Medial Thalamic Dysregulation in Idiopathic Restless Legs Syndrome

Abstract & Commentary

By Alexander Shtilbans, MD, PhD, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Shtilbans reports no financial relationships relevant to this field of study.

Synopsis: There is a reduced N-acetylaspartate/creatine-phosphocreatine ratio and N-acetylaspartate concentration at the level of the medial thalamus in patients with restless legs syndrome (RLS), suggesting involvement of the limbic system in the pathophysiology of RLS.

Source: Rizzo G, et al. Abnormal medial thalamic metabolism in patients with idiopathic restless legs syndrome. Brain 2012;135:3712-3720.

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a distressing urge to move the legs and occasionally the arms, usually accompanied by uncomfortable sensations in the affected limbs. The sensations occur particularly in the evening or at night and are relieved by movement. RLS can be primary or secondary due to metabolic abnormalities. The pathophysiology of primary RLS is poorly understood. A previously published functional MRI (fMRI) study1 revealed activation in the medial thalamus, putamen, middle frontal gyrus, and anterior cingulated gyrus in patients with RLS, implicating limbic system involvement.

The authors of this paper evaluated the metabolism and structural features of medial thalamic regions in patients with idiopathic RLS using multimodal MRI tests, which included proton magnetic resonance spectroscopy (H-MRS), diffusion tensor imaging, voxel-based morphology as well as volumetric and shape analysis. This was a cross-sectional study in which 23 patients with chronic idiopathic RLS and 19 healthy controls were studied. The patient group was comprised of drug-naïve patients as well as those treated with dopaminergic medications. The latter were off of their medications for at least 2 weeks prior to the study. The H-MRS study revealed a significantly reduced N-acetylaspartate/creatine-phosphocreatine ratio and N-acetylaspartate concentration at the level of the medial thalamus in patients with RLS. Interestingly, the lower N-acetylaspartate levels were associated with a family history of RLS in the studied patients. Volumetric and shape analysis, however, showed no difference between patients and controls. The reduced levels of N-acetylaspartate were similar in both previously treated and untreated RLS patients. No other magnetic resonance modality showed any differences between the patients and controls in the study. Based on the observed results, the authors suggested that the involvement of the medial portion of the thalamus could have a primary role in the pathophysiology of RLS because its function is modulated by dopaminergic afferents. It is also suggested that given a role of medial thalamus in sleep regulation, the observed decrease in N-acetylaspartate could be secondary to the sleep impairment. Furthermore, dopaminergic dysfunction may impair medial thalamic pain processing, implicating the endogenous opioid system in the pathogenesis of RLS. The authors concluded that the observed abnormal medial thalamic metabolism in RLS suggests a role of limbic system pathology in this disease.

Commentary

Previous fMRI studies showed activation of thalamus and anterior cingulated gyrus among other brain areas in patients with RLS. The authors of the current study evaluated metabolism and structural features of medial thalamic regions of the RLS patients compared to healthy controls. The study design shows slight predominance of women in the study group compared to controls. The patients were off of dopaminergic medications for at least 2 weeks prior to the study. It is not clear, however, if a 2-week washout period would be sufficient to completely eliminate the effect of these medications. The authors do not mention any medications that the controls might have been taking for any non-neurological conditions, which could be a confounder. Additionally, it is not clear whether other diseases potentially affecting the findings in either patients or controls have been excluded.

The reduction in N-acetylaspartate observed in the patient group was the only difference noted in the study, which utilized several imaging modalities such as diffusion tensor imaging, voxel-based morphometry, and volumetric and shape analysis. N-acetylaspartate is thought to be a neuronal marker, which previously was noted to be decreased in neurodegenerative conditions such as amyotrophic lateral sclerosis and multiple sclerosis. The decrease in such a marker could represent either neuronal loss or neuron dysfunction, the latter being more likely given that there are no structural differences noted between the groups. The authors suggest that the involvement of the medial portion of the thalamus might play a primary role in the disease and reflects an impairment of medial pain mechanism secondary to dopaminergic dysfunction.

The authors only used idiopathic RLS patients in this study, but it would be interesting to see if other forms of RLS, such as those related to pregnancy, iron deficiency, or renal impairment, would be also associated with decreased N-acetylaspartate in the medial thalamus. The authors acknowledged a limitation of the study related to lack of investigation of circadian changes in patients with RLS. But overall, the authors present important findings that could shine light on the pathophysiology of idiopathic RLS and hopefully broaden our knowledge of brain areas affected by this disease.

Reference

1. Astrakas LG, et al. T2 relaxometry and fMRI of the brain in late-onset restless legs syndrome. Neurology 2008;71:911-916.