Mechanisms of Body Weight Gain in Patients With Parkinson's Disease After Subthalamic Stimulation

C. Montaurier; B. Morio; S. Bannier; P. Derost; P. Arnaud; M. Brandolini-Bunlon; C. Giraudet; Y. Boirie; F. Durif

Disclosures

Brain. 2007;130(7):1808-1818. 

In This Article

Subjects and Methods

Subjects

The study enrolled 24 non-smoker patients with Parkinson's disease (17 men and 7 women) aged 61.1 ± 1.4 years. History of disease was 9.9 ± 0.6 years for the men and 10.1 ± 1.5 years for the women. Furthermore, 24 non-smoker healthy controls (17 men and 7 women) aged 66.7 ± 0.9 years patient-matched for height and body composition were recruited. Twenty-three patients with Parkinson's disease (16 men and 7 women) completed the whole study. One man refused to participate in the post-operative EE measurements but accepted the assessment of body composition. All patients were suffering from idiopathic Parkinson's disease according to the criteria of the 'Parkinson's Disease Society Brain Bank' (Hughes et al., 1992). The diagnosis of Parkinson's disease had been established for 5 years or more in all subjects. All subjects had taken a medical examination and had the go-ahead to undergo the surgery according to the French consensus conference of treatment of Parkinson's disease (Consensus Conference Proceedings, 2000). They all suffered from severe motor fluctuations and LIDs that were not improved by changes in their antiparkinsonian treatment. Selection criteria were: an excellent response to L-dopa tested during an acute L-dopa challenge (>50%), no postural instability during the best 'on' period (postural instability = 0 from item 29 of UPDRS part III), absence of dementia (Mini Mental Status >24, Mattis scale >130/144) and normal magnetic resonance imaging. Were excluded all subjects presenting diabetes, thyroid disease, psychosis related to the antiparkinsonian drugs, and severe depression with suicidal tendencies. All women were post-menopausal. The study protocol was approved by the regional Medical School Ethics Committee (AU474) and was performed according to the principles set out in the Declaration of Helsinki and to French legislation (the Huriet law). The nature and potential risks of the study were fully explained and written informed consent was obtained from each participant.

General Study Design

The study lasted for 4 months for each patient. After medical controls at inclusion, patients were studied 1 month before (M – 1) and 3 months after (M + 3) STN-DBS surgery. Before each measurement period, patients were asked to complete a 7-day dietary questionnaire. The same measurements were then taken over a first 4-day period at M – 1 and a second at M + 3. On day 1, a clinical examination and an interview on health and medical history were performed. Biological tests were carried out on day 2, and the patients entered the calorimetry chamber on the same evening. EE and heart rate were continuously recorded during the 36 h following entry into the calorimetry chamber. Therefore, patients were in the calorimetric chambers during day 3. They came out in fasted state on the morning of the fourth day. Basal metabolic rate (BMR) was then measured in resting conditions in the morning during an acute L-dopa challenge in both the 'off' and 'on' states at M – 1; at M + 3, this was again measured during similar acute L-dopa challenge but under two different stimulation conditions: stimulation switched 'on' and stimulation switched 'off'. Finally, body composition was assessed using dual X-ray absorptiometry (DEXA).

For the healthy subjects, the study lasted for 1 week. After medical control at inclusion, body composition was assessed using DEXA. The subjects then entered the calorimetry chamber in the evening, and EE was recorded during 36 h, as described for Parkinsonian patients.

Measurements in the Calorimetric Chambers

EE and heart rate were measured continuously using two open-circuit whole-body calorimetric chambers (Morio et al., 1997a, b). Gas analysers were calibrated every 12 h during the measurement period using standard gas mixtures. Gas exchanges were computed from the minute-by-minute measurement of outlet air flow, differences in gas concentrations, atmospheric pressure, chamber air temperature and hygrometry, and taking into account drifts in the gas analysers and variations in the volumes of CO2 and O2 in the chambers (Vermorel et al., 1995). The validity of gas exchange measurements was checked gravimetrically by comparing the amounts of gases (CO2, O2) analysed with the amounts expected from the weights of the gases (CO2, N2) injected into the chambers during a 24 h period (Vermorel et al., 1995). For chambers 1 and 2, O2 recovery rates were 95.4 ± 0.3 and 98.2 ± 0.2%, respectively, and CO2 recovery rates were 100.6 ± 0.2 and 102.5 ± 0.1%, respectively.

Twenty-four-hour urine was collected from 7 a.m. on day 3 to 7 a.m. on day 4 to determine urinary nitrogen excretion. EE was calculated using the Weir's equation (De Weir, 1949) based on the measurement of gas exchanges corrected for urinary nitrogen excretion.

Twenty-four-hour EE (daily EE) was calculated from 7 a.m. on day 3 to 7 a.m. on day 4. EE during the time awake was measured from 7 a.m. to 11 p.m. on day 3. EE during activities was computed over 15–30 min periods. Sleeping metabolic rate (SMR) was taken as energy expenditure during the least-active period of the night in the calorimetric chamber. This period averaged 137 ± 84 min. Increases in energy expenditure above 15% associated with heart-rate peaks were considered as resulting from waking up and were excluded from the SMR studies.

Activity program in the calorimetric chambers. The activity program in the calorimeters consisted of four 20 min cycling sessions without any load and at about 50 rpm. Meals were served at given times: breakfast at 8 a.m., lunch at noon and dinner at 7 p.m. Assistance with dressing was planned on each morning when necessary. Energy expenditure during this period of time was corrected when necessary. During the remaining time, activities were left to the patient's discretion. Patients were asked to use a patient diary to note as accurately as possible their activities and any periods of motor fluctuation. Investigators simultaneously maintained similar records.

Food intakes in the calorimetric chambers. Dietary energy supply was calculated individually using the factorial method (Morio et al., 1997a, b). For this purpose, daily EE was calculated from the duration and the energy cost of the various activities performed while in the calorimetric chambers (e.g. cycling) (Morio et al., 1997a, b) and a predicted BMR (Harris and Benedict, 1918). Dietary energy supply broke down as 50% of energy as carbohydrates, 35% as lipids and 15% as proteins.

Basal Metabolic Rate Measurements

BMR was measured after an overnight fast using Deltatrac II (Datex-Engstrom Division, Instrumentarium Corp., Helsinki, Finland). At M – 1, BMR was first measured for 45 min without L-dopa. Then, L-dopa treatment (200 mg, Modopar Dispersible, Roche) was administered and BMR was measured again for a further 45 min after a 60 min delay corresponding to the period when patients were in the 'on' phase. At M + 3, the patients were administered their L-dopa treatment at the same dose as pre-operatively, and BMR was measured for 45 min with stimulation switched 'on'. This situation is characterized by minimal involuntary movements. Then, STN-DBS was stopped and BMR was measured for a further 45 min after a 1 h delay, in order to suppress the main effect of the stimulation (Tuite et al., 2005; Perlemoine et al., 2005). BMR measured with L-dopa 'on' (M – 1) and stimulation 'on' (M + 3) were compared to predicted values given by the Harris and Benedict equation (1918).

Body Composition Measurements

Body mass was measured to the nearest 0.1 kg on SECA 709 scales (SECA, Les Mureaux, France). Height was measured to the nearest 0.2 cm. A total body scan was performed using DEXA (Hologic QDR 4501, Hologic Inc., Walthan, US) to determinate total and regional (arms, legs and trunk) body composition. Fat-free mass (FFM) was calculated as the sum of lean mass, soft tissue and bone mineral content (Treuth et al., 1994). FFM at M + 3 was corrected for the presence of the stimulator box (i.e. FFM was cut by about 40 g).

Blood Sampling

After an overnight fast, blood samples were collected and the plasma was kept at –80°C until further analysis. Plasma testosterone concentrations were determined using the Human Testosterone Assay (Immunoassay Kit, BioSource International Inc., Camarillo, California, USA).

Dietary Questionnaire

For 7 days before each measurement period, the patients were asked to fill in a dietary record: for each meal or snack consumed; they had to record the names of foods and drinks, the method of cooking and the seasoning used. The quantities of each food were recorded either by weight or estimated using domestic measures. On final day of each measurement period, this food record was double-checked with a dietician using a validated food picture book to estimate the quantities consumed (Le Moullec et al., 1996). Then, quantitative food data were converted into energy and nutrient intakes using 'Geni' dietetics software (Gestion des Enquêtes Nutritionnelles Informatisée, Micro6, Villers-lès-Nancy, France), which takes its composition tables from 'Regal' (Favier et al., 1995).

Surgery

A stereotactic frame (Lekesll G frame, Elekta, Sweden) was fitted with its repositioning kit (Elekta, Sweden) under local anaesthesia, without withdrawal of the antiparkinsonian drug therapy. Stereotactic 1.5 Tesla MRI (Sonata, Siemens, Germany) was then performed with a voxel size of 0.52 × 0.62 × 2 mm3 (field of view = 270 mm; matrix = 512 × 435; slice thickness = 2 mm). The stereotactic markers of the repositioning kit and the subthalamic anatomy of nuclei and bundles were visualized together by performing a T2-weighted sequence: Turbo Spin Echo (TSE) sequence, TR = 8000 ms, TE = 10 ms, 24 images in the coronal plane, acquisition time ≅ 10 min. A 10 mm exploration from the ventral thalamus to the anterior half of the STN and the Substantia Nigra was planned. On the following day, the frame was repositioned under conditions of local anaesthesia without antiparkinsonian therapy. Pre-operative X-ray controls were carried out during the procedure to check that the coordinates and the tracts followed the planning. The two quadripolar electrodes (DBS Medtronic 3389, Medtronic, Minneapolis, USA) were placed during the same procedure. For each side, the electrode was implanted after electro-physiological mapping using two exploration electrodes (Alpha Omega, Israel) introduced with guide tubes: one on the planned tract and a second one on the parallel tract located 2 mm anteriorly. Electro-physiological analysis consisted of micro-recordings of neuronal activity with 500 µm step checkpoints followed by monopolar acute stimulation tests with 1 mm step checkpoints. A neurologist (PD, MU) assessed the effect of acute stimulation for contralateral rest tremor, rigidity (wrist, elbow and ankle) and bradykinesia (thumb–index tapping). One contact of the DBS electrode was placed where the best efficacy of the acute stimulation was found. A few days later, the electrodes were connected to a pulse generator (Kinetra, Medtronic, Minneapolis, USA). Stimulation settings and the antiparkinsonian therapy were adapted post-operatively according to the efficacy of chronic stimulation.

Assessment of DBS-STN

One month before surgery, response to L-dopa was evaluated using part III of the Unified Parkinson's Disease Rating Scale (UPDRS, a standardized evaluation of all the motor signs of the disease, with a score range of 0 to 108) in the off-state after a 12 h withdrawal of antiparkinsonian medication and after taking 1.5 times the usual morning L-dopa dose, using a dispersible L-dopa formulation (Modopar Dispersible, Roche). The other tests included UPDRS part I (mental state, with a score range of 0 to 16), part II (activities of daily living, with a score range of 0 to 52), part IV (L-dopa complications), classification by Hoehn and Yahr stage and the Schwab and England scale which also measures activities of daily living (with a score range from 0 to 100%). At the 3-month follow-up visit, we systematically explored the acute motor effects of all four contacts of the electrode on each side to select the most effective one. We then assessed the efficacy of acute DBS-STN during an acute levodopa challenge using part III of UPDRS, under four conditions: (1) 'Off' stimulation and 'off' drug therapy after a 12 h withdrawal of antiparkinsonian medication and after stimulation had been switched 'off' for at least 1 h; (2) 'On' stimulation and 'off' drug therapy after stimulation had been switched 'on' for at least half an hour; (3) 'On' stimulation and 'on' drug therapy 1 h after intake of the same dose of levodopa as pre-operatively and (4) 'Off' stimulation and 'on' drug therapy after stimulation had been switched 'off' for at least 1 h. Each session was video-recorded. The same tests as performed pre-operatively were repeated. Dosages of antiparkinsonian medication were expressed as a total equivalent dose, and the stimulation were recorded bilaterally.

Statistical Analysis

Results are reported as means ± SEM. The paired Student's two-tailed t test was used for BMR and resting EE comparisons between 'on' and 'off' conditions. An unpaired Student's two-tailed t test was used for BMR comparisons between measured and predicted values. Repeated measure analysis of variance was used for comparisons between M – 1 and M + 3 values for body composition and energy expenditure. Analysis of variance with FFM as covariate, was used for comparison between male and female Parkinson patients and between patients and control subjects. Correlation coefficients are Pearson product–moment correlations. Results were considered statistically significant at the 5% level. Statistics were analysed using Statview 5.0 software (SAS Institute Inc., Cary, NC).

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