Principal findings
In this systematic review assessing the benefits and harms of deep brain stimulation for Parkinson's disease, we identified seven trials where 1125 participants were randomised to receive deep brain stimulation with antiparkinsonian drugs versus antiparkinsonian drugs only (primary comparison). All results had a high risk of bias and the certainty of the evidence was very low for all primary outcomes. The information size was insufficient when assessing all cause mortality. Meta-analysis showed that deep brain stimulation increased the risk of serious adverse events, mainly because of an increased risk of perioperative complications, such as cerebral haemorrhages and postoperative confusion, and events related to hardware, such as infection at the stimulator site, dislocation of the device, or reoperations. Meta-analyses indicated that deep brain stimulation might reduce symptoms specific to Parkinson's disease, but the assessments of disease specific symptoms had several methodological limitations.
Strengths and limitations of this study
Our systematic review had several strengths. We used up-to-date methods to assess the methodological quality of the included trials.21 50 51 Our methodology was predefined and described in detail before starting the literature searches,15 and was based on the eight step assessment, suggested by Jakobsen et al,21 and trial sequential analysis.23 Risk of bias was assessed with the Cochrane RoB 250 and overall certainty of the evidence with GRADE.51 Therefore, both risks of random errors (play of chance) and systematic errors (bias) were taken into account in our review.
Our systematic review had several limitations. Firstly, the maximum follow-up period in most trials was less than a year, and therefore long term beneficial and harmful effects could not be assessed. Secondly, all of the included trials were assessed as having a high risk of bias, mainly because of missing data, lack of blinding, and poor reporting without prespecified protocols, clinical trial registrations, or statistical analysis plans. Hence our results presumably overestimated the beneficial effects of deep brain stimulation.52–54 Thirdly, the overall risk of type I errors was increased because of the large number of outcomes, comparisons, and subgroup analyses. We adjusted our thresholds for significance only according to the total number of primary outcomes. Fourthly, the included trials differed in participant characteristics (eg, age, sex, and length of disease) and trial design (eg, follow-up time and placement of electrodes), increasing the risk of statistical heterogeneity. We investigated these concerns by performing subgroup analyses, when possible, but lack of relevant data limited the power of these analyses. Only the subgroup analysis comparing different lengths of disease when assessing serious adverse events (online supplemental figure S11) indicated evidence of a difference. This finding was mainly influenced by the study of Schuepbach et al enrolling participants with early motor complications.39 Although the relatively reduced risk of serious adverse events with deep brain stimulation seen in this trial could be attributed to the shorter length of disease, two smaller trials included in the same subgroup did not indicate any evidence of this trend.35 40 Therefore, whether a longer length of disease increases the risk of serious adverse events is not known.
Measurement of symptoms specific to Parkinson's disease in the included trials also had methodological challenges. Only one trial reported total UPDRS score when participants received antiparkinsonian drugs. Many studies focused on UPDRS III scores, which only evaluated motor scores, and only a few trials39 40 45 had predefined disease specific symptoms as their focus. Also, most trials assessed symptoms when antiparkinsonian drug treatment was paused. This situation is challenging to apply to the clinic where most participants are expected to receive antiparkinsonian drugs, although the efficacy of deep brain stimulation is perhaps more precisely assessed when drug treatment is paused.
Our results showed that participants receiving deep brain stimulation were likely to reduce their dose of antiparkinsonian drugs. This finding could be a result of more frequent hospital visits for stimulation, and adjustments to drug treatment, in the intervention groups receiving deep brain stimulation, or an effect of deep brain stimulation itself. Because antiparkinsonian drugs are known to have adverse effects, some of the beneficial effects in subsections of the UPDRS might be linked to the decrease in drug dose because of deep brain stimulation (eg, reducing fluctuations and adverse effects of drugs, as seen in UPDRS IV). This finding could also explain the beneficial effects seen in some subsections of the UPDRS of deep brain stimulation with antiparkinsonian drugs versus antiparkinsonian drugs only, when drug treatment was paused, as seen in UPDRS II and UPDRS III. These results from the meta-analyses are difficult to interpret, however, as the assessment scales used by the trialists were not related to predefined and evidence based minimal important differences.55–58 These methodological limitations need to be considered when interpreting the analysis results based on disease specific symptoms.
Comparison with other studies
Previous reviews have assessed deep brain stimulation for Parkinson's disease.59–62 Generally, these reviews showed a beneficial effect of deep brain stimulation on UPDRS score, troublesome dyskinesias, and quality of life.59–62 As well as methodological limitations, these reviews15 mainly focused on the effects of deep brain stimulation on motor symptoms, dyskinesias, and quality of life, whereas little or no information on adverse effects was reported. Furthermore, previous reviews have not considered the implications of using scales without predefined and validated minimal important differences to assess motor symptoms.
Study implications
The use of deep brain stimulation for Parkinson's disease is increasing and will likely become part of standard care.63 When an intervention has already been approved and integrated as part of standard care, setting up randomised clinical trials is often difficult because clinicians might question whether patients should be randomised to a treatment that does not include the intervention in question. Hence the results of our review highlight the urgent need for well conducted, long term randomised trials with patient important outcomes, including assessing adverse effects, before deep brain stimulation has been even further integrated as part of the standard care. Observational studies could supplement randomised trials, especially for investigating rare adverse events.
Conclusions
In this review, we found that the certainty of evidence was very low for all primary outcomes, and based on the included evidence, the beneficial effects of deep brain stimulation were questionable because of methodological limitations. Compared with only antiparkinsonian drug treatment, deep brain stimulation with antiparkinsonian drugs seemed to increase the risk of serious adverse events, mainly because of perioperative complications and hardware related events. Conducting randomised clinical trials of adequate methodological quality to effectively evaluate the effects of deep brain stimulation is crucial.