PD SURG was designed with quality of life as the primary endpoint to examine the efficacy of deep brain stimulation versus medical therapy on the daily lives of people with Parkinson's disease and thus provide practical information to inform future use. PD SURG included a representative sample of patients likely to be offered surgery at neuroscience centres in the UK, where apomorphine is readily available, thus enabling comparison of surgery with best medical therapy and providing evidence on the benefits of surgery in a real-world setting. The follow-up reported here was longer than in two other large trials of deep brain stimulation versus medical therapy,16,17
and thus gives statistically more reliable results and provides evidence on the longer term benefits of surgery (with less likelihood of a so-called honeymoon effect18
in the period just after surgery). Although one trial has investigated the effects of surgery for Parkinson's disease to 18 months, only 20 patients were included and thus the trial was underpowered; also, patients with earlier stage disease were recruited.19
From a purely scientific perspective, a long-term trial of surgery versus medical therapy would have been ideal; however, a realistic design acceptable to both patients and clinicians was necessary, and so surgery was permitted after 1 year in the medical therapy group. There were clear advantages for surgery compared with medical therapy alone at 1 year, both in patient-assessed quality of life and on clinical assessment. These benefits are likely to be meaningful to patients, as measured by use of the PDQ-39,20
and were found in domains of the PDQ-39 that surgery would be expected to affect (eg, mobility and activities of daily living), but not in others (eg, social support, cognition, and communication). These findings were mirrored by clinically meaningful differences on the UPDRS,21
including the patient-rated UPDRS part IV, which showed substantial benefits of surgery in the time and severity of dyskinesia and off periods—the most common reasons for patients to be considered for surgery. Greater benefits for the surgery group than the medical therapy group were seen for off-medication UPDRS assessments. However, this represents an artificial situation, created by a temporary withdrawal of medication and does not indicate an absence of drug because the washout period was not long enough. When considering the real-life on-medication assessment, the magnitude of the benefit seen in our trial is smaller than perhaps anticipated from the numerous small uncontrolled series that have suggested large effects of surgery.22,23
PD SURG, along with other reported randomised trials,16,17,19
shows benefits for surgery over best medical treatment in patients with advanced Parkinson's disease, even when apomorphine is available, while also confirming that there are risks associated with surgery. A meta-analysis of PDQ-39 summary index scores showed that the results of the trials are generally consistent with each other (test for heterogeneity, p=0·2; ), although there is evidence of heterogeneity of treatment effect between the trials with 6 months of follow-up and PD SURG with 12 months of follow-up (test for interaction, p=0·04).
Meta-analysis of 39-item Parkinson's disease questionnaire summary index score in trials of deep brain stimulation versus medical therapy
The PD SURG results at 1 year show smaller differences between the groups in the PDQ-39 summary index (4·7 points) than was seen in the two trials that reported results after 6 months (8·7 points).16,17
Although from a statistical perspective this difference is not substantial and might be a chance effect, it is worth considering potential alternative explanations based on differences in the trial designs. First, it is possible that there is a large immediate effect of surgery, whether real or in part related to an early so-called honeymoon effect,18
which gradually decreases over time. If the benefits of surgery are relatively transient, this would call into question the long-term value of surgery. Second, there might have been better drug treatment of Parkinson's disease in the medical group of PD SURG than in the other two trials, because of the use of apomorphine in over one-third of patients in this group. Apomorphine is an effective drug in advanced Parkinson's disease2
and can be given by continuous infusion to enable a more constant dose to be delivered to the patient, thereby smoothing out on–off periods and fluctuations. However, apomorphine is expensive, and thus in the UK tends to be used only when other drugs have failed to control the symptoms of Parkinson's disease adequately; that is, it might be used in the same situations as surgery for patients with advanced Parkinson's disease. Hence, a comparison of the effects of surgery plus medical therapy versus medical therapy, in a population of patients whose treatment could have included apomorphine (as in PD SURG), provides better evidence on the relative benefits of surgery than a comparison with medical therapy not including apomorphine. However, apomorphine is less widely used outside the UK, and was not reported as being widely used in the other trials.16,17
Administration of apomorphine is more complicated than for other Parkinson's disease drugs, requiring infusion and monitoring. Nevertheless, because of its efficacy, apomorphine use might become more common, and thus the results of PD SURG could have wider relevance in future. Optimisation of medical therapy might lead to a smaller comparative advantage for surgery. Nevertheless, surgery is still a valid treatment because patients would need to have only a one-off procedure (albeit with need for stimulator adjustment and replacement) rather than regular administration of an expensive drug. Whether technical aspects of the procedure, such as electrode location within the target site, are factors that could be improved are also important to consider.24,25
Substantially more patients in the surgery group had serious adverse events than did patients in the medical therapy group, confirming that deep brain stimulation surgery for Parkinson's disease is not without risks.26,27
Reporting of all serious adverse events, whether surgery related, disease related, or drug related, was mandatory in both the surgical and medical groups. Because a 6-month postoperation form that included serious adverse events was completed only in the surgical group, there could have been differential reporting of serious adverse events unrelated to surgery, despite efforts—through a case-note review—to collect these data in both groups. However, similar surgery-related serious adverse events were seen in the two other trials.16,17
Furthermore, recently raised concerns about the suicide rate27–29
after surgery were not confirmed in our study (only one patient attempted suicide after surgery), and only one patient died as a result of the procedure. A limitation of the study is that adverse events that were not serious enough to cause or prolong a patient's stay in hospital were not routinely recorded. However, adverse events are difficult to record accurately (eg, there were three times more adverse events in one of two comparable trials than in the other)16,17
and their combined effects should be reflected in the participants' perception of their quality of life.
Preliminary analysis of the neuropsychological outcomes, to be reported in detail elsewhere, did not suggest any major adverse effect of surgery other than on verbal fluency and vocabulary. The changes in group means for neuropsychological outcomes represent small decreases in individual scores that are not usually associated with clinically meaningful effects on any activities of daily living.30
Subclinical decreases in verbal fluency after deep brain stimulation or lesional surgery for Parkinson's disease have been reported,31–33
and are understood to be caused by disruption to projections from the basal ganglia to the prefrontal cortex, which are involved in language and executive skills. For example, after deep brain stimulation of the subthalamic nucleus, substantial associations have been reported between activation of areas including the dorsolateral prefrontal cortex and Broca's area, as measured with fluorine-18-labelled-fluorodeoxyglucose-PET, and performance on verbal fluency tasks.33
These changes are not associated with patient age, disease duration, or dose of dopaminomimetic drugs after surgery;34
however, a frequency-dependent reciprocal modulation of verbal fluency and motor functions in deep brain stimulation of the subthalamic nucleus has been reported.34
Discussions with potential candidates for surgery should include the potential risks and benefits of surgery. Deep brain stimulation is a costly procedure and therefore health economic issues need to be taken into account. However, the amount of drug therapy required in the surgery group was about one third lower than the amount required by those in the medical therapy group. Thus, the cost of surgery will be partly offset by the reduction in the amount of drug therapy required by patients who have had surgery. In particular, if apomorphine or continuous intestinal infusions of levodopa, with high recurrent costs, are the alternative drug treatment options, the cost-effectiveness equation might favour surgery (a full economic analysis of PD SURG will be reported elsewhere). Thus, it is important to identify patients who are or are not likely to benefit from surgery when the risks and costs are taken into account. Subgroup analyses are unreliable, with a high likelihood of chance effects being observed.35
The protocol-specified subgroup analyses did not provide clear evidence that the benefit of surgery differed in different types of patient, although, given the insensitivity of tests for interaction,36
the possible greater benefit in patients with more advanced disease, as measured by Hoehn and Yahr stage (p=0·2), is worthy of further investigation.
Some limitations in the design of PD SURG should be acknowledged, especially in relation to a potential placebo effect. Ideally, patients and assessors would have been masked to treatment allocation. However, sham surgery on patients in the medical therapy group (ie, to insert electrodes and stimulators but not switch them on) would not have been practical (eg, increased theatre time and cost). Furthermore, attempts at masking are likely to be ineffective because, in many cases, patients will be able to tell if their stimulator is switched on. Thus, patients' perception of their quality of life could have been influenced by their knowledge of the treatment they received. Use of independent masked assessors was beyond the resources available for this trial and, because the UPDRS was a secondary endpoint, was not considered essential. The use of the insensitive DRS-II as a measure of cognition was also a potential drawback, but this was deemed to be adequate to provide an overall assessment of the whole trial population, with a more detailed neuropsychological evaluation being done in a subset of patients. The absence of a standard definition of the on state in the protocol might also have been a limitation of the study, although all centres had experienced neurological teams familiar with doing the UPDRS and the comparative nature of the trial meant that any cross-centre differences would apply to both groups and would not introduce bias.
Follow-up of PD SURG will continue for several years and future papers will report on the longer term outcome of immediate surgery versus deferred surgery; subgroup and prognostic factor analyses; neuropsychological effects of surgery; the effect of surgery on carers; further details on the procedure and longer term outcomes; and health economic evaluation. Surgery is likely to remain an important treatment option for patients with Parkinson's disease, especially if the way in which deep brain stimulation exerts its therapeutic effects is better understood, if its use can be optimised by better electrode placement and settings, and if patients who would have the greatest benefit can be better identified.