ARTICLE IN BRIEF
Study investigators found that methylphenidate seemed to improve gait in patients with Parkinson's disease, but why that occurs is not clear. They speculate that the drug may improve alertness and awareness in patients with the disorder.
Methylphenidate (Ritalin) significantly improved gait problems in Parkinson's disease (PD) patients, investigators reported in the July issue of Lancet Neurology. But some neurologists who treat the disease suspect the improvement may be caused, or at least enhanced, by the drug's ability to boost attention and alertness.
The researchers hypothesized that since methylphenidate blocks dopamine and noradrenaline reuptake in the striatum and prefrontal cortex, it would increase the availability of dopamine to motor neurons and therefore improve walking ability. Three previous studies had supported this idea, but did not subject methylphenidate to a double-blind, placebo-controlled study of patients taking high daily doses of levodopa.
STUDY METHODS, DATA
The current study involved 69 Parkinson's disease patients from 13 movement disorders centers in France who had experienced at least a 40 percent improvement in gait stability and freezing after receiving bilateral subthalamic deep-brain stimulation, but then declined after a year. They were randomly assigned to receive up to 80 mg of methylphenidate or a placebo, with both divided into three doses per day for 90 days. Then, after 90 days, they were taken off levodopa and subjected to the stand-walk-sit (SWS) test to determine the primary endpoint — the number of steps needed to walk 14 meters. The patients also were given an acute levodopa challenge consisting of 150 percent of their normal morning dose, and tested again.
The 33 patients taking methylphenidate who completed the study took longer strides and therefore needed an average of only 31 steps to walk 14 meters in the SWS test, compared with 33 steps needed by the 32 patients on placebo. On levodopa, from a baseline of 29 steps before the study, the methylphenidate group reduced their number of steps to 27, while the placebo group still needed 29. Those on methylphenidate also experienced a decline in freezing episodes from 6 to 4, while those on placebo increased from 6 to 7, and they reduced their United Parkinson's Disease Rating Scale (UPDRS) part III score from 27 to 24, while those on placebo improved from 29 to 28.
Methylphenidate also decreased daytime sleepiness, which affects up to 50 percent of PD patients and often gets worse with dopaminergic treatments. Seven patients who had been experiencing moderate apathy displayed significant improvement after 90 days on methylphenidate, which may have been due in part to methylphenidate's ability to decrease daytime sleepiness, according to the authors.
However, those on methylphenidate experienced an increase in average heart rate from 70 to 74, and reported almost twice as many minor adverse effects, such as nausea, vomiting, and headache.
The researchers performed SPECT scans and found that methylphenidate did in fact reduce dopamine transporter binding in the striatum by about one-third, thereby increasing available dopamine at the synapse.
Aside from any improvement in gait produced by methylphenidate, the drug produced a subjective sense of well being in all the patients, producing improvement in their UPDRS part I score, which measures depression, cognition, and apathy.
“Almost all the patients asked for methylphenidate at the end of the study,” said lead author David Devos, MD, PhD, of the faculty of medicine at Lille University in Lille, France. “The gait disorders do not disappear, but I can guarantee that the benefits in daily living are real.”
The authors concluded that “methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stages of Parkinson's disease.”
DR. DAVID DEVOS: Alm...Image Tools
ANOTHER STUDY, DIFFERENT DATA ON GAIT
Their results contradict a similar study published April 5, 2011, in Neurology that found methylphenidate produced no improvement in gait in 27 PD patients taking the drug, and worsened measures of motor function, sleepiness, and quality of life.
However, most of the participants also asked to remain on methylphenidate at the conclusion of the study, according to that study's lead author Alberto Espay, MD, associate professor of neurology at the University of Cincinnati College of Medicine, and director of clinical research at the University's Gardner Center for Parkinson's Disease and Movement Disorders.
“Most of our patients were able to tell when they were on the drug, and most wanted to stay on the drug after the study even though there was no clear benefit to their gait,” Dr. Espay said. “We think the reason is that their attention got better. We didn't see a measurable effect on depression or improvement in daytime sleepiness, but they felt more attentive and alert.”
Although his study concluded that methylphenidate produced no improvement in gait, Dr. Espay and his colleagues found an improvement in gait during the first two weeks on the drug based on patient and caregiver reports.
“When patients came in at one month several said, ‘Well, two weeks ago I felt better,’” he said. “The doses were escalating over 4 weeks, so it could be that two weeks earlier they felt better because of some sort of inverted U-shaped pharmacokinetic response. By 3 months any benefits they experienced had vanished.”
Dr. Devos pointed out what he considers significant differences between his study and Dr. Espay's. For example, the subjects in his study had declined even after receiving subthalamic stimulation, while Dr. Espay's were not as impaired. Also, Dr. Espay's patients were taking doses of dopaminergic medication that were almost twice as high.
“Given these high baseline dopaminergic doses, the addition of another dopaminergic treatment may have had no further benefit,” Dr. Devos said. “Conversely, it could be argued that our patients were relatively undertreated, and that higher L-dopa doses could have afforded the same improvement seen with methylphenidate.”
DR. ALBERTO ESPAY, w...Image Tools
In addition, Dr. Espay's patients walked on a treadmill, which may not have elicited freezing of gait sufficiently, according to Dr. Devos, and the high dropout rate of 26 percent — versus 5.8 percent in his own study — “might have reduced their statistical power.”
Dr. Espay believes that any improvement in attention and alertness could have an effect in overall well being, which could translate into better motor control.
“When we use methylphenidate we have seen improvement in overall well-being, with attention seeming to be what makes people feel better, but that vanishes,” he said. “Whether it vanishes because the effect of methylphenidate diminishes over time, or because the disease continues to progress, we don't know. I suspect it's a combination of the two.”
MIXED RESPONSE FROM EXPERTS
Although the authors of the Lancet Neurology article found only a modest improvement in gait among patients taking methylphenidate, that improvement could be significant because freezing of gait increases disability and the danger of falls, said Janis Miyasaki, MD, associate clinical director and deputy physician-in-chief at the Movement Disorders Centre at Toronto Western Hospital. Also, any improvement in a patient's subjective sense of well-being is valuable. That's why she continues to consider methylphenidate as a possible treatment for PD.
“For a patient with both daytime sleepiness and freezing, methylphenidate may potentially improve both symptoms,” she said. “For a particular patient you might say yes, there's a risk, but there's also a chance of achieving two potential benefits from the same treatment.”
Besides, the heterogeneous nature of PD requires the physician to assess each patient individually, and remain open to all possibilities.
John Nutt, MD, co-founder and director of the Oregon Health & Science University Parkinson Center of Oregon, found the Lancet Neurology paper somewhat ambiguous because it failed to identify the mechanism behind patient improvement. Some patients on methylphenidate, for example, improved their score on the PDQ-39, a questionnaire that measures the status of PD patients on eight scales — mobility, activities of daily living, emotions, stigma, social support, cognitions, communication, and bodily discomfort. However, only the compiled scores were recorded.
“They could have looked into the PDQ-39 results more closely to see what actually improved,” Dr. Nutt said. “That might have shown that the improvements were in mood, apathy, and alertness rather than on walking per se. I think if you're more interested in what's happening, you'll probably perform better.”
• Moreau C, Delval A, Devos D, et al, for the Parkgait-II Study Group. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomized, placebo-controlled trial. Lancet Neurol 2012;11:589–596.
• Espay AJ, Dwivedi AK, Shukla R, et al. Methylphenidate for gait impairment in Parkinson disease: a randomized clinical trial. Neurology 2011;76(14):1256–1262.
• Williams-Gray CH, Hampshire A, Owen AM, et al. Attentional control in Parkinson's disease is dependent on COMTval158met genotype. Brain 2008;131:397–408.
©2012 American Academy of Neurology