Where are we with surgical therapies for Parkinson
Strauss I, Kalia SK, Lozano AM. Where are we with surgical therapies for Parkinson , 2014 Jan;20 Suppl 1:S187-91. doi: 10.1016/S1353-8020(13)70044-0.
This article was a discussion of current surgical therapies for Parkinson’s disease (PD). There are multiple treatments for PD and the typical primary therapy is the medicinal route (levodopa/carbidopa) which has shown to reduce common motor symptoms. However, after long-term medication use there are known side effects (45% of people taking them for greater than 5 years will experience them) including dyskinesia, “wearing off,” and fluctuant levels during the day causing “on-off” periods. Due to these challenges, surgical intervention is a secondary treatment option for people with PD (PWP). The article noted that multiple studies have shown the efficacy of DBS and that approximately 100,000 PWP have undergone DBS over the past 20 years. Even after 20 years though, there are still unanswered questions about this treatment, which the authors commented upon.
What about the timing of the surgery? Typically, surgical intervention is suggested later in the disease course when the PWP has severe symptoms, longer disease duration, and has more difficulties with the above-mentioned medicinal side effects. However, review of a 2013 randomized trial showed that when surgery was completed on younger PWP, earlier in the disease course, combined with optimal medication management compared to those only taking medication the PWP that underwent DBS reported higher quality of life and better motor scores. The surgery group also had less dyskinesias attributable to the medications. A challenge with earlier surgical intervention was reported to include the unknown long-term risks of this treatment, there are unresolved hardware issues, and risks associated with multiple surgeries needed as the PWP has the DBS for longer periods. Researchers also do not know the long-term risks to the brain, having continuous electrical stimulation on cognition or psychological functioning. Conversely, researchers also do not know about the possible beneficial effects of long-term stimulation from either a disease modification or protective point of view.
What is the optimal target for DBS? There has been a long-standing debate regarding the optimal target for DBS. Initially GPi was the focus but in the early 1990s, STN became the target of choice. As studies continued there were mixed findings regarding cognitive and psychological side effects from STN so focus returned to GPi. A 2013 European study compared the two targets concerning such side effects and the results did not show a significant difference between the two groups. The authors rightfully note that this debate likely will continue for quite some time.
What about non-motor symptoms? Although both targets are effective for reducing motor symptoms of PD, the DBS intervention has not been effective in treating the non-motor symptoms of PD. The basal ganglia is the target for treatment of motor symptoms but it is suggested that the nonmotor symptoms (speech, cognition, and gait) are mediated by different anatomical areas. This suggests that researchers may need to widen the scope for stimulation to other brain areas or possibly have multiple targets to address both motor and non-motor symptoms.
What about the methodology for DBS? Historically there has been a requirement for PWP undergoing DBS to be awake during the surgery to assist with verification of target placement as well as specific devices used (e.g. microelectrode recording, stereotactic frames). This can present a challenge to medical teams not having access to such tools as well as challenges to patients who may have fatigue or anxiety that would interfere with such participation in surgery. There have been a couple of studies that have attempted DBS implantation while the patient is instead under general anesthesia and with different specialized equipment that have found similar levels of accurate DBS placement which may make the treatment more tolerable and available to more patients.
There is still more to learn about DBS regarding maximization of stimulator settings to best control motor symptoms as well as minimize the need for battery changes and setting modifications. There are multiple hypotheses regarding closed loop systems within the brain done by the stimulators that would monitor the basal ganglia and instead of applying constant stimulation would provide specific stimulation based on the needs and functions of that individual’s basal ganglia recordings. So far, only animal studies have been done in this area with PD in creating a system that could accomplish such goals but treatment of other diseases (e.g. seizures) currently has similar technology.
What about other treatments? Ablation treatments (e.g. to the thalamus and globus pallidus) were much more common before DBS in treating motor symptoms of PD. Notably these treatments were non- reversible and often PWP would have cognitive side effects. The article discussed a newer type of ablative treatment done by a specific “MR-guided focused ultrasound (MRgFUS)” has shown promise for those PWP that cannot undergo DBS. The treatment can provide an immediate temporary lesion prior to a permanent lesion, which allows for an accurate specific individualized treatment.
The study of gene therapy for PWP has shown some mixed and some promising results after 6-18 months but more research needs to be completed in this area with improvements and standardization in methodology.