A prospective study of the cumulative incidence and course of restless legs syndrome in de novo patients with Parkinson’s disease during chronic dopaminergic therapy

Abstract

The authors report the cumulative incidence of Restless Legs Syndrome (RLS) over a 3 years follow-up period in 92 de novo Parkinson's disease patients under chronic dopaminergic therapy and the clinical course of the sensory-motor disorder over 12 months as from its onset. The overall cumulative incidence of RLS was found by 15.3%, i.e. 14 incident cases, and by 11.9%, i.e. 11 incident cases, after the exclusion of possible "secondary" forms of the disorder. These figures are higher than those reported in general population in Germany (Study of Health in Pomerania), confirming our previous findings of incidence rate of the disorder. At the end of the 3 years follow-up period the prevalence of "current" RLS was significantly higher than that previously found in drug naïve Parkinson's disease patients and in controls, supporting the view that RLS emerging in the course of chronic dopaminergic therapy is the main determinant of the co-morbid association with Parkinson's disease. During the 12 months period of observation the RLS showed a frequency of occurrence of 6.08 episodes per month on average and a remittent clinical course was prevailing in the 11 incident cases, with a significant frequency decrease in the second as compared to the first 6 months, i.e. 3.26 versus 8.9 episodes per month, and none of the patients developed augmentation in the same period. It is hypothesized that the remittent course could be due to long-term adaptation (downregulation) of the hypersensitive post-synaptic dopamine receptors in the spinal cord to a continuous dopaminergic stimulation, possibly coupled with compensatory up-regulation of pre-synaptic dopamine re-uptake mechanism, in the patients in which the hypothalamic A11 area, site of origin of the dopamine-mediated diencephalo-spinal pathway, is involved in the neurodegenerative process.

Restless Legs Syndrome and Parkinson Disease: A Causal Relationship Between the Two Disorders?

“…The increased incidence of RLS/WED in PD patients is supported by all three longitudinal studies ( 64 – 66 ), however the possible influence of dopaminergic therapy in inducing RLS/WED is reported in two out of three ( 64 , 65 ). Furthermore, neuroimaging showed a preserved dopaminergic pathway in PD+RLS/WED in comparison to PD alone.…”

“…These findings suggest that dopaminergic medication may be crucial for the development of RLS/WED in PD patients. The same authors reported an updated cumulative incidence and clinical course study in the same cohort of patients after a 3-year follow-up ( 65 ). This study confirmed that RLS/WED prevalence is increased in PD patients under treatment in comparison to general population and drug naïve PD patients.…”

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis

“… 43 Moreover, dopaminergic treatment of Parkinson's disease has been suggested to precipitate restless legs syndrome in some patients. 44 The risk locus on chromosome 15q23 (encompassing MAP2K5 and SKOR1 ) overlaps with GWAS signals of four different traits, including the posterior cortical atrophy variant of Alzheimer's disease ( appendix pp 39–41 ). The ORs of the shared SNP rs11637445 were 1·48 for posterior cortical atrophy and 0·89 for restless legs syndrome, which is consistent with the negative correlation between these two disorders.…”

An overview of sleep and circadian dysfunction in Parkinson's disease

“…Lee and colleagues, in fact, stated that the duration of anti‐parkinsonian therapy is the most significant contributor to the development of RLS symptoms in the PD population (Lee, Shin, Kim, & Sohn, ), and a similar conclusion has been strongly suggested by Calzetti and colleagues (Calzetti, Angelini, Negrotti, Marchesi, & Goldoni, ). Moreover, some researchers have only analysed RLS in patients with PD, without any direct comparison with the general population (Bhalsing, Suresh, Muthane, & Pal, ; Braga‐Neto, da Silva‐Junior, Sueli Monte, de Bruin, & de Bruin, ; Gomez‐Esteban et al., ; Guerreiro, Nishikawa, Ferreira, Melo, & Prado, ; Lang & Johnson, ; Lee et al., ; Marchesi et al., , ; Neikrug et al., ; Ondo, Vuong, & Jankovic, ; Peralta et al., ; Svensson, Beiske, Loge, Beiske, & Sivertsen, ; Tan, Lum, & Wong, ; Verbaan, van Rooden, van Hilten, & Rijsman, ; Ylikoski, Martikainen, & Partinen, ); in other instances a case–control study had been performed (Table ).…”

“…Moreover, some researchers have only analysed RLS in patients with PD, without any direct comparison with the general population (Bhalsing, Suresh, Muthane, & Pal, 2013;Braga-Neto, da Silva-Junior, Sueli Monte, de Bruin, & de Bruin, 2004;Gomez-Esteban et al, 2007;Guerreiro, Nishikawa, Ferreira, Melo, & Prado, 2010;Lang & Johnson, 1987;Lee et al, 2009;Marchesi et al, 2016aMarchesi et al, , 2016bNeikrug et al, 2013;Ondo, Vuong, & Jankovic, 2002;Peralta et al, 2009;Svensson, Beiske, Loge, Beiske, & Sivertsen, 2012;Verbaan, van Rooden, van Hilten, & Rijsman, 2010;; in other instances a casecontrol study had been performed (Table 4).…”