Designing a mHealth clinical decision support system for Parkinson's disease: a theoretically grounded user needs approach.

BACKGROUND: Despite the established evidence and theoretical advances explaining human judgments under uncertainty, developments of mobile health (mHealth) Clinical Decision Support Systems (CDSS) have not explicitly applied the psychology of decision making to the study of user needs. We report on a user needs approach to develop a prototype of a mHealth CDSS for Parkinson's disease (PD), which is theoretically grounded in the psychological literature about expert decision making and judgement under uncertainty. METHODS: A suite of user needs studies was conducted in 4 European countries (Greece, Italy, Slovenia, the UK) prior to the development of PD_Manager, a mHealth-based CDSS designed for Parkinson's disease, using wireless technology. Study 1 undertook Hierarchical Task Analysis (HTA) including elicitation of user needs, cognitive demands and perceived risks/benefits (ethical considerations) associated with the proposed CDSS, through structured interviews of prescribing clinicians (N = 47). Study 2 carried out computational modelling of prescribing clinicians' (N = 12) decision strategies based on social judgment theory. Study 3 was a vignette study of prescribing clinicians' (N = 18) willingness to change treatment based on either self-reported symptoms data, devices-generated symptoms data or combinations of both. RESULTS: Study 1 indicated that system development should move away from the traditional silos of 'motor' and 'non-motor' symptom evaluations and suggest that presenting data on symptoms according to goal-based domains would be the most beneficial approach, the most important being patients' overall Quality of Life (QoL). The computational modelling in Study 2 extrapolated different factor combinations when making judgements about different questions. Study 3 indicated that the clinicians were equally likely to change the care plan based on information about the change in the patient's condition from the patient's self-report and the wearable devices. CONCLUSIONS: Based on our approach, we could formulate the following principles of mHealth design: 1) enabling shared decision making between the clinician, patient and the carer; 2) flexibility that accounts for diagnostic and treatment variation among clinicians; 3) monitoring of information integration from multiple sources. Our approach highlighted the central importance of the patient-clinician relationship in clinical decision making and the relevance of theoretical as opposed to algorithm (technology)-based modelling of human judgment.

Restless legs syndrome and cerebrovascular/cardiovascular events: Systematic review and meta-analysis.

OBJECTIVE: We performed a systematic review and meta-analysis to evaluate the proposed association of restless legs syndrome (RLS) with cerebrovascular/cardiovascular outcomes. METHODS: We calculated the corresponding odds ratios on the prevalence of cerebrovascular/cardiovascular risk factors and standardized mean differences on the reported mean age at baseline between RLS patients and controls. We also calculated the corresponding risk ratios and adjusted for potential confounders hazard ratios (HRsadjusted ) on the reported outcomes of interest between RLS patients and controls. RESULTS: We identified 8 eligible studies (644 506 patients, mean age: 60.2 years, 36.2% males; 3.3% with RLS). RLS patients were found to have significantly higher prevalence of hypertension (P = .002), diabetes (P = .003) and hyperlipidemia (P = .010) compared to controls. In the unadjusted analyses of prospective observational studies, RLS patients were found to have significantly higher risk for cerebrovascular ischaemia (P = .01) and all-cause mortality (P = .04) compared to controls during follow-up, while in the adjusted for potential confounders analyses RLS patients were only found to have a higher risk of all-cause mortality (HR adjusted=1.52, 95% CI: 1.17-1.97, P = .002). CONCLUSIONS: The present report does not provide evidence for an increased risk of cerebrovascular and cardiovascular events in RLS patients, which highlights the vast presence of confounding factors.

Dopamine agonist monotherapy in Parkinson's disease and potential risk factors for dyskinesia: a meta-analysis of levodopa-controlled trials.

BACKGROUND AND PURPOSE: Dopamine agonists (DAs) are generally considered to be deprived of the highly dyskinetic effect of levodopa in Parkinson's disease (PD) patients. However, the risk for dyskinesia induced by DA monotherapy and the contribution of clinically significant factors in the development of this disorder have never been systematically assessed. METHODS: A systematic literature search was conducted for randomized, levodopa-controlled trials of DAs in early PD. A meta-analysis was performed to calculate the combined odds ratio (OR) for dyskinesia. Meta-regressions were subsequently performed on dyskinesia OR including individually as covariates the effects of mean disease duration, treatment duration and DA dose. In an additional analysis the effect of adjunct levodopa on the odds for dyskinesia was investigated. RESULTS: DA monotherapy resulted in an 87% lower risk for dyskinesia compared with treatment with levodopa (OR = 0.13, 95% confidence interval 0.09-0.19, P < 0.001). The risk for dyskinesia was independent of the dose of DA, disease duration and treatment duration. A dose-related pattern was revealed between adjunct levodopa in the DA group and dyskinesia. Nevertheless, the odds for dyskinesia in the DA group were constantly lower than in the levodopa group. CONCLUSION: Initial DA treatment encompasses a lower risk for dyskinesia even after the unavoidable introduction of levodopa that increases the risk for dyskinesia in a dose-related manner. As the dose and treatment duration with DAs are factors independent of the risk of dyskinesia, monotherapy with DAs in early PD is suggested at doses that ensure efficacy and delay the need for levodopa, always following an adequate evaluation of the risks DAs can pose in individual patients.

Nocebo as a potential confounding factor in clinical trials for Parkinson's disease treatment: a meta-analysis.

BACKGROUND AND PURPOSE: Nocebo refers to adverse events (AEs) generated by patient's negative expectations that medical treatment will likely harm instead of heal and can be assessed in placebo-controlled randomized controlled trials (RCTs). We examined AEs following placebo administration in RCTs for Parkinson's disease (PD). METHODS: After a systematic Medline search for RCTs for PD pharmacologic treatments published between 2000 and 2010, we assessed percentages of placebo-treated patients reporting at least one AE or discontinuing due to placebo intolerance and searched for factors influencing nocebo's extent. RESULTS: Data were extracted from 41 RCTs fulfilling search criteria. Of 3544 placebo-treated patients, 64.7% (95% CI: 53.6-74.4) reported at least one AE and 8.8% (95% CI: 6.8-11.5) discontinued placebo treatment due to intolerance. The number of AEs per 100 person-months was 25.9 (95% CI: 16.8-39.8). Nocebo dropout rate was positively related to study population size and year of publication. Increased number of AEs per 100 person-months was negatively correlated with the duration of treatment. AE rates, dropout rates, and AEs per 100 person-months in placebo- and active drug-treated patients were strongly correlated (r = 0.941, 0.695, and 0.824, respectively). CONCLUSIONS: Our analysis indicates a significant dropout rate related to nocebo in trials for PD treatment. Adherence and efficacy may be adversely affected with additional implications for clinical practice.

Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease.

The efficacy and safety of levetiracetam (LEV), administered for management of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD), was examined using a multicenter, double-blind, placebo-controlled, parallel groups, crossover trial. Because of having a period effect, data after crossover point was excluded from analysis. Levodopa-treated PD participants with LID (n = 38) received LEV 500 mg/day, were assessed, titrated to 1,000 mg/day and reassessed, before and after crossover. The placebo group followed the same routine. Primary efficacy was defined from percent change in "On with LID" time from patient diaries. Secondary efficacy assessment used "On without LID," "Off" time, unified PD rating scale (UPDRS), clinical global impression (CGI), and Goetz dyskinesia scale after levodopa challenge. Safety measures were also performed. On with LID time decreased 37 minutes (95% confidence interval [CI] 0.59, 7.15; P = 0.02) at 500 mg/day, 7.85% 75 minutes (95% CI 3.3, 12.4; P = 0.002) at 1,000 mg/day. On without LID time increased by 46 minutes (95% CI -1.55, -0.03; P = 0.04) at 500 mg/day and 55 minutes (95% CI -10.39, -1.14; P = 0.018) at 1,000 mg/day. UPDRS 32 showed decreased dyskinesia duration mean change 0.35 (95% CI 0.09, 0.5; P = 0.009) at 1,000 mg/day. CGI showed LID decreased by 0.7 (95% CI 0.21, 1.18; P = 0.006) at 1,000 mg/day. Patient diaries and UPDRS show no increase in Off time. This exploratory trial provides evidence that LEV in 1,000 mg/day, slowly titrated, could be useful in improving LID as was assessed with patient diaries, UPDRS, and CGI scales, safely, with minimal side effects.

How should we treat a patient with early Parkinson's disease?

Parkinson's disease (PD) is characterised by the progressive degeneration of dopaminergic nigro-striatal neurons and severe striatal dopaminergic deficiency, leading to bradykinesia. Levodopa was the first drug used for PD treatment and is still considered the most useful weapon for the control of PD symptoms. However, levodopa treatment induces motor complications, which is considered as a major problem as the disease progresses. Dopamine agonists, catechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors are some more recently developed drug categories which are expected to have a more favourable effect on motor complications. The choice of the best initial treatment in PD remains a controversial matter. Early therapeutic decisions in PD should balance the need for efficient short-term symptom control against long-term complication profile. The individualisation of the treatment seems to be the key for the best approach of early PD patients.

On-Body Sensor Position Identification with a Simple, Robust and Accurate Method, Validated in Patients with Parkinson's Disease.

The aim of this work is to implement and validate an automated method for the localization of body-worn inertial sensors. Often, body-sensor networks with inertial measurement units (IMU) used in rehabilitation and ambient monitoring of patients with movement disorders, require specific markings or labels for the correct body placement. This introduces a burden, which, especially for ambient monitoring, could lead to errors or reduced adherence. We propose a method to automatically identify sensors attached on a predefined set of body placements, namely, wrists, shanks and torso. The method was used in a multi-site clinical trial with Parkinson's disease patients and in 45 sessions it identified sensor placement on torso, wrists and shanks with 100% accuracy, discriminated between left and right shank with 100% accuracy and between left and right wrist with 98% accuracy. This is remarkable, considering the presence of parkinsonian motor symptoms causing abnormal movement patterns, such as dyskinesia.Clinical Relevance- This method can facilitate home monitoring of patients with movement disorders.

Effects of sibutramine and orlistat on mood in obese and overweight subjects: a randomised study.

BACKGROUND AND AIM: Intentional weight loss results in improvement in mood. Very few data exist regarding the effects of sibutramine on the mood of obese and overweight patients in general clinical samples. Moreover, no study has evaluated the effects of orlistat treatment on mood. The purpose of our study was to assess the effects of sibutramine and orlistat on mood in obese and overweight subjects. METHODS AND RESULTS: Sixty obese and overweight women were divided into three groups. The first group (n=20) received a low-calorie diet and sibutramine 10mg; the second group (n=20) received a low-calorie diet and orlistat 120 mg three times a day, and the third group received only the low-calorie diet. CONCLUSION: A psychiatric assessment was performed with the Hamilton Depression Rating Scale (HAMD) before and after 3 months of treatment. In all the groups a statistically significant decrease in HAMD scores was observed. However, the decrease in the sibutramine group was greater compared to that observed in the two other groups (P<0.01). These results suggest that sibutramine treatment may improve mood more than diet alone or orlistat therapy in a general clinical sample of obese patients.

Low RLS prevalence and awareness in central Greece: an epidemiological survey.

Restless legs syndrome (RLS) is a sensorimotor disorder with a general population prevalence of 3-10%. A single, previous epidemiological study performed in south-east Europe reported the lowest prevalence rate amongst European countries. We conducted a population-based survey of RLS in central Greece. A total of 4200 subjects were randomly recruited. We used the international RLS study group criteria for diagnosis and the severity scale for severity assessment in subjects with RLS. We also included questions to assess the level of awareness of RLS in our region. A total of 3033 subjects were screened. The overall lifetime prevalence was 3.9% with a female-to-male ratio of 2.6:1. Nearly half of RLS patients reported moderate to severe intensity of symptoms. After adjustment for multiple comparisons we found no association of RLS with education level, smoking, alcohol intake, caffeine consumption, shift work, professional pesticide use or comorbid illness. Our study revealed a low level of awareness amongst the population and physicians in our region and sub-optimal management. We provide further evidence for low prevalence of RLS in south-east Europe and a low level of awareness of RLS in our region.

A method for classification of transient events in EEG recordings: application to epilepsy diagnosis.

OBJECTIVES: The aim of the paper is to analyze transient events in inter-ictal EEG recordings, and classify epileptic activity into focal or generalized epilepsy using an automated method. METHODS: A two-stage approach is proposed. In the first stage the observed transient events of a single channel are classified into four categories: epileptic spike (ES), muscle activity (EMG), eye blinking activity (EOG), and sharp alpha activity (SAA). The process is based on an artificial neural network. Different artificial neural network architectures have been tried and the network having the lowest error has been selected using the hold out approach. In the second stage a knowledge-based system is used to produce diagnosis for focal or generalized epileptic activity. RESULTS: The classification of transient events reported high overall accuracy (84.48%), while the knowledge-based system for epilepsy diagnosis correctly classified nine out of ten cases. CONCLUSIONS: The proposed method is advantageous since it effectively detects and classifies the undesirable activity into appropriate categories and produces a final outcome related to the existence of epilepsy.

Astrocytoma-like multiple sclerosis.

Multiple sclerosis (MS) may sometimes mimic clinically and radiologically a brain tumor. The initial recognition of such cases is essential as it might avoid a surgical intervention and supplementary treatment. However, even in patients who underwent surgery, the appropriate preparation of the specimen is of crucial importance for the correct pathological diagnosis since tumors and non-neoplastic demyelinating lesions share some common histopathological features. We present such a case of multiple sclerosis presenting with features of an astrocytoma and was treated with surgery and additional radiotherapy.

Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.

BACKGROUND: In a recent acute study, amantadine was found to have antidyskinetic effect against levodopa-induced motor complications in patients with Parkinson disease. The longevity of this effect was not addressed but is of interest in light of the controversy in the literature regarding the duration of amantadine's well-established antiparkinsonian action. OBJECTIVE: To determine the duration of the antidyskinetic effect of amantadine in advanced Parkinson disease. DESIGN: One year after completion of an acute, double-blind, placebo-controlled, crossover study, patients returned for re-evaluation of motor symptoms and dyskinesias using a nonrandomized, double-blind, placebo-controlled follow-up paradigm. SETTING: National Institutes of Health Clinical Center. PATIENTS: Seventeen of the original 18 patients with advanced Parkinson disease complicated by dyskinesias and motor fluctuations participated in this study; 1 was lost to follow-up. Thirteen of the 17 individuals had remained on amantadine therapy for the entire year. INTERVENTIONS: Ten days prior to the follow-up assessment, amantadine was replaced with identical capsules containing either amantadine or placebo. MAIN OUTCOME MEASURES: Parkinsonian symptoms and dyskinesia severity were scored using standard rating scales, while subjects received steady-state intravenous levodopa infusions at the same rate as 1 year earlier. RESULTS: One year after initiation of amantadine cotherapy, its antidyskinetic effect was similar in magnitude (56% reduction in dyskinesia compared with 60% 1 year earlier). Motor complications occurring with the patients' regular oral levodopa regimen also remained improved according to the Unified Parkinson's Disease Rating Scale (UPDRS-IV). CONCLUSION: The beneficial effects of amantadine on motor response complications are maintained for at least 1 year after treatment initiation.

AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys.

OBJECTIVE: To evaluate the contribution of amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) glutamate receptors to the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias. BACKGROUND: Motor fluctuations and dyskinesias reflect, in part, altered function of glutamate receptors of the NMDA subtype. The possible role of AMPA receptors, however, has not yet been examined. METHODS: The authors compared the ability of an AMPA agonist (CX516) and a noncompetitive AMPA antagonist (LY300164) to alter parkinsonian symptoms and levodopa-induced dyskinesia in MPTP-lesioned monkeys. Eight levodopa-treated parkinsonian monkeys received rising doses of each drug, first in monotherapy and then in combination with low-, medium-, and high-dose levodopa. RESULTS: CX516 alone, as well as when combined with low-dose levodopa, did not affect motor activity but induced dyskinesia. Moreover, following injection of the higher doses of levodopa, it increased levodopa-induced dyskinesia by up to 52% (p < 0.05). LY300164 potentiated the motor activating effects of low-dose levodopa, increasing motor activity by as much as 86% (p < 0.05), and that of medium-dose levodopa as much as 54% (p < 0.05). At the same time, LY300164 decreased levodopa-induced dyskinesia by up to 40% (p < 0.05). CONCLUSIONS: AMPA receptor upregulation may contribute to the expression of levodopa-induced dyskinesia. Conceivably, noncompetitive AMPA receptor antagonists could be useful, alone or in combination with NMDA antagonists, in the treatment of PD, by enhancing the antiparkinsonian effects of levodopa without increasing and possibly even decreasing levodopa-induced dyskinesia.

Opposite rotation induced by dopamine agonists in rats with unilateral lesions of the globus pallidus or substantia nigra.

Normal rats with a unilateral ibotenic acid lesion of substantia nigra pars reticulata (SNR, n = 12) or globus pallidus (GP, n = 12) were challenged systemically with the mixed dopaminergic agonist apomorphine (0.5 and 1.5 mg/kg) and the indirect acting d-amphetamine (1.5 mg/kg). The low dose of apomorphine produced a weak contralateral rotation only in the SNR-lesioned group, which showed an intense ipsilateral rotation following the administration of the higher dose. GP-lesioned rats also showed ipsilateral rotation after the high dose of apomorphine. d-Amphetamine produced ipsilateral rotation in GP-lesioned rats, contrasting with a vigorous contralateral rotation in SNR-lesioned rats. The unexpected opposite rotation after apomorphine and d-amphetamine, observed only in SNR-lesioned animals, indicates that the role of SNR in basal ganglia functions is less clear and more complex than what is expected from our current model of basal ganglia circuitry and functions. On the other hand, the GP lesion resulted in a consistent and predictable ipsilateral rotation after both apomorphine and d-amphetamine, indicating a more determinant effect on the output of the basal ganglia than heretofore believed. Our results may contribute to the recently expressed views challenging the established model of basal ganglia organisation.

Antiparkinsonian and antidyskinetic activity of drugs targeting central glutamatergic mechanisms.

Motor dysfunction produced by the chronic non-physiological stimulation of dopaminergic receptors on striatal medium spiny neurons is associated with alterations in the sensitivity of glutamatergic receptors, including those of the N-methyl-D-aspartate (NMDA) subtype. Functional characteristics of these ionotropic receptors are regulated by their phosphorylation state. Lesioning the nigrostriatal dopamine system of rats induces parkinsonian signs and increases the phosphorylation of striatal NMDA receptor subunits on serine and tyrosine residues. The intrastriatal administration of certain inhibitors of the kinases capable of phosphorylating NMDA receptors produces a dopaminomimetic motor response in these animals. Treating parkinsonian rats twice daily with levodopa induces many of the characteristic features of the human motor complication syndrome and further increases the serine and tyrosine phosphorylation of specific NMDA receptor subunits. Again, the intrastriatal administration of selective inhibitors of certain serine and tyrosine kinases alleviates the motor complications. NMDA receptor antagonists, including some non-competitive channel blockers, act both palliatively and prophylactically in rodent and primate models to reverse these levodopa-induced response alterations. Similarly, in clinical studies dextrorphan, dextromethorphan, and amantadine have been found to be efficacious against motor complications. Recent observations in animal models further indicate that certain amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) antagonists alleviate, while others exacerbate, these complications. Thus, it appears that the denervation or intermittent stimulation of striatal dopaminergic receptors differentially activates signal transduction pathways in medium spiny neurons. These in turn modify the phosphorylation state of ionotropic glutamate receptors and consequently their sensitivity to cortical input. These striatal changes contribute to symptom production in Parkinson's disease, and their prevention or reversal could prove useful in the treatment of this disorder.

Topography of dopamine D-1 and D-2 receptor-mediated rotation after intrastriatal injections of dopamine-related drugs in normosensitive rats.

Naive rats were challenged systematically with apomorphine after receiving unilateral dorsal or ventral intracaudate injections of the dopamine D-1 receptor antagonist, SCH23390, or the D-2 receptor antagonist, sulpiride. Sulpiride injections into both the dorsal and ventral striatum induced a robust ipsilateral rotation, while SCH23390 elicited a weaker ipsilateral rotation only on injection into the ventral striatum. Both drugs were ineffective in saline-treated rats, although sulpiride injections into the ventral striatum after systemic saline elicited a small ipsilateral preference. The results from this rotational model mediated by normosensitive receptors indicate that only dopamine D-1 receptors in the ventral striatum mediate rotation while D-2 receptors in both striatal regions mediate rotation. A functional dichotomy between these two neostriatal regions is thus proposed.

Continuous transdermal dopaminergic stimulation in advanced Parkinson's disease.

The objective of the study was to determine the safety and efficacy of increasing doses of Rotigotine CDS in patients with advanced Parkinson's disease. The development of motor complications in Parkinson's disease has been linked to intermittent stimulation of dopamine receptors. Continuous, noninvasive, dopaminergic stimulation has not been available to date. Rotigotine CDS is a lipid-soluble D2 dopamine agonist in a transdermal delivery system that could fill this void. This inpatient study consisted of a 2-week dose escalation phase followed by a 2-week dose maintenance phase at the highest dose (80 cm2). Each individual's L-Dopa dose was back-titrated as feasible. The primary outcome measure was L-Dopa dose, and secondary outcome measures included early morning "off"-L-Dopa Unified Parkinson's Disease Rating Scale motor scores by a blinded evaluator and motor fluctuation data obtained from patient diaries ("on" without dyskinesia, "on" with dyskinesia, and "off"). Seven of 10 subjects provided data that could be evaluated. There were two administrative dropouts, and one individual was eliminated from the study because of recrudescence of hallucinations. The median daily L-Dopa dose decreased from 1,400 to 400 mg (p = 0.018, Wilcoxon test). Unified Parkinson's Disease Rating Scale motor scores were unchanged. Although diary variables improved in most individuals, only the reduction in "off" time attained statistical significance. Adverse effects were mild and consisted mainly of dopaminergic side effects and local skin reactions. The data suggest that Rotigotine CDS is an effective treatment for advanced Parkinson's disease and permits patients to substantially lower L-Dopa doses without loss of antiparkinsonian efficacy. Full-scale controlled clinical trials are warranted. In addition to potential therapeutic benefits, this drug can be used to test the hypothesis that continuous dopaminergic stimulation from the initiation of Parkinson's disease therapy will limit the development of motor complications.

Different patterns of rotational behavior in rats after dorsal or ventral striatal lesions with ibotenic acid.

Rats with total, dorsal or ventral ibotenic acid striatal lesions were challenged with DA agonists apomorphine and d-amphetamine. In rats with total lesions, both drugs induced an intense ipsilateral rotation, as did apomorphine in the dorsally lesioned rats. Amphetamine induced ipsilateral rotation in ventrally lesioned rats, but this effect may represent a non-specific potentiation of spontaneous ipsilateral rotation observed in this group. These results indicate that the neostriatum of the rat is not an homogeneous structure concerning the expression of rotational behavior after DA receptor stimulation.

White matter water diffusion changes in primary Sjögren syndrome.

BACKGROUND AND PURPOSE: Histopathologic studies have demonstrated WM damage in primary Sjögren syndrome. The purpose of this study was to evaluate WM microstructural changes by use of DTI-derived parameters in patients with primary Sjögren syndrome. MATERIALS AND METHODS: DTI was performed in 19 patients with primary Sjögren syndrome (age, 64.73 ± 9.1 years; disease duration, 11.5 ± 7.56 years) and 16 age-matched control subjects. Exclusion criteria were a history of major metabolic, neurologic, or psychiatric disorder and high risk for cardiovascular disease. Data were analyzed by use of tract-based spatial statistics, for which the WM skeleton was created, and a permutation-based inference with 5000 permutations was used with a threshold of P < .01, corrected for multiple comparisons to enable identification of abnormalities in fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. RESULTS: Tract-based spatial statistics showed decreased fractional anisotropy in multiple areas in patients with primary Sjögren syndrome compared with control subjects, located mainly in the corticospinal tract, superior longitudinal fasciculus, anterior thalamic radiation, inferior fronto-occipital fasciculus, uncinate fasciculus, and inferior longitudinal fasciculus. Increased mean diffusivity and radial diffusivity and decreased axial diffusivity were observed in most of the fiber tracts of the brain in patients with primary Sjögren syndrome, compared with control subjects. CONCLUSIONS: Patients with primary Sjögren syndrome show loss of WM microstructural integrity, probably related to both Wallerian degeneration and demyelination.

Investigation of unmedicated early onset restless legs syndrome by voxel-based morphometry, T2 relaxometry, and functional MR imaging during the night-time hours.

BACKGROUND AND PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.