Preparing the ethical future of deep brain stimulation

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Surgical Neurology 72 (2009) 577 – 586 www.surgicalneurology-online.com

Technique

Preparing the ethical future of deep brain stimulation Emily Bell, PhD a , Ghislaine Mathieu, MAa , Eric Racine, PhD a,b,c,d,⁎ a

Neuroethics Research Unit, Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada b Department of Medicine, Université de Montréal, Montréal, QC, Canada c Department of Social and Preventive Medicine, Université de Montréal, Montréal, QC, Canada d Department of Neurology and Neurosurgery & Biomedical Ethics Unit, McGill University, Montréal, QC, Canada Received 18 July 2008; accepted 24 March 2009

Abstract

Background: Deep brain stimulation is an approved and effective neurosurgical intervention for motor disorders such as PD and ET. Deep brain stimulation may also be effective in treating a number of psychiatric disorders, including treatment refractory depression and OCD. Although DBS is a widely accepted therapy in motor disorders, it remains an invasive and expensive procedure. The ethical and social challenges of DBS need further examination, and discussion and emerging applications of DBS in psychiatry may also complicate the ethical landscape of DBS. Methods: To identify and characterize current and emerging issues in the use of DBS, we reviewed the neurosurgical literature on DBS as well as the interdisciplinary medical ethics and relevant psychological and sociological literatures. We also consulted the USPTO database, FDA regulations and report decisions, and the business reports of key DBS manufacturers. Results: Important ethical and social challenges exist in the current and extending practice of DBS, notably in patient selection, informed consent, resource allocation, and in public understanding. These challenges are likely to be amplified if emerging uses of DBS in psychiatry are approved. Conclusions: Our review of ethical and social issues related to DBS highlights that several significant challenges, although not insurmountable, need much closer attention. A combination of approaches previously used in neuroethics, such as expert consensus workshops to establish ethical guidelines and public engagement to improve public understanding, may be fruitful to explore. © 2009 Elsevier Inc. All rights reserved.

Keywords:

Deep brain stimulation; Parkinson disease; Psychiatry; Depression; Ethics; Patient selection; Neuroethics; Resource allocation; Informed consent; Knowledge translation

1. Introduction

Abbreviations: CAPSIT-PD, Core Assessment Program for Surgical Intervention Therapies in PD; DBS, deep brain stimulation; ECT, electroconvulsive therapy; ET, essential tremor; FDA, Food and Drug Administration; IPG, implanted pulse generator; IRB, institutional review board; MRI, magnetic resonance imaging; NIH, National Institutes of Health; OCD, obsessive-compulsive disorder; PD, Parkinson disease; TMS, transcranial magnetic stimulation; TS, Tourette syndrome; USPTO, United States Patent and Trademark Office; VNS, vagus nerve stimulation; WHO, World Health Organization. ⁎ Corresponding author. Tel.: +1 514 987 5723; fax: +1 514 987 5763. E-mail address: [email protected] (E. Racine). 0090-3019/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.surneu.2009.03.029

Deep brain stimulation is a form of neurosurgery that is now widely used to treat PD and is emerging as a potential treatment for some neuropsychiatric disorders [4]. Deep brain stimulation involves the implantation of at least one electrode, typically in thalamic, subthalamic, or ventral pallidus regions (for PD or ET), which is connected by very small wires and electrically stimulated by an IPG in the upper portion of the chest (subclavicular region). Deep brain stimulation was approved by the US FDA in 1997 for the treatment of tremor in ET and PD and in 2002 was more widely approved for the management of refractory PD. Deep

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Table 1 Common contemporary neurostimulation techniques DBS involves unilateral or bilateral implantation of electrodes in specific structures of the brain, under stereotactic techniques, including MRI guidance, physiological mapping, and computerized surgical navigation. The electrodes are usually inserted after clinical examination and then connected to a pulse generator implanted in the infraclavicular region. The clinical effects of DBS appear similar to traditional neurosurgical ablation with added benefits such as greater safety and reversibility. VNS is a well-established and now standard procedure for the treatment of refractory epilepsy (approved in 1997 by the FDA for this use). VNS involves subcutaneous implantation of a pulse generator from which a bipolar electrode extends from the device and is wrapped around the left vagus nerve as it passes through the neck [49]. VNS, unlike DBS, results in diffuse effects on many regions of the brain. Although it rarely causes complete seizure remission, patients benefit from a significant reduction in epileptic seizure frequency [20]. Some clinical research has shown VNS to be a successful treatment in depression, and in 2005, the FDA approved, not without controversy, VNS for the treatment of severe depression. TMS refers to an external (not implanted) device that activates or deactivates brain function through magnetic stimulation. A magnetic field, generated by an electric current, induces an electric current within the brain. Results from several studies indicate that TMS has antidepressant properties [14]. TMS is generally considered a noninvasive, reversible, and relatively safe procedure. TMS does not involve surgical procedures.

brain stimulation is now an established therapy for PD and ET patients whose diseases are severe and drug refractory [26]. More than 35 000 patients worldwide have received DBS for those indications [39]. The current scientific and medical knowledge surrounding the mechanisms of action of DBS is still incomplete, but a widespread hypothesis is that DBS replicates the effects of neurosurgical lesioning [4]. In comparison to ablative surgery, DBS is considered reversible and nondestructive [42]. Other forms of neurostimulation techniques and devices currently used should not be conflated with DBS. Table 1 distinguishes DBS from 2 other forms of neurostimulation: VNS, whish is commonly used for the treatment of epilepsy, and TMS, which relies on the external stimulation of the brain to temporarily activate or deactivate cortical activity.

Recent studies claim that DBS is efficacious, and although not without major risks, it is relatively safe for the long-term management of severe ET, PD, and dystonia [10,56]. Investigations of DBS in other motor and nonmotor conditions have emerged, in refractory depression, TS, OCD, chronic pain, and in multiple sclerosis [36,46,53] given the efficacy of DBS in PD and based on the undesirable irreversibility of ablative surgeries. Currently, there is an emerging literature documenting the efficacy of DBS in these disorders, and researchers have highlighted some potentially promising results [4]. In addition, case reports of DBS used to treat an anxiety disorder [40] and morbid obesity [28] have lead to unexpected results: relief of a comorbid alcohol dependence in the first case and memory enhancement in the second case (without any effects on the anxiety disorder or the obesity problem). In fact, a new clinical trial investigating DBS for memory improvement in patients with Alzheimer disease has emerged from the results of the second case study (NCT00658125, NIH clinicaltrials. gov). The number of clinical trials investigating DBS in established and emerging areas is likely to expand as trials already underway produce results over the coming years. Table 2 shows the current NIH-registered and completed clinical trials using DBS in neuropsychiatric conditions such as depression, TS, and OCD. To realize the full potential of DBS, the ethical and social issues associated with this procedure must be addressed proactively. Some of these issues have already been acknowledged by leaders in the field of DBS neurosurgery [4] and neurosurgical ethics [16,17,19,38]. In this article, we provide what to our knowledge is a first overview and discussion of current ethical and social issues in the use of DBS for PD and motor disorders including challenges in the identification of good surgical candidates, in health care resource allocation, and in conveying an appropriate public understanding about the procedure and its outcomes. We also comment, where appropriate, on the challenges related to the emerging uses of DBS in psychiatry. Our approach is based on the belief that identifying ethical and social issues now

Table 2 Current and past NIH-registered clinical trials for neuropsychiatric disorders Clinical trial

Condition Open date

Status

Berlin Deep Brain Stimulation Study Deep Brain Stimulation for Treatment Resistant Depression Deep Brain Stimulation for Treatment-Refractory Major Depression Deep Brain Stimulation for Depression Deep Brain Stimulation for Refractory Major Depression Effectiveness of Deep Brain Stimulation for Treating People with Treatment Resistant OCD Subthalamic Nucleus Stimulation and OCD Unilateral Deep Brain Stimulation of the Nucleus Accumbens in Patients with Treatment Resistant OCD Deep Brain Stimulation for Treatment-Resistance OCD Pallidal Stimulation and Gilles de la Tourette Syndrome Thalamic Deep Brain Stimulation for Tourette Syndrome Deep Brain Stimulation for Alzheimer Disease

MDD MDD MDD MDD MDD OCD OCD OCD OCD TS TS AD

Recruiting Recruiting Active, not recruiting Enrolled by invitation Recruiting Recruiting Completed Completed Active, not recruiting Not yet recruiting Completed Recruiting

September 2007 September 2006 July 2005 January 2004 June 2002 October 2008 October 2005 February 2004 January 2001 June 2007 June 2005 March 2007

Data from Clinical Trials Database http://clinicaltrials.gov/. Accessed November 28, 2008. MDD indicates major depressive disorder; AD, Alzheimer disease.

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will contribute to further discussion and awareness in the future of DBS. We reviewed the neurosurgical, neurological, and psychiatric literatures on DBS along with the bioethics, psychological and sociological literatures to identify and characterize the current and emerging ethical and social issues in the use of DBS. We also consulted the USPTO database, the US National Institutes of Health Clinical Trial database, FDA regulations and report decisions, and the business reports of key DBS manufacturers.

2. Patient selection: carefully identifying good candidates for DBS based on sound ethics and science Selecting the appropriate candidates to undergo DBS is of fundamental importance. Established selection criteria should aim to identify candidates who will obtain and retain the greatest benefit from a DBS intervention and who are physically, cognitively, and emotionally capable of tolerating surgery and participating in their own postoperative care [41]. Being able to predict which patients are poised to achieve the greatest outcomes becomes important because first, the high costs of the procedure may act as a restrictive barrier for offering the therapy to all patients, and second, poorly selected patients may not obtain significant benefit from the procedure, implicating principles of beneficence and nonmaleficience. Having a well-defined procedure for patient selection, incorporating factors that are known to contribute to success, will maximize the clinical outcomes for DBS. This is best achieved by evaluating patients by a multidisciplinary team of neurologists, neuropsychologists, psychiatrists, neurosurgeons, and advance care nurses [38]. In this way, the screening of potential candidates by experienced DBS teams means each member makes his or her expertise profitable to the whole team, and in this context, the team is specialized to assess the diagnosis of the disease, the cognitive and psychiatric status of the patient(s), and their overall potential for success. Tools are available such as the CAPSIT-PD to aid in defining good candidates through the assessment of factors including age, motor symptoms, response to levodopa, neuropsychological and psychiatric status of the patient, presence of other medical illnesses, quality of life, presence or history of substance abuse or dependence, and presence of drug-induced psychosis [51]. The application of the CAPSIT-PD greatly reduces the pool of qualified candidates for the procedure. A recent study by Morgante et al [51] determined that of 641 patients with PD, only 1.6% proved to be potential candidates for DBS of the subthalamic nucleus (based on the CAPSIT-PD criteria). Among these variables, the input of a neuropsychological evaluation may be of particular importance [63]. A neuropsychological examination may uncover previously unforeseen issues, such as signs of dementia and psychiatric comorbidity or cognitive deficits in some patients. These neuropsychologi-

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cal occurrences may, at most, rule out DBS for some patients [2,34,62,63] and at the least would indicate a more thorough consideration of the patient as a candidate and allow preparations for tailored postsurgery support. It is likely that extending DBS therapy to psychiatric disorders will require renewed considerations about DBS patient selection taking into account the particularities of these patient populations and especially because comorbid conditions are likely to be frequent in psychiatric patients [3]. It has previously been recommended by Nuttin et al [54] of the OCD-DBS collaborative group (2002) that general criteria should be evaluated before DBS for any psychiatric candidate considering that these patients will be participants in investigational trials. These include oversight of the protocol and patient selection criteria by an IRB and determinations of patient inclusion made by a multidisciplinary assessment committee. Included patients should meet criteria for severity and functional impairment, should demonstrate adequate treatment refractoriness, and should be able to consent to their participation in the research trial. Unfortunately, it will take time to establish if DBS is an effective therapy in these patients and which clinical characteristics contribute to success or make patients more prone to clinical failure. Other considerations in selecting patients who will do “best” include examinations of family support, commitment, and expectation. Because patients may be required to stay conscious during the surgery to participate in functional mapping studies [80] and because patients and caregivers may need to devote large amounts of time, energy, and travel for screening appointments, device checks, programming, and medication management during preoperative and postoperative follow-up, they should be committed to the treatment regimen [62]. In the first 6 months postsurgery alone, this may amount to 4 to 8 device programming adjustments for patients and families [62]. Therefore, the ease at which candidate patients can access a clinical research center and expertise for postoperative care, device adjustments, and regular appointments may also be assessed at the time of patient selection [54]. However, although social support and access to care should remain important considerations in selecting patients for DBS, we must remain cognizant of the fact that to abandon patients without social support or equal access would create additional disparities in the level of care for these patients, further disadvantaging them. Maximizing the potential for success of DBS will also involve managing patient expectations. Patients should maintain a realistic expectation of the procedure and the probability of failure, and understand the impact the intervention will have on their symptoms. Although patients with different disorders will have distinct expectations about which sorts of symptoms will be improved with DBS, neither patients nor their families should expect DBS to be a cure [55,62]. This common misunderstanding should be dispelled from the onset of discussions. Deep brain stimulation aims at

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alleviating the symptoms of the disorder and improving the overall quality of life in daily tasks. If these issues are not thoroughly discussed, patients risk disappointment and potential perceived failure of the therapy. Unfortunately, Okun and Foote [55] suggest that even well-screened patients with motor disorder who have significantly improved motor symptoms can be disappointed by a failure to “meet a preconceived perfect outcome.” They suggest that clearly defined active education for patients about the procedure, expected success, and failures may help to manage expectations in patients and families [55]. However, expectations for success with DBS therapy are difficult to define for patients in psychiatric conditions at this early stage of clinical trials. Nonetheless, we would suggest that an evaluation of patient expectation is appropriate and could feature prominently in patient selection criteria for future uses of DBS for neuropsychiatric conditions.

3. Informed consent: conveying risks and benefits to vulnerable and desperate patients and caregivers Informed consent, that is, the patient or the authorized proxy's agreement based on a reasonable understanding and appreciation of the risks and benefits of a procedure, is a fundamental requirement of modern surgery and medicine. However, informed consent can represent a challenge because the disease process itself may impact cognitive function or disturb mood significantly [35]. For example, both in PD and in psychiatric disorders, deficits in executive function, attention, verbal fluency, and working memory can occur and render informed consent and physician-patient interactions related to informed consent challenging. A diagnosis of a neurological or neuropsychiatric disorder does not mean that patients necessarily relinquish their decisionmaking capacity. Empirical research has shown that in some neurodegenerative conditions, a diagnosis should not rule out the capacity for patients to express health care preferences and participate in decision making. Patients may prove to have a good understanding of the information regarding the procedure and/or understand related risks, benefits, and potential complications [35]. The application of DBS in patients with PD is well established [77]. However, there are a number of significant risks associated with DBS for PD, which reinforces the need for adequate informed consent and understanding on the part of patients and proxy decision makers. Overall complication rates can exceed 25%, and permanent neurological sequelae result in 4% to 6% of cases [27]. Preoperatively, patients should understand decisions related to medication withdrawal, stereotactic equipment and imaging modalities to be used, and brain target selection [61]. Related to the actual surgical procedure, patients should have an understanding of what the craniotomy entails and of what will be asked of them in terms of their participation in the optimal targeting of the brain nuclei. An appreciation of risks by patients entails

understanding the probability of occurrence of surgical complications, such as paralysis, or intracranial hemorrhage and postoperative complications, such as infection or hardware failure such as electrode malfunction [61]. Patients should also understand issues related to the device itself, for example, the replacement of the battery. In patients with PD, the life span of the IPG battery is approximately 5 years [68], and upon battery failure, to maintain therapeutic effect, surgical interventions are required to replace the battery. The patient and/or proxy decision maker need to have a proper understanding of all aspects of DBS therapy and of the complications that may arise throughout the procedure or while they retain the stimulator. Given that there are numerous aspects to the DBS procedure requiring commitment of patients and families to the therapeutic program, support for patients and caregivers is essential to optimize the informed consent process. Patients and caregivers can be directed to on-site physical and interpersonal resources such as counseling, family support groups, and resource centers. Because many people are likely to go online to find this information on their own, reliable sources of online information should be recommended, and patients should be educated about the common pitfalls of Internet health care information [59] and media reports about DBS [60]. Some centers have made common question-and-answer patient-oriented documents available online such as the Movement Disorders Center of the University of Florida and the Cleveland Clinic. Another important aspect shaping the informed consent process for DBS is the fact that DBS is often used as a lastresort procedure. Hence, patients and decision makers may feel desperate for this treatment option. Lack of support and frustration related to longstanding unsatisfied or incompletely satisfied health care needs for both the patient and/or the caregiver(s) can fuel this desperation. This scenario will likely be fundamental in psychiatric candidates for DBS who may have a long and difficult history of unsuccessful treatment interventions. When offered the chance to improve symptoms that have significantly impacted their health and family, patients or caregivers may be willing to consent too easily in spite of substantial or unknown risks because of their position of vulnerability [50]. Investigating consent in research protocols for patients with PD undergoing neural transplantation, researchers noted the “difficulties met in evaluating the perception of information despite intact intellectual capabilities in people prepared to risk everything” [45]. Such situations need to be handled with extreme care because expectations and desperation may create substantial challenges for free and informed consent. Modern surgical ethics has made respect for patient autonomy inescapable. However, overemphasis on patient autonomy has its own drawbacks and may suggest that the delivery of health information automatically translates into informed consent. To avoid such pitfalls, patient autonomy and informed consent should be understood in terms of a balance between the principles of autonomy and benefi-

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cence [15]. Hence, it is essential that patients and family members also receive beneficient guidance in avoiding unacceptable risks or trying to influence a patient's decision (in the case of caregivers), either because caregiving is becoming a burden or because of situations where caregivers value their fundamental role in ways that conflict with the potential improvement of the patient [38,66]. At the same time as neurosurgical teams must be in a position to recommend DBS if indicated, they must also be prepared to tackle pressures from patients and caregivers when DBS is not in the patient's best interests from a surgical and medical standpoint.

4. Resource allocation: facing the challenge of expenditures in underserved patient populations in overburdened health care systems Deep brain stimulation devices and procedures cost tens of thousands of dollars [21,25]. However, considering the burden of disease and cost of alternative best medical treatments, overall health care expenditures by patients may still be reduced by the DBS procedure. Several European studies have examined the direct costs (eg, cost of the surgical procedure, hospital stay) and indirect costs (eg, number of emergency department visits and neurological follow-ups) associated with DBS in PD. Estimated over the 6 months before and after surgery, the total costs of PD were shown to decrease from 10 087€ to 1673€ in a French study [21]. Researchers suggest that these savings allowed return on the procedure costs (approximately 37 000€) over 2.2 years. Another study assessed treatment costs in patients with PD followed up for 2 years after DBS implantation and concluded that PD treatment costs were increased 32% in the first year of DBS therapy but then decreased 54% in the second year when compared to preoperative expenses [48]. It would seem that these studies support the cost-effectiveness of DBS in treating patients with PD. Moreover, DBS has been shown to significantly reduce pharmacological expenditures in PD to approximately 3 799€, from approximately 13 208€ in patients treated with the alternative best medical treatment [76]. Despite the evidence demonstrating improvements in quality of life and motor symptoms and relative cost-effectiveness of DBS in PD, the outlay of cash for DBS represents an immediate and large investment, and this means that regulators, administrators, and insurers may feel obliged to restrict the amount of DBS procedures performed, resulting in downstream ramifications of increased wait times and waiting lists. Because it is still an investigational therapy for neuropsychiatric conditions, the impact of DBS on health care expenditures in the treatment of psychiatric conditions is still unclear. However, psychiatric conditions are responsible for some of the largest burden of years lost due to mortality and disability both in developed and developing countries [65]. The economic burden of mental illnesses in the United States

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has been estimated at more than $53 billion dollars [78]. Part of the large economic impact of these disorders comes at the expense of lost productivity in working patients, and it has been suggested that productivity losses are as great as in those patients with heart disease, diabetes, and hypertension [52,72]. The absenteeism due to depression alone is responsible for billions of dollars lost per year in the United States [44]. It is estimated that about 20% of the population may have a psychiatric or mental disorder, and it is suggested that 20% of those patients will become drug refractory [42]. In fact, there may be 2 million Americans living with treatment refractory depression [68]. However, for patients with severe refractory mental illnesses, such as refractory depression or OCD, there are limited treatment options and patients active in work or pursuing a career may remain disabled for several years. This fact demands a thorough cost analysis and effectiveness study for DBS in these prospective patients. In a previous study, it has been noted that treating depression reduces the number of days that patients are unable to work so significantly that it accommodates for the costs of treatment (assessed by information gathered from insurance providers) [81]. A legacy of underfunding in chronic neurological and psychiatric conditions is likely to impact budgetary constraints. A WHO study has shown that this is particularly true in mental illness, where national budget allocations to service mental illness are low compared with the burden of disease, even in developed countries [64]. The allocation of funding and resources for expensive therapies are perhaps greater issues in public health care systems where costs are contained at a population level. In fact, thorough analyses of the immediate- and long-term costs of DBS, including potential economic gains based on societal outcomes, would also likely be helpful in justifying the use of the high-cost therapy to improve the functional capabilities of patients. In the case of DBS, health systems may face difficulties emphasizing the importance of functional interventions over more acute lifesaving interventions without clear demonstration of the economic savings or gains in chronic illnesses. If resources for DBS are or need to be limited, then one of the problems faced by neurosurgery teams resides in how to present justifications for these limits and also in identifying who will explain those reasons to patients, caregivers, and other stakeholders. One of the most challenging situations surfaces when the surgeon has little input on the allocation process while being forced by necessity to explain the decision to patients and their caregivers [29]. At this point, not all jurisdictions have brought full clarification about how resource allocation for DBS needs to be addressed, and it would seem that resource allocation will increasingly be a challenge with the predicted extension of DBS in psychiatric illnesses. From the patient's and caregiver's perspective, resource allocation issues in DBS can translate into a number of challenging situations. For instance, a patient with PD who was a good candidate can develop comorbid conditions (eg,

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depression or dementia) while being on the waiting list for months, making him or her no longer a good candidate. In psychiatric patients, there may be additional concerns about keeping patients on a waiting list when in crisis. For example, how do we make decisions in refractory depressed patients with fluctuating periods of suicidality? Patients and caregivers may also find that there is a lack of clarity about current waiting-list processes and general uncertainty about when they will actually receive the intervention. These factors could significantly impact how patients and caregivers make plans for the future. At this point, patient and caregiver experiences and perspectives on DBS access would be a significant contribution to our understanding of current resource allocation challenges with DBS.

5. Transfer of knowledge and public understanding: dispelling miracle-like stories, promoting balanced public information, and transfer of knowledge between health care professionals Public understanding of the risks and benefits of the DBS procedure—like other medical technologies and procedures —can shape informed consent and expectations by patients and caregivers and may alter the reception of expanding clinical uses. One way that the public perception may be shaped is through media coverage of scientific advances and emerging therapies. Notable traits of media coverage of science and technology include failure to report important details such as cohort size and composition [57]; lack of explanation of underlying principles and technologies; selective coverage of risks [6]; hyped benefits of innovative or experimental procedures [58,82]; and reports based on abstracts that will never make it to peer-reviewed publications [69,79]. One study of US and UK media coverage of neurostimulation with a focus on DBS procedures found increasing coverage of neurostimulation and marked enthusiasm for the clinical translation of DBS, with many articles emphasizing “miracle stories” where patients were literally cured [60]. Some print media headlines have claimed that “… An electrical pacemaker implanted in the brain gives welcome relief to people afflicted by the shakiness of PD” [9] and suggested an expanding treatment role for DBS, “The potential of brain pacemakers: implanted devices may alter treatment of many disorders” [73]. Public discussion on the ethical, legal, and social issues of neurostimulation techniques differs from the extensive coverage of such issues in media coverage of genetics research. Only 14% of the analyzed articles included ethical content, whereas this figure is closer to 40% for print media coverage of genetics and genomics research [58]. Further, some ethical issues such as resource allocation and fair access were seldom discussed in the media in spite of the extensive resources needed to support DBS [60]. The impact of the media on patient behaviors and expectations is hard to assess, however. Historical accounts

of the hype associated with early psychosurgery techniques suggest overly enthusiastic reports for new surgical procedures can have consequences. For example, Diefenbach et al [12] have presented evidence that lobotomy benefited from optimistic media coverage in the 1930s and 1940s. Biased reporting in popular press articles may have been a factor influencing the quick and widespread adoption of lobotomy as a psychiatric treatment [12]. Additional influences in the public's perception of DBS extended to psychiatric disorders are likely to result from comparisons with earlier surgical interventions in psychiatry. Already the media have made a connection between psychosurgeries such as lobotomy and DBS [18]. Other comparisons to ECT may confound public understanding of DBS and may expose DBS as vulnerable to negative public perception. Since its introduction in the 1930s, ECT has been considered a therapeutic option for drug refractory psychiatric patients. Despite the fact that ECT has been shown to be an effective therapy for many psychiatric conditions, and in particular useful for rapidonset relief, media accounts have depicted ECT in a negative light [43]. In their 2005 survey to gauge the public's attitude toward ECT, Lauber et al [43] found that more than half (57%) of the respondents considered ECT a harmful therapy. Once proclaimed in media accounts as “Madness treated with electricity” [70], today the public perception of electrical brain stimulation through ECT is less favorable. Public perception of DBS has the potential to impact patient's, caregiver's, and provider's views on patient selection, potential benefits, and risks, creating misunderstandings that could impact informed consent. However, we should not ignore the fact that increasing the public profile of DBS could itself have positive effects. Increasing attention for the procedure and increased public pressure for access may mean increased funding of DBS programs. In addition, public understanding of DBS may decrease stigma toward patients with brain implanted devices. In fact, the public may view the application of an established medical treatment for motor disorders as solidifying the biological nature of psychiatric disorders, reducing the stigma associated with mental illness. The dilemma essentially becomes about where the greater risk lies: in communicating too much public information (too poorly) or in not communicating enough to make a positive impact. In the same way that the creation of perceptions and expectations in the public may be established by knowledge transfer in the media, communication between providers with DBS expertise and other health professionals may influence expectations for and advancements in care provided for patients seeking DBS or already implanted with stimulators. The movement of DBS from larger specialized academic hospitals, where initial studies for motor disorders took place and where clinical trials in psychiatric conditions are ongoing to smaller centers, highlights the need to advance knowledge translation to primary care workers. In a study of 9 patients with motor

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disorders implanted in other centers and followed up in a primary community center, Diamond [11] found that as many as two thirds of patients followed up in private practice had not been evaluated preoperatively by a movement disorders specialist. In addition, 46% of patients had misplaced electrodes and 37% had inadequately programmed stimulators [11]. These results capture the challenges to standards of care that exist with expanding DBS to smaller centers and also show the obstacles that may exist for physicians following up DBS patients in private practice. Current challenges may be amplified if DBS becomes approved for psychiatric indications, where psychiatric patients are followed up in their own community or become lost for follow-up in the mental health system. Strategies to communicate selection criteria for patient referral, risks and benefits of the procedure, as well as the development of clearly defined postsurgery follow-up programs may be needed to optimize care and transfer of knowledge.

6. Personhood, narrative, and identity: thinking ahead about a vastly extended use of DBS beyond the traditional framework of neurosurgery Deep brain stimulation has an established efficacy in treating motor symptoms experienced by patients who have ET and PD, and this has lead to its overall acceptance and approval in these conditions. The long-term cognitive, psychiatric, and behavioral effects of DBS, however, are less well established, and studies are much more inconsistent in their conclusions about the effects of DBS on cognition and behavior in motor disorders. Often, an evaluation of these issues is complicated by the fact that PD may be accompanied by cognitive decline or psychiatric comorbidity. In a recent study that pooled the outcomes of DBS in almost 1400 patients who underwent bilateral DBS, cognitive dysfunctions were noted in 41% of patients, and these deficits ranged from the verbal fluency domain to executive function, attention, working memory, and response inhibition domains [74]. Tir et al [75] observed a cognitive decline in 7.7% of patients (out of 100) on neuropsychological evaluation in a 1-year follow-up after DBS, and other long-term studies have demonstrated a cognitive decline 5 years after surgery [37,67], although this decline may be confounded by the natural progression of disease. However, several other studies have demonstrated there are no clinically significant cognitive deficits in patients after DBS [7,8,23]. Recently, Fraraccio et al [22] reported that they observed no deterioration on cognitive testing due to stimulation in their study of 15 patients with PD after DBS. Despite the fact that motor symptoms may improve in patients with PD, some studies suggest that the appearance or reappearance of psychiatric symptoms may occur after DBS. The extent of this observation varies quite significantly.

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Some studies report a worsening of depression in 3% of their sample [7], whereas others report depression rates of 8% [74] or 18% [75] in their patient groups after DBS. In particular, it would seem that a history of depression before surgery leaves patients more at risk for episodes after the DBS surgery [30,75]. Similarly, there are reports of anxiety disorders (12% in Castelli et al [7]; less than 2% in Temel et al [74]) in the follow-up of DBS patients and other psychiatric complications such as hypomania (4% in Temel et al [74]; 75% in Houeto et al [30]). However, Castelli et al also note that of the 72 patients they studied, 20% experienced an improvement in mood, and 23% experienced a reduction in anxiety after undergoing surgery. In addition, Drapier et al [13] found no depression after DBS in their patients and no change in preoperative levels of anxiety. The observation of depression in patients with PD after DBS surgery is one that is perplexing because this side effect would not generally be expected in patients whose motor symptoms have improved. Researchers have also struggled to explain why the incidence of suicides after DBS is higher than expected [71]. In 2004, the authors of one study observed a 4.3% rate of suicides among patients with movement disorder who were treated with DBS and expressed that “this observation is consistent with DBS being a possible risk factor for suicide completion in the population of movement disorders patients” [5]. In a more recent retrospective study of 200 patients, researchers observed that 1% of patients committed suicide and 2% attempted suicide after undergoing DBS for PD [71]. They concluded that suicide remains a potential risk in patients undergoing subthalamic DBS [71]. Inconsistency about the occurrence of behavioral, cognitive, and psychiatric complications after DBS surgery has far reaching impact and may impede a full risk assessment of the procedure. As well, uncertainty about factors that contribute to these occurrences creates additional challenges for the selection of patients and in managing patient expectations. Other uncertainties related to how patients adjust socially after a successful DBS intervention remain. There are obvious motor benefits gained by DBS, and patients may even find a renewed independence with the success of the intervention. For example, in their sample, Krack et al [37] have shown that most patients were living independently when assessed off medication 5 years after surgery. However, other studies have reported that patients face difficulties within their familial or marital relationships after surgery and feel conflicted about returning to work [1,66]. Schüpbach et al [66] examined 29 patients with PD before and 18 to 24 months after stimulation. Close individual follow-up and in-depth interviews with patients and their spouses and families revealed 3 major areas where some patients face social adaptation challenges after surgery: the patients' perception of themselves and their bodies, the couple, and the professional life [66]. Rapid clinical changes caused by DBS can lead to profound impact on the patient, his spouse, and his broader social environment. Some

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patients expressed difficultly accepting lost years of their lives after being relieved by DBS surgery, and others did not adapt to the sudden motor improvement and still associated with their “ill selves” [1]. The familial impact of these changes can be significant. In their study, Agid et al [1] found that 65% of those who were married experienced a “conjugal crisis” after DBS. Moreover, of couples studied, Schüpbach et al reported that 33% of the spouses had depression after their partners underwent DBS [66]. These issues demonstrate how mixed success can occur from DBS, illustrating what some have called paradoxically a situation where “the doctor's happy, the patient less so” [1] or “a distressed mind in a repaired body” [66]. Such considerations have not received broad attention but point to important issues regarding the patient's narrative and the impact of DBS on the “self,” on the spouse, or on caregivers. These points also bring to the forefront an important set of issues (personhood, narrative, and identity) to examine if DBS extends beyond PD and ET to neurospsychiatric disorders, where serious consequences may be anticipated in the psychosocial adjustment of patients over the longer term. Currently, we have a limited understanding of the impact that DBS may have in psychiatric patients and on their experiences of the world and themselves. Within the operating room, some depressed patients have reported significantly altered perceptions about the world around them. Mayberg et al [47] reported that depressed patients undergoing DBS spoke of “sudden calmness or lightness” and “a sense of heightened awareness, increased interest, connectedness.” Some patients also report feeling that a “painful emptiness” or “void” disappeared when the stimulation was turned on [47]. The psychosocial environment might change for psychiatric patients after DBS. As the parents of one patient treated by DBS for OCD suggest; “if she had made a pilgrimage, we would have thought a miracle had happened” [24]. In the future, we should endeavor to more systematically characterize cognitive and behavioral changes after DBS and its social impacts. Even more so, these effects could be monitored in emerging research trials, with the understanding that these potential effects could be seen as large ramifications for the psychiatric patients undergoing DBS.

7. Preparing the ethical future of DBS Our review of ethical and social issues related to DBS highlighted that several significant challenges, although not insurmountable, need much closer attention. It is obvious that the realization of the full potential of this technique will require attention to a number of important ethical and social issues, issues that may be accentuated if DBS moves rapidly into psychiatric conditions. A combination of approaches previously used in neuroethics, such as expert consensus workshops to establish ethical guidelines [32,33] and public

engagement to improve public understanding [31], may be fruitful to explore. Further, the international dimensions of some issues such as resource allocation and patenting activities will need to be addressed with approaches that make room for the interests of various national and international stakeholders. Knowledge translation beyond the DBS community is crucially needed to ensure that DBS patient care is informed by state-of-the-art practices. In that respect, model approaches for handling this issue (and others) need to be identified and shared in the neurosurgical community and beyond. Accordingly, tackling ethical issues in DBS is as much a scholarly task, to bring additional clarification and analysis, as a practical task, to enact wellinformed concrete actions. Acknowledgments Support for the writing of this article comes from the Institut de recherches cliniques de Montréal (ER, GM), the Fonds de la recherché en santé de Québec (ER), the Social Sciences and Humanities Research Council of Canada (EB), CIHR (NNF 80045, EB, ER) and CIHR New Investigator Award (ER). We would like to extend thanks to Nicole Palmour, Mary Pat McAndrews, Abbas Sadikot, and Lynette Reid. References [1] Agid Y, Schupbach M, Gargiulo M, et al. Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so? J Neural Transm Suppl 2006;70:409-14. [2] Amick MM, Grace J. Deep brain stimulation surgery for Parkinson's disease: the role of neuropsychological assessment. Med Health R I 2006;89:130-3. [3] Bell E, Racine E. Ethics in deep brain stimulation in alcohol dependence. (Comment on “Remission of alcohol dependency following deep brain stimulation of the nucleus accumbens: valuable therapeutic implications?”). J Neurol Neurosurg Psychiatry e-Letters 2007 Nov 21 (electronic publication). [4] Benabid AL. What the future holds for deep brain stimulation. Expert Rev Med Devices 2007;4:895-903. [5] Burkhard PR, Vingerhoets FJ, Berney A, et al. Suicide after successful deep brain stimulation for movement disorders. Neurology 2004;63: 2170-2. [6] Cassels A, Hughes MA, Cole C, et al. Drugs in the news: an analysis of Canadian newspaper coverage of new prescription drugs. Cmaj 2003; 168:1133-7. [7] Castelli L, Perozzo P, Zibetti M, et al. Chronic deep brain stimulation of the subthalamic nucleus for Parkinson's disease: effects on cognition, mood, anxiety and personality traits. Eur Neurol 2006;55: 136-44. [8] Contarino MF, Daniele A, Sibilia AH, et al. Cognitive outcome 5 years after bilateral chronic stimulation of subthalamic nucleus in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 2007;78: 248-52. [9] Davis H. Currents of hope. Buffalo News. Buffalo, 2002, A1. [10] Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med 2006; 355:896-908. [11] Diamond A. Problems with deep brain stimulation devices referred to private practice for follow up. Parkinsonism Relat Disord 2007;13: 520-3.

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Commentary Widespread acceptance of deep brain stimulation and constant introduction of new indications for this fascinating procedure bring up some rather unexpected challenges that have to do with a variety of social, economic, legal, and medical issues. In addition to approved use in tremor and PD, DBS today is used for dystonia and Tourette syndrome, cluster headaches, aggressive behavior, major depression, and obsessive-compulsive disorder. Other conditions such as obesity, anorexia, minimally conscious state, and Alzheimer's disease are becoming subjects of clinical investigations. The review by Bell et al is an excellent summary of current information on some of these problems. It provides a valuable insight on dealing with patients who may be cognitively impaired or otherwise unfit for DBS surgery and prepares the readers for multiple challenges that would be encountered once these new indications for DBS become common practice. The authors recommend development of ethical guidelines, and this does appear to be the soundest approach. It would help in some situations, although others may remain problematic because not every individual situation fits into the guidelines completely. Until this happens, however, it may be worthwhile to utilize existing ethics committees and, perhaps, common sense erring on the side of safety and protection of our patients from surgical risks. The need for realistic expectations, nicely underscored by the authors, is one of the main determinants of patient satisfaction. Having a multidisciplinary team seems to be another important determinant of successful outcome. All of this is wellknown, but still worth repeating. The era of new indications and significant increases in the number of neuromodulation procedures is just around the corner. The more prepared we are for the new demands and previously unaddressed problems, the better the service we will deliver to our patients. This article is probably a first step in such a preparation. Konstantin V. Slavin, MD Department of Neurosurgery University of Illinois at Chicago Chicago, IL 60612, USA