the quality of life in CD is warranted.

Susceptibility genes for restless legs syndrome are not associated with Parkinson disease

Restless legs syndrome (RLS) is a neurologic condition characterized by a distressing urge to move the legs, usually accompanied by an uncomfortable sensation described as a crawling, muscle ache, or tension. It is usually brought on by rest, worse in the evening or night and partially or totally relieved by movement. RLS is a common disorder with a prevalence of 1.2–15% depending on the population.1 Although the pathophysiology of RLS remains largely unknown, the worsening of symptoms later in the day and the therapeutic effects of levodopa and dopamine agonists support a hypothesis for dysfunction in the dopamine system.2 Parkinson disease (PD) is associated with progressive dopaminergic neuronal loss, for which dopamine agonists are typically prescribed as the first course of treatment. PD is characterized by bradykinesia, resting tremor, muscle rigidity, and postural instability3; it affects >1% of the population aged >55 years and is the most common cause of parkinsonism.4 Although still controversial, several studies have indicated a higher prevalence of RLS in …