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Movement disorders
Research paper
Effects of deep brain stimulation of the subthalamic nucleus on freezing of gait in Parkinson's disease: a prospective controlled study
  1. S Vercruysse1,
  2. W Vandenberghe2,
  3. L Münks1,
  4. B Nuttin3,
  5. H Devos1,
  6. A Nieuwboer1
  1. 1Department of Rehabilitation Sciences, KU Leuven, Leuven, Belgium
  2. 2Department of Neurology, University Hospitals Leuven, Leuven, Belgium
  3. 3Department of Neurosurgery, University Hospitals Leuven, Leuven, Belgium
  1. Correspondence to Sarah Vercruysse, Faculty of Kinesiology and Rehabilitation Sciences, Department of Rehabilitation Sciences, KU Leuven, Tervuursevest 101, Leuven 3001, Belgium; sarah.vercruysse{at}faber.kuleuven.be

Abstract

Background Freezing of gait (FOG) is a debilitating gait disorder in Parkinson's disease (PD) with partial responsiveness to dopaminergic medication. To date, notions about the effects of subthalamic deep brain stimulation (STN-DBS) on FOG remain controversial.

Objectives To compare the effects of bilateral STN-DBS and continued best medical treatment (BMT) on FOG occurrence, FOG severity and clinical outcomes in PD patients at 6 and 12 months follow-up.

Methods In this prospective, controlled study, 41 PD patients with at least 5 years disease duration participated. Twenty-four subjects (20 with FOG) were treated with STN-DBS and seventeen (15 with FOG) continued BMT. The primary outcome was the New Freezing of Gait Questionnaire (NFOGQ) at 6 months postsurgery. Other outcomes were the NFOGQ at 12 months and clinical outcomes (Unified Parkinson's Disease Rating Scale III (UPDRS III), timed gait, falls and quality of life) at both time points.

Results STN-DBS increased the likelihood to convert from being a freezer to a non-freezer at 6 and 12 months follow-up (relative risk reduction=0.4). However, 45% of baseline freezers still experienced FOG 6 and 12 months postsurgery although with reduced severity. Three baseline non-freezers (1/2 BMT-treated, 2/4 STN-DBS-treated) developed FOG during follow-up. STN-DBS-induced benefits on FOG were mostly mediated by baseline levodopa equivalent dose, altered medication-intake and reduced motor fluctuations.

Conclusions In contrast to continued BMT, STN-DBS reduced FOG occurrence and severity at 6 months postsurgery with largely sustained effects at 12 months follow-up. Longer follow-up periods are needed to test whether FOG improvements after STN-DBS persist with disease progression.

  • Movement Disorders
  • Neurosurgery
  • Parkinson's Disease
  • Gait
  • Motor Control

https://doi.org/10.1136/jnnp-2013-306336

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    Introduction

    Freezing of gait (FOG) is a common, debilitating symptom occurring mostly in the mid to later stages of Parkinson's disease (PD) and other parkinsonian syndromes.1 The responsiveness of FOG to dopaminergic therapy varies between PD patients.1 ,2 FOG manifests itself mostly during off-periods but can also occur in on-periods.1 Occasionally, pure on-FOG occurs only when the levodopa dose is increased.2 High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is the most commonly applied surgical treatment in PD patients with levodopa-induced motor complications and dyskinesias.3 Although the biophysical basis is incompletely understood, STN-DBS is thought to normalise pathological patterns of basal ganglia activity affecting thalamocortical and brainstem circuitries.4 ,5 STN-DBS improves parkinsonian motor symptoms and quality of life, allowing a reduction in dopaminergic medication and thus reducing levodopa-induced complications.6 ,7

    To date, the potentially beneficial effects of STN stimulation on FOG are less clear for three main reasons. First, laboratory assessment of FOG on and off stimulation is problematic due to its unpredictable nature and may not reflect FOG in daily life.1 Second, both improvement and worsening of FOG have been reported depending on voltage/frequency stimulation settings and follow-up time.8–11 Third, STN-DBS effects on FOG have never been compared with continued best medical treatment (BMT) in a controlled design.

    This study aimed to compare the effects of bilateral STN stimulation and continued BMT on FOG occurrence in PD patients after 6 and 12 months. Additionally, we compared the effect of STN-DBS and continued BMT on FOG severity and disease-related clinical parameters.

    Patients and methods

    Participants

    Participants were recruited in the Movement Disorders Clinic of the University Hospitals Leuven. All PD patients who were considered eligible for STN stimulation between 1 March 2007 and 1 April 2010 were invited to participate. The inclusion criteria were (1) PD diagnosis,12, (2) disease duration ≥5 years and (3) a combination of disabling motor fluctuations and dyskinesias or disabling medication-resistant tremor. The presence of FOG was not an inclusion criterion. Both freezers and non-freezers were included in order to capture spontaneous or STN-DBS-induced development of FOG.11 Patients were excluded if they (1) had a mini mental state examination (MMSE) score <24/30, (2) had severe psychiatric problems and (3) were older than 70 years. Informed consent was obtained. Participation in the study entailed that the patient could freely choose between undergoing DBS and continuing BMT and in both cases agreed to undergo a standardised clinical evaluation at baseline and 6 and 12 months later. Continued BMT denoted the use of pharmacological compounds, mostly levodopa, aimed at prolonging clinical on periods.1 ,2 Both in the DBS and BMT groups, adjustments of medication were allowed during the study if judged necessary by the treating neurologist (WV).

    Standard protocol approvals, registrations and patient consents

    Participants gave informed consent consistent with the Declaration of Helsinki. Ethics approval was received by the Commissie Medische Ethiek KULeuven.

    Study design and procedures

    The design was a prospective, controlled cohort study with a consecutive inclusion. Patients were evaluated at baseline (just prior to surgery in the STN group) and 6 and 12 months later. At each time point, we evaluated the occurrence and severity of FOG by means of the New Freezing of Gait Questionnaire (NFOGQ)13 using a FOG verification video. The NFOGQ consists of three parts: part I (item 1) assesses whether patients had experienced FOG during the past month during their on and/or off stage; part II (items 2–6) evaluates the frequency and duration of FOG episodes in general as well as during turning and gait initiation separately; part III (items 7–9) quantifies the impact of FOG on patients’ quality of life. The primary outcome was the occurrence of FOG (0/1 score on item 1 of the NFOGQ) at 6 months follow-up, irrespective of whether it occurred on or off medication. FOG occurrence after 12 months served as secondary outcome. The tertiary outcome was FOG severity in those who reported FOG, assessed by parts II and III of the NFOGQ. Other clinical outcomes were the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor examinations) and part IV (treatment complications), the Parkinson's Disease Questionnaire-39 (PDQ-39) (quality of life14), the timed get up & go test (TUG15) and fall occurrence during the previous 3 months (score 0=never, 1=once, 2=twice or more). Cognitive impairment was measured using the MMSE. Descriptive variables included age, gender, disease duration, levodopa-equivalent dose (LED) and Hoehn and Yahr stage. All evaluations were performed on medication and on stimulation (in the intervention group), reflecting the patients’ status in daily life.

    Operation and DBS parameters

    All patients in the STN group underwent DBS implantation by the same neurosurgeon. Patients were off medication for at least 24 h before operation. First, the bilateral implantation of a quadripolar electrode (3389, Medtronic Inc) in STN was carried out, followed by the implantation of a pulse generator (Kinetra or Activa PC, Medtronic Inc). The stimulator was inserted immediately after electrode implantation, or 1 week after stereotactic intervention. Stereotactic localisation of the electrodes in the motor part of the STN was determined by MRI, microelectrode mapping and electrical stimulation in the awake patient using CRW frame (Radionics), Framelink (Medtronic Inc) and microdrive for five microelectrodes (Ben's gun). The final electrode location was evaluated with postoperative imaging (MRI or CT, fused with preoperative MRI). Postoperatively, optimal stimulation parameters were determined considering symptoms and side effects. Six months after surgery, most patients were treated with monopolar stimulation (n=19/24, 79.2%), 60 µsec pulse width (n=19/24, 79.2%) and 130 Hz stimulation frequency (n=20/24, 83.3%). The mean voltage was 2.5 V, (range 1.1–5.0 V). Stimulation settings were largely similar at 12-months follow-up.

    Statistical analysis

    Data normality was checked using Kolmogorov–Smirnov tests. Baseline group differences were studied using χ2 statistics, Fisher's exact tests, Wilcoxon rank sum tests or unpaired t tests, as appropriate. Group differences in FOG occurrence and severity at 6 months were examined using Fisher's exact statistics and unpaired t tests. The Cohen effect size, number needed to treat (NNT) and relative risk reduction (RRR) for FOG occurrence were determined. Other clinical outcomes with normal distributions were compared between groups and time moments using a mixed repeated measures ANOVA model. Wilcoxon rank sum between-group comparisons and Friedman within-group analysis were applied for not normally distributed clinical variables.

    Generalised Estimating Equations (GEE) models were used to evaluate FOG occurrence over time in both groups while controlling for confounders with a posthoc sequential Bonferroni correction for all pairwise comparisons.16 Main effects of group and time and their interaction effect were consecutively entered into the model. The quasi likelihood under independence criterion (QIC), an estimate of goodness of fit, proved always better with the interaction effect included. We used a Wald χ2 statistic to investigate the significance of the interaction in the GEE model. As the GEE model excludes missing variables, missing data points were imputed using the last observation carried forward (LOCF) yielding a worst-case approach. Intention-to-treat analysis served to investigate whether the results were influenced by dropout. GEE statistics with a normal distribution model were used to analyse FOG severity. Exploratory analysis was conducted to understand the relationship between STN-DBS-induced conversion from being a freezer to a non-freezer, on the one hand, and change in clinical variables, on the other hand, using Rank Biserial correlations for binary outcomes (conversion yes/no) in STN-DBS-treated baseline freezers. If appropriate, a multivariate analysis was applied next. Statistical analyses were performed using SPSS, V.16. P values <0.05 were considered significant.

    Results

    Baseline characteristics

    Of the 42 invited patients, one declined to take part in the study. Twenty-four patients decided to undergo bilateral STN stimulation and seventeen chose to continue on BMT. One baseline freezer in the STN group was lost to follow-up at 6 months, but evaluated at 12 months. Five persons in the BMT group, who had FOG at 6 months, were lost at 12 months because an STN stimulator (n=3) or a levodopa/carbidopa enteral infusion system (n=2) was implanted (see online supplement 1 for a flowchart of the study).

    Table 1 shows that STN and BMT groups had comparable demographic and clinical profiles at baseline, except for LED, which was higher in STN (median=1113 mg/day) than BMT patients (median=680 mg/day, p=0.0009). There were no group differences in the dose of MAO-B inhibitors, amantadine and anticholinergic (N=1) medication (see online supplement 2). None of the patients were treated with methylphenidate. There were no baseline group differences regarding FOG occurrence (83% in STN group, 88% in BMT group). All freezers had off-FOG, and six patients in each group also experienced FOG during on. No pure on-FOG was observed throughout this study. Baseline characteristics did not differ between patients who dropped out of the study and those who completed all three assessments.

    View this table:
    Table 1

    Clinical characteristics of the STN and BMT groups at baseline, 6 and 12 months follow-up

    FOG occurrence

    STN group: Nine out of twenty freezers in the STN group still had FOG 6 and 12 months after surgery, of which five cases had FOG during on and off and four cases only during off. Eight baseline freezers converted to being non-freezers at 6 and 12 months follow-up. Three baseline freezers still demonstrated FOG at the 6 months time mark, but had no FOG after 12 months. Two patients in the STN group did not have FOG throughout the study period. Finally, two baseline non-freezers converted to being freezers, one case with FOG only during off and one with FOG during on and off.

    BMT group: In the BMT group, all 15 persons who had FOG at baseline continued to have FOG during follow-up. Moreover, four of the baseline off-freezers also developed FOG in on after 6 and 12 months. Of the two baseline non-freezers, one developed FOG during on and off at the two follow-up tests resulting in 9 on-and-off-freezers in the BMT group after 12 months. One patient showed no freezing at the three test moments.

    Comparison between STN and BMT groups: First, Fisher's exact statistics on the primary outcome revealed that at 6 months follow-up, STN-DBS patients were significantly less likely to demonstrate FOG than the BMT group (table 2). STN surgery was associated with a RRR of 0.40 and the NNT was 3 (95% CI, 2 to 10). Similar results were obtained at 1-year postsurgery.

    View this table:
    Table 2

    Freezing of gait occurrence at 6 and 12 months follow-up in the STN and BMT groups

    Second, main and interaction effects of group (STN, BMT) and time (baseline, 6 months, 12 months) on FOG occurrence were investigated via the GEE model. A significant interaction effect was found on the dataset with imputed cases (dropout at 6 months: N=1, at 12 months: N=5) in favour of the STN group (Wald χ2=7.86; p=0.02). Posthoc comparisons showed that patients in the STN group were less likely to freeze at 6 months follow-up (mean difference=−2.03; 95% CI −3.99 to −0.07; p=0.04) compared with the BMT group (figure 1). After adjustment for baseline differences in LED scores, the interaction effect of group × time was no longer significant (Wald χ2=1.12; p=0.57).

    Figure 1
    Figure 1

    Occurrence of freezing of gait (FOG) in the subthalamic nucleus (STN) group (n=24) and best medical treatment (BMT) group (n=17) at baseline, 6 and 12 months follow-up. *FOG occurrence of one freezer in the STN group was imputed at 6 months follow-up. †FOG occurrence of five freezers in the BMT group was imputed at 12 months follow-up.

    The difference in FOG occurrence between groups was more pronounced at 12 months follow-up (mean difference=−2.53; 95% CI −4.54 to −0.53; p=0.01). We found a significant within-group reduction in FOG occurrence in the STN group but not in the BMT group (Wald χ2=7.65; p=0.02). In the STN group, improvement in FOG occurrence was borderline significant at 6 months follow-up (mean difference=−1.27; 95% CI −2.57 to 0.02; p=0.05) and significant at 12 months follow-up (mean difference=−1.78; 95% CI −3.14 to −0.41; p=0.01) compared with baseline (figure 1).

    FOG severity

    FOG severity, analysed in freezers only, was significantly different between groups 6 months postoperatively (t=2.89, p=0.008) and borderline significant at 12 months (t=2.06, p=0.05). Similar to FOG occurrence, the GEE model produced a significant interaction effect of group × time based after imputation of missing data (Wald χ2=6.51; p=0.04). Figure 2 shows the posthoc comparisons of the GEE model. At 6 months follow-up, the STN group reported significantly less FOG severity (34.2% of the baseline score) than the BMT group (mean difference=−5.89 points on NFOGQ; 95% CI −9.70 to −2.09; p=0.03). These differences were maintained at 12 months follow-up (mean difference=−7.05; 95% CI −11.38 to −2.71; p=0.02). The interaction effect of group × time was no longer significant when accounted for baseline LED (Wald χ2=1.68; p=0.43).

    Figure 2
    Figure 2

    Freezing of gait severity in the subthalamic nucleus – (n=11) and best medical treatment groups (n=15) at baseline, 6 and 12 months follow-up.

    No within-group changes were observed in the BMT group, while the STN group obtained better NFOGQ total scores at 12 months follow-up (mean difference=−5.70; 95% CI −9.35 to −2.04; p=0.03) compared with baseline. There was a trend towards improvement (mean difference=−4.79; 95% CI −8.30 to −1.28; p=0.06) in the STN group from baseline to 6 months follow-up.

    Clinical evaluation

    Several clinical measures improved at follow-up in the STN group but not in the BMT group (table 1). As expected, LED doses were reduced in the STN group 6 and 12 months postsurgery compared with baseline (63.1 and 61.3% reduction, respectively, p<0.01) and BMT (p<0.01). The distribution of other medication doses remained similar between groups except for amantadine, which was more frequently administered in the BMT group compared with the STN group (p=0.04) at 12 months (see online supplement 2). Additionally, UPDRS motor scores, on/off fluctuations (UPDRS IVb) and PDQ-39 scores showed significant improvements at 6 and 12 months follow-up compared with baseline (p<0.01 for all comparisons), resulting in lower (better) scores than the BMT group. In the BMT group, MMSE scores had worsened at 12 months compared with 6 months and baseline assessment (p=0.02). No effects on timed gait tests or falls were shown.

    Association between improvement in FOG and clinical outcomes following STN-DBS

    We examined which clinical factors predicted the conversion from freezer-to-non-freezer. Freezer-to-freezer conversion at 6 months was marginally correlated with baseline LED (R=0.45, p=0.05), meaning that freezers with a higher baseline LED had a higher likelihood of converting to being a non-freezer after STN-DBS. There were no significant correlations with the change in other clinical variables, including LED change and UPDRS IVb. Freezer-to-non-freezer conversion at 12 months was significantly correlated with the relative reduction in LED (expressed as percentage of baseline LED, R=0.46, p=0.04) and with the reduction in on/off fluctuations (UPDRS IVb scores, R=0.47, p=0.03), meaning that freezers with a more pronounced reduction in LED and on/off fluctuations at 12 months follow-up have a higher likelihood to have become a non-freezer at this time point. Other correlations were not significant. To further examine the relative independence of LED reduction and UPDRS IVb reduction in explaining the freezer-to-non-freezer conversion, we applied a multivariate logistic regression model including these two factors. In this full model regression analysis, the change in UPDRS IVb scores entered the model first and explained 21% of the variance between ‘converters’ and ‘non-converters’ (R2=0.21, p=0.037). Next, the LED reduction entered the model and proved a secondary, independent factor explaining an additional 20% of variance (R2=0.20, p=0.026). Jointly, the two factors explained 41% of the variance between ‘converters’ (N=11) and ‘non-converters’ (N=9).

    Discussion

    This is the first prospective, controlled study into the effect of bilateral STN stimulation on self-reported FOG as experienced in daily life. The results were in favour of STN-DBS. Following surgical treatment, freezers were more likely to (1) convert to being non-freezers (RRR=0.4) and (2) experience a reduction in FOG severity. These effects were mediated by a reduction in patients’ LED and motor fluctuations. Patients who continued BMT showed worsening of FOG symptoms (more on/off FOG). In agreement with previous literature,6 ,7 we found that STN-DBS also led to improved motor symptom severity and quality of life.

    As quality of life improvement is a well-established finding,7 the current study examined the effects of STN-DBS on FOG in a non-randomised way for ethical reasons. This induced a small difference in subject number between groups at baseline. Patients who chose to undergo STN-DBS were comparable to BMT-treated patients at baseline on all clinical parameters, except for their higher LED score. It is noteworthy that this suggests a slightly more severe disease profile in the STN-DBS group, adding strength to the positive treatment outcomes found in this group. We did not assess FOG in a blinded way, which is a limitation of the current study.1 However, the NFOGQ is a validated tool to evaluate FOG occurrence and severity over a period of 1 month rather than in a single test session, which adds to the ecological validity of the findings.13

    The present study suffered from dropout (N=5) in the control arm due to the natural progression of the disease. We performed a thorough and conservative statistical control for this drawback through imputation and GEE modelling. Therefore, it is unlikely that dropout influenced the interpretation of the results.

    The mainstay of therapy for FOG is to prolong clinical ‘on’ periods.1 Stimulating the STN does not directly produce striatal dopamine release but may boost the dopamine motor system by inhibiting overexcited STN neurons,5 ,17 reducing the neuronal synchronisation in the vicinity of STN18 and altering connectivity of thalamocortical pathways.19 Similarly, methylphenidate, which enhances synaptic dopamine, was recently suggested to improve FOG in combination with levodopa and STN-DBS.20 Still, response to STN-DBS in relation to FOG is heterogeneous with presurgical levodopa responsiveness, disease duration and age as best predictors of outcome.11 ,21 An important finding of the present study was that the reduced levodopa dose equivalent and improved motor fluctuations discriminated between baseline freezers who no longer experienced FOG 12 months after surgery (55%) and those who did (45%). This is in line with a recent multivariate model in which increased LED, over and above its reflection of disease severity, was a significant predictor of FOG.22 On the other hand, a meta-analysis of long-term effects of DBS of STN and GPi23 suggested that the reduced levodopa dosages, enabled by STN-DBS, may be responsible for a quicker reappearance of postural and gait disturbances as compared with GPi-stimulated subjects after 2 years. These findings support the complex relationship between FOG and levodopa, suggesting that FOG is partially levodopa responsive and partially dependent on other neurotransmitter systems with extremes at both ends of the spectrum.1 ,2

    Our results of postsurgical improvement of FOG severity substantiate recent findings of Niu et al,24 who examined a similar follow-up period, but no control group and no freezer to non-freezer conversion. FOG can also emerge after STN stimulation.11 ,25 In our STN-DBS group, two of the four non-freezers at baseline developed FOG after surgery. Similarly, one of the two baseline non-freezers in the BMT group demonstrated FOG at 6 and 12 months follow-up. Emergence of FOG in some patients after STN stimulation may reflect disease progression rather than a side effect of stimulation, although our sample of non-freezers was too small to make firm conclusions. In the BMT group, disease progression was reflected by the increase from two to six patients experiencing FOG in both on and off.

    Freezers treated with STN-DBS who had converted to being non-freezers at 12 months follow-up all had stimulation frequencies of 130 Hz (n=11) or more (n=2). This result is interesting in the light of recent studies that suggest controversial results on lowering the stimulation frequency to specifically target axial symptoms and FOG in the short and/or long term.8–10 ,26 ,27

    Clinically, FOG is influenced by a range of motor and non-motor problems that may respond differently to STN-DBS.1 ,22 The central motor component of FOG relates to poor control of timing and scaling of movement that predisposes freezers’ locomotor pattern and other repetitive movements to a critical breakdown.1 ,28–30 In the context of freezing during upper limb motion, we recently showed that patients with FOG overactivated the STN, pallidum and putamen while prefrontal motor regions were underactivated compared with non-freezers and controls.31 As such, freezing-related alterations of brain activity were located within the striatofrontal circuitry, which is likely to be influenced by STN-DBS. Positive effects of STN-DBS on stride length,32 bilateral coordination,33 symmetry32 and turning 34 have been reported and could thus diminish FOG after STN-DBS. However, improvements of timed gait in the STN group in this study did not reach significance, suggesting a FOG-specific effect of STN-DBS as an alternative explanation. In line with recent neuroimaging studies suggesting a supplementary role of non-dopaminergic locomotor circuitries,35–37 low-frequency stimulation of the PPN may alleviate FOG without necessarily recovering background spatiotemporal gait abnormalities.38 Moreover, novel DBS approaches that simultaneously modulate gait control networks through STN, SNr and PPN39 ,40 may produce a synergistic effect on FOG.

    Conclusion

    In this prospectively controlled study, STN-DBS alleviated FOG in 55% of freezers at 6 and 12 months after surgery compared with worsening of FOG when treated with BMT. Freezers treated with STN-DBS were also more likely to experience reduced FOG severity during follow-up compared with patients who stayed on BMT. The improvement of FOG after STN-DBS may be partially driven by the dopamine-reducing effects and reduced on/off fluctuations. Future follow-up trials are warranted to evaluate whether therapeutic benefits persist with disease progression.

    Acknowledgments

    We are grateful to all participants for their willingness to participate. WV is a Senior Clinical Investigator of the Research Foundation—Flanders (F.W.O.). HD is a postdoctoral fellow of the Research Foundation—Flanders.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors SV, LM and HD contributed to analysis and interpretation of the data, and drafting and revising the manuscript. WV and AN contributed to the design and conceptualisation of the study , analysis and interpretation of the data, and drafting and revising the manuscript. BN contributed to the design and conceptualisation of the study, and drafting and revising the manuscript.

    • Funding This work was supported by the Research Council of Katholieke Universiteit Leuven, Belgium, grant number OT⁄07⁄074 and the Flanders Fund for Scientific Research, grant number G0691.08.

    • Competing interests None. Bart Nuttin holds a Chair for Stereotactic Neurosurgery for Psychiatric Disorders, a donation by Medtronic Inc.

    • Ethics approval Commissie Medische Ethiek KULeuven.

    • Provenance and peer review Not commissioned; externally peer reviewed.