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

Results

Surgery Outcomes

Acute motor effect of DBS-STN. In the off-medication state, acute stimulation led to a 60.5 ± 2.9% improvement in UPDRS part III (P < 0.0001). All the sub-scores of UPDRS part III improved: tremor score (+88.3 ± 19.4%, P < 0.0001), rigidity score (+64.7 ± 6.6%, P < 0.0001) and akinesia score (+51.8 ± 7.1%, P < 0.0001). Part II of UPDRS improved by 37.4 ± 7.4% (P < 0.0001). Schwab and England scale improved by 26.6 ± 4.7% (P < 0.0001). Finally, Hoehn and Yahr scale improved by 16.5 ± 6.4% (P < 0.01) ( Table 1 ).

Even in the on-medication state, UPDRS part III improved by 27.3 ± 6.4% with stimulation turned on (P < 0.01). UPDRS part III sub-scores also improved: tremor score (+90.9 ± 37.2%, P < 0.05), rigidity score (+36.5 ± 11.8%, P < 0.01) and akinesia score (+37.2 ± 10.9%, P = 0.01). There were no changes in activities of daily living scores using either the Schwab and England scale or the Hoehn and Yahr scale. In contrast, UPDRS part II worsened by 83.4 ± 2.3% (before surgery: 3.3 ± 0.7 vs after surgery: 6.0 ± 0.8; P < 0.01) ( Table 1 ).

Chronic effect of DBS-STN. Motor complications related to L-dopa treatment as assessed by UPDRS part IV dramatically improved. LID duration decreased by 83.3 ± 17.1% (P < 0.0001), LID disability fell by 90.8 ± 17.5% (P < 0.0001), and off-period duration fell by 59.2 ± 10.1% (P < 0.0001). L-dopa equivalent daily dose significantly decreased from 1173.8 ± 88.8 mg at baseline to 685.0 ± 66.8 mg at 3 months after surgery (i.e. –40.1 ± 7.8%, P < 0.0001) ( Table 1 ). The stimulation settings were: 2.7 ± 0.1 and 2.8 ± 0.1 V (right and left sides, respectively), 148.0 ± 4.5 Hz and 69.0 ± 5.3 µs. Seven patients showed worsened dysarthria following surgery. One patient suffered from transient hypomania, one presented an episode of depression, and one other was confronted with neuropsychological disorders such as apathy.

Body Composition

Before surgery. Before surgery, eight men and one woman were overweight (25 < BMI < 30 kg/m2) and one man and one woman were obese (BMI >30 kg/m2). FFM, appendicular muscle mass and trunk FFM were significantly higher in men than in women (P < 0.0001, Table 2 ). Fat mass and trunk fat mass (kg) were not significantly different between men and women. In contrast, fat mass expressed as percentage of body weight was significantly higher in women than in men (P < 0.05, Table 2 ).

Changes observed 3 months after DBS-STN. Three months after surgery, body weight was significantly increased by 3.4 ± 0.6 kg in men (ranging from –1.5 to 7.9 kg, P < 0.0001) and 2.6 ± 0.8 kg in women (ranging from 0.3 to 5.2 kg, P < 0.05). Hence, BMI increased significantly by 1.1 ± 0.2 and 1.0 ± 0.3 kg/m2 in men and women, respectively (P < 0.0001 and P < 0.05). However, BMI remained at roughly the same level in both men and women ( Table 2 ). FFM (+3.5 ± 0.6%, P < 0.0001), appendicular muscle mass (+4.5 ± 1.3%, P < 0.01) and trunk FFM (+2.7 ± 0.8%, P < 0.01) were significantly increased in men but remained unchanged in women (P = NS, Table 2 ). Fat mass and trunk fat mass significantly increased after surgery in both men and women (men: +8.6 ± 3.1 and +12.6 ± 4.6%, respectively, P < 0.05; women: +20.0 ± 8.3 and +26.0 ± 11.1%, respectively, P < 0.05) ( Table 2 ). Finally, in men, plasma testosterone concentrations in the on-medication state significantly decreased after surgery (2.44 ± 0.26 ng/ml) compared to baseline values (2.90 ± 0.32 ng/ml, i.e. –11.5 ± 8.3%, P < 0.05).

Energy Expenditure

EE of patients with Parkinson's disease before and after surgery are presented in Table 3 . EE was significantly higher in men than in women at all the periods studied (24 h, SMR, awake period, lunch, cycling, at rest, P < 0.05 to P < 0.0001, Table 3 ). Differences in FFM mostly explained these gender differences in EE, except for SMR before surgery and for lunch after surgery (P < 0.05).

EE before surgery. EE during resting activities measured in the calorimetric chambers (i.e. while reading, writing or watching television in standing, sitting or lying position) were significantly higher in 'off' periods compared to 'on' periods in both men (+19.3 ± 3.3%, P < 0.0001) and women (+16.1 ± 4.7%, P < 0.01, Fig. 1).

Figure 1.

Changes in EE while standing, sitting or lying during 'on' (open square) and 'off' (filled square) periods before surgery in 17 men and 7 women.

Effect of L-dopa treatment on BMR before surgery. BMR with L-dopa 'on' (i.e. 200 mg) was significantly higher than the predicted values in men (+11.5 ± 4.0%, P < 0.05, Fig. 2A) but not in women. Furthermore, in men, BMR was significantly higher without L-dopa treatment (L-dopa 'off') than with medication (L-dopa 'on') (+8.4 ± 3.2%, P < 0.05, Fig. 2A).

Figure 2.

Basal metabolic rate under conditions of L-dopa on (open square) and off (filled square) in 17 men and 7 women before surgery (A) and with stimulation 'on' (open square) and 'off' (filled square) (with L-dopa) in 16 men and 7 women after surgery (B).

Comparison between pre-surgery patients and matched healthy control volunteers. Healthy control volunteers were matched to Parkinsonian patients according to height, BMI, FFM and fat mass ( Table 4 ). Control-group men had a higher average age than Parkinsonian men (+6.8 years, P < 0.01), whereas there was no age difference in the women's groups. All body composition features were similar between pre-surgery Parkinsonian patients and healthy subjects ( Table 4 ).

SMR was significantly correlated to FFM for both female and male patients (r > 0.65, P < 0.05) (Fig. 3A). Relation between SMR and FFM was similar between female patients and controls (Fig. 3A). Furthermore, SMR adjusted for differences in FFM was similar between female patients and healthy controls (–3.4 ± 3.8%, P = NS). In contrast, slope and y intercept of the linear regression between SMR and FFM were significantly different between male patients and control men. Although SMR was lower in male patients compared to control (–8.2 ± 2.3%, P < 0.05), the difference was not significant after adjustment for differences in FFM (Fig. 3A).

Figure 3.

In Parkinson men (filled square, n = 17) and women (filled circle, n = 7), relationship between FFM and sleeping metabolic rate (A) before surgery and (B) after surgery, and daily EE (C) before surgery and (D) after surgery. Comparison with healthy-matched control men (open square, n = 17) and women (open circle, n = 7). Linear regression between EE and FFM are illustrated in dashed for Parkinson men and in light for healthy-matched subjects.

Furthermore, daily EE was not correlated to FFM in male and female patients (r < 0.50, P = NS) contrary to controls of both genders (r > 0.80, P < 0.001) (Fig. 3C). Despite similar FFM and activity programs, daily EE before surgery was significantly higher in male Parkinsonians compared to control men (+9.2 ± 3.9%, P < 0.05) but not significantly different between Parkinsonian women and healthy controls (+10.5 ± 7.0%, P = NS).

Effect of DBS-STN on BMR after surgery. Effect of DBS-STN on BMR was evaluated after patients had received a 200 mg L-dopa challenge. There were no significant changes in BMR in either men or women regardless of whether stimulation was 'on' or 'off' (P = NS, Fig. 2B).

Changes in EE 3 months after surgery. SMR remained unchanged in Parkinsonian women (–2.4 ± 2.4%, P = NS). It is interesting to note that SMR increased in men (+7.5 ± 2.0%, P = NS). However, it was not significantly different from pre-surgery values and from control men after adjustment for differences in FFM (Fig. 3B). Daily EE was significantly reduced after surgery in both men (–7.3 ± 2.2%, P < 0.01) and women (–13.1 ± 1.7%, P < 0.01, Table 3 ) and was not significantly different from that of controls (Fig. 3D). EE during the awake period (i.e. spontaneous EE not related to controlled physical activity) was similarly and significantly decreased in both men (–10.5 ± 2.7%, P < 0.01) and women (–15.0 ± 2.2%, P < 0.01). EE during resting activities was significantly lower in both men (–8.2 ± 3.4%, P < 0.05) and women (–13.4 ± 2.9%, P < 0.01) in comparison with the EE measured during the same activities during 'on' periods before surgery. EE while eating was significantly reduced after surgery in men (–8.8 ± 3.2%, P < 0.05), but not in women (+0.3 ± 11.0%, P = NS). Finally, after surgery, EE during the cycling sessions (i.e. controlled physical activity) was significantly decreased in both men (–9.6 ± 3.5%, P < 0.05) and women (–15.8 ± 5.1%, P < 0.05) ( Table 3 ).

Energy Intake Before and After Surgery

Energy intake in free living conditions was significantly higher in Parkinsonian men than in Parkinsonian women, before (10 138 ± 406 vs 7062 ± 167 kJ/day, respectively, P < 0.0001) and after surgery (9898 ± 507 vs 6596 ± 532 kJ/day, respectively, P < 0.01). There was no significant change in energy intake after surgery in either men or women (P = NS).

Search for Predictive Factors of Body Weight Gain After Surgery

Extent of BW gain was not correlated to the duration of the disease, patient age or the pre-operative L-dopa equivalent dose. No significant correlation was found between changes in daily EE and BW or fat mass gain after surgery. However, regarding the symptoms of Parkinson's disease, changes in daily EE were positively correlated with pre-operative UPDRS III score when 'off' L-dopa (r = 0.67, P < 0.001; Fig. 4A). This means that patients with high pre-operative UPDRS III scores did not significantly change their daily EE in the calorimetric chambers, while there was a significant decrease in EE in patients with low pre-operative UPDRS III scores. Interestingly, daily EE was significantly decreased in patients presenting a post-surgery UPDRS IV score higher than one (–13.5 ± 1.9%) compared to the others (UPDRS IV score equal to zero: –4.3 ± 2.3%) (P < 0.01). This can be explained by the fact that pre-operative UPDRS III score when 'off' L-dopa was significantly lower in the first group (UPDRS IV score higher than one: 27.7 ± 3.3) compared to the others (UPDRS IV score equal to zero: 37.9 ± 2.1) (P < 0.01).

Figure 4.

(A) Correlation between pre-operative UPDRS III score with L-dopa 'off' and STN-DBS-induced changes in daily EE as measured in calorimetric chambers in Parkinsonian men (filled square, n = 15) and women (filled circle, n = 6). (B) Correlation between pre-operative tremor sub-score with L-dopa 'off' and STN-DBS-induced changes in fat mass in Parkinsonian men (filled square, n = 17) and women (filled circle, n = 7).

In other respect, patients with high pre-operative UPDRS III scores (especially the tremor sub-score) when 'off' L-dopa presented a strong improvement in UPDRS III scores (especially tremor sub-score, r = –0.97, P < 0.0001) and a limited body weight or fat mass gain (r = –0.68, P < 0.0001; Fig. 4B). In other words, patients with the most severe UPDRS III scores before surgery showed the greatest improvement after surgery and were at the lowest risk for gaining BW. In contrast, there was only a tendency for a higher body weight or fat mass gain in patients with the highest pre- and post-operative UPDRS IV scores compared to the other (P > 0.10). As for changes in daily EE, this can be explained by the fact that pre-operative UPDRS III score when 'off' L-dopa was significantly lower in the first group (UPDRS IV score higher than one) compared to the others (UPDRS IV score equal to zero) (P < 0.01).

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