Interactions between deep brain stimulation and levodopa in Parkinson's disease.
OBJECTIVE
To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS.


BACKGROUND
Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown.


METHODS
Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores.


RESULTS
DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia.


CONCLUSIONS
DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.
Nutt
J G
JG
Department of Neurology, Oregon Health Sciences University, Portland 97201, USA. nuttj@ohsu.edu
Rufener
S L
SL
Carter
J H
JH
Anderson
V C
VC
Pahwa
R
R
Hammerstad
J P
JP
Burchiel
K J
KJ
D000328:Adult; D000368:Aged; D002230:Carbidopa / Q000008:administration & dosage / Q000009:adverse effects; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004599:Electric Stimulation Therapy; D005260:Female; D005917:Globus Pallidus / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D009460:Neurologic Examination / Q000187:drug effects; D010300:Parkinson Disease / Q000503:physiopathology / Q000628:therapy*; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000503:physiopathology; D016138:Walking / Q000502:physiology
D007980:Levodopa; D002230:Carbidopa