Fluorodopa Positron Emission Tomography

There have been three published PET studies using ¹⁸F-DOPA ligand in the evaluation of RLS. The small study by Trenkwalder and colleagues¹ compared 4 RLS subjects with 10 control subjects and found no difference in either caudate or putamen uptake of isotope between the groups. Turjanski and associates² compared 13 RLS subjects with 14 control subjects and found a significant decrease in isotope in the putamen but not in the caudate of RLS subjects. This decrease, however, was much less than that commonly detected in patients with Parkinson’s disease. About 40% of the RLS subjects in this study were receiving dopaminergic agents before the study; these medications were stopped about 36 hours before the scan. In a post hoc analysis, they compared the findings for 8 drug-naïve RLS subjects with findings for control subjects, but the results were not different. The dopamine-2 receptor (D2R) binding potential (BP) was also studied by PET (see later) in this same group of subjects, thus allowing for a comparison with ¹⁸F-DOPA results. They found a strong correlation (r = 0.62. p =.02) between ¹⁸F-DOPA K_i and D2R BP in the putamen for the RLS group. RLS severity and total sleep time did not correlate with any of the PET measures. Ruottinen and associates³ studied nine drug-naïve RLS subjects and found a significant decrease in both putamen and caudate compared with 27 matched control subjects. What is unclear from this study is the exact clinical nature of the supposed RLS group, because the authors refer to this group as having “RLS and PLMD (periodic limb movement disorder).”

The degree of decrease in ¹⁸F-DOPA isotope in RLS patients is relative small (about 10%) compared with that seen in patients with Parkinson’s disease or other neurodegenerative disorders.^4,5 Even if small, the real question is what does any difference, large or small, mean with regard to ¹⁸F-DOPA isotope? Studies of this basic question have lead to the conclusion that ¹⁸F-DOPA isotope defines a complex multisystem process: cell uptake, decarboxylation, vesicular uptake, release, and metabolism—all contribute in a dynamic way to the kinetics (K_i) of this isotope.^6,7 Therefore, the most that can be said about the findings is that there are subtle dynamic changes in the turnover of dopamine in the putamen (and possibly caudate) of RLS patients.

Studies of Dopamine-2 Receptor

There have been six studies using ¹²³iodobenzamide (IBZM) SPECT and two studies using ¹¹C-raclopride (RAC) PET techniques to investigate D2R BP in RLS. One study also used ¹¹C-FLB 457 to examine extrastriatal D2Rs.

Staedt and colleagues^8–10 were the first to evaluate RLS for possible changes in D2R BP using SPECT techniques. This involved a series of three reported studies in 1993 and 1995. All three studies reported a decrease in D2R BP in the striatum of RLS compared with control subjects. However, there were several critical issues in regard to methodology. First, the RLS population was poorly defined and included subjects with pure PLMD (i.e., no RLS symptoms). Second, in two of the three studies, subjects were undergoing treatment and were withdrawn only 36 hours before the SPECT procedure.^8,9 In the last study, the authors reported, “RLS patients were free of drugs interfering with central dopaminergic system.”¹⁰ It is unclear if those patients were drug-naïve or did not take drugs prior to the procedure. Finally, there were significant age differences, with the control subjects being hospital staff members and much younger than the RLS subjects. This is important, as a strong inverse correlation between age and D2R BP has been reported (see later).

Eisensehr and associates¹¹ studied 25 RLS subjects, of whom 56% were drug-naïve, and compared the findings of 20 age- and gender-matched control subjects. No significant between-group differences in SPECT BP were found. BP ratio did not correlate with the duration of RLS symptoms, levodopa dosage, serum iron, serum ferritin, periodic limb movement syndrome (PLMS), or sleep efficiency. However, there was a strong correlation (r = 0.65, p <.0001) between the age of the subjects (controls and RLS inclusive) and the BP ratio: the older the age, the lower was the BP. Tribl and associates¹² studied 14 pretreated RLS and 9 healthy gender- and age-matched control subjects and also found no difference between the groups for SPECT BP in the striatum. As with Eisensehr and coworkers’ study, BP ratio strongly correlated with age and D2R BP in both RLS (r = 0.7, p =.005) and control (r = 0.68, p =.032) groups. The BP ratio did not correlate with PLMS, sleep efficiency, or RLS duration.

Michaud and colleagues¹³ studied 10 drug-naïve RLS patients and found a significant reduction in striatal D2R BP compared with 10 control subjects. In addition, 9 of the 10 patients showed a mean striatal D2R binding below the control group mean. However, BP did not correlate with severity or PLMS. The only obvious difference between this study and that of Eisensehr and Tribl and colleagues is the time of day at which the procedure was done: Michaud and colleagues’ studies whereas done late in the day (4:30 P.M. to 9:30 P.M