Is deep brain stimulation therapy underutilized for movement disorders?

KEYWORDS:

• Deeb brain stimulation
• movement disorders
• Parkinson’s disease
• essential tremor
• dystonia

1. Background

Deep brain stimulation (DBS) is a powerful therapy for management of many movement disorders that are deemed refractory to pharmacological treatments. The therapeutic benefits of DBS have been well demonstrated by several Class I studies, which has led to FDA approval of this therapy for Parkinson’s disease (PD), essential tremor, and dystonia [1]. DBS has clear advantages in contrast to ablative surgeries such as thalamotomy, subthalamotomy, and pallidotomy used frequently in the past as surgical interventions. Implantation of DBS electrodes is a reversible procedure and the stimulation settings employed for programming are adjustable to accomplish minimum side effects and maximum clinical benefits. Then the ability to perform bilateral procedures safely and an association with a lower risk of postoperative cognitive, speech and swallowing problems are other beneficial features related to DBS [1]. Newer techniques such as MRI-guided focused ultrasound is now approved by the FDA for treatment of Essential tremor. MRI-guided focused ultrasound is incisionless and can real time monitor treatment intensity and targeting; however, similar to thalamotomy, it is primarily an ablative procedure, thus limiting its application for bilateral control of symptoms [2].

Despite FDA approval almost two decades ago along with many long-term studies showing persistent benefits, only about 140,000 surgeries have been performed worldwide [1]. DBS therapy has remained relatively underutilized for multitude of reasons; many of them are discussed in this opinion piece. In one study from a large tertiary referral center, only 1 in 34 essential tremor patients (2.90%) followed in their practice in a 5-year period were referred for DBS [3]. In a survey of US neurologists, concerns for DBS in PD were expressed for insufficient knowledge on appropriate candidates and optimal brain targets when treating specific symptoms. Additionally, post-surgery programming options were perceived to be limited and labor intensive [4]. Limited access to expert programming and familiarity with the large number of potential programming considerations may also negatively impact the decision to be considered or referred to surgery. In another survey, patients who are key stakeholders expressed fear of complications, daily life interruptions for a prolonged time and economic burden as important reasons that curbed their enthusiasm for the procedure [5]. Although DBS therapy is perceived as costly, costs have been found to be higher only in the first year of treatment. In comparison to multiple pharmacological therapies, the costs incurred have been noted to decrease over the following years. The cost–benefit ratio has shown even further improvement when indirect costs and social costs are added to the calculation [6].

Sometimes challenges specific to individual movement disorders have influenced the utilization of DBS therapy. In dystonia, accurate diagnosis has remained a challenge which may directly impact appropriate referrals for effective treatments. Patients with dystonia have heterogeneous clinical presentations and may have features overlapping with other common movement disorders. Dystonic tremor, a clinical feature that is a part of dystonia is misdiagnosed as PD tremor or Essential tremor in many patients [7]. Then a delay in accurate diagnosis can potentially impact DBS outcomes considering that there are better results with shorter disease duration prior to development of fixed contractures [8]. In contrast to PD and essential tremor, the clinical improvements seen with DBS in dystonia are often delayed by several months, despite frequent programming sessions in a well-positioned lead. Then the clinical improvement with DBS in dystonia is not guaranteed as a wide range of improvements (25–75%) is seen and there are no clear preoperative predictors for good outcomes [8]. Furthermore, there are also concerns over programming needs with DBS in dystonia which often involve high amplitudes and pulse widths for control of dystonia symptoms. Thus, battery consumption is quicker (battery life can be as short as one year) and patients are required to undergo frequent surgeries, which increases the risk of increased exposure to anesthetics, risk of perioperative infections and adds higher health costs incurred [8]. These concerns may become less of an issue as more patients are implanted with rechargeable batteries.

There is growing recognition for therapeutic potential of DBS in Huntington’s disease, complex dystonias [9], and unusual tremor syndromes [10]. However, the studies have mostly been small and open labeled, thus limiting the generalizability and validity of the data. In Tourette syndrome, while increasing evidence supports a beneficial role of DBS, there are several challenges that may explain a lack of regulatory approval for a widespread use of this therapy. There are no clear guidelines while selecting candidates for DBS. Then there is a significant variation in the methodology and target(s) chosen for DBS. The postoperative stimulation parameters are not well established with a significant variation across studies and only few series have reported long-term efficacy experience [11]. Furthermore, the risk of device infection, mechanical malfunction, and explantation is noted to be possibly higher in Tourette syndrome in comparison to other movement disorders [12].

2. Newer developments likely to impact DBS utilization

Recent studies in PD have shown DBS therapy implemented early in the course of disease (average disease duration about 7.5 years) instead of the usual time frame (average disease duration about 12 years) achieves better outcomes compared to best medical management. An earlier intervention is believed to effectively defer the psychosocial consequences of PD and when considering a significant burden of comorbidities with increasing age, delaying DBS to the advanced stages may not be in the best interest for many patients [13]. Although early DBS has not been compared against late DBS, FDA has revised its recommendation for DBS. They have granted approval for disease duration as short as four years and motor complications as early as four months. Some investigators have urged caution against placing too much focus on the duration of motor complications. In their perspective, decision for and against early DBS should be individualized based on specific disabling symptoms even in patients deemed to show a favorable risk-benefit ratio [14]. They believe the most relevant issue is not when to operate but on whom to operate and that early may not always be a better decision. Nevertheless, with a regulatory approval for earlier DBS intervention in PD, the number of referrals and procedures are expected to significantly increase in the ensuing years.

In another similar development, instead of the recommended 25 years of age for Tourette syndrome patients, consideration for DBS was shifted to an earlier age of 18 years as a delay in DBS was found to result in significant irreversible disability. Experts also recommended a case-by-case interdisciplinary evaluation and a local ethics committee involvement when individuals below the age of 18 years presented with significant medication refractory symptoms [15]. This new recommendation takes into consideration the deleterious effects of severe tics on social, emotional, academic, and vocational achievements during the formative years of adolescence. Since DBS in Tourette syndrome is not FDA approved, an International Deep Brain Stimulation Registry and Database was launched in an effort to uncover best practices, improve outcomes, and provide critical information to regulatory agencies [16]. In their first-year results, published recently, nearly a 40% improvement was observed seen in a global sample of about 185 Tourette syndrome patients [16]. These results indicate DBS is a promising therapy; however, larger studies with comparison across various treatment targets will better define its therapeutic potential.

In parallel with increase in clinical knowledge, there has also been an impressive growth in the field of DBS hardware, technology and targeting techniques. Newer DBS designs permit the shaping of the electrical field to improve stimulation of the desired target and simultaneously minimize the side effects by avoiding unwanted stimulation of adjacent structures. Several innovative programming techniques have been launched which are undergoing experimentation to improve the clinical outcomes. With the availability of 7T MRI, precision in targeting smaller structures such as subthalamic nucleus and zona incerta is expected to substantially increase. Some DBS centers are performing MRI guided DBS surgery which requires general anesthesia. This procedure is significantly valuable for pediatric DBS and adult DBS patients who cannot tolerate an awake surgery [17]. There is also increasing enthusiasm for ‘closed-loop’ system, which comprises of DBS pulse delivery only as and when needed in response to specific internal and/or external feedback signals. An improved control over the timing and intensity of stimulation is desirable as this will increase the battery life and reduce the risk of stimulation-induced side effects [1]. Many DBS systems are currently available for implantation in the community and not restricted to research settings. Early this year, FDA granted approval to the 8-contact Boston scientific lead for patients with PD (other approved systems are available through the Medtronic Inc. and the Abbott Inc.). We expect a commercial availability of multiple DBS systems will engender a healthy competition amongst the various marketing companies which may then contribute to further lowering of costs and increase in geographic availability. Newer closed-loop systems and direction leads with increased programming options will also likely increase the programming burden [18].

In our opinion, in the wake of these developments and advances, the number of DBS procedures performed over the next decade are very likely to increase. A growing evidence for newer indications, shifting to intervention early in the disease course and considering younger patients for surgery, will play important factors for increase in procedures. Technological advancements and availability of multiple systems with safer features will be additional key contributors. However, we hope an increase in the quantity will not lead to a compromise in the quality. We believe selection of candidates through careful interdisciplinary evaluation, education of all key stakeholders, and standardization of surgical procedures across DBS centers will always remain critical for an appropriate utilization of this powerful therapy.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was supported by grants from the National Institutes of Health [NIH K23 NS092957-01A1].