Stuart G. Finder

Subthalamic nucleus deep brain stimulation in early stage Parkinson's disease.

BACKGROUND Deep brain stimulation (DBS) is an effective and approved therapy for advanced Parkinsons disease (PD), and a recent study suggests efficacy in mid-stage disease. This manuscript reports the results of a pilot trial investigating preliminary safety and tolerability of DBS in early PD. METHODS Thirty subjects with idiopathic PD (Hoehn & Yahr Stage II off medication), age 50-75, on medication ≥6 months but ≤4 years, and without motor fluctuations or dyskinesias were randomized to optimal drug therapy (ODT) (n = 15) or DBS + ODT (n = 15). Co-primary endpoints were the time to reach a 4-point worsening from baseline in the UPDRS-III off therapy and the change in levodopa equivalent daily dose from baseline to 24 months. RESULTS As hypothesized, the mean UPDRS total and part III scores were not significantly different on or off therapy at 24 months. Medication requirements in the DBS + ODT group were lower at all time points with a maximal difference at 18 months. With a few exceptions, differences in neuropsychological functioning were not significant. Two subjects in the DBS + ODT group suffered serious adverse events; remaining adverse events were mild or transient. CONCLUSIONS This study demonstrates that subjects with early stage PD will enroll in and complete trials testing invasive therapies and provides preliminary evidence that DBS is well tolerated in early PD. The results of this trial provide the data necessary to design a large, phase III, double-blind, multicenter trial investigating the safety and efficacy of DBS in early PD.

Clinical and professional ethics guidelines for the practice of thyroidology.

Avariety of medical professional societies have developed ethics practice guidelines or position statements regarding specific ethics issues (1–6). The Endocrine Society published its Code of Ethics for practice in 2001 (1); however, none of the practice guidelines are specific to thyroidology. In the field of thyroidology, specific clinical ethics issues arise in different clinical contexts. For example, autoimmune thyroid disease raises different clinical ethics issues compared with thyroid oncology. Within thyroid oncology, each type of thyroid cancer raises unique and distinct clinical ethics issues and dilemmas. For example, the clinical ethics dilemmas that present in hereditary medullary thyroid cancer surrounding genetic screening are not the same as in thyroid cancers that are not familial or do not yet have defined germline genetic markers. The dilemmas associated with poorly differentiated and aggressive thyroid cancers (such as anaplastic thyroid cancer) and raising end-of-life issues such as code status, existential suffering, and palliative care are not the same that present in well-differentiated thyroid cancers that respond well to treatment. In many cases, there is clinical disagreement over what constitutes beneficent care for patients. Additionally, new clinical ethics dilemmas are resulting from drug shortages (e.g., recombinant human thyrotropin), medical isotope shortages (e.g., I), as well as nuclear disasters where priority-setting guidelines for distributing potassium iodide are not in place or not identified. Despite the prevalence of clinical ethics dilemmas in thyroid disease, clinical ethics guidelines specific to the thyroid disease context have been notably absent. Clinical ethics expertise can provide morally sound frameworks for (i) the nuances and complexities of diagnosis and treatment, and (ii) allocation of resources in situations where the demand is greater than the supply. The field of thyroidology comprises both clinical ethics and research ethics issues; in both arenas, complex professional ethics and research integrity dilemmas may arise as funding for basic research shrinks, investigators move from clinical to corporate cultures, and competition for funding increases. Conflicts of interest are often poorly understood, which can range from financial to interprofessional conflicts of interest. The clinical and professional ethics guidelines presented here are intended to provide clear guidance about specific, yet common, ethics dilemmas and questions that arise in this unique subspecialty. These guidelines mainly address two groups of ethics dilemmas that are typically encountered by thyroidologists: clinical ethics dilemmas—those that arise in the patient care setting; and professional ethics dilemmas— those that revolve around disclosure of conflicts of interest and professional integrity. These guidelines also provide clear guidance on research ethics issues, such as when innovative therapy becomes ‘‘research,’’ the role of an institutional review board, as well as publication and data-sharing integrity issues. Finally, as enormous changes begin to take effect consequent to The Affordable Care Act (www.healthcare.gov/law/ index.html), thyroid practitioners find themselves in a new clinical landscape involving numerous resource allocation decisions. As aggressive, non-iodine-avid thyroid cancer continues to rise in incidence, more questions about end-oflife care, palliative care, or clinical trial candidacy have arisen. We offer these guidelines in recognition of this unique subspecialty that confronts wide clinical and research diversity.

Strange, But Not Stranger: The Peculiar Visage of Philosophy in Clinical Ethics Consultation

Baylis, Tomlinson, and Hoffmaster each raise a number of critiques in response to Blitons manuscript. In response, we focus on three themes we believe run through each of their critiques. The first is the ambiguity between the role of ethics consultation within an institution and the role of the actual ethics consultant in a particular situation, as well as the resulting confusion when these roles are conflated. We explore this theme by revisiting the question of “Whats going on?” in clinical ethics consultations. Moving from those issues associated with the role of the ethics consultant to those associated with the role of inquiry within the practice of ethics consultation, we then take up the serious challenge that Bliton seems shackled by the assumptions and institutional dispositions embedded in the medical culture in which he is working. This reveals the second theme, namely that there is a risk of co-optation when acting in a role that derives its legitimacy from institutional sources. Finally, we focus on an even more problematic implication stemming from the first two, namely that the focus on institutional power as the crucial factor for determining ethical significance has the effect of distorting, and perhaps obscuring, other forms of relational, interpersonal, and moral meaning.

Traversing boundaries: Clinical ethics, moral experience, and the withdrawal of life supports

While many have suggested that to withdraw medical interventions is ethically equivalent to withholding them, the moral complexity of actually withdrawing life supportive interventions from a patient cannot be ignored. Utilizing interplay between expository and narrative styles, and drawing upon our experiences with patients, families, nurses, and physicians when life supports have been withdrawn, we explore the changeable character of “boundaries” in end-of-life situations. We consider ways in which boundaries imply differences – for example, between cognition and performance – and how the encounter with boundaries can generate altered meanings important for understanding decisions and actions in these contexts. We conclude that the reliance on mere roles to support the moral weight of withdrawing medical interventions is inadequate. Roles that lead us to such moments are exceeded by the responsibility encountered in such moments. And here, we suggest, is the momentous character of withdrawal: it presents the grave astonishment, the trembling awe, in the “not-being-there” of the other in death.

Responsibility after the apparent end: 'following-up' in clinical ethics consultation.

Clinical ethics literature typically presents ethics consultations as having clear beginnings and clear ends. Experience in actual clinical ethics practice, however, reflects a different characterization, particularly when the moral experiences of ethics consultants are included in the discussion. In response, this article emphasizes listening and learning about moral experience as core activities associated with clinical ethics consultation. This focus reveals that responsibility in actual clinical ethics practice is generated within the moral scope of an ethics consultants activities as she or he encounters the unique and specific features that emerge from interactions with a specific patient, or family, or practitioner within a given situation and over time. A long-form narrative about an ethics consultants interactions is interwoven with a more didactic discussion to highlight the theme of responsibility and to probe questions that arise regarding follow-up within the practice of clinical ethics consultation.

Maximal care considerations when treating patients with end-stage heart failure: ethical and procedural quandaries in management of the very sick

Deciding who should receive maximal technological treatment options and who should not represents an ethical, moral, psychological and medico-legal challenge for health care providers. Especially in patients with chronic heart failure, the ethical and medico-legal issues associated with providing maximal possible care or withholding the same are coming to the forefront. Procedures, such as cardiac transplantation, have strict criteria for adequate candidacy. These criteria for subsequent listing are based on clinical outcome data but also reflect the reality of organ shortage. Lack of compliance and non-adherence to lifestyle changes represent relative contraindications to heart transplant candidacy. Mechanical circulatory support therapy using ventricular assist devices is becoming a more prominent therapeutic option for patients with end-stage heart failure who are not candidates for transplantation, which also requires strict criteria to enable beneficial outcome for the patient. Physicians need to critically reflect that in many cases, the patient’s best interest might not always mean pursuing maximal technological options available. This article reflects on the multitude of critical issues that health care providers have to face while caring for patients with end-stage heart failure.

Deep Brain Stimulation for Early-Stage Parkinson's Disease: An Illustrative Case

Objectives:  Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective intervention in advanced Parkinsons disease (PD), but its efficacy and safety in early PD are unknown. We are conducting a randomized pilot trial investigating DBS in early PD. This report describes one participant who received bilateral STN‐DBS.

Deep brain stimulation in early stage Parkinson's disease may reduce the relative risk of symptom worsening

We thank the authors of this letter for their interest in the new findings from our study of deep brain stimulation (DBS) in early stage Parkinsons disease (PD). We agree that there is increasing off-label use of DBS in early stage PD, with anecdotes of success being recorded. It is important to note, however, that the Vanderbilt pilot trial does not establish the safety of DBS therapy in early stage Parkinsons disease. The U.S. Food and Drug Administration (FDA) limited the pilot study to 30 subjects (with 15 randomized to receive DBS). The safety of DBS in early stage PD can only be established in a phase III trial with a much larger cohort of participants. While the authors are correct that this manuscript does not discuss the surgical risks of DBS in early stage PD, our team has previously reported in detail the adverse events from the pilot trial, including perioperative adverse events [1,2]. There were four out of fifteen subjects in the DBS group who experienced clinically important worsening (27%), including the two subjects who experienced surgical or device-related adverse events. Therefore, the rates of clinically important worsening we report for the full cohort of the Vanderbilt pilot trial did include these two subjects. Comparatively, 54% of the optimal drug therapy group experienced clinically important worsening (7 out of 13). Overall, our results show that DBS in early stage Parkinsons disease imparts a 50% reduction in the relative risk of worsening when compared to medical therapy. This line of research has received some harsh criticism in the past centered on the ethics of offering a surgical intervention (and its associated risk) to research participants with early stage Parkinsons disease. Physicians and scientists expert in the field of Parkinsons disease can respectfully disagree on this issue. We are quite sensitive to the ethical issues raised, and it is for this reason that from the earliest stages of our pilot study we have striven to address such concerns. Most significantly, biomedical ethicists were actively engaged in the nd implementation of an expanded informed consent for the pilot trial. It emphasized both the importance of patient self-determination in making sensitive choices of this type and also allowed us to learn from potential participants how they understood the risks facing them should they enroll in the pilot [3,4]. It is important to note, moreover, that the pilot trial had a 97% retention rate over five years of clinical investigation, which we believe is in large part due to the expanded informed consent process [5]. We are strongly committed to having biomedical ethicists engaged throughout the informed consent process of our future clinical trial testing DBS in early stage Parkinsons disease. The FDA places the safety of clinical trial participants as paramount and has approved the conduct of a prospective phase III, pivotal, double-blind, placebo-controlled clinical trial testing deep brain stimulation in participants with early stage Parkinsons disease. This trial has the possibility to demonstrate that DBS in early stage Parkinsons disease may offer better management of PD motor features, reduce the development of medicationassociated complications, and provide a better quality of life. The following sites have completed all of the necessary materials to join an application to form a consortium of centers committed to carrying out this trial: Beth Israel Deaconess Medical Center, Case Western Reserve University, Duke University, Emory University, Mayo Clinic Rochester, Michigan State University, Northwestern University, Stanford University, The Ohio State University, University of California, Los Angeles, University of California, San Francisco, University of Cincinnati, University of Colorado Denver, University of Florida, University of Michigan, University of Minnesota, University of Utah, and Vanderbilt University.

Deep brain stimulation in early stage Parkinson's disease.

We thank the author of this letter for his interest in our study and for his concern for the safety of Parkinsons disease patients. We share his concern, as it was largely the motivation for the Vanderbilt pilot trial of DBS in Early Parkinsons Disease [1]. Our study was initiated in 2001, at a time when there was growing utilization of DBS for advanced PD, a trend toward earlier performance of the surgery, and animal studies suggesting neuroprotective properties of DBS [2]. Our group and others saw the potential value in testing DBS in early stage PD as it might improve symptom control and potentially alter disease course. Since the safety of such stimulation, however, could not be presumed at an earlier stage in the disease, we felt it important to perform a pilot trial to establish the feasibility of performing the surgery and the safety of stimulation at this point in the disease. The goal of this pilot study is not to promote or malign the therapy but to evaluate safety and tolerability without preconceived notion. Although in retrospect it seems obvious that surgery and stimulation would not have many of the deleterious effects that we monitored, such forgone conclusions should not be assumed when a new investigation begins. The importance of these evaluations was agreed upon by the investigators and regulatory reviewers. Since this was the first study to implant very early stage PD patients, peer review expressed concerns that patients early in the course of the disease may not exhibit sufficient off-period symptoms to confidently identify the optimal target for lead location. Furthermore, at that time MER was widely regarded as a necessary method for STN identification and rate models suggested that firing in the STN would be less distinct early in disease. Additionally the question was posed, “Could the actual effect of continuous stimulation on the brain in early stage PD cause some unforeseen consequence?” This question was particularly cogent, at that time, given the recent unanticipated experience of a significant portion of PD patients developing runaway dyskinesias after fetal cell transplant [3]. Regulators additionally requested that we monitor patients for the development of symptoms mimicking neuroleptic malignant syndrome due to the withdrawal of dopaminergic medications: this requirement was placed on the study by regulatory authorities to ensure the safety of participants. Our investigative teamwas therefore challenged to first conduct a pilot study to demonstrate that the actual effect of stimulation in early stage PD would not somehow worsen the patients condition or cause some unforeseen deleterious consequence. The pilot trial clearly demonstrated that it is possible to accurately implant and stimulate bilateral STN deep brain electrodes in patients with early stage PD and very mild symptomology [4]. Our intent in the paper is not to “congratulate” ourselves but simply to objectively report

Activities, Not Rules: The Need for Responsive Practice (On the Way Toward Responsibility)

to make substantive gains in improving the performance of IRBs, this is the place to begin. Toward this goal, it might be useful to think a step beyond the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979); beyond autonomy to community, incorporating the lessons of participant involvement in the development and design of clinical research; beyond beneacence to compassion, recognizing the support owed to those who are participating in hope; beyond justice to commitment, offering compensation and care to those who may be injured in research.