Introduction
Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system that is known to be frequently associated with various comorbidities, often adversely affecting the quality of life of the patients and the course or status of the disease [
1].
Restless legs syndrome (RLS) is a sleep-related movement disorder characterized by a distressing urge to move the legs and relief by movement, usually accompanied by unpleasant sensory perceptions like pain and paresthesia, predominantly occurring at night [
2]. The pathophysiology of RLS is not completely understood; however, there is evidence that RLS may be linked with central iron deficiency and disturbance [
3]. While a strong genetic influence in idiopathic RLS is assumed, conditions that cause secondary RLS include iron deficiency, pregnancy, and kidney disease [
3].
Prevalence and incidence of RLS is increased in MS, for which reason studies have suggested that MS is a cause of secondary RLS [
4,
5]. While RLS is reported to be approximately 7% in general population, its prevalence in MS patients ranges from 12.12 to 57.50% [
2,
4]. Furthermore, MS is associated with a fourfold increased odds for RLS.
The pathophysiological background that may lead to MS-related RLS is still under debate. As iron is also an important cofactor in the myelination of the central nervous system, disturbances in the brain iron metabolism have been suggested as possible mechanism [
6].
A lot of MS symptoms, especially motor deficits, can be attributed to certain lesions in the brain or the spine. Also, non-motor symptoms, like sensory phenomena and autonomous deficits, have been shown to be attributed to specified cerebral lesions sites [
7,
8].
Epidemiological studies found evidence of an association of RLS with the presence of cervical spinal cord lesions [
9,
10]. Analyzing the regional MS lesion loads, Manconi et al. [
5] demonstrated that the occurrence of MS-related RLS correlated with an increased presence of cervical spinal cord lesions.
However, little is known about the relationship between cerebral, especially supratentorial lesion sites and the development of RLS so far. Previous studies used a dichotomous descriptive statistical analysis or analyzed the lesion load by using a region of interest-based approach [
5,
9,
10]. To our knowledge, no neuroimaging study has systematically assessed possible correlations with specific lesion sites using a statistical voxel-wise analysis of the whole brain.
Therefore, in our study, we hypothesized that demyelinating MS lesions in the brain might contribute to RLS in people with MS (pwMS). To determine associations between occurrence of RLS related to MS and cranial MS lesion location, we applied a voxel-based lesion symptom mapping (VLSM) analysis [
11‐
13].
Discussion
RLS is known to be associated with MS, having a fourfold increased prevalence in pwMS than in the general population [
4]. However, the pathophysiological background for this relationship still remains unclear. Various neurological deficits and phenomena have been shown to be attributed to MS lesions in specific neuroanatomical regions [
7,
17]. In pwMS, previous studies found an association of RLS with the presence of cervical MS lesions [
5,
10].
However, especially the role and patterns of supratentorial lesions in the pathogenesis of RLS in MS remains unclear.
In the present study, we tried to identify brain regions associated with RLS in pwMS using a voxel-wise-based lesion imaging approach. The VLSM analysis identified specific sites of cerebral MS lesions to be associated with the RLS. The voxel-wise comparison of the absence or presence of RLS between patients with and without lesions in a given voxel (Table
2, Fig.
2) yielded associations between RLS and T2-weighted MS lesions in the white matter close to the cortex in the left hemisphere.
Current concepts of RLS assume a dysfunction of the dopaminergic system, and damages including demyelination along this route may cause a dysfunction manifesting as RLS [
4]. In fact, we did not detect lesions in brain regions predominantly involved in the dopaminergic motor control, like the striatum, thalamus, hypothalamus, substantia nigra, or the limbic system.
In our study, we found a lesion cluster associated with RLS in the white matter in proximity of the gyrus precentralis, which may indicate a damage of the corticospinal tract. A decrease of white matter volumes of the precentral gyri has been shown in RLS before [
23]. RLS and the periodic limb movements occurring in RLS patients share certain similarities with the Babinski sign, which is pathognomonic for an affection of the corticospinal neurons [
4]. Symptomatic dyskinesia in MS has been demonstrated to be associated, among others, with lesions in the central nervous motor system, like the basal ganglia and the pyramid tract [
17]. Interestingly, we did not detect any significant lesion cluster in lower structures like the basal ganglia and the infratentorial pyramidal tract, structures of the motor control or the efferent motor system that have been shown to be affected in other sorts of movement disorders in MS [
17,
24]. A reason for this may be the predilection of MS lesions for the periventricular white matter, as demonstrated in the lesion overlap (Fig.
1). Furthermore, we did not find any evidence for an involvement of afferent sensory pathways in the pathogenesis of symptomatic RLS in MS [
3]. Our study suggests a damage of those infratentorial motor pathways plays a minor role in RLS in pwMS, which could be more a result of disinhibition by a disruption of supratentorial structures.
The mechanisms leading to RLS due to supratentorial, e.g., subcortical, MS lesions remain unclear. Local demyelination may lead to a damage and a disruption of neurological pathways and interconnections, consecutively with an inhibition or disinhibition of secondary neurological structures [
25,
26]. As postulated before, spinal locomotor excitability may be caused by impairment of inhibitory supraspinal locomotor descending neurons to the spinal gray matter [
24].
Alternatively, demyelination may cause ephaptic activity, ephaptic spread, and hyperexcitability in the affected regions of the central nervous system, as proposed in paroxysmal dyskinesia in MS before [
17,
25]. In fact, demyelination is known to render axons hypersensitive [
27].
Notably, our detected lesion cluster was located in the left hemisphere, although patients did not report any lateralization of the RLS complaints in the study. The reason for this remains speculative. However, lesion lateralization has been reported in patients with bilateral pyramidal and extrapyramidal symptoms in MS before [
7,
17]. Also in RLS patients without MS, white matter abnormalities in areas of the efferent motor system and sensorimotor integration, lateralized to the left hemisphere, have been found using diffusion-tensor imaging [
28]. As a hypothesis, RLS in pwMS may occur due to a disinhibition because of distinct lesions in the lateralized central motor control or motor pathways in a dominant (left) hemisphere. Consequently, supratentorial lesions may only partially account for RLS in pwMS.
Subjects with symptomatic RLS had a higher disease duration, a factor that might increase the probability of a MS lesion localized in the efferent motor system that may lead to symptomatic RLS. Several studies have demonstrated a correlation between MS severity [
5] and the occurrence of symptomatic RLS [
3,
10]. However, the cerebral lesion load was lower in individuals with RLS in our cohort. Therefore, the previously reported higher clinical MS severity in RLS patients may possibly have resulted of a higher rate of lesions of the spinal cord.
In summary, in this study, we were able to detect a lesion cluster in the left white matter next to the gyrus precentralis associated with RLS in pwMS. As hypothesis, pwMS with symptomatic RLS may partially suffer from a dysfunction of the corticospinal tract due to MS lesions.
Limitations
Several limitations of this study need to be considered. The manifestations of MS are very heterogeneous. Because of the retrospective nature, the diagnosis of RLS based on patients’ records was not systematically assessed, which may have led to underreporting. Although patients were asked carefully, we cannot rule out that patients of the control group had no RLS. An exact classification of the type of RLS, although desirable, could not be realized. Therefore, other causes for RLS than MS were not definitely excluded. A more well-defined cohort of RLS due to MS or a higher sample size may have produced more clear results. MS disease duration was higher in pwMS with RLS than in the control group. As disease duration is associated with RLS severity, we cannot exclude that this may have affected our results. The higher age in the cohort is a confounding factor, too. Additional matching for age and disease duration was not realizable, so we cannot exclude that differences in these parameters between both groups may have biased our results.
We did not have a standardized MR protocol, which could have influenced the results. Although MRI slice thickness of 5 mm meets the criteria of the current guidelines for MS, a lower thickness would have been desirable [
14,
15]. Spinal lesions are known to cause restless legs syndrome in MS. Unfortunately, the VLSM approach is not validated for correlating spinal lesions. Methodically, this study only was able to examine cerebral lesions, which could have biased the results. However, it seems unlikely that the presence or absence of spinal cord lesions may have produced false-positive results, i.e., the cerebral lesion cluster in the Liebermeister analysis of the brain. Tissue damage in MS may be diffused and not detectable in MRI, but also impair neurons involved in the development of RLS in MS.
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