An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome

Methods.

Results.

In the patients, the mean FDOPA uptake value (K_i^occ) was reduced to a similar degree in both the caudate nucleus to 88% of the control mean value (p = 0.0008) and in the putamen to 89% of the control mean value (p = 0.0001) (table).

The K_i^occ values overlapped between the patients and controls, both in the caudate and in the putamen (figure). The K_i^occ of two patients fell below −2 SDs of the control mean in the caudate, and in the putamen, five patients’ K_i^occ values were below −2 SDs of the control mean value.

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Figure. Comparison of individual 6-[¹⁸F]fluoro-l-dopa K_i^occ values (×10⁻³ min⁻¹) in patients with periodic limb movement disorder (PLMD) and restless legs syndrome (RLS), and in healthy controls. The numbers refer to the motor score of the Unified Parkinson’s Disease Rating Scale (UPDRS). Bar = mean; NA = not available.

Six patients showed slightly increased muscle tone in arms during contralateral activation or mild bradykinesia in hand movements, which can be normal variants, especially in elderly individuals. The motor UPDRS scores ranged from 0 to 10 in the patients, and there was no significant association between the score and FDOPA uptake (r = 0.291, p = 0.484, n = 8 for the caudate nucleus; and r = −0.524, p = 0.182, n = 8 for the putamen; r = Pearson’s correlation coefficient [see the figure]).

Discussion.

Our results show a slight but significant decrease in striatal FDOPA uptake to a similar degree both in the putamen and in the caudate nucleus in patients with PLMD-RLS compared with healthy controls. This equal affection of the caudate and putamen differs, for example, from the dopaminergic dysfunction in Parkinson’s disease (PD), which affects the putamen earlier and more severely than the caudate. The caudate K_i^occ values in two patients and the putamen K_i^occ in five patients were more than 2 SDs below the control mean values. Also, in a previous PET study,4 there was clear overlapping between controls and RLS patients: all the patients’ individual caudate and putamen FDOPA uptake values were within the control range. Based on K_i^occ values alone, it is difficult to draw conclusions about whether an individual subject has PLMD-RLS because of the considerable overlapping. The individual patients with low FDOPA uptake values did not differ clinically from the rest of the PLMD-RLS patients.

PLMD occurs in 80% of patients with RLS.2 Pure PLMD and pure RLS may represent two ends of a continuum, as many patients have both of these syndromes, with PLMD predominating in some and RLS in others. PLMD might be a forme fruste of autosomal dominant RLS.7 Patients with PLMD have been shown to respond best to levodopa, whereas patients with severe RLS respond best to a dopamine agonist (pergolide).8 Our findings are in accordance with the hypothesis that the brain dopaminergic system is involved in the pathogenesis of PLMD and RLS, based on the effectiveness of dopaminergic medication in PLMD2 and the reversal of the therapeutic benefit by dopamine receptor blockers,2 or the worsening of PLMD with a blocker of dopamine release.2

The dopaminergic hypothesis of both PLMD and RLS has been supported by decreased striatal dopamine D₂ receptor occupancy in ¹²³I-IBZM SPECT studies in patients with PLMD-RLS or PLMD alone.3 In RLS patients, a mild but significant reduction in the putamen, both in the FDOPA uptake and in the dopamine D₂ receptor binding, has been reported.4 In contrast, no difference in striatal FDOPA uptake was found between four RLS patients and controls in another current report.5 However, it was not stated whether the patients also had PLMD.5 The dopaminergic function may differ depending on whether the patients have pure RLS or PLMD-RLS. In addition, because of overlapping between control and patient values in this study and others,4 significant differences are unlikely to be found between patients and controls in a small population.

Dopaminergic pathways in the CNS have been thought to be the primary transmitter system and the opioids the secondary one involved in PLMD and RLS. However, the pathophysiologic mechanism of PLMD-RLS probably is more complicated, including stimulating and inhibiting amino acids.9 In addition, it has been found with functional MRI that in patients with PLMD-RLS, the cerebellar and thalamic activation may participate in the generation of sensory symptoms.10 Functional MRI showed that PLMD in RLS mainly is associated with overactivity in the cerebellum, the red nuclei, and the brainstem. Reticular structures in the brainstem may be the primary generator of the RLS.10

The current study concerns only the nigrostriatal dopaminergic system. Detection of changes in other dopaminergic systems—possibly even more important in PLMD-RLS—remained outside of the resolution of our PET camera or the sensitivity of FDOPA. Our results of reduced FDOPA uptake in the caudate nucleus and putamen indicate mild striatal presynaptic dopaminergic dysfunction in PLMD-RLS.