Abstract
Objective: To use PET to study striatal dopaminergic function in restless legs syndrome (RLS).
Background: RLS is a common disorder experienced by as much as 5% of the population. It has been suggested that this condition is associated with a disturbance of dopaminergic transmission.
Methods: The authors measured nigrostriatal terminal dopamine storage with 18F-dopa and striatal D2 receptor binding with 11C-raclopride PET in 13 RLS patients, five of whom were receiving treatment with l-dopa at the time of scanning. RLS results were compared with those of age-matched control subjects.
Results: Mean caudate and putamen 18F-dopa uptake were mildly reduced in the RLS patients compared with control subjects, and this reached significance (p = 0.04) in the putamen. Mean D2 binding was reduced in the caudate (p = 0.01) and the putamen (p = 0.008) in RLS patients compared with control subjects. Six of the 13 RLS patients had caudate and putamen D2 binding reduced below the control range. Three other RLS patients showed only reduced putamen D2 binding. There were no significant differences in striatal 18F-dopa uptake or D2 binding between l-dopa–naive and l-dopa–treated RLS patients.
Conclusions: These PET findings support the hypothesis of central dopaminergic dysfunction in RLS.
Restless legs syndrome (RLS) is a chronic condition. It has a prevalence of 5% in the general population.1,2 This syndrome is well characterized clinically, although its underlying pathology is not fully understood.
RLS may commence at any age, even during childhood, although it is usually seen in adults.3 It has a fluctuating clinical course but tends to progress with age.4 When at rest, RLS patients experience unpleasant sensations and pain generally localized to the legs and associated with an urge to move these limbs. Characteristically, movement of the affected limbs (such as pacing the floor) induces relief, although in severe cases this is only transient. RLS has a circadian influence, with symptoms being predominant in the evenings or at night with consequent disruption of sleep.5 In 90% of patients, RLS constitutes a major cause of sleep disturbance6 and impairs performance of other leisure activities in repose. Despite this, however, the syndrome has been largely ignored by clinicians.4,7
RLS may be idiopathic or secondary to renal failure, iron deficiency anemia, or pregnancy.6 Idiopathic RLS is associated with a positive family history in approximately 90% of patients without neuropathy.8 Patients with RLS may also exhibit periodic leg movements (PLM) during sleep, which is also known as nocturnal myoclonus syndrome.6
Idiopathic RLS has been attributed to both peripheral and central nervous dysfunction. The clinical improvement observed with drugs that interact with the dopaminergic, adrenergic, and opioid systems suggests that a disturbance of these neurotransmitters may underlie this condition.4,9 There are several indicators, however, that a dysfunction of the dopaminergic system may play a major role in RLS pathogenesis. Dopaminergic drugs are the most effective treatment for RLS,6,8 whereas the use of dopamine antagonists is associated with an increased in its severity.10 Neuroleptics can also induce akathisia, which has overlapping features with RLS.3,11 Restlessness may be seen in dopamine-deficient patients with parkinsonism.3,8 A previous 123I-iodobenzamide (IBZM) SPECT study12 showed a reduction of striatal D2 receptor binding in patients with PMS and RLS. One patient with both RLS and PMS showed increased levels of dopamine and its metabolites in the CSF, suggestive of increased dopamine production.13
Using PET, we investigated the integrity of the striatal dopaminergic system in 13 patients who fulfilled clinical diagnostic criteria for RLS. Striatal dopamine storage capacity was assessed with 18F-dopa whereas striatal D2 receptor binding was measured with 11C-raclopride PET. RLS patient results were compared with corresponding control databases for each radioligand.
Patients and methods.
Patients.
Thirteen patients (seven women and six men) with RLS underwent both 18F-dopa and 11C-raclopride PET (table 1). Their mean age at the time of scanning was 58 years (range, 55 to 68 years). All patients fulfilled clinical diagnostic criteria for RLS14: they experienced dysesthesias (described variably as prickling, tingling, or crawling sensations either alone or associated with pain) that were localized to the legs and preceded an urgent need to move. Walking or movement of the affected legs was associated with relief of these sensory feelings. All individuals experienced these symptoms when at rest, particularly in the evening and at night. The condition was chronic in all patients, with a mean duration of 26 years (range, 4 to 41 years). PMS were reported by 6 of the 13 patients. Heat was recognized as an exacerbating factor in six patients whereas one patient mentioned worsening of the symptoms during pregnancy. A family history of RLS was reported by 9 of the 13 patients. All patients reported unpleasant feelings in both legs, although in 4 of the 13 patients there was a side predominance (right leg in two patients and left leg in two others). Severity of RLS was scored with the Restless Legs Rating Scale.15 This scale assesses the frequency, severity, and duration of restlessness and has a maximum score of 10 (table 2). Usual total nighttime sleep and restlessness in the arms were also recorded. Neurologic examination was normal in all but one patient. Patient 9 showed mild right-side bradykinesia without any other associated feature of parkinsonism and 35 years evolution of otherwise typical RLS. One patient had chronic Raynaud’s syndrome. At the time of 11C-raclopride PET, five patients were receiving treatment with l-dopa in daily doses ranging from 150 to 400 mg. Duration of treatment ranged from 5 months to 3 years. Patient 11 replaced l-dopa with ropinirole 0.75 mg/day 3 weeks before the 18F-dopa study. Other medications included codeine, diazepam, gabapentin, and temazepam (one patient each). None of the patients had a previous history of exposure to dopamine-blocking agents.
Clinical details of RLS patients
Severity of the syndrome in RLS patients
The mean interval between 18F-dopa and 11C-raclopride scans was 46 days (range, 1 day to 8 months).
Results of patients’ 18F-dopa PET studies were compared with a database of 14 control subjects with a mean age of 59 years (range, 20 to 84 years). 11C-raclopride PET results were compared with those obtained for nine control subjects with a mean age of 57 years (range, 32 to 74 years).
Methods.
Scan procedure.
PET was performed using a CTI 931/-08/12 camera (Sun Microsystems, Mountain View, CA), which provides a reconstructed spatial resolution of 7.0 × 8.5 × 8.5 mm (full width half maximum) for 15 simultaneously acquired transaxial slices.16 All PET studies were performed at the MRC Cyclotron Unit, Hammersmith Hospital, London, UK.
The patient’s head was immobilized while in the scanner using a comfortable, molded head holder. Patients were aligned with the orbitomeatal line parallel to the detector’s rings. A 10-minute transmission scan was collected using a retractable external source of 68Ga/68Ge to correct for attenuation of 511Kev γ-radiation by the brain and skull. All medication was withdrawn the night before the scan. On the morning of the 18F-dopa PET study, subjects ate a light breakfast. All individuals received an oral dose of 100 mg carbidopa, a peripheral dopa decarboxylase blocker, 1 hour before PET scanning, and an additional 50 mg 30 minutes before 18F-dopa injection.
For 18F-dopa PET, patients were injected with a mean dose of 158 ± 36 MBq of tracer, and for 11C-raclopride PET they received 332 ± 58 MBq in 5 mL normal saline as a bolus. Scanning began after a 30-second background frame, and a total of 22 serial time frames were collected during a 60-minute period for 11C-raclopride and 25 frames were collected during a 94-minute period for the 18F-dopa scan.
Although some patients reported discomfort in their legs during the scans, these symptoms did not require the interruption of any study nor did they lead to head movement.
Data analysis.
Image analysis was performed on Sun Sparc2 computer workstations. 11C-raclopride studies were analyzed using Analyze software (version 7.5.4; BRU, Mayo Foundation, Rochester, MN)17 whereas 18F-dopa studies were analyzed using in-house software written in IDL (Research Systems Inc., Boulder, CO). Regions of interest (ROIs) were defined by inspection of an image of integrated tracer activity collected 20 to 60 minutes after tracer injection for the 11C-raclopride study, and collected 20 to 90 minutes after tracer injection for the 18F-dopa study. ROIs were placed using a standard template arrangement. One square ROI (length of 10.4 mm) was placed over the head of each caudate and one elliptical ROI (25.8 × 10.4 mm) was placed over the putamen of each hemisphere. An additional circular ROI (diameter, 32.8 mm) was placed over each occipital and cerebellar hemisphere. All ROIs were defined in the two optimal adjacent planes. Regional time–activity plots were then obtained for each region by projecting these ROIs onto the dynamic time frames.
18F-dopa data were analyzed using a modified multiple time graphical analysis approach with the occipital lobe as a nonspecific tissue reference input function.18 This method generates influx constants (Ki values) for left and right caudate and putamen as well as side-to-side averaged values. The Ki is a rate constant that reflects uptake and decarboxylation of 18F-dopa to 18F-dopamine by the nigrostriatal terminals and therefore is a marker of their functional integrity.19
Regional time–activity curves of the 11C-raclopride studies were analyzed using a reference tissue model with a cerebellar input function.20 This method computes receptor binding potentials (BPs), which reflect the ratio of receptor availability to the dissociation constant (Bmax/Kd).21-23 Left and right caudate and putamen as well as side-to-side averaged BP values were obtained for each individual. Comparisons of mean 18F-dopa Ki’s and 11C-raclopride BPs between RLS patients and control groups were performed with Student’s unpaired t-test. Correlations between both radioligand bindings and with clinical data were examined with Pearson’s product moment correlation coefficient. A threshold of p < 0.05 was considered significant.
Results.
Mean RLS caudate and putamen 18F-dopa Ki values were mildly reduced compared with control subjects, and for the putamen this reached significance (p = 0.04), although all individual caudate and putamen Ki values were within the control range (table 3, figure 1).
18F-dopa uptake and 11C-raclopride binding potential in RLS and control groups
Figure 1. Scatter diagram of individual caudate and putamen 18F-dopa uptake in patients with restless legs syndrome treated (□) and not treated (▪) with l-dopa and in control subjects (•).
RLS mean D2 BPs were reduced significantly, by 13%, in both the caudate (p = 0.01) and the putamen (p = 0.008) compared with control subjects (see table 3). Six of the 13 RLS patients’ caudate and putamen D2 binding levels fell below the control range. Three more RLS patients had reduced putamen D2 binding alone (figure 2).
Figure 2. Scatter diagram of individual caudate and putamen D2 binding in patients with restless legs syndrome treated (□) and not treated (▪) with l-dopa and in control subjects (•).
There were no significant differences in mean striatal 18F-dopa uptake or 11C-raclopride binding between l-dopa–naive and l-dopa–treated RLS patients.
Comparison between control subjects and the eight l-dopa–naive RLS patients showed a significant reduction in mean putamen 18F-dopa Ki (0.0080 ± 0.0009; p = 0.02) and mean caudate (1.65 ± 0.23; p = 0.01), and in the putamen (1.63 ± 0.22; p = 0.01) D2 BP in the latter.
In only 4 of the 13 RLS patients was lateralization of their symptoms recorded. No significant differences were seen in side-to-side comparisons of radioligand uptake.
RLS patients showed a significant correlation between 18F-dopa Ki and D2 binding in putamen (r = 0.62, p = 0.02).
There were no statistically significant correlations between RLS rating scores or total nighttime sleep and striatal Ki and BP values.
Discussion.
The RLS group showed a mild (13%) but significant reduction of mean caudate and putamen D2 receptor binding and mean putamen 18F-dopa uptake compared with control subjects. Indeed, 9 of the 13 RLS patients showed putamen D2 binding below the control range.
Some clinical observations have already suggested that RLS may be associated with decreased dopaminergic neurotransmission6,8,12:
-
1. RLS improves with dopaminergic therapy.
-
2. Restlessness may be experienced by PD patients after administration of l-dopa but shortly before relief of their parkinsonism.24
-
3. Akathisia, which overlaps with RLS, appears during chronic exposure to dopamine receptor blockers.25
It has also been shown that RLS symptoms reach maximum severity at night,26 when plasma dopamine levels are at their lowest.27
A previous PET study28 in 4 RLS patients showed normal striatal 18F-dopa uptake; however, we have detected a small (12%) but significant reduction in mean putamen 18F-dopa Ki in our cohort of 13 RLS patients. Interestingly, this Ki reduction was more pronounced in those RLS patients with lowest putamen D2 binding, although no individual Ki values fell below the control range.
In contrast, PET studies in PD show a reduction in putamen 18F-dopa uptake of at least 30% associated with increased D2 binding in patients who are l-dopa naive.29 l-Dopa treatment leads to normalization of putamen D2 binding and reduced caudate binding.30 Reductions in putamen D2 receptor binding are most usually associated with striatal degenerations such as multiple system atrophy and Huntington’s disease.29,31 Although we are not aware of any postmortem report in RLS, MRI studies have not shown evidence of striatal atrophy or altered signal in this condition.32 An [18F]-fluorodeoxyglucose (18FDG) PET study also failed to demonstrate any significant metabolic dysfunction in RLS when patients were scanned in the absence of symptoms.28 These observations therefore suggest that reductions of putamen 18F-dopa uptake and striatal D2 binding in RLS are unlikely to result from striatal neuronal loss.
Decreased striatal D2 binding may therefore reflect receptor dysfunction or downregulation, or alternatively increased levels of site occupancy by endogenous dopamine. Data from microdialysis studies33 in monkeys suggest that a 1% reduction in striatal D2 binding results from an 8% increase in endogenous dopamine release.
In favor of the presence of increased synaptic dopamine levels, one RLS patient was reported to have a 10-fold higher level of dopamine and its metabolites in the CSF than in plasma.13 To our knowledge, however, this finding has not been replicated, and dopamine levels have not been measured serially in RLS. It is not known whether synaptic increases of endogenous dopamine levels affect 18F-dopa uptake, but unpublished results from our unit (personal communication with R. Ceravalo; November 1998) suggest that therapeutic doses of l-dopa do not affect striatal 18F-dopa Ki.
It has been suggested that the dopaminergic activity in the prefrontal cortex and striatal dopamine transmission may be inversely related.34,35 Our finding of reduced striatal D2 binding in RLS could conceivably result from changes in striatal dopamine transmission secondary to altered prefrontal function. An urge to move the legs even without preceding paresthesias is characteristic of RLS.14 Although functional MRI has failed to show cortical activation during sensory discomfort in patients with RLS,36 the underlying mechanism of this urge to move remains to be addressed. We were unable to measure cortical dopamine storage with PET because the camera used did not have sufficient sensitivity.
Our results are in agreement with a previous IBZM SPECT study12 in patients with PMS and restless legs, which also showed reduced striatal D2 binding. These results could suggest that a central dopaminergic dysfunction underlies RLS; alternatively, they could just reflect sleep deprivation in these patients. Interestingly, IBZM binding was lower in those patients with greatest sleep disturbance,12 and paradoxically it increased in patients treated with dopaminergic agonists, in addition to an improvement in their sleeping pattern.37 In rats, however, REM sleep deprivation induces upregulation of striatal D2 receptors.38 In our study we failed to find any correlation between striatal D2 binding and total nighttime sleep, probably because the latter was not quantified formally.
As in the previous SPECT study,12 we failed to find a correlation between striatal D2 binding and clinical severity of RLS. Although symptoms of RLS characteristically predominate at night, owing to technical reasons we had to perform diurnal PET scans and this may have reduced our chances of finding a correlation with dopamine binding changes.
In agreement with published diagnostic criteria, we based our RLS diagnosis on clinical grounds.14 The chronic evolution, normal neurologic examination, and the high prevalence of a positive family history seen in our cohort suggest that our RLS population represented mainly idiopathic patients. Patient 9 had isolated, mild bradykinesia and the highest striatal D2 binding in the RLS cohort; however, no side-to-side asymmetry of striatal 18F-dopa uptake was detected, which is against preclinical PD. The variability of putamen D2 binding in RLS may therefore reflect an underlying heterogeneity despite a similar phenotypic presentation.
Acknowledgments
Acknowledgment
The authors thank colleagues of the Chemistry and PET Methods sections, and the radiographers at the MRC Cyclotron Unit. They thank Dr. J. Opacka–Juffry and the anonymous reviewers for their valuable comments during the preparation of this manuscript.
Footnotes
-
See also pages 907, 938, 944, 1060, and 1064
- Received September 1, 1998.
- Accepted December 22, 1998.
References
Letters: Rapid online correspondence
REQUIREMENTS
You must ensure that your Disclosures have been updated within the previous six months. Please go to our Submission Site to add or update your Disclosure information.
Your co-authors must send a completed Publishing Agreement Form to Neurology Staff (not necessary for the lead/corresponding author as the form below will suffice) before you upload your comment.
If you are responding to a comment that was written about an article you originally authored:
You (and co-authors) do not need to fill out forms or check disclosures as author forms are still valid
and apply to letter.
Submission specifications:
- Submissions must be < 200 words with < 5 references. Reference 1 must be the article on which you are commenting.
- Submissions should not have more than 5 authors. (Exception: original author replies can include all original authors of the article)
- Submit only on articles published within 6 months of issue date.
- Do not be redundant. Read any comments already posted on the article prior to submission.
- Submitted comments are subject to editing and editor review prior to posting.
You May Also be Interested in
Cutaneous α-Synuclein Signatures in Patients With Multiple System Atrophy and Parkinson Disease
Dr. Rizwan S. Akhtar and Dr. Sarah Brooker
► Watch
Alert Me
Recommended articles
Normal IPT and IBZM SPECT in drug-naive and levodopa-treated idiopathic restless legs syndrome
In vivo studies on striatal dopamine D1 and D2 site binding in L-dopa-treated Parkinson's disease patients with and without dyskinesias
Restless legs syndrome
SPECT imaging of pre- and postsynaptic dopaminergic alterations in l-dopa–untreated PD