Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation.
Apathy has been reported to occur after subthalamic nucleus stimulation, a treatment of motor complications in advanced Parkinson's disease. We carried out a prospective study of the occurrence of apathy and associated symptoms, predictors and mechanisms in the year following subthalamic stimulation. Dopamine agonist drugs were discontinued immediately after surgery and levodopa was markedly reduced within 2 weeks. Apathy and depression were assessed monthly, using the Starkstein apathy scale and the Beck Depression Inventory. Dopamine agonists were re-introduced if patients developed apathy or depression. Preoperative non-motor fluctuations were evaluated using the Ardouin Scale. Depression, apathy and anxiety were evaluated both on and off levodopa. Analysis of predictors of apathy was performed using a Cox proportional hazard model. Twelve patients who developed apathy and a control group of 13 patients who did not underwent [11C]-raclopride positron emission tomography scanning before and after oral intake of methylphenidate. In 63 patients with Parkinson's disease treated with subthalamic stimulation, dopaminergic treatment was decreased by 82% after surgery. Apathy occurred after a mean of 4.7 (3.3-8.2) months in 34 patients and was reversible in half of these by the 12-month follow-up. Seventeen patients developed transient depression after 5.7 (4.7-9.3) months and these fell into the apathy group with one single exception. At baseline, fluctuations in depression, apathy and anxiety scores were greater in the group with apathy. Fluctuations in apathy, depression and anxiety ratings during a baseline levodopa challenge were also significant predictors of postoperative apathy in univariate analysis, but not motor and cognitive states or the level of reduction of dopaminergic medication. The multivariate model identified non-motor fluctuations in everyday life and anxiety score during the baseline levodopa challenge as two independent significant predictors of postoperative apathy. Without methylphenidate, [11C]-raclopride binding potential values were greater in apathetic patients bilaterally in the orbitofrontal, dorsolateral prefrontal, posterior cingulate and temporal cortices, left striatum and right amygdala, reflecting greater dopamine D2/D3 receptor density and/or reduced synaptic dopamine level in these areas. The variations of [11C]-raclopride binding potential values induced by methylphenidate were greater in non-apathetic patients in the left orbitofrontal cortex, dorsolateral prefrontal cortex, thalamus and internal globus pallidus and bilaterally in the anterior and posterior cingulate cortices, consistent with a more important capacity to release dopamine. Non-motor fluctuations are related to mesolimbic dopaminergic denervation. Apathy, depression and anxiety can occur after surgery as a delayed dopamine withdrawal syndrome. A varying extent of mesolimbic dopaminergic denervation and differences in dopaminergic treatment largely determine mood, anxiety and motivation in patients with Parkinson's disease, contributing to different non-motor phenotypes.
Universitée Lyon I, Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie C, Lyon, France.
Stéphane
S
Thobois
Claire
C
Ardouin
Eugénie
E
Lhommée
Hélène
H
Klinger
Christelle
C
Lagrange
Jing
J
Xie
Valérie
V
Fraix
Maria Clara
MC
Coelho Braga
Rachid
R
Hassani
Andrea
A
Kistner
Alexandra
A
Juphard
Eric
E
Seigneuret
Stephan
S
Chabardes
Patrick
P
Mertens
Gustavo
G
Polo
Anthonin
A
Reilhac
Nicolas
N
Costes
Didier
D
LeBars
Marc
M
Savasta
Léon
L
Tremblay
Jean-Louis
JL
Quesada
Jean-Luc
JL
Bosson
Alim-Louis
AL
Benabid
Emmanuel
E
Broussolle
Pierre
P
Pollak
Paul
P
Krack
D000328:Adult; D000368:Aged; D046690:Deep Brain Stimulation / Q000009:adverse effects; D003714:Denervation / Q000523:psychology; D003863:Depression / Q000209:etiology / Q000523:psychology; D018491:Dopamine Agonists / Q000009:adverse effects*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008032:Limbic System / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy / Q000523:psychology* / Q000601:surgery*; D011183:Postoperative Complications / Q000139:chemically induced / Q000209:etiology / Q000523:psychology; D011237:Predictive Value of Tests; D011446:Prospective Studies; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000523:psychology*
D018491:Dopamine Agonists