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.

RLS is a common sensorimotor disorder in which sensory unease evokes motor restlessness of the lower limbs. The symptoms, SLD and PLMs, fluctuate in severity with the diurnal cycle, worsening during the night-time hours.¹RLS encompasses eRLS, which is mainly idiopathic, and late-onset RLS, which is usually a secondary form.² eRLS affects younger patients with a positive family history and has been correlated with a gene variant (btbd9) that is associated with iron content in the midbrain.³ Histopathologic studies in idiopathic RLS have shown decreased iron staining in the substantia nigra and minimal transferrin-receptor staining in neuromelanin cells.⁴ MR imaging studies by using T2 relaxometry metrics have shown a lower iron content of the substantia nigra in eRLS⁵ and late-onset RLS.⁶With VBM, the brain volume has been assessed in patients with RLS, with conflicting findings. Small sample size, use of different techniques, inclusion of patients under medication, and lack of distinction between eRLS and late-onset RLS were probably responsible for the inconsistency in observations.^7–9fMRI studies have been conducted in patients with RLS with undefined disease onset¹⁰ and late onset.⁶ fMRI during episodes of combined sensory and motor symptoms has revealed activity in the cerebellum, red nucleus, and thalamus.¹⁰ Patients with late-onset RLS performing regular dorsiflexion and plantar flexion of the feet in hours of daylight demonstrated greater activation of the dorsolateral prefrontal cortex of the left middle gyrus and inferior frontal gyrus and, marginally, of the cingulate gyrus.⁶ Although VBM, T2 relaxometry, and fMRI have all been used in the study of patients with RLS, the 3 techniques have never been applied simultaneously in the same patient population. T2 relaxometry detects ultrastructural tissue changes by decline of the transverse component of the magnetization due to irreversible dephasing; it is influenced by water content, cerebral blood flow, and iron deposition.¹¹ VBM is an automated technique which, by using voxelwise statistical analysis, detects brain-volume differences with no a priori assumptions about their location.¹² fMRI evaluates brain function by detection of hemodynamic changes related to brain activation.¹³ Evaluation of the same eRLS population for brain volume changes, brain iron content, and brain activation during episodes of RLS symptoms could provide improved insight into the pathophysiology of the disease. In this study, patients with unmedicated eRLS were assessed by brain MR imaging by using VBM and T2 relaxometry metrics to analyze brain volume and T2 relaxation time, respectively. fMRI was performed in the night hours during episodes of exacerbation of symptoms.