Deep brain stimulation (DBS) for Parkinson’s disease (PD) is a neurosurgical procedure that involves implanting electrodes in a deep site within the brain. The only site this paper will address is the subthalamic nucleus (STN), although there are other areas. The first attempted stimulation of the STN was performed in 1993.1 The target was discovered mostly from work in MPTP monkeys showing there was hyperactivity in the STN that was critical in the pathophysiology of parkinsonian symptoms. Despite its 15-year history, there are limited long-term human data in the literature, and the longest studies so far published are around five years long.
The DBS implantation procedure is guided using a choice of methods, but magnetic resonance imaging (MRI) is an important tool for localisation of the target. Surgery is usually performed with the patient under local anaesthetic, which allows for testing of results in the operating room. By interacting with the patient as the procedure is under way, the surgeon can assess symptoms such as tremor, stiffness or bradykinesia in realtime. The benefits of STN-DBS can appear very quickly; there is even an improvement simply from implanting the electrodes, and turning the stimulation on adds even more. After the electrodes are positioned, a pulse generator is implanted subcutaneously in a separate surgery, usually performed under general anaesthesia. This generator is later programmed.
The main advantage of STN-DBS is that it improves the majority of parkinsonian symptoms in the off phase, particularly motor symptoms. Studies have found marked improvements in the clinical sub-scores for rigidity, akinesia, tremor, gait, standing up ability and balance in patients one year after surgery. Other aspects such as speech were not found to improve nearly as much.2 Nevertheless, the large range of symptoms that respond to this treatment means that many PD patients can potentially benefit from it. Dyskinesia is also improved in the long term. Clinical scores of dyskinesia and dystonia have been shown to improve significantly after surgery.3 Part of this improvement can be explained by a concomitant reduction in medication taken by the patient: on average patients reduce their dose of medication – in this case levodopa – by approximately half.3
Quality of Life
There is good evidence that patients’ symptoms improve with STN-DBS, but the real question is whether this translates into an improvement in their quality of life (QoL). Unfortunately, as most of the STN-DBS studies in the past have tended to focus on improvement in symptoms rather than QoL, the data sets that examine this issue are on average even shorter than those measuring clinical scores and Unified Parkinson’s Disease Rating Scale (UPDRS).
Siderowf et al. used the Parkinson’s Disease Questionnaire – 39 items (PDQ-39) to study post-surgical improvements in QoL in 18 PD patients. They measured sub-scores in mobility, activities of daily living (ADL), emotional wellbeing, stigma, social support, cognition, communication and bodily discomfort at baseline, six months and a final follow-up at 18–57 months. Some sub-scores such as mobility, ADL and stigma showed a substantial continual improvement, while others – most notably cognition and communication – actually worsened.4 Thus, overall improvement in QoL is equivocal.
A German study by Deuschl et al. examined QoL changes in 156 patients split into surgical and medical treatment groups, but over only six months. Using PDQ-39, the researchers found that there were differences in the amount of improvement in each QoL sub-scale. Once again, physical measures such as mobility, ADL, stigma and bodily discomfort showed substantial improvement in the surgery group compared with the medical group, while social support, cognition and communication showed only a non-significant trend to improvement.5 Figure 1 shows a summary of the papers published that examine QoLchanges following DBS in PD patients as measured by PDQ-39. It is clear that there is a trend for certain sub-scores to improve reliably, in particular mobility, ADL and bodily discomfort. However, while the follow-up time varies, it is rarely more than two years and cannot be considered long-term. There are also three domains that consistently fail to improve or, in certain cases, actually worsen: social support, cognition and communication.
These results are also seen with different QoL instruments. Lagrange et al. examined QoL using the PD Quality of Life (PDQL) questionnaire in 60 consecutive PD patients before surgery and 12 months after surgery. Once again, the emotional aspects improved less than the motor functions.6 These findings echo earlier papers in this report that illustrate the emphasis traditionally given to motor function over other aspects of PD.
Impact of Age
Only a few studies have looked at the role of age in response to STN-DBS. Empirically, many teams prefer not to operate on patients above a certain age, but there is still debate as to whether this is the right decision and, if so, where the upper limit should be.
A couple of recent papers have specifically examined this issue. Ory-Magne et al prospectively followed 45 patients between 40 and 73 years of age for 24 months. At 12 months they found no correlation between age and improvement in QoL: all patients had a relatively similar improvement. However, by 24 months a negative correlation had emerged between age and three QoL sub-sectors of the PDQ-39: mobility, ADL and cognition.7 This implies a lack of permanence for the initial DBS improvements. Using a different methodology, Derost et al. examined the role of age in response to DBS by dividing the patients into two groups, with a cut-off at 65 years of age. By charting their progress at three, six, 12 and 24 months, the researchers found that the younger group showed much greater improvement than the older group in mobility, ADL, stigma, cognition and communication. Certain aspects, such as emotion or social support, did not improve in either group.8 The same study also compared UPDRS scores between the two groups and found no difference between younger and older groups overall, although sub-scores dealing with axial symptoms were worse in the older group.8
Russmann et al. separated their 52 PD patients into three agedetermined groups, with cut-offs at 60 and 70 years of age. Results showed that UPDRS in the off state improved significantly in all three groups, but by diminishing amounts: more parkinsonian symptoms remained post-operatively in the older patients. Once again, axial symptoms were less responsive to stimulation across all groups, and even worsened in the oldest patients.9
Examining the situation from a different perspective, if there is a role of age in response to DBS, it should be used to predict outcome success. The first such study to examine this found a clear correlation in terms of clinical score, as measured by UPDRS, between percentage improvement with STN-DBS and age.10 This finding is confirmed by some studies11 and disputed by others.12–14 However, the methodologies employed differ among the studies, particularly with respect to the cut-off ages used: Welter et al., for example, found no correlation but used a surprisingly young cut-off point of 56 years.14
Side Effects Therefore, there is a feeling that older patients, although they can improve overall, derive less QoL benefit from STN-DBS, in part related to the decline in axial functions, particularly over the long term. There is also evidence that older patients face increased risk with neurosurgery. For example, Ory-Magne et al. found a significant role of age in the risk of bleeding, including four deaths of patients 69–71 years of age. There was also a correlation between age and post-operative apathy or depression.7 This increased risk is confirmed in other studies, along with evidence of older people being more prone to post-operative side effects,15 postural instability16 and death.17 Meanwhile, other studies have found no such correlation,8,9,18 although these studies included, on average, younger patients (<70 years of age). In terms of cognition, there is evidence that older patients (>69 years of age) have a higher risk of cognitive decline following surgery. Saint- Cyr et al. noted this effect, which was especially significant for working memory, mental processing, verbal fluency and verbal and visual learning.19 Other longitudinal studies have found evidence of onset of dementia in older patients, although some have speculated that this is secondary to the natural evolution of PD rather than a direct effect of STN-DBS.20,21 Once again, there is no consensus: some studies have not shown any evidence of a correlation between age and cognitive decline or dementia.7 Overall, in older patients there is generally a higher risk of a decline in balance and cognitive functions. Longitudinal studies in parkinsonian patients of all ages show similar trends: up to five years following STNDBS there is still an improvement in clinical score compared with baseline. However, comparing year one with year five highlights a decline in benefit, particularly for postural stability and gait. This is similar for on-drug as well as off-drug aspects, although dyskinesias retain improvement.22 Dementia was found to have developed in some patients in these four- to five-year longitudinal studies.17,20–23
Summary and Conclusions
Based on current data, STN-DBS appears to improve QoL for patients with PD in the medium term. Improvement is mainly confined to those QoL domains related to motor function. Emotional and social functions, on the other hand, can often deteriorate, and it is important to warn patients about this prior to surgery.
In older patients, improvement in QoL declines faster over time. Older patients are at risk of developing difficulties with balance and cognitive ability, and possibly other side effects. They also have an increased risk from surgery. Studies that have attempted to look at the long-term effect of STN-DBS have shown there is some decline in balance and suggestion of an increase in the incidence of dementia. Furthermore, there is an agelinked deterioration in axial signs and worsening cognition.
DBS should be considered very cautiously for patients in their late 60s onwards. In this populationthere is a risk of deterioration of balance and cognitive function and development of postural instability and dementia, as is the case with all PD disease patients, and this may be exacerbated by surgery.