Brain, Vol. 122, No. 8, 1597-1598,
August 1999
© 1999 Oxford University Press
Letter to the Editor |
Getting a grasp on research: does treatment taint testing of parkinsonian patients?
1 Department of Biobehavioral Sciences, Teachers College, and 2 Department of Rehabilitation Medicine, College of Physicians and Surgeons, Columbia University, New York, USA
Correspondence to:
Andrew M. Gordon, Department of Biobehavioral Sciences, Teachers College, Columbia University, 525 West 120th Street, New York, NY 10027, USA
The study of motor behaviour in patients with Parkinson's disease whilst on medication is widespread. The reasoning behind this is simple: (i) patients typically come to neurology clinics in the medicated state, making on-site testing in this state convenient to many investigators; (ii) testing in the unmedicated state may pose a hardship for patients; (iii) patients in the advanced stages of the disease may be less inclined to participate whilst off medication, skewing the subject pool; and (iv) testing patients in the unmedicated state may raise liability concerns. While all these issues are legitimate, there appears to be a common misconception that while medication may limit the interpretation of negative findings (i.e. lack of differences between patients and controls), positive findings are valid, or even more robust, if observed in the medicated state.
We believe that both positive and negative findings from medicated Parkinson's disease patients must be interpreted with caution. While the beneficial effects of L-dopa are extraordinary (at least temporarily), accumulating evidence suggests that L-dopa (and/or other anti-parkinsonian medications) may actually cause some of the motor deficits observed in Parkinson's disease. It is known from clinical observations that over-medication can result in over-striding during locomotion. In Parkinson's disease patients with self-described L-dopa-related worsening of motor performance, tapping and walking times have also been reported to increase following L-dopa administration (Nutt et al., 1988
; Merello and Lees, 1992). Ebner and his colleagues have reported decreased accuracy in wrist flexion-extension tracking following L-dopa intake in about half of the Parkinson's disease patients they tested (Johnson et al., 1994, 1996). Their findings were unrelated to the level of dyskinesia.
In our laboratory, we have been investigating the neural basis of impaired hand function in Parkinson's disease (Gordon, 1997, 1998; Gordon et al., 1997; Ingvarsson et al., 1997). Among other things, we found that patients with Parkinson's disease often exhibited excessive grasping forces when they grasped and lifted a small object using the precision grip. The excessive grasping forces, however, only occurred when Parkinson's disease patients were tested in the medicated state (on L-dopa). This finding is illustrated in Fig. 1, which depicts the mean (± standard error of the mean) grip and load forces for four patients with Parkinson's disease whilst off (thin lines) and on (bold lines) medication. All of the Parkinson's disease patients we tested who exhibited excessive grip forces in the medicated state were in a more advanced stage of the disease. While most had been taking dopaminergic medication for several years, few of these patients exhibited clinically identifiable dyskinesias. Nevertheless, L-dopa decreased the amplitude of isometric action tremor and tended to improve sequencing problems. Our findings suggest that while L-dopa did reduce some impairments in grasping, it actually caused other impairments.
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Dopaminergic medication is aimed at compensating for degeneration of dopamine-producing neurons in the nigrostriatal pathway to reduce, among other symptoms, the hypokinesia in Parkinson's disease patients (e.g. Hornykiewicz,1992). It is well known that long-term intake of dopamine can result in severe hyperkinesias (e.g. dyskinesias). Recent evidence suggests that patients with L-dopa-induced dyskinesia exhibit a pattern of regional cerebral blood flow response which is markedly different than non-dyskinetic patients (Rascol et al., 1998
). Interestingly, changes in regional cerebral blood flow in response to L-dopa have even been documented in patients with the propensity to develop L-dopa-induced dyskinesias at sub-dyskinesia levels of medication compared to non-dyskinetic patients (Hershey et al., 1998). The latter finding suggests that there may be a neural basis for changes in motor performance even in (advanced-stage) patients who do not exhibit dyskinesia. This is in agreement with the motor deficits observed in the above-cited motor studies, where deterioration in performance was often unrelated to the dyskinesia. (We want to emphasize, however, that the overall benefit of L-dopa almost certainly outweighs the detrimental side effects.) Testing the motor function of Parkinson's disease patients in the medicated state does provide useful information about how they perform tasks in everyday life. However, it may not provide information about the motor deficits caused by the disease process itself. Testing patients whilst off medication is therefore essential to study the pathophysiology of the disease, unless it has been thoroughly documented that a specific medication has no effect (positive or negative) on the motor task being studied. While this notion may appear self-evident, a large number of papers on Parkinson's disease are still being published with patients tested only whilst on medication, and many of these draw conclusions about the mechanisms underlying Parkinson's disease and basal ganglia function that, for the reasons given, may not be warranted. In our opinion, this has added unnecessary confusion to the literature on motor control in this population.
Motor studies that aim to investigate the pathophysiological aspects of Parkinson's disease should ideally have a subgroup of patients who have never taken L-dopa (L-dopa naïve patients). Since this is rarely possible, patients should at least be taken off their medication before they are tested. While this may impose some inconvenience to the patients and the investigators, the inconvenience can be minimized and the benefits associated with observing the untainted motor output associated with Parkinson's disease should outweigh the inconvenience. Although patients may not reach a true baseline (off) state until 3–5 days after the last dose of anti-parkinsonian medication, L-dopa has a half-life of only ~1.6 h (Esteguy et al., 1985). Hence, it is generally agreed that testing 12 h after the last dose is a reasonable compromise, resulting in a reproducible off-like state [see CAPIT discussion group (Langston et al., 1992)]. By admitting patients to the hospital for one day or by offering accompanied transportation to the laboratory prior to the morning dosage, liability can also be minimized. Unless patients are tested in the unmedicated state, it is not possible to separate deficits associated with the basic pathophysiology of Parkinson's disease or basal ganglia dysfunction from those induced by medication.
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Received December 17, 1998. Revised March 4, 1999. Accepted March 15, 1999.
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