Parkinson’s disease

Some of the initial attempts at long-term stimulation for chronic disease states were attributed to Shealy in the USA , and Bechtereva in Russia . However, before stimulation efforts, other surgical measures had been used to effect modulation of the nervous system including the ligation of the choroidal artery for movement disorders and targeted lesioning. Although DBS is currently used most often for movement disorders, there are many other indications. In this setting, implantation of stimulation devices generally targets the subthalamic nuclei (STN), globus pallidus internus (GPi), or ventralis intermediate nucleus (Vim) of the thalamus.

The exact placement of the stimulator has significant impact on the patient, resulting in symptom relief that is unique for each target. In terms of motor improvements, the targets and symptom relief can vary. For example, the target could include the GPi in cases of dystonia or the Vim in cases of non-parkinsonian tremor. In patients with Parkinson’s disease, targeting this subnucleus (Vim) does relieve the parkinsonian tremor but fails to modify the other chief symptoms of the disease . Although debate exists what is the ideal target for various movement disorders, the target is largely based on the type of expected symptom relief. Target selection is then matched to the nature of symptoms experience of the patient. To ensure the optimal surgical outcomes for patients with movement disorders, the medical team should carefully select the patient, exhaust the available medical treatments, choose the best target and surgical technique , optimize the DBS settings , and properly manage the post-surgery medication regimens.

Deep brain stimulation for Parkinson’s patients is complicated in part because of the spectrum of symptoms that are not just movement related. The stimulation effect reaches other aspects of the disease and does so to varying degrees depending on the target. Both the GPi and STN nuclei not only improve parkinsonian symptoms but also reduce drug-induced dyskinesias but, in addition, the STN is thought to also reduce medication burden. In the 2009 COMPARE trial, the authors demonstrated that motor score improvements were similar whether targeting the GPi or STN . Zahodne et al also noted that neither motor nor mood scores differed by these two targets, but the GPi target did demonstrate greater improvements in the subscale ratings related to mobility, activities of daily living (ADL), stigma, and social support. This relatively new claim warrants further research because the impact on patient quality of life is significant. With the negative impact of the disease on patient’s cognition, Heo et al believed that bilateral STN stimulation might lead to slightly more detrimental effects on frontal lobe function and memory . The authors inferred that improved outcomes with cognition might be obtained via GPi or unilateral targeting. The full impact of GPi versus STN targeting though is still an area of controversy, especially with respect to overall patient outcomes.

Results in quality-of-life studies have varied regarding the effects of surgical treatment in patients with movement disorders. And, the numbers of studies are sparse. Outcomes for movement disorders, particularly Parkinson’s disease, have used the unified Parkinson’s disease rating scale (UPDRS) part III, a standardized scale that primarily demonstrates the motor benefits subsequent to surgical intervention. Such measures can in part reflect subjective improvements from the point of view of the patient: for example, regaining motor dexterity and control (e.g. holding a cup of coffee without fear of spilling it). Admittedly, the patient’s relief in these circumstances is subjective, difficult to measure and appreciate. In a long-term follow-up study of STN DBS, Krack et al found that there were significant improvements in the postoperative UPDRS scale, specifically ratings were 59% lower at 3 months and 54% lower at 5 years . In this same study, the authors reported improvement in ADL functions by 49% compared with baseline functioning; they furthermore noted that, before surgery, most patients had depended on others to some degree but after surgery nearly all enjoyed independence throughout the entire follow-up period.

In a similar study assessing the psychological impact of deep brain stimulation, Schupbach et al demonstrated comparable results, that is, the UPDRS ratings showed 54% improvement at 5 years . The authors noted that 10 of 20 patients were able to withdraw completely from all parkinsonian medications. Although the measures of neuropsychological and mood assessments were unchanged by the surgical procedure, cognitive decline was marked. However, this decline was attributed to the natural progression of the parkinsonian disease rather than the intervention performed. Another important aspect of this study demonstrated that daily dosing of levodopa was reduced by 58% and very likely significantly impacted the patient’s perception of the disease. When medication regimens are simplified , patients can not only better control their disease symptoms but also notice significant impact on quality of life and cost effectiveness.

Essential tremor

Neurostimulation for tremor can significantly benefit a patient’s quality of life. Even while undergoing intraoperative testing, patients may feel tearfully happy about the prospect of better motor function. As discussed in other chapters, Vim or STN targeting is most often used in neurostimulation for essential tremor. Many of the research findings regarding tremor are included with information for Parkinson’s disease. Sydow et al documented long-term relief of tremor 6 years after surgery in the 19 of 37 patients available for follow up; significant reduction in tremor score and improvement in activities of daily living were found compared with baseline or in the stimulation-off mode . Zhang et al cited an 80.4% reduction in tremor and 69.7% improvement in handwriting in 34 patients with an average 56-month follow up . Interestingly, between 57- and 90-months follow up, no statistical difference was found in functional ability when evaluating tremor and handwriting. Subtle adjustments in programming, primarily increases in voltage, were needed by many patients during the 5-year follow up. At 7 years postoperatively, Hariz et al noted decreases in the efficacy of DBS for tremor; however, a notable positive impact on quality of life and ADL functioning remained , especially for the patient’s ability to eat and concerns with social life. The authors stated the more significant declines in the effects of DBS in most other areas, which began 6–8 years postoperatively, were likely due to aging, aging co-morbidities, and disease progression. At this endpoint, tremors significantly worsened when stimulation was turned off. Patients with tremors who had been unable to write their names or perform other common tasks found significant rewards with the renewed ability to function in ways often taken for granted by others.

Dystonia

Stimulation of the GPi is the most studied target for dystonia, both primary and secondary. In primary generalized dystonia (PGD), the mean improvement at 3- to 12-month follow-up ranged from 46% at 3 months and 80% at 12 months follow up in the Burke–Fahn–Marsden dystonia rating scale (BFMDRS) severity score, and 37% at 3 months, and 69% at 12 months follow up in the BFMDRS disability score . At 2-year follow up, mean improvement ranged from 34 to 82% in the BFMDRS severity scores and 32 to 75% in BFMDRS disability scores . At 3-year follow up, the motor improvement and quality of life (SF-36 questionnaire) observed at 1 year had been maintained . Significant benefits of this therapy were evidenced by the improvements in general health and physical functioning at 12-month follow up and 15% improvement in the unified dystonia rating scale (UDRS) which is statistically significant .

In children, the improvement reported at 6-month follow up was as high as 56% in the BFMDRS motor scores and 42% in the BFMDRS disability scores . Compared with adults, the better outcomes in children were associated with DYT1-positive genetic status and with less motor impairment before surgery .

Regarding the neuropsychological outcomes, there have been no reported significant changes in measures of mood and cognition after pallidal stimulation in dystonia patients in short- and long-term follow up . Some authors reported no significant reduction in the number of errors in the Wisconsin card sorting test (WCST) at 1-year follow up . Others showed that bilateral GPi DBS clearly improved functional abilities and quality of life , and noted some improvements in concept formation, reasoning, and executive functions .

Contact location greatly impacted outcomes: overall clinical improvements were as high as 89% with posteroventral contacts versus only 67% with anterodorsal contacts in the pallidum . There is also a chance of poor outcome because of lead misplacement. In addressing this topic, Ellis et al reported 12.8% improvement above the already-obtained improvement in the UDRS score after lead relocation .

Factors that predict poor outcome in generalized dystonia seem relate to a greater disability from symptoms (a high preoperative BFMDRS score) and long disease duration . There was greater improvement in children with the genetic form DYT1-positive than in children with non-DYT1 forms. The volume of the GPi stimulated also influences the outcomes, the greater the GPi volume, the greater the degree of improvement .

For primary focal and segmental dystonia, improvements in the BFMDRS score are in the order of 64% at 3 months and 75% at 1 year 75% . At 2-year follow up, ratings on the Toronto western spasmodic torticollis rating scale (TWSTRS) had improved nearly 60% for both disability and pain scores . In patients with cervical dystonia, there was a 43% improvement in the TWSTRS severity score and a 59% improvement when both the disability and pain scores were combined . A pilot study of bilateral pallidal stimulation in idiopathic cranial–cervical dystonia, BFMDRS motor and disability scores improved 72% and 38% at 6 months, respectively. Total TWSTRS scores improved 54% at 6-month follow up. Although the combined severity and disability subscores (BFMDRS) showed statistical improvement, the pain subscore only showed a trend toward improvement and was not statistically significant . General health and physical functioning and depression scores improved significantly. Some negative changes in neuropsychological tests (memory and verbal skills) were observed, but did not impact daily life or employment .

For secondary dystonia (i.e. dystonias due to brain injuries), the reported outcomes of the GPi DBS were less promising than for other dystonias . In a recent study that seems to refute some of these findings, Loher et al reported almost the same outcomes for both primary and secondary dystonias . In tardive dystonia at 3–6 months after surgery, there were improvements of 74% in BFMDRS-M score, 89% in BFMDRS-D score, and 70% in abnormal involuntary movement scale (AIMS). In another study, quality-of-life improvements were significant in physical components and affective states .

In a mixed group of secondary dystonia patients (i.e. myoclonic dystonia, tardive dystonia, post-traumatic hemidystonia) who underwent treatment with bilateral GPi stimulation, improvements in the AIMS score ranged widely from 0 to 73.9%; the patient with no improvement had post-traumatic hemidystonia that temporarily improved after surgery but returned to the baseline findings some days after the DBS was turned on . Some authors suggest that among the secondary dystonias, the drug-induced forms have potentially better outcomes compared with the secondary dystonias. That is, the BFMDRS severity scores improved 47.2% for the drug-induced group and 37% for the other mixed dystonias, and the BFMDRS disability scores were 54.6% and 34.4 %, respectively . In patients with secondary dystonia, it is important to note that anatomical preservation of the basal ganglia is related to surgical outcome .

Previous reports of the usefulness of thalamic DBS to control dystonia have shown questionable results. Since then, GPi stimulation has gained greater acceptance in the treatment of this syndrome . In a study of bilateral anterior dorsolateral STN stimulation in patients with predominantly cervical dystonia, significant improvement occurred in the motor, disability, and total TWSTRS scores. Outcomes were better in those who did not have fixed deformities. The mental component score of the SF-36 markedly improved, and neuropsychological function was not negatively affected as a result of surgery. However, there were no differences in the TWSTRS scores between stimulation-on and -off for the group as a whole . In another study of patients with writer’s cramp who underwent unilateral ventral oralis anterior/ventral intermediate (Voa/Vim) stimulation (one patient underwent both GPi and Voa/Vim DBS), Fukaya et al showed that BFMDRS scores improved 87.5% when the stimulator was turned on; this improvement was maintained at 2-year follow up. In the patient with dual DBS targets, the thalamic stimulation was superior to the pallidal stimulation ; however, superior results were obtained with pallidal stimulation in a previously Vim-DBS implanted patient with paroxysmal non-kinesiogenic dystonia . These last two studies showed some interesting results, but need further study.

In our review of the literature, we found no consensus on programming settings for either primary or secondary dystonia. Usually GPi DBS required more amplitude than the GPi or STN DBS for Parkinson’s disease, with wide ranges of pulsewidth and frequency settings for all groups . Some authors suggested that the pulsewidth should exceed 180 μs (in dystonias), and the rate should be between 130 and 185 Hz (high-frequency stimulation) . Other studies have reported significant improvement with low-frequency stimulation (50–60 Hz) . In a study focused on the frequency of pallidal stimulation in primary dystonia, optimized stimulation at 130 Hz resulted in a 43% improvement in the BFMDRS score 6–12 months post-surgery. Quality of life measured through PDQ-39, EuroQoL1, and EuroQoL had significantly improved after surgery when measured in all of the scales. However, in this same study, a significant deterioration was observed at lower frequencies (0, 5, 50 Hz) in all patients .

After DBS, mobile, phasic dystonic movements respond rapidly and are predictors of good outcome, whereas fixed postures are less likely to improve and are predictors of poor outcome at 12-month follow up, mostly due to muscle contractures . Although tonic components tend gradually to improve, some patients experience rapid improvement shortly after the DBS. Long-lasting benefits were not observed until 6–12 months later in most patients. The presence of microlesion effect immediately after pallidal DBS for dystonia also appears to be a good predictor of optimal clinical outcome, though this remains controversial .