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20 Things to Know about
Deep Brain Stimulation

20 Things to Know about Deep
Brain Stimulation
E R W I N B .   M O N T G O M E R Y, J R . , M D
M ED I CA L D I R EC TO R
G R EEN V I L L E N EU R O M O D U L AT I O N C EN T ER
T H E G R EEN V I L L E N EU R O M O D U L AT I O N S C H O L A R
I N  N EU R O S C I EN C E A N D PH I LO S O PH Y
T H I EL C O L L EG E
G R EEN V I L L E , PA

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Library of Congress Cataloging-in-Publication Data
Montgomery, Erwin B., Jr., author.
20 things to know about deep brain stimulation / Erwin B. Montgomery, Jr.
  p. ; cm.
Includes bibliographical references.
ISBN 978–0–19–933882–5 (alk. paper)
I. Title.
[DNLM:  1.  Deep Brain Stimulation—methods.  2.  Mental Disorders—therapy.  3.  Movement
Disorders—therapy. WL 368]
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2014029318
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. whose unfailing support made every house a home. and to Michael.To Lyn Turkstra. David. and Pat. whose love was always a source of comfort when needed most.

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Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Dystonia  101 11. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease  22 4. Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Tourette’s Syndrome  130 14. Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia  94 10. Postoperative Care for Essential Tremor  87 9. Could Deep Brain Stimulation Be Effective in the Treatment of Posttraumatic Stress Disorder?  186 18. Ethical Issues of Deep Brain Stimulation  226 20. Deep Brain Stimulation for Hyperkinetic Disorders  156 16. The Future of Deep Brain Stimulation  247 Index  261 . Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder  171 17. Deep Brain Stimulation Is Safe and Effective for Tourette’s Syndrome  122 13. Deep Brain Stimulation Is Safe and Effective for Essential Tremor  66 7. What Is Deep Brain Stimulation?  1 2. Why Deep Brain Stimulation?  14 3. Postoperative Management of Patients with Parkinson’s Disease  56 6. Deep Brain Stimulation and Insights to Pathophysiology and Physiology  216 19. Deep Brain Stimulation for Cerebellar Outflow Tremor  145 15. Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Parkinson’s Disease  37 5.CONTENTS Preface ix 1. Postoperative Management of Patients with Dystonia  115 12. Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Essential Tremor  74 8.

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Since 1997. in many ways DBS is revolutionary and. One would think that such a breakthrough would be enthusiastically embraced for the potential insights into pathophysiology and physiology of the brain and for the benefit physicians and healthcare professionals now can provide to their patients. . In 2000. The technical prowess of modern science generated many observations of how the brain reacts to DBS.PREFACE T WO PL E AS The First Plea In 1998. After deep brain stimulation (DBS). DBS has demonstrated its superiority over every other treatment option. he could beat them in basketball. as currently practiced. After the stimulation was turned on. Indeed. “Now I  can hold my baby. a father with young children suffered from Parkinson’s disease. or self-organizing physical universe. a breakthrough on par with the discovery of levodopa. much to the consternation and relief of his children. If only that were the case. humankind was given a gift. I cannot think of a single neurology resident who actively sought to participate in the DBS clinic to the point of having knowledge and skills in DBS even close to proficiency. She then said. depending on one’s perspective. Interestingly. much or little has changed. In many disorders. a 26-year-old woman laid on an operating room table with a set of electrodes implanted in the ventral intermediate nucleus of the thalamus of her brain. 1980). no mention of “Deep Brain Stimulation” or DBS is made in the Certification Examination in Neurology 2013 Content Blueprint published by the American Board of Neurology and Psychiatry (2012). only a short course on DBS programming. there was not a single presentation on DBS. in the field of Parkinson’s disease. At the American Academy of Neurology annual meeting in 2014. was reported in 1979 for psychiatric disorders (Dieckmann 1979) and in 1980 for movement disorders (Cooper et al.” She had given birth three months before. Whether by fate. Since DBS. her severe tremor due to her multiple sclerosis went away. providence. but it is no further in understanding why DBS creates what even the most jaded would have to admit are nearly miraculous changes in patients’ lives.

. make her suffer so much. to do good. is unclear. that is. and hope for the best. the license to practice is not a right but a privilege extended to physicians and healthcare professionals. and other more common disorders and treatments for the physicians’ and healthcare professionals’ attention. and the Geneva Declaration that most physicians swear to. I can commiserate with those physicians. Anyone who recognizes that it is a privilege to be a physician and healthcare professional also will recognize its obligations. Perhaps the physicians at the first institution were overly enthusiastic while latter physicians were appropriately skeptical. appropriately. However. There have been remarkable changes in the nearly 30 years I have been practicing medicine and not all of them good or helpful. only a single patient with cerebellar outflow tremor was referred. However. there is no choice but to remind everyone of the current situation in a clear-eyed. Further. The answer to the dilemma of providing all patients the care that they need. One of the most painful and difficult questions I have been confronted with is when the patient asks why did her physician wait so long. When confronted with spending what little discretionary time and intellectual capital they have on continuing education. before referring her for DBS? However. The continued increases in responsibilities accompanied by reductions in authority has hamstrung many physicians and healthcare professionals.x P reface In my experience. Those obligations are to beneficence. only a fraction of patients who could benefit are being provided that option. unrelenting analysis. physicians have an obligation to beneficence because it is extremely rare that a physician’s education and training were paid for by the physician but rather subsidized by society. In the10 subsequent years at other institutions. The years spent in school and in training do not convey any entitlement. the Oath of Maimonides. The shortage of physicians and increase in work hours makes any discretionary time that could be devoted to gaining knowledge and skills to provide DBS challenging and requires no small amount of self-sacrifice. which faces unfavorable odds when competing with epilepsy. Consequently. the fact remains that such disparities must argue for a profound dissonance as both groups of physicians probably read the same publications. But what is clear is that the answer will not come unless the proper questions are asked. in my opinion. the enthusiasm at potentially helping patients with severe tremor secondary to multiple sclerosis at one institution led to many patients being referred and. Even for disorders that are uncontroversial. I am not so naïve to think that this is sufficient. In addition. remind each and every one of their obligations. such as Parkinson’s disease. physicians and healthcare professionals do not choose DBS. which entail obligations. particularly as it relates to DBS. Yet it is the patient whose suffering could be alleviated with DBS that is paying the price. headache. and are articulated in the Hippocratic Oath. I wish that every physician and healthcare professional could have the experience of seeing one of their patients—whom they have suffered with as no medications helped—dramatically improve with the turning on of an electrical switch.

Drink deep. paradigm shifts come when the current paradigm fails increasingly . And the first clouds and mountains seem the last. Short views we take. or taste not the Pierian spring: There shallow draughts intoxicate the brain. But more advanc’d. Th’ eternal snows appear already past. Perhaps it would be far better for everyone just to say “we have no idea how DBS works” and then to begin with a clean slate. And drinking largely sobers us again. which only happens when we are not easily satisfied. This book is intended to drink deeper. nor see the lengths behind. The only prevention is to continual admonish ourselves to drink deeper. such paradigm shifts do not come easily. distant scenes of endless science rise! So pleas’d at first. Such statements will not make me popular particularly with those whose careers have been devoted to claiming sure knowledge. The Structure of Scientific Revolutions. In Kuhn’s historical analysis. Fir’d at first sight with what the Muse imparts. and as Thomas Kuhn (1963) beautifully described in his book. But all too often. Mount o’er the vales. Th’ increasing prospect tires our wand’ring eyes. behold with strange surprise New. But those attain’d. Hills peep o’er hills. and seem to tread the sky. However desirable that might be. 1711): A little learning is a dang’rous thing. Difficult Questions DBS is revolutionary and unlike any previous therapy. the potential of DBS is cut short by all too facile explanations presupposed by treatments of the past that cannot begin to capture the complexity of DBS. What is thought to be known actually are obstacles to truly knowing. It represents a paradigm shift.P reface xi The Second Plea The second plea is best conveyed by the lines of Alexander Pope (An Essay on Criticism. as it is a new era in the treatment of neurological and psychiatric disorders. In fearless youth we tempt the heights of arts. it is contrary to human nature. the tow’ring Alps we try. and its promises for the future are great. we tremble to survey The growing labours of the lengthen’d way. and Alps on Alps arise! DBS is remarkable. While from the bounded level of our mind. and it will demonstrate that the thirst to understand is far from being satisfied.

that is. Experts in DBS may find the discussion provocative at times. and taken away. statistical. without in the least altering the habits of mind of which false opinions are made. however. This book seeks to challenge notions often taken for granted in order to encourage the narrative with greater critical analysis. However.xii P reface to explain accumulating observations. As a caution. then. considered in their historical context. criteria ought to identify the patient whose probability of improvement is the lowest acceptable. The enormity of the issues calls for an analysis at a meta-level. Indeed. grabbed. confusion. for example. Paraphrasing Claude Bernard. require that before being offered DBS a patient with Parkinson’s disease show at least a 30% improvement in the Unified Parkinson Disease Rating Scales following a levodopa challenge test. not wanting to compound his foolishness by admitting it. Interestingly. as amply argued by Thomas Hobbs (Shapin and Schaffer 1985). and counterproductive recommendations result from failing to recognize various demands and their particular contexts. Indeed. for example.” One might think. political. It is not sufficient to know what the observations or facts are but whether they really are facts and how is it that they have come to be known. What one often thinks they know are presumptions that find there ways into habits of thinking. In the fable The Emperor’s New Clothes (Hans Christian Anderson). Discussions of DBS prove no exception in this respect. the emperor kept walking. Science does not bury dead theories as no one wants to admit they once held them. ethical. a tipping point is required before current paradigms are overthrown. Ideal candidates. Such a challenge is not meant to call into question the judgment of the many thoughtful and intelligent experts whose analyses and recommendations are critiqued herein. the boy who noted the emperor’s nakedness was called a fool. but I hope that they might also find it helpful. meta-cognition has never been popular or the strong suit of scientists. 2002). and in many cases exceed. that the place to start is an analysis of what we think we know. Yet application of this criterion would exclude many patients whose postoperative improvement was shown to match. clinical. and often immediate successors must be waiting in the wings. This textbook addresses a subset of important topics related to DBS. Further. social. faithful application of ideal-candidate criteria would end up eliminating from candidacy many patients who stand to benefit from DBS and who otherwise face suboptimal alternatives. Virtually every set of guidelines written by experts. DBS raises a myriad of questions that are scientific. those analyses and recommendations appear eminently reasonable. making it difficult to demonstrate their failings. we are more often fooled by things we think we know than things we do not. As befits its revolutionary nature. the patient most likely to benefit from the therapy. However. someone who says most of those about him are going in the wrong direction are seldom sought out and given a voice. and moral. But . called the father of modern physiology. Such a formula proves problematic for DBS as challenges to current paradigms are denied access to the marketplace of ideas and the questions are continually framed in the old paradigm. the words of John Stuart Mill (2009) are recalled: “I had learnt from experience that many false opinions may be exchanged for true ones. Some centers. Misunderstandings. includes criteria for the ideal or best DBS candidate. patients whose preoperative Unified Parkinson Disease Rating Scales demonstrated greater than 30% improvement (Charles et al. Rather than identifying the ideal candidate. are not the population of most concern. even back to the days of the origin of the Royal Society.

validity. For instance. have not. A  judgment made in the context of Evidence-Based Medicine presumes the epistemological.M A K I N G Epistemology is a domain of philosophical inquiry concerned with knowledge—its nature. Yet the credibility of the sole remaining option ought not to depend on the faults that toppled the others. which tends to be Evidence-Based Medicine. Credibility thus falls to the last option standing. case series. they cannot establish its clinical meaningfulness. The current vogue for Evidence-Based Medicine has served to increase epistemology’s importance. that which passes for meta-analysis in medicine is typically summation of randomized controlled trials (RCTs) or other empirical studies. EPI ST EM O LO GY O F C L I N I CA L D EC I S I O N . rather. These alternatives may include open-label studies and other clinical trials run without controls. however. Treating RCTs as the sole means of establishing claims’ credibility thus moots any epistemic question that would arise by contrast or challenge. depends primarily on RCTs. Rather. a plea for more meta-analytical thinking to inform the empirical. These alternatives may be found to contain faults and for this reason be eliminated as justification for a claim. To say that treatment A is effective requires considerations of risks. that medicine A  is an effective treatment of disease B. for example—according to how they are made. Evidence-Based Medicine.” facts. an RCT may claim that the effect of treatment A results in a statistically significant greater change in some measure of disease B compared to placebos.P reface xiii though historical context may have changed. Evidence-Based medicine appears to judge the veracity of claims— treatment A effectively treats disease B. To claim that RCTs represent the only epistemologically valid source of knowledge risks an error of reasoning known as the fallacy of limited alternatives. Neither a contrarian nor iconoclastic impulse informs this writing. Claims inferred from RCTs tend to be deemed more credible than those inferred from the results of uncontrolled trials. which RCTs are not designed to answer (Montgomery and Turkstra 2003). and methods of acquisition. and value judgments external to RCTs in order to convert statistical significance to clinical meaningfulness. Alternatives are neither entertained nor even recognized. Although RCTs may make statements as to a claim’s statistical significance (the basis for confidence in a claim). who tend not to be terribly introspective. One may construct a number of approaches to justify a medical claim. At no point does one find evidence of higher order abstraction. in its current invocation. which the very term “meta-analysis” suggests. For example. A  novel analysis of RCTs from the perspective of information-theoretic entropy and the Second Law of Thermodynamics is presented in ­chapter 15. particularly. while the faults or inherent limitations of RCTs go uncommented. and issues of healthcare resource allocation. benefits. They are also esteemed over observations drawn from clinical experience. and expert consensus. RCTs require the importation of “knowledge. case reports. . physicians. The reason it is not fully appreciated as such owes to the fact that current versions of Evidence-Based Medicine simply affirm a synonymy with RCTs. It is. One ought not infer from this finding.

which before the advent of antibiotics were used to treat syphilis (Lockhart and Atkinson 1919). while truly abnormal subjects who tested as normal would be categorized as false negatives. there remains to be determined the cost.05 as a cutoff for statistical significance in many. Applying this criterion is roughly analogous to using p < . partly depends on deciding whether a disease is in fact present.xiv P reface The Unique Nature of Medical Decisions Medical decisions require action. if not most. Determining the consequences of the false positive rate and false negative rate is the most appropriate means of establishing a cutoff for the purpose of translating a continuous variable into a dichotomous variable. for example. may fall anywhere on a spectrum ranging from absent to maximum possible. which allows one to make a decision. For example. and it is therefore unreasonable to think that a slight amount of treatment may be given.55% of normal subjects taking test A produce results interpreted as abnormal. for example. associated with missing a diagnosis and thus failing to . One approach involves basing the cutoff on a normal population’s statistical properties. It is impossible for a disease to be slightly present. clinical studies. Yet deciding whether symptoms are severe enough to warrant DBS surgery requires that one situate symptoms on one side or the other of a line dividing symptoms which sufficiently warrant surgery from those that do not. The rate of true negatives—patients who test negative for a disease they do not have—relates to the specificity. One may increase the sensitivity and reduce the risk of false negatives. For example. Yet the same does not hold true for arsenic compounds (Salvarsan). and thus admits of a limited set of alternatives (two in the present instance). the “abnormal” side of the dichotomy based on difference from the mean (median) of an appropriately determined normal population in terms of the variance of the normal population results (standard deviation). One may plot the effects of different cutoff on the sensitivity and specificity by using logistic regression and plotting the Receiver– Operator Curve. Again. There are a number of approaches to establishing a cutoff for a dichotomous medical decision. test result A  may be considered abnormal if the value is greater than two standard deviations from the mean of the normal population. The rate of true positive decisions—a particular patient’s having disease B. depending as it does on a “yes” or “no” answer to its central question. The magnitude of symptoms. but so doing usually results in a loss of specificity and greater rates of false positives. A large majority of medical decisions require a tradeoff between the rate of true positive decisions and false positive decisions. for instance—relates to the sensitivity of the diagnostic test. The decision is dichotomous. Yet doing so creates a situation in which 4. The decision whether to treat. Such false results can have enormous consequences. The dichotomous nature of the necessary decision belies the typically continuous data on which the decision relies. Normal subjects producing abnormal results would be categorized as false positives. one ought not to administer pure arsenic in any amount. this cutoff is based on the statistical properties of the populations. In other words. considered in its widest connotation. Exceedingly few medical decisions admit of a simple and explicit calculus enabling one to define a cutoff that effectively transforms a continuous variable to a dichotomous variable. One may then select the inflection point or another point on the Receiver–Operator Curve and use as the cutoff the value of test A associated with that point.

The effect on some measure of health. It remains unclear.P reface xv provide the appropriate treatment as opposed to making an incorrect diagnosis and thus providing unnecessary treatment (Montgomery and Turkstra 2003). such as a specific treatment on a sample of some number of subjects—face the critical problem of implementing and applying the inferences drawn from the sample to the individual patient (Montgomery and Turkstra 2003. one must examine the distribution of responses in both groups. The first consists of patients who would benefit from treatment A. Montgomery 2013). The task requires estimating the probability of the effect for the individual patient. Most diagnoses are based on a set of criteria that typically consists of the symptoms and signs associated with a single diagnostic category or some number of categories. and the second of patients who would not. would depend on . ethical. a RCT involves patients who are given either experimental medication A or placebo. then. A patient’s meeting these criteria is considered tantamount to her having the disease. economic. Sensitivity.  Thus it is clear that any subject receiving medication A will show improvement in the measure of health B. to see that RCTs in themselves do not address the consequences. sociological. Bayes’ Theorem Virtually every medical decision is a form of diagnosis. In order to establish the probability of an individual patient’s responding to medication A in some way distinct from a response to placebo. For example. Often the situation is that there appears some overlap. B. which are critical for determining the clinical meaningfulness of the inferences drawn from any RCT. and the diagnosing clinician must decide whether she belongs with the first or second group. whether a subject who may or may not be receiving medication A will see an improvement in the measure of health B. for example. One may evaluate DBS selection criteria in much the same way as one evaluates diagnostic criteria according to specificity and sensitivity. rephrasing treatment decisions as diagnostic questions allows one to apply to questions of treatment diagnostic tools and modes of thinking. A  physician may have to decide. political. A new patient appears to have disease B. Yet there may be considerable overlap in the two measures. As this example demonstrates. whether a particular patient has Parkinson’s disease or Essential tremor. therefore. This cost is at once medical. Patients whose diseases meet selection criteria fall under the diagnostic category of patients who enjoy a reasonable chance of benefiting from DBS. there are two groups of patients with disease B. Criteria for DBS surgery candidates are held in much the same regard. There may be considerable separation in the distributions of the measure of health B between those subjects who received the placebo and those who received medication A. and the situation is consequently less clear. psychological. was determined. The reverse also holds true: a therapeutic decision may be rephrased as a diagnostic issue. for example. For example. The n-of-One Problem Population studies—studies that report the mean and standard deviation of an effect. It is unsurprising. and moral.

which is 97% specific and 97% sensitive. Whether P(DBS+|SC+) . then the diagnostic test would result in as many false positive diagnoses as true positive diagnoses and as many false negatives and true negatives. because it is understood that Parkinson’s disease is more likely in older subjects. To consideration of specificity and sensitivity must be added consideration of prior probabilities.xvi P reface the probability that a patient who meets the selection criteria would respond well to DBS and specificity on the probability that a patient would respond poorly. A concern arises when P(DBS+|SC+) does not equal P(DBS+). The diagnosis that a patient who meets the selection criteria (SC+) enjoys a reasonable chance of DBS benefit (P(DBS+)) corresponds to the following formula. DBS carried no risks but refusing a patient DBS did carry substantial ones. If the prior probability (or prevalence) of Parkinson’s disease were higher. In typical diagnostic tests. which is expressed in terms of Bayes’ theorem. Again. is applied to a population of persons over the age of 65. then the negative prediction may be more important. in which case there would be patients who would benefit from DBS who do not meet the selection criteria. then the number of true positives diagnoses would exceed the number of false positives and. P(DBS+|SC+) represents the positive predictive value of the selection criteria. the numbers of true negatives would exceed the number of the false negatives (Montgomery 2013). which is given by P(DBS–|SC–) and indicates the probability of a poor DBS outcome for the subject who fails to meet the selection criteria. for example. P(DBS+) the probability that any appropriately diagnosed patient will respond well to DBS. Application of Bayes’ theorem allows one to appreciate the role played by prior probabilities in diagnosis. this prediction value is incomplete. For example. similarly. a test for Parkinson’s disease diagnosis. because one must also consider the negative predictive value. From use of the selection criteria would thus follow the consequence of some patients’ being inappropriately denied DBS benefit. however. In certain circumstances the important issue becomes the negative prediction P(DBS–|SC–). P(DBS–) is probability of a poor DBS outcome irrespective of selection criteria. Like the positive predictive value. Yet consideration of specificity and sensitivity remains insufficient. The goal behind any selection criterion is to determine P(DBS+|SC+). the negative predictive value may be determined according to the following formula: P(DBS–|SC–) = (P(SC–|DBS–) × P(DBS–))/P(SC–) where P(SC–|DBS–) is the probability that those subjects whose DBS outcome was poor would not have met the selection criteria. prior probability rests on the prevalence of the disease in the population of concern. and P(SC–) the probability of a possible DBS candidate population selection criteria’s going unmet by a particular patient. If. P(DBS+|SC+) = (P(SC+|DBS+) * P(DBS+))/P(SC+) where P(SC+|DBS+) is the probability that someone responding well to DBS meets the criteria. and P(SC+) the probability that any appropriately diagnosed patient will meet the selection criteria. If one assumes that the prevalence of Parkinson’s disease in this population is 3%. which indicates the probability of a beneficial DBS response.

healthcare providers. The first solution is that of an arbitrary decision explicitly or implicitly made. which is the measure of how frequently patients in the population of concern meet the selection criteria. There is thus no “objective” way to determine where may lie the cutoff that divides and sorts continuous variables into dichotomous categories. consist of continuous variables. the appropriate cutoff value results from the application of information. governmental agencies) are willing to provide. The problem of constructing the cutoff admits of at least two solutions. because it rests on an assumption that RCTs represent the sole route to clinical knowledge and therefore the sole basis for legitimate medical action. In order for patients to secure their interests they must be able to negotiate on the basis of sufficient knowledge. Though the current vogue for Evidence-Based Medicine certainly makes it appear reasonable. S O U N D E T H I C S. Merely transferring the enrollment criteria for patients with Parkinson’s disease used in RCTs to general practice is an example of an implicit arbitrary cutoff. Though I may not always explicitly apply Bayes theorem. They often delay or deny DBS treatment. it remains unknown. Assuming that P(DBS–|SC–) does not equal P(DBS–) represents much the same issue. By “contractual” one is to understand a patient’s acceptance of the extent and limits of the care responsible organizations (physicians. Defining as contractual the cutoff suggested by a specific selection criterion represents a second approach. of those probabilities which are not explicitly known. knowledge. namely. No justification beyond commercial or political interest exists for this approach. exercise of sound clinical wisdom requires that clinicians offer some expert estimate. wisdom. whether falling short of the selection criteria amounts to guaranteed failure to realized benefit from DBS. in themselves incapable of informing medical decisions. which indicates the probability that patients who underwent DBS without being submitted to selection criteria would retrospectively have been shown to have met them. and sufficient knowledge requires that a high degree . if not an injustice and patients who would benefit may be denied. This holds especially true in cases of Parkinson’s disease (see ­chapter 4). offer no information about clinical meaningfulness. as well as and all those who may not. moreover. and value judgments external to RCTs. insurers.P reface xvii does not equal P(DBS+) depends on P(SC+). SO U N D M ED I C I N E The discussion here makes clear that a specific selection criteria may fail to identify all those patients who may benefit from DBS. Indeed. the enrollment criteria for RCTs may prove counterproductive. RCTs. Because no study has been made to discover the value permitting the determination of P(SC+|DBS+). In other words. the theorem itself remains critical. The actual selection criteria. Indeed. Merely assuming that P(DBS+|SC+) equals P(DBS+) is a mistake. such a transfer contains an element of solipsism. and on P(SC+|DBS+). whereas a decision represents the imposition of dichotomous categories. Though one may lack all the probabilities necessary for a complete determination of Bayes’ theorem. Rather than emerging from RCTs. considered in isolation. through application of the appropriate RCTs or other means. To act on this assumption would be to ignore serious inherent limitations that render RCTs. I will employ Bayesian reasoning throughout the discussion to follow.

have led to the development of many treatments whose implementation lies beyond the capability of current healthcare delivery systems to provide. whether this assessment rests with the patient suffering the symptoms or the physician treating her. however. whether leaving this determination to the patient (or her legal surrogate) effectively forces the physician to do harm. do patients have knowledge sufficient for negotiating their interests. Little is at stake in negotiations turning on care of these. In order to practice wisely. These principles are beneficence. physicians and healthcare professionals must understand the epistemic basis for the decisions they must make. What. say a physician fails to keep abreast of the state of the art in treatment yet refuses to refer a patient to another physician who has kept abreast. laws define some ethical norms. In order to overcome this difficulty. For example. which they must acknowledge as such. natural or legal. whether the impact of these symptoms on quality of life is better determined by a patient or her treating physician. Yet not all laws reveal themselves as compatible with every moral system. Ethics involves the search for practical solutions to moral problems. the mental act by which one assimilates facts or knowledge to an understanding of their origin and their proximal and antecedent causes. Recognizing that most current medical decisions are ethical decisions represents yet another approach. an attempt may be made to define the common morality. Remarkable advances in medicine. however. Admittedly. In a sense. Whereas morality addresses issues of right or wrong. Has this first physician engaged in unethical behavior? These issues are addressed more fully in ­chapter 19. Indeed. that is. and whether denying a patient DBS is justified by the healthcare system’s inability to provide it. ethics addresses the navigation of the particulars of right and wrong action. then. autonomy. that is. Suffice it to say that in cases in which a treatment exceeds a system’s capabilities.xviii P reface of transparency characterize the proceedings. They factor in the decision as to whether a patient’s symptoms have become severe enough to warrant DBS. the “knowledge” . nonmalfeasance. I M P O R TA N C E O F M E TA. expecting them to have it is unreasonable. If it is a privilege then it is negotiable. patients presume that the loyalty of their physicians and healthcare professionals lies first and foremost with them. The requisite transparency cuts two ways. many conditions are untreatable but manageable. Whether healthcare is a privilege or a right is a moral question in medicine. and justice. Negotiations made under such conditions may be said to have been made in bad faith.R EFL ECT I O N Epistemology of medical decisions involves meta-reflection. In c­ hapter 19 and elsewhere these ethical issues will surface. responsible physicians and healthcare professionals face an ethical decision. is to be done? Reconciling ethics to morality proves difficult in a pluralistic society. Rarely. Various discussions of DBS presume that these principles are in force. For example. the system of principles that every moral person ought to uphold (Beauchamp and Childress 2013). Whether this situation was intended is debatable. Patients negotiate their interests from a disadvantageous position if their counterparties lack sufficient knowledge. but it is not if it is a right.

however. T H E ST R U CT U R E O F T H E B O O K The majority of this book deals with specific clinical indications for DBS. A computer’s proper function does of course depend on transistors.P reface xix that Parkinson’s disease. and (3) dopamine replacement in humans with Parkinson’s disease and parkinsonian laboratory animals improves the motoric symptoms. Technological limitations and other factors may explain the failure of fetal cell transplantation. Thus there may be considerable redundancy across chapters discussing selection criteria for other DBS indications. is a dopamine deficiency is derived from three proximate facts: (1) patient with Parkinson’s disease have a deficiency of dopamine in certain regions of the brain. which support the knowledge that Parkinson’s disease is a dopamine deficiency. Yet the failure may be a failure to recognize that simply replacing dopamine is insufficient. I did not want the reader to have to read other chapters that contained discussions relevant to the chapter on the specific issue. I hope readers will find it a valuable tool in the management of their patients. which is tantamount to attempting to repair a computer by opening it and tossing in a handful of transistors. but it would be mistaken to suggest that a computer malfunction owes to deficiency of them. at least its motoric symptoms. One need simply adopt a broader perspective to see that this is so. The problem lies with ignoring facts that argue against the inference in favor of facts that support the inference that Parkinson’s disease is dopamine deficiency (Confirmation Bias). and this is consequent to degeneration of dopamine neurons of the substantia nigra pars compacta. The question as to why the notion that Parkinson’s disease is a dopamine deficiency achieved preeminence over other theories of equal explanatory power finds an answer in historical antecedents that created a context in which the former notion would flourish and alternatives ignored. This redundancy was made necessary by the expectation that readers may return to specific chapters as their needs demand. is false. For that reason. While fanning the flames of intellectual curiosity. with due apologies to the reader. It is not that the aforementioned facts. For example. AC K N OW L ED G M EN TS I want to thank the professors at the Department of Philosophy at Washington University in Saint Louis between 1980 and 1990 who put up with the presence of a young assistant professor of neurology in their graduate seminars. Common elements obtain among movement and psychiatric disorders. (2) the findings in humans with Parkinson’s disease can be replicated in laboratory animals by lesioning (destroying) the animals’ dopamine neurons. are incorrect. the . replacing dopamine by medications or fetal cell transplantation does little or nothing to improve the symptoms of patients with advanced Parkinson’s disease. The knowledge following from these three proximate facts. the redundancy was retained. Most of the chapters are designed to stand alone. The experience was grueling and demanding (in some ways more difficult than medical school) but exhilarating.

Modern Concepts in Psychiatric Surgery.. however defined. Leviathan and the Air-Pump:  Hobbes. London: n. Cooper IS. Ph.28(4):413–415. Beauchamp TL. Miami: Seven Treasures Publications. Pope. a renowned bioethicist at Weil College of Medicine in New York. 1985. American Board of Psychiatry & Neurology. Principles of Biomedical Ethics.. Neurology 2002. Can Med Assoc J. Van Blercom N. 2003. Neurology Core Competencies Outline http://www.. In: Hitchcock ER Jr. Buffalo Grove. Meyerson MBA. The Structure of Scientific Revolutions. Ballantine HT. Dieckmann G. 1711. Predictors of Parkinson’s disease—not quite sound. pdf Shapin S.  Montgomery III.11:ix–xii.43(3–5):244–258. 1963.xx P reface professors also imparted discipline and an obligation and loyalty to truth. New  York:  Oxford University Press. Alexander.9(2):129–135.. Montgomery EB Jr. which provided unrestricted funds to support the editing.D. Princeton. Kuhn TS. Inc. . An Essay on Criticism. NJ: Princeton University Press. and the Experimental Life. 1980. Amin I. Certification Examination in Neurology 2013 Content Blueprint. 2012. Mill JS. I also had the privilege and pleasure of many conversations with Dr. Joseph Fins. IL:  American Board of Psychiatry and Neurology.abpn. Turkstra LS. Chronic mediothalamic stimulation for control of phobias. Autobiography. Evidenced based medicine: let’s be reasonable. Boyle. Upton AR.59(6):932–934. Reversibility of chronic neurologic deficits:  some effects of electrical stimulation of the thalamus and internal capsule in man. Appl Neurophysiol. 2009. I also want to acknowledge Erwin B. R EFER EN C ES American Board of Psychiatry and Neurology. 2013. 2013. 1979:85–93. et al. Predictors of effective bilateral subthalamic nucleus stimulation for PD. eds. and FHC. Administration of arsenic in syphilis. Amsterdam: Elsevier. Krack P. Lockhart WT.p. Schaffer S. Atkinson JR. J Med Speech Lang Pathol. Mov Disord. Charles PD. 1919. Montgomery EB Jr. without whose editorial assistance this writing would be largely incomprehensible.com/downloads/core_comp_outlines/2011_core_N_MREE. Childress JR. Chicago: University of Chicago Press.

despite treatment by capable physicians. In light of the pace of neurotechnological (in contradistinction to neuroscientific) development. DBS is the most powerful tool for controlling the symptoms and disabilities associated with neurological and psychiatric disease. DBS is the best in terms of greatest long-term efficacy and fewest long-term adverse effects (see c­ hapter 3). prospective randomized control trials would prove problematic to conduct. In fact. included subjects whose selection was determined by failure.1 What Is Deep Brain Stimulation? The most revolutionary treatment for neurological and psychiatric disorders to come along in centuries. 2003). of aggressive pharmacological alternative therapies primarily. however. it is more powerful than pharmacological agents or ablative neurosurgery. The absence of the normal vetting requiring demonstration of safety and efficacy by sufficiently powered randomized control trials led the FDA to require . In these subjects DBS successfully controlled their movement. Yet many false or counterproductive presumptions and assumptions currently constraining neuroscience have prevented the deployment of these latter neurotechnologies (Montgomery 2012). The United States Food and Drug Administration (FDA) has approved DBS for treatment of Essential tremor and Parkinson’s disease and granted it a Humanitarian Device Exemption for treatment of Obsessive Compulsive Disorder and Primary Dystonia. because fewer than 4. which for reasons of technical and ethical difficulties were not controlled in the sense of being blinded.000 patients with each of these disorders were expected to be treated in a year’s time. The improvement provided by DBS to date is greater than that provided by gene therapies aimed at reversing the neurotransmitter mechanisms of subthalamic nucleus neurons. Clinically speaking. In the few head-to-head comparisons of Parkinson’s disease and other movement disorders that make use of Evidence-Based Medicine randomized control trials. at least as far as motor control is concerned. The exemption rests on the notion that. DBS succeeds where brain transplant (fetal cell transplants in treatment of Parkinson’s disease. for example) fails (Olanow et al. Deep Brain Stimulation (DBS) is to date the most important research tool for understanding the physiology and pathophysiology of the human brain. Remarkable examples of neurotechnology include functional Magnetic Resonance Imaging (fMRI) and genetic manipulation. there are other sources of medical knowledge and understanding that most reasonable individuals would consider compelling (Montgomery and Turkstra 2003). Early clinical trials of DBS. this seems a bold statement. Besides randomized control trials. Indeed.

the IRB must approve the purchase of devices from manufacturers. Saying that a neurotransmitter has a specific behavioral function amounts to saying that an electron moving in a computer determines the function of the computer. I consider DBS a standard and accepted (off-label) therapy for cerebellar outflow tremor. neurological disorders (and likely psychiatric disorders) result from misinformation (Montgomery and Gale 2008) rather than from a structure’s relative overactivity or underactivity. Yet the information. Tourette’s syndrome. but the pattern of neurotransmitter release is determined in large part by the pattern of action potentials descending to the synaptic terminals. The information transmitted does involve precise and pulsatile release of a neurotransmitter from the presynaptic neuron and the pulsatile change in membrane potential in the postsynaptic neuron. Neurotransmitters are simply messengers between neurons. which neurological and psychiatric disorders one may deem beforehand as inappropriate for DBS is unclear. Indeed. The processing of information in the postsynaptic neuron is based on the integration of membrane electrical potential changes induced by neurotransmitters. cerebellar outflow tremor has been shown to respond to DBS in the vicinity of the thalamus (Montgomery 2008). If DBS is considered a symptom-based therapy. again. then one simply needs to demonstrate its safety and efficacy relative to the symptoms (see more extensive discussion in ­chapter 15). if not most. including epilepsy. such as those that arise from Huntington’s disease. and tardive dyskinesia (Montgomery 2004). in which the function of the whole is ascribed to a part. and Alzheimer’s disease. chorea-acanthocytosis. It is a greatly underappreciated fact that the brain is basically a device that processes and transmits information electrically. Surgeons may elect to use the device as an off-label indication. The second course makes it easier for manufacturers to document and number the cases of DBS surgery for indications approved under the Humanitarian Device Exemption. is integrated and processed electronically. A diseased-based treatment has the expectation that the safety and efficacy for every possible disease indication be established. Precise control of the dynamics of electron flows. DBS research is demonstrating that many. Clinical trials are underway for a wide range of neurological and psychiatric disorders. they are not the message itself. For DBS in treatment of Obsessive-Compulsive Disorder. or from the relative overabundance or paucity of a neurotransmitter or a particular . because the lead used is unique. the notion that behavioral functions may be attributed to a neurotransmitter falls victim to an error in reasoning known as the Mereological fallacy. however. The same FDA-approved. or they may seek IRB approval for its use as labeled for dystonia. Additionally. they carry important implications. Doing so would prove extremely problematic in treatment of rare disorders. Similarly responsive are hyperkinetic disorders.” As such. rather. These observations support the notion that DBS therapy is “symptom-based” rather than “disease-based. commercially available device for treating Parkinson’s disease and Essential tremor may be used for dystonia. dystonia of any cause. accounts for the power of the computer. Pain medication trials offer a useful analogy: every possible cause of pain does not require its own prospective clinical trial. for example the electron is responsible for googling. depression. In multiple sclerosis and a wide variety of other disorders. and hyperkinetic disorders of any etiology.2 2 0 T hings to K now A bout D eep B rain S timulation Institutional Review Board (IRB) supervision for obtaining informed consent.

their stimulation is nonetheless subsumed under DBS. Though there has been an increase in information concerning the way in which the brain and its elements at varying levels of organization respond to the DBS electrical pulse. DBS is often considered a specific example of neuromodulation. but these are not recommended. a cogent unifying understanding has yet to coalesce. T H E M EC H A N I C S O F D EEP B R A I N ST I M U L AT I O N DBS involves the implantation of electrical stimulating electrodes in various regions of the brain.2). The system is capable of a wide variety of stimulation patterns and strengths that are programmed by a telemetric-like device. As will be discussed later. at least. Electrical stimulation of the spinal cord and peripheral and cranial nerves is also performed for neurological and psychiatric disorders. because the same assumptions and presumptions underlying the current theories are likely to hamper any new theory or.1). The designation “deep” in “Deep Brain Stimulation” reflects the fact that the therapy’s original targets were subcortical. Current DBS involves inserting a long lead through an incision in a patient’s scalp and burr hole in the skull to reach a target in the brain. such as the anterior and posterior commissures and the line that connects them (AC–PC line. each contact measures approximately 1. Figure 1. One approach to subsequently identifying the potential DBS target is to measure specific distances from the anterior-posterior.5 mm in length. Targeting the brain structure to be stimulated is complex (Montgomery 2014). physiology contribute significantly to the failure in understanding of DBS mechanisms of action. medial-lateral. Though such cortical structures as the subgenu cingulum and motor cortex subsequently became potential targets.1. Separated from its fellows by 1.5 mm. One example of a DBS lead is a long insulated bundle of wires sporting four metal electrical contacts placed in a row along the long axis of the lead (Figure 1. its intuitive appeal notwithstanding (Montgomery 2012). current pathophysiological theories and. The extension wire travels beneath the skin to connect to the subcutaneously implanted pulse generator situated over the chest. It is insufficient merely to state that most current theories are incorrect in their implications for the DBS mechanisms. Montgomery 2010. most experts believe that image-guided (MRI or computerized tomography) surgical navigation is insufficient for two . Despite DBS’s remarkable effectiveness. little is known about its mechanism of action. more fundamentally.27 mm in diameter and 1. any serious entertainment of competing alternatives. which includes the other forms of simulation previously mentioned. DBS specifically relates to stimulation of the brain and brainstem. and dorsal-ventral from the midpoint of the AC-PC line. Because exact targets tend not to be visually discernible. What Is Deep Brain Stimulation?3 oscillation in local field potentials. Though there is some disagreement. These latter approaches reflect a one-dimensional push–pull approach to physiology and pathophysiology that is incorrect.) The other end of the DBS lead exits the burr hole and is connected to an extension wire behind the ear. DBS-related research clearly challenges long-held notions of physiology and pathophysiology (discussed in c­ hapter 18). surrogates are detected. It is a process that usually begins with an MRI or computerized tomography scan of the patient’s head. (Note that other DBS leads may have closer spacing.

For example. Though the ability of anatomy-based visual targeting systems to identify the sensorimotor region is uncertain. a sagittal section of an MRI scan showing a DBS lead placed in the vicinity of the subthalamic nucleus. In the United States. In frequent use. however. microelectrode recording of neuronal extracellular action potentials locates the optimal target prior to implantation of the DBS lead. the ability of microelectrode recordings is not. the FDA regulates the interstate commerce of such devices as the DBS system. Because not many people within these institutions are able to conduct a critical review without requesting such a privilege from physicians. . This is particularly important because the targets are physiological rather than anatomical. reasons:  (1)  normal biological variability in the optimal target’s exact anatomical locations and (2) increased variability (error or brain shift) introduced by the surgery itself. subthalamic nucleus. and globus pallidus interna is believed to be the optimal target.1  The DBS lead demonstrating the four electrical contacts. It has yet to regulate. the sensimotor region within the ventral intermediate nucleus of the thalamus. The administrations of institutions where DBS surgery takes place grant privileges and credentials at their discretion to surgeons. the manner in which DBS surgery is performed and prerequisite training of those performing it. Also.4 2 0 T hings to K now A bout D eep B rain S timulation Electrical contacts Figure 1.

Balkanization of health care providers further complicates this issue. limit. does the responsibility fall on a referring physician to ensure a surgeon’s competence? It certainly squares with a neurologist’s expertise to form some professional opinion of a surgeon receiving a referral. In the absence of an effective vetting process for surgeons. and the risk of death. the frequency of DBS lead revision in response to poor outcome.2  Panel A demonstrates an axial MRI scan. The average degree of improvement depends on the condition being treated and the measures taken to treat it. 0. Also seen are the anterior commissure (AC) and the posterior commissure (PC). however. These issues are addressed in ­chapter 19. Note that the terminology “DBS in the vicinity of the subthalamic nucleus” is used . There are frameless alternatives (see Montgomery 2014). An interesting ethical issue is the nature. if not an act of defiance. the risk of serious or permanent complications. As indicated. What Is Deep Brain Stimulation?5 A A R B AC PC Figure 1. 2% or less. which are fiducials in the external frame (shown schematically in B).5%. the risk of an infection necessitating removal of the DBS lead. and extent of the responsibility borne by a physician referring a patient to a neurosurgeon. Treatment of Parkinson’s disease should result in a 50% or greater improvement in the Unified Parkinson Disease Rating Scales and a 50% or greater reduction in medication use in the case of DBS in the vicinity of the subthalamic nucleus. administrations often find themselves granting privileges and credentials to surgeons on the basis of the surgeons’ good word alone. Often the targets for DBS are mapped by their distance from the midpoint of a line that connects the AC and PC. The white indicates one of the white dots. Questioning the ability of any fiefdom’s surgeon may thus be greeted with annoyance. Some general parameters enable one to judge a DBS program. these surgeons often have an inherent conflict of interest. the frame is held in place by four pins that insert into the outer table of the skull.1. Not a few institutions have become embroiled in this conflict. They resolve into veritable fiefdoms. The incidence of any infection around the implanted DBS system should be 4% or less. 2% or less.2% to 0. 2% or less.

The mistake is perpetuated by using the synecdoche. is a necessary prerequisite. there is considerable evidence that it does not (Montgomery and Gale 2008). Most patients continue their preoperative medications. each physician. Effective DBS is a team effort. These criteria necessitate the participation of neurosurgeons. Yet assembling such a team may prove problematic in the face of a paucity of neurologists and psychiatrists trained in postoperative DBS management and particularly in areas remote from the major medical centers that typically implant DBS systems. This is particularly true in Parkinson’s disease. particularly those previously uninvolved in the surgery itself or preoperative patient selection (Montgomery . The term “in the vicinity” is used to note that DBS in the vicinity of the subthalamic nucleus does not imply that the therapeutic effects as well as adverse effects arise from activations of neurons in the subthalamic nucleus. Indeed. Most current indications. therefore. which includes those members assigned postoperative management. it begins—and indeed depends on—effective postoperative management of DBS devices. which have a synergistic effect with the DBS. The most effective outcomes depend on balancing pharmacological and behavioral therapies. subthalamic nucleus DBS. depending on the circumstances. D EEP B R A I N ST I M U L AT I O N I S N OT A N EU R O S U R G I CA L T R E AT M EN T No matter the condition. Optimal postoperative outcomes will require not only accurate placement of the DBS lead and knowledge of programming but also expertise in pharmacological and behavioral therapies (Montgomery 2010). Unfortunately. such as an ability to tolerate the surgery and the presence of preexisting psychological issues. and behavioral therapies. there is the widespread notion that the efficacy of DBS in the vicinity of subthalamic nucleus is synonymous with change in subthalamic nucleus neuronal activities. most neurosurgeons lack the training or experience necessary for determining whether this criterion has been met. one may argue that a fully functioning team. healthcare professionals. In most cases. however. proceeding with DBS surgery may well be unethical. does facilitate desirable outcomes. and. then. Accurate placement by expert neurosurgeons. DBS’s efficiency rarely begins with the implantation of the DBS system. optimal care is typically achieved by managing both DBS and medications or managing behavioral therapies. In the case of movement disorders. and healthcare professional plays a role. surgeon. require as a major selection criterion exhaustion of all reasonable pharmacological and behavioral therapies (if appropriate). Rather. Many misunderstandings have prevented more physicians from involving themselves in postoperative care. The outcome is less assured should team discipline experience any lapses. which often patients may have begun prior to surgery. Without such a team assembled. which may well be incorrect. psychiatrists. medications. Other criteria do exist. I therefore believe that movement disorders neurologists and psychiatrists experienced in DBS should have the primary responsibility for vetting DBS candidates. Indeed.6 2 0 T hings to K now A bout D eep B rain S timulation instead of STN DBS or DBS of the subthalamic nucleus. as well as those expected in the near future. with their DBS. Appropriate patient selection also facilitates desirable outcomes.

Nor does it stand as evidence that safety and efficacy does not exist either. which challenge the capacity to provide DBS therapy. the absence of an opinion by the FDA is not a negative opinion on its use. Lack of federal jurisdiction over Internet-based and telemedicine services. the FDA defines its policies governing off-label use under the title “ ‘Off-Label’ and Investigational Use of Marketed Drugs. Use of a marketed product in this manner when the intent is the “practice of medicine” . however. and various evils followed. many of which are insufficiently developed. The evils in this case are the current healthcare system’s various limitations. it raises the question whether of healthcare provider systems are obliged to change this situation. “If you do not want to treat the disease. Identifying the limitations proves awkward.” At least in some cases. In the box also was hope. On its website. What Is Deep Brain Stimulation?7 2010). T H E I N V ER S E PA N D O R A’S B OX O F D EEP   B R A I N  ST I M U L AT I O N The goddess of Greek mythology Pandora received a beautiful box that she was instructed to leave unopened. Few would disagree with the claim that DBS is underused in treating even those indications approved by the FDA and other countries’ equivalent agencies. is the result. One wonders whether the professional community truly wants to know the nature of the problems plaguing healthcare delivery systems when it comes to providing DBS.1.” Similarly. and Medical Devices—Information Sheet: Guidance for Institutional Review Boards and Clinical Investigators”: Good medical practice and the best interests of the patient require that physicians use legally available drugs. Patients and their family members and caregivers commonly complain of the long delay that often precedes DBS recommendations from physicians. Biologics. much of it perhaps unnecessary. A particularly vexing issue is that of using FDA-approved devices for indications on which the FDA has not ventured an opinion. As Carl Sagan was said to observed. As such. they have the responsibility to be well informed about the product. Though the exact numbers are unknown. making the diagnosis carries with it an obligation to treat the disease. some 15% of patients with Parkinson’s disease are suitable for DBS. and to maintain records of the product’s use and effects. don’t do the test. and a mere 1% of DBS-suitable patients receive it. In human terms. biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling. hinders these efforts. and it therefore has no bearing on issues of safety and efficacy of an approved device’s use. this underuse means patient suffering. to base its use on firm scientific rationale and on sound medical evidence. “The absence of data is not evidence of absence. Efforts are underway to develop Internet-based postoperative care methods that use approaches characteristic of automated expert systems and telemedicine. She violated this command and in so doing released all sorts of evil into the world. and the current patchwork of state jurisdictions. and it was the last thing to escape. It used to be said in medicine. DBS represents something of the inverse of Pandora’s box: Hope was first to issue from it.

Imagine this same patient is admitted to a local emergency room. S O M E E T H I CA L I S S U ES As demonstrated. prospective randomized control trials. citing the Investigational Device Exemption as justification. Clinicians must note the difference between those treatments that are most powerful and those that are simply sufficient. no mention of Deep Brain Stimulation or DBS is made in the Content Blueprint 2013 published by the American Board of Neurology and Psychiatry (2012) for the education of future neurologists. Insurers. but traveling that same distance repeatedly to obtain appropriate postoperative management is inordinately burdensome. Whether a particular patient has symptoms sufficient to warrant consideration of DBS is a judgment call. Thus to render a considered judgment requires addressing the ethical issues. Considerable evidence supports the finding that DBS is more powerful than levodopa and other dopaminergic agonists in treating greatly advanced cases of Parkinson’s disease. A situation involving an extremely rare disorder presents a useful illustration. whose staff are unfamiliar with DBS and its management. under its own authority. moreover. The fact that these exemptions impose a cap. However. Whether or not the data supports the use of DBS for a specific indication is a judgment call. Investigational Device Exemption (IDE) or review by an Institutional Review Board (IRB) [italics added]. with the latter supported by substantial scientific and clinical data. it has yet to receive FDA approval for treating them. creates difficulty in providing continued care once the cap is reached. Patients and their family members and caregivers may be willing to travel to a distant major medical center to have a DBS system implanted. the most vexing questions are how to judge the knowledge thus far gained in order to make decisions relative to the provision of DBS.8 2 0 T hings to K now A bout D eep B rain S timulation does not require the submission of an Investigational New Drug Application (IND). Rather. Such is the case with DBS. the institution at which the product will be used may. What will become of him? Interestingly. The indications for DBS discussed in this textbook are either FDA approved or are considered appropriate off-label indications for FDA-approved devices. Chances are it never will. these questions are decided based on value judgments and value judgments invariably depend on ethical and moral stances. A cursory review of the literature reveals that. Yet postoperative management brings the benefits that justify the surgical risk. require IRB review or other institutional oversight. In the treatment of this disorder. Invariably. however. most of the issues related to DBS have little to do with the technology or knowledge base. though DBS is safe and effective for a wide variety of disorders. The FDA does grant Investigational Device Exemptions to physicians who intend to offer such off-label use to a number of patients. Yet most would consider lack of feasibility an inappropriate justification for denying the patient the treatment. are unfeasible. This issue is discussed at length in the context of DBS for hyperkinetic disorders (­chapter 15). In many patients with . may refuse to reimburse healthcare providers on the basis of the experimental nature of the proposed use. as demanded by Evidence-Based Medicine.

The wide discretion historically afforded to a patient and legal representative is contextual. risk and cost analyses favor pharmacological and behavioral therapies. this situation would require that physicians and healthcare professionals recognize the range of options and have knowledge sufficient for presenting it. Members of the lay group likely do not have the education and experience necessary for adjudicating options. Meeting this obligation is challenging because of the question:  who owns the right to decide whether patients receive DBS? Does the right belong to patients and patients’ family members or caregivers. associated costs (in its widest connotation) rather than power to reverse symptoms and disabilities governed the choice of therapy. then. understood in their widest sense. The issue becomes. Levodopa and other pharmacological agents may be sufficient in providing satisfactory relief from the symptoms and disabilities of Parkinson’s disease. this purpose of this book is to enable meaningful discussion of the DBS option between physicians and healthcare professionals and patients and their family members and caregivers. To expect them to have this education and experience is unfair. inasmuch as it represents a conflict of interest. Indeed. As gatekeepers to treatment options. such discretion often produces economic effects or creates risks. What Is Deep Brain Stimulation?9 Parkinson’s disease. the degree of improvement from the therapy typically . Informed consent also requires that patients or their legal representatives be provided with sufficient information on all available options. if not most. The notion of sufficiency as a guide for therapeutic options is problematic if for no other reason than its epistemological basis. as well as those faced by a physician or healthcare professional (the latter arguably represent the most important practical reasons for signed informed consent). in today’s healthcare delivery climate. thus becomes the first choice. In the disease’s early stages at least. pharmacological therapies had proven insufficient but DBS helped. The explicit or implicit means to determine sufficiency form this basis. In these cases. that is. the acceptance of risks representing the cost function. At the very least. physicians and healthcare professionals may base their medical opinions on certain assumptions and presuppositions that may be incompatible or at least inconsistent with those of patients or their legal representatives. One may argue that failing to discuss alternatives with a patient invalidates her informed consent. These issues are addressed in detail in ­chapter 19. A  physician or healthcare professional treating a patient whose informed consent has thus been invalidated may be guilty of battery. If two alternative treatments are equally sufficient. Physicians and healthcare professionals often assume these economic risks. that of identifying the individual who has the authority and right to judge.1. the option with the least risk and cost. or does it belong to physicians or healthcare professionals? The relationship between physicians and healthcare professionals on one side and patients and patients’ family members and caregivers on the other naturally admits of asymmetry. Yet the bedrock of informed consent is respect for the decision of patients or their legal representatives. Though serious or persistent (irreversible) adverse effects are rare in DBS—estimated to be 3% to 5%—their consequences can be severe. Many. Representing benefit is effectiveness. For practical purposes. it depends on the risks—those faced by a patient. However. clinicians would be shocked merely by having this issue raised. Their doing so may appear ethically suspect. one may cast the risk-to-benefit ratio as an analysis of cost effectiveness.

10 2 0 T hings to K now A bout D eep B rain S timulation in terms of relief from symptoms and disabilities. however. Physicians and healthcare professionals have no way of determining a sufficient degree of relief and the amount patients or their family members and caregivers will pay to realize it. In so doing. neurotransmitters are the messengers. dopamine levels are depleted by more than 99%. Where the effects of DBS on neurotransmitter function have been directly studied. DBS in the vicinity of the globus pallidus interna alleviates them. The DBS–surgical ablation nonequivalence rests on the qualitative difference between . Qualitative differences in behavior associated with DBS and behavior associated with levodopa therapy offer indirect evidence that. the question is whether physicians and healthcare professionals are in a better position to determine the amount a patient or his family member or caregiver will pay in order to gain relief. as in the case of Parkinson’s disease. namely. at least as inferred from the pharmacology. Consequently. 2003). effect of DBS is that of generating antidromic action potentials. that is.” and c is “improved Parkinsonism”). it is not primarily a means of affecting neurotransmitter function. Yet. which affect the excitability of the neuron that gave rise to the axon conducting the antidromic action potential. which may be formally expressed as if a implies c and b implies c. In advanced Parkinson’s disease. while cost is that which is paid in order to realize the benefit. The cost acceptable for gaining a potential of benefit is a value judgment. as described previously. DBS therapeutic effect is not synonymous with neurotransmitter function. overactive subthalamic nucleus neurons. typically in local field potentials in the range of 15 Hz to 30 Hz). it bypasses neurotransmitters altogether (Montgomery 2013). Strenuously argued early theories insisted that the similarity of DBS in the vicinity of the globus pallidus interna to pallidotomy was evidence for mechanisms common to both therapies. reduced activity of the globus pallidus interna.” b is “pallidotomy. Indeed. which is determined by the pattern or electronic neuronal action potentials arriving at the synaptic terminal. Yet no one would suggest that stroke and curare share the same mechanisms. or at least proximal. or excessive high beta oscillations (oscillations in neuronal activities. however. If one presumes that the loss of information attendant on the degeneration of neurons in the substantia nigra pars compacta is mediated by the sensorimotor-related components of the basal ganglia-thalamic-cortical system. The message is contained in the pulsatile pattern of neurotransmitter release. Such reasoning. then a implies b (where a is “DBS in the vicinity of the globus pallidus interna. D EEP B R A I N ST I M U L AT I O N I S R E VO LU T I O N A RY DBS is revolutionary primarily because of those things it does not do. falls victim to the fallacy of pseudotransitivity. Levodopa therapy may cause involuntary movements (dyskinesias). then it stands to reason that the proximate effects are mediated by the putamen. DBS does not directly or primarily target neurotransmitter functions that underlie most pharmacological therapies. DBS is not synonymous with surgical ablation. they are not the message. the removal of such “troublemakers” in the brain as putative overactive globus pallidus interna neurons. it is quite probable that the main. Stroke and curare poisoning both cause paralysis. therapeutic DBS is not associated with changes in dopamine function (Hilker et al. Properly posed.

the discovery of chemical neurotransmission served to diminish this importance. for example. The relevant time scales are such as to prohibit information encoding in the actions of pharmacological agents or surgical ablations. What Is Deep Brain Stimulation?11 the effects of the lesions on the globus pallidus externa that are associated with producing Parkinsonism and the effects of DBS in the vicinity of the globus pallidus externa that improve the symptoms of Parkinson’s disease (Vitek et al. Past concepts of therapies based on pharmacological replacement of depleted neurotransmitters or blocking neurotransmitter receptors do not apply to DBS. This success thus argues for the existence of some novel mechanism of disease affected by DBS that. on the other hand. Montgomery 2013). which is typically hours. Interestingly. In pharmacology-based treatments. whose various respective functions require orchestration (Montgomery 2013). DBS thus represents a new era for neurological and psychiatric therapeutics. which requires prior recognition of the situation. however. One recalls that the primary difference in a therapeutic DBS frequency of 150 pulses per second versus a nontherapeutic DBS frequency of 100 pulses per second is 3 ms or 3/1000th of a second between pulses. Some 160 years after Luigi Galvani established the importance of electricity and electronics in animal behaviors by eliciting them with external electrical stimulation. improve Parkinsonism. may be produced by lesions at multiple loci in the basal ganglia-thalamic-cortical system (Montgomery 2007. or changes in states over time (Montgomery 2007). and surgical ablative treatments. Of the many dimensions commonly occupied by DBS. Montgomery and Gale 2008). perhaps the most fundamental is that of dynamics. Yet the level of information is that at which DBS likely operates (Montgomery and Gale 2008. the time of action likely parallels the duration of action of the medication on brain activities. the second a consequence of the first. Parkinsonism. A person prevents a cup from tipping by grasping it and returning it to its proper position. execution of this behavior requires fewer than 200 ms. DBS at many of these same loci. meanwhile. is not inherently neurochemical. is executed over many different muscles. Past concepts imputed responsibility for disease manifestation (pathophysiology) on specific structures within systems. The time scale of DBS actions is milliseconds. It is intuitively appealing therefore to argue that pallidotomy and DBS in the vicinity of the globus pallidus interna suppresses this troublesome structure. as creating states conducive to generation of more normal information. It bears mentioning that the reasoning behind this equivalence falls victim to the fallacy of pseudotransitivity as described previously. Indeed. DBS succeeds where pharmacological therapies fail. . From the instant information is generated to the instant it is implemented by the muscles. This volitional behavior. initial evidence of chemical neurotransmission arose from an equating of the effects of the chemical acetylcholine on the heart to the effects of electrically stimulating the vagus nerve (Valenstein 2005). in the case of Parkinson’s disease. pharmacological treatments. rather. Surgical ablation. is static. Current theories. Patterns of neuronal activities are an example. posit a causal relationship between overactivity of the globus pallidus interna and dopamine depletion associated with Parkinson’s disease.1. 2012). Yet these concepts did not precede DBS conceptually. the cause (pathoetiology) notwithstanding. DBS is revolutionary because it has no conceptual antecedents. Pharmacological agents and surgical ablations must be viewed.

Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in Parkinsonian humans. it provides unparalleled opportunities for insight into brain function and dysfunction.18(1):41–48. Cooper et al. The remarkable benefits yet their uneven application raises serious concerns about distributed justice and the responsibilities and obligations of individual physicians and healthcare professionals. A remarkable and revolutionary therapy. It must suffice at present to note that widespread failure to appreciate the importance of dynamics owes to a lack of a need to do so—a lack with a history that reaches back to Aristotle and includes such noted neuroscientists as John Hughlings Jackson and Sir Charles Sherrington. These leaders posited the dynamics in nature generally and the brain specifically as one-dimensional push–pull systems (Montgomery 2004). Many reasons exist for this inattention. 1980). Amsterdam: Elsevier. Neurosurg Focus. In: Hitchcock ER Jr. DBS promises to change the lives of patients living with movement disorders. is to generate normal movements. Mov Disord. IL:  American Board of Psychiatry and Neurology. as inferred from abnormalities of movement. Ghaemi M. Deep brain stimulation for hyperkinetic disorders. Realization of this promise depends on knowledgeable physicians and healthcare professionals who remain committed to helping their patients.12 2 0 T hings to K now A bout D eep B rain S timulation Before the advent of DBS for psychiatric disorders in 1979 and movement disorders in 1980. et al. 2004. R EFER EN C ES American Board of Psychiatry and Neurology. Reversibility of chronic neurologic deficits:  some effects of electrical stimulation of the thalamus and internal capsule in man. Similarly.43(3–5):244–258. Ballantine HT. Meyerson BA. 2012. eds. Montgomery EB Jr. Cooper IS. Voges J. Upton AR. Dieckmann G. Chronic mediothalamic stimulation for control of phobias. If the basal ganglia’s role. Indeed. Modern Concepts in Psychiatric Surgery.17(1):E1. its promise extends to Obsessive Compulsive Disorder and other psychiatric indications. Buffalo Grove. 2003. Being thus novel. Appl Neurophysiol. 1979:85–93. S U M M A RY DBS is a therapy like no other. . its revolutionary nature provides challenges to clinical use. Its mechanisms of action cannot be subsumed by any antecedent conceptual approach such as from anatomy or pharmacology. Amin I. Indeed. Certification Examination in Neurology 2013 Content Blueprint. a few researchers had noted the importance of dynamics (Dieckmann 1979. Hilker R.. but full discussion of them lies beyond the scope of this chapter. DBS may require a change in the mode of thinking of which nonsurgeons are unaccustomed. then the fact that so little work has been done on its necessary dynamics is puzzling.

Zhang J.32(3):388–407. Practice and Cases. Montgomery EB Jr. Biologics. Ann Neurol. Front Integr Neurosci. Olanow CW. Goetz CG.fda. Montgomery EB Jr. Kordower JH. Montgomery EB Jr. Neurophysiology. and Medical Devices—Information Sheet. Nonlinear Studies. “Off-Label” and Investigational Use of Marketed Drugs. 2003. 2012. eds. In:  Tarsy D. 2008. Montgomery EB Jr.11:385–421. 2013:258–280. The Handbook of Parkinson’s Disease. . 2013: 3–19. Neurostimulation: Principles and Practice.. et  al. Dynamically coupled. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Turkstra LS.1.gov/ regulatoryinformation/guidances/ucm126486. Montgomery EB Jr. 2014. In Pahwa R. Chichester: John Wiley & Sons. eds.54(3):403–414. The epistemology of deep brain stimulation and neuronal pathophysiology. high-frequency reentrant. In: Ejamel S. Exp Neurol. J Med Speech Lang Pathol. Slavin KV. 2004. Okun MS.233(1):581–58.13(8):455–465. Deep brain stimulation: mechanisms of action. Neurosci Biobehav Rev. Evidenced based medicine: let’s be reasonable. Basal ganglia physiology and pathophysiology:  a reappraisal. Thalamic deep brain stimulation for other tremors. What Is Deep Brain Stimulation?13 Montgomery EB Jr. 2005. New  York:  Humana Press. Lyons KE. http://www. 2007. Mechanisms of action of deep brain stimulation (DBS). 2003. Deep Brain Stimulation Programming:  Principles and Practice. New York: Columbia University Press. New  York:  Oxford University Press. Vitek JL. Deep Brain Stimulation in Neurological and Psychiatric Disorders and Psychiatric Disorders. Hashimoto T.6:78. Starr PA. eds. Gale JT. Intraoperative Neurophysiological Monitoring for Deep Brain Stimulation:  Principles.11:ix–xii. Montgomery EB Jr. Vitek JL. Montgomery EB Jr. 2012. Montgomery EB Jr. Oxford: Oxford University Press. et  al. Parkinsonism Relat Disord. non-linear oscillators embedded in scale-free basal ganglia-thalamic-cortical networks mediating function and deep brain stimulation effects. 2008:215–228. 2010.htm Valenstein ES. Boca Raton: CRC Press. Montgomery EB Jr. External pallidal stimulation improves Parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network. US Food and Drug Administration. The War of the Soups and Sparks: The Discovery of Neurotransmitters and the Dispute over How Nerves Communicate.

such as medically intractable seizures for two years despite use of three first-line anticonvulsants. or excessive neural oscillations in the low beta frequencies. However. indeed in some cases curative. there should not be any difference in the decisions each framing produces. particularly if DBS is viewed as just another way to affect neurotransmitters. a form of paternalism called soft paternalism (Beauchamp and Childress 2013). but historically this has not been the case. Framing DBS as the most effective therapy reserved only because of surgical risks makes DBS an active consideration from the start. Ideally. The underreferral is despite well-established guidelines. there is a worldwide underreferral for epilepsy surgery (Uijl et al. the importance of emphasizing opportunity can be seen from what is called the framing problem. resulting in prolonged.2 Why Deep Brain Stimulation? T H E F R A M I N G PR O B L EM Why Deep Brain Stimulation (DBS)? The answer is opportunity—the opportunity to help patients when all else fails. unsuccessful pharmacological management (Erba et al. Among the reason for not referring patients—particularly patients thought appropriate by experts—physicians argued that the patient’s seizure burden was insufficient and thus did not discuss the potential for surgery. Framing DBS as something that one defaults to. In an Italian study. 2012). has parallels in epilepsy surgery. 2012).” While perhaps subtle. as an underutilized safe and effective therapy. fails to distinguish DBS from pharmacological treatments. When framed as something to be considered in the setting of failed pharmacological therapy. Despite the long history of successful epilepsy surgery. Consider the statement “DBS can be used when all reasonable alternatives fail” compared to “DBS is the most effective therapy and is only held in reserve because of surgical risks. The situation of DBS. The differences may be seen in thresholds for each decision. overactivity of the globus pallidus interna. . it fails to emphasize the value of DBS in its own right and may result in an inappropriate reticence to recommend DBS. This reasoning could just as well describe the attitudes of many neurologists to DBS. physicians who did not refer expressed less positive expectations for outcomes and viewed surgery as the last resort. the differences in connotation are significant. One might argue that the opportunities are obvious at least for conditions recognized as safe and effective by the US Food and Drug Administration or by scientific data in the case of “off-label” uses.

The influence of pathophysiology theories on acceptance of therapies is seen in the resurgence of interest in DBS in the late 1980s. For example. Valldeoriola et al. as the evidence suggests that DBS is not mediated by its effects on dopamine (Hilker et  al. was used for psychiatric disorders in 1979 (Dieckmann 1979) and for movement disorders in 1980 (Cooper et al. as currently practiced. 2003) for which DBS has been called upon to control. but the same issues are relevant for brain disorders in general. it is interesting that stem cell dopamine replacement therapies should find such favor over DBS. yet DBS. Nothing about EvidenceBased Medicine explains DBS’s superiority. powderized kitchen sink porcelain was shown better than placebo at relieving a certain disease’s symptoms. Dams et al. As is discussed later in this chapter. 2013). 2007. At least with respect to risk. Evidence-Based Medicine can test claims as to why DBS is better. This theory posited overactivity of the globus pallidus interna as a consequence of dopamine depletion. The overactivity was thought to cause suppression of neuronal activity with the . Alternative therapeutic approaches that do not clearly demonstrate an intuitive relationship with the putative pathophysiological mechanisms do not appear to gain traction with physicians and healthcare professionals. If. it was the resurgence of interest in pallidotomies that paved the way for DBS. many patients with fetal dopamine cell transplants for Parkinson’s disease develop runaway dyskinesia (Olanow et al. The delay did not await new technologies or new realizations of the need for surgical therapies. Further. then anyone who endorses Evidence-Based Medicine must also endorse powderized kitchen sink porcelain. justifies confidence in dopamine replacement therapy. these are greater than DBS. Randomized controlled trials can demonstrate that DBS produces greater changes in some measures but cannot explain why or how the treatment relates to the pathophysiology. for example in the number of penetrations of the brain in order to deliver therapy. for example. Even randomized controlled trials appear to be unconvincing. specifically the Globus Pallidus Interna Rate theory. 1980). 2003). I M P O R TA N C E O F PAT H O PH YS I O LO GY Notions of pathophysiology are critical to acceptance of therapies that are thought to address the pathophysiology. 2005. Certainly. Rather. the notion that Parkinson’s disease is a dopamine deficiency.2. DBS provides an opportunity to reexamine many of the assumptions and presumptions affecting the presumptions and assumptions operative in acceptance of therapies by physicians and healthcare professionals. such as by oral agents and stem cell transplants. These issues play out most clearly in Parkinson’s disease. DBS provides better symptom relief than pharmacological treatments for many disorders. The resurgence of interest pallidotomies was because of the development of a theory that had explanatory power. but it cannot generate the hypotheses that constituted claims. even if false. Also. Why Deep Brain Stimulation?15 DBS provides an opportunity to decrease healthcare costs by demonstrating less cost than medical therapy in patients with Parkinson’s disease (Meissner et al. notions of pathophysiology plays a significant role in acceptance of new therapies. The presumption that Parkinson’s disease is a dopamine deficiency state may prejudice physicians and healthcare professionals against DBS. For example.

A second example involves a case in which 130 pulse per second (pps) stimulation proves effective. is at least on the order of tens of minutes. as inferred from the clinical response. for example the development of DBS for minimally conscious states. characteristic of pharmacology may hinder a greater understanding of DBS’s mechanisms of action. Radioisotope displacement studies using Positron Emission Tomography imaging demonstrate that therapeutic DBS does not increase dopamine release in the basal ganglia (Hilker et al. thus placing therapeutic advances in jeopardy. Notions of pathophysiology and physiology (the latter often derived from inverse reasoning from the former) will be important in the future development of DBS. dopamine pharmacologically administered through its prodrug. 2003). then. The blood levels of levodopa increase immediately after administration. Also. DBS provides significant incremental benefit in cases in which dopaminergic pharmacological agents are maximized—with medications or fetal cell transplant. at least.16 2 0 T hings to K now A bout D eep B rain S timulation ventral oral posterior thalamus and subsequently in the motor cortex. These issues are addressed in ­chapter 20. The dynamics of levodopa therapy presents a useful example. Rather. The onedimensional push–pull dynamics. but it enabled the resurgence of interest in DBS. Such is not likely to be the case with dopamine—or. DY N A M I C S DBS is not simply another means of affecting neurotransmitters. Thus the falling out of favor of the Globus Pallidus Interna Rate theory did little to dampen acceptance of the notion of Parkinson’s disease as a dopamine deficiency state. and have a half-life of approximately 90 minutes (though the half-life of brain response. There is a move to evaluate DBS from a physiological rather than anatomical perspective by seeing DBS as a positive intervention. This theory has since been proven wrong. but 100 pps stimulation proves ineffective. may be considerably longer early in the disease). peak approximately 30 minutes after administration. Whatever mechanisms underlie DBS’s therapeutic effect thus operate on a time scale that is on the order of milliseconds. The dynamics of the levodopa effect. The difference in the interstimulus pulse interval is on the order of 3 ms. Most applications of DBS have replicated previous ablations preceded from the assumption that DBS is equivalent to surgical ablations. a presumption that has been proven incorrect. levodopa (a prodrug is an agent other than the primary agent that is . The dynamics of DBS are different. for example. the relative excess or deficiency of neurotransmitters that excite or inhibit. DBS produces in patients with Parkinson’s disease some effects that are the converse of levodopa.000th of a second. Dynamics refers to changes in state (the nature of the system under consideration) over time. or 3/1. Such benefit would be unlikely if DBS produced a dopamine-like effect. The Globus Pallidus Interna Rate theory was derivative of the concept of Parkinson’s disease as a dopamine depletion state. Parkinson’s disease treatment makes readily apparent the difference between DBS and pharmacological therapies.

Pharmacologically administered dopamine and cell transplant–administered dopamine’s respective time courses do not begin to match the naturally occurring time course. Dopamine neurons are normally phasic:  they precisely modulate the release of dopamine over the course of a few hundred milliseconds (Figure 2. More important than constant application of electrical energy by DBS. One may argue that the continuous application of electrical pulses differs little from continuous application of dopamine by fetal cell transplantation or other means. This increase lasts a few hundredths of a millisecond. .1). The dynamics in the pathophysiology clearly operate on a time scale that pharmacological agents cannot match. This is correct. But DBS can match it. The raster shows the relative time of occurrence of each neuronal spike as a dot. These same issues arise for Essential tremor. and other movement disorders. dystonia.2. It is thus highly unlikely that pharmacological applications of dopamine will be able to replicate the normal dynamics of dopamine neuron physiology (with permission (Schultz and Romo 1990)). however.1  Peri-event raster and histogram of the neuronal activity (assessed by recording extracellular action potentials [spikes]) of a dopamine in a nonhuman primate trained to perform an arm movement in response to a cue. fault lies with the manner in which the dopamine is replaced. At baseline. dopamine neurons are extremely inactive. Why Deep Brain Stimulation?17 transformed into the primary agent by metabolism). Reward predicted Reward occurs CS R Figure 2. and each row of dots shows the neuronal activity over the multiple trials. One may argue that in the cases of pharmacological or cell transplant repletion of dopamine. The histogram shows average neuronal activities over multiple trials. The dynamics of DBS are discussed more fully in c­ hapter 18. are the aforementioned pulses occurring at millisecond intervals. What controls the precise modulation of dopamine by the substantia nigra pars compacta? It is the integrated electrical activities that fall on individual substantia nigra pars compacta neurons. but they dramatically increase their firing in response to a cue to make a movement. rather than over the uncontrolled hours required by pharmacologically administered dopamine or the years required by cell transplant–administered dopamine.

is different than the mechanisms that cause the behavioral (motor) abnormalities. as therapeutic DBS must be affecting those mechanisms. Because a critique of reductionism is beyond the scope of this discussion. DBS. 2011). such conflation of pathoetiology and pathophysiology may explain the greater favor for dopamine cell replacement therapeutic despite its much more problematic nature and doubts about whether such therapies can attain the efficacy and safety of current DBS techniques. particularly the external segment. Parkinsonism has been associated with lesions of the globus pallidus. which may account for the failure of DBS’s wider adoption. is not mediated by dopamine yet it reverses at least some pathophysiological mechanisms which are unlikely to involve dopamine. It is hard to see how stem cells will fare any better than the failure of fetal dopamine cell transplant and much enthusiasm must stem from preoccupation with pathoetiology rather than pathophysiology. Conceptually what does it mean to say that pathoetiology and pathophysiology are not synonymous? It implies that there is some “mechanistic” distance between the proximate consequences of dopamine cell loss in the substantia nigra pars compacta and the eventual changes in orchestration of the activities of motor units (the combination of muscle fibers and their innervating lower motor neuron in the brainstem and spinal cord). This proves an opportunity to intervene at those sites proximate to abnormal motor unit activity that are independent of mechanisms proximate to dopamine cell degeneration. Loss of dopamine attendant on degeneration of neurons in the substantia nigra pars compacta relates to the pathoetiology. This is evidenced the fact that virtually all the same abnormalities of motor unit activity. There is another level where conflation of pathoetiology and pathophysiology is problematic. because conflating the two leads to the mistaken notion that correcting the pathoetiology is the best way to affect the pathophysiology and thus improve the functional disability. Increasingly. as described. it must suffice to . the paradigm of pathoetiology as pathophysiology. The bias in favor of treatments directed more at pathoetiology than pathophysiology rests on this mistaken notion.18 2 0 T hings to K now A bout D eep B rain S timulation C O N FL AT I O N O F PAT H O E T I O LO GY A N D PAT H O PH YS I O LO GY Using DBS for Parkinson’s disease as the archetypical example to consider DBS in a wider context. at least as far as Parkinson’s disease is concerned. ventral oral posterior thalamus (the relay nucleus of the basal ganglia output to the cortex). pathophysiology. therapies addressing the pathoetiology have been successful but not completely and certainly not to the extent that therapies addressing the pathophysiology have. namely. Thinking according to this paradigm reduces science to more elemental notions. producing the same symptoms and signs as those associated with dopamine cell depletion. and the supplementary motor area (Montgomery et al. The mechanisms proximate to abnormal motor unit activity are distant from those proximate to dopamine cell degeneration. can be produced by lesions not involving dopamine neurons. it is clear that there is a dissociation between the mechanisms that cause idiopathic Parkinson’s disease. is a second factor. Pervading physicians’ thinking. Clearly. Differentiating between pathophysiology and pathoetiology is important. the pathoetiology (the term “pathogenesis” is not specific enough). these elemental notions are viewed as molecular. Indeed.

on the other hand. Directly comparing DBS. it is not simply a matter of which is most efficacious and has the fewest side effects. as a more general domain encompassing neuropharmacology. by the same token. Why Deep Brain Stimulation?19 suggest that studying Complex Systems theory offers insight into the pathoetiology as pathophysiology paradigm’s shortcomings. Indeed. Rather. DBS surgery. because one gains the sense that DBS and neurochemistry. and now molecular. Indeed. Pharmacological treatments therefore remain treatment mainstays. It has its origin in the early 1940s. (Discussion of these issues appears in subsequent chapters. when it was shown that pharmacological agents applied to the heart produced the same response as did stimulating the heart’s vagus nerve (Valenstein 2005). which is the real appeal of reductionism. When applied to a consideration of DBS’s remarkable effect in the face of pharmacological treatments’ failure. pharmacological treatments are potentially reversible and relatively safe—though there does exist a risk of levodopa dyskinesia in patients of Parkinson’s disease. each has its disadvantages as well. and other therapies is problematic. and caregivers and the patient’s general state of health.) One ought not consider simultaneously DBS and pharmacological therapies. who argued that explaining behavior requires a conception of networks. a demonstrated failure to respond to all reasonable pharmacological approaches is a main criterion for candidacy for DBS surgery. pharmacological. Suffice it to say that blame for this way of thinking belongs to Santiago Ramón y Cajal. consideration must be given to many other factors. the functional demands on the patient. (That which constitutes a reasonable approach is discussed later. are not synonymous. Further confusion is sown by the notion that understanding a single synapsing neuron is sufficient to understand neurophysiology. Also. family members. a discussion of this topic is beyond the scope of this writing. DBS in Parkinson’s disease cases decisively recommends itself—provided no consideration is given to surgical risk. mechanistic accounts over electrical preceded the present era of molecular neurobiology. however.2.) . in other words. Again. This observation engendered two influential notions: (1) synaptic transmission is chemical in nature. Each therapy has its advantages. This notion is known as the Neuron Doctrine. Complex Systems theory thus shatters the reductionist’s hope that an organism may be reconstructed from fundamental molecular mechanisms. S U M M A RY Judgment requires balancing pharmacological and surgical approaches. Consequently. But. these notions come into question. such as a risk of side effects (permanent as opposed to reversible). According to Complex Systems theory. mathematical and other systems reducible to fundamental functions and axioms are capable of unpredictable behavior. His ideas should have ceded to those of Camillo Golgi. because due deliberation must always end in a preference for the latter. A bias favoring pharmacological. carries a risk of irreversible complications. and (2) neurochemistry is synonymous with neurophysiology. if for no other reason than that of the risk attending DBS surgery. None of the foregoing discussion is meant to disparage pharmacological approaches to movement disorders treatment.

Volkmann J. Walker HC. Deep brain stimulation in late stage Parkinson’s disease:  a retrospective cost analysis in Germany. Cooper IS. 2013. though outmoded. 2003.20 2 0 T hings to K now A bout D eep B rain S timulation This book seeks to establish that the field of DBS is fraught with misunderstanding.28(6):763–771. Schreiter D. if for no other reason than that given by father of modern physiology Claude Bernard. Dieckmann G. 1990. et al.53(1):35–43. because knowing an idea or claim’s origin is often as important as knowing an idea or claim itself. et al. Childress JR. 1962]). Uijl SG. High-frequency deep brain stimulation of the putamen improves bradykinesia in Parkinson’s disease. Epilepsia 2012. judgment—the application of reason and wisdom—is required. Upton AR. Siebert U. The Structure of Scientific Revolutions [Chicago: University of Chicago Press. 1980. Mov Disord. J Neurophysiol.63: 607–624. Romo R. Modern Concepts in Psychiatric Surgery. Huang H.54(3):403–414. Ghaemi M. et  al. Barriers toward epilepsy surgery: a survey among practicing neurologists. et al. and a new generation grows up that is familiar with it” (quoted in T.252(2):218–223. New  York:  Oxford University Press. 2003. Cost-effectiveness of deep brain stimulation in patients with Parkinson’s disease. Amsterdam: Elsevier. Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans. Montgomery EB Jr. . Mov Disord. “It is what we think we know already that often prevents us from learning. 2005. outdated. Kordower JH. This owes to the fact that important questions concerning it are poorly framed and thus met with poor answers. et  al.43(3–5):244–258. Beghi E. Goetz CG. 2011. Kuhn. et al. Reversing this legacy will be difficult. Dams J.101(3):210–216. and counterproductive. Epilepsy Res. Ballantine MBA.S. Moja L. Moons KG. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. In the final analysis. 2013. “A new scientific truth does not triumph by convincing its opponents and making them see the light. but rather because its opponents eventually die. Hilker R. Schultz W.. who wrote. 2012.” One hopes are that such reversal does not come to pass according to the process described by Max Planck.26(12):2232–2238. Voges J. Mov Disord. Yet the requisite wisdom presupposes active and genuine meta-reflection on possible error. Erba G. J Neurol. Ann Neurol.. Olanow CW. R EFER ENCES Beauchamp TL. Principles of Biomedical Ethics. et al. Epilepsy surgery can help many more adult patients with intractable seizures. Bornschein B. eds. who observed. In: Hitchcock ER Jr. Chronic mediothalamic stimulation for control of phobias. Amin I. continues to influence thought about it. Reversibility of chronic neurologic deficits:  some effects of electrical stimulation of the thalamus and internal capsule in man. Appl Neurophysiol.18(1):41–48. Dopamine neurons of the monkey midbrain:  contingencies of response to stimuli eliciting immediate behavioral reactions. It also suffers a legacy that. Meissner W. Leijten FS. 1979:85–93.

Prospective comparative study on cost-effectiveness of subthalamic stimulation and best medical treatment in advanced Parkinson’s disease.2.22(15):2183–2191. New York: Columbia University Press. Why Deep Brain Stimulation?21 Valenstein ES. et  al. 2005. Tolosa E. Valldeoriola F. . Mov Disord. 2007. Morsi O. The War of the Soups and Sparks: The Discovery of Neurotransmitters and the Dispute over How Nerves Communicate.

for example. the issue is simply that of demonstrating an effect that justifies further evaluation. In the case of an early study. less than 5% are being referred. T H E FACTS The Measures The first consideration is that of determining a measure and its means of application for improvement or worsening following DBS for Parkinson’s disease. Its complexity is reflected in the fact that different physicians may look at the same data and come to different conclusions. Examples of the latter include a choice between open-labeled studies and blinded studies.3 Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease J U D G I N G EFFECT I V EN ES S Deep Brain Stimulation (DBS) is remarkably effective for the treatment of Parkinson’s disease. At any rate. It is difficult to explain the large variance and referral bias according to published facts that attest to DBS’s remarkable efficacy and safety. it may be best to conduct an open-label study in which a patient acts as her own control may be reasonable prior to more controlled. a choice between prospective studies and retrospective studies. the consensus of most experts is that DBS is underutilized. and the composition of any control or comparison group. it is estimated that. Indeed. Each has its particular advantages and disadvantages. Something else is obviously operating under the surface. . prospective studies. Some physicians readily recommend patients for consideration of DBS surgery. the effectiveness of DBS is a complex calculation. The primary concern in the early study is a type II error in which an effect of a treatment (assuming here beneficial) is missed and a prospective treatment abandoned. although 15% to 20% of patients are candidates for DBS. others seldom do. Early in the development of a new therapy. However. which must be considered in the context of specific goals.

The rationale is that the experimental and control groups will experience the same number of enrolled subjects with confounding problem A.” Yet RCTs’ numerous weaknesses make their application to clinical decisions highly problematic (Montgomery and Turkstra 2003). and “on with dyskinesia. (4) quality of life measures. Subjects actually enrolled in an RCT often have little in common with those individuals in the general population for whom the treatment was intended. hypertension may confound studies of stroke prevention. Confounding problem A thus affects both groups to an equal or nearly equal degree. The RCT provides no means by which to determine the effect of the confound so that it may aid the care of the individual patient (see discussion in ­chapter 15 regarding population statistics and the Second Law of Thermodynamics). Evidence-Based Medicine based on RCTs has become the “gold standard. which is determined by use of part 2 of the UPRDS. However. (5) a patient’s global perspective. Consequently. Included among the measures are the following examples:  (1)  symptom-based assessments as the motor examination of the Unified Parkinson Disease Rating Scales (UPDRS). A  potential difference is that the subjects studied were substantially different from those to whom the treatments were applied in general use. each measure is unique in terms of advantages and disadvantages.” which means that the primary symptoms have improved but the patient is manifesting some limiting side effect.) Again. The greatest disadvantage lies in the fact that the means that render RCTs possible to begin with—increasing statistical power and controlling for confounding factors. and (7) such a specific and perhaps ad hoc criterion as a patient’s being “off” and maximally symptomatic.3. as evidenced by many treatments that have been modified or outright abandoned following RCTs consequent to post–US Food and Drug Administration approval experience. as assessed according to such a measure as the Hohen and Yahr scale. thereby cancelling each other out. for example—limit the possible generalization to an individual’s optimal treatment. (6) global perspective of a patient’s caregiver. the hope is that randomization will result in as many patients with hypertension in the experimental group as are in the control group. (3) degree of gait and balance involvement. this discrepancy between RCT results may vary greatly from actual use in practice. Original descriptions of Evidence-Based Medicine included a range of different types of evidence and did not necessarily include value judgments as to the priority of the different levels. A wise physician or healthcare professional integrates from the diverse measures to establish an approach best suited to an individual patient. . the involuntary movement is dyskinesia. (2) a functional assessment as the ability to carry out activities of daily living. an individual patient simultaneously has and does not have hypertension. 6)  a physician or healthcare professional’s global perspective. For example. The former include strict inclusion criteria. (In this last example. “on” insofar as many primary symptoms have improved. which typically involve prospective studies whose subjects and evaluators are blinded to the experimental condition. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease23 Evidence-Based Medicine has become an important standard for interpreting facts in the interest of improving medical care and has become synonymous with randomized controlled studies (RCTs). RCTs depend on randomization to counterbalance confounding issues that cannot be controlled by elimination according to strict enrollment criteria. Indeed.

Note that the term “in the vicinity of” a specific structure is used to emphasize that the therapeutic effects have little to do with the target in which the DBS lead is implanted (Montgomery and . (2)  presumption of greater objectivity.3% improvement in the motor UPDRS at six months between patients receiving DBS in the vicinity of the subthalamic nucleus being off or on while the patient was off medications. is sufficient to meet a patient’s needs. These discussions indicate how physicians and healthcare providers are to view and interpret the range of available facts. and healthcare professionals (Deep-Brain Stimulation for Parkinson’s Disease Study Group 2001). It reviews. however. T H E S A L I EN T ST U D I ES The discussion to follow offers no extensive review of the literature on the efficacy of DBS for Parkinson’s disease. Other studies reviewed are to illustrate various principles that may guide future studies and their interpretation and implementation in the care of patients. The specific surgery was selected by a patient’s treating physician.24 2 0 T hings to K now A bout D eep B rain S timulation The most typical are symptom-based measures due to (1) similarity to the types of evaluations routinely performed by physicians and healthcare professionals. The presumption is that control of the symptoms. a minimal amount of rater interpretation. may not predict quality of life. From a motoric perspective. Published in 2001. 2006). The study demonstrated a 51. and (3)  customary use of the degree of symptoms as that which most concerns physicians and healthcare professionals. because sole reliance on RCTs may not be in patients’ best interests. Yet most appear to depend on the emotional or psychological response to a disorder and its treatment on the part of a patient or her family member or caregiver. (3) on medications and off DBS. and they argue for a consideration of the full range of facts. An example of the difficulties in choosing the proper measure is observed in patients whose motoric symptoms have greatly improved but whose quality of life has not. These measures were taken under the following four conditions: (1) on medications and on DBS. Another measure was the duration of a presumably good state. a number of studies that are particularly important in assessing current efficacy. that is. Physicians and healthcare professionals must choose or weigh more heavily those measures they think most germane to a patient’s situations. Patients underwent DBS in the vicinity of the globus pallidus interna or subthalamic nucleus DBS but were not randomized. It was written by the Deep Brain Stimulation Study Group. specifically. surgeons. patients’ needs have increasingly been interpreted in terms of quality of life. Some of the major findings were based on a symptomatic measure—the motor examination of the UPDRS. directly or as a marker of benefit. one of the first major studies appeared in the New England Journal of Medicine. Attempts to assess a patient’s needs is observed in the use of measures based on the degree of dependence for performing activities of daily living. However. (2) off medications and on DBS. DBS in the vicinity of the subthalamic nucleus may be a success even if the patient and family are worse off (Schupbach et al. Even these measures. Measures therefore exist that attempt to define quality of life. a consortium of physicians. as well as the needs of her family member or caregiver. rather. (4) off medications and off DBS. “on” but without dyskinesia taken before and after the incorporation of DBS. namely.

Conversely. . in which all available data is collected and analyzed according to the group to which patients were originally assigned. The response to this criticism is that patients with advanced Parkinson’s disease are essentially “off” their medications a great percentage of the day.8%. some experts consider the assessment of symptomatic improvement with DBS while the patient is off medications. Originally designed to avoid possible biases resulting from data censoring for incomplete data or protocol violations. if by being “off” it is meant that the symptoms returned despite the fact that medication was taken. this situation is analogous to the intention-to-treat analyses of clinical trials. given the study treatment. despite the fact that the difference was significant statistically or. Thus it is reasonable to believe that the difference in the DBS effect off medications is germane to the 49% of the waking day where patient would have been off without DBS. intention to treat may better reflect the population efficacy of the treatment in general use.8% difference did not appear to be significant clinically. Perhaps these observations justify the use of DBS by demonstrating a direct benefit immediately attributable to DBS rather than the medications. there have a number of prospective controlled studies demonstrating similar findings (Weaver et al. Though a purely utilitarian argument is occasionally made as to whether proven placebos should be used clinically. in the case of the control group. Some have argued that comparison with the stimulation on and off in the medication off condition is not really relevant. the degree of improvement following DBS while off medications is relevant. however. a context in which some (perhaps many) patients will be noncompliant. In the condition of medications on. Their proving to do so may be analogous to a philosophical position that any treatment must be better than placebo. the improvement with the stimulator powered on was 25. at the very least. Although these findings are relatively irrelevant to clinical judgment on efficacy. even if some patients were noncompliant or. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease25 Gale 2008). The exception was the Veteran’s Affairs cooperative study. Consequently.8% improvement while on medications. Since the paper by the DBS for Parkinson’s Disease Study Group.3. Similar findings were obtained with DBS in the vicinity of the globus pallidus interna: off medications in such cases showed a 44. most clinicians reject it. The benefits of DBS in the vicinity of both the subthalamic nucleus and the globus pallidus interna. These critics hold that the comparison between the stimulator powered on and powered off during the on medication conditions that is most relevant. provided one recognizes that purely clinical benefit alone cannot differentiate a priori the mechanisms of any treatment from those of a placebo. The percentage of waking hours in the off condition was 49% prior to DBS in those patients whose subthalamic nucleus was targeted comparted to 19% with DBS on. the attractiveness of this assessment may relate to the presumption that assessment off medications more clearly demonstrates the effects of DBS.3% and a 26. which demonstrated a lesser degree of benefits. Both were statistically significant. There was similarly a reduction of off time from 37% to 27% with DBS in the vicinity of the globus pallidus interna. because patients usually continue to take medications. The unspoken criticism is that the 25. In some ways. that it justified the expense and risks of the surgery. because most patients are not off medications. Greater weighting of the improvements while on medications and DBS is most relevant to judgments of clinical efficacy in that this condition enjoys ecological validity with respect to an individual patient. 2009).

therefore. To claim that were the non-RCTs accepted as evidence it would be somehow less valid than evidence obtained by RCTs leaves unestablished the latter’s a priori superiority. These studies consistently demonstrate greater symptomatic improvement than those brought about by best medical therapies. failure of medical therapy was an enrollment criterion. Substantial evidence exists to encourage confidence in the conclusion that DBS. clearly” may claim that the previous studies. Is it important to ask whether a comparison between DBS and best medical therapy has been made. do not constitute evidence. Perhaps the most significant act would be to blind patient and raters. have demonstrated validity and reliability in other blinded studies.” The very idea of comparing DBS to best medical therapy belies a mode of thinking. which were not RCTs. the question becomes whether DBS is better than the best medical therapy. and quality of life in patients with Parkinson’s disease. One may reasonably assume that these patients did receive best medical therapy. More important. One asks whether the considerable expense of the subsequent RCTs was justified. functional disabilities. One wonders whether there could be other. Most of these studies also involved experts in the treatment of Parkinson’s disease. In addition. however.26 2 0 T hings to K now A bout D eep B rain S timulation were statistically significant. In those early studies. that this validity is sufficiently different from the validity established in the case of DBS. This reason recalls the reason Sir Edmund Hillary gave for scaling Mount Everest: “Because it was there. C O M PA R I S O N TO PH A R M AC O LO G I CA L T R E AT M EN TS The decision to offer DBS surgery depends on alternatives. improve motor symptoms. for example. Several prospective randomized studies have compared DBS in the vicinity of the globus pallidus interna and the subthalamic nucleus to best medical therapies (Weaver et al. The phrases “sufficiently important” and “sufficiently different” raise questions as to that which is denoted by “sufficiently” and the way one measures it. It may be argued that this question was already answered in the DBS for Parkinson’s Disease Study Group study and other initial studies (Deep-Brain Stimulation for Parkinson’s Disease Study Group  2001). Presumably RCTs are conducted because they had not previously been conducted. Perhaps the funds devoted to those RCTs could have been put to better use. The argument may be made that subsequent RCTs merely replicated at great expense that which was already known (Weaver et al. less expensive ways to rule out the placebo effects—prolonged observation. One would have to argue. in the vicinity of both the subthalamic nucleus and the globus pallidus interna. because to do so would be to mitigate placebo effect and expectation bias. 2009). UPDRS and other such measures. 2009). Those who would answer “Yes. “Sufficiently” in this case means that an anticipated result justifies the efforts required to determine it. in the event that it has not yet been made? What is the presumed or anticipated consequence of making such a comparison? Is the situation such that if DBS was . which typically focused on medications. In this case. I disagree with that claim. quality of life and other outcome measures have demonstrated statistically significant improvements. should money be spent to make it.

on the other hand. serious adverse effects from DBS are possible. However. then the issue of delaying DBS is not a serious one. If the time required to determine whether best medical therapy is insufficient would subject the patient to excessively prolonged disability. Though the overall rate of adverse effects after six months of DBS is less than those randomized to best medical therapy (Weaver et al. caution is required in the interpretation of the reported facts as to adverse effects. It is therefore unlikely that DBS would win priority over medical therapy. such as experiencing adverse effects. 2009) cannot directly answer this question. methods of healthcare delivery system that limit every decision to adjust medications to the traditional three. The reasonable approach would be to determine the probability that DBS will be sufficient. 2009). The latter are commonly deemed less detrimental. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease27 demonstrated more effective than best medical therapy. If best medical therapy can be achieved in a reasonable period of time. First. may be irreversible. The former are considered errors of commission and the latter errors of omission. such thinking is outmoded (see ­chapter 19). This latter circumstance illustrates that there are risks to undergoing DBS and risks to not undergoing DBS. The risks of not undergoing DBS are the adverse effects of suboptimally treated Parkinson’s disease—falls. Some may argue that it may be more effective to take patients to DBS surgery earlier rather than prolong the disabilities while pursuing best medical therapy. If one assumes that the potential patient has exhausted all reasonable attempts at medications and failed to achieve satisfactory control.to six-month follow-up is likely to excessively prolong the process. or at least more nearly sufficient. Certainly. Patients who have exhausted all reasonable attempts at medications have no alternative except that of continued disability. Ethically speaking. Note that the Veteran’s Affairs–National Institutes of Health cooperative study (Weaver et al. the issue is how adverse effects are defined. The issue is not whether DBS results in greater improvement in the UPDRS. Some physicians and healthcare professionals feel that it would be worse were they to recommend DBS surgery and an adverse effect to arise than were they not to recommend DBS and the patient experience a serious complication for the poorly treated Parkinson’s disease. Again. then the problem lies with the clinician and not the therapy. for the patient for whom the best medical therapy is insufficient. however. Some surgery-related adverse effects. A DV ER S E EFF ECTS Improvements must be considered in the context of the possible price to be paid. patients would be routinely be offered DBS as first choice? Though rare. the potential effectiveness of DBS should be considered in the context of the available alternatives. subjecting the patient to DBS because of a healthcare systematic failure to optimize medical therapy efficiently and in a timely fashion appears to run counter to medicine’s proper purpose.3. the adverse effects of medications are typically reversible. for example. It is whether DBS produces sufficient benefit for an individual patient in whom medical therapies have failed. In many clinical trials the definition of adverse effects is the definition devised by the US Food and Drug Administration: “An adverse event is any .

” (http://www. interpreting the literature is problematic because of the nature of adverse events reporting in clinical trials. risks may be conceptualized as those risks associated with the surgical procedure—infection. Given that these putative adverse effects are easily reversible and indeed. involves side effects consequent to unintentional spread of stimulation current to adjacent structures. production of paresthesias owing to spread of stimulation current to the medial lemniscus that courses behind the subthalamic nucleus is routinely produced during postoperative DBS programming. or changes in impulse control may have . Some effects of stimulation may be quite adverse. if a DBS surgery results in poorly placed electrodes owing to failure to prevent intracranial air and subsequent displacement of the brain (Montgomery 2010). In Parkinson’s disease and particularly with DBS in the vicinity of the subthalamic nucleus. The last risk includes a special risk I refer to as the “tyranny of partial benefit. it does not seem reasonable to call them adverse effects with the consequence of causing undue concern. Such spread of electrical stimulation may produce tonic muscle contraction. against the incremental benefit that might be gained. Unfortunately. Indeed. However. sudden changes in mood. these side effects are frequently encountered. either euphoria or depression. bleeding. For example. however. albeit typically slight. often purposefully produced. The judgment of effectiveness must also include assessments of risks. The question is whether spread of current should be considered an adverse effect. This issue of what constitutes an adverse effect is seen in the Veteran’s Affairs Cooperative study.” The benefit in DBS is directly proportional to the severity of the symptoms to be treated. the risk of these effects were reported as undifferentiated adverse effects. for example. which would require repeat surgery. In the situation of DBS in the vicinity of the subthalamic nucleus. it does not appear that the conduct of the clinical trials allowed for this distinction. These side effects may be relieved with adjustments to the stimulator. or seizures. If the incremental benefit is considered as insufficiently justifying the risks. The subsequent decision whether to revise the poorly placed DBS lead must weigh the risk. a patient is confined to the partial benefit obtained. This reduction may be related to finally establishing an optimal DBS electrode configuration and stimulation parameters. an unsophisticated clinician might be misled by reports of high complication rates associated with DBS. The incremental benefit is less because of the partial benefit achieved by the first DBS system.htm). during the course of routine postoperative DBS programming. which is the same as the initial surgery.28 2 0 T hings to K now A bout D eep B rain S timulation undesirable experience associated with the use of a medical product in a patient.gov/safety/medwatch/howtoreport/ucm053087. and. the reported initial risk of adverse effects at six months were resolved in 99% of cases. the patient may experience only a partial benefit. one cause of adverse effects. This is yet another example of how the structure of clinical trials limits the utility of their results to the management of patients as part of routine care (Montgomery and Turkstra 2003). at times purposely. Greater preoperative disability means a chance at much greater benefit. such as a spread to the corticospinal tract in the posterior limb of the internal capsule. For example.fda. Risks are associated with the act of stimulation. In the case of DBS. consequently. for example—and the risk of lead misplacement.

most studies can quantitate various outcome measures. and deaths have occurred with a risk of 0. It is not clear how many physicians and healthcare professionals have gained the wrong impression. The risk of sudden stimulator failure is often directly proportional to the degree of benefit. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease29 serious consequences. but there are likely to be a few. I  recommend checking the battery on a weekly basis from the start in order to establish a habit.3. Probability of detection may be assessed using Bernoulli-type statistical studies. Thus should a DBS system fail. Prevention of failure is therefore the best medicine. Also. is mild to moderate. there is little or no medication to compensate. It must therefore figure in the overall assessment of the risk–benefit ratio. the probability of detection is related to the frequency these problems appear. As many of these nonmotoric effects are not constant but episodic. As with any medical intervention. Clinical trials of DBS have shed light on the nonmotoric aspects of Parkinson’s disease following DBS—issues of impulse control and suicide. the frequency at which these potential problems were clinically assessed. Adequate surveillance may mitigate the risks of DBS. it is important that they have the device used for checking the battery with them. one of the most consistent cognitive complications directly relatable to DBS surgery is a reduction in verbal fluency. such as a broken electrical wire or sudden loss of power to the implanted pulse generator. however. . these complications may have been more prevalent in the DBS clinical trials because study design necessitated closer scrutiny. The problem is that long battery life leads to complacency. in the sense that greater benefit often is associated with greater reduction in concurrent medications. however. there are risks. for example. The degree of clinical impairment. DBS surgery carries risks of irreversible or significant complications on the order of 1% to 3%. Not doing so risks misrepresentation. This may owe to battery exhaustion or failure to recharge the implanted pulse generator for those patients who have been implanted with a rechargeable system. Clearly. For these issues. Yet interpreting them in light of clinical meaning is highly problematic. Patients accordingly suffer. for the patients and their family members or caregivers to be able to check the battery. it is unclear whether DBS was actually associated with an increased risk of these complications or whether these would be otherwise present by virtue of the disease regardless of the DBS.2%. For the duration of follow-up. This risk should be low. the frequency at which they are assessed (sampling rate). Attempting to restore medications to compensate is problematic because the time required to re-establish the medications prohibits it. These adverse effects may often be relieved by adjustment of the electrode configuration or stimulation parameters (Montgomery 2010). if physicians and healthcare professionals educate patients and patients’ family members/caregivers in how to check battery status. and the duration of observation. Another source of risk is the sudden failure of the system to provide therapeutic stimulation. For example. If the side effects described from inadvertent spread of electrical stimulation to adjacent structures prevented the titration of stimulation to produce therapeutic benefit. which to my knowledge have not been conducted. The frequency and quality of risk assessments also has to be determined in light of their prevention or reversibility. There can be a sudden stimulation failure due to hardware failure. the side effects are appropriately described as adverse effects and therefore constitute risk.

30 2 0 T hings to K now A bout D eep B rain S timulation R ED U CT I O N O F M ED I CAT I O N S Many patients with Parkinson’s disease do well from a motoric perspective with medications but are unable to tolerate effective doses. but even this is complicated by the mechanisms by which the long-term savings are realized and by whom (Tomaszewski and Holloway 2001. particularly DBS in the vicinity of the subthalamic nucleus. The initial insurer may not directly reap the benefit for the investment of surgery while a subsequent insurer may. 2013). this is a relatively minor issue because most long-term studies have demonstrated long term benefits (Rodriguez-Oroz et al. the stimulation may control the dyskinesia and allow the patient to be treated medically with greater aggressiveness. One approach is to assess the respective economic consequences of doing and not doing DBS. PH A R M AC O EC O N O M I C C O N S I D ER AT I O N S Medical decisions are increasingly being taken out of the hands of individual patients and their physicians or healthcare professionals. Admittedly. Shan et al. however. Studies demonstrate the cost benefit of DBS surgery over the long term. Valldeoriola et  al. 2005. The benefit of DBS may be increased by corresponding reduction in medications allowed by successful surgery. Dams et al. For example. for example. . Valldeoriola et al. In the case of DBS for Parkinson’s disease. 2007. The insurer of the initial surgery may not realize the return on that investment before the patient moves on to another insurer. It is not clear. that initial insurer may realize the return when another patient becomes a client of the insurer and had DBS done previously. then all parties would benefit in the long term. and. This issue will become central in DBS for other conditions. One of the benefits of DBS is reduction of medication-induced side effects following successful DBS surgery. In a healthcare system in which patients change insurers every few years. if every insurer were to provide for DBS. However. at least in the case of DBS in the vicinity of the globus pallidus interna. a patient may experience very good symptomatic control with medications but be unable to tolerate the hallucinations and delusions that resolve when the medications are reduced. 2013. The clinician clearly does not wish to subject a patient to the risks of DBS surgery if the benefit will be short-lived. such as DBS in the vicinity of the thalamus DBS for cerebellar outflow tremor in patients with multiple sclerosis. long-term concerns are more problematic. Meissner et  al. D U R AT I O N O F B EN EFI T The duration of benefit is a critical question. whether such rationale is typically implemented by insurers. 2012). 2011. Again. How a patient may be treated is increasingly determined by those entities that pay for the treatment— private and governmental agencies. DBS allows for control of dyskinesias. This also is the case for patients who do well with symptomatic control but develop disabling dyskinesia. for example.

and who should provide the postoperative care. but one cannot delegate responsibility. have little value in themselves alone. Therein lies the problem. One can delegate authority or choose not to exercise it. It would seem that the implicit responsibility physicians have for their patients would obligate them to refer to a reasonably competent surgical team. One is epistemological. Though such studies are highly problematic to conduct. A N D PR OV I D I N G T H E  P O STO PER AT I V E CA R E DBS surgery is complicated by any measure. Yet there appears to be little consensus of how to place the DBS lead. responsibility means that they must have a sound understanding of that which may be optimally achieved by DBS and of whether the surgical team and those providing postoperative care may reasonably achieve the optimum. At the least there appears to be consensus that it is important to place the DBS lead in the sensorimotor region of the subthalamic nucleus. It is presented in this manner because enumerated statistics. This is evidenced by the relative paucity of patients actually referred for DBS. In order to achieve any clinical meaning. What is clear is that making the decision is not a responsibility that can be avoided. prospectively proven methodologies. The balkanization of healthcare delivery and the restrictive constraints on patients certainly limits the prerogatives of the latter to maximize their utility as far as healthcare expenditures are concerned. Further. Referring physicians or healthcare professionals may delegate the authority by virtue of referring strictly within their healthcare provider network in the belief that they may avoid responsibility with respect to the competence of the neurosurgeon and to the managers of the healthcare provider network. This variance is worsened by the lack of well-substantiated. and ventral intermediate nucleus of the thalamus. For referring physicians. Admittedly. and the clinician is left to make a decision that is based on reason. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease31 C O M PE T EN C E O F T H O S E S EL ECT I N G PAT I EN TS. the complexity is evidenced by the controversies in the literature regarding who and when should be selected. There is not even agreement as to how one might develop a consensus about how to place the DBS lead. FACTS A N D A D D I T I O N A L FACTO R S The following discussion is more from a conceptual perspective rather than an enumeration of the various outcome measures and incidences of adverse effects. the complexities usually mean that there is likely to be significant variance in the skills of the physicians and healthcare professionals involved. At the very least. It is . Yet it is unclear how often they are used. there are basic principles that can and should provide guidance (Montgomery 2010). it is not clear how patients may simply be asked to wait. I M PL A N T I N G D B S SYST EM S. however “reason” is defined. the statistics must be placed in context. The epistemic (how facts come to be known) and ontological (what those facts are) implications do not obviate the need to make decisions. Epistemology deals with how one knows that which one purports to know. globus pallidus interna. and the other is ethical. There are at least two necessary contexts. how the surgery should be done.3. such as those discussed previously.

2011). and motor cortex (the latter two considered “off-label” use of an FDA approved device). The severity of the intracerebral hemorrhage is a function of the volume or extent of the hemorrhage. This continuum must be divided into slow. zona incerta (Khan et al. normal. The second perspective is ethical because the questions of benefit and risk require at least two pieces of knowledge. however. DBS in the vicinity of the subthalamic nucleus appears to have the consensus as being the most effective. in which an error of commission (referring a patient for surgery) outweighs an error of omission (not referring a patient). ventral intermediate thalamus. This notion of Omission bias is outmoded. A physician or healthcare professional’s notion of nonmalfeasance may be affected by omission bias. Outcome measures are typically continuous—the speed of movements. is on the order of 1% to 2%. globus pallidus interna. 2012). This calculation is made more problematic by the occasionally opposing ethical principles of a patient’s (or a patient’s legal surrogate’s) autonomy and the principle of nonmalfeasance (refraining from causing harm). because the decision must be made whether to operate or not to operate. and putamen (Huang et al. A patient alone knows how much risk she is willing to face. The different targets demonstrating clinical benefit in large-scale studies are discussed first. for example. those include the subthalamic nucleus. This is very much like comparing apples to oranges. because it does not bear on the patient’s ultimate quality of life (see ­chapter 19). The first is the necessary dichotomization of data situated on a continuum (see c­ hapter 13 for an extensive discussion). which the statistics of outcome measures and incidence of adverse effects cannot answer. because they may vary in the benefits and risks (direct surgical risks excepted). or fast. The primary evidence for this is fact that early clinical trials demonstrated greater improvement in the motor UPDRS with DBS in the vicinity of the subthalamic nucleus compared to the vicinity of the globus pallidus interna . pedunculopontine nucleus. Currently. Alternatively. physicians and healthcare professionals must recognize that they cannot possibility know the extent to which a patient’s disease affects quality of life. Incidence of symptomatic hemorrhage. Incidence of intracranial hemorrhage is consistent across disease indications and targets. 2014). Patient or their surrogates cannot force a physician or healthcare professional to do something that the latter would consider malfeasance. The second piece of knowledge is how to compare benefit to risk so as to know what ratio can be dichotomized into either too little or sufficient benefit relative to the risk. The symptoms relate to the regional anatomy although with respect to weakness related to involvement of the corticospinal tract is close to all of the targets with the possible exception of the putamen. Also demonstrating benefit in experimental or anecdotal studies are the globus pallidus externa (Vitek et al.32 2 0 T hings to K now A bout D eep B rain S timulation therefore important to understand the source of some measures used to assess benefit and risk and to assess their validity in judging benefit and risk. The risk of an intracerebral hemorrhage is on the order of 10% based on postoperative neuroimaging. D EEP B R A I N ST I M U L AT I O N TA R G E TS There are a number and perhaps increasing targets for DBS in Parkinson’s disease. which particularly bear on physicians.

thereby creating a greater inducement to reduce medications. DBS in the vicinity of the globus pallidus interna directly reduces dyskinesia and thereby may reduce the inducement to reduce medications. Early studies (Deep Brain Stimulation for Parkinson’s Disease Study Group 2001) demonstrated statistically significant improvement in posture and gait scores within the motor UPDRS with subthalamic nucleus stimulation and not statistically significant difference with stimulation of the globus pallidus interna. This may only mean that if there was a difference it could not be found. The implication was that DBS in the vicinity of the subthalamic nucleus addresses a wider range of symptoms and is therefore clinically superior. The proper question regards demonstrating inferiority or noninferiority of one group vis-à-vis another. Clinical studies have been inconsistent in demonstrating no difference in cognitive problems between DBS of the two structures. because the effects of DBS of the two structures on medication-related dyskinesia render it so. It is therefore not clear that the greater improvement with DBS in the vicinity of the subthalamic nucleus reflected overall increases in experience and skill that benefited those latter patients who predominantly had DBS in the vicinity of the subthalamic nucleus. patients were not randomized to the subthalamic nucleus or globus pallidus interna. or when there was a difference. If the sample size was sufficient—an 80% probability of demonstrating a difference of p <. Such demonstration requires a very different approach (Wellek 2010). Comparison between the associated medication reductions between DBS in the vicinity of the subthalamic nucleus and the globus pallidus interna may be taken as an indication of the relative efficacy with the presumption that greater medication reduction will occur with use of the more powerful treatment.05. Subsequent studies in which patients were randomized to DBS either in the vicinity of the subthalamic nucleus or the globus pallidus interna did not demonstrate any statistically significant differences. This is problematic. however. The more appropriate test is to determine what a meaningful difference between DBS in the vicinity of the subthalamic nucleus and globus pallidus interna would be and then estimate the power based on this difference and the variance determined in the study. However. There does appear to be a consensus that DBS in the vicinity of the globus pallidus interna is associated with fewer cognitive complications than DBS in the vicinity of the subthalamic nucleus. Such a conclusion may reflect a type II error rather than any truly existing difference. Those patients who underwent DBS in the vicinity of the globus pallidus interna tended to be done earlier in the study compared to those who had DBS in the vicinity of the subthalamic nucleus. if dyskinesia is a major factor. despite the fact that the mean (or median) changes are different between the experimental and control group.3. however. A possible explanation is that the subthalamic nucleus . Yet DBS in the vicinity of the subthalamic nucleus initially may cause an increase in dyskinesia. for example—then it may be concluded that DBS in the vicinity of the subthalamic nucleus and globus pallidus interna effects are equivalent relative to the motor UPDRS (Wellek 2010). This is problematic. because failure to demonstrate a statistically significant difference is not synonymous with the claim that there is no difference. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease33 (Deep Brain Stimulation for Parkinson’s Disease Study Group  2001). the incidence of cognitive problems were less with globus pallidus interna DBS. A study may fail to demonstrate a statistically significant difference as a consequence of variability in the outcome measures.

44 (Montgomery 2012). Their other symptoms were minimal. Other structures are under consideration for the treatment of Parkinson’s disease. although the experience thus far makes definitive recommendations problematic. the potential effects of DBS in the vicinity of the thalamus on speech. As such it makes avoiding nonmotor (limbic and cognitive) regions of the subthalamic nucleus more difficult than is the case with the globus pallidus interna. . The effect of DBS in the vicinity of the thalamus on the symptoms other than tremor cannot therefore be excluded. Yet this may not be accurate. Parkinson’s disease is a systems disorder whose pathophysiology results from altered physiology of the entire basal ganglia-thalamic-cortical system. Nevertheless. inasmuch as it concerns the context of using microelectrode recordings for target localization. the fact that DBS of virtually any structure within the basal ganglia-thalamic-cortical system may improve Parkinson’s disease argues that Parkinson’s disease is not the consequence of a disorder in any single component— the globus pallidus interna. especially for gait and postural problems. Some have argued that unilateral DBS in the vicinity of the thalamus may be very effective in patients with unilateral and sever tremor. militates against the use of DBS in the vicinity of the thalamus. Current theories suggest the opposite. The problem is that the symptoms are unlikely to remain only tremor. because clinical evidence suggests that it may help with gait and upper extremity function. The relative differences in efficacy and adverse effects between DBS in the vicinity of the subthalamic nucleus and the globus pallidus internal must be taken in the context of the technical requirements of placing the DBS lead. There is clear evidence that thalamic DBS improves the tremor of Parkinson’s disease. However. assuming the patient has idiopathic Parkinson’s disease as opposed to other conditions such as Essential tremor or dystonic tremor. because most patients subjected to DBS in the vicinity of the thalamus were selected predominantly on account of their tremor. Conspicuously absent in the discussion is DBS in the vicinity of the thalamus DBS. In one study.34 2 0 T hings to K now A bout D eep B rain S timulation is a more compact structure. The number of penetrations by the same group in globus pallidus were at least 3 penetrations in order to define the posterior limb of the internal capsule (unpublished observation). particularly in patients with bilateral disease who may need bilateral DBS in the vicinity of the thalamus. It is interesting that. In my opinion. If the DBS in the vicinity of the subthalamic nucleus fails to improve gait and posture. In a patient with significant gait and postural disturbance. the DBS in the vicinity of the subthalamic nucleus may be the initial choice. the number of microelectrode penetrations to reach the physiologically defined optimal target in the subthalamic nucleus was 1. 2011). DBS in the vicinity of the globus pallidus interna is technically more complicated than DBS in the vicinity of the subthalamic nucleus. Perhaps most discussed is the pedunculopontine nucleus. Khan et al. then DBS in the vicinity of the pedunulopontine nucleus may be considered. The presumption is that DBS in the vicinity of the thalamus is less effective for other symptoms such as bradykinesia. stimulating virtually anywhere within the basal ganglia-thalamic-cortical system improves the symptoms of Parkinson’s disease. for example. DBS in the vicinity of the pedunculopontine does not appear to be very effective for upper extremity function (Stefani et al. 2007. To date. Rather. notwithstanding the fact that for some targets experience is too meager to recommend clinical use.

Montgomery EB Jr. 2001. et  al. Br J Neurosurg. Bornschein B.27(11):1387–1391. Cost-effectiveness of deep brain stimulation in patients with Parkinson’s disease. Acta Neurol Taiwan 2011. Montgomery EB Jr. Chan LY. et al. et al. Stefani A. Volkmann J. Neurosci Biobehav Rev. 2010. give rise to adverse effects. Watts RL. Microelectrode targeting of the subthalamic nucleus for deep brain stimulation surgery. S U M M A RY DBS in the vicinity of the subthalamic nucleus or globus pallidus interna is effective and relatively safe. 2011. Deep brain stimulation in late stage Parkinson’s disease:  a retrospective cost analysis in Germany. Effects of deep brain stimulation frequency on bradykinesia of Parkinson’s disease. Deep Brain Stimulation Is Effective for Patients with Parkinson’s Disease35 Because DBS anywhere within the system is efficacious. Deep Brain Stimulation Programming:  Principles and Practice.11:ix–xii. 2014.29(2):203–206. Mechanisms of action of deep brain stimulation (DBS). Krack P.25(2):273–280. Lozano AM. Outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with Parkinson’s disease. et  al. It may well be that some targets have few adjacent structures that..130(Pt 6):1596–1607. Huang H. Khan S. Deep-Brain Stimulation for Parkinson’s Disease Study Group. Mov Disord.32(3):388–407. Brain 2007. Cost-utility analysis of Parkinson’s disease. when stimulated. et al. Mooney L. DBS is a reasonable option. Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology 2006.28(6):763–771.345(13):956–963. Indeed. Montgomery EB Jr. Schupbach M. Most adverse effects are related to unintended stimulation of structures adjacent to the main target. 2012. Mov Disord.20(1):65–72. In patients who have exhausted all reasonable attempts at medication therapy. 2008. Long-term outcomes of surgical therapies for Parkinson’s disease. The surgical risks while significant are infrequent. Plaha P. Welter ML. 2005. Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. it appears unreasonable not to consider DBS. . The putamen is a possible example. 2013. Rodriguez-Oroz MC.3. R EFER ENCES Dams J. Mov Disord. J Med Speech Lang Pathol. Gargiulo M. 2012. Peppe A. Oxford: Oxford University Press. Schreiter D. Montgomery EB Jr. et al.66(12):1811–1816. clinical decisions are based on motor-adverse effects. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. Evidenced based medicine: let’s be reasonable. Gale JT. Siebert U. Turkstra LS. N Engl J Med. Meissner W. J Neurol.252(2):218–223. DBS provides greater improvement and causes fewer long-term side effects than best medical therapy.. Mov Disord. Montgomery EB Jr. Shan DE. 2003. Moro E.27(14):1718–1728. Wu HC.

Weaver FM. Cost analysis of the treatments for patients with advanced Parkinson’s disease:  SCOPE study. Hashimoto T. Vitek JL.301(1):63–73. 2010. et al. J Med Econ 2013. Mov Disord. 2007.233(1):581–586. External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network. et  al. et al.36 2 0 T hings to K now A bout D eep B rain S timulation Tomaszewski KJ. Puig-Peiro R. JAMA 2009. Stern M. et  al. Zhang J. Morsi O. Holloway RG: Deep brain stimulation in the treatment of Parkinson’s disease: a cost-effectiveness analysis.57(4):663–671. 2012. FL: CRC Press. Boca Raton. Wellek S. Prospective comparative study on cost-effectiveness of subthalamic stimulation and best medical treatment in advanced Parkinson’s disease.16(2):191–201. Puig-Junoy J. Tolosa E. Valldeoriola F. Valldeoriola F. Exp Neurol. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Testing Statistical Hypotheses of Equivalence and Noninferiority. . Neurology 2001.22(15):2183–2191. Follett K.

only the extremes are easily recognized. Yet there is something appealing to dealing with dichotomized criteria rather than grappling with data on a continuum. presuppositions. . When consideration reaches to discussion among surgeons. “The first set make the . Thus the criteria often take the appearance of a checklist. One tendency is to also dichotomize the otherwise continuous criteria. for example. is continuous. Appreciation that the decisions are not nearly so neat is lost. The question is where to draw the line in the continuous range so that the dichotomous decision can be made. However. unless the purpose is to “cherry-pick” so as to have the best outcomes. The decision to offer Deep Drain Stimulation (DBS) is a dichotomous variable with only two conditions. a range of disabilities. While generally there is relatively little contention when the best patient presents. either recommend or not recommend. and limits of supporting data. this would be a violation of the obligation to beneficence and justice to those who are on the edge of candidacy (see c­ hapter 19). typically. but the real issue in patient selection is not identifying the best patient.] have two modes of explanation.4 Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Parkinson’s Disease T H E L E AST AC C EP TA B L E? The title seems counterintuitive. In a continuum. and healthcare professionals. and a range of cognitive involvement. and this has driven conceptualizations since Aristotle and his notions of the contraries. . the discussion reveals the epistemic nature of the information or data on which decisions are based compared to the nature of the decision. Patients have a range of responsiveness to levodopa. the discussion often exposes the means of reasoning. wherein each criterion is described as present or absent.” Aristotle wrote. physicians. More important. the challenge is when the less than perfect patient who has failed all other hopes at relief presents for consideration of DBS. The data on which the decision is made. “The physicists [.

Yet understanding the primary care physicians’ and healthcare professionals’ respective roles is nonetheless important. particularly medical science. At least 5% of patients diagnosed with Parkinson’s disease are likely to be misdiagnosed (Newman et  al. The second set. Movement disorders specialists usually do not initiate the selection process.S EL ECT I O N C O N T E X T Patient selection should be considered within the context of healthcare care delivery systems. Admittedly. For example. the selection process often begins with the primary physician or healthcare professional who fields the first mention of a complaint referable to Parkinson’s disease. It is an irony that it is precisely the advance of science. no DBS recommendation is likely to issue from a patient’s initial visit. Indeed. 2009). as described previously. according to Aristotle. a number of door-to-door community surveys found that 24% to 42% of subjects with Parkinson’s disease. Now these are contraries which may be generalized into ‘excess and defect. Not only is this unfair to patients. Extrapolation suggests considerable numbers of patients are not being offered the potential benefits of DBS. but it is a disservice to nonexpert physicians and healthcare professionals who are expected to be the gatekeepers for access to DBS. consist of “contrarieties [that] are contained in the one and emerge from it by segregation” and that also produce “other things from their mixture by segregation” (Aristotle 2001). ultimately. whom the survey sought to identify. Aristotle dismissed the second set. Indeed. This reflects a failure of the healthcare delivery system’s primary care services. The appeal of dealing only with the best candidates or noncandidates by defining criteria applicable to only the best or unacceptable candidates is understandable. if for no other reason than their already few numbers are dwindling. It was the outrageous actions of medical scientists that culminated in the Belmont Report that established ethical supervision for the conduct of human research (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979). Even within science there has been a discussion of whether science must be value free (Douglas 2009). had gone undiagnosed (cited in de Lau and Breteler 2006).38 2 0 T hings to K now A bout D eep B rain S timulation underlying body one—either one of the three or something else which is denser than fire and rarer than air—then generate everything else from this. Perhaps one source of cognitive discomfort is the realization (explicitly or implicitly) that. the decision on where to draw the line is a value judgment that immediately entails ethical concerns. These ethical concerns seem out of place in medicine that has been invaded by scientism since the late 1800s. while other patients may be inappropriately subjected to the risks of DBS surgery because of being misdiagnosed with Parkinson’s disease. and obtain in multiplicity by condensation and rarefaction. some of the most vociferous objections to the publication of the Code of Ethics by the American Medical Association in 1847 were the academic physicians who believed that scientific advances would make ethical concerns obsolete. It is not reasonable to heap upon the .’ ” (Aristotle 2001). that has generated even more ethical concerns and the relevance of addressing them. T H E PAT I EN T.

” This is a form of argumentum ignorantium. while the criteria that formed the basis of the sequent recommendations were for research. The subsequent recommendations are for clinical care. who may in turn refer her to a movement disorders neurologist. The question becomes: on what basis was the clinical criterion prohibition based on cognitive problems made? It certainly is not based on reasonable experience with DBS in patients with cognitive problems. offer an extensive and evenhanded analysis of possible selection criteria. the two criteria are fundamentally different given their intent. Lang and colleagues (2006). it is taken that preexisting cognitive problems represent unacceptable risk. A primary care physician may refer a patient to a general practice neurologist. as did the clinical research trials. “The absence of evidence is not evidence of absence. complications. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease39 many demands already borne by primary care physicians and healthcare professionals the additional responsibility of being movement disorders experts as well. At the very least. Some considerations focus on the epistemology behind the reigning criteria. In truth. for example. as Carl Sagan was said to say.4. Suspicion of Parkinson’s disease represents the first selection criterion. Current clinical recommendations exclude patients with any cognitive problems. that is. for example—increased . which is but the first of several. and other aspects of experience with DBS. as the experience excluded those patients. Yet they drew much of the data informing their analysis and subsequent recommendations from publications reviewing benefits. Evidence suggestive of either criterion offers sufficient grounds for referring a patient to the next level of expertise. or arguing from ignorance. therefore. However. When constructing a system of DBS patient selection. applied the Core Assessment Program for Surgical Interventional Therapies in Parkinson’s disease and found that 1. A typical example is the issue of preexisting cognitive problems. for example. Yet that is precisely the effect of most published selection criteria. physicians or healthcare professionals must address the problems attending their initial fateful decision. the recommendations are circular because the patients whose response to DBS provided the basis for the recommendation had been previously subjected to prior selection criteria. It is clear that selection criteria may exert a significant influence. There is thus no way to know how the previous selection criteria might skew the current recommendations. Application of criteria of greater flexibility—a higher age limit of 75 years. There is no data on the effects of DBS on patients with preexisting cognitive problems. The following discussion distills various considerations of some of the more problematic criteria. as the actual use of such criteria implies a high level of movement disorders sophistication. and insufficient symptomatic benefit with a Parkinson’s disease diagnosis represents the second. EPI ST EM O LO GY O F S EL ECT I O N C R I T ER I A Several publications treat the matter of selection criteria. Morgante and colleagues (2007).6% met the DBS in the vicinity of the subthalamic nucleus consideration criteria. as described in the following. the basis on which rest the claim or inference informing a criterion rather than a criterion’s particular content.

(3) lack of any cognitive deficits that limit subsequent benefit despite improvement in motor symptoms. (2) multisystems atrophy (MSA). Talmant et al. . (2)  exhaustion of all reasonable medication options. however. Each criterion is discussed in the following. (4) surgery tolerance. If the relaxed criteria were more appropriate. Reason demands that the cutoff in use be adjusted to provide the best balance between the consequences. (5)  normal pressure hydrocephalus. which is discussed extensively in the Preface). 2014). diagnosis of idiopathic Parkinson’s disease. Test sensitivity is determined by the percent of patients with the disease who test positive. Lambrecq et al. and specificity is the percent of persons without the disease who test normal. which may be any one of the following criteria: (1) diagnosis of idiopathic Parkinson’s disease. typically increases the risk of false negatives and vice versa. (3) progressive supranuclear palsy (PSP). No perfect test for diagnosing idiopathic Parkinson’s disease exists. One may thus adjust the number of false positives relative to the number of false negatives by adjusting the cutoff of the diagnostic measures. Chou et al. then adhering to the previous strict criteria would result in a significant number of patients being denied DBS inappropriately. 2003. involves but is not limited to the following syndromes: (1) idiopathic Parkinson’s disease. (6)  drug-induced parkinsonism. Positive predictive value and negative predictive value depend on the sensitivity and specificity of the test. or neuroimaging. and (8) Kuff’s disease or another rare neurodegenerative disorder. Diagnosis of Idiopathic Parkinson’s Disease The first criterion. Measures of the effectiveness of diagnostic tests are understood as positive predictive value (the probability that a positive test actually indicates the presence of the disease) and the negative predictive value (the probability that a negative test actually indicates the absence of the disease).40 2 0 T hings to K now A bout D eep B rain S timulation that number to 4. diagnostic measures demonstrate overlap between idiopathic Parkinson’s disease and such conditions as MSA and PSP. In addition to the specificities and sensitivities. (7) Wilson’s disease. or (5) adequate postoperative management. Greatest proximity to actual provision of surgery determines the ultimate selection criterion. 2004. An understanding of any diagnostic procedure’s epistemic basis is important. Whether tests are derived from patient history. physical examination. prior probabilities—the prevalence of the disorder—are combined to produce the positive predictive value and negative predictive value (both are based on Bayes theorem. of a false positive or a false negative diagnosis. 2008.5%. Zhu et al. Most selection criteria are therefore directed at minimizing the risk of performing DBS on patients with other-than-idiopathic Parkinson’s disease. 2006. failed to improve or worsened their symptoms (Tarsy et  al. as experience has shown in most cases. Currently indicated for idiopathic Parkinson’s disease. The existing imperfect test faces significant risk of producing false positives and false negatives. DBS in patients with other-than-idiopathic Parkinson’s disease. Reducing the number of false positives. or differential diagnosis of Parkinson’s disease according to its clinical manifestations. in the widest sense. (4) vascular Parkinson’s disease.

4. they may gain some benefit. Furthermore. The criteria have to be such that not too many patients with MSA or PSP are mistakenly sent to surgery and not too many patients with idiopathic Parkinson’s disease are denied surgery and its subsequent benefit. Yet in a situation in which the population is 80% patients with idiopathic Parkinson’s disease and 20% patients with MSA or PSA. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease41 One must bear in mind the practical consideration that a number of different diagnoses of Parkinson’s disease vary according to the consequences of either misdiagnosis (that of Parkinson’s disease in patients who in fact have a different disease) or missed diagnosis. then 16 of the 20 patients with MSA and PSA would receive a correct diagnosis and thus avoid ultimately ineffective surgery. If the consequence is levodopa prescription. For every one patient with MSA or PSA who is protected from ineffective DBS. If the consequence is DBS surgery. Is this ratio acceptable. This raises the ethical issue of the number of patients with idiopathic Parkinson’s disease who go without a potentially life-changing treatment relative to the number of patients without idiopathic Parkinson’s disease who receive it. As the consequences vary under different circumstances. moreover. particularly as they touch upon the choice of therapeutic intervention. levels that many would consider suitable for diagnosis. so too do the diagnostic criteria vary. and 16 would not. The criteria in the latter case will clearly be more stringent. Consider a hypothetical test whose specificity is assumed to be 80% and its sensitivity 80%. would receive an incorrect diagnosis of idiopathic Parkinson’s disease and consequently undergo ineffective surgery. 64 of 80 patients with idiopathic Parkinson’s disease would be diagnosed correctly and offered DBS. If the total population consists of 100 patients. because the prevalence (prior probability) of idiopathic Parkinson’s disease to other forms of parkinsonism is quite high. the degree of confidence associated with any set of diagnostic criteria cannot rest on any absolute judgment. Regardless of the criteria. however. whose consequences are serious but rare. four patients with idiopathic Parkinson’s disease will be denied effective DBS. what ratio would be? No calculus or set of facts promises to answer to this question. a generally well-tolerated medication. the risk of denying a patient with idiopathic Parkinson’s disease is high. if the consequence of making a diagnosis is to begin a patient on levodopa. How slowly must a patient perform a hand opening–closing task for the rate of speed to be deemed symptomatic of bradykinesia in support of a . mistakenly diagnosing idiopathic Parkinson’s disease in patients with MSA or PSP admits of a small downside beyond that of an inability to provide patients and their family members or caregivers with the appropriate prognosis. mistakenly diagnosing idiopathic Parkinson’s disease in patients with MSA or PSP admits of a large downside in the form of major risks with little or no accompanying benefit. The remaining four patients. the criteria are far less stringent than does proposing DBS as a treatment. A test for distinguishing patients with idiopathic Parkinson’s disease from those with MSA or PSA offers a useful example. The critical task becomes that of determining the set of criteria for the diagnosis of idiopathic Parkinson’s disease that is just barely sufficient to justify DBS. however. For example. Indeed. Because it is situated on a continuous rather than a dichotomized scale. Levodopa seldom harms patients who are believed to have Parkinson’s disease but who in truth have MSA or PSA. the test will identify 20% of patients with MSA and PSP as having idiopathic Parkinson’s disease. ethically speaking? If it is not.

at the very least. The more problematic first criterion is discussed in the following. It is not at all clear that the best interests of a clinical trial necessarily are the same as patients’ best interests. et al. (2)  absence of significant depression. (2) disease duration of five years or greater. into clinical criteria. the issue of inappropriately excluding a patient with idiopathic Parkinson’s disease is not an issue—another patient with idiopathic Parkinson’s disease can be found. The problem is that these research criteria appear to have been translated. The consequence would be a reduction of statistical effect size and an increase in statistical variance. primarily unilateral or asymmetric presentation rests heavily on the issue of tremor and the question of whether the patient has tremor-predominant . (6) absence of symptoms suggestive of cerebellar dysfunction. Current Typical Criteria Related to the Diagnosis of Idiopathic Parkinson’s Disease The following requirements determine the typical criteria for DBS candidacy: (1) unilateral onset of symptoms or. thereby increasing the costs to the clinical trial. or some other form of parkinsonism for which DBS is likely not indicated (Hughes. It appears these criteria for DBS candidacy for clinical purposes are essentially the same as for clinical trials research. Clinical criteria should reflect patients’ best interest. (5) absence of early and advanced autonomic dysfunction. The second and third additional criteria are based on experience following DBS surgery. these criteria in clinical applications need to be reexamined in the context of patients’ best interests. that may result in diagnosis of Parkinson’s disease in patients who actually have MSA or PSP. which would necessitate a large sample size.42 2 0 T hings to K now A bout D eep B rain S timulation diagnosis of idiopathic Parkinson’s disease? What degree of action tremor remains within the diagnostic bounds of idiopathic Parkinson’s disease rather than entering the diagnostic bounds of MSA or Essential tremor? Answers to questions of this sort ultimately depend on the physician’s degree of confidence. These criteria are very appropriate for research as they are thought to exclude patients with atypical parkinsonism who would expect to be less responsive to treatments. Autopsy-controlled studies suggest that as many as 25% of patients thought to have idiopathic Parkinson’s disease instead had MSA. As a criterion. Daniel. in an excessive numbers of patients. et al. asymmetric severity. The criteria for “weeding out” patients with MSA and PSP are based on the United Kingdom Brain Bank study of postmortem clinical–pathological correlations (Hughes. At the very least. and (7) absence of evidence of upper motor neuron syndrome. For the trial. (3) history of levodopa responsiveness (either by patient history or formal evaluation). Ben-Shlomo. One might add to the list the following three requirements: (1) absence of significant cognitive dysfunction. as well as the willingness of patients and their family members or caregivers to accept some uncertainty. The criteria enumerated previously are thought to be effective at reducing inclusion of patients with such atypical parkinsonism such as MSA or PSP. and (3)  absence of significant impulse control issues. 1992). (4)  absence of early dementia. 1992). These criteria were designed to reduce the number of false positives arising during selection of patients with idiopathic Parkinson’s disease—false positives. PSP. whole-cloth and rather uncritically.

must be based on the prevalence of idiopathic Parkinson’s disease relative to MSA and PSP. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease43 idiopathic Parkinson’s disease or Essential tremor. however. Most physicians and healthcare professionals would agree that requiring a patient to wait an additional four years is unreasonable. as argued for. Consideration of prior probabilities. In terms of an idiopathic Parkinson’s disease diagnosis. 75 subjects will actually have the disease. then 23% in the first group and 67% in the second group had symmetric disease. however. whereas a 25% chance of a false positive appears to attend demonstrated levodopa response. et  al. time must pass before a patient’s symptoms reveal themselves as belonging to any one of those diseases. which may benefit physicians and healthcare professionals but does little for patients. Daniel. The requirement for demonstration of levodopa responsiveness derives from clinical–pathological correlations. then a study of early intervention is moot. Evidence exists. Of 100 subjects presenting for consideration of DBS for idiopathic Parkinson’s disease. a patient with idiopathic Parkinson’s disease who meets all other criteria after the first year must wait an additional four years before she is offered the potential benefit of DBS. Approximately 25% of patients with MSA or PSP realize a benefit from levodopa that ranges from slight to moderate. as this would exclude many who have idiopathic Parkinson’s disease. The presumption is that patients with Essential tremor are more likely than are patients with idiopathic Parkinson’s disease to present with bilateral and symmetric tremor. The criterion therefore cannot be taken literally. Yet doing so has the advantage of simplifying the decision. which is 75% to 25%. The assumption is that more effective DBS would lead to an overall greater degree of function. A Sydney multicenter study on the use of bromocriptine found that patients who had a sustained response to bromocriptine had a higher rate of asymmetry of 77% compared to those who failed bromocriptine (asymmetry rate  =  36%. If one assumes that the patients meet reasonable criteria for idiopathic Parkinson’s disease. The requirement that a patient have parkinsonism for at least five years is based on the observation that early in the course of a patient’s disease it is difficult to distinguish MSA or PSP from idiopathic Parkinson’s disease. The issue of time of consideration for DBS has spawned an interest in studying DBS in subjects with less than or equal to three years of disease (Deuschl et  al. . 2006). Again. 1994). that shows tremor is often asymmetric in both Parkinson’s disease and Essential tremor. However.4. Hely et al. this point of differentiation has not been subjected to the type of analyses necessary to establish diagnostic tests. These correlations established that 97% of patients with autopsy-proven idiopathic Parkinson’s disease had a history of responsiveness to levodopa (Hughes. a 3% chance of a false negative appears to attend lack of levodopa responsiveness. respectively. According to this criterion. MSA and PSP advance more rapidly than does idiopathic Parkinson’s disease. if one is willing to give up the criteria that a patient has to wait five years. Failure to respond to levodopa indicates a mere 3% probability that a patient has idiopathic Parkinson’s disease. Careful tremor analysis in 48 patients with Parkinson’s disease and 47 patients with Essential tremor found no group-side interactions on an analysis of variance and that patients with Essential tremor were asymmetric (Farkas et  al. Thus asymmetric symptoms may not be appropriate criterion. 1992). 2013). These false positive and false negative rates relate to the specificity and sensitivity of levodopa responsiveness.

As other studies have demonstrated. 2002). Though the study by Charles et al. or 25% of the remaining 25 subjects with MSA or PSA. a mere 3 subjects with pathologically demonstrated idiopathic Parkinson’s disease received an incorrect diagnosis of atypical Parkinson’s disease—a diagnosis that would have led to their being improperly denied DBS. which means that the levodopa response explained only 33% of the outcome. whereas of 76 total. all of patients who would had levodopa improvement of less than 30% did as well as some patients who had over a 39% improvement. . nonetheless experienced significant benefit from DBS (Morishita et al. which improved symptoms by less than 30%. it does have value in the consideration of selection criteria. because the area under the Receiver–Operator Characteristic curve provides a reliable estimate of diagnostic utility by showing the tradeoff between specificity and sensitivity evident at different cutoffs (degrees of improvement with levodopa). One must decide whether the fact that more patients will undergo unnecessary DBS surgery than will be denied it represents a reasonable tradeoff. the correlation coefficient is not a proper measure of diagnostic utility. (2002) was not intended to distinguish idiopathic Parkinson’s disease from other-than-idiopathic Parkinson’s disease. The false positive rate will be 6. Sixteen patients with atypical Parkinson’s disease would have been misdiagnosed as having idiopathic Parkinson’s disease and subjected to ineffective DBS surgery. Some centers have established a criterion of a 30% improvement according to the motor scales of the Unified Parkinson’s Disease Rating Scales.32. The adjusted R 2 was 0. Application of the levodopa-responsiveness criterion to all 100 subjects leads to the denial of DBS to 2 patients with idiopathic Parkinson’s disease and unnecessary DBS surgery on 6 patients with other-than-idiopathic Parkinson’s disease. A diagnostic utility derived from the United Kingdom Brain Bank criteria has been shown to have an 82% accuracy rate. One study compared the preoperative levodopa response to the postoperative improvement in the motor Unified Parkinson’s Disease Rating Scales (Charles et al. Daniel. et  al. 1992). The presence of early dementia is thought to be more consistent with atypical Parkinson’s disease. More appropriate would have been a Receiver–Operator Characteristic curve analysis.44 2 0 T hings to K now A bout D eep B rain S timulation Of those approximately two (or 3%) will go undiagnosed because they will fail to respond to levodopa. Sixteen of 24 subjects with atypical Parkinson’s disease met the criteria for idiopathic Parkinson’s disease. Also. one must doubt the accuracy of selection according to United Kingdom Brain Bank criteria. 2011). Insufficient epidemiological evidence exists to permit precise accounting of the diagnostic value of these individual criteria. patients with severe tremor or dyskinesia induced by levodopa. I  require some evidence of levodopa responsiveness and have found that patient history offers sufficient evidence. In this case. Some centers formalize the assessment of levodopa responsiveness by evaluating patients before they take some dose of levodopa and again after they take it. That study demonstrated a correlation between the degree of levodopa improvement shown during the challenge test and the degree of improvement shown after it. Given this possibility. the presence of cerebellar signs and corticospinal tract involvement were thought to be more indicative of atypical parkinsonism. which is the combined rate of true positives and true negatives (Hughes. however.

if a patient took less than 6 mg per day and were not experiencing any dose-limiting side effect. A number of studies limited the dose of ropinirole to 12 mg per day and the average doses were very near that limit. A  similar analysis can be performed relative to adverse effects. for instance. the data most likely reached a “ceiling effect” that would prevent determination of a dose beyond which there is futile hope of increased efficacy or tolerance. then . then one must perform an independent clinical trial of each of the nearly 2. trying every possible combination would require over 300 years. The point on such a plot that becomes asymptotic would indicate the dose at which no further increase has a significant probability of achieving additional benefit.047 possible combinations. The first question is whether any agent used was used in sufficient quantity. sustained. The task becomes. Unfortunately. and transdermal. Sufficient quantity is defined as that dose that (1) achieves a sufficient level of relief (not relevant in the consideration of DBS candidacy). and two catecholamine-o-methyltransferase (COMT) inhibitors are available in the United States. Similarly. The latter requires a dose–response analysis that plots the number of patients who achieve a satisfactory level of control at a particular dose. requires at least two months’ time to complete. If one assumes that a trial of each combination. A  plethora of medications might be used. one has to adopt some strategy based on the most relevant question. we must therefore develop a plan according to Reason-Based Medicine (Montgomery 2012).000 combinations. (2) is limited by some adverse effect that cannot be circumvented. and the standard deviation suggested that most reached the maximum dose allowed. If one faithfully follows the stipulations of Evidence-Based Medicine. or (3) attains a dose where any further increase is futile. Evidence-Based Medicine is unfortunately of no help. Only slightly fewer are the possible combinations of MAO-B and COMT inhibitors. Clinical trials that include an initial dose titration period could provide some insight into the dose–response curve unless there was a maximum dose and a significant number of subjects reached the maximum dose. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease45 Exhaustion of All Reasonable Attempts at Nonsurgical Management By “reasonable attempts at nonsurgical management” is primarily meant medications. To the extent that it is synonymous with randomized control trials (RCTs). which are rarely used in monotherapy for purpose of controlling symptoms.4. then. In that study 67% completed the study. two monoamine oxidase type B (MAO-B) inhibitors. a number of studies limited pramipexole to 4. A dose-ranging study of pramipexole had a maximal dose of 6 mg per day.5 mg per day as the average daily dose. Instead. that of reducing combinations to some reasonable number. suggesting that a significant number of patients can tolerate doses of pramipexole of 6 mg per day (“Safety and Efficacy of Pramipexole” 1997). among others). At least two forms of levodopa-containing medications (regular and sustained-release). which consists of a titration period and evaluation period. Consequently. These 11 forms of medication therapy admit of 2. This is clearly unacceptable. In view of the large number of possible combinations of medications. Extrapolating to candidacy for DBS. five dopamine agonists (regular. these studies do not answer the question: at what dose is further increase futile either because of lack of increased efficacy or adverse effects.

When immediate-release levodopa is taken with medications that affect the bioavailability of levodopa such as entacapone. Unfortunately. In the Deep-Brain Stimulation for Parkinson’s Disease Study. and 100 times the pramipexole dose. one study demonstrated that 8 mg/day was the minimum dose necessary to achieve a significant effect (Nicholas et al. Concerns have been raised about their use in older patients. one study prospectively treated 90 patients ages 35 to 92 years (mean 55. An interesting and potentially helpful approach is to look at the total daily dose of medications as levodopa equivalents. 2014).uk). rasagiline. this has not been borne out by a meta-analysis (Katzenschlager et al. tolcapone. standard deviation 13.46 2 0 T hings to K now A bout D eep B rain S timulation one might consider further upward titration. However. and levodopa as 2.000 mg per day assuming no dose-limiting adverse effects. as significantly higher doses greatly increase the risks associated with systemic inhibition of MAO. The dose at the 95% of the one-tailed normal distribution would put the dose at 2. There has been the assumption that anticholinergics are better for tremor and dystonic features. . 30 times the rotigotine.5 the tolcapone and then added to the total daily levodopa dose.11 times the duodopa dose. and these patients were not disproportionately older (Nishiyama et al. rotigotine as 12 mg per day.9. 0.4) of which only 8 developed cognitive problems. 1. The question arises as to the status of anticholingeric. Similar findings were found in a separate clinical trial (Deuschl et  al.75 times the total daily dose of controlled-release levodopa. Rather. particularly levodopa (Deep Brain Stimulation for Parkinson’s Disease Study Group 2001). 2003). selegiline. With respect to transdermal rotigotine. after extensive search in PubMed. 80 times sublingual selegiline dose and then added to the total daily levodopa dose. it is offered as a suggestion for consideration. However. 1998).ac. no mention was made as to the maximum dose. including amantadine (as used for Parkinsonian symptoms rather than dyskinesia). and 100 times rasagiline dose and then added to the total daily levodopa dose (www. the total daily levodopa dose is multiplied by 0. however. I could not find sufficient data to determine a dose beyond which further efficacy would be futile or would have a high risk of adverse effects. and rasagiline are limited to 10 mg and 1 mg. The doses of the MAO-B inhibitors. the total levodopa equivalence in the patients undergoing DBS in the vicinity of the subthalamic nucleus was 1. I have adopted a maximal dose of ropinirole as 24 mg/day. In calculating the levodopa equivalents one adds to the total daily immediate-release levodopa dose 0. I have no experience with this approach nor do I know of any data published that bear directly on it. Unfortunately. pramipexole as 6 mg per day. and it may well be that 8 mg per day was the maximal dose allowed in the study. Doses of entacapone are limited by their plasma half-life and typically are taken as adjunct to levodopa.218 mg per day with a standard deviation of 575 mg.33 times the entacapone and then added to the total daily levodopa dose. respectively. One must bear in mind that some doses may exceed those described in FDA-authorized package inserts and FDA–compliant online medical texts. 20 times the ropinirole dose. Nevertheless. The consensus appears to minimize their role despite evidence of effectiveness and relative safety (Katzenschlager et  al. 10 times the oral seleiline dose and then added to the total daily levodopa dose. and selegiline. 2003).164 mg per day in levodopa equivalence if one assumes there was no upper limit on the agents that could be used in combination. 2006).birmingham.

First addressed is the peak-dose efficacy. efficacy can be considered as peak-dose effect and duration of effect. but in the absence of data that directly bears on the question. In . then failure of drug B could be taken to obviate the need to try drug A. Similar considerations are true of controlled or extended-release agents. Issues of Efficacy A significant problem is the lack of any structured data that bears on the issue and the complexity of the pharmacokinetics and pharmacodynamics relative to efficacy. Just because drug A may be much more effective than drug B in a population does not mean that an individual patient who fails drug A will not respond to drug B. provides the continuous optimal control. For example. when data is compared across subjects) rather within-subject data is not helpful. In situations with short plasma presence. shown to be more effective than drug B in population studies. The question is whether. and hence in the brain. There is considerable evidence that maintaining a constant level of levodopa in the blood. For example. It is important to note that plasma and brain levels are not synonymous necessarily. Consequently. The pharmacokinetics makes this problematic for medications that have a short effective plasma presence or functional half-life. This approach certainly would make the problem of excluding all reasonable attempts at medication therapy more tractable. agonists and controlled-release preparation of levodopa may be more efficacious for problems with duration of effect but perhaps not with peak-dose effect. one could just take the position that drug A. Similarly. To precisely answer the question. early in Parkinson’s disease. it may be practical and hence constitutes an accepted approach to reducing the number of medication combinations to a feasible number. with more advanced disease the functional half-life begins to approximate the plasma half-life. For example. if drug A has a higher incidence of the same spectrum of adverse effects compared to drug B. assessment of exhaustion of reasonable medications based on efficacy must separately address peak-dose effect and duration of effect. will obviate the need to try drug B should drug A fail. It is important to note that population-collapsed data (in other words. often approximated by the peak plasma level. for a patient who failed maximal use of drug A. The duration of effect relates to the duration of sufficient symptomatic relief. There is considerable but indirect evidence that levodopa is more efficacious than dopamine agonists alone. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease47 The next issue is the sequential use of different agents.4. The issue of efficacy can be divided into peak-dose effect and duration of effect. Given the paucity of data that directly bears on this subject. Thus an agent can have an acceptable peak-dose effect but an insufficient duration of effect. However. a study would have to identify subjects who failed drug A and then test whether they improved with drug B. the plasma presence of levodopa and immediate-release carbidopa/levodopa approximates its plasma half-life of approximately 90 minutes. Early in the disease patients may do well with dosing three times per day. it is necessary to attempt drug B either because of efficacy or adverse effects. Such an approach would be arbitrary. Peak-dose effect is the clinical response when the medication is at its highest brain level. indicating the functional half-life is considerably longer than the plasma half-life. the functional response to levodopa can far outlast or have a longer “functional half-life” (related to the duration of the clinical effect) than the plasma half-life.

or extended-release carbidopa/levodopa has greater duration of action. However. However. the dopamine agonists have an advantage of a longer plasma half-life and therefore may be adjunctive to levodopa regimens associated with wearing-off effect. in my judgment it is unlikely that a patient failing immediate-release carbidopa/levodopa will have any greater peak-dose efficacy with controlled. including ropinirole. or intraduodenal levodopa preparations than with any other. 2012). there is no reason to believe that higher peak-dose effects can be achieved with controlled. Three patients (8%) had tube stoma infections. it is not clear that adjunctive use of dopamine agonists ameliorate insufficient peak-dose effects from levodopa.or extended-release carbidopa/levodopa problematic. It appears that the between-individual variability in absorption makes the use of controlled. However.or extended-release carbidopa/levodopa. controlled. if levodopa proves insufficient in terms of peak-dose effect. This method carries surgical risks. and the same may be true for intraduodenal infusions of levodopa.48 2 0 T hings to K now A bout D eep B rain S timulation prospective trials involving randomization to either dopamine agonists. In my experience. 2007). However. 2000). ropinirole and pramipexole. problems with duration of effect are a different issue with dopamine agonist effective for wearing-off effect. versus levodopa. the use of controlled. Rascol et  al. In some countries governmental approval is pending for the use of constant intraduodenal infusions of levodopa-containing medications. This might suggest that patients who have not had sufficient efficacy with levodopa should be tried on dopamine agonists as adjunct.or extended-release carbidopa/levodopa may provide greater duration of effect and thus be of benefit in situations of wearing-off effect compared to immediate-release carbidopa/levodopa. Thus patients who have not had sufficient peak-dose benefit with dopamine agonists still may benefit from the addition of levodopa. however. Thus if the tablet of controlled or extended release is only . pramipexole. in the absence of adverse effects and without consideration of wearing-off effects. Consequently. and one patient (3%) had peritonitis. A  similar consideration applies to intraduodenal infusions of levodopa preparation. the clinical trials do not appear to differentiate the added value of dopamine agonists on peak dose versus duration of effect. controlled. which is expected to be effective in improving insufficient duration of peak-dose effects (Palhagen et  al. There are a number of studies demonstrating increased efficacy with the use of dopamine agonists adjunctive to levodopa (Mizuno et al.or extended-release carbidopa/levodopa appears to have fallen out of favor despite clinical trials that demonstrate significant peak-dose effects and an advantageous duration of effect. it is reasonable to conclude that adjunctive use of dopamine agonists. If the issue is peak-dose efficacy.or extended-release carbidopa/levodopa. immediate-release carbidopa/levodopa. substantial numbers of subjects required adjunctive levodopa to their dose of dopamine agonists (Parkinson Study Group  2000. However. The primary reason is that. Uncertain at present is whether the risk–benefit ratio is such that intraduodenal levodopa infusions should be considered prior to considering DBS.or extended-release carbidopa/levodopa. it is not clear that a patient who has not received a sufficient peak-dose effect from levodopa would obtain a sufficient peak-dose effect from dopamine agonists alone. It is unclear whether immediate-release carbidopa/levodopa has the greater peak-dose efficacy than controlled. and rotigotine. are unlikely to increase the peak-dose efficacy. because a catheter must be inserted in the duodenum. Levodopa can only be absorbed in the distal jejunum. Clearly.

one cannot know a priori whether an individual patient will have a consistent and effective response. However. However. with ropinirole and rotigotine having less risk than pramipexole. If one MAO-B inhibitor also failed to provide the patient adequate symptomatic control. anti-Parkinson medications vary in their risk for confusion or disorientation with immediate-release carbidopa/levodopa having the least risk (Etminan et al. For example. which can be quite variable between subjects and within a subject. there is insufficient evidence to suggest anything is to be gained by switching to a different MAO-B inhibitor. there are concerns about hepatotoxicity with the use of tolcapone. Absorption of levodopa from controlled.4. In other words. Similar rationales extend to the adjunctive use of MAO-B and COMT inhibitors. Thus controlled. Many are treatable by the choice of anti-Parkinson medications used or by adjunctive use of other medications. First are peak-dose dyskinesias where the risk for dyskinesia follows the same considerations as peak-dose effects. Similarly. less levodopa will be absorbed and less clinical effect will be achieved. which is greater than ropinirole (Chitnis et al. Dopamine agonists also vary in their risk for cognitive side effects. adjunctive use of MAO-B and COMT-inhibitors may provide greater relief of wearing-off effect compared to immediate-release carbidopa/levodopa alone.or extended-release carbidopa/levodopa if wearing off is a problem. However. Adverse Effects Two types of adverse effects are considered. However. making achieving a consistent response problematic.or extended-release carbidopa/levodopa may be unpredictable. Nausea often can be treated with adjunctive use of plain carbidopa or domperidone. as there is nothing in principle to suggest that high plasma levels of levodopa cannot be achieved with immediate-release carbidopa/levodopa alone as compared to levodopa with adjunctive MAO-B or COMT inhibition. Thus it is reasonable that the patient should be given the benefit of the doubt and treated with controlled. 2012). one can try adjunct of amantadine up to 300 mg per day. such as dopamine agonists. The same relative ranking in risks for cognitive problems appears to be similar to those producing paranoia and hallucinations. as the former inhibits COMT in the peripheral while the latter inhibits COMT in the periphery and in the central nervous system. The same situation may be different among the COMT inhibitors where tolcapone may be more effective. Alternatively. 2003).or extended-release carbidopa/ levodopa is dependent on gastrointestinal motility. then switching to medications with lower risks of dyskinesia may be effective if they have not been attempted previously. Consequently. There are many and diverse adverse effects from the treatment of Parkinson’s disease in addition to dyskinesia. there are few head-to-head comparisons. particularly where a patient fails at one agent then improves on another. if peak-dose dyskinesia is the factor limiting medication use. orthostatic hypotension can be treated by migrating away from agents with the greatest risk. The latter can be treated with atypical neuroleptics such as quetiapine and clozapine with the latter the most effective. With respect to efficacy within the dopamine agonists there is evidence to suggest that rotigotine is greater than pramipexole. agents or combinations of agents with the greatest peak-dose effect are more likely to produce dyskinesia. such . to those with the least risk. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease49 partially dissolved by the time the medication reaches the distal jejunum.

RCTs performed under the auspices of Evidence-Based Medicine is partly responsible for this difficulty. In addition. one must determine whether the risk is high. there are few if any direct studies comparing all the options within a category such as agents for hallucinations. Doing so would be to potentially deny patients the DBS benefit.50 2 0 T hings to K now A bout D eep B rain S timulation as immediate-release carbidopa/levodopa. a decrease in verbal fluency has been described regularly. An approach anchored in Reason-Based Medicine is to invent a heuristic to deal with this issue. orthostatic hypotension can be treated with thigh-high antiorthostatic hypotension stockings giving 30 to 40 mm Hg compression with caution to avoid letting the stockings bunch. or roll as this may cause a tight ligature and interfere with circulation in the lower extremities. Also. In many ways. gather. One option is to maintain possibly quite restrictive requirements while awaiting the results of Evidence-Based Medicine RCTs that may never be conducted. If the cognitive impairment is such that anticipated improvements in motoric function would not significantly improve the patient’s quality of life. If the issue is risk of cognitive decline following DBS surgery. Admittedly. Evidence-Based Medicine also provides no means of mitigating the impact of the exact conditions under which the associated RCTs were conducted. however. If it is. No studies have demonstrated any predicative value of cognitive measures for patient outcomes. . These observations are only of partial help. on the supposition that they would experience greater complications from the DBS surgery. one which may be deemed unacceptable. the DBS RCTs provide no data or knowledge for fair resolution of the issue of preoperative cognitive impairment. rather. This may owe in part to a need for a certain degree of variability in subjects’ cognitive functions in the correlation study in order to parse the effects of cognitive function on the outcome measure. One quite reasonable heuristic is thus to assess the degree to which preexisting cognitive decline impairs the patient’s quality of life. The Issue of Preexisting Cognitive Impairment A lack of directly relevant data makes the issue of preexisting cognitive impairment difficult to address. there is insufficient variance by which to establish any correlations. As patients with cognitive problems were excluded. these data are difficult to extrapolate to individuals. While population studies may suggest one agent may be more efficacious or have lower risk of adverse effects. then it may be reasonable to presume that patients with preexisting cognitive impairment face higher risk of further cognitive decline. because it is unknown whether the risk for surgically induced significant decline is different for patients with significant preoperative cognitive impairments as these patients generally have not been allowed DBS. and so on. but the effect is mild to moderate. It does not appear to be the case that DBS surgery carries a high risk of significantly worsened cognitive function. then proceeding to DBS is of little value. The task becomes that of determining the best way to proceed in the absence of definitive evidence. mineralocorticoids and sympathomimetic drugs can be used such as droxidopa and midodrine. Patients with significant preoperative cognitive impairments were excluded despite a lack of any clear evidence of significant incremental risks. As has been the case. Their exclusion was based. In other words.

some institutions enforced a rigid age restriction they had been uncritically imported from DBS clinical trials. must be in place prior to DBS surgery. however. This does not mean. 2007). patients of advanced age face no undue risk and may therefore benefit from DBS (Ory-Magne et al. is undesirable if no follow-up on the issue is expected.4. on the other hand. increased surveillance and methods for intervention. It may simply mean. Operating on patients with limited but significant cognitive impairment. depending on biological (overall condition and comorbidities) as opposed to chronological age. RCTs suggest that this is not the case (Weintraub et  al. that a physician or healthcare professional needs to establish a prior plan for psychiatric surveillance and intervention. There is some concern that DBS may increase impulsivity. Rather. Impulse Control Problems Impulse control problems are common in patients with Parkinson’s disease irrespective of treatment. Selection for DBS is appropriate in cases in which the diagnosing physician is confident that these problems are the result of medications rather than the underlying disease. Drug-induced cognitive or psychological impairments represent a special case. . Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease51 A second option is to proceed with careful observation in some type of open-label study that is conducted in much the manner as is a quality-control program. Implanted cardiac defibrillators and other conditions may contraindicate DBS surgery. the few successes in this area notwithstanding. Ability to Tolerate Surgery The patient must not have any psychological or physical health problems that increase the risk of complications or reduce the potential for benefit. potential risk of increased depression following DBS surgery must not be discounted. Patients whose psychiatric disorders may warrant electroshock or electroconvulsive therapy must consider forgoing DBS surgery. such as those devised to mitigate suicide risk. Nevertheless. 2013). rather. Patients must therefore be screened preoperatively. that impulsivity is an exclusionary criterion. It is therefore reasonable to expect improvement in drug-induced cognitive and psychological problems. Considerable evidence suggests that. Many patients are able to substantially reduce their medications. Patients for whom DBS surgery is contraindicated may wish to consider pallidotomy or thalamotomy. The Issue of Depression Following DBS surgery. Age Early in the history of DBS therapies. This does not mean that significant depression represents an exclusionary criterion unless there is concern that this depression adversely affects a patient’s ability to make decisions. Patients who are likely to be exposed to strong environmental electromagnetic fields may be advised to forgo DBS surgery. there is concern that patients with Parkinson’s disease face a risk of suicide that. is significant. though small.

Ethical standards have long stipulated that physicians and healthcare professionals respect wide discretion on the part of patients or their surrogates. a patient’s medications must be adjusted as well. Only patients or their surrogates may determine the degree to which the disease compromises their life and what they are willing to risk. Despite what one might expect. but traveling that same distance repeatedly for postoperative DBS management does.52 2 0 T hings to K now A bout D eep B rain S timulation Degree of Severity Potential benefits. In such circumstances. Consequently. Certainly. Patients’ postoperative DBS management requires more than an implanted pulse generator adjustment. the majority of neurologists appear unwilling to offer postoperative DBS management. particularly as it relates to medications and other nonsurgical therapies adjunctive to the treatment of Parkinson’s disease. or who acts in a manner contrary to a patient’s decision. consultation with a bioethicist may help (see c­ hapter 19). This is not an inconsequential concern. . Persuading them to take on the additional responsibility of DBS management is problematic. Yet physicians and healthcare professionals cannot be forced to provide treatments they deem malfeasant. she may not be in the best position to provide postoperative care. serve. Plans for Postoperative Care No DBS benefit is realized until such time as an implanted pulse generator is activated and programmed. Yet a physician must nonetheless play a supervisory role. Most neurologists are very busy. it could be considered unethical to proceed with DBS surgery without prior assurance of timely and appropriate postoperative DBS management. A physician or healthcare professional’s role is to ensure that patients or their surrogates have sufficient understanding for making an informed decision. when measured against risks and alternatives. In most cases nurse practitioners and physician assistants may attend to the DBS system’s day-to-day management. industry representatives are helpful in consulting as to the electronics. yet physicians and healthcare professionals cannot just avoid the question of whether to refer for DBS surgery. violates that patient’s autonomy and thus commits an ethical breach. Further. There is very little evidence that would directly bear on the choices one has to make in considering referring a patient for surgery. Exercise of Judgment and Sharing the Decisional Burden It is quite clear from this chapter that once one looks beneath the general descriptions of selection criteria. which are clearly related to the severity of the disease. but asking them to do more is unfair to the representatives as well as the patient. Using available data requires highly inexact extrapolations from highly imperfect data. The severity of the disease is not measured by the motor examination of the Unified Parkinson’s Disease Rating Scales or any quality-of-life measure. industry representatives likely do not have sufficient breadth and depth of knowledge. Any physician or healthcare professional who decides for a patient. Unless a neurosurgeon has extensive knowledge and experience in medication adjustments. as the basis for a decision to proceed with DBS surgery. Traveling a great distance to undergo DBS surgery may pose no problem. they become highly problematic.

the physician and healthcare professional can educate the patient or surrogate as to the current state-of-knowledge. Rather. however imperfect. appropriate for clinical practice? At the least. this should not occasion nihilism or adventurism. patient selection produces occasional false positives (patients who face high risk but enjoy no prospect of benefit) and false negatives (patients who enjoy a decent prospect of benefit but who are denied DBS). and society are asked to make comparisons that do not have the same basis or reference. 2012. ed. Both eventualities must be carefully considered. Charles PD. Neurology 2002. Predictors of effective bilateral subthalamic nucleus stimulation for PD. particularly if patients or patients surrogate is included in the decision making (as they should be).122(1):22–25.” A  place to start is first critically examining what one thinks one knows.59(6):932–934. The uncertainly should not engender cognitive paralysis. and appropriate selection criteria must strike a balance between them.4. such analysis establishes the epistemic context that then creates the bounds of confidence within which a decision must be made. and enlist the patient or surrogate into a joint decision. New York: Modern Library. et al. S U M M A RY DBS provides remarkable relief of the suffering and disability of patients with Parkinson’s disease. patients. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease53 A choice to defer is a choice to withhold DBS.. nor is it necessary. Outcomes from switching from rotigotine patch to alternate therapies in Parkinson’s disease. Dewey RB. The Basic Works of Aristotle. Van Blercom N. Chitnis S. R EFER ENCES Aristotle. the patient or surrogate makes the final decision. At this time it is not possible for a physician or healthcare professional to answer exactly the question of whether a particular individual patient meets the least acceptable criteria for candidacy for DBS surgery. there is a paucity of data that address the direct concerns in patient selection for DBS. . Rather. Jaffery M. For example. the current situation should engender equipoise. one might ask:  where did current recommendations originate? Are those circumstances. the physicians and healthcare professionals are expected to use their best judgment based on what evidence is available. Krack P. Judgment is difficult. However. McKeon R. as physicians. if from clinical trials. patient surrogates. The lack of perfect knowledge does not mean that the patient or surrogate cannot make an informed decision that has ethical status. The physician and healthcare professional can not only discuss the state of knowledge but also the epistemic limits or uncertainty of that knowledge. 2001. Int J Neurosci. Criteria developed for DBS RCTs are inappropriate when adopted whole-cloth without prior critical review. if only to refuse DBS. As can be seen. often having to compare “apples to oranges. Ultimately. Like any diagnostic test. healthcare professionals. If anything. It is highly unlikely that the data necessary for unambiguous resolution of who is the least appropriate patient for DBS will be available.

Lambrecq V. Rev Neurol (Paris) 2008. et al. Krack P. et al. Costa J. Drug Saf. Gill S. Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson’s disease:  concept and standards of the EARLYSTIM study. 2006. Hasegawa K. [Deep-brain stimulation of the internal pallidum in multiple system atrophy]. Douglas HE. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. 2007. Morgante L. Science. Reid WG. Daniel SE. Dis.55(3):181–184. et al. How many parkinsonian patients are suitable candidates for deep brain stimulation of subthalamic nucleus? Results of a questionnaire.100(3):553–556.19:56–61. 2007. Epidemiology of Parkinson’s disease. Morris JG. et al. J Neurol Neurosurg Psychiatry 1992. 2012. Daniel SE. Policy and the Value-Free Ideal. Hely MA.42(6):1142–1146. The Belmont Report: Ethical Principles and Guidelines for the . Anticholinergics for symptomatic management of Parkinson’s disease. Lancet Neurol. A randomized trial of deep-brain stimulation for Parkinson’s disease. Parkinsonism Relat Disord. Neurodegen. The Sydney Multicentre Study of Parkinson’s disease: a randomised.22(13):1860–1865. What features improve the accuracy of clinical diagnosis in Parkinson’s disease? A  clinicopathologic study. Morishita T. Schade-Brittinger C. 2006. Montgomery EB Jr. Kilford L. Samii A: Comparison of the risk of adverse events with pramipexole and ropinirole in patients with Parkinson’s disease:  a meta-analysis. N Engl J Med. et  al. de Lau LM. 2003. Mizuno Y. 2004. Schüpbach M. et  al. Houeto JL. J Neurosurg. Deep brain stimulation: preoperative issues. Hughes AJ. Lang AE. Deuschl G. 2003. 2001.21(Suppl 14):S171–S196. Mov Disord. Mov Disord. Moro E.345(13):956–963. et al. 2013. Parkinsonism Relat Disord.5(6):525–535. N Engl J Med. Szirmai I. Etminan M. et al. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease:  a clinico-pathological study of 100 cases.12(1):49–55. Neurology 1992. Cochrane Database Syst Rev. et al. 2006. Trojanowski JQ. et al. et  al. Morgante F. et al. et  al. Breteler MM. Rahman M. Meissner W. DBS candidates that fall short on a levodopa challenge test: alternative and important indications. Pittsburgh:  University of Pittsburgh Press. Epistemology of medical decisions and the need for reason-based medicine. Parkinsonism Relat Disord. Farkas Z. Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy: Case report. 2(1):95–97.54 2 0 T hings to K now A bout D eep B rain S timulation Chou KL. Foote KD.(2):CD003735. 2009. Abe T. Knudsen K.164(4):398–402. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Hughes AJ.355(9):896–908 Deuschl G. 2006. Krim E. Deep-Brain Stimulation for Parkinson’s Disease Study Group. Manage. Ropinirole is effective on motor function when used as an adjunct to levodopa in Parkinson’s disease: STRONG study.13(8):528–531.26(6):439–444. Ben-Shlomo Y. Sampaio C. Csillik A. Krack P.17:263–268. prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. Neurologist 2011.57(8):903–910. Asymmetry of tremor intensity and frequency in Parkinson’s disease and essential tremor. Katzenschlager R. Forman MS. J Neurol Neurosurg Psychiatry 1994.

84(10):1113–1118. Adverse effects of subthalamic nucleus DBS in a patient with multiple system atrophy. 2012. 2009. et  al. and Welfare. Duda JE. Simonetta-Moreau M. Stilhart B. 2007. Identifying the Least Acceptable DBS Candidates Among Patients with Parkinson’s Disease55 Protection of Human Subjects of Research. Effects of deep brain stimulation in relatively young-onset multiple system atrophy Parkinsonism.162(3):363–370. Ondo WG. et  al.284(15):1931–1938. Accuracy of Parkinson’s disease diagnosis in 610 general practice patients in the West of Scotland. Korczyn AD. et  al. Patterson J. Chana P. 1979. Ory-Magne F. N Engl J Med 2000.. Borgohain R. et al.4. Newman EJ. controlled trial. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Does ageing influence deep brain stimulation outcomes in Parkinson’s disease? Mov Disord.22(10):1457–1463. Weintraub D. [Subthalamic stimulation in a patient with multiple system atrophy:  a clinicopathological report]. JAMA 2000. Talmant V. Kurisaki H. Rascol O. Washington. Interim analysis of long-term intraduodenal levodopa infusion in advanced Parkinson disease. DC: Department of Health. 2014. Tarsy D. Rev Neurol (Paris) 2006. et  al. Neurology 203. Brooks DJ. A randomized study of rotigotine dose response on “off” time in advanced Parkinson’s disease. Nicholas AP.61(2):247–249. 2014. Safety and efficacy of pramipexole in early Parkinson disease:  a randomized dose-ranging study. Esposito P. Parkinson Study Group. Nishiyama K. J Neurol Neurosurg Psychiatry 2013. Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson’s disease: results from a randomised. Dizdar N. Acta Neurol Scand. Education. JAMA 1997. Hauge T. Mov Disord. et al. et  al.24(16): 2379–2385. Advance online publication.278(2):125–130. Breen K. 1998. J Parkinsons Dis. Intern Med. et al. Pan TH. Ryan P. et  al. Zhu XY.342(20):1484–1491.37(6):514–518. J Neurol Sci. Palhagen SE. Sugishita M. et  al. .126(6):e29–e33. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. Brefel-Courbon C.342(1–2):42–44. Apetauerova D. Carlson K. Reversible memory disturbance and intelligence impairment induced by long-term anticholinergic therapy.

One may control the size. In the brain the stimulation pulses generate a localized electrical field that primarily excites neuronal axons. methodological descriptions and algorithms are published to aid programmers (Montgomery 2010). Despite DBS’s remarkable benefits. one should not be postoperative DBS programming’s inherent difficulty. Programming is admittedly complex. were extremely disabled. Few experiences gratify a physician or healthcare professional like that of observing the immediate. and pulse frequency. IPG management serves the purpose of stimulating sufficiently intended brain targets while at the same time avoiding stimulating unintended targets which would produce adverse effects.5 Postoperative Management of Patients with Parkinson’s Disease EN S U R I N G T H E B EN EFI TS A N D M I N I M IZI N G T H E R I S KS The benefits of Deep Brain Stimulation (DBS) accrue solely upon activation and programming of the implanted pulse generator (IPG). These adjustments maximize benefit . moments before activation. intensity. Also. which include the per-pulse amount of electrical current or voltage applied to the electrical contacts. reimbursement for efforts in postoperative care is reasonable. because they cannot find physicians and healthcare professionals reasonably close to home to provide it. Many would no doubt deem it unjust to deny patients DBS on the basis of their place of residence. ongoing postoperative management. for example—may provide most postoperative management. management of the IPG requires that one program electrode configurations (the combinations of active negative and positive electrical contacts of an implanted lead) and electrical stimulation parameters. Yet the clinical task is made tractable by an understanding of the basic and fundamental principles of neuroanatomy and physiology. Of the various reasons that exist for why postoperative DBS care provisions have not been more widely adopted by healthcare professionals. pulse duration. Merely one part of postoperative DBS management. In most cases. shape. and distribution of the electrical field by adjusting the electrode configurations and stimulation parameters. many variables intervene. particularly if one considers that healthcare professionals—nurse practitioners and physician assistants. patients with implanted DBS systems encounter difficulty receiving adequate. often dramatic response to DBS by patients who.

2012). Though the principles and practice of IPG programming are beyond the scope of this chapter. Further. DBS enjoys the great advantage of providing individualized therapy by virtue of its many combinations of electrode configurations and stimulation parameters. Efficient. in other words. it is inappropriate to defer stimulator management to an industrial representative who lacks the knowledge. Surgeons may change electrode configurations and stimulation parameters. Because pharmacological management of Parkinson’s disease also lies beyond the scope of this text. and regional anatomy. They see patients frequently and may therefore be the first to notice suboptimal control of the patient’s symptoms. in a patient’s postoperative management. education. Such division of labor is to be discouraged.5. Postoperative Management of Patients with Parkinson’s Disease57 and minimize adverse effects. surgeons who implant patients’ electrode assume DBS programming responsibility. or other factors. Deep Brain Stimulation Programming:  Principles and Practice (Montgomery 2010). At the same time. Treating physicians and healthcare professionals are the first to observe a potential DBS adverse effect. but leave subsequent medication changes to treating physicians or healthcare professionals. readers may find them treated in my other text. cost-effective DBS programming follows from employment of basic principles of electronics. and vice versa. and skills necessary to adjust both the stimulator and the medications. R O L E O F PH YS I C I A N S A N D H E A LT H CA R E PR O F ES S I O N A L S N OT D I R ECT LY I N VO LV ED I N D EEP   B R A I N ST I M U L AT I O N PR O G R A M M I N G Though they may not provide programming. who may lack sufficient knowledge and experience to complete this task. Changes to patients’ DBS programming tend to affect their medication requirements. particularly medication that act synergistically with DBS. postoperative management of medication therapies are integral to stimulator adjustments. but they may delegate the task of managing patients’ medications to referring or treating physicians. DBS and the medications work synergistically. particularly if they referred the patient for DBS surgery. Optimal programming therefore requires that . Indeed. associated healthcare professionals. The way in which they act in response to their observation depends on their understanding of the adverse effect. by election or default. The present text discusses issues of postoperative DBS care that go beyond IPG programming. or industry representatives. This is not optimal. Patient care stands to be improved by an increased ability to recognize suboptimal DBS therapy: treating physicians and healthcare professional are able to send their patients back to DBS programmers. neuronal electrophysiology. For that reason. a physician or healthcare professional assuming responsibility for a patient’s postoperative DBS management may find the large array of combinations daunting. changes in medications. treating physicians or healthcare professionals nonetheless continue to be involved. readers are referred to Movement Disorders (Watts et al. In some circumstances. They must determine whether it is related to DBS. postoperative management must address other forms of therapies.

particularly those most likely to be associated with the dyskinesia. suggests that the degree of medication reduction. Physicians and healthcare professionals must make a point of inquiring into a patient’s ability to control his movements prior to taking his first morning dose of anti. reverting to that which they did know. often because they did not fully understand DBS programming. depression. which significantly reduce quality of life of patients and those who care for them. Indeed. Resorting to medications essentially amounts to refusing to provide the patient with optimal benefit.Parkinson’s disease medications. On observing dyskinesia a DBS programmer unfamiliar with appropriate medication adjustments is likely to reduce stimulation intensity. and other nonmotoric symptoms. the use of medications. 2012). My experience. the patient taking them would have not needed DBS. Situation of this sort are unfortunate. A Veterans Affairs and National Institutes of Health cooperative clinical trial of DBS in the vicinity of the subthalamic nucleus has served to substantiate this experience (Weaver et al. however. because had medications been effective in the first place. is an indicator of DBS programming’s success. and the degree of medication reduction was lower as well. which tends to reduce DBS benefit in the bargain. is the better approach. I have seen DBS programmers who quickly and prematurely became frustrated. I N D I CAT I O N S T H AT F U RT H ER I M PL A N T ED PU L S E G EN ER ATO R PR O G R A M M I N G O R M ED I CAT I O N A D J U ST M EN TS A R E N EC ES S A RY Because the majority of patients with Parkinson’s disease continue to require medications.58 2 0 T hings to K now A bout D eep B rain S timulation one adjust the DBS and medications together. Though DBS is also remarkably effective in reversing motoric symptoms. Physicians and healthcare professionals must therefore distinguish DBS effects from those of the medications and the disease. an increase in whose intensity produces dyskinesia. it typically does not improve nonmotoric symptoms of Parkinson’s disease. The importance of distinguishing the efficacy of DBS from that of medications rests on its ability to aid physicians and healthcare professionals’ subsequent efforts at adjusting DBS or medications. One approach to drawing such a distinction is to determine whether the patient depends primarily on medications or DBS. Leaving the stimulation intensity unchanged and instead reducing medications. The degree of improvement as measured by changes in the Unified Parkinson Disease Rating Scales in that study was significantly less than it was in other comparable studies. A patient’s continued dependence on medications suggests that her DBS programming may be suboptimal. movement control prior to the first anti-Parkinson’s disease . It is not necessarily to reduce medications arbitrarily. DBS may worsen impulse control disorder. the effectiveness of the medications and possible adverse effects from the medications must be distinguished from those of the IPG. A  case illustrative of this point is that of DBS in the vicinity of the subthalamic nucleus. Because DBS systems typically remain activated around the clock. particularly in the case of DBS in the vicinity of the subthalamic nucleus. The goal of DBS is to provide optimal relief of symptoms and disabilities. namely.

In such cases efforts ought to be directed toward IPG programming. One may also ask the following additional questions: (1) Do your symptoms get better or worse through the course of the day? (2) Can you (or your caregiver) tell when it’s nearly time to take your anti-Parkinson’s disease medications? (3) Do your symptoms worsen if you forget to take. I focus on those medications that would be most responsible for any adverse effects the patient experiences. If they have. desired. and because the medications have proven themselves insufficient (the patient would not have otherwise undergone DBS surgery). In such cases. or delay taking. the patient appears to be doing well in the morning. this practice carries significant risks that owe to the fact that it is impossible to determine a priori the exact degree of medication reduction. her medications are again reduced.5. Through the immediate postoperative period. and further efforts at programming the IPG are therefore necessary. Postoperative Management of Patients with Parkinson’s Disease59 medication dose reflects the degree to which DBS is responsible for that control. His DBS is therefore failing to provide sufficient benefit. because the DBS effect is insufficient to prevent a patient’s symptoms from worsening as the brain levels of medications fall. A “wearing off” effect. suggests that the patient continues to depend on medications. Some centers make an immediate and arbitrary reduction in medications postoperatively. In my opinion. A caveat concerning interpretation of symptoms’ status upon a patient’s waking: some patients with Parkinson’s disease may enjoy a remarkable sleep benefit. the medications are reduced. in which symptoms worsen about the time a patient is to take his next dose. In this case. especially if the patient’s symptomatic control should fluctuate during the course of the day. . The patient and her family members and caregivers are warned that a loss of symptomatic control is expected and. The patient returns for reprogramming and is observed to determine whether her symptoms have improved. it may be the sleep benefit rather than any optimal DBS that explains a patient’s state. Sustained insufficient symptomatic control suggests insufficiency of both DBS and medications. the first effort should be directed at the IPG programming. for example. The patient’s IPG is programmed to provide the maximum benefit possible without adverse effects. My practice is to make a conscientious effort at minimizing patients’ medications. A patient’s showing significant symptoms indicates that DBS does not play a sufficient role in controlling them. One must look to other helpful information. If however. It is possible that a patient may experience sustained insufficient symptomatic control rather than fluctuations in the symptoms. Which medications to reduce first is a problematic issue. If the benefit is sustained. your anti-Parkinson’s disease medications? An affirmative answer to any of these questions indicates that the patient continues to depend on medications. because DBS is more likely to provide sustained benefit. I maintain a patient on the same dose of anti-Parkinson’s disease medications. because it permits symptoms to manifest sufficiently to provide a target for subsequent IPG programming. which is done in an iterative fashion. This process is continued until the patient receives maximally effective DBS at a minimal dose of anti-Parkinson’s disease medications. then it is likely that the IPG is providing sufficient benefit. indeed. experiencing symptom relief independent of any specific treatment. The patient is observed for a period of time to ensure that the benefits are sustained—one week in the case of Parkinson’s disease.

medications. If a patient with dyskinesia takes an MAO-B or a COMT inhibitor along with levodopa and dopamine agonists. for example. levodopa-containing compounds would be the first to be targeted on account of their propensity to produce dyskinesia. IPG reprogramming often improves these problems. They may give up too early. Alternatively. however. it may cause a physician and healthcare professional to lose heart when confronted with a patient whose DBS appears ineffective. As such. Unintended stimulation of these regions may cause such mood abnormalities as depression and euphoria. (2) the corticospinal tract (muscle contraction). would first have the dopamine agonist reduced. It may be due to involvement of upper motor neurons in the corticobulbar tract. Experience at major DBS centers has shown that many patients referred to them as DBS failures gain remarkable benefit from expert reprogramming (Okun et al. Their presence suggests. the dopamine agonist would be the first to be reduced on account of its greater propensity to cause hallucinations and delusions. If so. (4) the brachium conjunctivum (ataxia). These adverse effects are DBS target-specific.60 2 0 T hings to K now A bout D eep B rain S timulation In patients taking both a dopamine agonist and levodopa-containing compounds who experience hallucinations and delusions. diplopia. or it may cause increased impulse control disorder. The electrical field from the DBS may extend medially or ventrally to the limbic and associative regions of the subthalamic nucleus. The number of electrode configuration combinations and stimulation parameters is extremely large. then her least effective medications are reduced first. continued increase in the stimulation electrical current may not produce facial muscle contraction. (3) the fascicles of the oculomotor nerve (dysconjugate gaze. that IPG reprogramming is necessary. or the patient’s underlying disease easier. . In the case of DBS in the vicinity of the subthalamic nucleus. rather. the effects on speech may be intrinsic to the subthalamic nucleus and not related to unintended spread of stimulation electrical current (or voltage) to the corticobulbar fibers. and (5) corticobulbar fibers. for example. Speech involvement by DBS in the vicinity of the subthalamic nucleus can be problematic. the MAO-B or COMT inhibitor would be the first to be targeted for reduction. These symptoms are unlikely to be caused by anti-Parkinson’s disease medications. adverse effects result from inadvertent stimulation of the following structures: (1) the medial lemniscus (paresthesias). If dyskinesias are a significant problem. In this case. eyelid apraxia). If the patient experiences no adverse effects. Propagation of electrical current to unintended structures is the basis for most of DBS’s adverse effects. further increasing the stimulation voltage or current should elicit facial muscle contraction. which is greater than that of the dopamine agonist. It is important to increase the stimulation current (or voltage) in order to clarify which situation prevails. Patients taking both a dopamine agonist and levodopa-containing compounds. 2005). A DV ER S E EF F ECTS An understanding of the regional anatomy around the DBS lead makes determining whether any adverse effects are related to DBS.

Again one can discontinue DBS temporarily to observe the effects and at the same time watch for any exacerbation of the patient’s parkinsonism or the development of a neuroleptic malignant-like syndrome. speech involvement with DBS in the vicinity of the ventral intermediate nucleus may be due to stimulation of the thalamus and not to corticobulbar fibers. however. A physician or healthcare professional may discontinue DBS temporarily to observe whether the adverse effects resolve. patients may experience depression. Patients experiencing these problems may benefit from IPG reprogramming. i. some patients appear to experience an emotional and psychosocial breakdown (Schupbach et al. bright lights and other visual hallucinations). As with DBS in the vicinity of the subthalamic nucleus. family members or caregivers seem to lose a sense of self-worth that depended on giving care to an extent rendered unnecessary by DBS. 2013).e. (2)  the corticobulbar system (speech difficulties). Although rarely performed in patients with Parkinson’s disease. which is the relay nucleus for cerebellar output to the cortex. Impulse control problems can be similarly addressed. This situation should be assessed with increased stimulation as described previously.. which are presumed to owe to stimulation of the ventral intermediate nucleus of the thalamus. such as depression or euphoria related to DBS. patients with DBS in the vicinity of the ventral intermediate nucleus of the thalamus may experience occasional gait problems. and (3) the optic tract producing (phosphenes. In the first few weeks following the beginning of DBS. However. the mechanisms of which are unknown. if inadvertently stimulated. inadvertent stimulation may produce adverse effects in the following anatomical structures:  (1)  the corticospinal pathway (muscle contraction). Care must be taken in this. one must stand ready and prepared to intervene. and (3) the corticospinal tract (muscle contraction). PSYC H O SO C I A L D I S LO CAT I O N Despite an immediately prior remarkable improvement in their motoric symptoms. One must eliminate other possible causes. the following structures: (1) the ventral caudal nucleus of the thalamus (paresthesias). Many patients whose symptoms were considerably improved by medications experience similar emotional and psychological difficulties. Postoperative Management of Patients with Parkinson’s Disease61 In the vicinity of the globus pallidus interna. 2006) unlike the kind typical of depression or psychosis. Though this depression typically improves spontaneously. Case reports exist that describe neuroleptic malignant-like syndromes manifesting with abrupt DBS discontinuation (Urasaki et al. while the patient receiving their care comes to demand greater autonomy. DBS in the vicinity of the ventral intermediate nucleus of the thalamus may affect. problems such as gambling can be devastating . One conjecture is that the remarkable improvement on the part of the patient disrupts the psychosocial situation that had evolved during the patient’s period of great disability. because severe worsening of a patient’s symptoms and disabilities may result. Other adverse effects less likely to owe to DBS suggest referral to the patient’s pharmacological management or the status of her underlying disease. (2) the corticobulbar fibers (speech).5. During the immediate postoperative period.

The patient was managed by use of neuroleptics (dopamine antagonists) until the IPG was replaced. Patients with DBS may have seizures. In events in which expert physicians and healthcare professionals in DBS management are unavailable. A number of acute and urgent problems attend the use of an implanted DBS system. DBS controlled the dyskinesia. a patient who underwent fetal cell transplantation for Parkinson’s disease developed severe runaway dyskinesia. however. Because it is close to the brain. emergency-room personnel may be tempted to consult industry representatives. Unfortunately. Though unusual. the dyskinesia again became severe.62 2 0 T hings to K now A bout D eep B rain S timulation before they are recognized. that emergency-room personnel may take to resolve an emergency. Postoperative care must therefore include monitoring. and many. D E A L I N G W I T H EM ER G EN CY S I T UAT I O N S I N VO LV I N G A  PAT I EN T W I T H D EEP B R A I N ST I M U L AT I O N As patients with implanted DBS systems increase. Similarly. Seizure prophylaxis is therefore indicated. neurologists called in to aid are likewise unfamiliar. As in any emergency situation. Sudden failure of DBS may cause significant exacerbation of the very symptoms for which the DBS was implanted. causing tonic muscle contraction that may continue until such time as the DBS is turned off or reprogrammed. their presenting in emergency situations will also increase. rather. Risk of infection increases from skin erosion caused by the hardware. 2011). may also result. most emergency-room personnel are unfamiliar with the management of patients with DBS. The implanted DBS system itself may cause subdural hematomas. are added the potential DBS-related complications. Patients who have a seizure within a week following DBS surgery appear to run no greater risk of subsequent seizures than those who do not (Pouratian et al. Intracranial hematomas. and the presence of the DBS system itself may affect the way in which they manage a patient in an emergency situation. Some emergency personnel leap to the inappropriate conclusion that the condition is related to the DBS. patients may have persistent paresthesias owing to the current’s spreading to the medial lemniscuses posterior to the subthalamic nucleus. There are some basic steps. electrical current may spread to the corticospinal tract. any immediate threats to life or limb must first be addressed. as well as individual and family counseling. To the usual differential diagnosis. which tend to occur during the immediate postoperative period but may occur any time postoperatively. For example. Because one is able . however. Once the DBS system’s batteries were exhausted. As foreign objects. Seizures occurring later in the postoperative period are associated with increased risk of recurrent seizures. urgent problems may be caused by brain stimulation. A patient’s circumstances may be such as to necessitate short-term treatment with anticonvulsants. they are at increased risk of infection. For example. if not most. Yet industry representatives rarely have the necessary expertise or skills to deal with emergencies. Differential diagnosis in patients with an implanted DBS system is no different than it is patients without DBS who present in the same manner. the site at which the DBS lead exits the skull presents a particular cause for concern in the event that it becomes infected.

In situations in which oral medication is impossible. even if doing so inconveniences the implanting surgeon. Patients and their family members or caregivers must be given a device that checks the IPG’s battery status and instruction in its use. Patients and their family members and caregivers must be advised to keep the IPG status-checking device with them at all times. the following common causes: (1) lead or extension fracture. transdermal rotigotine is an option for worsening symptoms referable to Parkinson’s disease. appropriate backup support must be arranged in advance. especially if MRI or CT scan personnel are unavailable. I recommend that routine AP and lateral skull. Postoperative Management of Patients with Parkinson’s Disease63 to determine whether a battery is low. the presence of the implanted DBS system may affect a patient’s subsequent diagnostic workup and management. Because the implanting surgeon may be unable to be available on a continuous basis. Physicians and healthcare professionals bear the responsibility of ensuring that patients and their family members and caregivers understand these instructions. Also. I recommend that emergency facilities maintain a supply of transdermal rotigotine for emergency situations. In those circumstances. because even during a short errand an accident necessitating emergency care may happen. sudden DBS failure may be prevented. unaware of these risks. and chest X-rays be taken immediately after DBS system implantation.5. Certain head MRIs may be performed under specific circumstances and by use of specific techniques. In addition to battery exhaustion. for instance—a patient is given medications to manage acute and severe symptom exacerbation attending DBS failure. The IPG status-checking device must never be stowed in luggage that cannot be accessed during a long trip. For their part. attempts to compensate sudden DBS failure with medications often encounter substantial delays in reaching efficacy. Some physicians. Unless something about the situation forbids it—inability to take medications orally or the presence of an ileus. Patients with implanted DBS systems are more likely to present emergently for reasons other than those related to their DBS. order MRIs for a patient with an implanted DBS system. It is urgent that an IPG whose battery indicates eminent failure be replaced. (3) DBS lead migration that shifts the electrodes’ electrical contacts from their proper positions. may result in injury and DBS malfunction. among others. Difficult at best. One thus avoids the need for medication compensation by never allowing an IPG battery to fail. These X-rays then serve as an important reference and may be easily compared to similar X-rays obtained in the emergency situation. provided that the . because they do not have at hand medical equipment necessary to control the DBS. it is likely that the emergency-room personnel may need to rely on the patient’s device. patients and their family members or caregivers must make a habit of checking. for example. because they are neither commonly known nor intuitively obvious. (2) poor or loose connection between the DBS lead and the extension or between the extension and the IPG. As a matter of standard and accepted care. I recommend that patients and their family members or caregivers begin checking immediately after DBS implantation surgery so they may fall into the habit. cervical spine. and (4) various other types of hardware failure. all physicians and healthcare professionals involved in postoperative DBS management must routinely check the IPG for its remaining battery life. Exposing patients with implanted DBS systems to high-strength electromagnetic energy. sudden DBS failure may owe to.

render postoperative DBS management effective and efficient. including but not limited to ultrasound or radiofrequency diathermy. are contraindicated with the current technology.66(12):1811–1816. Gargiulo M. In order to prepare for the event of treating a patient with DBS.64 2 0 T hings to K now A bout D eep B rain S timulation DBS system is powered down beforehand. Pourfar M. Certain procedures. which may cause them to withhold certain evaluations or managements and. J Neurosurg. spine. or abdomen. . All parties involved— patients. The presence of the DBS hardware on X-rays or other imaging studies may obscure underlying tissue and thus possibly confuse the radiology staff.115(2):310–315. In the situation of emergency cardioversion. 2011. Arch Neurol. Deep Brain Stimulation Programming:  Principles and Practice. Welter ML. Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology 2006. Physicians and healthcare professionals are strongly encourage to study educational materials and manuals provided by the device manufacturers. Understandably. on the other hand. in so doing. MRI of the chest. given the complexity of its postoperative management and the unfamiliar electrophysiology involved. et  al. S U M M A RY Physicians and healthcare professionals are likely to find providing DBS for patients with Parkinson’s disease a remarkably gratifying experience. Tagliati M. Okun MS. Those physicians and healthcare professionals who refrain from offering most operative DBS programming may nonetheless become involved in postoperative management of patients with DBS. Yet there are some fundamental principles that. Reames DL. novice physicians and healthcare professionals may be somewhat reluctant to provide this therapy. Comprehensive analysis of risk factors for seizures after deep brain stimulation surgery:  clinical article.62(8):1250–1255. The presence of the DBS pulse artifacts on an EKG or EEG may also cause confusion. Pouratian N. care must be taken to minimize electrical current flow through the IPG. Schupbach M. 2005. place a patient with DBS at even greater risk. et al. Physicians and healthcare professionals must also vie against a tendency toward being overly cautious. physicians. emergency personnel are urged to consult with the device manufacturers and establish evaluation and management plans. et al. are contraindicated with current technology. Frysinger R. healthcare professionals—must prepare themselves for any such eventuality. New York: Oxford University Press. 2010. whether as a consequence of medical management of the patient’s Parkinson’s disease or some urgent situation. R EFER ENCES Montgomery EB Jr. The presence of an implanted DBS system may complicate surgical care: a surgeon working near the implanted DBS hardware may damage it. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. once mastered.

Standaert DG. Neurology 2012. J Clin Neurosci. Hirose M. Fukudome T.79(1):55–65. Randomized trial of deep brain stimulation for Parkinson disease: thirty-six-month outcomes. Weaver FM.20(5):740–741. Watts RL. New  York:  McGraw Hill. Movement Disorders. et al. 2012. 2013. Follett KA. Obeso J. Postoperative Management of Patients with Parkinson’s Disease65 Urasaki E. et  al. . Neuroleptic malignant syndrome (parkinsonism-hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus.5. Stern M.

Unlike most patients with Parkinson’s disease. Along with tremor at rest. patients with Essential tremor may manifest cogwheel. Essential tremor is often mistaken for Parkinson’s disease. Recent imaging of the dopamine transporter. however. Positive and negative predictive values. patients with Essential tremor also experience tremor when they bring their fingertip to the tip of their nose or engage in similar actions. Adding to the difficulty of a differential diagnosis is the fact that bradykinesia may be seen in patients with Essential tremor to the same degree as it does in patients with early Parkinson’s disease (Montgomery et al. Bradykinesia is an example. Because symptomatic tremor may be present when a patient is at rest. Though tremor frequency is thought to be generally higher in Essential tremor (6  Hz to 15 Hz) than it is in Parkinson’s disease (approximately 4 Hz). Essential tremor is a disorder that causes tremor as one of the more prominent symptoms.6 Deep Brain Stimulation Is Safe and Effective for Essential Tremor D EEP B R A I N ST I M U L AT I O N: A S A FE A N D EF F ECT I V E T R E AT M EN T FO R ES S EN T I A L T R EM O R Of unknown etiology. specifically in early or . Though tremor may occur at any age. patients with Essential tremor may also exhibit tremor while holding their arms outstretched or maintaining other sustained postures. A clinician typically looks for other symptoms that distinguish Essential tremor from Parkinson’s disease. it typically occurs in adults. however. The significant prevalence of tremor in relatives of patients with Essential tremor argues for a genetic cause:  incomplete or complex inheritance or additional contributing factors. have reportedly revealed a preserved sense of smell in the former. Though rarely present in Parkinson’s disease. like patients with early Parkinson’s disease. Rest tremor in an elderly patient with Essential tremor may therefore have the same frequency as does rest tremor of someone with Parkinson’s disease. 1999). It may be difficult at times to distinguish Essential tremor from tremorpredominant Parkinson’s disease. which compare scans of patients with Essential tremor with those of patients with Parkinson’s disease.or ratchet-like resistance to passive joint rotations. And. have not been determined for the most relevant clinical scenario. Tremor of this kind may also be present in patients with Parkinson’s disease. patients with Essential tremor often preserve a normal sense of smell when corrected for age and sex. it has been shown that rest tremor’s frequency of Essential tremor may slow with age.

particularly relative to the anterior and posterior commissure. the patients taking them. give up their search for benefit (Lyons et al. When these medications prove ineffective. which must be avoided to prevent limiting paresthesias with stimulation. Further. see c­ hapter 19 for a discussion of these issues). can identify the ventral intermediate thalamus. It is usually easy to distinguish Essential tremor from Parkinson’s disease in cases in which the disease is advanced. It is important to identify the appropriate homuncular representation associated with the most bothersome symptoms. Because tremor in Essential tremor. is most often distal in the upper extremity. as they do in many cases. one cannot be confident that the image-based targeting. because their treating physicians. Also. Also to be avoided is the head homuncular representation of the ventral intermediate nucleus of thalamus. for example.6. First. While this may be true in an anatomical distance between the nuclei within an individual. fewer patients with Essential tremor than patients with Parkinson’s disease undergo Deep Brain Stimulation (DBS). T H E N AT U R E O F D EEP B R A I N ST I M U L AT I O N FO R   ES S EN T I A L T R EM O R The primary target for DBS is the ventral intermediate nucleus of the thalamus. First. The ventral intermediate nucleus of the thalamus is the relay nucleus for information that originates in the cerebellum and travels to the motor cortex. no imagining technique differentiates the ventral intermediate nucleus of the thalamus compared to the posterior ventral caudal thalamus. Conversely. DBS is considered an appropriate “off-label” use of a device approved by the US Food and Drug Administration. The . and swallowing problems. such as tremor related to multiple sclerosis. For cerebellar outflow tremor. patients may be unaware that DBS is an option for them. I recommend that microelectrode recordings be used to localize the target. who in most instances are not neurologists. there are case reports of other targets being effective as well. in some forms of cerebellar outflow tremor. it is important to identify the specific homuncular representation within the ventral intermediate thalamus. despairing of any other treatment options. language. it cannot be assumed true when biological variance between individuals and increased variance due to technical issues are considered. many patients or their physicians may think that patients’ tremor does not warrant DBS (physicians’ deeming patients’ tremor insufficiently debilitating to warrant DBS raises certain ethical issues. The proximal representation is therefore targeted. Consequently. Propagation of electrical current from DBS to the head representation is thought to increase the risk of speech. Though Essential tremor is more common than Parkinson’s disease. may be unaware of the fact that DBS is safe and effective. 2003). the tremor is more proximal. Deep Brain Stimulation Is Safe and Effective for Essential Tremor67 mild Parkinson’s disease in which differential diagnosis between Essential tremor and tremor-predominant Parkinson’s disease is most acute. This tendency may owe to a number of causal factors. Many patients see a neurologist initially and are prescribed medications. One could argue that the posterior ventral caudal thalamus is sufficiently distant from the ventral intermediate thalamus. however. the representation of the distal extremity must be targeted.

habit is commonly confused for knowledge. However. however. One may argue that a surgeon’s choice rest mostly on habits developed in apprenticeship training. immediate and unconditional transference of concerns about bilateral thalamotomy to bilateral thalamic DBS probably is likely unreasonable because thalamic DBS is reversible. Early in its history. The latter is particularly true for surgeons who are not assiduous in avoiding intracranial air. Unfortunately. it also limits the stimulation intensity in order to avoid posterior extension of the field to the tactile region of the ventral caudal thalamus. language. To some extent it may be related to biological variability or to other factors related to variability in the DBS surgical methods. Of aid would be a movement to total accountability and reimbursement based on outcomes. The source of the variability is debatable. injured patients must be able to recognize that poor practice has done them the injury. ventral caudal nuclei of the thalamus. language. For whatever reason. no imaging studies differentiate the ventral intermediate. or various homuncular representations within the ventral intermediate nucleus of the thalamus. Forgoing microelectrode recordings and relying instead on imaging are thus suboptimal practices. the position of the neurophysiologically defined optimal target and the target relative to the midpoint of the line connecting the anterior and posterior commissure vary considerably. For the threat of lawsuits to motivate reasonable practice. The ventral intermediate nucleus of the thalamus is large (particularly in the medial-lateral direction). In a five-year follow-up study—which consisted of 26 patients with Essential tremor and 19 patients with . however. In many respects. but they seldom receive instruction in how to become so. surgeons and physicians alike rarely stand to account for their practices unless they are sued. makes such enforcement problematic. One who foregoes microelectrode recordings must use distances for the midpoint on the line that connects the anterior and posterior commissure.68 2 0 T hings to K now A bout D eep B rain S timulation rare patient may have lower extremity or orthostatic tremor. which indicates that the lower extremity representation should be targeted. and swallowing. This is particularly true because the ventral intermediate thalamus. which is narrow in the anterior-posterior direction. particularly for speech. thus causing significant brain shifts. To date. It is therefore impossible to cover the entire structure by indiscriminant placement of the DBS lead within the ventral intermediate thalamus. however. it must be credible. and for the threat to be credible. Significant concerns relate to whether bilateral ventral intermediate nucleus DBS increases risks. bilateral thalamotomy was found to carry unacceptable risk for speech. which may expand as it warms to body temperature. Neurosurgeons are certainly not absolved of the responsibility of being reasonable (and neither are physicians and healthcare professionals of any disciple). this concern owes to the legacy of thalamotomy. The current balkanization of healthcare delivery into feudal fiefdoms. and swallowing difficulties. Surgeons may also become wedded to their methods for psychological reasons (Fins 2008). Yet a patient is usually the party least aware of whether a practice was good. The situation appears to lead to the conclusion that a referring physician is perhaps in the best position to enforce effective surgical practice and may do so merely by selecting the surgeon to whom to refer (see ­chapter 19). As a matter of practice. These would provide incentive for all to practice reasonably as a way of ensuring optimal outcomes. limits the volume of tissue activation. As a consequence.

and swallowing complications. One possible advantage of DBS in the vicinity of the subthalamic nucleus. It is reasonable to conclude. among the former of whom 18 had unilateral and 8 had bilateral thalamic DBS—the incidence of speech problems was 17% for unilateral and 63% for bilateral thalamic DBS (Pahwa et  al. that DBS exceeds best medical therapies in effectiveness. they are solipsists. Medications . In a five-year follow-up of 26 patients. a second thalamic DBS on the contralateral side would constitute an off-label use of a Food and Drug Administration–approved device. language. Early studies demonstrating the effectiveness of DBS in the vicinity of the ventral intermediate thalamus required that patients exhaust all reasonable attempts at medication therapies prior to undergoing DBS surgery. I am aware of no randomized control trials (RCTs) that directly compare DBS to best medical therapy in treatment of Essential tremor. those patients with unilateral DBS in the vicinity of the ventral intermediate nucleus of the thalamus DBS experienced a 75% improvement in tremor. Deep Brain Stimulation Is Safe and Effective for Essential Tremor69 Parkinson’s disease. it be staged in such a way that the patient is observed following a unilateral procedure to ensure that the thalamus suffered irreversible damage. 2006). is an issue of little clinical relevance. EF FI CACY Numerous studies demonstrate safety and efficacy. 2010). and those with bilateral implants experienced a 65% improvement (Pahwa et al. No unilaterally implanted patients and 25% of bilaterally implanted patients exhibited gait disorders. Yet. Clinicians must therefore employ their best reasoning in light of available evidence. such RCTs would be welcome. From a clinical standpoint. Those who suggest that RCTs alone are capable of providing reasonable evidence are at best incapable of understanding the nature of RCTs and their fundamental limitations. therefore. these studies will likely never be conducted. 2006). Even in those subjects. Sufficiently many other studies have demonstrated that the placebo effect is an unlikely explanation for the sustained benefit of DBS in the vicinity of the ventral intermediate nucleus of the thalamus DBS. As it stands presently. At worst. an indication considered “off-label” (Blomstedt et  al.6. the other symptoms of which are essentially treated in advance of their subsequently becoming manifest. if its efficacy is assumed to be equivalent to the efficacy of ventral intermediate nucleus DBS. because the cost promises to be quite high. In any event. Provided they are relatively inexpensive. is lower risk of speech. DBS was remarkably effective. the task is that of determining a therapy that adequately controls a patient’s symptoms and relieves her disability. however. I recommend that if bilateral thalamic DBS is considered. Whether DBS is more effective than best medical therapy. Surgical risks of permanent harm argue for continuing to exhaust all reasonable medical therapies before considering DBS. This risk may be reduced further in the event that an actual diagnosis is tremor-predominant Parkinson’s disease. it is hard to argue for selecting the subthalamic nucleus over the ventral intermediate nucleus as the target. which would increase the risks associated with a second surgery on the contralateral side. Some case series suggest that DBS in the vicinity of the subthalamic nucleus may be effective for tremor owing to Essential tremor.

DBS will not surpass the medication therapy in effectiveness.70 2 0 T hings to K now A bout D eep B rain S timulation that provide sufficient benefit and carry less risk of irreversible significant adverse effects are preferred to DBS surgery. having succeeded with medications. one cannot know whether these represent the same population. at least for those subjects who did well on the medication therapy to which they were randomized. one would have to design the study in such a way that the subjects are randomized to one treatment and discontinued on it before proceeding to a second treatment. a RCT that rests on a population approach is incapable. Certain longer term risks. one expects in this case that medications’ failure is not predictive of DBS failure. (The 1847 Code of Ethics of the American Medical Association contains language evocative of the Flexnerian revolution. is not likely to aid clinical decision-making. This belief is generally true. . DBS surgery or continued suffering become a patient’s sole remaining options. (2) seizure. because. those that will fail with medications but benefit from DBS. they are subsumed under surgical risks. for example. the notion that they are so is likely an inheritance from the Flexnerian revolution in medicine championing scientific medicine but whose success was largely political and reflected more the dominance of allopathic medicine than it did any inherent superiority of scientific medicine of the day. risks may be classified as those associated with surgery and those associated with stimulation. which shows that the former provides better or different benefits than does the latter and which suggests that the latter involves a different set of physiological mechanisms than does the former. As such.) R I S KS At a conceptual level. however. One usually thinks of surgical risks as attending the perioperative period. there would be no reason to offer DBS surgery. The issue becomes whether success or failure of medications is predictive of success or failure of DBS. As demonstrated clearly in early non-RCT trials. (3) infection. because even if one could demonstrate that 50% of patients fail medication therapy and 50% succeeded with DBS. Also. in terms of sufficiency of response. Those who insist on a RCT that directly randomizes subjects to DBS or best medical therapy may cherish a scientific bias. Such RCTs may offer important insights into the nature of DBS versus the nature of medication therapy. Though it is doubtful whether scientific questions and clinical questions are synonymous. The mindset is most likely one in which scientific questions are believed to be synonymous with clinical questions. because those patients would not need it. (5)  acute but self-limiting depression. In order to know this. namely. Design of this kind is unethical. To remove subjects from an effective medical therapy and expose them to the significant risks of DBS surgery is unjustifiable. it would lead those who hold it never to entertain the issue. If it were. are primarily associated with the DBS system hardware. As such. however. Failing availability of such medications. A RCT involving patients who have been randomized to best medical therapy or DBS and compared is incapable of determining whether medication failure is predictive of DBS failure. Among the acute perioperative risks are the following complications: (1) intracerebral hemorrhage. This finding. which is relative to referring patients for DBS surgery. (4) symptoms related to withholding medications.

The risk of necessary DBS lead removal relates to the proximity of the infection to the DBS lead. the extension wire must also be removed. Infections and skin erosions require urgent care. Planned trajectories must avoid any visible blood vessels. Also. or multiple negative contacts. Whether implemented by a surgeon or a referring physician. Later infections often occur at sites where DBS hardware has eroded the skin. (7)  speech. it should be considered in a setting of neurological complaints arising at any point following DBS lead implantation. these recommendations should be a part of quality control supervision. Published evidence suggests that the infection rate is higher with subsequent IPG replacements (Pepper et al. Most of the intracerebral hemorrhages are therefore small and asymptomatic. 2013). Most infections occur at the implanted pulse generator (IPG). as well as any accompanying mass effect or cerebrospinal fluid flow obstruction. The symptomatology of intracerebral hemorrhage depends on the hemorrhage’s location and extent. the infection treated. Deep Brain Stimulation Is Safe and Effective for Essential Tremor71 (6)  ataxia. A surgeon planning the electrode trajectories may reduce the risk of intracerebral hemorrhages by use of contrasted Magnetic Resonance Imaging scans as a way to visualize vasculature. and the sulci (Piacentino et  al. DBS lead replacement unfortunately requires a second full implantation surgery. If the infection occurs near a DBS lead. language. particularly in those patients for whom rapid battery exhaustion is either an actuality or a likely possibility—patients who require high stimulus voltage or current. Occasionally. The risk rates reported herein. Though intracerebral infection following DBS lead implantation is exceedingly rare. it typically occurs during the initial few postoperative weeks. redness. or leaking fluid. although immediate postoperative imaging suggests that a rate of all hemorrhages is approximately 10%. Risk of symptomatic intracerebral hemorrhage is on the order of 1%. The mortality risk of intracerebral hemorrhage is approximately 0. are typically those observed at large centers whose personnel is of high expertise. large pulse widths. the lateral ventricles. Though infection may occur at any time following DBS surgery. high frequencies of stimulation. however. swelling. patient histories must be reviewed for medication that may increase the risk of bleeding. and the number of generic formulations and combination medications argues for a formal review by a pharmacist prior to surgery. the lead must be removed. I have found risk of it to be extremely small. Though in the short term rechargeable IPGs are much more expensive. Infections are divided into two types: (1) infections that present a high risk of necessary DBS lead removal and (2) infections that present a lower risk of necessary DBS lead removal. and (8)  general risks associated with surgical procedures. 2013. They may be treated with antibiotics and with removal of the IPG. Again. evaluation of the incidence of intracerebral hemorrhage should be part of any quality control program. Patients and caregivers must therefore be advised to inspect the areas beneath which runs the DBS hardware for signs of skin erosion such as soreness. the choroid plexus. Montgomery 2014). This observation argues for the use of rechargeable IPGs.2%. . Its possibility must therefore be kept in mind for any patient experiencing neurological compromise following DBS lead implantation surgery. and swallowing problems. and the DBS replaced after an appropriate interval. The number and types of medications are large. Though subdural hematoma may occur at any time following DBS surgery.6. the thalamostriate veins.

There arises the question of antibiotic coverage for medical or surgical procedures performed subsequent to DBS system placement. In situations in which clear speech or safe swallowing is paramount. Avoiding DBS lead placement in the head representation may reduce but will not eliminate the risk. Additional adverse effects may be related to stimulation of . and I defer to the surgeon. raises serious ethical issues. more general surgical experience may serve as a guideline. Patients with histories of significant depression require anticipatory close postoperative supervision. The precise mechanisms responsible for the difficulty are unknown. Adverse effects related to stimulation likely owe to stimulation current’s unintended propagation to nearby structures. Subacute seizures are quite reasonably treated with prophylactic medication. Adverse effects of thalamic DBS on speech. stimulation at higher intensities or frequencies may be used. one must know its location. Microelectrode recordings are the sole existing means of doing so. the value of which is reinforced by the unsettling sight of a patient seizing (Pouratian et al. a psychiatrist may need to intervene. Patients may experience self-limiting depression following thalamic DBS lead implantation surgery. which may make long-term cost saving appear less attractive. In some cases. Patients must use caution during this time. Their DBS systems need not even be activated. Yet literature on this subject is meager as well. There is little published data on the issue. The general consensus is that seizures occurring a few days after DBS lead implantation are less likely to increase the risk of subsequent and ongoing seizures.72 2 0 T hings to K now A bout D eep B rain S timulation they may be less expensive in the long term. they may prevent DBS from reaching stimulation parameters that are sufficient to control a patient’s tremor. The two categories require different approaches to treatment. It is known that the thalamic target is usually the cerebellar relay nucleus. For some patients it is necessary to allow selection of two (or more) stimulation settings. stimulation intensity or frequency may be reduced. 2011). Some IPGs permit one to program different sets of stimulation parameters and allow a patient or caregiver to alternate between them. Generalization from experience with ventriculoperitoneal shunts might offer some reasonable indication. For two weeks following DBS surgery patients may experience difficulty with walking. Disruption of this system may produce ataxia and may owe to local edema that resolves with time. Seizures occurs in some 1% of cases and fall into one of two categories: (1) those that are likely to increase the risk of subsequent seizures and (2)  those that are unlikely to do so. whereas seizures starting latter may give rise to increased risk of subsequent seizures. Stimulation of the adjacent corticospinal tract in the posterior limb of the internal capsule may cause tonic muscle contraction. In situations in which tremor control is more important than are clear speech or swallowing. Should these adverse effects arise while active stimulation is being set. The self-limiting depression mechanism is unknown. language. A physician may elect to treat acute onset of seizures with seizure prophylaxis. and swallowing may be particularly disconcerting. A transient bacteremia may seed hardware sites and thus breed infection. The nature of healthcare reimbursement. Current propagation to the tactile region of the ventral caudal thalamus may cause paraesthesias at stimulation intensities lower than are necessary to control tremor. Yet in order to avoid the head representation. In this case.

6. Deep Brain Stimulation Is Safe and Effective for Essential Tremor73

the ventral intermediate nucleus of the thalamus, particularly speech, language,
and swallowing problems. The majority of time DBS may be adjusted to avoid
these effects. Indeed, they often occur during the course of programming, and
their appearance may be useful in understanding the regional physiological
anatomy around the DBS electrical contacts (Montgomery 2010). It is therefore
unclear whether the appearance of such reversal stimulation induced effects as
paresthesias or muscle contraction should be regarded as adverse effects, as they
often are in publications of RCTs.

S U M M A RY

Though there are significant surgical risks associated with DBS in the vicinity of
the ventral intermediate thalamus for essential tremor, adverse effects are relatively
rare. For patients for whom all reasonable attempts at medication therapy have
failed, DBS remains an effective option.
R EFER ENCES
Blomstedt P, Sandvik U, Tisch S. Deep brain stimulation in the posterior subthalamic
area in the treatment of essential tremor. Mov Disord. 2010;25(10):1350–1356.
Fins JJ. Surgical innovation and ethical dilemmas: precautions and proximity. Cleveland
Clinic Journal of Medicine 2008;75(Suppl. 6):S7–S12.
Lyons KE, Pahwa R, Comella CL, et  al. Benefits and risks of pharmacological treatments for essential tremor. Drug Saf. 2003;26(7):461–481.
Montgomery EB Jr. Deep Brain Stimulation Programming:  Principles and Practice,
New York: Oxford University Press; 2010.
Montgomery EB Jr. Intraoperative Neurophysiological Monitoring for Deep Brain
Stimulation:  Principles, Practice and Cases. New  York:  Oxford University Press,
2014.
Montgomery EB Jr., Baker KB, Lyons K, et al. Abnormal performance on the PD test
battery by asymptomatic first-degree relatives. Neurology 1999;52:757–762
Pahwa R, Lyons KE, Wilkinson SB, et al. Long-term evaluation of deep brain stimulation of the thalamus. J Neurosurg. 2006;104(4):506–512.
Pepper J, Zrinzo L, Mirza B, et al. The risk of hardware infection in deep brain stimulation surgery is greater at impulse generator replacement than at the primary procedure. Stereotact Funct Neurosurg. 2013;91(1):56–65.
Piacentino M, Zambon G, Pilleri M, et al. Comparison of the incidence of intracranial
hemorrhage in two different planning techniques for stereotactic electrode placement in the deep brain stimulation. J Neurosurg Sci. 2013;57(1):63–67.
Pouratian N, Reames DL, Frysinger R, et  al. Comprehensive analysis of risk factors for seizures after deep brain stimulation surgery:  clinical article. J Neurosurg.
2011;115(2):310–315.

7

Identifying the Least Acceptable
Deep Brain Stimulation
Candidates Among Patients
with Essential Tremor

D EFI N I N G T H E R ES P O N S I B I L I T I ES FO R
CA N D I DAT E S EL ECT I O N

There is a logical error that is rampant in medicine regarding the selection of patients
for any particular treatment. Even a causal review will demonstrate that, in nearly
every case, the criteria are described as for the best candidate, that is, the candidate
with the best chance of the best outcome. But seldom is that the real issue. The more
vexing question is: what are the criteria that identify a patient with the least acceptable chance of improvement relative to the risks? Focusing on the best criteria risks
“cherry-picking,” which, while improving surgical and hospital outcomes, violates
the ethical obligation to beneficence to those patients who entrust their care to physicians and healthcare professionals. Consideration of the least acceptable patient
may challenge the ethical presumptions of physicians and healthcare professionals,
which typically do not arise when considering patients who meet the criteria for the
best candidate. The obligation to treat the least candidate may be deontological—a
moral duty to treat—or it may be contractual (even informally or implicitly) where
a physician has a fiduciary responsibility. Any treatment by a physician and healthcare professional necessitates informed consent, which necessitates explanation of
all potential treatments according to what is reasonable to a patient, not necessarily
reasonable to a physician or healthcare professional. Those with the least acceptable
criteria are no less deserving of the therapy.
The criteria for the best candidate are easy because they are uncontroversial
and liable to be readily accepted by all involved, including a patient or a patient’s
surrogate. The borderline cases may invite differences of opinion. A patient or her
surrogate ultimately holds the trump card: refuse therapy. The more problematic
situations arise when a patient or her surrogate wants the treatment and physicians
or healthcare professionals are uncertain. The reason for the problematic situation

7. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor75

is that ultimately it is a value judgment. The question thus arises as to whose values,
a patient or surrogate or the physician and healthcare professional, ought to prevail. Because only a patient or surrogate knows acceptable risk in light of potential
benefit, greatest credence should be given to her. Though physicians and healthcare
professionals are not obligated to provide therapies they feel would violate the ethical principle of nonmalfeasance, respecting a patient or her surrogate is consistent
with the principle of autonomy and with statements of ethics from professional
organizations.
S EL ECT I O N C R I T ER I A

The selection criteria for patients with Essential tremor considering Deep Brain
Stimulation (DBS) resemble those of other indications. There are two levels: a relatively low threshold held by physicians and healthcare professionals who are not
expert or experienced with DBS and an appropriately higher threshold by those
with expertise. This concept may be understood in terms of the specificity and
sensitivity of a diagnostic test, in this case the diagnosis is one of DBS candidacy.
The percent sensitivity means the percentage of patients identified as candidates
who actually are candidates for DBS. Percent specificity means the percentage of
patients identified as not candidates who are actually not candidates.
The appropriate balance between sensitivity and specificity is determined by
the consequences, as there are no a priori standards. More stringent criteria will
result in a great specificity but typically at the cost of patients being inappropriately
excluded from DBS. On the other hand, less stringent criteria will result in fewer
candidates being inappropriately discouraged from DBS but more patients undergoing DBS that perhaps should not have.
The appropriate specificity and sensitivity are based on the consequences, which
in turn depend on a judgment of the risks, potential benefits, efforts to realize
continued benefits, and, importantly, alternatives. I  recommend a set of criteria
for nonexperts that has a high sensitivity even at the expense of a low specificity.
Conversely, an expert should have a high specificity. Because the final assessment
of an individual’s unique risk, potential benefit, efforts for continued benefit, and
alternatives is often complicated, this judgment ought to be made in the context of
an experienced expert in DBS. The expert then has sufficient experience to exert
high specificity in recommending DBS. However, the expert is usually dependent
on a referring physician for patients. If the referring physician has a high specificity, then there is a risk of low sensitivity. Appropriate patients may therefore not
be referred. A  high sensitivity may mean that the referring physician may refer
patients who are not necessarily appropriate for DBS. Yet the costs for such referral are far lower than the costs associated with a patient’s continued disability as a
consequence of ineffectively treated disease.
Because the complex decision to offer a patient DBS often involves a multidisciplinary team, it is not reasonable to expect a nonexpert physician without such
a team to make a decision as to a patient’s candidacy, despite calls that she do so
(Martinez-Ramirez and Okun 2014). This is clearly the case when a major criterion
is failure of all reasonable alternatives. It is not clear the every nonexpert physician knows or has the experience to know when that criterion has been satisfied.

76

2 0 T hings to K now A bout D eep B rain S timulation

In a study comparing the pharmacological treatments of patients with Essential
tremor, there were significant differences between movement disorders specialists
and general neurologists. The latter tended to undertreat. For example, only 37.8%
of general neurologists’ patients had taken primidone or propranolol, which are the
mainstays of treatment (Diaz and Louis 2010).
Every physician ought to recognize when his efforts fail to provide complete
relief of a patient’s symptoms. It is at that point he should refer to the DBS expert.
The cost is a consultation fee. Yet this is little compared to the cost of failed therapies. In addition, the most frequent cause of patients being inappropriate candidates is a failure to exhaust all reasonable medications. A DBS consulting physician
thus often provides recommendations for further treatment, which offsets the cost
of a consultation that does not lead to DBS surgery. The considerations described
here are particularly acute, because most neurologists do not see many patients
with Essential tremor in their practice. Indeed, many are followed by an internist,
because often a patient and internists are discouraged by the previous referrals that
often do not lead to effective treatments, the nature of Essential tremor influencing
this outcome (Louis et al. 2010).
The admonition to refer all patients who have not received an acceptable response
to medication therapies is not to suggest that every patient ought to expect a complete response to medications or DBS. The problem, however, is that there is no a
priori method of predicting which patients will benefit from DBS. It would seem
appropriate to assume that every patient may potentially benefit. Should they meet
the criteria established by DBS experts, then they ought to be given the opportunity
to benefit.
The difficult decision is the definition of acceptable response to medication therapies and, more important, who decides the definition. Is it a physician, a patient, a
family member or caregiver? The failure to provide beneficence does not constitute
violation of the ethical principle of nonmalfeasance (do no harm). A patient’s right
to expect beneficence is unclear. In the British system, a physician is the one who
decides what therapies are offered. In the United States it is more likely the standards of practice (Note I am not an attorney and am not offering a legal opinion
here.) Often the standards of practice are what reasonably similarly situated physicians would do. The extent to which such physicians consider patients’ desires when
they may not resonate with the opinion of the physician is not clear (see ­chapter 19).
An excellent study examined the factors the influence acceptance of DBS surgery in patients with Essential tremor (Louis and Gillman 2011). The severity of the
tremor was only a modest factor but perhaps one that might motivate a physician
and healthcare professional. The most important factor from a patient’s perspective
was the degree of her embarrassment. Unless a physician clearly assesses the degree
a patient finds the tremor embarrassing and socially disabling, a physician is likely
to base his recommendation on the severity of the tremor, which may have less
relevance to a patient’s needs.
The degree of embarrassment is clearly contextual. Though it appears obvious,
it may not be appreciated that it is a patient’s perspective that determines when the
embarrassment is intolerable. Further, only a patient knows how much he is willing
to risk for relief of the embarrassment.
The selection criteria follow the same general approach as other disorders, such as
Parkinson’s disease. Among the elements of the approach are the following: (1) an

7. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor77

appropriate diagnosis of a condition that will respond to DBS, (2) exhaustion of all
reasonable lower-risk treatments, (3) ability to tolerate the procedure, and (4) assurance of postoperative follow-up.

Diagnosis
The diagnosis of Essential tremor is based on the symptoms and signs. There is as
yet no imaging or laboratory test that has been validated to differentiate Essential
tremor from those conditions that are in the differential diagnosis of tremor. The
diagnosis is strictly phenomenological, resting on the appearance of the tremor and
the conditions under which the tremor is present. Tremor is described as being at
rest, with sustained posture, (holding the hand and arm outstretched, for example),
and with action (bringing the tip of one’s finger to her nose, for example). In addition, the frequency of the tremor is noted. In the upper extremity, the distribution
of the tremor (in the proximal or distal musculature, for example) is also noted.
Unfortunately, nothing unique to these criteria is pathognomonic for Essential
tremor. As with Parkinson’s disease, for example, Essential tremor may occur at
rest. In contrast to Parkinson’s disease, the tremor of Essential tremor is high frequency (6 Hz to 10 Hz), whereas the tremor of Parkinson’s disease is approximately
4 Hz to 6 Hz. The frequency of tremor in Essential tremor slows with aging, such
that the tremor in an older patient with Essential tremor may be the same as a
patient with Parkinson’s disease.
Among the other features that support a diagnosis of Essential tremor are (1) a
chronic condition; (2)  reduction of tremor with alcohol ingestion (although the
absence of an effect is not evidence against Essential tremor); (3) a family history
of tremor (although studies demonstrate a considerable prevalence of significant
tremor in first-degree relatives of patients without tremor [Louis et al. 2001]; a family history may therefore not have sufficient positive or negative predictive value);
(4) absence of evidence of neurological symptoms beyond tremor, such as evidence
of sensory, pyramidal, or hyperkinetic extrapyramidal (e.g., dystonia) system
involvement.
The differential diagnosis for the type of tremor relevant to Essential tremor is
fairly long and includes a variety of neurodegenerative, toxic, and metabolic disorders (Buijink et al. 2012). Every patient has a degree of tremor. Yet it is not to the
severity typically associated with Essential tremor. However, a number of conditions
and medications, including those obtained without a prescription, may exacerbate
physiologic tremor. These include, but are not limited to, the following: (1) hyperthyroidism, (2)  hyperadrenalism, (3)  phenochromocytomas, and (4)  sympatheticomemitic medications. A number of other medications can produce tremor, such
as valproic acid, neuroleptics, lithium, selective serotonin reuptake inhibitors,
β-agonist (albuterol), central nervous system stimulants (methylphenidate), central
nervous system depressants, and rebound phenomena (ethanol, benzodiazepines;
Elias and Shah 2014). Also to be considered are tremor-predominant Parkinson’s
disease, drug-induced parkinsonism, dystonic tremor, and psychogenic factors.
Some investigators have advocated the use of electrophysiological measures
using electromyographic and accelerometer data. In one study, use of such measures demonstrated a sensitivity of 97.7% and a specificity of 82.3% for Essential

a history of certain drug usage correlated with the history of the tremor would favor a toxic tremor. What are the odds of a patient having both Essential tremor and hyperthyroidism? Such a presumption implies that somehow the probability of having Essential tremor lowers the probability of having hyperthyroidism. what is the probability of the second flip also being heads? From the prior probability (before any flips) that there would be two head in a row being 25%. Specificity and sensitivity. for example. The presence of abnormalities of sensory. a patient with tremor and a family history of tremor is almost immediately diagnosed as having Essential tremor without further consideration of possible contemporaneous presence of another cause of tremor. I know of no data by which to assess the prior probabilities. signs. There is no way. But the correct answer is that the probability of the second flip being heads after the first flip being heads is 50%. Given the population of patients seen in the clinic of the investigators. however. After the diagnosis of Essential tremor. Where to draw the line is a matter of judgment rather than habit or default. Because there is nothing pathognomonic about the nature of the tremor of Essential tremor.1% and the negative predictive value was 91. and histories that would be inconsistent with Essential tremor and indicative of other conditions. relying on determining whether there are symptoms. and laboratory tests. It may be infeasible to exclude every other possible cause of tremor. to assess the diagnostic value of the electrophysiological studies. one might say that the probability of the second flip being heads following the first flip of heads is 25%. In the case of the differential diagnosis of tremor. For example. pyramidal. the probability of hyperthyroidism is sufficiently high to warrant the appropriate history. therefore. it is the percentage of those who actually have Essential tremor from others that have another tremor syndrome. is inconsistent with Essential tremor. the probability of hyperthyroidism remains undiminished. the positive predictive value was 95. and hyperkinetic extrapyramidal systems. the most frequent being tremor-predominant Parkinson’s disease (as distinct from other presentations of Parkinson’s disease). The question becomes: what are the prior probabilities in the specific context of the referring physician and healthcare professional? Before applying such criteria to DBS for patients with tremor. much like the gambler who believes that past losses means that he is due for a win. Thus the mere diagnosis of Essential tremor is insufficient to warrant exclusion of other simultaneous causes of tremor. thanks to the Gambler’s fallacy and the premium often placed on jumping to the diagnosis without consideration of a differential diagnosis. one must first consider the prior probabilities for patients seeking DBS. The issues of differential diagnoses is problematic.78 2 0 T hings to K now A bout D eep B rain S timulation tremor (Gironell et al. . More appropriate are positive and negative predictive values based on prior probabilities (the prevalence of patients with essential tremor and other tremor conditions). are inappropriate measures of diagnostic utility. A coin toss presents a useful example. If the probability of hyperthyroidism was sufficient to pursue the possible diagnosis of hyperthyroidism. After the first flip resulting in heads. the probability is no lower following the diagnosis of Essential tremor. Also. In this case. 2004). Symptoms and signs of hyperthyroidism may suggest a metabolic tremor. What is the probability of two heads in a row? The answer is 25%. such as hyperthyroidism. the diagnosis of Essential tremor in many ways remains one of exclusion. physical examination.1%.

Hence. In order to do so. Though a patient’s tremor would probably improve (Stover et al. it would not be patients with obvious Parkinson’s disease. Patients selected for DBS in the vicinity of the ventral intermediate thalamus are selected on the basis of the predominant symptom of tremor. The response to the trihexyphenidyl in a patient who did not respond to levodopa may mitigate to some degree the fact that she did not have Parkinson’s disease. 2011). Patients with Essential tremor may have bradykinesia to the same extent as patients with early Parkinson’s disease (Montgomery et al. and the latter can have postural and action tremor as well. Also. there is little to be gained by undergoing expensive and invasive tests such as SPECT scans. it would be patients with tremor-predominant Parkinson’s disease rather than Essential tremor. for example. Unfortunately. Fourteen percent of patients diagnosed with Parkinsonism had a normal SPECT scan. and one patient. One study focusing on tremor-predominant Parkinson’s disease versus non-parkinsonian tremor found that 10% of patients diagnosed with non-parkinsonian tremor experienced reduced ligand uptake. As discussed previously. At least if a patient is referred for DBS in the vicinity of the posterior subthalamic area. If a patient with Parkinson’s disease is misidentified as having Essential tremor. will not be controlled by DBS in the vicinity of the thalamus. Distinguishing between Essential tremor and tremor-predominant Parkinson’s disease may be problematic for a number of reasons. In this case. the tremor frequency of older patients with Essential tremor may be the same as that of patients with Parkinson’s disease. The important point is to avoid DBS in the vicinity of the globus . conventional wisdom holds that other symptoms. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor79 Perhaps the most frequent diagnosis to exclude is tremor-predominant Parkinson’s disease. one would have to demonstrate sufficient positive and negative predictive value. Yet this uptake occurred only symmetrically (Sixel-Doring et al. 2005. If one assumes that future studies substantiate those described here. Should it be the case that symptoms other than tremor in patients with Parkinson’s disease improve with DBS in the vicinity of the ventral intermediate nucleus of the thalamus. there is no data for DBS in the vicinity of the globus pallidus interna for Essential tremor. 2000) as well as micrographia (MartinezHernandez and Louis 2014). Other symptoms undergo little evaluation. 2008). there is some evidence that a patient’s Essential tremor may be helped (Blomstedt et  al.7. the real question is: what would be the consequence? A patient with Essential tremor may be falsely identified as having Parkinson’s disease and undergo DBS in the vicinity of the subthalamic nucleus or the globus pallidus interna. In a study of nine patients with Parkinson’s disease. Yet this demonstration must be based on prevalence of the relevant populations. who failed to respond to levodopa. a significant number of patients presumed to have Parkinson’s disease have tremor that is unresponsive or only partially responsive to levodopa. Some experts have advocated use of dopamine transporter ligand imaging—single photon emission computerized tomography (SPECT). levodopa unresponsiveness is problematic as a criteria to differentiate Essential tremor from tremor-predominant Parkinson’s disease. which may appear years later. she may undergo DBS in the vicinity of the ventral intermediate thalamic nucleus. nonetheless experienced nearly complete reduction in tremor with trihexyphenidyl (Koller 1986). Lind et al. 2010). five experienced less than or equal to 50% reduction in tremor. There is little evidence to support the conventional wisdom.

. What often goes unreported is the statistical distribution of the response of each subject. the mean is likewise 50%. without knowing the underlying distribution. Thus. The practical result may be an overestimation or an underestimation of the potential benefits that may be expected (perhaps related to the degree the physician and healthcare professionals are optimists or pessimists). because there is no evidence that DBS in the vicinity of the globus pallidus interna improves Essential tremor. Better estimates when the distribution is unknown or not reported are the medians and quartiles. Targeting the head representation. The mean value is only meaningful if one knows the distribution. The exception may be patients whose head tremor is the only symptom warranted consideration of DBS in the vicinity of the ventral intermediate nucleus of the thalamus. To report these mean improvements is to convey a misrepresentation. Contrary to the practice in the vast majority of publications. The final decision is ultimately based on the judgment of experienced experts. If a version of the first example involves a case in which 1 million subjects realized 100% improvement and 1 million subjects realized 0% improvement. and confidence intervals. One must know the distribution of results from which the mean was obtained. language. it is essentially a flip of the coin whether a particular patient would experience benefit. One might object by claiming that no one would base a judgment on a mere two subjects. One finds an example of this in the situation in which one subject realizes 100% improvement and a second 0% improvement. Yet the standard deviation is uninformative if the distribution is heavily skewed or platykurtic (of more uniform distribution). Yet should both subjects realize a 50% improvement. there is little question that a patient would benefit. and probably in the vicinity of the subthalamic nucleus. standard deviations (or the derivative confidence intervals) are provided in addition to the mean. Botulinum toxin produces even less. The mean improvement is 50%. probably significantly increases the risk for speech. In some studies. one finds it difficult to have confidence in such descriptive statistics as mean. Exhaustion of All Reasonable Less Invasive Alternative Therapies According to historical data. DBS in the vicinity of the ventral intermediate nucleus of the thalamus produces an approximate mean 75% improvement. standard deviation. is more effective than medications and intramuscular injections of botulinum toxin. which rests on the best available information. 50% improvement and the probability that any one patient would benefit would be a flip of the coin.80 2 0 T hings to K now A bout D eep B rain S timulation pallidus interna for patients for whom the diagnosis is between Essential tremor and tremor-predominant Parkinson’s disease. In the second situation. a strong argument may be made that DBS in the vicinity of the ventral intermediate nucleus of the thalamus. whereas medications produce less than 50%. which would be necessary for the treatment of the head tremor. because the calculation of the standard deviation is heavily influenced by outliers and therefore overestimates the actual variance. publishing mean improvement in response to any therapy is meaningless. In the first situation. and swallowing complications. the mean remains the same: To wit.

in which the initial agent with the highest probability of efficacy with a corresponding low risk of adverse effects is titrated to the maximal dose. a physician or healthcare professional must use judgment guided in many cases by the principles or spirit of statistical inference (Montgomery and Turkstra 2003) while respecting the necessity of values. one would need 7 years to exhaust the entire 28 agents or 9 months if only one agent is attempted from each category.108. If one assumes that he will need DBS. a physician or healthcare professional is confronted with the immediacy of a patient’s needs. One may argue that only one agent in each category need be attempted (an assumption not tested by randomized control trials). These conclusions were based on group data (Lee et al. for a total of 268. If each combination was tried for three months before rendering a verdict. it is discontinued. which would require 40 years and 6 months to test. Left unasked was the most important question: How many . For example. Rather.435. a study was cited in which patients were treated with arotinolol 30 mg per day and propranolol 160 mg per day (lesser doses were studied but those results are not relevant to the present considerations). then it would take 67. in which case the combinations would be 15.7. according to efficacy or tolerance. 2013). one may confront the assessment of whether a patient has exhausted all reasonable attempts at medication and botulinum toxin injection. which were comparable in efficacy and tolerance. the number of combinations is 162. One may take a sequential approach. If one assumes that each of these steps takes 3 months. If the initial agent provides some benefit and is tolerated. he would have to endure diminished quality of life for nearly four years before receiving definitive treatment. For example. Yet it is important to note that only crossover studies in which the same patient was exposed to all the medications being compared can provide useful data for consideration of stratification. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor81 Unlike science. A second agent is introduced and managed in the same way as was the initial agent. The adequacy of prior nonsurgical treatments may be posed as two questions: Were enough different treatments considered? Was each treatment maximized to the point where any further increase in the intensity of the treatment would be futile? With respect to the range of treatments and combinations attempted. If the initial agent provides no benefit. 2003).455 combinations. is license neither to act indiscriminately nor to refrain from acting. The lack of statistically complete data.864 years. and 3 neuroleptics for a total of 28 agents (Zappia et al. 2013)  provided some data for stratification of agents with categories. The combinations are even greater if intramuscular botulinum toxin injections are included. in which a conclusion may be postponed until additional subjects or laboratory animals can be utilized. it is retained. If one assumes that it is only necessary to test two agents from each group. The review by members of the Italian Movement Disorders Association (Zappia et  al. A newly diagnosed patient with Essential tremor suffers diminished quality of life. such as would be expected in randomized controlled trials in Evidence-Based Medicine. Immediately one is confronted by the fact there are more combinations of different agents than could be tried in any patient. 11 anticonvulsants. With a trial of each combination requiring three months. The necessary presumption is that each agent within each group has exactly the same efficacy and safety. a review listed 14 beta blockers. it would take three years and nine months to try them all.

1979). an adequate trial is defined by three results: (1) a dose that produces adequate relief and is tolerated. In that study. The p value. clonazepam. The complicated criteria is at what dose would any further increase be not likely to produce benefit. In one study employing propranolol up to 800 mg per day. 86% were on two. higher doses did not help (Koller 1986). The second criteria is rather unproblematic. nine patients went to 250 mg per day. however. which holds that a dose associated with an adverse effect that cannot be circumvented constitutes a reasonable trial. 13% were on three. the dose of propranolol should logically be increased to 320 mg per day. Generally. propranolol. Another study cited studied five different beta blockers in each of nine patients (Jefferson et al. the evidence is insufficient to rule out the use of one agent if another agent failed. The first criteria is not relevant to patients considering DBS. An analogous situation exists in the treatment of epilepsy with concern to overtreatment. Reanalysis using a Friedman’s Analysis of Variance on ranks with repeated measures demonstrated no statistically significant differences.067. (2) a dose at which there is a limiting adverse effect that cannot be circumvented. The agents included placebo. Thus it would seem futile to go beyond three agents and. this higher risk is not germane because of criteria 2. The subjective reports on efficacy for tremor were reported for each patient. suggested a trend. surgery for epilepsy may be indicated. This depends on establishing a dose–response curve for each agent. comparable data does not exist for patients with Essential tremor (or most other indications for DBS). In one study of patients with newly diagnosed and chronic epilepsy seizure-free for at least a year. propranolol.82 2 0 T hings to K now A bout D eep B rain S timulation patients did not benefit on one agent but did benefit on the other? In this case. Doses of primidone were increased until a patient’s tremor was under sufficient control or experienced limiting adverse effects. and all of those went on to 1.000 mg per day. A patient . At the least it states that some patients tolerate but do not appear to have any greater benefit with doses higher than 250 mg per day. although such higher doses are likely associated with a much higher risk of adverse effects. and topiramate is addressed next. Rather. To conclude that the medications are equivalent is therefore to commit a type II statistical error of inferring that there is no difference when one truly exists. Based on this study. Unfortunately. Eight patients went to 750 mg per day. and 1% were on four drugs (Stephen and Brodie 2002). provided one requires a 95% confidence in the evidence. A dose-ranging study for primidone based on 22 subjects was reported. that the five different beta blockers were all the same. sotalol. which was. for select patients. One must not conclude. the maximum effect of propranolol on tremor for all subjects was at 320 mg per day in total daily dose. Their analysis appears to have pooled data across subjects rather than examine the differences between the responses to each agent within an individual subject. The issue of what constitutes an adequate trial of primidone. However. One aspect of overtreatment is the number of medications simultaneously used (polypharmacy). and atenolol. and (3) a dose beyond which there is little likelihood of benefit owing either to lack of efficacy or the risk of adverse effects. However. although the results are not described to the level of detail for the purposes here (Koller and Royse 1986). the crossover design allowed for a higher powered study but failed to address the most pressing issue that would allow one to stratify the regimen. the study probably was underpowered as a consequence of the small sample size and variability among the subjects.

yet there is no a priori knowledge that automatically reduces the range of medications that might be effective. Distal hand tremor could be treated. all can take comfort by believing that the most reasonable decision has been made based on the proper balance of uncertainty that might continue attempts at non-DBS treatment versus how pressing is the need to relieve the tremor. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor83 that took up to 250 mg per day could be considered to have maximized the dose of primidone. Botulinum toxin injections are suggested for patients with predominately head tremor (particularly “no-no” tremor) and are mentioned for distal upper extremity tremor for consideration by a patient. The lack of knowledge as to what constitutes exhaustion of all reasonable medications should not instill therapeutic nihilism or panic but rather equipoise. propranolol. Ability to Tolerate Deep Brain Stimulation Surgery Unlike patients with Parkinson’s disease. but even if a patient reached that dose. suggesting a skewed distribution toward higher doses. This study thus suggests that at least 400 mg per day would be expected. there is insufficient knowledge to effectively determine when all reasonable medical treatments have been exhausted for patients with Essential tremor considering DBS. When carefully explained to a patient or the surrogate and when the patient and/or surrogate has an understanding of the epistemic status of the issue. cognitive issues appear to be less pressing in patients with Essential tremor. equipoise can be achieved by including a patient or a patient’s surrogate in the decision-making process.7. Certainly. clonazepam. there is the risk of weakness adversely affecting hand function. 2006). The final attained dose for topiramate was 292 (assuming mean) with a standard deviation of 129 mg/day topiramate. A study of topiramate utilized a dose-escalation procedure to the maximum tolerated or reaching a sufficient therapeutic effect. and topiramate. if there is a significant dementia. one could not assume that no further doses would provide sufficient benefit. Unfortunately. a dose–response curve was not provided to see at which dose the response became asymptotic suggesting a limit to any further increases (Ondo et al. however. 375 mg/day. This suggests that a very large percentage of patients reached maximal doses. No dose–response data for clonazapine in Essential tremor could be found on PubMed search. particularly for “no-no” tremor. a “shotgun” approach where every possible medication is attempted is not feasible. The maximum dose for that study was 400 mg per day at 50 mg increments. and this issue is discussed in more detail in ­chapter 10. Injections for “yes-yes” tremor likely will increase the risk for dysphagia. In the final analysis. it is necessary to clearly judge whether any reduction in tremor would have any . I recommend a history of adequate trial of primidone. This means it is unknown whether higher doses would have produced greater benefit. The same questions attend the adequacy of intramuscular injections of botulinum toxin as for other disorders. A  median. Further. Clearly. Intramuscular injections of botulinum toxin injections into the sets of antagonist muscles whose reciprocal activations are causing tremor can be considered. was reported.

experience. and credentials in managing the medications as well as the DBS system. DBS adjustment requires simultaneous adjustments of medications and. S U M M A RY Patient selection for DBS in the vicinity of the ventral intermediate nucleus of the thalamus depends on demonstrating the appropriate diagnosis. skills. Nonetheless. Assurance of Appropriate Postoperative Care Benefit does not accrue with the surgical implantation of the DBS lead but rather when electrical stimulation is begun and adjusted. However.84 2 0 T hings to K now A bout D eep B rain S timulation meaningful impact on a patient’s quality of life considered in its widest connotation. Declining to address the issue by avoiding discussion of DBS as an option is not tenable or ethical. language. it is important to be cognizant of the risk and where necessary assure the capability of urgent psychiatric intervention postoperatively should that be needed. The postoperative care requires physicians and healthcare professionals with sufficient knowledge. skills. but this typically resolves. Transient worsening of gait also may be seen. ability to tolerate the surgery. family members and caregivers expect that the physician and healthcare professionals provide advice based on a rational analysis of the best data available. Optimal placement of the DBS lead necessitates its being placed in the appropriate homuncular representation. experience. and swallowing problems are of concern. the only method for such localization is intraoperative neurophysiological monitoring. typically the distal upper extremity although the lower extremity may be indicated for orthostatic tremor. Ethical considerations are discussed in ­chapter 19. Patients with significant speech. surgery may be accomplished successfully with the use of dexmedetomidine anesthesia. consequently. DBS programmers must have sufficient knowledge. exhaustion of all reasonable medications. Though it is optimal to have a patient awake during the intraoperative microelectrode recording and test stimulation through the DBS lead. DBS adjustment may require relatively frequent visits for adjustments. significant deference should be given to a patient’s or the patient’s surrogate as to the quality of life a patient has and how much a patient or a patient’s surrogate would be willing to risk. patients. Depression or an exacerbation of depression may occur postoperatively. Deciding when a patient has exhausted all reasonable nonsurgical alternatives is highly problematic given the paucity of knowledge directly bearing on the relevant questions. . language. although the presence of these symptoms are unusual in Essential tremor preoperatively. Consequently. their presence should alert the physician and healthcare professional as to an alternative diagnosis. and swallowing problems. and credentials to manage medications as well as the DBS systems. Currently. It is also important to avoid the head representation in order to minimize the risk of worsened speech. and assurance of adequate postoperative care. As per previous discussions in other chapters.

Liepe K.25(10):1350–1356. Louis ED.15(3):511–515. Contarino MF. Eur J Neurol. Montgomery EB Jr. 2010.and long-term results and critical target area. Sixel-Doring F. Koller WC. 2014. Louis ED:  Survey of medication usage patterns among essential tremor patients: movement disorder specialists vs. Frucht S. Royse VL. Turkstra LS. Louis ED.17(6):482–485. Neurology 1986. . How to tackle tremor—systematic review of the literature and diagnostic work-up. Henchcliffe C:  How are we doing with the treatment of essential tremor (ET)? Persistence of patients with ET on medication: data from 528 patients in three settings. Deep brain stimulation in the posterior subthalamic area in the treatment of essential tremor. Koelman JH..311(9):948–954. Rios E. Parkinsonism Relat Disord. 2000.16(9):604–607. Mild tremor in relatives of patients with essential tremor:  what does this tell us about the penetrance of the disease? Arch Neurol. Pascual-Sedano B. 2012. J Med Speech Lang Pathol 2003.17(6):882–884. A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor. Schechtmann G.29(7):960–961. Kim JW. Buijink AW. Lind G. Louis ED:  Macrographia in essential tremor:  a study of patients with and without rest tremor. Baker KB. Efficacy of primidone in essential tremor. Mollenhauer B. Routine neurophysiologic tremor analysis as a diagnostic tool for essential tremor: a prospective study. 1986.11:ix–xii.86(4):253–258. Louis ED. 2008.43(1):42–43. general neurologists. Sandvik U. 2010.60(1):38–48. Koller WC.9(6):341–347. Kulisevsky J. Identifying the Least Acceptable DBS Candidates Among Patients with Essential Tremor85 R EFER ENCES Blomstedt P. Gerontology 2014. 2011. Connor GS. Mov Disord. Diaz NL. Lyons K.. 2003. Topiramate in essential tremor: a double-blind. Okun MS: Rationale and clinical pearls for primary care doctors referring patients for deep brain stimulation. Elias WJ.66(5):672–677. Tisch S. Stereotact Funct Neurosurg. Montgomery EB Jr. Motor initiation and execution in essential tremor and Parkinson’s disease. 2004. Pharmacologic treatment of parkinsonian tremor. Marsden CD. et al. JAMA 2014.258(12):2147–2154. J Neurol. Front Neurol. Subthalamic stimulation for essential tremor. beta-Adrenoreceptor antagonists in essential tremor. et al. Jankovic J. et al. Dose–response relationship of propranolol in the treatment of essential tremor. Lee KS. Neurology 2006. et al. J Neurol Neurosurg Psychiatry 1979. Arch Neurol. et  al. The role of 123I-FP-CIT-SPECT in the differential diagnosis of Parkinson and tremor syndromes: a critical assessment of 125 cases.42(10):904–909. Ford B. Gillman A: Factors associated with receptivity to deep brain stimulation surgery among essential tremor cases. Jefferson D. 2010. Gironell A. Martinez-Ramirez D. Mov Disord. 2011. Mov Disord. J Clin Neurophysiol. Shah BB: Tremor. Lind C. 2001. et al.7. Parkinsonism Relat Disord. Ondo WG. Evidenced based medicine: let’s be reasonable. Koller WC. short.21(6):446–450. placebo-controlled trial. Kim JS.36(1):121–124.3:146. Parkinsonism Relat Disord.58(10):1584–1589. Jenner P. 1986. Arch Neurol.43(2):126–127. et al. et  al. Martinez-Hernandez HR.

Evatt ML.62(1):141–143. Brodie MJ: Seizure freedom with more than one antiepileptic drug. J Neurol. Seizure 2002. et  al. 2013. Arch Neurol. Treatment of essential tremor:  a systematic review of evidence and recommendations from the Italian Movement Disorders Association.260(3):714–740. et  al. Stimulation of the subthalamic nucleus in a patient with Parkinson disease and essential tremor. Bruno E. Zappia M. 2005. Okun MS.11(6):349–351. .86 2 0 T hings to K now A bout D eep B rain S timulation Stephen LJ. Stover NP. Albanese A.

8 Postoperative Care for Essential Tremor C H A L L EN G ES Postoperative care centers mostly around Deep Brain Stimulation (DBS) programming. such as the tactile region of the ventral caudal thalamus producing intolerable paresthesias. patients with Parkinson’s disease can experience severe psychosocial stress even as their symptoms improve (Schupbach et al. The same considerations apply to DBS programming of DBS in the vicinity of the subthalamic nucleus. and (4) the impact of the postoperative status on psychosocial issues. The adverse effects related to stimulation may be specific. (3)  adjustments of other treatments such as medications. EF FI CACY Detailed discussions of programming of DBS in the vicinity of the ventral intermediate nucleus of the thalamus is beyond the scope of this chapter. This chapter addresses primarily DBS vicinity of the ventral intermediate nucleus of the thalamus rather than other targets that have been proposed for Essential tremor. Alternatively. meaning explainable by spread of electrical current to unintended targets. pulse width. Discussed here are some of the basic considerations of issues that might involve the nonprogramming physician and healthcare professional. though not exclusively. The large number of potentially relevant combinations of electrode . 2006). stimulation can produce adverse effects that are not clearly related to the structures in the immediate anatomical regions but may be related to stimulation of the ventral intermediate nucleus of the thalamus. Thus the approach to DBS programming is important for efficient and effective programming. (2) adverse effects related to the stimulation. which is discussed in c­ hapter 5. and stimulation frequency or rate). There are literally thousands of combinations of electrode configurations (the set of active electrical contacts on the DBS lead) and stimulation parameters (voltage or electrical current. For example. and addresses several issues: (1) efficacy. and readers are referred to Montgomery (2010).

Programming with a constant voltage implanted pulse generator does not directly control the electrical current and thus does not directly control the amount of electrical charges onto the neuronal . At the least. Unfortunately. Web-based programs are being developed to assist those without sufficient or ongoing experience to provide expert postoperative programming. potentially leading to ineffective and inefficient programming and. 1999). these observations point to the critical importance of careful postoperative programming and of surveying a sufficiently large number of electrode combinations and stimulation parameters. It may be that these stimulation parameters are just what 68% of patients need. most programmers do not venture far. based on the nature of the data. The critical issue is how far from the mean stimulation parameters and typical electrode configurations the programmer is willing to venture. However. Quite often. 2005). and inconveniences related to DBS surgery.81 volts (V). it may be that these parameters are just what were tried in 68% of the patients. Such patients may be falsely labeled as DBS failures and fall back to the referring physician and healthcare professional no better off for the risks. continued requirements of medical regimens that were proven ineffective for the patient in the first place. such as the axons (Montgomery 2010). Patients may be willing to travel hundreds of miles for DBS implantation surgery yet not willing to make the same trip on a biweekly or monthly basis for programming. With respect to frequency. the mean and standard deviation suggests that the range of voltages used was from 1.72 pps. While considering a wider range of possible electrode configurations and stimulation parameters increases the demands on programmers to be efficient. there is a significant problem. For example.36 pulses per second (pps) with a standard deviation of 24. consequently. This would mean that the range of frequencies for 68% of the patients would be from 131.6 to 181. Alternatively. The total number of negative electrical charges is determined by the electrical current and the duration of the electrical pulse. In my experience.17 with a standard deviation of 0. The benefit does not come from the DBS lead being implanted but with the stimulator turned on and programmed. It should be noted that studies of patients thought to be DBS failures demonstrated that 50 of them had good outcomes with reprogramming (Okun et al. The critical factor underlying efficacy is delivery of negative electrical charges onto the surface of the neural elements. the number of programs not venturing far from the mean or median is much greater. With the awareness of the importance of postoperative programming to the benefit of DBS. One of the major problems facing patients with DBS is finding appropriate postoperative care.36 to 2. in one study the mean voltage was 2. the voltages provided by the typical implanted pulse generators are ordinal. setting those concerns aside. there are a number of techniques that can be used to facilitate efficient programming (Montgomery 2010). noninterval values rendering application of typical parametric summary statistics problematic.88 2 0 T hings to K now A bout D eep B rain S timulation configurations and stimulation parameters could bewilder some programmers. One could argue that it is unethical to implant a DBS system without prior arrangements for postoperative care (see ­chapter 19).98 V in 68% of patients. discomforts. overestimates the actual variance. the mean was 156. the programmer will start from those electrode configurations and stimulation parameters described in the literature as the mean or most typical. When the fact is recognized that the standard deviations described.1 pps (Limousin et al.

but typically this is self-limiting. For patients with preexisting depression. some patients can be acutely more depressed in the immediate postoperative period. and lead migration. I recommend obtaining an anterior-posterior and lateral skull and chest X-rays to demonstrate the physical status of the system and position of the DBS lead in the brain relative to skull structures. This can be avoided by the use of constant current implanted pulse generators. Often it is not necessary to increase the strength of the stimulation. In both cases. continued suspicion of the possibility of an intracranial hemorrhage in the event of a late adverse neurological change is needed (Chung et al. A DV ER S E EFF ECTS Adverse effects can be related to the surgical procedure and from stimulation. Generally. The danger is that habit can be confused with knowledge. electrical discontinuity. such as lead fracture. . The consequence can be a marked change in efficacy. In the event of a change in efficacy. Rather. including battery failure. Postoperative Care for Essential Tremor89 elements. Also. 2014). Management of this complication is no different from intracranial hemorrhage or infarction from any other cause. It is important to note that intracranial hemorrhages may be delayed and. it is important to be prepared for a significant worsening of the tremor. some patients develop an adaptive plasticity such that the tremor continues after the DBS has stopped. such as the battery running out. increased surveillance postoperatively would be indicated. Interesting. Also related to surgery is the risk of infection discussed in the following. hence. which can vary substantially. The former typically involve the risks of intracranial hemorrhage and infection. Typically this is self-limiting. The postoperative consequences of intracranial hemorrhage depend on the location and extent of the hemorrhage. the effects of the stimulation voltage are mediated by the impedance. Habituation may develop limiting continued tremor control (Barbe et al. 2011). There can be a number of reasons for failure. If this is correct. Many patients can regain tremor control by changing electrode configurations or stimulation parameters. failure to recharge the battery in rechargeable units. then one has to wonder what drives the approach to postoperative programming: principles or habit. Occasionally. ataxia may be seen postoperatively even before active DBS.8. an easily obtained repeat skull and chest X-rays may demonstrate a break in the electrical connections or DBS lead migration. For patients with significant histories of depression. arrangements for urgent psychiatric intervention postoperatively might be made. with sudden and potentially severe exacerbation of the underlying disease for which the DBS was indicated. patients are advised to turn the stimulator off at night. For some patients with significant tolerance. it does not seem popular. Despite the significant technical and neurophysiological advantages of constant current DBS. Sudden changes in efficacy can be due to failure of the DBS system. and particularly for those experiencing some tolerance. Any abrupt change in the impedance at the DBS electrode–brain interface can change the effective current being delivered to the brain when using a constant-voltage implanted pulse generator. a weeklong “holiday” from stimulation may be recommended.

Reduction of medications should be strategic. To date and contrary to DBS for Parkinson’s disease. can identify the homuncular representation. While this does not appear to be a major problem for most patients with Essential tremor. In most cases. For these patients. the adverse effects can be related to spread of stimulation current to unintended structures. and some surgeons believe that transient paresthesias in the contralateral hand is evidence sufficient for DBS lead implantation. For example. Stimulation of the head homuncular representation can be associated with increased risks of problems with speech. language. and swallowing. prevention of this complication is important and can only be accomplished by identifying the homuncular representation during DBS lead implantation surgery. it may be possible to program a set of alternative stimulation configurations and parameters. language. 2012). the program can be switched to one with a lower voltage or current. and swallowing for when tremor control is at a premium. this requires the use of intraoperative microelectrode recordings (Montgomery 2014). starting with those medications causing the most significant adverse effects. For example. or swallowing can be relieved by programming by selecting negative contacts (cathodes) that avoid the head representation. However. and . as one study of microstimulation demonstrated that the regions of paresthesias do not correspond to the homuncular representation identified by microelectrode recordings (Grill et al. M ED I CAT I O N A D J U ST M EN TS Many patients can substantially reduce medications following successful DBS (Resnick et al. To date. beta blockers can be associated with fixed cardiac output syndrome. The choice of surgeon to whom the patient is referred is a choice for the methods used. and swallowing are a premium. friends. It is not infrequent that no combination of electrode configurations and stimulation parameters effectively relieve tremor without also affecting speech. Spread to the posterior limb of the internal capsule can result in tonic muscle contraction. or swallowing. This is not the case. In these cases. Sometimes disorders of speech. there has been little published related to the psychosocial complications associated with the patient’s change in psychosocial status with family. spread to the tactile region of the ventral caudal thalamus can produce paresthesias. When speech. bradycardia. The remarkable and somewhat abrupt improvement in patients with Parkinson’s disease can disrupt the relationships that evolved when the patient was more limited. Thus confining the volume of tissue activation by using narrow bipolar configurations to confine the volume of tissue activation above or below the head representation may help. one program may stimulate at a higher current or voltage in order to control the tremor but temporarily sacrificing speech. The question is whether the referring physician has a responsibility to choose surgeons employing what reason would argue as the most appropriate methods (see ­chapter 19). For example. and coworkers (Schupbach et al. which typically is in the center in the dorsal ventral axis and medial. these adverse effects can be circumvented by programming (Montgomery 2010). some degree of surveillance might be appropriate. 2005). There is a mistaken notion that macrostimulation. language.90 2 0 T hings to K now A bout D eep B rain S timulation Adverse effects may be related to the DBS stimulation. such as through the DBS lead. language. language. 2006).

However. the information obtained may be entirely justified given clinical concerns (Chhabra et al. physicians and healthcare professionals unfamiliar with DBS will be overly concerned and avoid diagnostic or treatment procedures that otherwise should be done. Many will be in areas where there are no expert physicians and healthcare professionals. There have been some concerns about Computed Tomography scans. It is important to recognize that programming and medication adjustments are done in an iterative fashion. particularly when the programmer lacks the knowledge. As these patients age. failure to do so may be a departure from the standards of care. either related to their DBS. and credentials to adjust medications. typically but not exclusively electrical. Often. In many situations where DBS may interfere with a diagnostic test. the DBS is adjusted rather than the medications increased. with adequate preparation for worsening of the underlying disorder for which the DBS system is being used. electromyography. Postoperative Care for Essential Tremor91 heart failure. This latter goal often is not appreciated by DBS programmers. For example. the underlying disease for which the DBS system was implanted to treat. (These energies cause rapid atomic motion that generates heat by friction. or ultrasound. The primary goal is to obtain sufficient control of tremor and minimize adverse effects whether by stimulation in combination with medications or by stimulation alone. when performed carefully using only a head coil. Readers are referred to Morishita et  al. magnetic. experience. skill. Diathermy is contraindicated. (2010). Magnetic Resonance Imaging scans using a body coil typically are contraindicated (Oluigbo and Rezai 2013). Alternatively. D EEP B R A I N ST I M U L AT I O N – R EL AT ED EM ER G EN C I ES The number of patients with implanted DBS systems continues to expand. For example. Primidone often causes confusion and lethargy. and electroencephalography. The process continues until the medications are minimized and the tremor control maximized. a secondary goal should be minimizing the medications while optimizing DBS with an effort to reduce any adverse effects from the medications and to gain economic benefit for medication reduction. Indeed. if the tremor worsens. such as an industry representative. Imaging of patients with implanted DBS systems can be dangerous to the patient and to the DBS system. Suggestions include consult with the manufacturer of the implanted DBS . 2010). these physicians and healthcare professionals will perform procedures that place the patient and the DBS systems at risk.8. such as for electrocardiograms. must be done with caution. A full discussion of emergencies in patients with implanted DBS systems is beyond the scope of this book. the DBS is programming is done to optimize tremor control. the DBS system can be turned off temporarily. and.) All physicians and healthcare professionals are advised to consult with the device manufacturer before exposing patients to any form of external energy. The fundamental principle that should be kept in mind by all physicians and healthcare professionals working with patients with implanted DBS systems is that any procedure that involves the application of energy. Then the medications are reduced. or other conditions that may be complicated by the presence of the DBS system. However. it will become increasingly likely that they will present with urgent medical conditions.

Deep brain stimulation in the nucleus ventralis intermedius in patients with essential tremor: habituation of tremor suppression.112(3):497–502. when in doubt as to what is going on. Chhabra V. No studies bearing on this issue could be found in PubMed. The issue of prophylactic antibiotics for medical procedures is problematic. However. any infection that is tracking up the DBS extension or is over the head necessitates immediate attention and probable explantation of the DBS system. The issue probably should be referred to the surgeon who implanted the DBS system. R EFER ENCES Barbe MT. Intracranial hemorrhages most often occur in the immediate postoperative period. No intracranial hemorrhages were experienced.258(3):434–439. et al. J Neurol Sci. for example subdural hematomas. and. Patients or caregivers often are given devices that allow the DBS system to be turned off and typically are advised to keep such devices with the patient. Sung E. Liebhart L. 2014. et al. 2010. and. I have been involved in a number of cases of DBS for patients in atrial fibrillation. If the physician and healthcare professional elect to turn the DBS system off. S U M M A RY DBS is highly effective but depends on appropriate postoperative programming. This problem often is exacerbated by the fact that many patients have reduced their medications significantly. Infections can arise at any time. Although rare. possible skin erosions over the implanted hardware are a source of infection. thereby having little synergistic treatments to rely on if the DBS system is turned off. J Neurosurg. However. they need to be prepared for a marked exacerbation of the underlying disease the DBS was intended to treat. Mewes K. 2011. However. Most patients tolerate DBS well. After the immediate postoperative period.342(1–2):202–203.92 2 0 T hings to K now A bout D eep B rain S timulation systems. Kim MS and Kim SJ:  Delayed intracranial hemorrhage after deep brain stimulation in two Parkinson’s disease patients. they may need to use the device provided by the patient or the patient’s caregiver. Most surgical-type complications occur in the perioperative time period but can also present late after surgery. Anticoagulants are discontinued prior to surgery and then restarted postoperatively. turn the DBS system off. . Chung EJ. Safety of magnetic resonance imaging of deep brain stimulator systems:  a serial imaging and clinical retrospective study. there have been intracranial infections. in the worst-case scenario. The question is whether patients with implanted DBS systems can be on anticoagulation for infarction prevention or in the setting of atrial fibrillation. DBS can be stopped if it produces intolerable adverse effects. delayed hemorrhages are possible. Runge M. When the physician and healthcare professional do not have access to the professional DBS programming devices. Most infections occur at the site of the implanted pulse generator and on occasion may be successfully treated with antibiotics and sometimes with explantation of the implanted pulse generator. J eurol.

Postoperative Care for Essential Tremor93 Grill WM. New  York:  Oxford University Press.116(5):1227–1234. Foote KD. et  al. Temporal excitation properties of paresthesias evoked by thalamic microstimulation. Morishita T.62(8):1250–1255. Resnick AS. Sustained medication reduction following unilateral VIM thalamic stimulation for essential tremor. 2005. . Burdick AP. 2014.66(3):289–296. et al.and postoperative urgencies and emergencies. Practice and Cases. et al. et  al. Montgomery EB Jr. et  al. Malapira T. J Neurol Neurosurg Psychiatry 1999. Oluigbo CO. Intraoperative Neurophysiological Monitoring for Deep Brain Stimulation:  Principles. Schupbach M.116:73–76. Tagliati M. Welter ML. 2012. 2010.66(12):1811–1816. Speelman JD. 2013.8.1(1):2. Pourfar M. Identification and management of deep brain stimulation intra. Simmons AM. New York: Oxford University Press. Arch Neurol. Handb Clin Neurol. Montgomery EB Jr. Clin Neurophysiol. Rezai AR: Magnetic resonance imaging safety of deep brain stimulator devices.16(3):153–162. Multicentre European study of thalamic stimulation in parkinsonian and essential tremor. Okun MS. Gielen F. Limousin P. Gargiulo M. Management of referred deep brain stimulation failures: a retrospective analysis from 2 movement disorders centers. Cooper SE. Parkinsonism Relat Disord. Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology 2006. Okun MS. Tremor Other Hyperkinet Mov. et al. 2010. 2005. Deep Brain Stimulation Programming:  Principles and Practice.

even if the degree of benefit is less than what might be seen in primary dystonia? Further. There is an immediate practical difference in that the US Food and Drug Administration (FDA) has approved DBS for primary dystonia under a Humanitarian Device Exemption. Rossi et al. “Primary” in this case originally indicated that the syndrome was idiopathic (of unknown cause). S EC O N DA RY DYSTO N I A Primary dystonia originally applied to patients without a discernible historical cause related to some such event as perinatal hypoxic/ischemic injury or a demonstrable pathology. According to the FDA at least. The latter does not do as well. Included in this category are the genetic generalized dystonias. Such a distinction is not merely semantic. In either circumstance. reimbursement for physicians providing DBS to patients with secondary dystonia is problematic. There is a tendency not to judge DBS for patients with secondary dystonia according to the merits specific to secondary dystonia. What difference does it make if a patient with secondary dystonia obtains a clinically meaningful benefit without adverse effects. There are significant clinical implications. physicians make comparisons in the respective outcomes for Deep Brain Stimulation (DBS) for primary and secondary dystonia. Secondary dystonias are associated with known such causes as tardive dystonia secondary to neuroleptic use and postanoxic dystonia typically associated with lesions in the globus pallidus. The inference is that patients with secondary dystonia are somehow less eligible for DBS. Chapter 15 contains an extensive discussion of the off-label use of FDA-approved drugs and devices for hyperkinetic disorders The historical evolution of the notion or primary versus secondary diagnoses provides interesting insight into the evolution of medical thinking. This technically leaves DBS for secondary dystonia as investigational (under Medicare definitions. 2014) or off-label.9 Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia PR I M A RY DYSTO N I A . . For example. Yet these diagnoses remain under the category of primary dystonias. DBS for secondary dystonia is well within a physician’s purview in the practice of medicine. Many of these dystonias have known causes—specific genetic abnormalities and the like. the presupposition that primary dystonias respond better than secondary dystonias is suspect.

and other conditions that left telltale signs of physical injury to the brain. such as ingestion of neuroleptic agents block dopamine receptors. the most prominent physician of his time. whose practice is based on an exclusive dogma. The first Code of Ethics published by the American Medical Association in 1847 claimed the high ground of science by stipulating that “no one can be considered as a regular practitioner.d.” It is likely that the reference to “exclusive dogma” refers to the ancient Greek dogmatic school of medicine. at  least 25 genetic mutations are associated with generalized torsion dystonia. because the actual treatments they . And though only a few patients with cervical dystonia have a known genetic abnormality. trauma. and organic chemistry (italics added)”. was his ability to merge physical diagnosis with pathological studies (Bliss 1999).). the probability of a family member also having dystonia is approximately 24% (Groen et al.—to make a proper discrimination between true science and the assumptions of ignorance and empiricism. This suggests that it is only a matter of time before other putative genetic causes are discovered.9. The secondary dystonia include dystonia consequent to perinatal hypoxic-anoxic injury.) and to empiricists who argued observation alone without reference to underlying and unseen mechanisms were sufficient for medical practice (Marcum n. with advances in molecular neurobiology and imaging. The Code of Ethics also sought to enlist the public’s help in protecting the profession: “The public ought likewise to entertain a just appreciation of medical qualifications.d. The distinction of a scientific basis claimed by allopathic physicians claiming is interesting. maintaining a distinction between primary and secondary dystonia becomes increasingly problematic. This distinction received its greatest boost with the expansion of the field of microscopic pathology by Rudolf Virchow (1821–1902) and with the Germ Theory of the mid-nineteenth century. Clinical correlations with specific events. which posited that reason alone is sufficient to practice medicine (Marcum n. and of the aids actually furnished by anatomy. For example. to the rejection of the accumulated experience of the profession. One of the reasons for the remarkable fame of William Osler (1849–1919).—to afford every encouragement and facility for the acquisition of medical education. It seems reasonable to claim that nearly every disease was primary at some point. 2012). It is interesting to note that the distinction of allopathic medicine (forerunner of modern medical doctors) rested on its purported scientific basis. I M P O R TA N C E O F (SC I EN T I FI C) CAU S A L M EC H A N I S M S With the advent of molecular neurobiology. pathology. or a fit associate in consultation. as well as such focal dystonias as cervical dystonia and the condition commonly known as writer’s cramp. it would appear inconsistent to describe these patients as primary generalized torsion dystonia. and. Primary dystonia traditionally included such disorders as generalized torsion dystonia (dystonia musculorum deformans). that every disease will someday be secondary. Though only a minority of patients with generalized torsion dystonia have an identifiable genetic abnormality. Kernicterus. Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia95 This leaves the syndrome of secondary dystonia to cover those diseases whose cause is known. physiology. generate a new secondary dystonia: tardive dystonia.

have been striking. The question is the origin and nature of the outside knowledge. for example. as might be suggested by the choice of pulverized porcelain (reminiscent of the empiricists rejected by the allopathic physicians in the 1847 Code of Ethics of the American Medical Association). occurring early in life in a patient who has a family history of similar conditions and without any known neurological insult. The emergence and present dominance of Evidence-Based Medicine. This is based on the accumulated clinical experience that such patients experience significant improvement in their dystonia following DBS. such as the DTY1 genetic abnormality (or others). presumably those with secondary dystonia? One may argue that the common features suggest a good prognosis to DBS. whereas disparate features present in those who do not do as well may imply a poor prognosis. These authors paid close attention to those features that were unimproved with DBS. which has become synonymous with randomized control trials (RCTs). It would be hard to believe that any medical scientist would suggest choosing a treatment to test willy-nilly. If. RCTs represent the supreme standard of medical knowledge and the most (if not sole) legitimate director of patient care. Yet the only reason this would not happen is some other knowledge. The question becomes: what is it about the cluster of features described here that prognosticates the potential for improvement with DBS? More important. as well as other features that may account for the variability in clinical efficacy. Conceptually speaking. presumably scientific. The features that are conjunctive and those that are disjunctive may be used as selection criteria for candidacy for DBS. symptom or sign X is always associated with a poorer prognosis. T H E I M P O R TA N C E O F D I AG N O S I S One may say that the combination of clinical symptoms and signs consistent with dystonia. Indeed. many of the practices engaged in by William Osler were much the same as those of Galen’s followers (Bliss 1999).96 2 0 T hings to K now A bout D eep B rain S timulation offered was little different than those earlier physician who held to the ideas of Galen (130–200 ad). There is nothing in either that requires any kind of causal mechanism in the diagnostic selection criteria or in the choice of treatments to study. One may say therefore that DBS is a treatment for the symptom of dystonia and not for any particular cause of dystonia. This does not require the presence of a known cause. what is the cluster of features in patients for whom DBS does not bring sufficient relief. is brought to bear on the RCT. there is nothing scientific about Evidence-Based Medicine and RCTs. Their analysis was hampered by the relative dearth of randomized controlled prospective studies and . EFFI CACY Vidailhet and colleagues (2005) published an extensive review of the literature relative the clinical efficacy of DBS for many forms of dystonia. there is nothing within either that would prohibit a study of pulverized porcelain. would likely benefit from DBS. then it is likely (though not proven) that dystonia without symptom of sign X is associated with a good prognosis regardless of etiology. Yet.

This resembles failure for these symptoms to improve with DBS for Parkinson’s disease and other conditions. Based on case reports and small series. DBS is a symptomatic treatment rather than disease-specific treatment. Eight of 26 patients with DYT1 generalized torsion dystonia experienced worsening that required placement of a second DBS lead (Cif et al. This probably owed to the selection criteria. The similar degree of improvement in dystonia over these different dystonic syndromes suggests that pathogenesis does not affect therapeutic efficacy. 2009). demonstrated a wide range of improvements. This lends support to the notion that. Unfortunately. In the latter. which required an Ashworth scale of less than 2. events related to stimulation. with many reaching the degree of improvement observed in primary generalized torsion dystonia. the most frequent concerns related to intracranial hemorrhage and infection. Patients with cervical dystonia improved to a similar degree as did patients with primary generalized torsion dystonia and patients with such myoclonus-dystonia disorders and cranial dystonias. With respect to both. however. studies across a number of disease indications and . their review suggested a degree of improvement in symptom or physical sign– based assessments. therefore. for dystonia. Vidailhet and colleagues (2005) included tardive dystonia as a primary dystonia and noted improvements not inferior to those described earlier in this chapter. no improvement was observed in speech or swallowing. leaving a population with predominantly chorea. In the attempt to exclude spasticity as a confound. 2006). such as the Burke-Marsden-Fahn Rating Scales. Vidailhet and colleagues (2005) included among the secondary dystonias dystonia-choreoathetotic cerebral palsy and a group of neurodegenerative or metabolic abnormalities. With respect to perioperative complications. Yet it also is affected by dystonia (Gordon et al. and nonspecific effects. Interestingly. 2010). the study probably also excluded patients with significant dystonia. The study of patients with dystonia-choreoathetotic cerebral palsy demonstrated a wide range of improvement—24% on average but as much as 55% in some cases (Vidailhet et al. because it is unlikely that any patients had significant dystonia. A DV ER S E E V EN TS Adverse events may be distinguished conceptually as events associated with DBS surgery. the relevance of this study for dystonia secondary to perinatal hypoxic-ischemic injury is problematic. such as Meige syndrome and blepharospasm. and events related to the psychosocial impact of the treatment. events associated with hardware failures. on the order of 50% to 60% for primary generalized torsion dystonia in more than 200 patients.9. of which Pantothenate kinase–associated neurodegeneration is an example. Adverse effects related to stimulation include those related to the spread of electrical current to unintended structures in the regional anatomy around the DBS lead. The presumption is that the Ashworth scale is specific for spasticity. only the group with NAIB (a neurological disorder associated with abnormal iron accumulation in the brain). It is not. of whom half improved and none worsened. effects related to stimulating the intended target. Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia97 lack of consistent outcomes measures. Interestingly. in these patients with cranial dystonias.

DBS of nearly every structure within the basal ganglia-thalamic-cortical system may improve the symptoms and signs of Parkinson’s disease. however. The question becomes which target to recommend. a finding consistent with the general impression that infections at the IPG site are more common that they are at the DBS lead implantation site. however. The large majority of infections occurs in the area of the chest associated with the IPG (Sillay et al. Overall risk is thus approximately 1%. In either case. Alternatively.6%. Both of these notions are incorrect (Montgomery 2012). partial removal of the hardware—the IPG. D EEP B R A I N ST I M U L AT I O N TA R G E TS In reviews of the literature. the posterior lateral globus pallidus interna has been the most common target (Vidailhet et al. There have been reports of DBS in the vicinity of the thalamus and the subthalamic nucleus. for example. all of which have been associated with improvements in dystonia. the area in which it is placed being the most frequent site of infection. In Parkinson’s disease. Sillay and colleagues (2008) reviewed their vast experience and found that their infection rate was approximately 4.6%. One rests on the confidence that stimulation of a specific target will provide sufficient efficacy and minimize the risk of adverse events. Often these hemorrhages are subdural in origin. the removal of the DBS lead or the IPG results in an interruption in the patient’s treatment and a return of symptoms and disabilities. because the choice was supported by the theory of globus pallidus interna hyperactivity as causal to Parkinson’s disease and the notion that high-frequency DBS was analogous to pallidotomy. the choice may be made according to theories of pathophysiology. there have been instances of hemorrhages remote in time to DBS lead implantation surgery. There are several aspects to the choice of target. A mere 10% or so of these. The nature and severity of complications relate to the location and extent of the hemorrhage. The incidence of intracranial hemorrhage is on the order of 10% when actively sought with postoperative imaging. the globus pallidus interna was favored initially. 2008). presumably—was attempted and met with success in 9 patients. Removal of the DBS lead clearly results in a second surgery to replace it.6%. Though most intracranial hemorrhages occur acutely.98 2 0 T hings to K now A bout D eep B rain S timulation DBS targets suggest that the risks are generally the same. DBS in Parkinson’s disease is likewise a result of . In a review. Infections are conceptually distinguished as those that necessitate removal of the DBS lead and those that do not. The incidence of infections solely with IPG replacement was 17. In the case of Parkinson’s disease. Of 14 patients with infection. are significantly symptomatic. 2013). The notion of hyperactivity of the globus pallidus interna as central to Parkinson’s disease was extrapolated to its role in other movement disorders of the basal ganglia. The overall risk of infection necessitating DBS lead removal is thus approximately 2.6%. then the risk of having to replace the DBS lead is approximately 47%. In some cases it may be necessary to remove the implanted pulse generator (IPG). If the other 5 patients from whom the DBS hardware was removed entirely also involved failures to salvage the DBS lead. This fact suggests that Parkinson’s disease is not a disorder of the globus pallidus interna but rather of the entire basal ganglia-thalamic-cortical system. the overall risk of infections associated with DBS surgery was 5.

Deep Brain Stimulation Is Safe and Effective for Patients with Dystonia99 an effect on the entire basal ganglia-thalamic-cortical system. Many secondary dystonias achieve the same level of benefit. in other words many ways to damage to neurons. It would not be unreasonable to suggest that the greatest confidence related to efficacy is with DBS in the vicinity of the globus pallidus interna. If there is relatively little confidence that DBS in the vicinity of the thalamus or subthalamic nucleus is efficacious. thalamus. it is important to keep the notion of pathophysiology separate from notions of pathoetiology. DBS in the vicinity of the globus pallidus interna is simply incidental and represents merely one route to introduce neuronal activations to the basal ganglia-thalamic-cortical system. “Do no harm” (Primum non nocere). However. there have not been controlled studies where patients are randomized to the globus pallidus interna. The average improvement in dystonic symptoms is approximately 50% to 60% in primary dystonia. is embodied in the physician’s motto. given the relative lack of data. the patient would not be a candidate. One must therefore ask whether maintaining a distinction between primary and secondary dystonia for the purpose of considering DBS . Risk of adverse effects must be weighed against possible benefit. This is a lesson learned from pathophysiological studies of Parkinsonism (Montgomery 2007). Patients with dystonia who have exhausted all other reasonable therapies face continued suffering and danger from the risks associated their dystonia if no DBS surgery is offered to them. There is another alternative:  not offering surgery to patients who have no other alternative. Whether the concept of a systems disorder applies to the pathophysiology of dystonia is unclear. This bias. the no-surgery alternative may be given more ethical weight as a consequence of Omission bias. However. which is endemic. They are entirely warranted. the issue of risk becomes practically moot. to argue that it would not be the case for dystonia. Confidence relative to the efficacy related to DBS of specific targets is problematic. T H E D EC I S I O N TO PR O C EED W I T H S U R G ERY Though is it common knowledge that one must weigh risks against benefit. This is not to suggest that future clinical trials of the thalamus and subthalamic nucleus are unwarranted. but the consequence that alters the physiology to produce the symptoms and signs of dystonia may not be specific to the mechanisms that cause neuronal injury. there are no other reasonable alternatives for patients with dystonia who are under consideration for DBS. many alternatives are often overlooked. and there is little reason. The no-surgery alternative is certainly considered in the context of benefit. For example.9. or subthalamic nucleus. To be sure. because benefit is directly consequential to performing the surgery. The globus pallidus interna represents a possible exception. Were reasonable alternatives to exist. S U M M A RY DBS is safe and effective. By definition. This motto suggests that errors of commission are worse than errors of omission (see ­chapter 19). a priori. however. In large part this is due to relatively little knowledge of pathophysiology of human dystonia. there may be many causes of dystonia.

Vasques X. Kallen MC. Deep brain stimulation for dystonia. DBS of the globus pallidus interna has generally a low risk of these complications. Rossi PJ.8(8):709–717.edu/medicine/ Montgomery EB Jr. In Internet Encyclopedia of Philosophy. Keller JL. The epistemology of deep brain stimulation and neuronal pathophysiology. Sillay KA.352(5):459–467.6:78. et al. Medicare coverage of investigational devices:  the troubled path forward for deep brain stimulation.35(6):375–381. Other complications related to DBS surgery— seizure. 2007. Cif L. Phenotypes and genetic architecture of focal primary torsion dystonia. Front Integr Neurosci. N Engl J Med. et  al. JAMA Neurol. Okun MS. J Neurol Neurosurg Psychiatry 2013. et  al. 2006. Vercueil L. Yelnik J.100 2 0 T hings to K now A bout D eep B rain S timulation makes sense. death—are exceptionally rare. 2014. and the risk of infections that necessitate the removal of the DBS lead is approximately 2%.13(8):455–465. n. http:// www. 2009. J Neurol Neurosurg Psychiatry 2012. Houeto JL. Montgomery EB Jr. Lancet Neurol. Deep brain stimulator hardware-related infections: incidence and management in a large series. Stashinko EE. The risk of serious intracranial hemorrhage is approximately 2%. Parkinsonism Relat Disord. 2010.iep. 2005. . Larson PS. et  al. Vigilance is nonetheless required. Grabli D. Vidailhet M. depend on the DBS target.: Bilateral pallidal deep brain stimulation for the treatment of patients with dystonia-choreoathetosis cerebral palsy: a prospective pilot study. The risk are relatively small. Vidailhet M. R EFER ENCES Bliss M. Long-term follow-up of DYT1 dystonia patients treated by deep brain stimulation:  an open-label study. Neurosurgery 2008.25(3):289–299. Philosophy of medicine. van de Warrenburg BP. 2012. Mov Disord.84(9):1029–1042. 1999. Machado A. et al. Basal ganglia physiology and pathophysiology:  a reappraisal. Lagrange C.83(10):1006–1011. Vidailhet M. Gordon LM. Starr PA. which are difficult to attribute to surgical trauma or stimulation of unintended structures. Marcum JA. William Osler: A Life in Medicine. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. New York: Oxford University Press.62(2):360–366. Groen JL. et al.utm.d.71(5):535–536. Gonzalez V. Other adverse effects associated with DBS. Adverse effects attributable to the spread of electrical current to unintended structures usually resolve with careful DBS programming. Can spasticity and dystonia be independently measured in cerebral palsy? Pediatr Neurol. discussion 366–367. Jutras MF.

With DBS the incidence of irreversible risks relates primarily to surgical risks. In many instances medications carry greater risk of irreversible consequences. The much harder question is which patient has the minimum acceptable criteria for an outcome whose benefit outweighs the risks. One must bear in mind that many other risks associated with DBS are usually reversible. A presumption prevails that severe adverse effects associated with medications are reversible. To reverse them one either adjusts the stimulation or ceases it altogether. But that is not where the difficulty lies. Physicians.10 Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Dystonia The chapter title sounds counterintuitive. one must pause to consider exactly the factors involved. has approved DBS for primary dystonia under a Humanitarian Device . for example used in treating dystonia and other hyperkinetic disorders. PR I M A RY DYSTO N I A V ER S U S S EC O N DA RY DYSTO N I A In medical literature and by the US Food and Drug Administration (FDA). the present selection criteria indicate who the best candidates are. provided patients are selected carefully. These risks have been consistent over multiple indications and in multiple DBS targets. a distinction is drawn between primary dystonia and secondary dystonia. whereas those associated with surgery are irreversible. may produce Tardive Dyskinesia and Tardive Dystonia. which are quite small—on the order of 2% to 4% for serious or permanent disability. Neuroleptics. Among the risks is possible irreversibility. In nearly every other publication. Though careful selection would seem to apply to patients undergoing any treatment. in fact. patients. Considerations of the ratio of risk to potential benefit are certainly germane to any treatment. The conceptual basis of this topic is discussed in detail in ­chapter 4. Deep Brain Stimulation (DBS) is remarkably effective in treating dystonia. and patients’ family members and caregivers may hold a bias that unduly colors their impression of DBS surgery. The FDA.

If one assumes this to be true. I believe that comorbidities associated with some forms of secondary dystonia reduce DBS efficacy. Where no approval has been given. This distinction may guide consideration of patients with secondary dystonia for DBS. Spasticity is thought to be related to increased excitability of the alpha lower motor neurons. The Burke-Marsden-Fahn scale. 2006). it is likely that the relative poorer outcomes with DBS in the vicinity of the globus pallidus interna is due to the effects of residual spasticity. There is no reason to believe a  priori that DBS would prove an effective treatment for spasticity and consequently. DBS proves effective in treating some cases of secondary dystonia as it is in treating primary dystonia. however. and insurers may refuse to cover it. which it is not. This would enable clinical trials to determine whether the lower degree of DBS benefit in patients with dystonic cerebral palsy correlates to the degree of spasticity. As discussed in ­chapter 9. the selection criteria discussed here observe no distinction between primary dystonia and secondary dystonia. Because DBS should be considered standard and accepted off-label use of an FDA-approved device.102 2 0 T hings to K now A bout D eep B rain S timulation Exemption. however. excessive excitability of the reflex arch involving the muscle spindles and the alpha lower motor neuron is ruled out as a cause. Evidence (Gordon et al. because they consider it experimental or investigational. meanwhile. The Ashworth scale and other clinical rating scales do a poor job of distinguishing dystonia from spasticity. Because many muscle spindles are sensitive to velocity. Physicians may refuse to offer it. Muscle tone that is constant despite the velocity of joint rotation. Though the precise mechanism of dystonia-related increased muscle tone are unknown. likely owes to dystonia. It has not. approved DBS for secondary dystonia. Methods available or under development may be able to distinguish spasticity from dystonia and provide a quantitative estimate of each. often present with considerable spasticity. pose . for example. A  detailed discussion of the issue of “off-label” use of FDA approved devices is discussed in c­ hapter 15 with respect to hyperkinetic disorders. Speech and swallowing. The distinction between spasticity and dystonia according to velocity of joint rotation relates to the mechanisms underlying the increased muscle tone. a phenomenon that is often difficult to distinguish from dystonia. This is supported by the observation that the deep tendon reflex involves muscle spindles and the alpha lower motor neuron in an exaggerated manner in spasticity and does not do so in dystonia. and the ethics are addressed in c­ hapter 19. Another example of a comorbidity that confounds assessment of DBS efficacy may be found in those cases of cranial dystonia in which speech and swallowing do not improve and may indeed worsen. particularly if one notes a “catch” and “release” associated with the joint rotation. Patients with dystonic cerebral palsy. on the other hand. lack of approval may be perceived as pejorative and may prevent patients with secondary dystonia from receiving a therapy that would otherwise benefit them. is not specific to dystonia (Gordon et al. Muscle spindle feedback results in an exaggerated output of the alpha lower motor neurons that increases resistance to muscles’ stretching in response to joint rotation. one would not expect dystonia to depend on velocity. however. 2006) and clinical experience exist to suggest that muscle tone (resistance to passive joint rotation) that depends on velocity is likely spasticity. greater rapidity of joint rotation elicits greater muscle spindle output to the alpha lower motor neuron resulting in increased resistance.

then DBS is not likely to make a meaningful difference. Over half of patients with Tardive Dyskinesia experience spontaneous remission of their symptoms. If these comorbidities are the limiting factor to improvement. I exclude from selection criteria the diagnosis of primary or secondary dystonia. A disease-duration threshold in turn predicts the threshold at which probability of spontaneous recovery is sufficiently low to justify a DBS referral. The mean number of years for remission was 5. however.6  years. Tardive Dystonia The task of determining the probability of spontaneous remission is an appreciable concern when treating Tardive Dystonia. This disorder is typically consequent to exposure to agents that block dopamine receptors.2 following diagnosis and 2. Unfortunately. Traditional neuroleptics. because it is impossible to foretell whether any particular young patient with the condition will experience an improvement in his symptoms.6 years following discontinuation of the offending agent suggests that. I recommend that the comorbidities be carefully considered.10. one may feel reluctant to subject a patient to DBS risks if that patient enjoys even a small chance of spontaneous remission. such as haloperidol or chlorpromazine. The task thus becomes that of determining the probability of a spontaneous remission in a particular form of dystonia. The question is whether this is relevant for dystonia. then DBS is not likely to result in a satisfactory or acceptable improvement. Rather.6 following discontinuation of the neuroleptic. One could argue that a mean of 2. if one assumes the data conforms to a Gaussian distribution. fewer than half of patients experienced spontaneous remission after 2. demonstrated a spontaneous remission rate of approximately 14% (Kiriakakis et al. If a patient has spasticity severe enough to limit her quality of life. but in one study none of the nine participating patients improved or remitted (Gimenez-Roldan et al. Data distribution highly skewed to the left results in a mean that is likely to be heavily influenced by . The authors noted a fivefold greater chance of remission in patients with fewer than 10 years of symptoms over those with more than 10 years. I  was unable to find any published “survival curves” of the Kaplan-Meier type that would provide a threshold in terms of disease duration. It remains uncertain whether this expectation is realistic. Many atypical neuroleptics carry this risk as well. Nonetheless. 1998). then lack of their improvement should not deter physicians from offering DBS surgery. failure of alternative therapies notwithstanding. for example. If DBS is directed to some other aim than improving speech and swallowing. Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia103 problems to DBS for Parkinson’s disease and other conditions. 1985). are widely recognized as carrying a risk of producing Tardive Dystonia. because they are more common in secondary dystonias and thus unlikely to be helped by DBS. For the aforementioned reasons. A larger retrospective study of 107 patients. P OT EN T I A L FO R S P O N TA N EO U S R EM I S S I O N Attending cases of Tourette’s syndrome is an expectation that the symptoms will decrease in severity over time (see ­chapter 13 for a detailed analysis).

because it lapses into an error in reasoning known as argumentum ad ignorantiam (argument from ignorance). 6 of 226 participating patients (2. the longer a patient lives with symptoms. 1990). Though the statement may be made. given the probability of spontaneous remission. Of course. A number of studies present findings that suggest a spontaneous remission rate of 20% (Jahanshahi et al. Cervical Dystonia Similar considerations pertain to patients with cervical dystonia. A mean duration of 4. the median span from onset to remission being three years (Castelbuono and Miller 1998). a Kaplan-Meier type survival curve would be helpful in predicting the potential for spontaneous remissions based on the duration of symptoms. patients who have lived with cervical dystonia for fewer than five years may wish to consider delaying DBS surgery if they deem a 20% chance of spontaneous remission acceptable. One may argue that it cannot be known whether these six patients actually had generalized torsion dystonia instead of psychogenic dystonia or some other reversible form. to have had a history of spontaneous remission (Cooper et  al. Generalized Torsion Dystonia In one study. the lower the probability that he will experience spontaneous remission.7%) were shown. fewer than half of patients living with symptoms for more than 2. half of patients who experienced remissions did so in the first three years of symptoms. The more persistent the dystonia. however. The most appropriate criticism is whether . In one study. upon retrospective chart review. In other words. the possibility of spontaneous remission against the dystonia’s severity and impact on her quality of life.85 years indicated that the distribution was heavily weighted toward shorter durations. patients must discuss with their physicians the feasibility of DBS. when in discussion with her treating physician. which rests on the notion that an assertion’s validity derives from an inability to assert the contrary. and direction of head deviation predicted the chance of a sustained remission. The range was from 3 months to 22 years. a median remission duration of three years was observed in nine of the participating patients. Again. gender. 27% of participating patients experienced remission.104 2 0 T hings to K now A bout D eep B rain S timulation outliers in those whose remission required a greater amount of time. age at onset. the less likely becomes spontaneous remission. For approximately 70% of participating patients. Again.6 years would experience spontaneous remission. it lacks force. form of torticollis. Blepharospasm and Meige’s Syndrome In one study. a significant number of relapses. A patient with Tardive Dystonia who is assumed to have exhausted all reasonable alternative needs to weigh. 1976). The study’s authors reported that 87% of the spontaneous remissions occurred in the first five years. Depending on severity of symptoms and impact on the quality of life. There followed. If such were the case.

a physiological dystonic posture proves sufficiently strong to thwart any active and passive attempts at . On occasion. however. may create abnormal postures indistinguishable from cervical dystonia. muscles. Physiological Dystonic Postures Versus Anatomical Dystonic Postures The distinction between physiological and anatomical dystonic postures is predicated on the notion that anatomical changes in bones. Dystonia produced by such changes is known as fixed dystonia.10. Kyphoscoliosis. is found in the effectiveness of partial denervation surgery. Indeed. These tests were unavailable at the time the study was conducted. Anatomical changes that prevent DBS or other therapies from fully relieving dystonia may result from physiological driving of abnormal postures and thus confound the distinction between physiological and anatomical dystonic postures. then any sampling issues remain the same.6% spontaneous remission therefore continues to be relevant to physicians. all patients with dystonia. for example. To claim otherwise courts error in the form of the Fallacy of Induction. Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia105 the patients studied in the retrospective chart review—the sample—truly represented the population of concern. Reduced penetrance evident even in individuals with identified genetic abnormalities indicates that the presence of the gene does not guarantee the development of dystonia. Evidence for this notion. never of the population itself. If one assumes that a physician diagnosing generalized torsion dystonia is as competent as those physicians who made the diagnosis obtained for the retrospective study. The dilemma is that one can never be sure that there exists an unobserved non-black raven. Postures limited by anatomical changes are not likely to respond to DBS. becomes immediately falsified upon encounter with a single raven whose coloring is something other than black. at least in the case of cervical dystonia.6% chance of spontaneous remission is sufficiently clinically meaningful to dissuade a patient with generalized torsion dystonia from undergoing DBS surgery. namely.” which rests on the observation of the uniform blackness of all ravens heretofore encountered. Yet cases of dystonia involving known genetic abnormalities represent only 20% to 30% of the cases (Dressler 2011). joints. The issue is whether a 2. for example—or passively by the examiner. the statement “all ravens are black. is a common complication of generalized torsion dystonia. it is the most appropriate criticism because it is perennially pertinent: One may gain exhaustive knowledge only of an investigator’s sampling of the population. that enable one to test for known genetic disorders as part of the diagnostic procedure. Physiological dystonia suggests that the abnormalities owe to abnormal brain activity’s driving muscles to form the abnormal postures. Its fallaciousness owes to the fact that the possibility remains open that an unexamined entity otherwise belonging to that kind may lack that quality. In fact. One may distinguish anatomical dystonic postures from physiological by observing the degree to which a dystonic posture is corrected actively by the patient— the geste antagoniste maneuver as performed by patients with cervical dystonia. Cervical spondylitis. Tests exists today. For instance. The sample of the review that found a 2. the risk for secondary anatomical changes argues for early aggressive treatment. and tendons contribute to or create dystonic postures. in which an observed common quality among entities that are regarded as belonging the same kind is presumed to enjoy universal validity. for example.

Some. Also. Neurodegenerative Disorders and Metabolic Disease Neurodegenerative disorders and metabolic disease that present with dystonia include mitochondrial disorders. if it does. These facts. Medications must be attempted at dosages . which will not. Segawa disease and late-onset tyrosine hydroxylase deficiency may improve with levodopa therapy. in children. some patients are refractory to these treatments. zinc. Nieman Pick C. Later in childhood (adolescence particularly). It is traditional to discuss the differential diagnosis. Hedera 2014). and DBS may be effective (Sidiropoulos et al. However. in its widest connotation. trauma may result in bony. which suggest atypical dystonia. such as cerebellar astrocytomas. and ammonium tetrathiomolybate. or anatomical (fixed) dystonia. 2013. guanidinoacetate methyltransferase deficiency. organic acidemia. may present with unusual head postures (Caress et al. of most genetic generalized torsion dystonias affecting young children. many do not. differential diagnosis (of cervical dystonia particularly) is skewed eye deviation. a condition that children intuitively learn to correct by assuming an unusual head tilt. Though many diseases present in infancy. homocystinuria. then the only material effect of a specific diagnosis is whether there is some unique medical treatment. If one assumes that DBS would be reasonably effective. which will relax when they are in such a state. in any of the conditions listed previously. A variety of congenital bony abnormalities present in children as anatomical dystonias. pantothenate kinase-associated neurodegeneration. may be precipitated by specific conditions. Interestingly. FA I LU R E O F A LT ER N AT I V E T H ER A PI ES Because most treatments other than DBS have a very low incidence of life-threatening or irreversible complications (intrathecal baclofen and intraventricular baclofen being exceptions). abnormal dopamine metabolism (Segawa disease or late-onset tyrosine hydroxylase deficiency. In such cases. 1996). Many diseases are rare and are associated with other neurological features. they must be exhausted before a patient is exposed to the risks of DBS. moreover. children with posterior fossa tumors. Wilson’s disease is treated by D-penicilamine. glucose transporter type 1) deficiency. to what degree and in what aspect. dystonia secondary to perinatal hypoxic-ischemic injury may present earlier. However. observing patients while they are sleeping or sedated enables determination of whether theirs is physiological dystonia. Fahr’s disease. should invite further investigation. Some may be treated with special diets. and tendonous abnormalities that present as anatomical dystonia. and Wilson’s disease. Dystonia in Children Children are prone to both physiological and anatomical dystonia (Herman 2006). glutaric aciduria type 1 (Pierre 2013). trientine. For example. it is important to identify those actions that constitute a reasonable attempt at these other therapies. Also. but the question is whether it matters and.106 2 0 T hings to K now A bout D eep B rain S timulation correcting it. muscular.

a strategy based on relative efficacy and adverse effects. Haloperidol has been found to be effective in cases in which such atypical neuroleptics as risperidone have been found to be ineffective (Albanese et al. the anticholinergics were reduced and discontinued. Adding to the difficulty is a lack of rigorously controlled trials and any direct comparisons. and such gamma-aminobutyric acid–related agents as baclofen and the benzodiazepines. social. In the case of dose–response curves for efficacy. one may take the point of the graph (provided it displays saturation kinetics) and select the dose at which the curve becomes asymptotic. Every patient may have different threshold for tolerance based on his particular medical. The same approach with respect to adverse effects is not likely to prove fruitful. Within each class are multiple agents. because the degree of tolerability is highly specific to the patient. One thus draws the reasonable. Worsening depression and increased risk of suicide are important considerations in any review of these findings. rather. dopamine antagonists. If the anticholinergic medication provided some benefit (presumably without intolerable side effects). The use of dopamine antagonists has been reported as useful. Exhausting every possible combination is clearly problematic. . inference that those who fail baclofen are unlikely to benefit from clonazepam. Patients were started on anticholinergics that were titrated up to either the maximum tolerated dosage. Failure of anticholinergics. does not predict failure with baclofen. Greene et al. psychological. Approximately 20% of patients who failed to achieve satisfactory benefit from anticholinergics improved with baclofen. This dose suggests that further dosage increases will accomplish little. the rarity of these conditions notwithstanding. Unfortunately. of various options (Albanese et al. there exist no pharmacological studies that provide dose– response curves for efficacy or adverse effects. The benefit realized by use of levodopa in patients with Segawa disease and late-onset tyrosine hydroxylase deficiency argues for a therapeutic trial. The possible number of combinations is thus 31 among the five classes and 1. or the level of sufficient benefit. 50 mg per day. if a patient fails anticholinergics. 2012). One must construct. and economic contexts. in other words. (1988) stated that patients did not respond as well to clonazepam as they did to baclofen. Using a hierarchical approach. Medications The various classes of agents used include the anticholinergics.10. another agent was added. Greene and colleagues (1988) performed a retrospective chart analysis of 600 charts.023 if two agents from each class are considered. 2006). Those patients who failed anticholinergics were then started on another agent. albeit tentative. Thus. baclofen should be tried. dopamine-depleting agents. 2006). Otherwise. within and between classes. Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia107 sufficient to render negligible the probability of improvement with further increases or doses that produce intolerable yet unavoidable side effects. dopamine agonists (levodopa particularly). Tetrabenazine and similar dopamine-depleting agents have been reported effective in treating dystonia (Chen et al.

For those patients who are discovered to be resistant to one serotype of botulinum toxin. for example. when feasible. It is important that an adequate trial of intramuscular injections be conducted. if perhaps temporary. With its control. At least two important issues bear on this question: (1) secondary nonresponders. patients in whom develop neutralizing antibodies subsequent to an initial response that cause botulinum toxin injections to fail. therapeutic trial with alternative serotypes is indicated. the offending muscles may be widespread. In one retrospective study. The issues of whether a dose can be found such at any dose higher would be futile in terms of efficacy or have an unacceptable risk of adverse effects are discussed in c­ hapter 15. Nonresponse in secondary nonresponders may also owe to such technical issues as changes in the pattern of muscles involved in the dystonia. Among all patients with cervical dystonia. Even patients with generalized dystonia may experience sufficient improvement in their quality of life if the most offending muscles are few and accessible. The difficult question is whether a patient who presents for consideration of DBS and whose previous attempts at intramuscular injections of botulinum toxin appear to have failed is truly refractory or unlikely to benefit from further attempts. some 5% are secondary nonresponders. Secondary nonresponders’ nonresponse to intramuscular injections of botulinum toxin may be related to neutralizing antibodies. therefore. as a consequence of the sampling thereof. the curve became asymptotic at six injections. 4 of 24 patients were found to be primary nonresponders (17%. In patients with Tardive dystonia. for example. In cases in which there occurs some cross-reactivity between serotypes A and B. This is particularly true when the intramuscular injections of botulinum toxin were delivered without electromyographic guidance (Dressler 2000). intramuscular injection of botulinum toxin. leads to failure to adjust technique. Berman et al. from a technical standpoint. which. that is. and (2) failure owing to technique. relief to the distal lower extremities of some patients with generalized torsion dystonia. Botulinum toxin may bring similar. and of all nonresponders. 2005). Botulinum Toxin Because it has proven remarkably effective. trials of alternative serotypes should be considered. a result that suggests that this number represents the minimum . the nonresponse of 2% owes to neutralizing antibodies (Kessler et al. Eligible patients are typically those whose distribution of quality-of-life–limiting dystonias are amenable to intramuscular injections at safe doses. a patient may regain satisfactory quality of life. In a dose–response study based on improvement with consecutive doses in the severity of dystonia. consideration should turn to therapeutic trials of botulinum injections in the frontalis muscle or another muscle that. Yet of the various symptoms. is the treatment of choice for dystonia. presents few difficulties to injecting it and observing its response. and amendable to intramuscular botulinum toxin. 1999). oral-mandibular dystonia may be the most limiting.108 2 0 T hings to K now A bout D eep B rain S timulation Many of the agents described here are the same as those used in the treatment of other hyperkinetic disorders. Because testing serum of neutralizing antibodies presents difficulties.

As it relates to targeting and injecting the muscle that contributes to the dystonia. respectively. whereas those associated with DBS are usually resolved by programming adjustment or. technical complexity creates a situation in which experience and skill makes a significant difference. Poor power may have engendered a type II error. discontinuation of stimulation. rather. respectively. One patient who underwent DBS experienced severe intracranial hemorrhage.” 60% were patients with DBS and 5% were patients who had undergone selective peripheral nerve denervation. In a retrospective study that focused solely on selective peripheral denervation. is to determine a clinically meaningful degree of change in the outcome measure and then conduct a sample-size calculation to determine whether a sufficient number of subjects were enrolled (Wellek 2010). “Fair to good” responses represented 26. Changes in sensation experienced by patients with selective peripheral nerve denervation were most commonly whereas problems with hardware and altered speech. it my opinion that a patient with a documented failure to respond to intramuscular injections be evaluated by a physician with extensive training. Adverse effects were reported in 75% of patients who underwent selective peripheral nerve denervation. compared to only 1 of 15 patients who were undergoing DBS. in which no difference is found where one truly exists. there truly is no difference. Of participating patients who reported experiencing “marked improvement. Because experience and skill may vary among physicians. follow-up after three months demonstrated that 77% of the 162 available subjects experienced moderate to excellent improvement in their head position. 2014). One cannot claim that because a difference was not found by use of typical hypothesis testing statistical measures. Of the 8 patients who from a group of 24 were selected to undergo DBS in the vicinity of the globus palldius interna. . most improved in such a way as there was no statistically significant differences in the outcome measures compared to those with peripheral denervation (Huh et al. Eleven of 20 (55%) of patients who had initially undergone selective peripheral nerve denervation required a second surgery. compared to 60% of those underwent DBS. which these patients experienced while occupying the DBS group.3% and 65%. at worst. These figures are comparable to those reported for DBS in the vicinity of the globus palldius interna. Selective Peripheral Denervation In all cervical dystonia except that of severe anterocollis.10. experience.7% and 30% of participants. those results are uninterpretable. selective peripheral denervation may be considered. and skill in using electromyographic targeting. 2010). Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia109 number of injections necessary to determine the degree of relief a patient might expect. and bad outcomes 13. In a comparison within a single institution where 20 patients underwent selective peripheral nerve denervation and 15 underwent globus palldius interna DBS. and 81% experienced moderate to marked improvement in their pain. However. The appropriate method. the outcomes were considerably better in patients undergoing DBS (Contarino et al. It is important to realize that adverse effects from selective peripheral denervation are likely permanent.

. 8 of 11 patients demonstrated improvement in upper extremity function great enough to be deemed meaningful (Motta et al. This is supported by the effectiveness of intrathecal baclofen for spasticity resulting from disorders that develop independently of dystonia. however. the placement of the tip of the intrathecal catheter is such that the upper extremity would fail to see improvement. 4. and 1% experienced pump problems. Intrathecal and Intraventricular Baclofen Intrathecal baclofen is administered through a catheter that is inserted in the lumber spine interspace and. In summary. Nineteen (14%) noted only minor relief. Cacciola et al.1% developed catheter problems. and 34 moderate relief (24%). however.4 years (Cohen-Gadol et al. Complications occur more frequently with intrathecal baclofen than they do with DBS. Concern has been expressed over the fact that in intrathecal baclofen for treatment of upper extremity dystonia (and spasticity). DBS in the vicinity of the globus pallidus interna is unlikely to offer sufficient benefit. 2009). 18 (13%) reported complete relief of their symptoms. the long-term follow-up (typically on the order of 30 months) of patients with cervical dystonia undergoing DBS found that. 2010). which is commonly seen in patients with perinatal hypoxic-ischemic disease. Motta and Antonello (2014) reported that of the 430 patients who participated in their study. Intraventricular baclofen has been reported to have fewer complications than intrathecal baclofen. For such patients. the experience is insufficient for generalization (Albright and Ferson 2009). In patients with combined dystonia and spasticity. For example. 25% experienced at least one complication.110 2 0 T hings to K now A bout D eep B rain S timulation Of those who experienced moderate to excellent improvement. only 1 patient failed to experience sustained benefit (Hung et al. threaded as high as the cervical region. however. In one study. intrathecal baclofen is highly effective. A 155-patient retrospective study whose mean follow-up was 32. depending on the distribution of the dystonia or spasticity.8 months gathered follow-up results on 140 patients who underwent selective peripheral denervation. Of those 140 patients. of 20 patients combined in two studies. 71% retained the benefit for a mean postsurgical duration of 3. Of patients with significant spasticity who undergo intrathecal baclofen. A number of reports demonstrate general improvements but do not specify the distribution of those improvements.9% experienced leakage of their cerebrospinal fluid. 2007. they do not indicate whether improvement was seen in upper extremities or lower. By comparison. 9. A recurrence rate of 11% was noted. 15. Intrathecal baclofen and intraventricular baclofen in patients may help patients for whom spasticity is a major contributor to impaired quality of life. though selective peripheral denervation and DBS produce comparable improvement. 50 significant relief (36%). the improvement is less sustained in patients with selective peripheral nerve denervation. Intrathecal baclofen is particularly effective in treating spasticity of the lower extremities. and the remaining 19 (14%) no improvement (Braun and Richter 2002).3% developed infections. 2003) meaning that 55% of patients continued to experience moderate to excellent relief.

Thus DBS surgically is ideally performed on patients who have received local anesthetic rather than undergone . These ethical issues are discussed in c­ hapter 19. and healthcare professionals’ judgment in technical matters. most patients or patients’ family members are not physicians or surgeons and are therefore in no position to dictate the technicalities of care. This form of hard paternalism violates informed consent. to recommend DBS if spasticity is not a limiting factor. A B I L I T Y TO TO L ER AT E D EEP B R A I N ST I M U L AT I O N S U R G ERY The patient’s overall health. Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia111 experience is limited.10. The relatively high rate of complications associated with this treatment serves. Optimal microelectrode recordings and microstimulation require a patient’s ability to participate. surgeons. moreover. This subtler form is instantiated when physicians and surgeons fail to provide patients with information or include them in a decision. she violates the ethical principle of autonomy. or respect for the patient. In instances of hard paternalism—which. Any physician who preempts a patient by making the determination stands guilty of paternalistism. DYSTO N I A O F A S E V ER I T Y S U FFI C I EN T TO WA R R A N T   D EEP B R A I N ST I M U L AT I O N Determining whether a patient’s dystonia is of sufficient severity to warrant DBS poses a challenge. and ability to cooperate with DBS surgery are important considerations. I believe that optimal DBS benefit depends on a DBS lead’s accurate placement. Patients and their family members do implicitly consent to defer to physicians. to which microelectrode recordings and microstimulation are critically important. which requires that patients or surrogates be informed of all reasonable alternatives. A reasonable alternative is any that contains information that might affect the decision of the patient or her surrogate. This inability is understandable. An alternative that contains information that might affect the physician’s decision does not qualify as reasonable. do continue to occur—physicians override the expressed wishes of the patient or his surrogate. Beauchamp and Childress (2013) draw a distinction between “hard” paternalism and “soft” paternalism. Yet physicians and surgeons may exceed the scope and limit of this consent should they interpret it as license to render general decisions as to the extent of a patient’s suffering. Hard paternalism may take a subtler form. or his caregivers will agree to face in order to gain relief. One finds examples of soft paternalism in those occasions in which a patient or his family member is unable to render a decision. notwithstanding the fact that they can know neither the suffering of the patient in question nor the amount of risk he. Adding to the challenge is the tendency of physicians to reserve to themselves jurisdiction over the determination. his family members. Any physician who treats a patient without receiving her informed consent beforehand risks committing assault and battery. comorbidities. though rare.

Eur J Neurol. microstimulation performed on patients sedated with dexmedetomidine. Long-term safety. One must bear in mind. R EFER ENCES Albanese A. DBS surgery must therefore await the arrangement of postoperative DBS management. When feasible. 2009. Kumar R.97(Suppl. Barnes MP. to an extent. and development of resistance with botulinum toxin type B in cervical dystonia. DBS benefit comes not when the DBS lead is placed surgically but when the stimulation begins and it. It is attended. . 2006. Any risk assumed by a patient before and during surgery is recompensed by the benefit realized in an outpatient clinic. DBS presents a sound option to patients who have exhausted all reasonable alternatives. intramuscular injections of botulinum toxin should be exhaustively pursued. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force. Failing this.20(2):233–237. PR OV I S I O N O F P O STO PER AT I V E D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G The misconception prevails that DBS is a neurosurgical treatment. et  al. DBS should remain a consideration from the outset. Richter HP. by a higher reoperation rate and a greater chance of significant. S U M M A RY Safe and effective for dystonia. however. 2013. Ferson SS. Selective peripheral denervation presents an alternative in certain circumstances.13(5):433–444. In less ideal circumstances. oral medications may prove effective. Mov Disord. 2005. New  York:  Oxford University Press. Albright AL. 2002. it may produce comparable benefit to that produced by DBS. Seeberger L. Beauchamp TL. dosing. along with any medication. because the risk faced by a patient would lack any compensatory future benefit. however. is adjusted. Provided the situation is not that of anterocolis. Selective peripheral denervation for spasmodic torticollis: 13-year experience with 155 patients. J Neurosurg. Bhatia KP. possibly irreversible complication. Childress JR. Braun V. 2):207–212.112 2 0 T hings to K now A bout D eep B rain S timulation sedation (Montgomery 2014). Quality-of-life–limiting spasticity in patients with a mix of dystonia and spasticity may benefit from intrathecal baclofen. Doing otherwise is unethical. Responsibility for adjusting stimulation and medication typically falls to a neurologist. microelectrode recordings may be made and. Clinical article. Though a relative minority of patients may experience satisfactory improvement with medications. that adults taking tolerable doses often realize inadequate results. Intraventricular baclofen for dystonia:  techniques and outcomes. Berman B. J Neurosurg Pediatr. efficacy. It is not. Principles of Biomedical Ethics.3(1):11–14.

Acta Psychiatr Scand.1315:16–23. Dashtipour K. The natural history of dystonia.100:513–538. et  al. Chen JJ.13(3):301–306. Tetrabenazine for the treatment of hyperkinetic movement disorders: a review of the literature. Clin Ther. Adv Neurol. Comparison of treatment results between selective peripheral denervation and deep brain stimulation in patients with cervical dystonia. Bhatia KP. J Neurosurg Pediatr. Gordon LM. Mateo D. Practice and Cases. Selective peripheral denervation for the treatment of intractable spasmodic torticollis: experience with 168 patients at the Mayo Clinic. . Treatment of Wilson’s disease motor complications with deep brain stimulation. 1996. J Neurol. 2003. 1985. Matsumoto JY. 2006. J Neurosurg. et al.3(1):46–60. 2012. Ann NY Acad Sci. Fuchs H. Nonprimary dystonias. et al. et  al. Motta F. Analysis of complications in 430 consecutive pediatric patients treated with intrathecal baclofen therapy:  14-year experience. Herman MJ. Neurology 2007. Caress JB.88(4):234–238. 2014. 2010. J Neurol. Fahn S. Antonello CE. Castelbuono A. Quinn NP.47(5):548–552.121(Pt 11):2053–2066. Electromyographic evaluation of cervical dystonia for planning of botulinum toxin therapy.98(6):1247–1254. 2000. Tijssen MA. Eur J Neurol. Skutta M. Greene P.246(4):265–274. 2014. et  al. Arch Neurol. Mov Disord. et al. Spontaneous remission in patients with essential blepharospasm and Meige syndrome. Lozano AM. Huh R. Identifying the Least Acceptable DBS Candidates Among Patients with Dystonia113 Cacciola F. 2011. Van Den Munckhof P. et al.14:157–169. Neurosurgery 2010. Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia. Torticollis in infants and children:  common and unusual causes.126(3):432–435. Jahanshahi M. Stignani C. Eldridge PR. Montgomery EB Jr. Farah JO. Kiriakakis V. Shale H. 2014.7(6):713–718. Riklan M.261(2):300–308.68(6):457–459. Brain 1998. and antibody frequency. Torticollis acquired in late infancy due to a cerebellar gangliocytoma. 2006. Motta F. 2014. Bartolome P. Analysis of open-label trials in torsion dystonia using high dosages of anticholinergics and other drugs. Hamani C. Instr Course Lect. Hung SW.10.35(6):375–381.34(7):1487–1504. Marion MH. 1998. Natural history of adult-onset idiopathic torticollis. Stereotact Funct Neurosurg. Ahlskog JE. Selective peripheral denervation:  comparison with pallidal stimulation and literature review. Cohen-Gadol AA. New  York:  Oxford University Press. 1976. Cooper IS. 1988.67(4):957–963. Han IB. Chung M. Stashinko EE. J Pediatr Orthop. Contarino MF. Dressler D. 1990. Dressler D. 2009. Can spasticity and dystonia be independently measured in cerebral palsy? Pediatr Neurol.71(5):488–494. Cullinan T. 1999. Long-term treatment of cervical dystonia with botulinum toxin A: efficacy. et  al. Hedera P. Handb Clin Neurol.55:647–653. Upper limbs function after intrathecal baclofen therapy in children with secondary dystonia. Antonello CE. Ondo WG. et al. Miller NR. Keller JL. Gimenez-Roldan S. Marsden CD. Benecke R. Nohria V. Bilateral deep brain stimulation for cervical dystonia: long-term outcome in a series of 10 patients. Intraoperative Neurophysiological Monitoring for Deep Brain Stimulation:  Principles. Int J Pediatr Otorhinolaryngol. safety.29(7):817–821. Kessler KR. Tardive dystonia and severe tardive dyskinesia:  a comparison of risk factors and prognosis. Am J Ophthalmol. The natural history of tardive dystonia:  a long-term follow-up study of 107 cases.36(1):39–44.

Sidiropoulos C. Wellek S. Testing Statistical Hypotheses of Equivalence and Noninferiority. 2010. Neurodegenerative disorders and metabolic disease. Mestre T. Boca Raton. 2013. FL: CRC Press. Mov Disord. Hutchison W. 2013.28(9):1292–1295. Arch Dis Child. et al.98(8):618–624. .114 2 0 T hings to K now A bout D eep B rain S timulation Pierre G. Bilateral pallidal stimulation for Wilson’s disease.

without consideration and adjustments of concomitant medications—the person responsible for postoperative DBS management must know thoroughly the disease treated in its fullest medical. must not be an end or intent but a necessary means to the end of providing benefit. The complex cognitive skills required similarly necessitate ongoing experience to maintain. There is. or harm. As DBS programming cannot happen in isolation—that is. Doing harm violates the ethical principle of nonmalfeasance (Beauchamp and Childress 2013). as are also healthcare professionals under the supervision of neurologists. are expected to have the prerequisite skills and experience to provide postoperative DBS care. nothing inherent in postoperative care that prevents any physician or healthcare professional from obtaining and maintaining these skills. typical neurosurgical training does not lend itself to gaining and maintaining them. The benefit from DBS accrues not with placement of the DBS hardware but with the initiation and adjustment of actual brain stimulation. moreover. economic. and though any neurosurgeon may obtain these skills. The ethical issue is whether the possession of those skills implies an obligation on the part of neurologists to assume responsibility for providing postoperative DBS care (see ­chapter 19). the balkanization of healthcare provision tends to obscure . because no provision is in place to assure that the surgery is a means to a benefit. Unfortunately. the malfeasance. The Principle of Double Effect attempts to reconcile the infliction of malfeasance with the provision of benefit. social. It is not. If she fails to do so. Though there are neurosurgeons who have these skills. To justify the infliction of malfeasance in order to provide benefit.11 Postoperative Management of Patients with Dystonia There is the misconception that Deep Brain Stimulation (DBS) is a surgical therapy. One may reasonably argue that a surgeon who performs DBS surgery without assuring appropriate postoperative care makes the surgery and its accompanying malfeasance ends. ethical. even if the harm is no more than the risks of serious complications and the pain and self-limiting disability associated with the postoperative recovery. however. Potential for benefit justifies the malfeasance. Neurologists. she harms a patient during the course of surgery. Another interesting issue is whether it is ethical for a neurosurgeon to implant a DBS system without first assuring feasible and reasonable postoperative care. and political context (necessitated by the complexities in healthcare insurance and provision of care). psychological.

T H E U N I Q U E PR O B L EM O F D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G I N DYSTO N I A This section discusses general approaches. initial polarity (negative or positive) at a specific electrical contact. patients must be observed for 30 minutes following their final DBS adjustment in order to ensure that their gait and balance are optimal. allowing fast titration of electrode configurations and stimulation parameters. are generally a reasonable predictor of improvement in gait and balance. adverse effects related to inadvertent stimulation of adjacent structures—tonic muscle contraction. diplopia. and frequency at which the pulse is delivered (Montgomery 2010). tremor. In one study of DBS parameters in dystonia selected patients. Many of the symptoms of dystonia may require hours weeks or months to respond. titration in a single clinic visit may yet prove impractical. Even with a response that comes after one hour. Tremor responds to effective DBS in seconds. the effects of DBS on gait and balance may take tens of minutes to manifest. Such other changes as mood and affect may require a few tens of a second to appear. It is therefore impractical to use assessments of gait and balance for titrating the DBS in the clinic visit. Stimulation parameters include voltage or electrical current for each pulse (the first phase of the biphasic pulse). DBS programming for dystonia presents principle care providers with challenges they usually do not face with DBS programming for Parkinson’s disease. In Parkinson’s disease. 2003). Phasic symptoms refer to symptoms that often accompanies the tonic symptoms. such as tremor. In the clinic it is thus possible to attempt an assessment of the effects of many different combinations of electrode configurations and stimulation parameters within a reasonable period of time. Similarly. subjects showed improvement of at least 30% in the Burke-Marsden-Fahn Dystonia Scale within an hour of the stimulation adjustment (Kupsch et  al. It is hoped that many physicians and healthcare professionals would help patients by providing DBS programming. however. Yet. because this is not always the case. or hyperkinetic disorders. Dystonic symptoms may be categorized as tonic and phasic. The effects of DBS on more rapidly responding symptoms of tremor. changes in speech—appear in a few tens of a second. width of the stimulation pulse. A  detailed discussion is beyond the scope of this project and is addressed elsewhere (Montgomery 2010). The symptoms of these latter disorders respond fairly rapidly. and bradykinesia. Conventional wisdom holds that tonic and phasic symptoms may respond differently to such medications . Though patients’ principle care providers may not be the ones who perform DBS programming. The electrode configuration is a combination of active negative (cathode) and positive (anode) electrical contacts. Yet this hope may go unrealized. it is important that they understand a patient’s experience.116 2 0 T hings to K now A bout D eep B rain S timulation responsibilities that transcend the boundaries of a physician or healthcare professional’s specialty. muscle tone. Tonic symptoms refer to the abnormal sustained postures. Bradykinesia associated with Parkinson’s disease and hyperkinesia responds in a few tens of a second.

The inductive approach first articulated by Francis Bacon (1561–1626) typifies the descriptive approach. This issue deserves further study. 2005). This means that titration must take place over an extended period of time. The recommendation made by Kupsch and colleagues (2011) to begin DBS programming at 130 pulses per second (pps) presents a useful example. Their rationale appears to be that 130 pps is used in the majority of published studies. If they prove to be predictive. A  number of publications have reviewed the published literature in an attempt to codify general approaches (see review in Kupsch. Application of such statistical measures as mean or median with respect to DBS frequencies is nonsensical.11. which involved 130 pps at 3 months and at 12 months. virtually all of them adopt a descriptive as opposed to a normative approach. It is unlikely. In another study. 2011). Whether phasic symptoms of dystonia are predictive of tonic symptoms’ response is unknown. Experience may certainly be quantified and subjected to population statistical analysis. EPI ST EM O LO G I CA L C O N S I D ER AT I O N S Epistemology refers to critical analysis of the acquisition and validation of knowledge. Though none of the primary sources justified their selection. It emphasized observation and hypothesis generation and testing. et al. One might argue that empirical Baconian science is less prone to bias and systematic errors than is Cartesian rationalism. all but 5 participating patients continued their DBS at that rate (Vidailhet et al. Though one may claim that the sole motivation was habit . then one might titrate to the desired effect of the phasic symptoms. This appears to be the case for DBS as well: Phasic symptoms often respond rapidly to DBS changes and may be used for titration within the clinic visit. Experience suggests that phasic responses may be predictive. the presumption being that the tonic symptoms will respond in due course. Kupsch and colleagues’ (2006) recommendation to begin DBS programming at 130 pps may only be called descriptive. With the exception of this textbook. primarily by use of mathematics. From summary statistics may be drawn from recommendations for appropriate means. At any rate. with DBS adjustment performed every few weeks rather than every few minutes (see review by Kupsch. because 130 pps was the sole frequency used in nearly all cases. Rene Descartes (1596–1650) advanced a competing notion that emphasized reasoning from scientifically established principles. that the tonic symptoms will respond rapidly to severe titration in the clinic. et  al. Kupsch and colleagues (2003) reported that patients responded better at 180 pps and 250 pps. the experience with DBS for Parkinson’s disease likely informed their selection. A tension between descriptive and normative approaches in science has long characterized science. Another study cited only DBS performed at 130 pps (Kupsch et al. By “descriptive” I mean basing recommendations on experience rather than principle. Postoperative Management of Patients with Dystonia117 as anticholinergics or the dopaminergics. 2006). 2011). phasic symptoms merit treatment in their own right. but to do so would be naïve. Yet there is no reason to presume that such descriptive analyses are inherently superior to those that are based on principle. Yet. however.

Guiding the choice of electrode configurations is a goal of maximizing the volume of tissue stimulated for efficacy. unless there is some a priori method for it.118 2 0 T hings to K now A bout D eep B rain S timulation generated by extrapolation from experience with Parkinson’s disease. The third goal is to reduce any relevant medications. because doing so while also programming DBS proves difficult. to the greatest possible degree that remains consistent with the first goal. 150 µs. The ultimate goal is that of maximizing reduction in disabilities while minimizing adverse effects. Excessive extension of the electrical field at the site of stimulation produces adverse events. one must determine the time required to observe any evidence of effectiveness with stimulation parameters where electrode configurations are largely related to the regional anatomy around the DBS lead and. Determination of electrode configurations (the set of active cathodes [negative contacts] and anodes [positive contacts]) is largely determined by the adverse effects. symptoms of the type that require weeks to improve will likely also require more than a single programming session. A PPR OAC H ES TO D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G A rational approach begins by defining DBS programming goals. Kupsch and colleagues themselves admit that in developing their recommendations they included visit schedules of clinical trials. Kupsch and colleagues (2011) are to be commended for the wide-ranging scope of the recommendations. The recommendation appears to rest on the only study that involved systematically varied pulse widths of 60 µs. thus. They recommended a practical initial follow-up at 4 to 12 weeks and. if the patient is stable. because the conditions constructed for a clinical trial may be irrelevant to a patient managed in actual practice (see c­ hapter 4). The second goal is to achieve the first goal as rapidly as possible. Though this cannot be . adverse effects. The recommendation by Kupsch and colleagues (2006) to begin DBS programming at 90 microseconds (µs) merits similar analysis. every 6 months thereafter. It is not clear why 90 µs was preferred to 60 µs. I have observed that there is a tendency to begin with reported “average” or “typical” settings in the literature and to avoid venturing terribly far from them. and 450 µs and found no difference. Their recommendations are therefore descriptive rather than normative. These recommendations prima facie lack validity. Second. one finds immediately two reasons for suspicion. The purpose of the forgoing discussion is not to recommend different starting points for dystonia DBS programming. reducing medication should be avoided. Rather it is to point out the fact that the lack of substantial evidence for the recommended stimulation parameters and electrode configurations simply indicates the importance of considering alternatives. The suggested schedule probably reflects the typical follow-up interval in most clinics. particularly those that produce adverse effects. In order to achieve the second goal of rapidly reducing disability. First. Such importation may represent a logical error of the categorical type (Ryle 2002). selection of frequencies used in Parkinson’s disease likely owe more to force of habit. It is unclear whether these recommendations are influenced by those cases in which the DBS stimulation was initiated within the immediate postoperative period.

11. Postoperative Management of Patients with Dystonia119

determined beforehand, one might get a sense of it from the monopolar survey, in
which stimulation is applied to each contact to a maximal voltage or current. The
voltage or electrical current is increased until the symptoms associated with the
disability change, the patient experiences an adverse effect, or a maximal voltage
(up to 10 volts) or current (4 milliamps) is reached. Depending on the electrode
impedance, such voltages or electrical currents may exceed the maximum safety
limit (programmers must consult the manufacture’s operation manuals for the
devices).
One approach to programming is to start with initial stimulator parameters at
those associated with the reported maximum for benefit. Studies have shown relatively little benefit in pulse widths that exceed 120 µs. Chronaxie is the pulse width
that produces a response that is one-half of the response of a theoretical infinitely
long pulse width. In computational modeling and in experiments, chronaxie values ranged between 100 µs and 200 µs and became asymptotic with slightly higher
pulse widths (see Miocinovic and Grill 2004). The recommended stimulation frequency is 185 pps.
The time required for a change in the appropriate symptom offers an estimate
of the length of time a patient would have to be observed at each set of stimulation parameters in order for a change to become evident. If the change becomes
evident in a reasonable period of time, titration within a DBS programming clinic
session may be possible. There may not be any response observed during a reasonable period following a change in stimulation parameters. Lack of response suggests that titration during a single DBS programming clinic visit may be infeasible.
An alternative approach is to start minimal setting and then increase as needed
and then titrate upwards as needed. This minimizes current drain from the
implantable pulse generator. It is important to recognize that an improvement
observed during a single DBS programming clinic session does not mean that it
is maximal for the specific set of stimulation parameters. It is therefore important
to program the DBS stimulation parameters to the minimal pulse width first and
frequency second. Doing so ensures a response and minimizes the drain on the
battery. A patient is discharged and asked to report back to her DBS programmer
immediately upon a plateau in her response, no matter whether if it happens in
hours or days. One may schedule programming at comparable intervals according
to the time to plateau.
In the event that no improvement becomes evident during an initial monopolar
survey, one may assume that any improvement in symptoms may require a longer
duration of stimulation and that titration within a single DBS programming clinic
session is therefore infeasible. A different approach becomes necessary.
Those patients whose symptoms associated with disability show no response
within the time of the DBS programming clinic session may have their stimulation parameters set at a pulse width of 120 µs and frequency of 185 pps (for reasons
discussed earlier), and they may have their voltage or current increased until they
experience an adverse event. On instance of an adverse event, stimulation voltage
or current is reduced by 10% to 15% in accordance with Kupsch and colleagues’
(2006) recommendation. A patient is asked to report the amount of time required
to experience a change in the appropriate symptoms and the specific moment at
which that change plateau. These times offer a means of establishing a reasonable
schedule for DBS programming sessions.

120

2 0 T hings to K now A bout D eep B rain S timulation

Because many DBS devices enable patients and their family members and caregivers to adjust stimulation parameters outside the physician or healthcare professional office, some physicians enlist these parties in the titration process. Caution
is necessary. Physicians must establish the limits within which a patient or a family
member or caregiver may adjust the stimulation in order to avoid exceeding safe
levels. Patients and family members and caregivers must observe the limits established by physicians.
It may be difficult for a patient or a family member or caregiver to observe a change
in symptoms that occurs over a long period. Absent some objective assessment, an
implicit shift in the reference or scale may occur. Expectations of patients or their
family members or caregivers may similarly influence subjective observations.
D EEP B R A I N ST I M U L AT I O N – I N D U C ED PL AST I C I T Y

Long duration of stimulation prior to improvement in some symptoms of dystonia suggests the existence of changes beyond those that are immediately produced
by the DBS stimulation pulses. There is, in other words, some plasticity, the time
course of which is variable. Some studies suggest that it may require hours or days
for symptoms to return or worsen following discontinuation of DBS. Indeed, some
patients with Essential tremor continue to experience reduced tremor long after
their implantable pulse generator battery has been drained. Such patients exemplify
positive adaptation. Conversely, there have been instances in which initial improvement disappeared after a few hours or days. In such cases it is often unnecessary to
increase stimulation strength. Because it appears that a brain may adapt—or, more
accurately, maladapt—to specific stimulation parameters, it is frequently necessary
simply to stimulate with different parameters (Montgomery et al. 1999).
Among the mechanisms one may exploit to improve DBS response are long-term
potentiation (LTP) and long-term depression (LTD), the latter of which is also
known as spike timing-dependent plasticity or Hebbian learning. LTP and LTD are
long-term changes that follow a high-frequency volley of input to a neuron, such as
that which occurs with stimulation. LTP induces an increase in excitability; LTD
reduces excitability. Both LTP and LTD carry important implications for computation in neural systems.
It is unclear whether high-frequency DBS is able to produce LTP or LTD. Though
pulses are delivered at high frequency, a mere 10% of them result in axonal excitation, as evidenced by recordings of antidromic action potentials (Walker et  al.
2011). A neuron may experience an effective stimulation rate of only 13 pps, despite
the fact that the DBS system delivers 130 pps.
Another form of Hebbian learning happens when a synaptic input, typically a
depolarization, occurs at site of prior postsynaptic depolarization—a previous synaptic input, for example (see Caporale and Dan 2008). When two synaptic inputs
share a source, LTP results. Yet two inputs need not share a source; they need simply to occur near the same time. Indeed, a potent way of inducing LTP or Hebbian
learning is to induce back-propagation of the action potential to the soma (cell
body) and the entire dendritic tree. This increases the odds that some inputs will
follow depolarization from the antidromic potential, the result of which is Hebbian
learning.

11. Postoperative Management of Patients with Dystonia121

A possible source of back-propagation of action potentials, DBS prompts antidromic activation. As such, it recommends itself as a source of LTP and LTD, which
in turn produce plasticity. It remains to be seen whether an effect on plasticity
explains the time course of some symptomatic responses or a prolonged response
following discontinuation of DBS. However, it is possible that, when coupled with
rehabilitative therapies and training, DBS plasticity may produce a marked synergistic effect. Research support should be allocated to the study of this possibility.

S U M M A RY

DBS is safe and effective for the treatment of dystonia. The time course of response
of symptoms and disabilities to initiation and changes in DBS presents problems
for postoperative DBS programming. The rapid response of some symptoms make
titration during a single DBS programming clinic session feasible. Slower response
of other symptoms makes titration difficult. Strategies must be developed to accommodate lag times. Some arbitrary time frame, selected because it accommodates a
physician or healthcare professional’s schedule, is suboptimal, because it may simply prolong the time needed to achieve a satisfactory response. It therefore also prolongs a patient’s discomfort and disability, as well her exposure to risks associated
with her condition.

R EFER ENCES
Beauchamp TL, Childress JR. Principles of Biomedical Ethics. New  York:  Oxford
University Press; 2013.
Caporale N, Dan Y. Spike timing-dependent plasticity: a Hebbian learning rule. Annu
Rev Neurosci. 2008;31:25–46.
Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med. 2006;355(19):1978–1990.
Kupsch A, Klaffke S, Kuhn AA, et al. The effects of frequency in pallidal deep brain
stimulation for primary dystonia. J Neurol. 2003;250(10):1201–1205.
Kupsch A, Tagliati M, Vidailhet M, et  al. Early postoperative management of DBS
in dystonia:  programming, response to stimulation, adverse events, medication
changes, evaluations, and troubleshooting. Mov Disord. 2011;26(Suppl. 1):S37–S53.
Miocinovic S, Grill WM. Sensitivity of temporal excitation properties to the neuronal
element activated by extracellular stimulation. J Neurosci Methods 2004;132(1):91–99.
Montgomery EB, Jr., Baker KB, Kinkel RP, et al. Chronic thalamic stimulation for the
tremor of multiple sclerosis. Neurology 1999;53(3):625–628.
Montgomery EB Jr. Deep Brain Stimulation Programming:  Principles and Practice.
New York: Oxford University Press; 2010.
Ryle G. The Concept of Mind. Chicago: University of Chicago Press; 2002.
Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain stimulation of the globus
pallidus in primary generalized dystonia. N Engl J Med. 2005;352(5):459–467.
Walker HC, Watts RL, Schrandt CJ, et al. Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease. J Neurophysiol.
2011;105(3):1112–1121.

12

Deep Brain Stimulation Is Safe and
Effective for Tourette’s Syndrome

U N I T ED STAT ED FO O D A N D D R U G
A D M I N I ST R AT I O N STAT U S

Deep Brain Stimulation (DBS) for Tourette’s syndrome represents an “off-label”
use of an US Food and Drug Administration (FDA)-approved device. In other
words, the FDA has approved the DBS systems, yet it has done so for Parkinson’s
disease and other indications. The FDA has not offered any position on the
use of DBS for Tourette’s syndrome. It is important to recognize that the use
of FDA-approved devices and drugs for indications on which the FDA has no
stated position is often considered standard and accepted. Indeed, in many cases
it would be considered malfeasance not to use certain FDA-approved drugs in an
off-label manner. The FDA recognizes the prerogative of physicians to treat in the
best interests of their patients. It does not stipulate how medicine is to be practiced. The FDA does require that if drugs, biologics, and devices are used in an
off-label manner it is done in a responsible manner. There must be established scientific evidence of safety and efficacy, even if the level of evidence does not reach
the level typically accepted by the FDA in its approval process (see ­chapter 15 for
an extensive discussion).
The use of off-label indications does present some challenges. First, insurance
companies often deem experimental or investigational any use of an FDA-approved
device or drug for any indication not expressly approved by the FDA. This is inappropriate. Yet nothing prevents an insurer from making the claim, which presents a
sufficient enough hurtle that most physicians will simply defer to the insurer’s position. According to most canons of medical ethics, such action could be considered
unethical, because the principle of beneficence requires that physicians provide the
best treatment. Second, programmatic denial of off-label uses violates the ethical
principle of justice, because whether a patient receives the benefit of an appropriate off-label use depends solely on her insurer. The benefit of off-label use, in other
words, becomes a lottery (Beauchamp and Childress 2013).
One may argue that patients may choose the insurer they contract for insurance
coverage. Most individuals, however, cannot predict the future illnesses or injuries that will befall them. This places insurance companies at a significant advantage in contract negotiations. Indeed, as a consequence of the Patient Protection

12. Deep Brain Stimulation Is Safe and Effective for Tourette’s Syndrome123

and Affordable Care Act of 2010 (otherwise known as Obamacare), thousands of
policy holders in the United States had their insurance cancelled. A major reason
is that the insurance policies did not meet the minimum protections required by
the Patient Protection and Affordable Care Act. This strongly suggests that a great
many policy holders were unable to recognize or afford a reasonable health insurance program.
Lack of FDA approval may be considered by some physicians and healthcare professionals as evidence of a lack of safety and efficacy. In this they commit an error
in reasoning known as argumentum ad ignorantiam (arguing from ignorance). An
example of argumentum ad ignorantiam is found in the statement, “Because I do
not know that you are an honorable person, you must be dishonorable.”
Considerable valid evidence indicates that DBS is safe and effective for the treatment of Tourette’s syndrome, and consistent with FDA guidelines, DBS is appropriate for patients with Tourette’s syndrome.
D EEP B R A I N ST I M U L AT I O N TA R G E TS A N D
T H E C O N D I T I O N S T R E AT ED

There are a number of targets for DBS. These include the intralaminar nuclei
of the thalamus, specifically the centromedian-parafascicular nucleus, the
posterior-lateral region of the globus pallidus interna, the anterior-medial region
of the globus pallidus interna, the globus pallidus externa, the nucleus accumbens, and the posterior limb of the internal capsule. All of these targets have
been reported to produce varying degrees of benefit. The plethora of targets may
be unsettling, owing to the suspicion that all these targets are unlikely to affect
the basic underlying mechanisms. Any benefit is thus unrelated to the underlying
causal mechanism.
Thinking in neurology has long been dominated by the notion that various
brain functions are parsed out among specific structures and that most functions are a consequence of an assembly line–like process. In the basal ganglia,
for example, the caudate nucleus and putamen are considered the input stage,
whereas the globus pallidus interna and substantia nigra pars reticulata are considered the output stage. This clearly suggests a one-dimensional sequential process. A  specific brain function is attributed to the putamen, for example, and
a different function attributed to the globus pallidus interna. This notion of a
modular approach, in which interactions are sequential and hierarchical, is also
observed in the attribution of the symptoms, signs, and disabilities of Parkinson’s
disease to hyperactivity of the globus pallidus interna. This a notion has since
been refuted (Montgomery 2004).
This mode of thinking may rest on a mereological fallacy, which attributes
the function of the whole to its parts. The role of generating movement falls to
the control exerted by the globus pallidus interna. Lesions of nearly every structure within the basal ganglia-thalamic-cortical system, however, have been
described as causing parkinsonism, and DBS of nearly every structure in the basal
ganglia-thalamic-cortical system has been described as improving parkinsonism.
Either there are as many different mechanisms that produce and alleviate parkinsonism as there are lesions and DBS targets, or there is one that involves all the

The second notion is that of inferring physiology from anatomy and neurochemistry (Montgomery 2004). Reports demonstrate improvements on the order of 20% to 80% for DBS in the vicinity of the centromedian-parafascicular and globus pallidus interna (reviewed by Kim and Pouratian 2014). and cognitive effects. A number of patients failed to improve or remain improved . In the case of Tourette’s syndrome. Most studies have been individual or small case series. including depression. The interactions between macroneurons is inferred from their neurotransmitter. 2012). It is possible that DBS of different regions within the targets have different effects on the varied symptoms. Parkinsonism is the result of a disordered system and not simply a disordered globus pallidus interna.124 2 0 T hings to K now A bout D eep B rain S timulation structures of the basal ganglia-thalamic-cortical system. There appears to be more evidence in the literature related to DBS in the vicinity of the globus pallidus interna. segments that interact with the limbic and cognitive systems. One outcomes measure is the Yale Global Tic Severity Scale. one may come to understand the function of an anthill. The function of the basal ganglia-thalamic-cortical system is inferred from the arrangements of macroneurons. which has demonstrated reductions from 23% to 75% over a range of targets. EF FI CACY A N D A DV ER S E E V EN TS The choice of target then depends on the symptoms and disabilities considered to have the highest priority. patients with Tourette’s syndrome also experience psychological problems. The notion of a modular sequential and hierarchical organization has been facilitated by two prevalent but incorrect notions. If. and attention deficit hyperactivity disorder. for example. the tics are the major factor limiting the quality of life. The first is the Neuron Doctrine. Some efficacy measures for psychological impairments include the Yale Brown Obsessive Compulsive Scale. These include the posterior-lateral globus pallidus interna and possibly the centromedian-parafascicular nuclei. Indeed. In addition to involuntary movements. For example. Nuclei. Porta et al. may have relatively little effect on tics but significant benefit on psychological problems. Yet there have been two prospective studies with blinded assessments that have demonstrated benefit of DBS in the vicinity of the thalamus or globus pallidus interna (Servello et al. then targets most related to the motor functions should be targeted. 2010. As reviewed by Hariz and Robertson (2010). reports of DBS effect frequently have not distinguished among motor. Conversely. another consideration is that the symptomology is complex and multifaceted. given understanding of a single ant’s properties. Generally the results have demonstrated significant improvements in tics. obsessive-compulsive symptoms. which is derivative of the Cell Theory. psychological. The basal ganglia-thalamic-cortical system is thus considered a small group of macroneurons. DBS in the vicinity of the sensorimotor region of the posterior-lateral globus pallidus interna may have significant benefit for tics but relatively little effect on the psychological problems. The consequence has been to identify the neuron as the basic unit of brain function. by virtue of the collection of neurons. the anatomical structure is viewed as one large neuron (macroneuron). described as tics. This mode of reasoning suggests that. then become a higher expression of the basic brain function. DBS in the vicinity of the anterior-medial globus pallidus.

one finds it problematic to randomize patients to undergoing DBS surgery but not being stimulated for any period of time. even when the risks associated with DBS are thought to be higher. especially if the length of observation necessary to have confidence in the results is quite long. provided there is also a compensating belief that DBS will be more effective. which have become synonymous with Evidence Based Medicine. One may randomize patients to DBS versus best medical therapy. This is an inordinately narrow view of Evidence Based Medicine (Montgomery and Turkstra 2003) and would be solipsistic. Kim and Pouratian (2014) raised concerns about increased risks in patients with Tourette’s . constitute evidence. The general approach is to respect the patient’s preference (the ethical principle of autonomy) and adhere as closely to the ethical principles of beneficence. nonmalfeasance. R I S KS Risks may be apportioned to those related to the surgery. The case reports themselves provide no evidentiary support to offering DBS for care outside a RCT. It is difficult to control by blinding a patient to the presence or absence of DBS. Deep Brain Stimulation Is Safe and Effective for Tourette’s Syndrome125 over time. Such comparisons are nonetheless required nearly every day in medicine. despite no direct benefit to a patient. All the case reports only serve to indicate the potential of benefit and risk so as to motivate the appropriate RCT. A considerable majority of authors of papers describing benefits have indicated the importance of prospective randomized controlled trials (RCTs). would generally be unethical. The problem is one of clinical equipoise as a necessary condition of ethical clinical trials. This approach to equipoise. Surgical risks predominantly involve bleeding and infection. The equality can exist as a consequence of the fact that no one has any idea about the risks and potential benefits of each option. When attempting to establish equipoise. Equipoise is achieved when a researcher believes that two or more options are equal relative to the risks and potential benefits of each option. which might compensate for the risk of randomization to an option that has a poorer risk–benefit ratio. No calculus exists with which to equate incommensurables without the same units of measure. Given the number of centers already performing DBS for Tourette’s syndrome and the generally positive results. those related to the DBS target. for example. One approach would be to declare by fiat that only RCTs. however. and those related to the disease. The subject may also obtain benefit of another kind for participating. and rarely the obsessive-compulsive disorder symptoms worsened (reviewed by Kim and Pouratian 2014). such studies are expensive and difficult to design. The risk of doing harm (the avoidance of doing harm is the ethical principle of nonmalfeasance) that would be difficult to offset if there were no prior evidence of possible benefit. It is important to consider risk and potential benefit in the widest connotation.12. particularly because adverse effects associated with active stimulation make it so. Those benefits may be social. Risks with respect to intracranial hemorrhage and infection have been consistent across different DBS targets and different conditions. and justice. Unfortunately. One often finds oneself in the situation of comparing incommensurables. there is no simple calculus. assuming the form of increased knowledge that may benefit future patients.

for example. These are generally caused by spread of electrical current to unintended structures. and voltage or current). Unintended spread of electrical current from the centromedian-parafascicular nucleus to the medical dorsal nucleus may account for the reported cognitive adverse effects. In addition. the improvements may cause severe stress to patients and caregivers alike. In a prospective study of DBS in the vicinity of the globus pallidus interna and subhthalamic nucleus for Parkinson’s disease. motivation. Spread of electrical current from the centromedian-parafascicular nucleus to the interstitial nucleus of the medial longitudinal fasciculus may cause vertical eye deviations and perhaps other deviations that may impair vision. There are complications related to the stimulation. The centromedian-parafascicular nucleus is also immediately ventral to the medial dorsal nucleus of the thalamus. Even when DBS for Parkinson’s disease is successful at controlling the motoric symptoms. The centromedian-parafascicular nucleus lies medially and ventrally in the thalamus. 2009). Servello and colleagues report that the rate of intracranial complications. Similar concerns are raised with respect to infections and hardware failure. The target for motor symptoms in the globus pallidus interna. for example. It is extremely close to the interstitial nucleus of the medial longitudinal fasciculus.9%. memory. The posterior limb of the internal capsule lies immediately posterior to the target in the globus pallidus interna. apathy. Unintended stimulation spreading to the internal capsule may produce tonic muscle contraction. The adverse effects related to the spread of electrical current to unintended structures may be resolved with proper adjustment of DBS electrode configurations—a combination of active cathodes (negative contacts) and anodes (positive contacts) and stimulation parameters (pulse with. and the relative low rate of complications risks a type I  statistical error (finding a difference when none truly exists). rate or frequency. The effects of DBS. of which nearly all were resolved within six months. may interfere with speech. primarily as a consequence of stimulation. which may not be attributable to electrical current spreading to neighboring structures. 83% experienced adverse effects. for example. This is suggestive of resolution with appropriate DBS programming (Weaver et al. whether successful or unsuccessful. and emotions. and lethargy (Muller-Vahl et al. was 3.126 2 0 T hings to K now A bout D eep B rain S timulation syndrome. which may explain changes in sexual function and other adverse effects. The problems with the study by these authors are the small sample size (36 patients). which is involved in vertical eye movements. A reasonable estimation would thus be a 1% to 2% risk of intracranial hemorrhage with significant or permanent disabilities and a rate of 2% to 5% for infections that necessitated removal of the DBS lead. Much of the stress may be related to the relatively sudden changes in psychosocial relationships between the patient . which occurred primarily as hemorrhages. the centromedian-parafascicular nucleus appears to be involved in sexual function and attentional mechanisms. which is involved in cognition. for example. DBS in the vicinity of the globus pallidus interna. Yet these are not due to stimulation of an adjacent structure. 2011). There may be adverse effects from stimulating the target. Excessive electrical current may spread to the optic track and produce phosphenes or other visual disturbances. on the larger context of the disease must be considered. lies extremely close to the optic tract. citing a study by Servello and colleagues (2010).

A patient may then weigh the relative risks against possible benefits in light of the degree of confidence that current medical knowledge provides and with the recognition that the only real alternative is to do nothing. the same cannot be said when the psychiatric. she must realize that she is committing the patient to continued suffering and disability. then one may proceed to DBS with greater confidence of a good outcome. There is insufficient experience to understand psychiatric. An important concept in support of DBS in the vicinity of the globus pallidus interna for tics is the effectiveness of DBS for a variety of hyperkinetic disorders. among others. hemiballismus secondary to stroke. because a beneficent manager may change and thus occasion concern and mistrust. psychological. Patients and their family members or caregivers have evolved to a certain psychological and social equilibrium dictated by patients’ motor disabilities. psychological.12. The high prevalence of psychiatric. primary and secondary dystonia. However. and chorea secondary to pantothenate kinase-associated neurodegeneration. Unfortunately. Huntington’s disease. A D EQ UAT I O N O F PAT I EN T TO TA R G E T The lack of RCTs renders recommendations as to the appropriate target somewhat problematic. Admittedly. as a symptomatic treatment. tardive dyskinesia. Informed consent requires the patient to be made aware of alternatives. patients should be made aware that the recommendation for DBS is based on limited experience. The alternatives presented to the patient cannot be determined by a physician’s opinion. I believe that there is sufficient clinical experience to warrant consideration of DBS in the vicinity of the globus pallidus interna and the centromedian-parafascicular nucleus. DBS in the vicinity of the globus pallidus interna is effective for drug-induced dyskinesia. Patients may be more demanding of their independence and the family’s role. I  attempt to determine the overall controlling problems that most significantly affect the patient’s quality of life. psychological. and failure to inform the patient of that alternative may obviate the informed consent implicit (or explicit) in every patient–physician relationship. If they are motoric. This logic would support the notion that. Deep Brain Stimulation Is Safe and Effective for Tourette’s Syndrome127 and family members/caregivers. and sociological comorbidities are dominant limiting factors. This argues strongly for the view that DBS in the vicinity of the globus pallidus interna is a symptom-specific treatment rather than a disease-specific treatment (Montgomery 2004). a patient has a right to be made aware of the possibility of DBS. chorea secondary to acanthocytosis. and sociological comorbidities greatly complicates the decisions to proceed with DBS. and sociological dynamics in patients with Tourette’s syndrome. Yet it is . Suddenly changing a patient’s functional abilities disrupts that equilibrium. DBS in the vicinity of the globus pallidus interna DBS should be effective for the tics of Tourette’s syndrome. It must rest on that which a reasonable patient would want to know. the lack does not relieve the physician from making a decision other than not to offer DBS. Before a physician defaults to not offering DBS. One of the issues that the physician must decide is his relative confidence in the data that does exist. At least from a fiduciary perspective.

Interestingly. One of the advantages of the globus pallidus interna being relatively large is the cognitive and emotional components are spread out over a larger volume and are thus more easily avoided. however. the same cannot be said for DBS in the vicinity of the centromedian-parafascicular nuclei of the thalamus. The proximity of the centromedian-parafascicular nucleus to structures whose unintended stimulation may result in significant adverse effects is more of a problem for the centromedian-parafascicular nucleus than it is for the globus pallidus interna. 2012). I believe it is. . They ignored case series. especially when the experience of DBS in the vicinity of the globus pallidus interna for other hyperkinetic disorders (see c­hapter  15) is considered based on the notion that DBS is a symptom. Unfortunately. a Canadian consensus group did not recommend DBS for Tourette’s syndrome. S U M M A RY While the number of patients receiving DBS for Tourette’s syndrome is relatively small. DBS would therefore never be recommended by any group that deems RCTs the only permissible evidence. Confidence in DBS of the centromedian-parafascicular nucleus is more problematic. the benefit of DBS in the vicinity of the globus pallidus interna for other hyperkinetic disorders lends the aforementioned support. These recommendations were based on the findings in only three RCTs. thanks to the relative paucity of controlled studies and publication bias against negative or poor results. finding it investigational (Steeves et al. The issue of DBS for the nonmotoric symptoms and disabilities of Tourette’s syndrome are more problematic. Well-conceived clinical trials of DBS in the vicinity of the centromedian-parafascicular nuclei of the thalamus should be conducted. because the likelihood of conducting the type of prospective RCTs is poor.128 2 0 T hings to K now A bout D eep B rain S timulation not clear that the standard DBS directed at the sensorimotor region of the globus pallidus interna would be effective for the nonmotoric symptoms of Tourette’s syndrome. This position is contrary to the actions of the FDA’s approval of DBS for primary dystonia. as well as the concept of DBS as a symptom-specific rather than disease-specific treatment. which was based on the weight of accumulated case reports and in the absence of prospective RCTs. The issue is whether this is sufficient to consider DBS in the vicinity of the globus pallidus interna for the motoric symptoms of Tourette’s is reasonable. According to anatomically connections. Insofar as motoric symptoms and related disabilities are concerned. it would appear that DBS of the centromedian-parafascicular nucleus would be more effective than the sensorimotor region of the globus pallidus interna. I favor DBS in the vicinity of the globus pallidus interna. Though there is a relative paucity of controlled studies regarding DBS in the vicinity of the globus pallidus interna specifically for Tourette’s syndrome.rather than a disease-specific treatment. most studies demonstrate improvement and relative safety. The Canadian recommendations are a disservice to patients.

32(7):1128–1134.301(1):63–73. Pouratian N. Eur Child Adolesc Psychiatry 2011. et  al. Steeves T. Follett K. Montgomery EB Jr. Deep brain stimulation for hyperkinetic disorders. 2012. Robertson MM. 2004. JAMA 2009.57(3):144–151.154(11):2029–2041. Montgomery EB Jr. . Nonlinear Studies 2004. Cath DC. Long-term. et al.11:ix–xii. 2014. Servello D. Deep brain stimulation for Tourette syndrome. Acta Neurochir (Wien). Eur J Neurosci. Gorman D. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. high-frequency reentrant. 2010. Brambilla A. et al. Cavanna AE. Neuromodulation 2010. Montgomery EB Jr.13(3):187–194. Hariz MI. European clinical guidelines for Tourette syndrome and other tic disorders. Evidenced based medicine: let’s be reasonable. non-linear oscillators embedded in scale-free basal ganglia-thalamic-cortical networks mediating function and deep brain stimulation effects. Childress JR.17(1):E1. Muller-Vahl KR. 2003. Canadian guidelines for the evidence-based treatment of tic disorders:  behavioural therapy. Neurosurg Clin N Am. Sassi M. 2013. and transcranial magnetic stimulation. et al. Gilles de la Tourette syndrome and deep brain stimulation.20(4):209–217. McKinlay BD. J Med Speech Lang Pathol. New  York:  Oxford University Press. Deep Brain Stimulation Is Safe and Effective for Tourette’s Syndrome129 R EFER ENCES Beauchamp TL. et al. Turkstra LS. Stern M. Can J Psychiatry 2012. post-deep brain stimulation management of a series of 36 patients affected with refractory Gilles de la Tourette syndrome. Principles of Biomedical Ethics. Part IV: deep brain stimulation.12. Zanaboni C. deep brain stimulation. Weaver FM. Porta M. Dynamically coupled. Neurosurg Focus..25(1):117–135.11:385–421. Deep brain stimulation for treatment of refractory Tourette syndrome:  long-term follow-up. Servello D. Kim W.

which is the presence or absence of some feature. and the presence or absence truly reflects whether some threshold is exceeded. Nearly every published criteria identifies those criteria that identify the best candidate. the criteria. However. The complexity of the clinical phenomenology of Tourette’s syndrome presents an opportunity to review critically selection criteria for DBS. The clinical trials organized around these exclusionary selection criteria rendered less generalizable results. In light of real-world need. The basis of that criticism was the fact that those criteria were imported whole-cloth from clinical trials criteria. the .13 Identifying the Least Acceptable Deep Brain Stimulation Candidates Among Patients with Tourette’s Syndrome T H E L E AST AC C EP TA B L E CA N D I DAT E As discussed in other chapters. In order to increase the effect size and decrease the variance. Chapter 4 contains criticism of commonly accepted DBS selection criteria for patients with Parkinson’s disease. the majority of criteria published are based on dichotomous criteria. the real challenge is doing due diligence to those that are not ideal. Yet rarely does clinical experience admit of a dichotomous variable. were created to exclude patients with atypical parkinsonism who were unlikely to benefit and who were more likely to suffer other complications. the notion of establishing selection criteria for the least acceptable candidate for Deep Brain Stimulation (DBS) appears counterintuitive. Yet in doing so the clinical trials distanced themselves from those patients who were likeliest in need of DBS. and perhaps that is the reason the published criteria focus on the best candidate. Far more often the degree of a feature must be considered. then. this is least relevant to actual clinical practice. which were a convenience to the clinical trials. The review models the method by which selection criteria for other indications are created. These epistemic issues are discussed more fully in ­chapter 4. Further. While there seldom is disagreement when the best candidate is considered.

The issue of ascertainment cuts both ways with respect to selection criteria of DBS surgery. these adults met the same Diagnostic and Statistical Manual of Mental Disorders (fourth edition. although not necessarily concurrently. or 18. This consensus appears as something of a meme. Indeed. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 131 criteria appear arbitrary as they may unfairly exclude patients who would benefit from DBS. criteria rest on a kind of consensus created by wide distribution of print and electronic scientific publications. one cannot make the same criticism about suggested clinical criteria for DBS candidacy for patients with Tourette’s syndrome.. but for some reason they went unnoticed in the eight adult patients who had no history of tics prior to age 18 years. (3) onset occurs before age 18 years. The notion that Tourette’s syndrome is exclusive to childhood does not square the experience of many movement disorders specialists who treat adults. ascertainment is a critical issue.g. it is attended by number of significant psychiatric comorbidities. many epidemiological studies demonstrate onset in early childhood. such as attention deficit hyperactivity disorder (ADHD) and Obsessive Compulsive Disorder (OCD). The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association 2012) offers the following four-part definition of Tourette’s syndrome:  (1)  both multiple motor and one or more vocal tics have been present at some time during the illness. Jankovic and colleagues (2010) found 46 adult patients (19 years of age or older) with Tourette’s syndrome. D I AG N O S I S O F TO U R E T T E’S SY N D R O M E A key criteria is the onset of symptoms prior to age 18 years. there is too little experience to justify retrospectively defining and prospectively testing variables predictive of success. .6%. because most of them involved children drawn from primary schools. Yet the question remains whether these epidemiological studies confirming the age of onset prior to age 18 years employed circular reasoning.13. In a retrospective study. Shaped by expert opinion. Though Tourette’s syndrome is predominantly associated with simple and complex motor and vocal tics. The choice reflects a potential bias of convenience sample and a presumption that Tourette’s syndrome is a childhood disease. Also. with the exception of age on onset.. American Psychiatric Association 2000) criteria as did a comparison group of 100 patients with Tourette’s syndrome under age 18 years. text revision. (4)  the disturbance is not attributable to the physiological effects of a substance (e. cocaine) or another medical condition (e. (2) tics may wax and wane in frequency but have persisted for more than 1 year since their onset. In any retrospective study. Because large-scale clinical trials have not been conducted. experienced no tics prior to age 18 years. postviral encephalitis).g. Perhaps every adult did show symptoms prior to age 18 years. A  PubMed survey reveals virtually no age-specific incidence of Tourette’s syndrome beyond childhood. The proposed criteria thus offer insights into experts’ thoughts and present an opportunity for an epistemological analysis that may improve them. It is important to note that. of whom 8. Huntington’s disease.

it is 1. M I N I M U M AG E FO R S U R G ERY According to some expert reviews. if one assumes for the moment that age of onset of symptoms prior to 18 years has been discounted. the European Society for the Study of Tourette Syndrome. In other words 8 of every 100 individuals who present for DBS and who meet all the diagnostic criteria except that of onset of symptoms prior to age 18 would be denied the potential benefits of DBS were diagnosing physicians to insist on that criterion because they are wish to remain consistent with the Diagnostic and Statistical Manual of Mental Disorders. Indeed. First. and if symptoms appear before age 18 years the probability would be P(T+|18+). and P(18–) is the probability of being free of symptoms for the first 18 years of life. P(T+|18–) is consequently very low. By use of Bayes’ theorem. This argument fails for two reasons. Thus results the following formula: P(T+|18–) = (P(18–|T+) * P(T+))/P(18–) where P(18–|T+) is the probability of the first 18 years without symptoms if one has Tourette’s syndrome. P(T+) is the probability of having Tourette’s syndrome. Interestingly. These age requirements are not . suggested a diagnosis of Tourette’s syndrome or chronic tics (Muller-Vahl et al. it is 0. the probability that one has Tourette’s syndrome may be expressed as T+. These probabilities are known as prior probabilities. experienced symptoms that went unnoticed before they reached age 19 years. the minimum age is 25 years. (2010). 2011). P(T+) is very low and P(–18) is very high. (P[18–]) is 0. to insist on symptoms onset prior to age 18 years is to discriminate against those who. The first reason rests on an application of Bayes’ theorem. A review by Piedad and colleageus (2012) cited a five-case series in which four cases included a diagnosis according to Diagnostic and Statistical Manual of Mental Disorders criteria. perhaps wishing to avoid the aforementioned issues. In the general population. According to others. The probability of experiencing no symptoms for the first 18 years of life. because all the patients presenting for DBS display symptoms that are consistent with Tourette’s syndrome. The forgoing discussion is not merely academic. The argument in support of maintaining as a criterion the onset of symptoms prior to 18  years of age likely rests on the negligibly small probability of having Tourette’s syndrome but having no history of it prior to age 18 years.132 2 0 T hings to K now A bout D eep B rain S timulation Even if it were absolutely true that all patients with Tourette’s syndrome experience onset of symptoms prior to age 18 years and that the “outliers” were those in whom a history of tics prior to age 18  years went undiscovered. which is just 1 – P(T+|18–). 18 years is the minimum age for DBS candidacy. for whatever reason.08. According to data presented by Jankovic et al. the probability of Tourette’s syndrome in the population of concern—the population being considered for DBS—is not very low.08 in the population of concern. The problem is that the prior probabilities discussed here are not relevant to the situation of deciding candidacy for DBS. the probability of having Tourette’s syndrome if symptoms appear after age 18 years would be P(T+|18–). The probability of experiencing no symptoms for the first 18 years of life is not low in this population.

the US Food and Drug Administration (FDA) has approved DBS for treatment of primary dystonia under a Humanitarian Device Exemption. Even a minimum age of 25 years leaves unknown the number of patients whose symptoms will fail to remit. However.1). Leckman and colleagues (1998) demonstrated that by age 18 approximately one-half of the patients who participated in their study were free of symptoms. 90% of the participants continued to experience tics. the time course of tic severity in any one patient does appear to be unpredictable. a child’s head has reached 95% of its eventual adult circumference. Extrapolation from a population statistic to that of an individual is highly problematic.4 standard deviation). were asked to participate in another video-recording. This age roughly correlates with age of maximum tic severity noted by Leckman and colleagues (1998. for example. but no correlation was found in the duration of time that elapsed between the earlier and later video-recordings. The real determination. is the number of patients under consideration for DBS who will spontaneously remit in a period that is sufficiently reasonable to render DBS unwarranted. the mean age of symptom onset during childhood was 7. physicians do not deal with a population. though most were observed to have diminished since childhood. however. 22% experienced tics so disabling that they interfered with schooling. Yet when considering DBS candidacy. It is believed that by age seven years.1). all participants considered themselves free of tics. At the time of the later video-recording.2 years (± 2. A  minimum age of at least 18  years is unlikely to help . Those who seek to make this determination often invoke Leckman and colleagues’ article. One notes that in the study by Leckman and colleagues (1998) the time course of worsening tic symptoms is a composite score consisting of data pooled across individuals.2. A correlation was found in tic severity between childhood and adulthood. DBS lead displacement consequent to later skull growth thus does not present a significant issue. they deal with individuals. The minimum age requirement rests on the rationale that symptoms of Tourette’s syndrome are often self-limiting. ±3. Of the 36 subjects contacted as adults. which would obviate the need for DBS surgery. Fifty-six adults with Tourette’s syndrome. A strict DBS–candidacy age threshold fails to resolve the issue of maximum severity of the tics. Yet application of Leckman and colleagues’ data to the issue of a minimum age for candidacy requires extrapolation rather than interpolation (see Figure 13. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 133 based on issues of safety in children. Interestingly. see Figure 13.5 standard deviation years).13. Of study participants. 10 of the 31 subjects experienced objectively worse tic symptoms at the time of the later video-recording. For children as young as seven years. Though one must bear in mind that failure to find a correlation may represent a type II statistical error (failure to find a truly existing correlation). which Leckman and colleagues (1998) found to be approximately 10 years of age. 31 agreed to be reevaluated (mean age 24.2 years (±2. It is presumed that any patient under age 18 enjoys a significant chance of a spontaneous remission. A retrospective study conducted by Pappert and colleagues (2003) involved the use videos of patients that were assessed by a blinded rater. who had video taken of themselves as children. particularly if allowances are made—slightly deeper DBS lead placement or extra length in the extension that connects the DBS lead to the implanted pulse generator. The mean age at the time of the initial video-recording was 12.2 standard deviation). Among the study participants.

1  Plot of tic severity over time for data compiled for the first 18 years of life. which some experts would establish as minimum age for DBS consideration. the extrapolation must deviate from linearity. Indeed. a patient with severe Tourette’s syndrome who began to experience symptoms at age 20 years and . however. Because this clearly is not the case. 1998). the originators of Evidence-Based Medicine recognized the validity and value of expert consensus. Yet the appropriate nonlinearity of the extrapolation cannot be known beforehand.134 2 0 T hings to K now A bout D eep B rain S timulation Plot of mean tic severity. Shown here are two hypothetical extrapolations that illustrate the implications. One observes that the data does not extend to age 25 years. suggests continued probability of improvement beyond age 25 years (modified with permission from Leckman et al. because the prospect of a patient’s spontaneously improving is unlikely. This is not to suggest that such consensus is uninformative. which in turn suggests that beyond some age tic severity improves no further. One group has suggested that the psychosocial consequences of tics are greatest at age 18. This conclusion is highly suspect. considerable injury to the child is likely if definitive treatment is delayed until age 18 years. Relative tic severity (ARRTS) 5 4 3 2 B 1 Actual Means Estimates from Model 0 5 10 15 C 20 A 25 Age (y) Figure 13. Again. ages 2 to 18 years. For example. In such case DBS is warranted. children who might benefit from DBS. because no evidence appears to support it. The extrapolation represented by line C. these recommendations were not referenced and may represent a consensus based on anecdotal experience. D U R AT I O N O F SY M P TO M S The European Society for the Study of Tourette Syndrome (Muller-Vahl et  al. Unlike many other recommendations. Yet the recommendation does pose problems. it appears that no patient age 23 or older would experience symptoms. Studies have demonstrated marked increase in susceptibility to peer influence at ages 13 to 16 years (Turkstra 2000). The extrapolation represented by line B suggests a curve asymptotic to a horizontal line. 2011) recommends that a patient experience symptoms for at least five years and severe symptoms for at least one year. If one extrapolates linearly from the final phase of the model (line A).

creates this type of situation. There is no reason to assume that a five-year history of symptoms or a one-year history of severe symptoms is sufficient for any individual patient. a time series with a relatively long period between events is highly variable. is it fair to expect a patient to suffer for an additional four years in order to meet the criteria? What if the prognosis cannot be established in a five-year observation period? Does not proceeding after five years expose the patient to the possibility of unnecessary surgery? The key is to detect a change in the frequency of severe tic exacerbation. a patient with Tourette’s syndrome who began to experience symptoms at age 17 years and whose severe symptoms have persisted for four years—must she be required to suffer another year before she undergoes DBS? PR ED I CT I N G C H A N G E I N SY M P TO M S E V ER I T Y OV ER T I M E Motivating the search for a proper minimum age for DBS and sufficient duration of symptoms—severe symptoms. Detecting any worsening of tics would certainly help. individuals are more often fooled by things they think they know than there are by things they do not know. The long history of this bias is encapsulated in the proverbial directive. These criteria appear ad hoc and are at best extrapolations from anecdotal experience. in which an attempt is made to minimize the time to detect a fault. The recommendations’ anecdotal nature raises the real possibility of Omission bias. no studies have taken these approaches. Also. As Claude Bernard observed. These factors affect the period of observation needed for prognostication. Harm may therefore result by commission (operating too early) or omission (operating too late or not at all). A Bayesian approach and other statistical approaches have been developed (Barry and Hartigan 1993). and it may make likelier a patient’s DBS candidacy. detecting an unlikelihood for positive change is helpful as well. As such it renders detecting a change quite difficult. . A time series with an extremely short inter-event interval and very low variability.13. “First. Such detection depends heavily on the statistical nature of the time series of severe tic exacerbation. do no harm” (Primum non nocere). bias toward inaction because it is preferable to acting in a harmful way. For example. E X H AU ST I O N O F A L L R E ASO N A B L E A LT ER N AT I V E T H ER A PI ES Medications Medications are grouped in three general classes: (1) alpha agonists (of which there are two). If it could be established that the prognosis of spontaneous remission is essentially zero within one year. but to my knowledge. becomes relatively easy to detect. Process control. that is. on the other hand. This directive rests on an outmoded ethical concept and tends to make physicians rather than patients feel better (see ­chapter 19). Both the inter-event time interval as well as its variability are critical to the determination of prognosis for spontaneous change. However. (2) antipsychotics (four generally recommended but more are possible). particularly—is a concern about exposing a patient who might yet spontaneously remit to DBS surgery risks. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 135 who presents with DBS meets the duration criterion but fails to meet the age criterion.

and two others showed no statistically significant differences in efficacy against tics (Pringsheim and Marras 2009).5 years would be required to test all of them. particularly lethargy (Ross and Moldofsky 1978). The task becomes that of deciding whether multiple agents in a group must be attempted prior to considering DBS.5–20 0.75 years if the latter were changed every three months. and it would take 1. One study. Exhausting all reasonable medical options would take 3. If each possible combination required six months—the usual amount of time that elapses between clinic visits—then 63. Table 13-1. however.5–4 0.5 years if the latter were changed every six months.5 0. the following caveat: failure to demonstrate a statistically significant difference is no demonstration of a lack of difference.136 2 0 T hings to K now A bout D eep B rain S timulation (3)  a dopamine depletory (Kurlan 2014. A great deal depends on the power of the statistical analysis and sample size. which directly compared either pimozide or haloperidol to fluphenazine in patients with Tourette’s syndrome. The appropriate approach is therefore to define a clinically meaningful difference in outcome measures and calculate the sample size for reasonable probability (power) in order to find a statistically significant difference at the appropriate cutoff (p value). the more similar the agents are in the outcome measure the harder it is to demonstrate sufficient statistical power. a treating physician or healthcare professional must compare all 127 drug combinations. Daily dose (mg) 0. In order to exhaust all possibilities for medical therapy.5–100 . Even if changes in medication regimens were possible every three months. *FDA-approved for this indication. one study demonstrated pimozide to be inferior to haloperidol. One must bear in mind. Tic-Suppressing Medication Alpha agonists  Clonidine  Guanfacine Antipsychotics  Haloperidol*  Fluphenazine  Pimozide*  Risperidone Dopamine depletory  Tetrabenazine Note: This list is not comprehensive. Also. In a Cochrane Database of Systematic Review. A number of studies have compared pimozide to haloperidol. suggested equal efficacy but fewer adverse effects with pimozide (Singer et al.1). Most studies demonstrated fewer side effects with pimozide. 1985–1986).5–10 0. the question may be divided into questions of efficacy and questions of adverse effects. The few studies comparing pimozide to risperidone have demonstrated no statistically significant differences (the aforementioned caveat applies in this case). see Table 13.05–0. 31 years would be required to exhaust all the combinations thereof.5–16 12.5–20 0. then the possible combinations are seven. As with similar considerations in the case of Parkinson’s disease. If only one agent from each group required testing.

These recommendations greatly increased the number of antipsychotic agents for consideration. Yet the review presented no comparisons for the additional six agents. they also increased the possibility for proliferation of the number of combinations that one may need to consider before recommending DBS. It is therefore impossible to recommend ways of streamlining the choice among these options.13.5 to 20 Low-quality evidence Quetiapine Weak recommendation Children: 25 to 400 Adults: 25 to 400 Very low-quality evidence Ziprasidone Weak recommendation Children: 20 to 40 Adults: no data on Low-quality evidence adult treatment Source: Pringsheim et al.5 to 3 High-quality evidence Fluphenazine Weak recommendation Children: 0. .25 to 3 Adults: 2. (2012).5 to 3 Adults: 0. Table 13-2. GRADE Recommendations for Antipsychotics for the Treatment of Tics Suggestions for medication dosing (mg per day) Medication GRADE Pimozide Weak recommendation Children: 1 to 4 Adults: 1 to 6 High-quality evidence Haloperidol Weak recommendation Children: 0. It is likely that no such comparisons were made. Strict adherence to the directive that all medication options be exhausted prior to considering DBS risks preventing certain patients from ever receiving DBS. The review associated with the Canadian recommendations provided the same data as previously discussed.5 to 10 Low-quality evidence Metoclopramide Weak recommendation Children: 0.5 to 10 Adults: 2.25 to 3 Adults: 0.25 to 6 High-quality evidence Aripiprazole Weak recommendation Children: 2 to 15 Adults: 2 to 20 Low-quality evidence Olanzapine Weak recommendation Children: 2.5 mg/kg Adults: no data on Low-quality evidence per day. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 137 Pringsheim and colleagues (2012) issued clinical guidelines that made the recommendations shown in Table 13. As a result. up to 40 mg adult treatment (children age 6 years and older) Risperidone Weak recommendation Children: 0.2.

Yet what is to become of a patient who scores 34? If she is considered for DBS. a trial of pimozide may be reasonable. Integration of metoclopramide. however. Meta-analyses of the use of antipyschotics has demonstrated an increased risk of sudden unexplained death in the elderly. olanzapine. aripiprazole. haloperidol produces intolerable adverse effects in a patient who has not tried pimozide. it may not be necessary to try the other. (4) contingency management. (3)  self-monitoring. 2012). With use of atypical antipsychotics especially. Of importance in this case is the judgment whether the failure of one medication justifies attempting the other. if one fails. 2013). S E V ER I T Y S U F FI C I EN T TO R EC O M M EN D D EEP B R A I N ST I M U L AT I O N Most experts agree that in order to warrant DBS surgical and postoperative stimulation risk a patient’s tics must be sufficient severity. however. Alpha Agonists A search of PubMed revealed no studies that directly compared guanfacine and clonidine in patients with Tourette’s syndrome. A number of groups have written that the score on Yale Global Tic Severity Scale (YGTSS) should reach 35 points or more (Leckman et al. If. Caution is advised. Yet at least one study suggested that prolongation of the QT interval was not associated with increased risk of sudden cardiac death (Leonard et al. and ziprasidone into a single approach for antipsychotic use is simply impossible. 1989). Studies on the use of these agents in hypertension. Behavioral Intervention A recent consensus report examined six types of behavioral intervention:  (1)  habit-reversal therapy. ought not a patient who scores 33 also win the same consideration? .138 2 0 T hings to K now A bout D eep B rain S timulation A reasonable conclusion is that no great difference exists between pimozide and haloperidol. A search on PubMed reveals no comparison studies of guanfacine and clonidine in terms of relative frequency and severity of adverse effects in Tourette’s syndrome. No judgment regarding the advantage of one over the other is therefore possible. Literature on the risks associated with typical and atypical antipsychotics has been inconsistent (Murray-Thomas et al. prolongation of the QT interval in electrocardiograms has been observed. (5) exposure and response prevention. have been conducted. (2)  massed negative practice. it is unlikely that risperidone will succeed. 1986). quetiapine. If pimozide fails. only habit-reversal therapy and exposure and response prevention underwent clinical trials in sufficient number for the consensus committee to recommend the former as effective treatments. Of those six types of behavioral intervention. and they have revealed that there is little difference between them in terms of adverse effects (Wilson et al. and (6) generic cognitive-behavioral treatment (Steeves et al. 2013).

impulse control problems. Because the consequences are highly contextual and specific to the individual. The overall impairment score correlates the phonic score with a Pearson r = 0. it occupies a range of values. Such transitions often employ a thresholding process. those who advocate the use of the YGTSS appear to rely on combined motor and phonic tic scores instead of the impairment score. Decisions require a dichotomous variable:  a surgeon must either operate or not operate. Cavanna and colleagues (2013) recently reviewed issues surrounding development of quality of life measures. The phonic tic scores thus explain approximately 18% of the overall improvement score (Storch et al. improvements in OCD or ADHD must not be the intent behind recommending DBS for Tourette’s syndrome. (2)  phonic tics. Growing evidence of the effectiveness of DBS in . and economic contexts. If the endpoint is improvement in a patient’s quality of life. Psychiatric and psychological comorbidities greatly affected most quality of life measures. Use of the total tic score from the YGTSS raises additional concerns. moral. These are suggested by the failure of the total tic score to correlate with the TNO-AZL Children’s Quality of Life scale in children (Bernard et al. duration of symptoms.18. political. and (3)  overall impairment. Further. particularly during childhood. which must be considered in their particular medical. 2009). For the present. Nothing in the data itself suggests an appropriate threshold or cutoff. Interestingly. Because the structure of most tic severity and quality of life measures is effectively continuous. especially in children.81. Though evidence suggests that DBS may alleviate some OCD symptoms. it is difficult to accept how severity. Measures of ADHD and OCD correlated better. DBS in the vicinity of the sensorimotor region in the posterior lateral aspect of the globus pallidus interna is unlikely to benefit OCD or ADHD. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 139 The YGTSS consists of three components:  (1)  motor tics. the square of which is 0. age. The presence of an implanted DBS system increases concern for patients who engage in self-injurious behavior. or any other possible cutoff may be unilaterally established by physicians. self-injury— are common enough to be of concern.66. Some means of converting continuous or multivalued continuous data to a dichotomous value is therefore needed.42. I cannot recommend it. the square of which is 0. Other significant psychiatric and psychological comorbidities—depression. And though these symptoms may benefit from DBS in the vicinity of the centromedian-parafascicular nucleus. ethical. C O M O R B I D I T I ES ADHD and OCD occur in patients with Tourette’s syndrome so frequently as to be thought part of the syndrome. ADHD and OCD play a prominent role in the quality of life. because I have not seen sufficient evidence. social. 2007).13. The correlation between overall improvement and motor tic score is 0. This means that the motor tic score only accounts for two-thirds of the overall impairment score. Yet even patients whose “pure” Tourette’s syndrome bespoke of no significant comorbidities experienced diminished quality of life as a consequence of their severe tics. then it is not certain that the YGTSS represents the most appropriate measure. The appropriate approach requires that one determine the cutoff by examining the consequences (Montgomery and Turkstra 2003).

140 2 0 T hings to K now A bout D eep B rain S timulation the vicinity of the anterior limb of the internal capsule for OCD (approved by the FDA under a Humanitarian Device Exemption). Such bias is avoided if one recognizes it as a possibility and consciously attempts to counteract it. As discussed in c­ hapter 3. Entry to DBS surgery traditionally lies through a neurologist. The consequences must be considered in their widest extent. Many physicians. This is not to say that the presence of depression is a contraindication to DBS surgery. and the chemotherapy agent was the cause of death (O’Brien et al. . Medications enjoy no inherent advantage over surgery. Yet the fact remains that medications can be more dangerous than surgeries. R E A L I ST I C AS S ES S M EN T O F R I S K A N D A LT ER N AT I V ES The decision to proceed to DBS surgery must rest on dispassionate analysis and rational. which are typically related to intracerebral hemorrhages. the risk of serious morbidity with DBS surgery is on the order of 2% for serious or permanent complications. The determination depends on how readily any increase in risk for self-injurious behavior may be detected and treated.5% mortality rate within 30 days of chemotherapy commencement. Yet one study demonstrated a 7. Of course. and 2% for infections that necessitate removal of a DBS lead. whose tools of the trade are medications. Admittedly. then I advise them that DBS will offer no significant benefit. which in turn must be considered in light of the consequences of every alternative decision. Admittedly. if ultimately irrational. This mortality rate is much higher than the mortality rate of DBS surgery. Relevant here is the issue of Confirmation bias. provided there is no expectation of also improving their tics. in which an individual admits only those data or experiences that resonate with his particular experiences and expectations. suggests that DBS in the vicinity of the anterior limb of the internal capsule may be an option for patients with severe OCD. Presence of significant depression is a concern. The concern is that physicians will object reflexively to offering surgeries. 2006). Mortality is quite rare. patients with active self-injurious behavior may need to be excluded. It is to say. rather. If they estimate only a slight improvement. that physicians default to medications. Experience with DBS for Parkinson’s disease and Essential tremor has shown an increased risk for depression or exacerbation of depression following DBS. for example. all the options must be weighed in terms of their advantages and disadvantages. physicians are prone to the same biases and failures of logic as anyone else (Johnson-Laird 2006). Programmatically preferring medications to surgeries is therefore unreasonable. that physicians and healthcare professionals must be proactive in anticipating worsened depression and have contingency plans in place. It is therefore unsurprising. I  ask patients or their family members/ caregivers to estimate the degree to which quality of life would improve with relief from tics. chemotherapy and DBS surgery are somewhat incommensurate. The effect of self-injurious behavior is more problematic. have few reservations about prescribing chemotherapy. A patient with Tourette’s syndrome for whom ADHD and OCD are the main limiting factors for quality of life are unlikely to benefit from DBS in the vicinity of the posterior lateral globus pallidus interna. Sometimes the depression or exacerbation is transient. however. Whether the history of self-injurious behavior is sufficient to exclude a patient is difficult to determine.

Patients or their surrogates may aid them by helping to manage otherwise ineradicable uncertainty. The criticism focuses. no published criteria offer any modifier or measure that captures the specific context in which a patient is bound. the current criteria appear to fail to accomplish the desired end. Scientists and computers compare incommensurables. This holds especially true for any criterion associated with a fixed threshold. the current state of knowledge and the obligation it places on physicians. H OW Q U EST I O N S A R E FR A M ED A N D W H AT T H E Y R E V E A L A B O U T T H O S E W H O FR A M E T H EM The way one sets about identifying the best DBS candidates among patients with Tourette’s syndrome speaks volumes about physicians and healthcare professionals. Patients or their surrogates may determine an acceptable degree of uncertainty attending both risk and benefit. one must not consider it so. Any uncertainty in the data is thus considered noise. rather. Physicians and healthcare professionals. for example. which represents the central tendency. Uncertainty will remain. When examined critically from an epistemological standpoint. Scientists faced with uncertainty may run more subjects or conduct more experiments. Hard and fixed cutoffs violate a patient’s autonomy (Beauchamp and Childress 2013). The aforementioned Omission bias represents the fear associated with taking action that has immense consequences for others. Yet there has been published no selection criteria that offers any formal means of soliciting and incorporating patients’ individual value systems. Uncertainty is the lot of physicians and healthcare professionals. Montgomery 2011). Yet quality of life is highly contextual. complex decision-making. Physicians and healthcare professionals are not alone in this task. which compel them to act assuredly. The exact same degree of symptom severity in one patient may result in less diminished quality of life in one context and more diminished quality of life in another. no matter how many subsequent randomized controlled trials are conducted (Montgomery and Turkstra 2003. is synonymous with the entity sought. who must think scientifically but must also adopt other frames of mind. rather. Though the forgoing criticism may appear deflating. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 141 D EC I S I O N S I N T H E FAC E O F U N C ERTA I N T Y The foregoing critique of proposed selection criteria does not extend to the various motivations that prompt physicians and healthcare professionals to help patients and avoid preventable harm. These devices are insufficient for a physician. Limiting patients’ participation in the DBS decision to that of accepting or rejecting offers constructed by physicians and healthcare professionals represents a form of paternalism that is unacceptable . must regularly compare the incommensurables of risk and benefit. Patients’ needs trump the demands placed on physicians and healthcare professionals. Indeed.13. They alone may determine the amount of willingness that attends any risk–benefit assessment. The criticism certainly does call for nuanced. Honest reflection clearly demonstrates. Uncertainty for scientists is reduced by the presumption that the median or mean. on the means by which this help is given. It reflects. on the other hand. many criteria that impose hard and fixed cutoff thresholds militate against enlisting patients in the DBS decision. such as “apples and oranges” only with great difficulty. As yet. that any assessment of degree of severity is really an attempt to measure a patient’s quality of life.

however. what may be said regarding DBS in the vicinity of the globus pallidus interna may not be said of DBS in the vicinity of the centromedian-parafascicular nucleus. Washington. but there is insufficient evidence to warrant its use as a standard and accepted off-label use of an FDA-approved device. and their physicians on symptoms and signs. relevance to an individual’s unique context. DBS in the vicinity of the globus pallidus interna is an effective symptomatic treatment for Tourette’s syndrome and other hyperkinetic disorders. the therapy must be considered investigational. They therefore know that symptoms and signs are part of disease pathophysiology. Unfortunately. that is. happiness—is poor (Janse et al. which hard. Offering a patient DBS produces one outcome. Criticisms of selection criteria require considerable nuance. . their family members.and sign-based assessment instead of quality-of-life measures (assuming that valid ones are available) may lack ecological validity. Yet it represents an honest attempt by physicians and healthcare professionals who may themselves be cowed by the complex nature of the decision and therefore doubt a patient’s ability to decide. Diagnostic and statistical manual of mental disorders (5th ed. The symptoms and signs are thus closer to the real disease than they that are too vague and perhaps indiscriminate quality-of-life measures. DC: American Psychiatric Association. 2012. must be supplemented by the experience that has shown DBS in the vicinity of the globus pallidus interna to be effective for a wide range of hyperkinetic disorders. S U M M A RY Sufficient evidence exists to support the use of DBS directed at the sensorimotor region of the globus pallidus interna for the treatment of disabling tics or tics that significantly reduce the quality of life of patients with Tourette’s syndrome.). A decision must ultimately rest on its consequences and not some set of rules imposed on it. these criteria must be understood. DBS in the vicinity of the globus pallidus interna DBS should be considered an accepted and standard use of an FDA-approved device. fixed cutoff criteria render impossible. Physicians and healthcare professionals perform symptom. In this sense. Indecision carries consequences as surely as does any decision. The limited direct clinical experience associated with this use. because the former may not translate to any relevant patient concern. as a basis for conversation with the patient in order to assure ecological validity. rather.142 2 0 T hings to K now A bout D eep B rain S timulation in the modern medical community. Rather.and sign-based assessments all the time. Studies have shown relatively consistent agreement among patients. Yet agreement by these same parties on subjective measures—quality of life. The use of symptom. In the case of DBS in the vicinity of the centromedian-parafascicular nucleus. 2004). The latter may be effective for such a comorbidity as OCD. and not offering it produces another. R EFER ENCES American Psychiatric Association.

European clinical guidelines for Tourette syndrome and other tic disorders. Can J Psychiatry 2012. New York: Oxford University Press. Cochrane Database Syst Rev.57(7):653–661. Mortality within 30  days of chemotherapy:  a clinical governance benchmarking issue for oncology patients. Pringsheim T. O’Brien ME. Goetz CG. Course of tic severity in Tourette syndrome: the first two decades. J Am Acad Child Adolesc Psychiatry 1989. Johnson-Laird PN. 2009. 2003. Uiterwaal CS.28(4):566–573.25(13):2171–2175.27(1):83–93. Pappert EJ. et al. Leckman JF. Neurotherapeutics 2014. Behav Neurol. Washington. Murray-Thomas T. Rigg A.. Quality of life:  patients and doctors don’t always agree: a meta-analysis. Canadian guidelines for the evidence-based treatment of tic disorders: pharmacotherapy. Louis ED. Pimozide for tics in Tourette’s syndrome. Barry D. Piedad JC. Riddle MA. 2013. David K. Patel D. Cavanna AE. 2000. Neurology 2003. 2011.11:ix–xii. et al. Determinants of quality of life in children with Gilles de la Tourette syndrome. Identifying the Least Acceptable DBS Candidates Among Patients with Tourette’s Syndrome 143 American Psychiatric Association. Br J Cancer 2006. Cardiovasc Psychiatry Neurol. Leonard CE. Doja A. Jankovic J. Principles of Biomedical Ethics. What patients with Gilles de la Tourette syndrome should be treated with deep brain stimulation and what is the best target? Neurosurgery 2012. Gemke RJ. . Pediatrics 1998. DC: American Psychiatric Association. Borthwick A. Evidenced based medicine: let’s be reasonable. Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database.12:1–15.. Zhang H. J Clin Exp Cardiolog. Health-related quality of life in Gilles de la Tourette syndrome: a decade of research. Ask the expert:  what is your interpretation of the ADAGIO study and has it influenced your clinical practice? Neurodegen Dis Manage. Rickards HE. Gorman D.57(3):133–143. 1:21–23. Turkstra LS.102(1 Pt 1):14–19. Beauchamp TL. Vitale A. Cavanna AE. Janse AJ. Hartigan JA. Freeman CP. 6):1–9.). Stebbins GT.71(1):173–192.20(4):209–217. Bernard BA.10(Suppl. Marras C. 2004. et  al. Diagnostic and statistical manual of mental disorders (4th ed. Kurlan RM. Tourette’s syndrome in adults. Gelineau-Kattner R. 2009. Childress JR. Eur Child Adolesc Psychiatry 2011. Davidson A. The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. et al. 2006. J Med Speech Lang Pathol.88:309–319. Cath DC. Jones ME. 2013. Siegel S. 2013. Montgomery EB Jr.95(12):1632–1636. Journal of the American Statistical Association 1993.61(7):936–940. et al. How We Reason. Mov Disord.(2):CD006996. Pringsheim T. Antipsychotics and the risks of sudden cardiac death and all-cause death:  cohort studies in Medicaid and dually eligible Medicaid-Medicare beneficiaries of five states. Cavanna AE. New  York:  Oxford University Press. J Clin Epidemiol. Leckman JF. et  al. 2013.11(1):161–165. et al. Bandera V. Hardin MT. et al.24(7):1070–1073. et al. A Bayesian analysis for change point problems. 2010. et al. et al. Mov Disord.13. Montgomery EB Jr. Muller-Vahl KR. Treatment of Tourette syndrome. text rev. Part IV: deep brain stimulation. Objective assessments of longitudinal outcome in Gilles de la Tourette’s syndrome. Newcomb CW.

1986. Gorman D. Murphy TK. Comparison of guanfacine versus clonidine for efficacy. safety and occurrence of withdrawal syndrome in step-2 treatment of mild to moderate essential hypertension. Quaske S.144 2 0 T hings to K now A bout D eep B rain S timulation Ross MS. Lewin A. 2007. Gammon K. Wilson MF. Moldofsky H. Storch EA. and transcranial magnetic stimulation. Haloperidol. fluphenazine and clonidine in Tourette syndrome: controversies in treatment. A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette’s syndrome. et al. Should my shirt be tucked in or left out? The communication context of adolescence. Canadian guidelines for the evidence-based treatment of tic disorders:  behavioural therapy. McKinlay BD. Am J Cardiol.14:349–364. Haring O. Factor-analytic study of the Yale Global Tic Severity Scale.149(1–3):231–237. et al. Am J Psychiatry 1978. deep brain stimulation. . Singer HS.12:71–74. Pediatr Neurosci. Can J Psychiatry 2012. Aphasiology 2000.135(5):585–587. Psychiatry Res. 1985–1986. et al.57(9):43E–49E. Steeves T. Turkstra L.57(3):144–151. Fernandez M.

would be to violate the law and FDA policy. accepted first-line therapies. DBS for these indications thus constitutes “off-label” use of an FDA–approved device. because some off-label uses are considered standard.” Physicians who use a product for an indication other than those listed in the approved labeling must become well informed about the product. base its use on firm scientific rationale and sound medical evidence. biologics. and devices according to their best knowledge and judgment. for instance. state laws and legal court decisions exist to protect the privilege of physicians prescribing drugs or devices for off-label use. the institution at which the product will be used may.” Indeed. “However.” the FDA guidelines continue. the FDA states that “[g]‌ood medical practice and the best interests of the patient require that physicians use legally available drugs. and maintain records of the product’s use and effects. as well the ethical principle of benevolence.14 Deep Brain Stimulation for Cerebellar Outflow Tremor FO O D A N D D R U G A D M I N I ST R AT I O N STAT U S The US Food and Drug Administration (FDA) has approved Deep Brain Stimulation (DBS) in the vicinity of the thalamus’s ventral intermediate nucleus for treatment of Essential tremor and Parkinson’s disease-related tremor. . In its regulatory guidelines. They must discover. Investigational Device Exemption (IDE) or review by an Institutional Review Board (IRB). whether any specific prohibition exists against the use of FDA-approved drugs. To do so. Physicians must weigh several factors when considering DBS in the vicinity of the thalamus as treatment for cerebellar outflow tremors. posttraumatic tremor. and devices in treating conditions on which the FDA has not established a position. “Use of a marketed product in this manner when the intent is the ‘practice of medicine’ does not require the submission of an Investigational New Drug Application (IND). The FDA has yet to comment on DBS as treatment for postanoxic tremor. The issue is whether lack of approval prohibits use of DBS to treat tremor due to other conditions than Essential tremor and Parkinson’s disease. One may simply decree that no treatment be offered without FDA approval. under its own authority. and tremor related to Multiple Sclerosis. require IRB review or other institutional oversight. biologics. however.

does not rest on the results. Thus. “the absence of evidence is not evidence of absence. the patients entered into the study had already received best medical care. Yet lack of an FDA position is not license to do as one pleases. of two studies—a randomized two-limb (separate control and experimental groups) and blinded study and a single-limb study with blinded assessments with the patient serving as her own control— the first study is deemed more credible. the first study may appear superior from a strictly academic perspective. Any medical decision rests on an assessment of risks. therefore. Indeed. The study randomized to a second limb arrived at essentially the same conclusions as the first nonrandomized study (Deep-Brain Stimulation for Parkinson’s Disease Study 2001). An expensive study sponsored by the National Institutes of Health and the Veterans Affairs administration offers a useful example. it could be argued that the randomized study was unlikely to result in any difference. Indeed. In a sense. This claim leaves one wondering about the way in which the second study is better. Yet from its superiority it derives no necessary justification for regarding its results as more meaningful than the second study’s results. any presumed superiority rests on the confidence one has in the results. and alternatives. or at least from a perspective that privileges purity of method over any conclusions. Any superiority. However.” Lack of an FDA position on a particular off-label use is therefore no evidence at all of the FDA’s disapproval of that use. A 2001 study conducted by experts in the management of Parkinson’s disease (Deep-Brain Stimulation for Parkinson’s Disease Study 2001)  found that patients who had exhausted all reasonable attempts at medical therapy and arguably failed best medical therapy experienced. It was found that patients treated with DBS enjoyed better control of their symptoms and experienced fewer long-term side effects than did patients who received best medical therapy. 2009). It is often the case that the value one assigns to the facts matters as much as the facts themselves. As Carl Sagan famously observed. Whether an incremental improvement was worth the millions of tax dollars spent to realize it remains debatable. A purist may argue that the study that randomized to a second limb (Weaver et al. Indeed. The second group was randomized to either DBS in the vicinity of the subthalamic nucleus or globus pallidus. if one accepts this position. the results of the 2001 study would be superior to the latter randomized study because the former would be a within-subject design because it more directly addresses the question of whether a patient who failed medications would benefit from DBS. I personally hold the opinion that it was not. degrees of improvement theretofore unseen with medications. Rather. the second study did not randomize to a control group of patients having best medical therapy.146 2 0 T hings to K now A bout D eep B rain S timulation To claim that lack of FDA approval indicates the ineffectiveness or inferiority of off-label uses is to commit an error in reasoning known as arguing from ignorance (argumentum ad ignorantiam). 2009) was better than the initially nonrandomized study (Deep-Brain Stimulation for Parkinson’s Disease Study 2001). after undergoing DBS. A physician must base her choice to pursue an off-label use on reasonable scientific evidence. potential benefits. . The two studies must be compared according to the strength of their evidence rather than the meaningfulness of their respective outcomes. In it patients with Parkinson’s disease were randomized to two groups: (1) best medical therapy and (2) DBS (Weaver et al.

jeopardizing the lives of five individuals standing downfield. The so-called trolley car dilemma offers an example of Omission bias at work (Foot 1978. A sixth individual observes this situation. Sin of omission in such cases is that of not providing DBS. however. would send the trolley down a siding rather than into the five endangered individuals. as well as the confidence felt in those estimates by the decision-maker. however. consisting solely of two options (to treat or to refrain from treating). Should she give that large man the fatal shove? Asked to put themselves in the place of the sixth individual. The sixth individual no longer stands near a switch but on a bridge near a large man who holds a heavy bag. and alternatives. In most cases in which DBS is being considered. Thomson 1985). as any sin of commission. Surgical risks relate primarily to the risk of intracranial bleeding and infection. “Do no harm” (Primum no nocere). Along the siding downfield. Deep Brain Stimulation for Cerebellar Outflow Tremor147 Voltaire famously observed that “the best is the enemy of the good. They must make care decisions as patients stand before them. who subsequently judges the balance between risks and potential benefits in light of alternatives. respondents tend to show greater willingness to throw the switch than shove the man. if thrown. stand two individuals who would be struck by the trolley should the switch be thrown. Yet doing so is to fall victim to Omission bias.” The physician and healthcare professional must constantly decide whether the good is good enough. Scientists may simply take their time reaching a conclusion and run more experiments. is dichotomous in nature. which is every bit as bad. ethically speaking. whether the individual near the switch should throw it. A subsequent variation on the trolley car dilemma further complicates the issue. The fact that patients’ lives and health are at stake makes this anything but an academic discussion. which enjoys long historical standing but is in truth faulty. A PPR O PR I AT E M E AS U R ES Medical decision-making requires that decision-makers balance risks. Because it is dichotomous. The question becomes. which every physician and healthcare professional confronts. she could stop the runaway trolley and save the other five individuals downfield. no alternatives exist. Throwing the switch seems a less personal act than does shoving the man. potential benefits. The decision to treat or not to treat. A similar tendency pervades medicine as currently practiced. allows physicians or healthcare professionals beset by uncertainty to beat a retreat. Proximity of the actor to the consequence perhaps explains this tendency. despite the fact that throwing the switch results in double the deaths. Review of the literature suggests . which holds that sins of commission are worse than sins of omission. and their risks include those associated with the decision not to provide DBS. Physicians and healthcare professionals. admitting of no middle way or compromise. DBS carries a number of different types of risks. enjoy no such luxury. The sixth individual realizes that were she to shove the man from the bridge and onto the tracks. the best being unrealizable. The imperative.14. She notices also that she stands near a switch that. To refrain from deciding is to decide not to treat. then. A  trolley car experiences brake failure and goes hurtling down the tracks. the decision rests on estimations of risks and potential benefits.

Despite the fact that its actual consequences remain unknown. The presumption is that patients with significant dysphagia. dysarthria. As . The adverse effects with stimulation in the vicinity of the ventral intermediate nucleus of the thalamus are therefore unlikely to be significantly different in patients whose cerebellar outflow tremor owes to other causes. The decision for excluding patients with Multiple Sclerosis and significant dysphagia and dysarthria presents a difficult ethical problem. DBS in the vicinity of the ventral intermediate nucleus of the thalamus. Neither can one have any confidence in any position. The risks are estimated to be 1% to 2% for intracranial hemorrhage and for infection serious enough to necessitate the removal of the DBS lead (risk of infection around the implanted pulse generator is significantly higher). 2013). between the preoperative status and the postoperative response. The range of severities would be insufficient to establish a correlation. pro or contra. respect for a patient. but risk for hemorrhagic or infection complication appears the same. a systematic review by Troche and colleagues (2013) found no significant overall change in swallowing functions. face greater risk of exacerbation should they undergo DBS in the vicinity of the thalamus. Experience to date. however. any assumption of prudence presupposes Omission bias. In the patient. harm takes the form of adverse effects. on DBS for patients with significant dysphagia. dysarthria. Whereas it seems prudent to exclude patients with significant preexisting dysphagia. In society. The caveat that other comorbidities may influence the effects of DBS must be borne in mind. dysarthria. For example. It is unknown whether a patient’s preoperative stability (exacerbation frequency and recentness) is predictive of nonspecific exacerbation. because patients with significant dysphagia. for example. At issue is autonomy. or language problems. This presumption has yet to find any evidence to support. Risks associated with actual brain stimulation are specific to the DBS target and the surrounding functional anatomy. that is. suggests that the adverse effects of stimulation of the thalamus are no different between patients with Essential tremor and those with Parkinson’s disease.148 2 0 T hings to K now A bout D eep B rain S timulation that these DBS risks differ little from one disorder to another and from one target to another. or language problems. The review did note that a majority of patients experienced only mild swallowing problems prior to DBS surgery (Troche et al. for example. It is therefore reasonable to extrapolate the risks of these surgical complications to such other indications as Parkinson’s disease and Essential tremor and to extrapolate risks associated with DBS to cerebellar outflow tremor. for example. in terms of predictive value. may be different than stimulation in the vicinity of the subthalamic nucleus. because there is no evidence to justify it. or language problems. Patients with Multiple Sclerosis. recent exacerbation may be a reasonable criterion for excluding patients. that is. or language problems are generally excluded from DBS consideration. an ethical obligation to do no harm. it takes the form of medical costs. One therefore cannot know whether these patients are at risk. In force is the principle of beneficence—an obligation to improve a patient’s symptoms and disabilities— which admits of an obverse in nonmaleficence. especially if a decision must be made. The consequences may vary according to target and the functional– anatomical systems affected. A second caveat is this: Patients with different disorders may be susceptible to nonspecific risks. may experience an exacerbation of the sort that occurs with infection or any other source of stress. dysarthria.

particularly if one recalls that few other medical or physical therapy options exist (Samkoff and Goodman 2011). the physically assessed measure is the tremor’s character. Scales were therefore developed to measure the quality of life enjoyed by patients. which were physically assessed by physicians and healthcare professionals. which seeks to weigh the good realized by offering DBS against the good realized by refraining from offering it. as well as patients’ family members and caregivers. In patients with Multiple Sclerosis. It does not reflect. which is fairly straightforward. common outcome measures were symptoms. Degree-of-difficulty ratings tend to vary according to the rater. Historically. autonomy is difficult to invoke. It is not at all clear. The tasks become that of determining and measuring benefit. improvement in a patient’s life. This of course presupposes that one may calculate and compare good. however. the fact that it effectively treats the proper symptoms notwithstanding. is a fourth ethical principle: justice (Beauchamp and Childress 2013). The criteria for the amount and quality of care patients may expect may also come to be determined by deontological argument. they cannot exercise autonomy. Justice redresses a libertarian position that otherwise resolves around the situation.and sign-based assessments relate to a disorder’s pathophysiology and pathoetiology. Any changes in symptoms or signs may consequently be attributed to a specific causal mechanism and thus appear to validate the treatment. This duty clearly is not that of upholding autonomy. Deep Brain Stimulation for Cerebellar Outflow Tremor149 it bears on making a decision. If it is dedicated either to benefice or nonmalfeasance. like the exercise of autonomy. however these criteria come to be determined. it requires having proper knowledge. The decision of whether to offer patients DBS in the case of cerebellar outflow tremor admits of a third alternative. perhaps. Symptom. that symptom. The libertarian perspective holds that the amount and quality of care available to patients is determined by social contract and that society has the right to dictate the contract’s terms. however that improvement is defined. meanwhile. which insists on the duty attending the healthcare professions. because maintaining that patients and their legal representatives have a right to pursue ineffective treatments violates the principle of nonmalfeasance. The few possibly effective options may be assessed in short order. An egalitarian position. A treatment evaluated according to quality-of-life scales may be judged a failure. which is typically its amplitude. however. which is another reason some physicians prefer them. Called for in this situation.or sign-based outcome measures reflect any true value to a patient or society. however. studies utilizing the Expanded Disability Status . these measures are sensitive to influences not directly affected by the treatment. admits of some uncertainty. rests on a notion of fair and just application of criteria for the amount and quality of care patients may expect. The degree to which a disorder impairs such ordinary activities as eating and dressing (assessed according to the amount of independence evident) presents an alternative outcome measure. Yet the exercise of autonomy depends on having proper knowledge. They may come to be determined by way of utilitarian calculus. This alternative. If patients and their legal representatives lack proper knowledge. And. Highly subjective. In the case of cerebellar outflow tremor. for example. and signs.14. Yet to whom or what they owe this duty is unclear. which were voiced by patients. The differences in the outcome measures affect the conclusions drawn. it may bring consequences few would value or deem appropriate.

150 2 0 T hings to K now A bout D eep B rain S timulation Scale frequently demonstrated no significant change following DBS in the vicinity of the ventral intermediate nucleus of the thalamus. medication therapies for tremor are few). which were shown to improve). Distal rather than proximal tremor (this criterion rests on my experience. or speech problems. 3. Tremor—action tremor. An absence of significant weakness or sensory loss in the extremity targeted for DBS (contributing to tremor are weakness and sensory loss. has been suggested by a series of cases of tremor associated with neuropathies. this criterion seems prudent for the reason that it delays DBS treatment only slightly). impaired gait and other problems appear to worsen. The Expanded Disability Status Scale is heavily weighted toward effects on ambulation. 7. or driving a motorized wheelchair. Improvement restricted to the single upper extremity. G EN ER A L S EL ECT I O N C R I T ER I A While remaining cognizant of the lack of prospective controlled studies. on the other hand. may indicate relative independence when performing such tasks as eating finger food. and some try primidone. in that others must contribute care. Even if the tremor remains under satisfactory control. while unknown. Absence of significant dysarthria. dysphagia. dialing a telephone. 5. An absence of significant problems with depression or impulse control problems (arrangements must be made prior to the surgery for postoperative intervention should these problems begin to affect patients). any benefit attributed to reduction of tremor in a single upper extremity would not affect the Expanded Disability Status Scale. typically—severe enough to interfere with the patient’s quality of life directly as well as indirectly. The explanation for this improvement lies in the fact that Multiple Sclerosis is a progressive disorder. 2. 8. 9. If the patient already had significant gait involvement. Failure of all reasonable attempts at medication therapies (though many physicians try amantadine. Increased risks associated with medications that may interfere with wound healing or result in infection (of particular concern are patients with Multiple Sclerosis and their medical regime). 6. Degree of preexisting cognitive problems (though this is a problematic criterion because there is no method with which to predict risk for . I employ the following selection criteria: 1. Other symptoms or disabilities not responsive to DBS should lack the degree of severity sufficient to hinder quality of life even if the expected tremor relief follows. At least a six-month absence of symptom exacerbation in patients with Multiple Sclerosis (though insufficient evidence exists to suggest that DBS may increase exacerbation risks. 4. the amenability to DBS of whose mechanisms. Yet these same studies demonstrate marked and continued improvement in tremor. which has shown that proximal tremor is more difficult to relieve than is distal tremor).

Deep Brain Stimulation for Cerebellar Outflow Tremor151 subsequent worsening. tremor generated at more proximal muscles is more common in patients with cerebellar outflow tremor than it is in patients with other kinds of tremor. particularly in patients with Multiple Sclerosis. A  DBS lead placed in the distal hand representation is similarly less likely to help a patient whose tremor is more proximal. Those using ordinal noninterval scales. the quantity for which was determined to be approximately 60% to 70%. improvement ranged from preoperative scores of 4 (a score indicating inability to perform such a task as bring a cup to the lips) to postoperative scores ranging from 0 to 2 (the latter a score indicating an amplitude between 1 cm to 3 cm). DBS tolerance does not appear to require ever increasing stimulation strength to overcome it. I therefore generally recommend that patients power off stimulators when they are least needed—during sleep hours. This requires that the DBS lead be placed in the appropriate homuncular representation. for example. The motor homunculus within the ventral intermediate nucleus of the thalamus is also larger than the effective volume of tissue affected by the typical DBS stimulation parameters. It is unlikely that a DBS lead placed in the leg representation will help to relieve tremor in the upper extremity. TA R G E T I N G C O N S I D ER AT I O N S In my experience. particularly—is a tolerance that develops with continuous use. M U LT I PL E SC L ER O S I S DBS is effective in treating patients whose severe tremor owes to Multiple Sclerosis. significant improvement in tremor notwithstanding). A review of 12 studies found that all of the 75 participating patients were documented as experiencing improvement in tremor (Montgomery 2008). It is extremely important. however. A somewhat unique feature in patients with cerebellar outflow tremor—cerebellar outflow tremor owing to Multiple Sclerosis. to advise patients who take such a holiday that tremor will recur once they resume DBS and that they may experience adverse effects.14. which often means the more proximal representation than is typical for Essential tremor. a patient’s preexisting cognitive status must not be such as to severely limit his quality of life. Sometimes reducing stimulation strength may help patients to regain control. Patients who rapidly develop tolerance may benefit from a stimulation “holiday” of a week’s duration. . P O STO PER AT I V E PR O G R A M M I N G DBS programming for patients with Multiple Sclerosis is similar to that provided for patients with Essential tremor (see ­chapter 8 and Montgomery 2010). particularly in such cases where the goal is control of a single upper extremity’s use. Patients may gain significant improvement in the clinic and then worsen days or weeks later.

2009. 2011. (3)  Fragile X-Associated Tremor (Mehanna and Itin 2014). Reese et al. There could arise the temptation to require full-blown prospective randomized control trials before general acceptance of DBS in the vicinity of the ventral intermediate nucleus of the thalamus for these disorders. Breit et  al. Shields et al. provided they meet the criteria listed earlier. (4) posttraumatic tremor (Follett et al. Among these unusual causes are the following:  (1)  Klinefelter syndrome (Koegl-Wallner et  al. (10) mitochondrial encephalopathy (Kovacs et  al. 2004. . 2011). however. (11) phenylketonuria-associated tremor (Payne et  al. As discussed previously. (9) spinocerebellar degeneration (Shimojima et al. and (13) poststroke tremor (Yamamoto et al. (7) fragile X-associated tremor (Senova et  al. 2005).S PEC I FI C. (2)  dystonic tremor (Fasano 2014). P O STA N OX I C A N D P O ST T R AU M AT I C T R EM O R Common forms of disabling tremor. One must recognize that behind these reports may lie negative-report bias: some patients experience ineffective DBS and therefore go unreported. 2007). 2009. 2014). 2009. continued tremor improvement occurs as other disabilities related to the Multiple Sclerosis accumulate. postanoxic and posttraumatic tremor may be reduced by DBS (Umemura et al. (5) abetalipoproteinemia (Mammis et al. 2011). (8)  neuropathies (Bayreuther et  al. Too few prospective patients for the trials. 2004). whether to recommend DBS in the vicinity of the ventral intermediate thalamic as standard and accepted treatment for these patients. 2005).S PEC I FI C Case reports and small-cases series conjure the impression that DBS in the vicinity of the ventral intermediate nucleus of the thalamus is effective for a wide variety of disorders. or allow them otherwise to continue suffering their tremor. N OT D I S E AS E. Whether a two-year benefit justifies DBS-associated risks and expenses becomes the pertinent ethical consideration—one that is better addressed by society than by physicians or insurers. (12) Behr syndrome (Schramm et al. OT H ER T Y PES O F T R EM O R Case reports indicate improvement in tremor owing to a variety of unusual causes. 2013). then. all have shown continued tremor control. these conditions are typically not degenerative. SY M P TO M . 2006).152 2 0 T hings to K now A bout D eep B rain S timulation Of the few long-term studies conducted in this area. Freund et  al. 2006. The choice becomes. 2005. 2004. (6) Holmes’ tremor from structural lesions (Nikkhah et al. Sanborn et al. DBS in their treatment. 2012). likely leads to sustained improvement. would likely be found in order to muster statistical power enough for drawing any inferences. 2012). the latter of whom face a highly problematic conflict of interests (see c­ hapter 19). and this phenomenon serves to limit the benefit of tremor control in a single upper extremity. Aydin et al. Foote et al. One study found that a large majority of patients’ DBS was helpful for about two years (Montgomery 2008). Unlike Multiple Sclerosis. 2014). therefore. Park et al.

et al. irrespective of its cause. Seignourel P. 2009. Bove F. Bilateral deep brain stimulation of the ventral intermediate nucleus of the thalamus for posttraumatic midbrain tremor. The FDA has approved DBS for primary dystonia and some other indications and has based its approval on extensive case reports and case studies rather than traditional randomized control trials. Principles of Biomedical Ethics. Yet many disorders. moreover. Unilateral thalamic VIM and GPi stimulation for the treatment of Holmes’ tremor caused by midbrain cavernoma: case report and review of the literature. 1978. Follett MA. The treatment of dystonic tremor:  a systematic review.80(2):235–236.17(3):289–291. Childress JR. et al. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. Complicating the issue is the possibility that some insurers will specifically exclude off-label use on the mistaken belief that such use is experimental or investigational. Randomized controlled trials of pain medications are not conducted for every conceivable cause of pain. this exclusion would prove unfair to many patients. DBS in the vicinity of the ventral intermediate thalamus should similarly be considered specific to relief of the symptom of tremor rather than any particular disease. Fernandez HH. The rarity of some disorders. The Problem of Abortion and the Doctrine of the Double Effect in Virtues and Vices. 2001. Schols L. et al. Follett KA. 2013.14. J Neurol Surg A Cent Eur Neurosurg.58(4 Suppl 2):ONS-280-285. Borg M. Breit S.74(4):271–276. prevents conducting randomized control trials to demonstrate disease-specific efficacy. Foot P. et al. Neurosurgery 2006. Abuzayed B. Torres-Russotto D. J Neurol Neurosurg Psychiatry 2009.24(14):2157–2158. Deep brain stimulation of the ventral intermediate thalamic nucleus for severe tremor in anti-MAG neuropathy. Deep Brain Stimulation for Cerebellar Outflow Tremor153 An alternative is to consider DBS in the vicinity of the ventral intermediate thalamus as a symptom-specific treatment rather than disease-specific treatment. Kiziltan G. Wachter T. are so rare as to render infeasible the collection of a sufficient number of cases. Delmont E. Mov Disord. it is sufficient to demonstrate that a medication be shown effective for pain.345(13):956–963. Beauchamp TL. which may be helped by DBS. J Neurol Neurosurg Psychiatry 2014.85(7):759–769. Effective thalamic deep brain stimulation for neuropathic tremor in a patient with severe demyelinating neuropathy. 2013. Fasano A. Foote KD. Oxford: Basil Blackwell. New  York:  Oxford University Press. Rather. Bayreuther C. discussion ONS-285-286. Deep-Brain Stimulation for Parkinson’s Disease Study Group. Neuromodulation 2014. . R EFER ENCES Aydin S. it must win acceptance as an off-label use of an FDA-approved device. Were it to happen. N Engl J Med. Dual electrode thalamic deep brain stimulation for the treatment of posttraumatic and multiple sclerosis tremor. Lang AE. S U M M A RY Though thalamic DBS is effective for the relief of tremor in a wide variety of disorders.

et  al. Neurosurgical treatment of tremor in mitochondrial encephalopathy. NJ: Humana Press. Mov Disord. Shields DC. 2004. Treatment of phenylketonuria-associated tremor with deep brain stimulation: case report.27(6):797–799. et  al.147(6):679–683. Neurosurgery 2011. Subthalamic-thalamic DBS in a case with spinocerebellar ataxia type 2 and severe tremor-A unusual clinical benefit.19(9):783–788. discussion E868. Barnikol UB. et  al. Neuromodulation 2011. Neurol Clin. Deep Brain Stimulation in Neurological and Psychiatric Disorders. Ranalli NJ. Pendl T. Samkoff LM.29(2):449–463. Ventral intermediate thalamic stimulation for monoclonal gammopathy-associated tremor:  case report. Park YS.94:1395–1415. . et al. Katschnig-Winter P. discussion 218. Scheihing M. Flaherty AW. J Neurosurg.13(2):222–225.22(5):732–735.100(6):1079–1083. Starr PA. 2008:215–228. discussion 683.1985. Montgomery EB Jr. Pal E. Thomson JJ. Okun MS. 2014. Deep brain stimulation for the treatment of tremor and ataxia associated with abetalipoproteinemia. et al. Montgomery EB Jr. Totowa. Sanborn MR. et  al. 2006. Hellwig B. Chang WS. Jarraya B. In Tarsy D. Successful deep brain stimulation in a case of posttraumatic tremor and hemiparkinsonism. Reese R. et al. Brown BL. Unilateral thalamic stimulation safely improved fragile X-associated tremor ataxia: a case report. Thalamic stimulation for disabling tremor in a patient with spinocerebellar degeneration. 2013. et al. Nikkhah G. Swallowing and deep brain stimulation in Parkinson’s disease:  a systematic review. 2012.68(5):E1464–1467. Cerebellum 2014. Tremor Other Hyperkinet Mov. 2011. et  al. Parkinsonism Relat Disord. Hashimoto T. Senova S. Which approach is better? Bilateral versus unilateral thalamic deep brain stimulation in patients with fragile X-associated tremor ataxia syndrome. Rasche D. Troche MS. Mehanna R. Thalamic deep brain stimulation for other tremors. Tremor associated with Klinefelter syndrome—a case series and review of the literature. Koegl-Wallner M. Acta Neurochir (Wien). 2005. et al. Kim J. 2010. 2009. Danish SF. Goodman AD. Mammis A.20(3):323–327. eds.87(2):128–133. et al. Balas I. Deep Brain Stimulation Programming:  Principles and Practice. Mov Disord. Parkinsonism Relat Disord. Symptomatic management in multiple sclerosis. Mov Disord. Yale Law Journal. 2012. Shimojima Y. Kovacs N. Stereotact Funct Neurosurg. Kaneko K. Deep brain stimulation of the nucleus ventralis intermedius for Holmes (rubral) tremor and associated dystonia caused by upper brainstem lesions: report of two cases. Schramm P.14(3):214–218. Stereotact Funct Neurosurg. Prokop T.83(4):131–134. Thalamic deep brain stimulation for midbrain tremor secondary to cystic degeneration of the brainstem. 2011. 2007.154 2 0 T hings to K now A bout D eep B rain S timulation Freund HJ. Neurosurgery 2005. Feigin A. et al. Foote KD. et  al. Falk D. Rao J.56(4):E868. 2005. The trolley problem.26(10):1954–1955. et  al. Payne MS.1(1):2. Herzog J. New York: Oxford University Press. Brandimore AE. Itin I. Nolte D. Eskandar EN. Vitek JL. Iwamuro H. Mov Disord.21(12):2227–2230. Behr syndrome variant with tremor treated by VIM stimulation. Management of a DBS system in patients with traumatic brain injury: case report. Pourfar M.

106(4):280–283. . essential.14.301(1):63–73. Weaver FM. et al. Stern M. Follett K. 2004. JAMA 2009. Deep Brain Stimulation for Cerebellar Outflow Tremor155 Umemura A. Clin Neurol Neurosurg. Jaggi JL. 2004. Yamamoto T. Katayama Y. Samadani U. J Neurosurg. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Kano T.101(2):201–209. and poststroke tremor: a suitable stimulation method and changes in effective stimulation intensity. Deep brain stimulation for the treatment of parkinsonian. et al. Thalamic deep brain stimulation for posttraumatic action tremor. et al.

2013. although the epistemic presuppositions are presumed rather than explicitly recognized. (2) Huntington’s disease (Hebb et al. 2012. yet the issues discussed most frequently are how to enforce compliance rather than asking whether such guidelines are valid or appropriate or the degree to which they are valid and appropriate (Montgomery and Turkstra 2003). 2011. 2008. n = 1). Fasano et al. Many face no alternative besides DBS. n = 1. These disorders have the potential to devastate a patient’s quality of life. Hurtado et al. 2013. 2013. appears to be dictated by Evidence-Based Medicine. n = 12. n = 50). n = 1). . including case series. n = 1. Wihl et al. and perhaps the most important question: what is the nature of the evidence? This extends to the question that must be asked first: what is the nature of acceptable evidence? The nature of acceptable evidence. n = 8. 1999. Umemura et al. which increasingly has become synonymous with randomized control trials (RCTs) even though the original version of Evidence-Based Medicine recognized other legitimate forms of evidence. is remarkably effective and safe for variety of hyperkinetic disorders. 2004. case reports. 2012. even in cases in which all other alternatives have failed. and expert opinion. n = 1. (4) pantothenate kinease deficiency (Ge et al. which is: what is the evidence or data? However. The question is an epistemic one. n = 2. Interestingly. 2004. 2013. Kang et al. discussed here specifically in the vicinity of the sensorimotor region of the globus pallidus interna. 2011. n = 1. There is the ontological question. Lim et al. n = 1. n = 1). 2009. Interestingly. although one case report suggested no improvement in one patient. a PubMed review of “physician acceptance” and “Evidence-Based Medicine” readily demonstrates that significant numbers of physicians do not follow Evidence-Based Medicine–derived guidelines (Grol 2001). thereby placing a large burden on families and societies. n = 1. (5) choreaacanthocytosis (Miquel et al. Velez-Lago et al. n = 2. there is the question. The question for a clinician is whether sufficient evidence exists to justify offering DBS to a patient. Included among the latter are the following five indications: (1) tardive dyskinesia (Martinez et al. at least in academia. 2001. the US Food and Drug Administration (FDA) recognizes the privilege of physicians to use their professional judgment that does not exclusively rely on RCTs in the form of off-label uses of FDA-approved drugs and devices. Shin et al.15 Deep Brain Stimulation for Hyperkinetic Disorders Deep Brain Stimulation (DBS). Moro et al. Mentzel et al. n = 1). (3) hemiballismus (Vitek et al. 2006.

The issues are not technical. which in turn leads to significant harm. an issue discussed later. physicians and healthcare professionals would perhaps reflexively adhere to the directive. it quickly presented an ethical issue. The interesting question is why would academic physicians. given the limitations of Evidence-Based Medicine described here. A study of biases in moral judgments in children and adults found that “participants at all ages judged that it was worse to produce harm when harm occurred (a) through action rather than inaction (omission bias). and the Evidence-Based Medicine RCT committed would have to let patient with those conditions continue to suffer. that RCTs can only demonstrate findings that are statistically significant. consequently. The data is as it appears. do no harm” (Primum non nocere). The small number of cases described for each aforementioned condition could be taken as prima fascie evidence of insufficient evidence. No amount of wishing it to be something more obviates decisions confronted by patients and their surrogates. Nevertheless. which in themselves do not translate into clinical meaningfulness (Montgomery and Turkstra 2003). Even more critical is the mathematical fact that there likely would never be sufficient Evidence-Based Medicine that is synonymous with RCTs that are exclusively and directly relevant to the individual patient (Montgomery and Turkstra 2003). as well as the children around her. Refusing to vaccinate a child places her at significant risk of harm to herself. The problem is that it is unlikely there ever would be such evidence. However. Child vaccination is an example. at least implicitly. is heir to prejudicial presuppositions. who presumably have the same ethical obligation of beneficence to their individual patients. This notion results in Omission bias (Powell et  al. that has led to an overestimation of the power of RCTs. Indeed. which has pervaded academic medical institutions since the mid-1800s. so readily promulgate Evidence-Based Medicine RCT–derived guidelines? Is the ethical obligation to beneficence somehow different for a private practice compared to an academic physician? Perhaps it is scientism. 2012. Mamede and Schmidt 2014). the most fundamental aspects of the issue of DBS for hyperkinetic disorders are neither scientific nor technical. It is not difficult to understand the reticence of many physicians. it also can be taken as evidence of the rarity of DBS candidates among patients with the conditions listed here and thus as evidence for the impossibility of satisfying Evidence-Based Medicine demand for RCTs. physicians. Because doing so suggested possible bias against DBS. In the past. particularly those in private practice. Deep Brain Stimulation for Hyperkinetic Disorders157 The truly Evidence-Based Medicine–RCT committed would have to act as though there is no evidence in support of the use of DBS for the conditions described previously. The directive “First. do no harm” rests on an outmoded ethical notion that sins of commission are worse than sins of omission. For DBS the question regarding the nature of acceptable evidence turns on the surgical nature of DBS and. The methods employed by DBS for hyperkinetic disorders are exactly the same as those employed for other such accepted DBS therapies such as Parkinson’s disease and primary dystonia. and (c) when the harm was produced as a direct means to an end rather than as an . and healthcare professionals. Perhaps it is because they recognize. this disparity can only mean that some group of patients may not be receiving the most reasonable and rational care.15. “First. (b) when physical contact with the victim was involved (physical contact principle).

What remains unclear. recommendations of professional organizations. the ethical principle of autonomy demands that they receive deference. Indeed. They thus evolved to standards that a “reasonable” peer-physician might observe (Peters 2000). does not absolve physicians and healthcare professionals of their obligation to patients with respect to DBS. physicians and healthcare professionals who make referrals engage in a direct act. is physicians and healthcare professionals’ deferral to their own psychology or emotions ethical? The paucity of DBS referrals for hyperkinetic disorders and most other accepted indications suggests that psychologically or emotionally motivated reticence is common. Indeed.] no concessions for a lack of relevant experience. 186). . The task becomes. the risk of harm is little different from actual harm done a patient—undergoing evaluations and surgery except in degree. Finally. The difference in performance of the two relates to the degree by which the new doctor may be expected to consult and seek assistance to compensate for their relative lack of knowledge or skill. 2012. Understanding (and perhaps overestimating) risks. but the vast expansion of clinical guidelines. is whether it is appropriate or ethical for these psychological and emotional factors to play a role in the action (or inaction) of physicians and healthcare professionals. These factors are highly relevant to physicians and healthcare professionals who must decide whether to offer DBS to patients with hyperkinetic disorders. and increased sophistication on the part of legal professionals and juries appear to have strengthened the requirement for reasonableness. performing DBS surgery would be impossible without them. Yet the standards of care are evolving. A number of psychological and emotional factors that underlie Omission bias underlie biases toward procrastination. physicians and healthcare professionals who have established relationships with patients are obliged to treat them according to standards of care. Physicians and healthcare professionals need not be experts in DBS. The effect of referral is moreover tantamount to a physical act. “and a doctor in the first day of a new post is expected to work to the same standard of public safety as one who is on the last day of the post. . the Code of Ethics published in 1847 by the American Medical Association called on physicians to seek consultations. for example. They need not actually decide whether patients with hyperkinetic disorders should undergo DBS. then. At any rate. Though these factors are certainly present in patients and their surrogates. and maintaining the status quo as well.” Indeed. Lack of expertise. .” according to Bryden and Storey (2011). Courts recognized that risk criteria based on early standards of care may serve more physicians and healthcare professionals’ interests than those of patients. “There are [. Any of these possibly results in denying patients benefit of DBS (Anderson 2003). Early standards of care amounted to standards observed among peer physicians. p. however. The complex and extensive ethical issues surrounding DBS are addressed more fully in c­ hapter 19. cognitive inertia. DBS surgery would be impossible without the direct action of referring physicians and healthcare professionals. The notion of “reasonable” is clearly problematic. determining reasonableness of DBS for hyperkinetic disorders. The latter types of unavoidable harm are clearly intentional.158 2 0 T hings to K now A bout D eep B rain S timulation unintended but foreseeable side effect of the action (intention principle)” (Powell et al. however.

When presented with the mean alone. 13. 10. particularly with respect to unusual data distributions. Offering a useful example is the situation in which the inputs are the values. which suggests that the effects are counterbalanced . for example. 15. information exists in a physical state. however. and 12. Yet this help remains incomplete. it is impossible to know the values of the individual subjects. respectively). Its restoration requires the addition of energy. as is common in the reports of large RCTs. Counterbalancing potential confounds in RCTs by matching for confounds or by randomization implies a loss of information. Virtually every medical decision involves uncertainty. Evaluating the effects of a medication for stroke. Shannon’s Information theory and the Second Law of Thermodynamics (Mahesh Karnani et  al. Any increase in entropy is a loss of information. and 15. 25. Calculating a mean results in a loss of information. which has undergone some change. The Second Law of Thermodynamics is reversible:  The original state of a physical system. will be confounded by the presence or absence of such factors as hypertension and diabetes. Indeed. When presented with the mean alone. because a large number of different sets of values also has a mean of 15. it concerns not the contents of knowledge but the method and nature of their acquisition. One may discuss uncertainty according to two directly related elements: amount of information and quality of information. By logically irreversible operations is meant operations whose output does not uniquely define its inputs. What is gained by reducing uncertainty. Entropy—randomness in a physical system—affects information as well. 20. In a real sense. it may only be converted from one form to another. the energy dissipates. 3. RCTs absorb uncertainty owing to individual variation by translating individual variations to population description or information. 14. which in turn renders it impossible to know the generalizability of population statistical inferences to an individual patient.15. such as 1. The mean of these values is 15. Deep Brain Stimulation for Hyperkinetic Disorders159 EPI ST EM I C STAT U S O F D EEP B R A I N ST I M U L AT I O N FO R H Y PER K I N E T I C D I SO R D ER S Epistemology refers to analyses and understanding of the nature of knowledge. 5. The process of calculating the mean is an example of a logically irreversible operation. Physically isolated systems tend to maximum entropy (maximum information loss). which owe to biological variability and idiosyncratic vulnerabilities if nothing else. usually by restraining the information content by the central tendency (statistic means and medians) and the variance (standard deviations or quartiles. as suggested by the parallels between Claude E. It cannot be recovered from the population information. Information contained in the original state is lost. comes at the cost of being able to retroactively apply population data to an individual patient (Montgomery 2011). 2009). Yet information concerning the individual is lost. one cannot recreate the initial values. In order to manage confounds. subjects are randomized in the hope that the experimentally and placebo treated groups show the same prevalence of confounds. Similar dynamics applied to logical systems demonstrate an irrevocable loss of information if systems undergo logically irreversible operations (Landauer 2000). Uncertainty cannot be eliminated. some measure of the variance may help. 2. may be restored. parametric or nonparametric data. In most natural systems. Admittedly. leaving the physical system unable to return to its original state. In such cases it is known as Information–Theoretic entropy.

RCTs and Evidence-Based Medicine are tools. mathematicians. . One may argue that it is unnecessary to reverse precisely the logical operations and that the approximations enabled by descriptors of the central tendency (the mean. necessarily lose information. or statisticians. Stratifying the results negates the value of the computations for the population descriptors and reduces the statistical power. if for no other reason than they are subject to the Second Law of Thermodynamics. Such information as knowledge and values external to the RCT must invariably be brought into the RCT in order to obtain meaningful results (Montgomery and Turkstra 2003). The second concern is that to call for clinical trials is to presuppose some defect in the case series. The plethora of hyperkinetic disorders that respond to DBS suggests the DBS is a symptom-specific rather than a disease-specific treatment. any clinical trial will use some measurement of statistical effect size that will be affected by patient variability and that necessitates a certain sample size. Like any tool. It is not the rarity of the condition per se—type-2 pantothenate kinase deficiency. one notes with some bemusement case series reports on rare conditions that conclude clinical trials are warranted. First. If one adds to this the multitude of patients with Parkinson’s disease whose levodopa-induced dyskinesia improved with DBS. The foregoing discussion should not be construed as denigrating the importance of RCTs and Evidence-Based Medicine.160 2 0 T hings to K now A bout D eep B rain S timulation and presumably negated. This would not be true. then the number of cases supporting the symptomatic use of DBS becomes overwhelming. for example) are sufficient descriptors of the inputs to the logical operations. The information lost is precisely that which is necessary to apply the RCTs results to treatment of individual patients. A possible solution to the question of clinical trials for rare causes of hyperkinetic disorders is to consider DBS a symptomatic treatment. In the references cited earlier. Indeed. Calculating the population statistical descriptors is a logically irreversible operation. because information is irrevocably lost therein. for example. If it is the former. which diminishes the importance of their use in clinical decisions. the analyses on subpopulations with increased uncertainly resting on type I and type II statistical errors. one does not have to conduct a RCT of a pain medication for every conceivable cause of pain. because the output does not uniquely identify such inputs as exactly which subjects have hypertension or diabetes. however. rather. It cannot eliminate them. After all. which have become synonymous with Evidence-Based Medicine. Such recommendations raise two serious concerns. This practice may only manage confounds. If this is the case. in the situation of counterbalancing confounds. they must be used in accordance with their design limitations. then there always will be a prejudice against offering patients with rare conditions the possibility of improved quality of life. the extremely small subset of those patients that would be considered candidates for DBS. It is highly likely that there will be an insufficient number of subjects to power a clinical trial for rare conditions. then there occurs a change in conceptions about the scientific support of efficacy: The effectiveness and safety for one hyperkinetic syndrome is supportive evidence for the use of DBS in treating another hyperkinetic syndrome. The forgoing discussion does not suggest that it is feasible or even desirable that clinicians in some sense be physicists. It is. for example) and the variance (standard deviation. RCTs. approximately 92 patients with hyperkinetic disorders have demonstrated the effectiveness and safety of DBS.

15. Deep Brain Stimulation for Hyperkinetic Disorders161

Unfortunately, the same may not be said about those who provide advice, particularly when such advice is reduced to simple bullet points or cookbook recipes.
Because it is never so simple, clinicians must at least treat with skepticism advice
that appears simple. The decision to refer patients with hyperkinetic disorders is
certainly not simple. Where are these clinicians to look to for guidance? The FDA
is not the place to look, at least inasmuch as off-label indications are concerned. The
use of DBS for these indications, which would be off-label, lack FDA approval. The
issue of off-label use thus creates considerable confusion on the part of patients,
patients’ family members and caregivers, physicians, healthcare professionals,
and insurers. Because the stakes are high for all parties involved, it is important to
review the issues of off-label use.
O F F- L A B EL U S ES O F U S FO O D A N D D R U G
A D M I N I ST R AT I O N – A PPR OV ED D E V I C ES

It seems counterintuitive to suggest that the FDA is not a good source for information regarding off-label use of FDA-approved drugs and devices. “Off-label” means
that the FDA has not rendered an opinion on the intended use. In other words, on
those indications under consideration for off-label use, the FDA is effectively silent.
To some physicians, healthcare professionals, and insurers, the silence speaks volumes. For these parties the lack of position by the FDA is considered negative. Yet
as Carl Sagan observed, “the absence of evidence is not evidence of absence.”
As levodopa-induced dyskinesia and dystonia is typically not subsumed in the category of a hyperkinetic disorder such as chorea occupies, there is no hyperkinetic
disorder for which the FDA has approved DBS. A wealth of peer-reviewed publications demonstrating the efficacy and safety of DBS for hyperkinetic disorders,
however, comports to FDA regulations related to off-label use of FDA-approved
drugs and devices. “Good medical practice and the best interests of the patient
require that physicians use legally available drugs, biologics and devices according
to their best knowledge and judgment,” reads the FDA’s policy, which appears on
its website:
If physicians use a product for an indication not in the approved labeling, they
have the responsibility to be well informed about the product, to base its use
on firm scientific rationale and on sound medical evidence, and to maintain
records of the product’s use and effects. Use of a marketed product in this
manner when the intent is the ‘practice of medicine’ does not require the submission of an Investigational New Drug Application (IND), Investigational
Device Exemption (IDE) or review by an Institutional Review Board (IRB).
However, the institution at which the product will be used may, under its own
authority, require IRB review or other institutional oversight. (FDA 2014)
Most physicians encounter little difficulty in using FDA-approved drugs and
devices in an off-label way. This is particularly true in pediatrics and oncology.
Indeed, there are many situations in which such use is standard practice, and forgoing it constitutes malfeasance (Noah 1994; Radley et al. 2006). Indeed, the original
approval for DBS in the vicinity of the ventral intermediate nucleus of the thalamus

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was restricted to unilateral DBS in patients with Parkinson’s disease and Essential
tremor. The use of bilateral DBS in the vicinity of the ventral intermediate nucleus
of the thalamus is therefore off-label although most physicians do not make a qualitative distinction between unilateral and bilateral DBS in the vicinity of the ventral
intermediate thalamus. Some states have mandated that insurers cover off-label
use, provided that there are at least two scientific studies attesting to the safety and
efficacy of the intended use have been published.
Such physician prerogatives to use FDA-approved drugs and devices consistent
with FDA policy may not be extended by insurance companies that equate “experimental” or “investigational” with any FDA-approved drug or device approved for
indications other than the indication approved by the FDA. Legal scholars have
argued that the definitions of “experimental” and “investigational” are statutory
and found in the Code of Federal Regulations (section 312.3[b]‌for “experimental”
and section 50.3[c] for “investigational”). The definition of these terms rests entirely
on research rather than medical practice. For insurers to label as “experimental”
or “investigational” the intended use because an otherwise approved device lacks
approval for that use requires novel definitions that may be indefensible.
Whether the terms of “experimental” and “investigational” necessarily apply to
the off-label use of FDA-approved drugs or devices may be seen in various court
cases in which plaintiffs have argued that failure of a physician to inform the patient
that the intended use represented an off-label use amounts to a failure to obtain
informed consent. Courts have ruled that physicians need not inform patients
regarding the off-label use of an FDA-approved drug or device and that “off-label”
connotes no medical information, which would not be the case if the off-label use
truly was “experimental” or “investigational.” For example, in Klein v. Biscup. (109
Ohio App. 3d 855 [Ohio Ct. App., 1996]), the court held that “[t]‌he decision whether
or not to use a drug for an off-label purpose is a matter of medical judgment, not of
regulatory approval. By analogy, the off-label use of a medical device is also a matter of medical judgment, and as such, subjects a physician to professional liability
for exercising professional medical judgment. Off-label use of a medical device is
not a material risk inherently involved in a proposed therapy which a physician
should have disclosed to a patient prior to the therapy” (cited in Riley and Basilius
2007). Admittedly, physicians may be held accountable for their off-label use should
it fail to conform to the standards of care. Riley and Basilius go on to suggest that
“whenever a physician prescribes a drug [device] for off-label use, it should be based
on: (1) the doctor’s own expert medical judgment; (2) peer-reviewed articles reflecting sound scientific evidence; (3) documented medical practice; (4) if possible, the
opinions of the physician’s local colleagues; and (5) a desire to directly benefit the
patient for whom it is prescribed” (p. 37).
It would seem that off-label uses of FDA-approved drugs and devices (when
used in conformity with FDA policy) have the same status as do uses specifically
approved by the FDA, at least from the physician’s and healthcare professional’s
perspective. The question thus becomes:  what is a physician’s or healthcare professional’s responsibility in terms of advising patients about the potential use of
off-label drugs and devices? The answer is complicated, and readers must bear
in mind that I am not an attorney and that my remarks are not legal opinions or
advice. One possible standard is that which similarly situated reasonable physicians
and healthcare professionals would do. If the standard of practice is to inform the

15. Deep Brain Stimulation for Hyperkinetic Disorders163

patient, then a physician’s failure to inform a patient may be considered in breach
of the standard of practice. Alternatively, when a physician and healthcare professional obtain informed consent, generally they are obliged to inform a patient of all
reasonable alternatives, which could well include off-label treatments. The definition of reasonable alternatives has been described as those that would be of concern
to, or would have affected the decision of, a reasonable patient rather than a physician or healthcare provider.
The FDA policy cited previously refers to a potential role of the Institutional
Review Board (IRB) that may prove problematic. IRBs’ mandate is to regulate
human research. According to the FDA’s own policies, off-label use excludes
research. The question thus arises as to the appropriateness of IRBs to regulate the
off-label uses. Indeed, the Belmont Report, which set the field of biomedical ethics
and was responsible for the genesis of IRBs, specifically differentiated innovative
therapies from research, advocated IRB jurisdiction only over research, and did not
require IRB approval for innovative therapies. Distinctions were made between the
goals of a provider of innovative therapies and those of research. The former’s goals
are unique and specific to a patient; a patient is therefore the end to which effort
is directed. The latter seeks to increase generalizable knowledge. In that regard, a
patient becomes a means to an end rather than an end in herself. This presumes,
however, that there is no other conflict of interest, pecuniary or otherwise (Taylor
2010). Some institutions establish committees separate from the IRB to rule on
appropriate use of innovative treatments.
S EL ECT I O N C R I T ER I A

Selection criteria of DBS candidates resemble the selection criteria for other conditions. Among the latter are included the following: (1) a diagnosis of a condition
that is likely to benefit and improve the patient’s quality of life, (2) exhaustion of
all reasonable alternative treatments, (3) a patient’s ability to tolerate the DBS procedures, and (4) assurance of appropriate follow-up management, including DBS
programming.

Diagnosis
The criterion of a condition that may benefit appears to clash with the aforementioned notion of DBS as a symptomatic treatment. As applied in the case of hyperkinetic disorders, however, the criterion is to address causes of hyperkinesia that
require other than symptomatic treatments. Among those are disorders related
to medication use or underlying metabolic abnormalities—chorea gravidarum
related to the use of oral contraceptives or other hormones, for example. Among
other causes are the following: (1) vitamin B12 deficiency (Souza and Moloi 2014);
(2) anti-NMDA receptor encephalitis (Sharma et al. 2014); (3) pseudoathetosis
secondary to sensory loss; (4) such medications as dopamine agonists, sympathomimetic, amphetamines, and cocaine (crack dancing) and such anticonvulsants
as phenytoin (Nausieda et al. 1979), tricyclic antidepressants (Fann et al. 1976),
and calcium channel blockers; (5) such autoimmune disorders as systemic lupus

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erythematosus, Sydenhams, and lupus anticoagulant syndrome; (6) polycythemia
vera; (7) psychogenic disorders; and (8) beta-ketothiolase deficiency (Buhas et al.
2013).
Tardive dyskinesia may spontaneous remit and therefore represents a special
case. The data on this issue is mixed, however, with some studies demonstrating
no remission. In one study, 33 of 53 patients followed over a long term experienced
complete resolution of the tardive dyskinesia. The time to remission, however,
was not described (Fernandez and Friedman 2003). Some 25% to 50% of patients
improved within one year. According to one case review of patients who experienced late spontaneous remissions, three patients improved after two and a half
years, two patients improved after three years, and two patients improved after
four and a half years (Klawans et al. 1984). (This situation is analogous to that of
Tourette’s syndrome; see ­chapter 13).
The task becomes that of determining the amount of time a patient must wait
before the prospect of spontaneous remission appears unlikely. Such a determination may be modeled as a negative binomial (or Pascal) distribution in statistics.
Unfortunately, insufficient data exists to enable such modeling. There is no point
in time at which probability of spontaneous remission may be said to be zero. One
must determine, rather, the point at which probability of spontaneous remission is
low enough to urge consideration of DBS on a patient. This requires one to determine a patient’s willingness to face surgical risk. Patients alone must determine
their level of willingness.

Exhaustion of All Reasonable Alternatives
The criterion of a condition exhaustion of all reasonable and less risky alternative
therapies are specific to symptomatic relief of hyperkinesia. Treatments specific to
the underlying diagnosis were addressed previously. Alternative treatments include
medications and intramuscular injections of botulinum toxin. Medications typically act to deplete dopamine or block its action at the dopamine receptor (dopamine antagonists).
There are several issues related to the question of exhaustion of all reasonable
alternatives. The first issue relates to the adequacy in the trial of an individual treatment. The second issue concerns whether a sufficient range of treatments have been
attempted. With respect to the first question, that which is needed is a dose-response
curve that displays the number of patients at each dose who achieved sufficient control and also the dose at which each patient experienced a limiting adverse effect.
The task thus becomes that of determining the dose at which a dose-response curve
becomes asymptomatic, because this suggests that any further increases would be
futile or would introduce a high risk of limiting adverse effects.
Efficacy and safety present somewhat different issues in deciding whether a
patient has exhausted all reasonable alternatives. The issue is not comparative effectiveness in samples of patients treated with different agents. One is not tasked with
determining, for example, whether traditional neuroleptics are any more effective
than atypical neuroleptics. Rather, the task becomes that of determining whether
a patient who has failed on one specific agent will find another agent efficacious.
Similarly, one must determine the probability that a patient unable to tolerate a

15. Deep Brain Stimulation for Hyperkinetic Disorders165

traditional neuroleptic will be able to tolerate an atypical neuroleptic. Such determinations require a controlled cross-over study conducted on single subjects rather
than populational studies over many.
Absent any of the suitably designed studies described here, one must consider population-based studies while acknowledging such studies’ limitations.
Acknowledgment of these limitations need not occasion therapeutic nihilism.
Indeed, physicians and healthcare professionals are accustomed to making decisions involving imperfect and categorically different data. Given the large number
of potential agents, one cannot simply attempt every combination, because doing
so would result in a number of combinations impossible in a single lifetime. Some
reasonable strategy is therefore required.
The dopamine antagonists typically are organized into traditional and atypical neuroleptics. In terms of efficacy, the only completed study that may bear on
the question was a meta-analysis of risperidone versus traditional neuroleptics in
Tourette’s syndrome, which can be considered a type of hyperkinetic disorders
(Cheng et  al. 2012). In that study, the atypical neuroleptic risperidone appeared
to match the efficacy of traditional agents and was better tolerated. It is unknown,
however, whether a patient who failed one agent would respond to the other. I was
unable to find data published in the literature to establish a dose-response curve
in order to demonstrate the maximal dose beyond which treatment would be
ineffective.
Tetrabenazine is a dopamine-depleting agent that has been approved by the FDA
for the treatment of the chorea associated with Huntington’s disease (Poon et al.
2010). Evidence-based guidelines recommend tetrabenazine for the treatment of
Tardive dyskinesia, but this would be considered an off-label use. Tetrabenazine has
been effective in treating hemiballismus (Grandas 2011). Also, case reports demonstrated that tetrabenazine improved post-pump chorea in a 77-year-old (Saft et
al. 2011) and hyperglycemic-induced hemi-chorea (Sitburana and Ondo 2006). The
multitude of etiologies responsive to tetrabenazine argue for the conclusion that
tetrabenazine should be considered a symptomatic treatment for hyperkinetic disorders irrespective of etiology.
As to adequate dosing, some insight may be gained in the RCT for the treatment
of Huntington’s disease (Huntington Study 2006). Tetrabenazine was titrated up to
a maximal dose of 100 mg per day. Forty-five percent of subjects reached this dose.
Unfortunately, it is not clear from the study whether those who did not reach the
maximum dose did so because limiting adverse effects prevented them or because
the subject had obtained a satisfactory control. The sole conclusion therefore is that
some patients may require and tolerate more than 100 mg per day.
In another study of patients with Huntington’s disease who took stable doses
of tetrabenazine, the mean and standard deviation of the dose in the group with
the highest mean was 62.5 mg with a standard deviation of 38.1 mg (Frank et al.
2008). The enabling assumption being that the standard deviation was representative of the true variance, 68% of subjects took total daily doses of tetrabenazine that
ranged from 24.4 mg to 100.6 mg in total daily dose. If the typical maximal daily
dose assumed by the physicians is 100 mg per day, this means that a significant
percentage reached the maximum. Thus it cannot be known whether higher doses
would be effective for other subjects (the subjects of this study were all stable and
adequate responders). For patients whose genotype of CYP2D6 suggests extensive

4 of 24 participating patients were found to be primary nonresponders (17%. 2013). The distribution of doses reached was fairly normal. the question arises as to how many trials of intramuscular botulinum toxin injections should be attempted before it is considered futile. the FDA recommends a maximum of 100 mg per day (Mehanna et al. particularly microelectrode recordings. Refusing to address the issue is no answer. This dose exceeds the maximum recommended by the FDA. one must learn whether an alternative serotype was attempted. for example.5 mg per day). As noted. As in the dose-response issue for medications. the curve became asymptotic at six injections.2 mg per day with a standard deviation of 40.9 mg (Frank et al. because it obviates a patient’s opportunity to benefit from DBS. This suggests that the mean and standard deviations are representative of the sample. a result that suggests that this number represents the minimum number of injections necessary to determine the degree of relief a patient might expect. In refractory patients. There is also the possible effect of neutralizing antibodies. Ability to Tolerate Deep Brain Stimulation Surgery Patients must be cleared for DBS surgery just as they would be for any other major surgery. In one retrospective study. Achieving 95% confidence that a patient being considered for DBS for hyperkinetic disorders (which assumes the data for Huntington’s disease is relevant to other causes of hyperkinetic disorders) would not respond to a higher dose of tetrabenazine requires that the dose be at least 150 mg per day.166 2 0 T hings to K now A bout D eep B rain S timulation metabolizers of tetrabenazine. 2008). the mean dose was 74. it is important to substantiate the reason for failure. An adequate trial of intramuscular injections must be conducted. Genotyping should be considered when evaluating the adequacy of dosing in the event that the patient is a poor or extensive metabolizer of tetrabenazine. It is extremely important that one utilize intraoperative neurophysiological monitoring. Intramuscular injections of botulinum toxin may be effective in the treatment of hyperkinetic disorders. more than 95% of patients were treated with 150 mg or less (based on dose increments of 12. Berman et al. particularly if the muscles associated with movements most affecting the quality of life are fairly restricted. In a dose-response study based on improvement with consecutive doses in the severity of dystonia. If the forehead test suggests resistance to one serotype of botulinum toxin. Physicians and healthcare professionals must therefore use their judgment. Specifically. there is a paucity of data that informs the questions most relevant to establishing the candidacy for DBS according to exhaustion of all reasonable alternatives—medication and intramuscular injections of botulinum specifically. This being the case. one must learn whether electromyographic guidance was used and whether the injections were given by an experienced physician. Subcutaneous injections into the frontalis muscle (forehead test) may be an assay for botulinum toxin sensitivity (Hanna and Jankovic 1998). In those patients for whom otherwise reasonable intramuscular injections of botulinum toxin have failed. 2005). in order to accurately and . In a third study in which doses were permitted to range to 200 mg. it is important to ensure that no technical issues related to injections caused the failure.

Dexmedetomidine enables one to anesthetize patients unable to remain awake during the intraoperative neurophysiological monitoring while continuing to use microelectrode recording.20(2):233–237. My experience has shown that such assurances have not always been in place. 2003. In the globus pallidus interna.15. These indications are neither “experimental” nor “investigational. The fact that such a wide variety of disorders are responsive to DBS suggests that DBS of the globus pallidus interna must be considered a symptom-specific rather than a disease-specific treatment. particularly if the medications produce adverse effects.” It may befall physicians and healthcare professionals to advocate on their patients’ behalf for access to these therapies. Psychol Bull. the somatotopic or homuncular representation is larger than the volume of tissue activation possible with most DBS leads (Montgomery 2014). Long-term safety. The lack of FDA position on these indications is not evidence against efficacy and safety. Bryden D. . Arrangements for Postoperative Deep Brain Stimulation Management Arrangements for postoperative DBS management must be assured before the patient undergoes DBS surgery. the evidence is strong for efficacy and safety. Duty of care and medical negligence. Seeberger L. Deep Brain Stimulation for Hyperkinetic Disorders167 precisely identify the optimal target. The latter is very important. Contin Educ Anaesth Crit Care Pain 2011. The rarity of many of these disorders makes RCTs and hence level-1 Evidence-Based Medicine criteria unattainable. if head movements are the most clinically limiting. efficacy.129(1):139–167. Though most industry representatives are well versed in the technology of the devices. S U M M A RY DBS is effective for a wide range of hyperkinetic disorders. This is inappropriate. Storey I. Kumar R. Berman B. If the DBS lead is placed in the lower limb representation. the patient may not receive the expected benefit. When case experiences are summed over the range of etiologies. Thus it is important to identify the homuncular representation associated with the part of the body whose involuntary movements are the greatest contributor to a patient’s diminished quality of life. and development of resistance with botulinum toxin type B in cervical dystonia.11:124–127. dosing. the head representation must be targeted. Most information is derived from case series. Mov Disord. Often postoperative DBS programming is left to an industry representative. The psychology of doing nothing: forms of decision avoidance result from reason and emotion. 2005. R EFER ENCES Anderson CJ. they are not trained to perform appropriate neurological evaluations or adjust medications. For example.

 Res. Hebb MO. Ma Y. A treatable new cause of chorea: beta-ketothiolase deficiency. Successful deep brain stimulation surgery with intraoperative magnetic resonance imaging on a difficult neuroacanthocytosis case: case report. 2008. [A meta-analysis of the effectiveness of risperidone versus traditional agents for Tourette’s syndrome]. J Neurol Neurosurg Psychiatry 2011. Med Care 2011.82(3):272–277. 1984.89(3):162–166. et  al. IBM J. Klawans HL. Classification and treatment of tardive syndromes. Clin Neuropharmacol. Mouse bioassay versus Western blot assay for botulinum toxin antibodies: correlation with clinical response. 2011. Friedman JH. Mehanna R. Fasano A.31(3):127–133. Bernard G. Handb Clin Neurol 2011. Cooper S.37(4):359–365. Fukao T. Grandas F. Neurology 1998.28(2):210–215. Lim TT. Kang GA. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2012. Annila A. 2013.465:2155–2175.28(8):1054–1056. Neurosurgery 2013. Cheng W. Neurologist 2003.5:183–191. Irreversibility and heat generation in the computing process. 2013. Fernandez HH. Mov Disord. 2014. Hanna PA. et  al. Ge M. Hurtado P. discussion E383. Sullivan JL.58(2):E383. Frank S. Carrero E. Richman BW. The reversibility of “permanent” tardive dyskinesia.7(2):153–159. The physical character of information.Uribe GA. Analysis of CYP2D6 genotype and response to tetrabenazine. Bilateral subthalamic nucleus stimulation in the treatment of neurodegeneration with brain iron accumulation type 1. Mov Disord. . et al. Fernandez HH. Neurosurgery 2006. Successes and failures in the implementation of evidence-based guidelines for clinical practice. Med Educ. Dev.9(1):16–27. 2009. Kimmo PK. et al. et al. Hunter C. Schmidt HG. Acta Neurochir Suppl. Rothlind J.23(9):1289–1292.128:490–493.73(1):E184–E187. Hemiballismus. et  al. Stereotact Funct Neurosurg. GPi-DBS in Huntington’s disease:  results on motor function and cognition in a 72-year-old case. Fahn S. Guo S. 2008. Functional neurosurgery for secondary dystonia: indications and long-term results. Clin Neuropharmacol. Barr A. Fann WE.50(6):1624–1629. Bilateral stimulation of the globus pallidus internus to treat choreathetosis in Huntington’s disease: technical case report. Huntington Study Group. Rev Esp Anestesiol Reanim. Vidarte OA. Dyskinesias associated with tricyclic antidepressants. Mamede S. Zhang K.48(1):34–43. Grol R.56(3):180–184. Davidson A. Salvador L. [Anesthesia considerations for deep-brain stimulation in a patient with type-2 pantothenate kinase deficiency (Hallervorden-Spatz disease)]. Ondo W. discussion E188.117:61–66. et  al. et al. Br J Psychiatry 1976.66(3):366–372. 2013. Jankovic J. Mazzone P. Piano C.100:249–260. Mov Disord. Tanner CM. et al. Martinez JA.168 2 0 T hings to K now A bout D eep B rain S timulation Buhas D. Proc Royal Soc A 2009.39(8 Suppl 2):II46–54. Landauer R. Lin L. 2000. Long-term follow-up of pallidal deep brain stimulation in two cases of Huntington’s disease. The twin traps of overtreatment and therapeutic nihilism in clinical practice. Mahesh Karnani MK. Gaudet P. Garcia R. Heath S. Neurology 2006. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. A study of chorea after tetrabenazine withdrawal in patients with Huntington disease.

Kang GA.73(11):1434–1438. Deep Brain Stimulation for Hyperkinetic Disorders169 Mentzel CL. Spampinato U. PLoS One 2013. J Med Speech Lang Pathol. Derbyshire SW. Sitburana O. and lessons from stem cells.56(2):290–294.113(1):186–193. Globus pallidus interna deep brain stimulation improves chorea and functional status in a patient with chorea-acanthocytosis. Tetrabenazine for hyperglycemic-induced hemichoreahemiballismus. J Neural Transm. Efficacy and safety of deep brain stimulation in patients with medication-induced tardive dyskinesia and/or dystonia: a systematic review.91(2):129–133. 2000. Evidenced based medicine: let’s be reasonable. Weiner WJ. Saft C. et al. Stafford RS. Asian J Psychiatr. Ann Pharmacother. Physicians’ liability for off-label prescriptions.90(4):273–277. 2006.. 2014. .7(1):92–94. J. et  al. et al.11:ix–xii. Bilateral globus pallidus stimulation for Huntington’s disease. Moro E. Handa R. Basilius PA. Mov Disord. 1994. Pallidal deep brain stimulation for longstanding severe generalized dystonia in Hallervorden-Spatz syndrome: case report. 2003. Dolinskas CA. 2004. et al. 2014. Intraoperative Neurophysiological Monitoring for Deep Brain Stimulation: Principles. Anti-NMDA receptor encephalitis: a neurological disease in psychiatric disguise. Tenback DE. Finkelstein SN.. Powell NL. Souza AD and Moloi MW. Stereotact Funct Neurosurg. Riley JB Jr.45(4):291–305. J Clin Psychiatry 2012. Noah LA.32(4):699–701. Montgomery EB Jr. Cho AR. Hematology & Oncology News & Issues 2007. Overseeing innovative therapy without mistaking it for research:  a function-based model based on old truths. Practice and Cases.1:21–23. et  al. Post pump chorea in a 77-year-old male. Ki CS.16:139. 2006. Poon LH. Strafella AP. Ann Neurol. Differential and better response to deep brain stimulation of chorea compared to dystonia in Huntington’s disease. Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis. Streuer M.8(11):e79241. Tijssen MA. 2013. 2013. Taylor PL. Constraints on off-label uses.21(11):2023–2025.100(4):706–709.166(9):1021–1026. Turkstra LS. et al. Reber D. Umemura A. 2004. Prod. 2014. 2011. J Law Med Ethics 2010. Neurol Res. Off-label prescribing among office-based physicians. Velez-Lago FM.57:163–205. et al. Washington. Guttentag RE. Jaggi JL. Latxague C.21(7):43–47. DC:  US Food and Drug Administration. 1979. Neurol Sci. Sharma B. Oyama G. Peters PG. and medical devices—information sheet. et al. Wash Lee Law Rev. New York:Oxford University Press. 2011.44(6):1080–1089. 2012. Lee AJ. J Exp Child Psychol. J Neurosurg. Lang AE. Miquel M. Role of tetrabenazine for Huntington’s disease-associated chorea. Advance online publication. Thompson A. & Toxics Liab. 2012. Nausieda PA. Prakash S. “Off-label” and investigational use of marketed drugs. Ask the expert: what is your interpretation of the ADAGIO study and has it influenced your clinical practice? Neurodegen Disease Manage. biologics.15. 2010. Montgomery EB Jr. Involuntary movements due to vitamin B deficiency. Arch Intern Med. et al. Ondo WG. US Food and Drug Administration. Shin H. The quiet demise of deference to custom: malpractice law at the millennium. Montgomery EB Jr. Clinical and experimental studies of phenytoin-induced hyperkinesias. Stereotact Funct Neurosurg. Koller WC. Biases in children’s and adults’ moral judgments.38(2):286–302. new capacities. Radley DC.

Allert N. Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. .46(1):22–35.170 2 0 T hings to K now A bout D eep B rain S timulation Vitek JL. 2001. Deep brain stimulation of the internal pallidum did not improve chorea in a patient with neuro-acanthocytosis. et  al. Zhang JY. Ann Neurol. Wihl G. et al. Chockkan V. 1999.16(3):572–575. Volkmann J. Mov Disord.

and other significant psychiatric comorbidities. As a movement disorders neurologist. Admittedly. which becomes readily evident in the approach to such a therapy as DBS. My involvement owed to a belief. It departs from this tradition. is more perceived than real and rests more on physicians and healthcare professionals’ presuppositions than it does on actual psychiatric diseases. which pose real challenges to the practice of psychiatry. in terms of the considerations that attend it. compulsive behaviors. then prevailing and since substantiated. however. may have escaped my awareness. because it may help me to avoid the temptation of regarding psychiatric disorders as cases distinct from other medical disorders in terms of DBS treatment. certain social and political realities. Patients with Parkinson’s disease experience depression. I have participated in early clinical trials of Deep Brain Stimulation (DBS) in treatment of Obsessive-Compulsive Disorder (OCD). that many similarities obtain between the assessment and management of patients with such psychiatric disorders as OCD and those with such movement disorders as Parkinson’s disease. I do not suggest that psychiatrists believe OCD and other psychiatric disorders to be something other than medical disorders. experience DBS-induced hypomania. I  hope this chapter represents a unique contribution to discussions of the treatment of OCD and other psychiatric disorders. Indeed. I seek to establish the idea that any distinction between psychiatric and neurologic disorders. As a treatment for OCD. DBS for OCD has been approved by the US Food and Drug Administration (FDA) under a Humanitarian Device Exemption (HDE). I simply wish to acknowledge that psychiatrists must contend as much with matters of perception as they do with medical fact. patients with Parkinson’s disease. This approval marks DBS’s first psychiatric indication although the first description of DBS (in its current form) as a treatment for DBS appeared in 1979. DBS is not without precedent. . It follows a tradition established by ablative surgery. as movement disorders neurologists may attest. Yet I deem this partial ignorance a possible advantage. obsessive and compulsive symptoms.16 Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder Though I am not a psychiatrist. and changes in mood. Similarly.

lithium. black bile. it is easier to understand the difficulty faced by psychiatrists of yesteryear. and superego and the dynamics of personality development. because scientists no longer found it necessary to couch their explanations of human behavior in metaphysical. and antidepressants emptied institutions of their mentally ill inmates. however.172 2 0 T hings to K now A bout D eep B rain S timulation Patient selection and informed consent typically endure greater scrutiny in cases of psychiatric disorder than they do in cases of movement disorders. neuroleptic medications clearly reveals the importance of physical abnormalities to psychopathology. If one recalls. all other treatments have failed him. which divided mind from body. Images of the days before neuroleptics should be remembered. Sherrington’s theory. left the soul free of any mechanistic taint. It was on the basis of these abstractions that Freudian psychologists and psychoanalysts opposed electroconvulsive therapy (ECT). the reputed father of neurophysiology and a religious man. and yellow bile (Arikha 2007). res extensa). In fact. ECT. they became able to anchor their inquiries in the physical realm. that the sole alternative to these harsh therapies was institutionalization. ego. explicitly credits Descartes for enabling him to pursue neurophysiology free of any metaphysical or theological constraints. a treatment attuned more to a physical than to a mental conception of psychiatry. phlegm. The development of Freudian psychology and psychoanalysis presented the pathophysiological mechanisms of psychiatric disease in terms of id. The advent of ECT and. when a psychiatric patient is under consideration for DBS. particularly religious. DBS for psychiatric disorders thus raises questions as to how psychiatric disorders stand distinct from other disorders. . one discovers a source in seventeenth-century French philosopher Rene Descartes’s metaphysical dualism. Neuroleptics. An absence of disorders signaled a balance among the humors. like his institutionalized forebears. treatment of disorders affecting the mind demanded a wholly different approach. which posited all animal behavior as an effect of simple physical reflex arcs conducted through the spinal cord. however. As it turned out. Sir Charles Sherrington. speculation. Rather. Galen viewed all human physiological and psychological activity as governed by four bodily humors—blood. The rise of Cartesian dualism had positive and negative effects: The identification of the mind as an entity distinct from the brain encouraged the advent of neurophysiology. more comfortable psychiatric treatments currently practiced. The presence of a disorder signaled an imbalance. If one regards the question from the perspective of genesis and validity. The rise of Cartesian dualism also had a negative effect: Because the human mind came to be regarded as consisting of substance distinct from the substance constitutive of the human body (the substance of thought Descartes designated res cogitans and the substance of matter. later. The answer perhaps lies in an examination that blends epistemology and the history of science. The idea nonetheless persists that one may control a mental disorder by controlling the mind it disorders. because. Drawing on Aristotle’s mechanistic hypotheses. the notions of the ancient Roman physician Galen prevailed. Various historical attempts at physical treatments of major psychotic illnesses—ice baths. Prior to Descartes. lobotomy—appear barbaric in light of the gentler. The effect was profound.

2013.” the FDA literature states. Variability in the measurements may owe to biological or instrumental influences. The low number of participating patients reflects the fact that it is difficult to conduct randomized control trials of treatments for relatively rare diseases.” The significance of the FDA’s findings becomes quite apparent in light of the fact that. requires that the effect be much greater than the noise in order to generate data sufficient to average out the latter. Morishita et al. the FDA’s HDE approval notwithstanding (Blomstedt et al. The literature goes on to elaborate “a distinction between ‘use’ of a HDE and ‘investigational use’/‘clinical investigation’ of a HDE.16. the weighted average improvement in the Yale Brown Obsessive Compulsive Score was 41%. and the variability of the measurements. and more information will be needed to move this therapy beyond an FDA Humanitarian Device. Thus the IRB is not expected to make such determinations. Some experts maintain that DBS for treatment of psychiatric disorders is experimental. at least as it applies to the ventral and anterior limb of the internal capsule. For DBS in the vicinity of the anterior limb–ventral striatum DBS.” Morishita and colleagues’ position is difficult to justify. This result is particularly remarkable in light of the . A great deal of “noise” in the form of variability in a measure.C O M PU L S I V E D I SO R D ER The status of DBS for OCD has occasioned debate. The issue turns on the outcome measure. the former basing its approval on sufficient evidence of safety and efficacy and the low number of patients treated (few than 4. when unmodified. http://www.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm110194. the FDA does not require that the IRB obtain protocols from the surgeon or decide on individual patients. patients may be deprived of possible benefit. The unstated purpose of IRB involvement is to ensure an appropriate informed-consent process in order to compensate for the fact that the FDA approval process did not follow the typical process for most drugs and devices. The term ‘use’ in this document. they are all small research trials. “An HDE approval is based on safety and probable benefit.” according to Morishita and colleagues (2013). In a certain sense. The FDA does require that an institution interested in offering DBS for OCD obtain approval from an Institutional Review Board (IRB).htm).000 annually. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder173 T H E STAT U S O F D EEP B R A I N ST I M U L AT I O N FO R O B S ES S I V E. the respective positions of the FDA and experts claiming DBS’s experimental status are irreconcilable.fda. Though the exact procedures for obtaining IRB approval may vary according to the institution in question. One emphasizes that the FDA already has determined that DBS for OCD is safe and reasonably likely to benefit patients. 2013). because insurers may claim that the use of DBS for OCD is experimental or investigational. the magnitude of the effect as measured. for example. refers to the use of a HDE according to its approved labeling and indication(s). Statements made by experts that DBS for OCD is experimental serve merely to complicate an otherwise a rather clear issue and thus increase the chance of insurers’ rejection. “Though there are several trials available. “DBS remains an experimental treatment for medication refractory OCD because of the mixed outcomes and the lack of standardized patient selection methods. The FDA maintains the position that a device under a HDE is not experimental if it is used for approved indications.

when the task becomes that of defining “reasonable. The results of such standardized randomized control trials are more likely to overestimate benefit and minimize risk. however.” If one defines it as a quality of anything that proceeds from understanding or judgments formed of logic. Present-day scientism perhaps has its roots in the original code of ethics published by the American Medical Association in 1847. the already established potential for benefit represents minimum benefit and is therefore sufficient for the purpose of gathering informed consent. There are many examples in which the benefits of DBS equal or exceed the benefits of ablative surgical procedures. Rampant radical skepticism and solipsism partly engendered by a misreading of Evidence-Based Medicine (Montgomery and Turkstra 2003) do not appear to leave much room for logic. meeting it presents problems. faith in the methods of science to remove uncertainty.” that is. From examples of the benefits of ablative therapies. Selection criteria may also limit variability and so increases statistical power and thus decreases sample size and trial costs. find “correct” answers. Interestingly. Selection criteria that are less standardized resemble those that govern the “intent to treat” clinical trials that are more relevant to the poststudy phase. Though the need is critical. it was concluded that DBS produces similar benefits. thalamatomy and DBS in the vicinity of the ventral intermediate thalamus. effects that may engender misrepresentations in the informed-consent process. Describing DBS for OCD as experimental presents a classic instance of making the perfect the enemy of the good. These include pallidotomy and DBS in the vicinity of the globus pallidus interna. The standardization under discussion typically exists for the convenience of investigators who conduct the clinical trials.174 2 0 T hings to K now A bout D eep B rain S timulation fact that these patients were refractory to every reasonable pharmacological and behavioral therapy. because it risks reducing the availability of DBS benefits to many patients. The standardization advocated by Morishita and colleagues (2013) may even prove counterproductive. which was intended to distinguish allopathic medicine from other forms then current. Even if one were to argue that such standardization may improve benefit. One may argue that deference to such standardized (aka “scientific”) experiences represents a form of “scientism. Zhan et al. they do not appear to have adversely affected the potential for benefit. Such selection criteria increase the risk that the results from the study of a select group may not be generalizable to the actual population in need of treatment and for whom DBS for OCD would be reasonable (Montgomery and Turkstra 2003). and subthalamotomy and DBS in the vicinity of the subthalamic. and guide “correct” actions. 2013. one discovers that inductive reasoning is in operation specifically. some of the strongest opposition . Whatever the limitations of the lack of standardized patient selection methods. The risk of misrepresentation highlights the need for surveillance of treatments once they have reached market. The issue is whether it is reasonable to extrapolate from the capsulotomy experience to support DBS for OCD. because the selection criteria may be biased in favor of those patients who stand the likeliest chance of benefiting. to paraphrase Voltaire. Additional support for DBS of the ventral capsule/ventral striatum comes from the demonstrated effectiveness and safety (relative to the risks of untreated severe OCD) of capsulotomy for OCD (D’Astous et al. A problem arises. 2014). Participating patients may be cherry-picked.

like the former. moral. Given the fact that there had been conducted a number of prior nonrandomized clinical trials that demonstrated DBS to be safe and effective. The reverse action—applying descriptive statistics of population to an individual in order to eliminate the original individual variability—is impossible. Uncertainty may be said to obey a law similar to the law obeyed by energy: it is neither created nor destroyed but simply transformed. At issue may not be whether the VA–NIH study essentially recapitulated previous findings as to the safety and effectiveness of DBS for Parkinson’s disease. They were convinced that scientific advances would render the need for any such code obsolete. Notwithstanding the fact that the participating patients were randomized between DBS and best medical therapy. the sine qua non of Evidence-Based Medicine. political.” Their reason for calling for this remains unclear. Uncertainty that results from individual variation is mitigated by an appeal to descriptive statistics of population. one had little reason to believe that the VA–NIH trial would produce a different result. One thus finds to be an expression of solipsism the belief in randomized control trials as the sole route to secure knowledge. It is a delusion to think one can eliminate it. involved experts and included patients for whom medication therapy had failed. Consider the Veteran Affairs–National Institutes of Health (VA–NIH) randomized clinical trial of DBS in the vicinity of the globus pallidus interna and subthalamic nucleus for Parkinson’s disease (Weaver et al. Montgomery 2011). Finally. This holds particularly true in an era of finite resources. especially when one considers the expense attending the widespread randomized control trials that would be needed to secure FDA premarket approval. economic. Rather than remove uncertainty. will remove uncertainty is scientific faith indeed. The decision to fund the VA–NIH study was made at the same time as a decision not to fund other research. These experts were comparable to—if not the same—experts who were involved in the best medical therapy limb of the VA–NIH trial. whereas that which is clinically meaningful remains beyond its reach. social. There should not be anything pejorative about labeling a device and indication as approved under an HDE. this argument misrepresents the nature of the Humanitarian Device Exemption which is not based on the nature of the evidence but by the number of patients potentially benefiting. The standardized experiences encouraged in a regime of Evidence-Based Medicine demonstrate merely that which is statistically significant. the VA–NIH trial differed little from previous trials. However. The VA–NIH grant presupposed that alternative methods of knowledge . Rendering randomized control trials meaningful requires importation of value judgments that rest on its ethical.16. and medical consequences (Montgomery and Turkstra 2003). The very means by which one attempts to contend with individual variation thus serve to distance randomized control trials’ results from an individual patient’s management (Montgomery and Turkstra 2003. Morishita and colleagues (2013) insist on the necessity of “mov[ing] this therapy beyond an FDA Humanitarian Device. randomized control trials merely recast it in a new guise. which. but whether there were sufficient grounds to believe that the findings would be different when the time arrives for deciding to proceed with the VA–NIH study. unless the subsequent need for obtaining IRB approval proves unreasonably onerous. 2009). Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder175 to the code was mounted by the new breed of scientific physicians. The presumption that randomized control trials. Absence of any previously conducted randomized control trial is insufficient reason to perform one.

Compulsions are repetitive behaviors or mental acts often performed in order to avoid anxiety. what is worse. Its measure is the amount of disruption it introduces into the activities of an individual’s life. that is. Popular representations of it have been predominantly negative.” failed to identify psychiatric disorder symptoms suggests that many patients suffer in obscurity. because peculiar drawbacks limit the utility of randomized control trials in guiding treatment (Montgomery and Turkstra 2003). occupational. nearly 10% are refractory to pharmacological and behavioral therapies. ECT offers a telling example. The general public tends to look more favorably on psychotherapy and lifestyle treatments than it does on medical treatments for schizophrenia and depression . or mental images that impair normal. T H E B U R D EN O F O B S ES S I V E. most of which lacked any “label. Obsessions are persistent thoughts. Themes involved in obsessions and compulsions are often linked. in other words. 2002). however. the task of avoiding the tendency of attributing the illness to something a patient should be able to overcome—a tendency that moreover imposes a sense of illegitimacy on that patient’s wish to seek medical help. The history of psychiatric disorders. they attribute the unusual and undiagnosed symptoms of OCD to situational disturbances rather than psychiatric disorders (Furnham and Winceslaus 2012). In the 1980s. a short-lived ban on ECT performed within the city limits of Berkeley. impulses. Of this 2% of patients. following the viewing the number of medical students who stated that they would advise against ECT increased from 10% to 25% (Walter et al. Obsessions and compulsions may cause severe functional. Such is not the case. everyday life. Two of 1. Patients with OCD and depressive features also face higher risk of suicide (Diaconu and Turecki 2009). such as they are in an individual’s repeatedly checking locked doors to ensure that they are indeed locked. California. Such a measure renders difficult.176 2 0 T hings to K now A bout D eep B rain S timulation are inferior to randomized control trials. many of characteristics of OCD are observed in highly successful individuals. their treatment. however. a behavior indicative of a desire to avoid harm. eating disorders. find no relief from their suffering (de Koning et al. Also. Many lay people make “normalizing attributions”. and social disability. impute to caregivers a sinister intent of controlling the patient (McDonald and Walter 2009). Interestingly. and their reception by the general public has been a troubled one. ended only by court order.C O M PU L S I V E D I S O R D ER A common disorder. Added to the debilities associated with obsessions and compulsions are significant depression and. Indeed. when presented descriptive clinical vignettes.000 individuals. The difference between a highly successful individual and an individual with OCD is thus one of degree rather than kind. 2011). Negative attitudes toward ECT among medical students who participated in one study increased following a viewing of popular films in which the treatment was portrayed. OCD has a prevalence rate of approximately 2% among psychiatric patients. this phenomenon on the part of physicians is also observed in the context of patients presenting to primary care physicians—the usual entry to medical care. The fact that a mere 15% of the general public. among women especially. They bear little resemblance to current practice and.

It is likely that it is the proximity of the physician to the harm that might be done that is the significant factor. Chapter  19 contains a discussion of countertransference in the context of the ethical problem known as the trolley car dilemma. 1997). When considering whether psychotherapy and lifestyle treatments are alternatives to medical treatments. patients’ family members. Also. with the inference that patients with OCD . Because it was thought to impair a patient’s decision-making capability. From the perspective of a patient’s quality of life. CBTs did not reduce the relapse rate but did improve “mental states” and increased medication compliance (Pilling et al. into the brain. L AC K O F PER S PECT I V E A N D C O N T E X T Numerous statements have been made about patients with psychiatric disorders and DBS surgery. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder177 (Jorm et  al. 2002). and healthcare professionals. Studies have demonstrated that patients with OCD are no more willing to take risks (based on the Iowa Gambling Test) than are normal subjects (Boisseau et al. These observations belie the notion that patients with OCD are more vulnerable and thus need paternalistic protections.16. a stroke caused by operating on the internal carotid artery is no more or less “invasive” than is a stroke (or hemorrhage) related to DBS surgery. For example. 2012). Hard paternalism may take active forms and passive forms. 1997). In a meta-analysis of cognitive-behavioral therapies (CBTs) in schizophrenia. One presumes that the superior ability of psychiatrists and mental health professionals to diagnose mental illness renders them less likely to make normalizing attributions. by one’s hand. nondelusional patients with OCD showed themselves no more likely to draw hasty conclusions than were nonclinical control subjects (Jacobsen et al. One should not gather from this that CBT is ineffective in treatment of OCD but rather the opposite: CBT improves OCD by 40% to 60% in about 50% of patients. The perceived difference in the “invasiveness” of DBS and endarterectomy to prevent stroke is in the perception of the physician and represents an inappropriate countertransference. CBT must therefore be exhausted prior to any consideration for DBS surgery. At issue are not psychiatrists’ and mental health professionals’ perceptions but patients’ perceptions and the effects these perceptions have on their pursuit of treatment.” Yet one doubts that it is any more invasive than is an endarterectomy. However. OCD may invite the “hard” paternalism of which Beauchamp and Childress warn (2013). the difference is only perceived by the physician. one must recognize that the development of medications brought about the emptying and closing of most institutions for the mentally ill. Yet DBS is safer than carotid endarterectomy (Goldstein et  al. Operating on the carotid artery resulting in a stroke seems removed from placing an electrode. the public may hold unrealistic notions about the importance of medical and surgical treatments for psychiatric disorders. Thus the danger is that the unrealistic and unsympathetic attitudes on the part of the public may unduly influence patients. not the patient. physicians. Much has been made of the fact that as many as 40% of patients undergoing DBS for OCD expressed unhappiness. 2013). However. One example of a passive form is that of failing to raise the possibility of such an alternative treatment option as DBS. many authors describe DBS as “highly invasive.

If DBS for OCD is justified. for example. 20 were continuously hospitalized. It may well be that DBS of the anterior limb of the internal capsule—the ventral capsule/ventral striatum target. A utilitarian moral theory. and alternatives to DBS. 27% of patients admitted to a psychiatric hospital improved. holds that helping them is a matter of ethical duty. potential benefits. That Egas Moniz received the Nobel Prize in 1949 for frontal lobotomies offers some indication of the desperate state of mid-twentieth-century schizophrenia treatment. On the other hand. though crude in their approach.178 2 0 T hings to K now A bout D eep B rain S timulation somehow face greater risk of disappointment. The stigma associated with neurosurgical therapies for psychiatric disorders perhaps owes its existence to the almost theatrical lobotomies performed by Walter Freeman in the 1940s. on the other hand. that other reputable physicians performed lobotomies on patients with severe schizophrenia because the progressive nature of the disease and absence of alternatives compelled them (Hegarty et al. because failing to do so carries the consequence of unduly reducing the potential for DBS relief. A deontological theory. However. then. one must ask whether treating patients with OCD differently than patients with Parkinson’s disease is ethical. Lobotomies eventually diminished with the introduction of neuroleptics in the 1950s. meanwhile. One may ask whether this result is different than it is for patients with OCD. Jean Talairach sought a safer alternative to lobotomies by targeting the anterior limb of the internal capsule (Leveque et al. Such reticence may owe less to patients’ attitudes than they do to those of physicians and healthcare professionals. holds that the greater good is served by relieving patients of the pain and suffering caused by OCD. risks. however. One must bear in mind. extending such protection may well constitute an act that violates two ethical principles—the principle of autonomy and the principle of beneficence—that for patients’ sakes must be observed. for example—owes its existence to transorbital or prefrontal lobotomies. An egalitarian moral theory. A libertarian theory. finally. no matter the ethical or moral theory applied. There follows. In a study of DBS in patients with Parkinson’s disease. 11 never gained employment following their discharge. any reticence in offering it to patients with this condition is puzzling. 2013). These latter are elements critical to the informed consent. were on the right . Of the 31 patients who failed to improve. posits that a person’s fate should not be determined by forces beyond his control. 52% failed to improve. one wonders whether surgeons performing lobotomies. notwithstanding the fact that doing so violates virtually all moral theories. it is unfair to hold them to a different standard than standards applied to patients with Parkinson’s disease or other conditions. 2013). and 5% committed suicide (Stephens et al. In one retrospective study of schizophrenia. holds that freeing patients from bondage to OCD maximizes their individual liberty and is therefore good. Known as a capsulotomy. the unsophisticated extrapolation that patients with OCD are vulnerable and in need of special protection. Because the extrapolation from capsulotomies to DBS was extremely short. Because it is doubtful that individuals develop OCD as a consequence of their own actions. the treatment developed by Talairach subsequently became an accepted option for patients with intractable OCD. 2000). 1994). 8 of 30 patients (27%) experienced a subjectively negative result from DBS (Maier et al. Of the 13 patients who improved. patients with OCD do experience increased difficulty in understanding the nature. In 1949. If it is not.

one must bear in mind that “crude” achieves sense solely in light of contrasting contemporaneous alternatives. Early following the introduction of ECT for severe depression. To violate another person’s right to bodily integrity is to commit battery. in any given situation. the principle of serving a patient’s good. In the 1950s there began a backlash. justice—cannot be adjudicated in the abstract. The weight falling on any particular ethical principle derives uniquely from the specific situation. these principles are in conflict.” Though there now exists a wealth of effective pharmacological therapies for major psychiatric disorders that mitigate the need for extreme cures. Yet.” Hippocrates wrote. AU TO N O M Y The ethical principle of autonomy most commonly connotes respect for a patient’s right to determine her fate. “extreme methods of cure [. . . it is important to view the use of ECT in the context of severe major depressive illness at the time ECT was introduced. For instance. whether he also enjoys the right to receive treatment is unclear. However. Physicians and healthcare professionals are committed to beneficence. not by more modern times following the introduction of powerful antidepressants. Yet it is not clear that a patient enjoys the right to demand DBS (­chapter 19 contains a discussion of this issue of the right to receive DBS. Often it is solely assigning some weight to any particular principle or subset of principles that a satisfactory resolution possible. This process of determining and applying weights by appealing to context is known as specification (Beauchamp and Childress 2013). The former could often expect little besides suffering. Though one enjoys the right to refuse treatment. Autonomy derives. autonomy. nonmalfeasance.) Indeed. Likewise. Law. a patient enjoys an uncontested right to refuse DBS. only 11% of patients with bipolar and 22% with unipolar did not experience further episodes. In a retrospective study of patients hospitalized for major depressive illness between 1913 and 1940. Patients in the 1940s confronted quite a different situation than that faced by present-day patients. from the right to bodily integrity. however. only pertinent laws and contracts that specify minimum coverage make any assertions to this effect. Ethical principles— beneficence. Every ethical deliberation requires an awareness of context. physicians and healthcare . those present-day patients for whom every reasonable alternative treatment has failed have little hope beyond that held out by DBS. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder179 track. This connotation particularly applies to human clinical trials that have followed such scandals as the Tuskegee Syphilis Study and the Willow Brook School. which everyone does enjoy. the treatment was well received. as did 56% of patients with unipolar disease (Stephens et al. like patients of the 1940s. rather. 2000). and policy specifies a patient’s right to autonomous decision in human research. that is. Often.] are most suitable. “For extreme diseases. it is hubristic to judge physicians of the past according to present relative comforts. One thus commits a categorical error should one apply the ethics characterizing one situation to another (Ryle 2002). Seventy-seven percent of patients with bipolar disease had to be hospitalized.16. Outside of human clinical trials the right to autonomy becomes more complicated. No one enjoys a legal right to autonomy per se.

Quine (2013) demonstrated this indeterminacy in his seminal text. No calculus exists that allows physicians to weight the symptoms and signs associated with risks against risks associated with potential benefit and with leaving a disease untreated. Symptoms and signs are not. “Risk” and “invasive. Admittedly. The patient. Autonomy involves more than respect for a patient’s right to make medical decisions. disabilities and handicaps are functions of patients and their particular ecologies. physicians and healthcare professionals are well able to estimate the potential benefits and harms in terms of physical and psychiatric symptoms and signs. Such paternalism. both on patients or their surrogates as well as physicians or healthcare professionals. A dose of humility remedies paternalism. which one may reduce somewhat by appeal to context.O. According to Quine. notwithstanding the most painstaking deconstruction. who argued that individuals are to be treated as ends in themselves and never merely as means to some further end. is an end herself. If it becomes evident. Human beings do a remarkably good job of it most of the time. for example—then it is fairly certain that the patient has been made a means. or quality of life. such as may be had by a reasonable person. however. Service to that end becomes evident in her enhanced health. however. of consent or an idea communicated to her. Overly restrictive conditions may prevent patients from receiving treatment. then.” for example. Rather. disabilities. are fraught terms in medicine. The value placed on the consequences of risks and benefits on disabilities and handicaps is therefore critical. Obtaining informed consent by way educating and understanding choices made by patients or their surrogates necessarily involves an invocation of meaning. such irremediable indeterminacy owes to the inscrutability of reference. in which he points to inscrutability of reference and indeterminacy of translation. Of relevance is the ethical theory of nineteenth-century German philosopher Immanuel Kant. If patients with OCD are presumed to be unreasonable. which violates the principle of autonomy. that another end is being served—a physician’s sense of self-satisfaction. is often instanced when a physician or healthcare professional imposes his value system on the patient. which words alone communicates only imperfectly. even this practice is limited because it is ultimately indeterminate. despite its imperfections. which she does in the context of the patient’s unique ecology. well-being. The philosopher W. it is . Some allowance is thus necessary to avoid overly restrictive expectations on informed consent. and handicaps. Lack of common reference renders every communication between individuals tentative. Quine’s concepts of inscrutability of reference and indeterminacy of translation discourage one from cherishing any notion as to the exactitude of language. Though symptoms and signs may be the purview of physicians and healthcare professionals. Such a bind is usually escaped by way of appeal to a normative understanding. Yet they admit of a range of variance. the same as impairments. whether one uses it to convey information or to give consent.180 2 0 T hings to K now A bout D eep B rain S timulation professionals are committed to nonmalfeasance—the principle of doing no harm. but they in fact stand guilty of paternalism. Physicians who act in this manner may cherish the notion that they have acted with beneficence. He argues that no common reference ever grounds meaning. One should not conclude from the foregoing discussion that communication is futile. The language of risk is different from the language of benefit. Nonetheless. It also involves respect for the patient in his own right. Only a patient or her surrogate may assign this value.V.

only one individual would produce that score. which lies at a depth at which the internal capsule becomes fenestrated with islands of interposed striatal tissue. the study involving the largest number of patients (68) focused on the ventral capsule/ventral striatum. was 41%. Commercial use of these DBS leads currently requires IRB approval. D EEP B R A I N ST I M U L AT I O N I S EFFECT I V E Consideration now turns to efficacy of DBS of the ventral capsule/ventral striatum. Greater than 35%. particularly in comparison to a situation in which half of the 10 participating patients produced a score of 4 and the other half a score of 6 with the average remaining 5. DBS leads commercially available for certain targets have been implanted in targets other than those specified. in the studies listed by Morishita and colleagues (2013). Though the average is 5. the noted improvements occurred in patients whose condition was refractory to all reasonable . Nonetheless. Also. This improvement needs to be put in context. As Morishita and colleagues (2013) note in their review of the literature. First. Morishita and colleagues describe a study that reported improvement in the Yale Brown Obsessive Compulsive Score by 16 of 26 participating patients. for which exists a reasonable amount of experience. The ventral capsule/ ventral striatum is typically accessed via the anterior limb of the internal capsule. Illustrative of this point is a situation that involves 10 patients. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder181 the case that the very presumption violates the principle of beneficence as well as autonomy.16. It is conceivable that these leads could find off-label use as FDA-approved devices for other indications. but the current paucity of experience appears insufficient to justify such use. Physicians and healthcare professional must examine their presumptions and be prepared to abandon them if necessary. In this case the average is virtually meaningless. Other targets include the nucleus accumbens and the inferior thalamic peduncle. however. Such targets as the anterior limb of the internal capsule and the ventral capsule/ ventral striatum have been implanted with a special DBS lead whose contacts are long and widely spaced. each of whom produced different scores that ranging from 1 to 10 in increments of 1. Morishita and colleagues (2013) reviewed the efficacy. The study involving the next largest number of patients (23) focused on the subthalamic nucleus. D EEP B R A I N ST I M U L AT I O N TA R G E TS A number of DBS targets have been studied. The average is virtually meaningless unless it is attended by some understanding of the distribution of the raw data. Their information is problematic. the average change. weighted by the number of subjects. This method of access is consistent with the FDA-approved method of accessing the internal capsule’s anterior limb. this improvement was deemed clinically significant. because the average composite scores—scores generated by more than one patient in any study—were reported without any description of the variance.

A few patients experienced worsened OCD when their stimulators were powered off. 2007).8% of the group) developed a superficial infection. are reported to produce improvements on the order of 40% to 60% in a mere 50% of patients treated. 2010).8% of the group) experienced a lead break. particularly exposure and response prevention. those related to stimulation.182 2 0 T hings to K now A bout D eep B rain S timulation pharmacological and CBTs. 2 of 26 participating subjects (7. associated with trials of different electrode configurations and stimulation parameters. Consensus guidelines for alternative medication and behavioral therapies indicate treatment with CBT. which antibiotics remedied. In one of the largest studies of DBS of the ventral capsule/ventral striatum. and one patient experienced OCD when his stimulator was powered on. in light of other accepted therapies. and those related to the disease. selection criteria for OCD DBS include (1) refractoriness to all reasonable medication and behavioral therapies. Thus. The other context is the degree of benefit with DBS. Thus it appears that the results obtained with DBS are comparable to those obtained with CBT. Pharmacological treatments consist primarily of serotonin reuptake inhibitors and selective serotonin reuptake inhibitors (SSRIs). D EEP B R A I N ST I M U L AT I O N I S S A FE In terms of conceptual arrangement. (4) feasible access to postoperative DBS programming. adverse effects may be categorized as those that are related to a surgical procedure. The National Institute for Health and Clinical Excellence (2005. CBTs. (2) the degree to which a possibly treatable handicap represents a rate-limiting factor in a patient’s quality of life. such as changes in sensation and muscle contractions. One patient (3. Though the different SSRIs may be similar in their efficacy. for example. There was one report of hypomania and one of increased domestic problems. There were readily reversible adverse effects. These surgery-related complications are on par with many studies of DBS of other targets for other indications. tolerance to them appears to admit of some idiosyncrasy (Work Group on Obsessive-Compulsive Disorder et  al. United Kingdom) recommends at least 10 hours of CBT. (3) whether the benefits a patient may reasonably expect outweigh the risks.6%) experienced intracranial hemorrhage from which they made full recovery (Greenberg et  al.8% of the group) experienced a single seizure in the immediate postoperative setting. This in itself is remarkable. then DBS should be considered equally efficacious. Surgical procedure adverse effects relate primarily to risks of intracranial hemorrhage and infection. If CBT is considered efficacious solely from the perspective of benefit. Three patients each experienced four incidents of increased depression or suicidal ideation as a side effect of stimulation. even in the difficult population studied. One patient (3. S EL ECT I O N C R I T ER I A Similar to those for other indications. One patient (3. including those associated with such comorbidities such as depression and suicide. if one .

These presuppositions are perhaps unfounded:  There is little reason to believe that a nondelusional patient with OCD is any less capable of providing informed consent than is a patient with Parkinson’s disease or some other movement disorder. healthcare professionals. one should feel emboldened to engage in systematic exploration of the parameter space from which it may be possible to deduce general principles. The situation with SSRIs is similar to the situation in which dopamine agonists are used to treat Parkinson’s disease. must continue to guide exploration. It is also possible that by relating efficacy to specific anatomical locations or developing such rapidly responding predictive biomarkers as DBS-evoked EEG potentials one may aid the development of those algorithms. Patients whose dystonia symptoms are phasic or active symptoms respond quickly to changes in DBS. For example. Rapid changes in anxiety and mood allow for a titration upward in electrode configurations and stimulation parameters. specifically—is safe and effective for treating OCD that is refractory to pharmacological and behavioral therapy. it is not unusual for IRBs to require an independent committee to oversee the selection process. by selecting appropriate electrode configurations and stimulation parameters (Montgomery 2010)  that produce no adverse effects.16. Educated trial and error. If subsequently demonstrated to be predictive. It is important to note that a DBS surgery site’s IRB may impose other requirements. It remains unclear whether such a change is predictive of subsequent improvements in OCD. In some patients the most immediate response is a change—often for the better—in anxiety and mood. effective. To insist otherwise is to violate the ethical principles of beneficence and autonomy. then one is free to consider whether a different SSRI may prove effective. then a different SSRI may bring benefit. its acceptance is complicated by many presuppositions on the part of patients and patients’ families. However. Such an approach has been suggested by Nuttin and colleagues (2003). Rather than be discouraged by the lack of definitive. One may also attempt to maximize the stimulation effects. In one study. which would help to expand experience rapidly. A  similar phenomenon characterizes DBS for dystonia. and efficient programming algorithms. and the public. as well as physicians. to ensure the patient meets the criteria. S U M M A RY Though DBS—of the ventral capsule/ventral striatum. and to assure appropriate informed consent process. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder183 SSRI proves ineffective and no adverse effects limit it. all 26 participating subjects who underwent ventral capsule/ventral striatum DBS experienced a plateau in their response at three months. changes in anxiety and depression may act as biomarkers in early adjustments. if adverse effects prevent a patient from reaching a maximal dose of one SSRI. D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G Most studies of DBS for OCD report a long latency to improvement. meanwhile. . Of great help would be a registry.

Childress JR. D’Astous M. Like many present-day patients with OCD. 1997. New  York:  Oxford University Press. whether with medication. Curr Psychiatry Rep.13(4):274–282.70(11):1551–1556. Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets. Sjoberg RL. et al. Hegarty JD. et al. The relationship between decision-making and perfectionism in obsessive-compulsive disorder and eating disorders. Belief systems of the general public concerning the appropriate treatments for mental disorders. Baldessarini RJ.80(3–4):e31–e39. Tohen M. World Neurosurg. et  al. Radiosurgery for the treatment of psychiatric disorders: a review. Goldstein LB. Malone DA Jr. and subjective perceived outcome related to clinical measures in . et  al. R EFER ENCES Arikha N. Obsessive-compulsive personality disorder and suicidal behavior:  evidence for a positive association in a sample of depressed patients. Korten AE. Beauchamp TL. past patients with psychiatric disorders faced no alternative other than continued suffering. any reasonable attempt at treatment. 2012. Passions and Tempers: A History of the Humours. Rodgers B. Gabriels LA. Deep brain stimulation in the treatment of obsessive-compulsive disorder.44(3):316–321. or indeed even lobotomy and ECT. Roy M. the fraught legacy of mid-twentieth-century lobotomy and ECT exerts perhaps undue influence. Horstkoetter N. Winceslaus J. Complication rates for carotid endarterectomy. Soc Psychiatry Psychiatr Epidemiol. Mol Psychiatry 2010. World Neurosurg. Psychopathology 2012.51(1):84–99. Thompson-Brenner H. Regis J. J Behav Ther Exp Psychiatry 2013. Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. The actions of a few unethical surgeons and physicians of yesteryear should not impugn those of the majority of their colleagues. Salkovskis P. 2013. Robertson JT. van den Munckhof P. et al. Cottin S. Freeman D. Patients’ expectations of deep brain stimulation.32(8):468–473. Principles of Biomedical Ethics. 2007. Jorm AF. Reasoning bias and belief conviction in obsessive-compulsive disorder and delusions: jumping to conclusions across disorders? Br J Clin Psychol.84(11):1208–1213. Stroke 1997.184 2 0 T hings to K now A bout D eep B rain S timulation Admittedly.. Boisseau CL. Diaconu G. Hansson M.28:889–890. et al. Blomstedt P. Greenberg BD. Leveque M. et  al. This being the case. Psychiatric literacy and the personality disorders. Lewis CJ.45(1):29–41. Moore WS. must appear as a ray of hope. 2013. Turecki G.151(10):1409–1416. Bilateral stereotactic anterior capsulotomy for obsessive-compulsive disorder: long-term follow-up. Figee M. et al. Jacobsen P. DBS. Carron R. de Koning PP. Furnham A.15(1):64–79. et  al. Maier F. J Neurol Neurosurg Psychiatry 2013.80(6):e245–e253. New York: HarperCollins. 2011. Pratt EM. J Clin Psychiatry 2009. who no doubt are honest and motivated by compassion. One hundred years of schizophrenia:  a meta-analysis of the outcome literature. 2013. Am J Psychiatry 1994.

2014. 2005. The Concept of Mind.1:21–23. Turkstra LS: Evidenced based medicine: let’s be reasonable. Word and Object. Neurosurgery 2003. Int Rev Psychiatry 2009. 2010. Cambridge. discussion 1272–1264. et  al. J ECT 2002. Follett K. meta-analysis of family intervention and cognitive behaviour therapy. 2000. Montgomery EB Jr. Rey JM. Kuipers E. Walter G: Hollywood and ECT. JAMA 2009. 2007. Washington. Morishita T. J Neurol Neurosurg Psychiatry 2013.18:43–46. et  al. Medical student knowledge and attitudes regarding ECT prior to and after viewing ECT scenes from movies.17(4)312–319. et  al. Neuromodulation 2013. Goodman WK. Ryle G. Stern M.188(4):202–208. McHugh PR. Chicago: University of Chicago Press. Surgical neuroanatomy and programming in deep brain stimulation for obsessive compulsive disorder. 2002. Work Group on Obsessive-Compulsive Disorder. Li D. Walter G.119:91–95.11: ix–xii.. Practice Guideline for the Treatment of Patients With Obsessive-Compulsive Disorder. J Med Speech Lang Pathol. McDonald A. Koran LM. Weaver FM. 1913 to 1940. Montgomery EB Jr. Clin Neurol Neurosurg.301(1):63–73.52(6):1263–1272. 2003. MA: MIT Press. Long-term electrical capsular stimulation in patients with obsessive-compulsive disorder. Nuttin BJ.32(5):763–782. Montgomery EB Jr. Hanna GL. . Stephens JH. London: National Institute for Health and Care Excellence. Long-term follow-up of bilateral anterior capsulotomy in patients with refractory obsessive-compulsive disorder. Cosyns PR. 2013. et  al.16. Fayad SM. Deep Brain Stimulation Programming:  Principles and Practice. APA Practice Guidelines. NICE Clinical Guideline 312005. Liu W. Richard P. Ask the expert: what is your interpretation of the ADAGIO study and has it influenced your clinical practice? Neurodegen Dis Manage.21(3):200–206. Obsessive-Compulsive Disorder:  Core Interventions in the Treatment of Obsessive-Compulsive Disorder and Body Dysmorphic Disorder. 2002. Pilling S. New York: Oxford University Press. Psychological treatments in schizophrenia: I.84(11):1273–1281. National Institute for Health and Care Excellence. DC:  American Psychiatric Association. Psychol Med. McDonald A. et  al. Quine WVO. Deep Brain Stimulation Is Safe and Effective for Obsessive-Compulsive Disorder185 Parkinson’s disease:  a mixed-method approach. Zhan S. Long-term follow-up of patients with a diagnosis of paranoid state and hospitalized. 2011. J Nerv Ment Dis. Gabriels LA. et al. Bebbington P. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. et al.

Often it is difficult to know. in the case of research. are necessarily incomplete or indirect—but rather to certain presuppositions and prejudices. who are no doubt highly intelligent. Of no concern here are issues of honest differences of opinion. it also provides thorough context for reviewers’ responses. Many criticisms and their consequent recommendations would appear entirely reasonable by approaches and concepts implicitly held. The research proposal reproduced in detail here models the construction of a preliminary or pilot clinical research protocol. for example. Many decisions concerning approval of innovative clinical research rest on value judgments with respect to risk and benefits. The purpose here is not to argue DBS’s effectiveness in treating PTSD or to call for clinical trials to begin. Therein lies the paradox. because risk and benefits may only be estimated. however. and resume their reading with the discussion of the reviewers’ responses. It is. to discuss the challenges faced in conducting a clinical trial. because they frame questions and determine beforehand criteria for evidence that supports the proposed clinical trial. Resistance comes in response not to the facts themselves—which. This chapter considers the reception of the idea of DBS as a PTSD therapy and the implications this reception carries for future innovative clinical trials of DBS. accomplished. The intent behind this chapter is not to criticize individual reviewers. uninformed predispositions betray habits of thought that actually oppose innovative research. rather. In the case of innovative clinical research. . Readers may wish to skip the latter. and respected. Indeed. In order to preserve a sense of fairness. when there exists preclinical data sufficient to justify a transition to clinical trials. particular value judgments are necessary.17 Could Deep Brain Stimulation Be Effective in the Treatment of Posttraumatic Stress Disorder? This chapter concerns future Deep Brain Stimulation (DBS) therapies such as Posttraumatic Stress Disorder (PTSD). which are the focus of the discussion that follows the text of the proposal.

The design of research clinical trials of DBS is complicated. Alternatively.17. The anterior cingulum is part of the limbic system that controls fear responses and psychological distress. Similarly. It is the possibility of offering these patients an effective alternative therapy that drove the proposed research. Patients with PTSD invited to join the study face a stark choice: either participate or continue to suffer a debilitating condition. is an impractical approach. a proposed clinical trial is necessary. Considerable scientific evidence suggests that a part of the brain called the anterior cingulum may be involved in PTSD. Current clinical research also demonstrates that DBS can help patients with severe depression following failure of alternative medications and psychological therapies. three or four of 100 patients who undergo DBS surgery experience paralysis or another serious. electrodes are implanted in various parts of the brain and are connected to a stimulator placed under the skin of the chest. Further. Physicians and healthcare professionals wish to avoid harming patients. some patients may respond positivity even if the DBS was inherently ineffective. some experience no benefit from any standard therapy. Risks must nonetheless be considered. and substance abuse. A coin that is slightly biased in favor of heads may take many flips before one can be sure that the coin is biased. suicide. particularly when they involve surgery. Patients avoid public places. Humans with PTSD have experienced benefit from a form of electrical stimulation that is introduced to the brain through the scalp and skull rather than by implanted electrodes (Transcranial Magnetic Stimulation). DBS surgery carries risks comparable to those attending surgery to unblock an artery in the neck or heart. This outcome inspired confidence in the idea that DBS may help patients with PTSD. a tendency that limits their interactions with family and community. Because one cannot know the likelihood of DBS benefit for PTSD. Deciding the exact time to begin human clinical trials of a new treatment is always difficult. Although many patients benefit from medications and psychological therapies. it may take a considerable number of patients to benefit from DBS for PTSD to know whether there is a real . They also relive the terrifying experience that led to their PTSD. DBS has been approved to relieve the suffering of patients with severe Obsessive-Compulsive Disorder (OCD) following failure of medications and psychological therapy. As measured against potential benefit. The question becomes whether the refusal to offer a therapy results in greater harm. Though it may seem frightening. possibly permanent complication. One wishes to assure participating patients that following their participation they and the rest of society will know whether patients stand to benefit from DBS. DBS may be helpful. DBS has helped other types of psychiatric or psychological disorders. This. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?187 R ES E A R C H PR O P O S A L PTSD may be severely disabling. Further complicating the situation is that the placebo or an actual benefit may vary among patients. Electric stimulation of the limbic system has improved symptoms in an animal model of PTSD. even life-threatening. In DBS. They face high risks of depression. given the psychological and possible physical placebo effects. The anterior cingulum has been shown to be abnormal in humans with PTSD. however.

The proposed research sought to improve estimates of that sufficient number. Further. reexperiencing. PTSD is often refractory to the best pharmacological and behavioral therapies. Yet often it is not possible to determine ahead of time how many subjects should be planned for. whereas rates of panic disorder. Yet one finds it difficult to know how many patients would need to undergo DBS before one may claim with confidence that DBS helps. Symptoms often overlap with depressed mood and exacerbate feelings of hopelessness and helplessness. The rate of attempted suicide in PTSD is estimated to be 20%. and major depression in PTSD patients are significantly higher than they are in the general population (Davidson 2001). which. Though numerous treatment modalities have produced a partial response in many patients and complete recovery in some others. Another option is clearly needed. analogous to the number of coin flips to be performed as described previously. and hyperarousal. In that case. The proposed research thus represents a necessary intermediate step toward full-fledged studies that seek to establish DBS as an effective treatment of PTSD. Quite serious when taken individually. PTSD incorporates three well-known symptom clusters: avoidance. Indeed. The cognitive effects of these symptoms interfere with patients’ ability to socialize normally. Involved in the proposed research was implantation of DBS systems in patients with severe refractory PTSD for the purpose of developing methods for optimal brain stimulation. not to demonstrate whether or not DBS is clinically effective but rather to determine the effect size of the treatment and the variance in the primary outcome measure in order to determine sample size. The issue is how to proceed in this demonstration. is about half the number needed to prove that DBS works. Though effective nonsurgical therapies do exist. substance abuse. or muster the wherewithal to visit the doctor or the supermarket. remain employed. maintain family relationships. a pilot project can demonstrate the feasibility of a subsequent full-scale clinical trial. When designing a clinical trial to demonstrate whether or not a treatment is effective. one can conduct a pilot study. B AC KG R O U N D A N D S I G N I FI CA N C E A significant cause of morbidity and mortality. as turns out. For example. Unemployment costs taxpayers some $3 million (Davidson 2001). on this issue there are probably as many different opinions as there are individuals holding them. Some advocate beginning with a large-scale study powered to demonstrate efficacy and safety. the former typically requiring much larger sample sizes.188 2 0 T hings to K now A bout D eep B rain S timulation possibility that DBS may help. a significant number of patients are refractory to or ineligible for these therapies. demonstrating an adequately clinically . one first has to determine the number of subjects to be entered. J U ST I FI CAT I O N FO R PR O P O S ED R ES E A R C H ST R U CT U R E The proposed research sought to demonstrate that DBS of the anterior cingulum is a safe and effective therapy for patients with PTSD. there exist treatment-resistant cases that defy even the most vigorous regimen. these symptoms may lead to total incapacitation and even suicide when taken in combination.

[. A sample size of 15 subjects. There is the precautionary principle in ethics. . [. the objective is to pursue a degree of safety that is comparable to that of established therapy. As DBS-related research ethics expert Joseph Fins (2008) has noted. The exercise of this judgment is often more problematic in surgical trials.] The challenge posed by innovation or novelty creates the possibility of untoward events. balancing risk and potential benefit remains a matter of judgment. There is unfortunately no calculus to relate risk to benefit. urges us to “give greater weight to the prognosis of doom than to that of bliss. It leads to invocation of the precautionary principle. One makes judgments about the advisability of actions based on a prior assessment of foreseeable risks and benefits. The proposed research could thus elicit some appreciation for the potential benefit of DBS. . . the former finding a difference when one does not exist and the latter not finding a difference when one exists (see “Sample Size Justification” section). The population of concern would possibly have a greater effect size and lower variance. grant reviewer. Judgments are affected by the psychological impact of the medical decision on the clinician. . which requires exposing fewer subjects to risk. autonomy. [. scientist. . Operating within those limits. according to Fins (2008).] When the precautionary principle is implicitly invoked in making judgments about research. which. urges caution and prudence when facing unknowns and is an antecedent sort of utilitarianism. Extending the effect size and variance to estimates of the population of patients refractory to medical and behavioral therapy is highly problematic. Most would agree that it is unreasonable to place so many patients at risk in a full-scale clinical trial without some prior assurance that DBS will be safe and effective. however. requires the judgment of reasonable women and men.17. would have an acceptable probability of providing a reasonable estimate of the mean and variance on the outcome measure. Risk involves at least two aspects: frequency and severity. such ethical principles as beneficence. . Benefit likewise includes the frequency and magnitude of benefit. Rather. E T H I CA L I S S U ES I N PR O P O S I N G T H E R ES E A R C H PR O J ECT Every medical decision involves assessing risk and potential benefit in the context of alternatives and finding a balance between the two. or Institutional Review Board (IRB) member making it. Admittedly. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?189 meaningful 10% improvement in the Clinician Administered PTSD Scale (CAPS) would require a sample size of 30 subjects. nonmalfeasance. These estimates are based on published data for subjects with a wide range of severity. and justice may constrain the limits of clinical research. A  sample size of 15 provides a 53% probability of detecting an adequately meaningful effect. Yet any study with a smaller sample size risks both type I  and type II statistical errors. which. however. echoing the admonitions of the philosopher Hans Jonas. Better estimates are needed to plan appropriate large-scale studies.] [W]‌hat is known—the status quo—and what is unknown is invariably . surgical clinical trials in which the actions of the surgeon are more proximate to the surgical outcomes are much more personal (Fins 2008).

Concerning risks directly related to stimulation of the anterior cingulum. Asch et al. One may argue that animal studies should be conducted prior to any human ones. Conversely. 2010). lest it lead to Omission bias in which psychological reaction to the threat of harm through an action outweighs larger risks associated with not acting. The injunction “do no harm” has been a cornerstone of medicine since Hippocrates. Concerning benefit. When faced with the certain security of stasis or the potential dangers of innovation. Requiring additional animal studies will necessarily delay the translation to human studies. ’in no direction at all. 1991. To date. Should there be any stimulation-induced adverse effects. The grant reviewer. there are at least two aspects in which animal studies facilitate discussion of clinical trials. . the precautionary principle will invariably choose stasis. A lapse into Omission bias may engender therapeutic nihilism (Tversky and Kahneman 1991. a study in the rodent model of PTSD demonstrated significant improvement with DBS-like stimulation of the amygdala (Langevin et al. as the legal scholar Cass Sunstein notes. would be inappropriate. this is antithetical to innovation because discovery invariably requires scenarios that involve novelty and unknown risks. In the case of the proposed clinical trial. every reasonable pharmacological and behavioral treatment must fail. The incidence and nature of adverse events directly related to surgery have been consistent across many different disorders and targets. As a consequence. because. the harm of not offering DBS for this particular set of patients is that of a high probability of continued disability and suffering. DBS in no way compares with the safety of established therapies that include pharmacological and behavioral treatments. From a standpoint of assessing surgical risk. further animal studies are unnecessary. Ritov and Baron 1990. Yet even this must be kept in balance. It is therefore reasonable to extrapolate from that experience to the potential for surgical risk in the proposed study. it is a topic that admits of a wide range of honest opinions. then.190 2 0 T hings to K now A bout D eep B rain S timulation more risky than the familiar.” As concerns patients with PTSD in general. one does not want to subject a patient to risk of harm. IRB member. Spranca et al. many patients will suffer in the interim. How to balance this potential harm of omission with the potential harm of commission is difficult. Indeed. There are thus no established treatments for these patients and no level of safety to which the proposed research may be compared. in order for them to be considered. 1994). however. there has not been any evidence of persistent stimulation-induced adverse effects that have continued once DBS was ceased. These relate to potential for benefit and for risk. the subject or safety monitoring committee could order the stimulation stopped. Indeed. The decision of when to make the translational jump from animal to human studies is always problematic. provided they are given the opportunity. subjects will also weigh the risks of omission versus those of commission. leading us. and physician are fortunately not alone in dealing with this question. To apply this aspect of the precautionary principle to subjects to be enrolled in the DBS clinical trial.” Needless to say. With respect to the latter there is sufficient experience regarding the safety of DBS in humans (see later discussion). Lozano and colleagues (2008) report no adverse effects in 20 subjects having undergone DBS in the vicinity of the anterior cingulum for depression.

and motivation (Shackman et al. pain prediction and avoidance. They hypothesize that the primary role of the cingulum is to integrate and thus to exert cognitive control . 2010). The parallel to domains affected by PTSD in humans is striking. there did occur significantly reduced fractional anisotropy values in the right posterior cingulum and bilateral hippocampal body (Wang et al. 2008. The anterior cingulate demonstrated significant neurometabolic changes in response to the experience of intense negative affect. T H E B AS I C SC I EN C E O F T H E A N T ER I O R C I N G U L AT E A N D T H E P OT EN T I A L R EL E VA N C E TO P O ST T R AU M AT I C ST R ES S D I SO R D ER Richard Davidson and colleagues (Shackman et  al.17. Drabant et al. Children and young adults with PTSD following traumatic brain injury (TBI) were more likely to experience recurring symptoms when the anterior cingulate was relatively intact (Herskovits et al. and neuronal recording in the cingulate of humans demonstrate correlations in neuronal activity changes with painful stimuli (Hutchison et  al. 2011)  reviewed the extensive literature on ways the anterior cingulate provides support to the integration of the expression of affect. and thus it plays a significant role integrating affect. Delgado et al. 1999). 2010. the anterior cingulate is activated in nonhuman primates in response to an imminent threat (Kalin et al. The anterior cingulate interconnects with the ventral striatum. particularly anticipation (Sehlmeyer et al. 2011). may parallel similar functions in the anterior cingulum (Williams and Goldman-Rakic 1998). It is conjectured that there may be some analogy to the anticipation of intense negative affective conditions and the hypervigilance symptoms of PTSD. 2011). and cognitive function. Davidson and colleagues reviewed considerable evidence demonstrating that the cingulum overlaps in its involvement with negative affect. response to pain. and cognitive function. 2002). 2009. Indeed. motivation. which in addition to its role in reward mechanisms is also involved in the anticipation and avoidance of pain and other aversive stimuli (Jensen et al. 2006). Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?191 E V I D EN C E FO R A R O L E O F T H E A N T ER I O R C I N G U L AT E C O R T E X I N P O ST T R AU M AT I C ST R ES S D I S O R D ER Though whole or regional magnetic resonance imaging (MRI) brain volumes of PTSD-positive subjects who were involved in a coal-mining disaster in China were not significantly different from PTSD-negative subjects. 2011). 2005). particularly reinforcers. Via projections from the substantia nigra pars compacta to the anterior cingulum. 2010). Robinson et al. Changes are noted in the anterior cingulate in response to pain and other adverse experiences (Vogt 2005). Similar findings were reported in Japanese Sarin gas attack survivors suffering from PTSD (Abe et al. Davidson and colleagues hypothesized a rich integration of these functions within the cingulum. the last of which heretofore having been believed to act independently. 2009. 2003. Levita et al. response to pain. motivation. Increased unpredictability of a physical threat also activates the anterior cingulum (Alvarez et al. Mobbs et al. activities in the substantia nigra pars compacta related to prediction of aversive stimuli.

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over all these domains. Again, it is interesting to speculate that PTSD may reflect
an impaired cognitive control mechanism involving the anterior cingulum. This
hypothesis and its supporting observations described previously provide a cogent
rationale for the proposed study.
I N D I R ECT E V I D EN C E I N S U PP O RT O F A P O S S I B L E D EEP
B R A I N ST I M U L AT I O N B EN EFI T

The anatomical target for DBS demonstrates abnormal neurometabolic activity
in patients with PTSD (Felmingham et al. 2003). Using changes in skin conductance as a marker of emotional responsiveness, investigators recorded in subjects
with PTSD a reduction in the blood oxygen level dependent response in functional
MRI (fMRI) of the ventral anterior cingulum region compared to normal for non–
trauma-related stimuli that elicited skin conductance changes. This region is analogous to the proposed target of DBS.
Boggio et al. (2005) demonstrated that 20 Hz repetitive Transcranial Magnetic
Stimulation over the dorsal lateral prefrontal cortex improved PTSD symptoms,
as measured by the PTSD Checklist and Treatment Outcome PTSD Scales, which
still were significant at 3 months following treatment. In addition, depression was
improved. Importantly, there was no evidence of cognitive worsening. Cohen et al.
(2004) reported similar results. Interestingly, DBS-like stimulation of the basolateral nucleus of the amygdala unilaterally improved behavior in the rodent model of
PTSD (Langevin et al. 2010).
I M PR OV EM EN T O F OT H ER
N EU R O PSYC H I AT R I C D I SO R D ER S

Though it is highly problematic to generalize from other disorders, such as OCD
and depression, DBS has demonstrated benefit in the face of failed pharmacological and behavioral therapies. DBS of the anterior limb of the internal capsule and
the subthalamic nucleus (Mallet et al. 2008) improves OCD. DBS of the subgenu
cingulum (area 25) (Kennedy et al. 2011) improves depression.
All of these treatments share certain ethical issues. In all cases a decision had to
be made between the unknown but possible benefit compared to the known risks
and, more important, of the risks of not intervening. In the latter case, subjects
quite literally had no other alternative than to continue to suffer. Such would also
be the case of potential subjects of the proposed research.
AS S ES S M EN T O F R I S K

As in any medical decision, potential benefits must be weighed against risks.
Though the potential benefits of DBS in PTSD are unknown, some observations
have been made that suggest the potential benefit described previously. Many
aspects of the risk assessment, however, are relatively well known. In this case, risks
may be categorized as those related to the surgical implantation of the DBS device;

17. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?193

those related to the effects of stimulation such as psychiatric, psychological, as well
as neurological; and those related to the psychosocial consequences of changes—
either in the direction of improvement or of further deterioration—in the PTSD.
Risks related to surgical implantation of the DBS system are well known, thanks
to extensive published experience. For example, the Veterans Affairs–National
Institutes of Health cooperative study in which 299 subjects with Parkinson’s disease underwent DBS had a surgical complication rate of nearly 50%. This rate is
most likely related to the definitions used for adverse events, which include transient side effects routinely experienced during DBS programming. These are not
generally considered adverse events. Evidence for this is the fact that 99% of events
considered adverse were resolved in 24 months (Weave et al. 2009). The validity of
extrapolating these complications to possible surgical risks in PTSD is reasonable,
because the same rates of surgical complications have been seen in such other types
of DBS surgery as OCD, Essential tremor, and dystonia. The surgical complication
rates thus appear to generalize well across different diagnoses. They should be relevant to surgical risk assessments for subjects with PTSD.
There may be risks associated with stimulation that are unique to the stimulated structure. Stimulation of the globus pallidus interna, for example, risks
temporary tonic contraction as a consequence of the proximity of the DBS electrodes to the corticospinal tract, and it risks temporary phosphenes (visual hallucinations of bright lights) as a consequence of the proximity of the stimulation
site to the optic tract. Similarly, DBS in the vicinity of the subthalamic nucleus
has been associated with depression or euphoria when stimulation is excessively
ventral and medial in the subthalamic nucleus. These problems typically resolve
with adjustments of the stimulation configurations and parameters. Published
literature of DBS in patients with depression, which involves the same targets as
those in the proposed research, demonstrates few adverse effects that would be
specifically referable to DBS of subgenu cingulum. In 20 patients with DBS of the
anterior cingulum, over the initial 12 months the following adverse effects were
observed: wound infection and hardware removal (three patients); reinsertion of
DBS hardware (one patient); wound infection (in one patient; managed with antibiotics alone); perioperative seizure (one patient); worsening mood or irritability
(two patients); perioperative headache (four patients); and pain at pulse generator site (one patient). Seven patients experienced no adverse effects (Lozano
et al. 2008). Follow-up after 3 to 6 years demonstrated continued efficacy without
additional adverse effects except that of completed suicide in 2 of the 20 subjects
(Kennedy et al. 2011).
There may appear adverse effects related to the psychosocial consequences of
changes—either in the direction of improvement or of further deterioration—in the
PTSD. This possibility has been demonstrated in patients with Parkinson’s disease
following DBS (Schupbach et  al. 2006). Disturbances, psychosocial dislocations,
and dissatisfaction with family may occur despite clear symptomatic improvement.
The types of adverse effects unique to PTSD unfortunately cannot be anticipated,
because no experience with DBS in PTSD yet exists. These types of adverse effects
may indeed be significant. The study will therefore include close surveillance. The
experience of thousands of patients undergoing DBS for other indications; however, demonstrates that these effects are reversible with the discontinuation of DBS,
which will be an option in the proposed study.

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T R AU M AT I C B R A I N I NJ U RY AS A P OT EN T I A L C O N FO U N D

The tension that drives the TBI-related selection criteria is an interest in minimizing
structural changes in the brain undetectable with MRI that would reduce, perhaps
years after a traumatic event, the effectiveness of DBS (effect size) or increase the
variance of the outcome measures. Given that MRI done at enrollment may miss
significant brain injury, such as diffuse axonal shearing, a behavioral-historical
assessment is needed. The goal is to minimize the potential confounding effect
while maintaining a sufficient sample, particularly one that remains relevant to the
ultimately intended population. Consequently, any subject with mild or greater TBI
would have been excluded, at least initially. Four criteria for mild TBI are (1) any
period of loss of consciousness; (2)  any loss of memory for events immediately
before or after the accident; (3)  any alteration in mental state at the time of the
accident (e.g., feeling dazed, disoriented, or confused); and (4) focal neurological
deficit(s) that may be transient but where the severity of the injury does not result
in loss of consciousness of approximately 30 minutes or less, loss of consciousness
after 30 minutes, and initial Glasgow Coma Scale of 13 to 15, or posttraumatic
amnesia of less than 24 hours in duration (Kay 1993). It is recognized that these criteria suffer from recall problems particularly with remote TBI. Nonetheless, these
historical criteria, where obtainable, will be used.
Though most patients who sustain mild TBI recover within several months, a
subset of patients will experience lingering symptoms, known collectively as postconcussive syndrome, which can mimic those of PTSD. Such symptoms include
irritability, emotional liability, difficulty concentrating, and slowed mental processing. Though these lingering TBI symptoms typically do not include such PTSD
symptoms as avoidance, reexperiencing, and hyperarousal, they may present difficulties when attempting to differentiate PTSD and postconcussive syndrome in a
clinical population (Stein and McAllister 2009). Additionally, both TBI and PTSD
can result in changes in such psychosocial functioning as difficulty socializing,
problems maintaining employment and relationships with family and friends, and
difficulty in effectively engaging in activities of daily living. It is important to consider the cause of these psychosocial functioning deficits when assessing patients’
and their family members’ perceptions of the effectiveness of the DBS procedure. If
a the patient continues to experience deficits in psychosocial functioning following
the DBS procedure, it is important to know whether a prior history of TBI rather
than the PTSD contributes most to the current deficits. Studies of patients and their
family members’ perceptions and experiences are critically important to any future
large-scale clinical trial.
Though subjects with significant TBI—as demonstrated by a positive history of a
concussion or worse trauma—would not have been enrolled, it is widely recognized
that there may be significant brain injury with less severe trauma. The selection criteria would minimize the potential confound of concomitant TBI, but it would not
eliminate it. Some effort was therefore necessary to establish a measure that reflects
the psychosocial sequelae of mild to moderate TBI as opposed to those of PTSD.
It is important to account for the potential of enrolling subjects with TBI of lower
severity than that which constitutes the cutoff. Though TBI may not produce the
symptoms of avoidance, reexperiencing, and hyperarousal typical of PTSD, overlaps do exist (Stein and McAllister 2009). Following the recommendations of the

17. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?195

PTSD Work Group appointed by the intergovernmental Common Data Elements
Interagency Steering Committee, investigators would pay careful attention to TBI.
Investigators would also follow the committee’s recommendations for various
instruments (Kaloupek et al. 2010).
Attempts to differentiate subjects with PTSD alone (without TBI history) from
those with combined PTSD and TBI have, unfortunately, not been successful
(Bahraini et al. 2009). This likely owes to the fact that there have been relatively
few studies, perhaps because current therapies do not require such differentiation.
The situation may be different, given the surgical risks associated with DBS. It is
important to note that the proposed research was not a study of PTSD versus TBI.
If these measure correlated with DBS outcomes in the proposed study, however,
they would have been even more important in follow-up large-scale clinical trials
in which enrollment would be extended to include those patients who suffer more
significant TBI.
Some studies of long-term (>10 year) cognitive sequelae from TBI have been conducted. Persistent deficits have been demonstrated in mental processing speed (e.g.,
the Symbol Digit Modalities Test, memory (Rey Auditory Verbal Learning Test),
and executive function. Interestingly, no differences were observed between subjects with PTSD and normal controls in the Rey Auditory Verbal Learning Test
(Brenner et  al. 2009). Visual memory is similarly affected in mild to moderate
TBI (Miotto et al. 2010) and does not appear to be affected in PTSD (Vasterling
et al. 1998; Neylan et al. 2004). Digit span is also normal in PTSD (Neylan et al.
2004). The California Verbal Learning Test score is normal in PTSD but abnormal in TBI subjects tested 3 to 5 years after injury (Dikmen et al. 2003). The Digit
Span, Spatial Span, Family Pictures, and I and II subtests of the Wechsler Memory
Scale–III would therefore have been investigated. In addition, the Benton Visual
Form Discrimination would have been administered. These measures would have
been correlated with DBS outcome for the purpose of future selection criteria for
the large-scale follow-up study. For example, does an abnormal California Verbal
Learning Test score predict a poorer DBS outcome?
Deficits that are consistently shown in post-mild TBI patients include slowed
mental processing speed, diminished memory, and impaired executive functioning (Mathias et al. 2004; Lundin et al. 2006). Neuropsychological testing in those
with PTSD typically shows deficits in attention and memory (Vasterling et  al.
1998; Horner and Hamner 2002). Processing speed and executive functioning do
appear to be potential areas in which the two groups diverge (Neylan et al. 2004).
The following neuropsychological measures would have been administered preand post-DBS to assess any changes in cognitive functioning following surgery.
Additionally, the measures may be beneficial in assessing for any effects that TBI
may have on outcome.
1. Trail Making Test Parts A and B
2. Stroop Color-Word Test
3. Wechsler Adult Intelligence Scale–IV Digit Symbol Coding
4. Wechsler Adult Intelligence Scale–IV Symbol Search
5. California Verbal Learning Test, Second Edition
6. Rey Osterrieth Complex Figure Test
7. Controlled Oral Word AssociationTest

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8. Wisconsin Card Sorting Test
9. Weschler Test of Adult Reading

PR EL I M I N A RY ST U D I ES

This would have been the first foray into a clinical trial of DBS for PTSD. No preliminary studies exist. However, related studies, such as the effects of repetitive
Transcranial Magnetic Stimulation on PTSD and the effects of area 25 DBS for
depression, offer the investigators assurance that the proposed studies are worthwhile (see “Background and Significance” section).

D ES I G N A N D M E T H O D S

Overview
The general design of this clinical trial would have involved placement of DBS
leads in the subgenu cingulum (area 25g) bilaterally. Subjects would then have
been randomized initially to two limbs of Part A: A-start and A-delayed. Part
A  would have consisted of a double-blinded (subject blinded) dose-ranging
adjustments of the DBS systems, which would have begin approximately two
weeks following lead implantation (Part A-start) or following sham DBS adjustments for six months (Part A-delayed) analogous to a “delayed start” protocol.
Once programming has been optimized according a plateau in efficacy over a
time of observation of at least three months and an absence of bothersome side
effects, subjects would have entered a double-blinded study (Part B) in which the
DBS systems are randomized, according to a blinding protocol described later,
to being left powered on or powered off for six months. A crossover would have
followed this having the stimulation powered off (if previously on) or powered
on (if previously off), again according to a blinding protocol. Note: The safety
monitoring committee could override the protocol should any significant concerns arise from the crossover between “on” or “off” DBS. Should this occur, the
observations up to the point of intervention by the safety monitoring committee
would have been carried forward.
The CAPS (primary clinical outcomes measures) would have been obtained at
the preoperative baseline and then upon the completion of the “on” stimulation
and “off” stimulation phases of Part B. Note: The same outcomes measure would
have been obtained at monthly intervals throughout but would have been treated
as secondary measures to be carried forward in the event of subject dropout. For
example, measures would have been obtained at the end of Part A-start and at the
start of active DBS in Part A-delayed in order to assess effects related to enrollment
in a closely supervised clinical trial and to nonspecific effects of the surgical procedure rather than to active DBS. A compassionate use open-label extension study
would have been offered to subjects who complete Parts A through B. Healthcare
professionals providing postoperative care would have been able to adjust medications as indicated by routine care principles.

cannot be excluded. it is not clear that subjects would be able to tolerate being off medications. Requiring abstention from medications or an unchanging medication regimen would have risked loss of the ability to generalize from the clinical trial to real-world use. which also reference various measures from the Common . which could thereby prevent optimization of DBS. there is no way to establish how long a subject would have to be off medications to rule out medication effects. whether these settings would have proved optimal for PTSD cannot would have been established in advance. inability of reduce medications may exert a “ceiling” effect on DBS titration. Note:  Raters would have been be blinded throughout the study.17. will allow some estimation of within.and between-subject variance in the outcomes measures that would have been important for future studies. In addition. after detrending. healthcare professionals would have been at liberty to adjust medications. These experiences could either have been be stressful or reassuring. D ESC R I P T I O N S O F PR O C ED U R ES A N D M E AS U R ES Instruments to be applied follow from the PTSD Work Group appointed by the intergovernmental Common Data Elements Interagency Steering Committee (Kaloupek et al. Rather. in which the subject but not the DBS programmer would have been blinded to the stimulation adjustments. The programmer thus needed to enjoy flexibility in DBS programming. the monthly results. 2010). One could require stable (unchanging) doses of medications prior to enrollment. the potential for DBS to reduce medication needs and potentially medication-related side effects would be lost. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?197 Rationale Parts A and B. are necessary. Indeed. if being off medications is a selection criterion. and thus they affect the PTSD symptoms. the duration of wash-in and wash-out effects are not known in advance. as they would under routine medical care. the purpose of the interim CAPS assessments was to determine the possible presence and duration of “wash-in” and “wash-out” periods that would have been important for any follow-on large-scale clinical trial. changes in medication use would have been one of the secondary outcomes measures. The sham DBS programming phase would have allowed determination and control for these potential unintended effects. Second. First. Potential synergistic effects between DBS and medications. and this could pose considerable risk. Sham DBS programming (Part A-delayed) would have been necessary to control for the effects of the close postoperative care and testing. Also. For several reasons. There are two potential consequences. Yet there exists no prior information to guide this decision. First. Although the initial DBS programming settings and subsequent adjustments would have been modeled after those used in DBS of the subgenu cingulum for depression. Consequently. CAPS obtained monthly would have been secondary and not used to determine the possible therapeutic effect size unless the last secondary observation has to be carried forward in the event of a dropout. particularly those considered adverse. Allowing the healthcare professional to improvise adjustments to medications reflects future intended clinical use.

Confirmed diagnosis of PTSD that a. Patient should be resistant to at least four medications from at least three different classes—selective serotonin re-uptake inhibitors (Stein et al.198 2 0 T hings to K now A bout D eep B rain S timulation Data Elements for TBI (Maas et al. and eye . antipsychotics. as measured by the Columbia Suicide Severity Rating Scale. Absence of significant dementia as determined by the Dementia Rating Scale. 2006). 4. Exhaustion of all reasonable attempts at pharmacological and behavioral therapies. (3)  Hamilton Anxiety Scale (Ham-A). 2. (5) behavioral history— advanced. bupropion. and (6)  screening for mild/moderate TBI.tbi-impact. Thurmond et al. c. Short Form). 5. 1996). The following additional measures would have been applied at various times during the study: (1) CAPS (primary outcome measure). 2010. Absence of suicidal risk. D E V ELO PM EN T O F S EL ECT I O N C R I T ER I A Because there are no known selection criteria. stress management. If that appeared to be the case. (2) socioeconomic status: education and social role—advanced. which were taken from the Common Data Elements for TBI (http://www. SF-12 Quality of Life measure (Ware et al. 2009). and (4) Life Stressor Checklist. (3)  Traumatic History Screen. and tricyclic mirtazapine—as well as resistant to an evidence-based psychotherapy intervention such as prolonged exposure therapy or cognitive behavioral therapy. The rationale is that structural changes may interfere with surgical navigation and intraoperative neurophysiological mapping. (4)  Columbia Suicide Risk screen. > 3 cluster C and > 2 cluster D symptoms (Bahraini et al. 2010). The study will also include the following additional four measures: (1) Combat Exposure Scale. b. (3) significant medical history—advanced. (4)  history of exposure to TBI (the Ohio State University TBI Identification Method. (2) Hamilton Depression Inventory (Ham-D). serotonin–norepinephrine reuptake inhibitors.org/cde/):  (1)  demographics— advanced. Included are the following selection criteria: 1. 3. the proposed research would have used criteria based on best medical practices. on > 1 cluster B. To be obtained at enrollment were the following six measures. (2) Structured Clinical Interview for DSM-IV Diagnosis. patients with nothing greater than mild TBI would have been enrolled. Absence of structural brain damage as evidenced on MRI scan. Has been made on a subject who is 19 years or older. 6. The stringent criteria regarding TBI may have made it difficult to enroll sufficient number of subjects. Meets CAPS criteria for PTSD. Meets the Structured Clinical Interview for DSM–IV Disorders—PTSD module criteria for PTSD. Absence of significant TBI (see “Traumatic Brain Injury as a Potential Confound” section). which includes a history of traumatic event(s) and a score of at least 3 on criteria A1 and A2.

Because the study involves surgical risks. Rey Osterrieth Complex Figure Test 18. and one neurologist not involved in the project. consisting of at least one psychiatrist. An MRI scan consistent with the recommendations of the working group on the Common Data Elements in Radiologic Imaging of Traumatic Brain Injury (Haacke et al. or other platelet inhibitors. 9. Ham-D 9. History of exposure to TBI (the Ohio State University TBI Identification Method. (3) T2-weighted fluid attenuated inversion recovery.17. An independent committee to assure candidacy. 7. SF-12 Quality of Life measure 12. Life Stressor Checklist 7. the patient must have demonstrated a resistance to any other intervention. aspirin. CAPS (primary outcome measure) 8. Wisconsin Card Sorting Test 20. Ham-A 10. The remaining measures would have been subjected to data . Traumatic History Screen 6. 2010) in the context of chronic TBI will include the following five elements: (1) T1-weighted imaging. California Verbal Learning Test—Second Edition 17. Wechsler Adult Intelligence Scale–IV Symbol Search 16. The ability to provide informed consent. No current treatment involving valproic acid. Any measure that fails to demonstrate an adjusted R 2 of at least 0. Short Form) 2. Screening for mild to moderate TBI 4. (2) T2-weighted imaging. Controlled Oral Word Association Test 19. Combat Exposure Scale 5. Stroop Color-Word Test 14.3 would have been excluded from subsequent analysis. Columbia Suicide Risk screen 11. Wechsler Adult Intelligence Scale-IV Digit Symbol Coding 15. Trail Making Test Parts A and B 13. would have reviewed case information for each subject in order to determine that the subject has indeed exhausted all reasonable medical and behavioral therapies. (4) T2*-weighted gradient-echo imaging. Specific measures that would have been obtained for consideration in future selection criteria include the following: 1. one neurosurgeon. Behavioral history—advanced 3. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?199 movement desensitization and reprocessing according to the Cochrane Database (Bisson and Andrew 2007). Weschler Test of Adult Reading An initial univariate regression analysis for each measure described here against the change in the CAPS would have been performed. and (5) diffusion-weighted imaging. 8.

P O STO PER AT I V E D EEP B R A I N ST I M U L AT I O N PR O G R A M M I N G A N D M A N AG EM EN T Postoperative DBS programming follows from well-established neurophysiological and anatomical principles (Montgomery 2010). based on these measures. Bipolar configurations. The exploration of electrode configurations and stimulation parameters would have been conducted according to previously published and well-established algorithms (Montgomery 2010). Use of multiple cathodes can increase the volume of tissue activation. The principles instantiated in the algorithms differentiate between problems of efficacy and problems of side effects. would have both anticipate and correlate with outcomes. would have been performed. This will be followed by a hierarchical series of logistic regression analyses that has proven effective in developing predictions using diverse data will be used as described in peer-reviewed publications (Montgomery et al. Phase is the time of passing current in either the negative or positive direction. These parameters are known to and controlled by the programmer. provide a more intense volume of electrical charge. Safety limits with respect to the effects of electrical current on brain tissue are well established. the handheld device for programming (N’Vision programmer. that being less than 30 μC/cm2/phase.200 2 0 T hings to K now A bout D eep B rain S timulation reduction by use of principle components analysis. monopolar stimulation (cathodes in the DBS lead and the Implanted Pulse Generator case as the anode) provides a larger though less intense volume of electrical charge than does a bipolar stimulation (in which the cathodes and anodes use the most dorsal and most ventral electrical contacts). Alternatively. One approach is to reduce the voltage (this risks reduction in efficacy). MN) has built-in warning systems that activate when unsafe stimulation currents are approached.. Medtronic Neuromodulation. Multivariate and logistic regression analyses. progressively narrower bipolar configurations can reduce the volume of tissue activation. including Receiver-Operator-Characteristics-Curve analyses. Specific Hypothesis Values from these quantitative measures would have been normalized by z-score transformation according to means and variances taken from normal controls in the published literature. . For example. Minneapolis. however. Increased stimulation voltage can also increase the volume of tissue activation. Inc. Problems of efficacy are approached by increasing the volume of tissue activation and electrical current density in the volume of tissue activation. 2000). A regression model. The cm2 is the surface area of the active electrical contacts. The number of microcoulombs is determined from (voltage/impedance) × (pulse-width). Tripolar configurations can further constrain the volume of tissue activation. Problems with side effects would have been approached by constraining the volume of tissue activation. In addition.

This has been documented in patients with DBS of the subgenu cingulum for depression (Lozano et  al. Subjects were asked to guess whether the stimulator was on or off. though the order within the schedule was randomized to ensure five conditions in which there was a transition between on to off and on to remaining on. VA L I DAT I O N O F S I N G L E. The same procedure would have been used in the proposed research. the DBS was pseudorandomly turned off or continued in the on condition. Specific Hypothesis The mean difference scores—effect size. The programmer would have then randomly turned the DBS off or leave it on and would have asked the blinded subject to guess whether the stimulation is on or off. In an unpublished study. Specific Hypothesis It was anticipated that subjects will be operating at chance in guessing whether the DBS stimulation is off or on. preoperative scores (minus postoperative scores)—and the variance of these measures would have been determined. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?201 Specific Hypothesis At least some programming assessment measures will demonstrate a dose– response effect as demonstrated in subject correlation between the outcomes measure and the stimulation parameters that are based on multivariate regression analyses. Every five minutes. Nine of the 10 subjects were at chance levels when deciding whether the stimulator was turned off or left on. The pseudorandom schedule was a fixed schedule. It was . O U TC O M ES M E AS U R E The primary outcome measure is the CAPS.B L I N D I N G PR O C ED U R E Past experience indicates that while patients may know when the DBS is turned on.05.17. 10 subjects with thalamic and subthalamic nucleus DBS for Parkinson’s disease or tremor were all turned to their “on” DBS condition. according to a Fisher exact test with a p < . The unblinded programmer would have turned the DBS on to assess the clinical response. 2008). they do not know when it is turned off. as it will allow for controlling subject bias in reporting subjective symptoms used for titration of DBS. This would have demonstrated that single-blinded procedure can be of use in follow-on large-scale clinical trials. One of the 10 subjects who guessed above chance levels later reported persistent paresthesias when in the on DBS condition.

Adverse Event and Product Problem Monitoring The US Food and Drug Administration (FDA) definitions of adverse events would have been used: Adverse event: Any incident where the use of a medication (drug or biologic. at any dose. and (4) Columbia Suicide Risk screen. (4) history of exposure to TBI (the Ohio State University TBI Identification Method. End of Part A (at such time as a stable response is achieved or after three months. or safety of any medical product. the IRB. (3) Ham-A. (2) Ham-D. Short Form). (9) Traumatic History Screen. (11) CAPS. defects/malfunctions):  Any report regarding the quality. performance. (6) screening for mild/moderate TBI. The Adverse Event and Serious Adverse Events reporting forms from the NINDS Common Data Elements program would have been used (US FDA). (8) Structured Clinical Interview for DSM–IV Diagnosis. whichever comes first): (1) CAPS. . This category is selected when reporting device malfunctions that could lead to a death or serious injury if the malfunction were to recur. rather.. Note: The analyses would not have tested whether DBS produces a statistically significant improvement in the CAPS score (this would require a much larger scale study). Product problem (e. T EST I N G SC H ED U L E Preoperative: (1) demographics—advanced. 1996). (2) socioeconomic status: education and social role—advanced. the IRB definitions and policies would have been followed. or cellular or tissue-based product (HCT/P). (5) behavioral history—advanced. (15) SF-12 Quality of Life measure (Ware et al. tissue. (3) significant medical history—advanced.g.202 2 0 T hings to K now A bout D eep B rain S timulation anticipated that the mean effect size and variance would have permitted sufficient power for a follow-on large-scale study of efficacy in a feasible sample size. The primary outcomes would have been. (7) Combat Exposure Scale.05. including human cell. and the morbidity and mortality conference in the Department of Surgery. (14) Columbia Suicide Risk screen. (10) Life Stressor Checklist. or a medical device (including in vitro diagnostics) is suspected to have resulted in an adverse outcome in a patient. (13) Ham-A. At each quarterly meeting the committee will determine whether the incidence of events or problems exceeds those reported in the literature by the Fisher exact test using a p < . (12) Ham-D. All incidents of adverse effects and product problems would have been reported to the independent safety monitoring committee. In addition. and (16) diagnostic MRI. reasonable estimations of effect size and variance in the primary outcomes measure and estimates to PTSD– DBS specific adverse effects.

and (4) Columbia Suicide Risk screen. D EEP B R A I N ST I M U L AT I O N SYST EM I M PL A N TAT I O N Bilateral DBS systems would have been implanted because studies of DBS for depression and OCD have utilized bilateral stimulation (Burdick et  al. and. as has been increasingly the case with DBS in the treatment of Parkinson’s disease (Walker et al. The methods are well established and will therefore not be reviewed here. Postoperative Lead Localization The lead would have been imaged postimplantation to confirm lead location according to current neurosurgical procedures (this may include postoperative MRI scans or preoperative MRI fused with CT images). 2011). and as a consequence a potentially important therapy may be abandoned prematurely. (3) Ham-A. Minneapolis. 2009). Interim visits: (1) CAPS. MN) would have been used including the Model 3387 DBS lead and the Activa PC Implanted Pulse Generator. 2004). (2) Ham-D. however. Future follow-on studies may examine the efficacy of unilateral DBS. whichever comes first): (1) CAPS. Microelectrode Recordings for Target Localization Microelectrode recordings would have been conducted as previously described (Baker et  al. like its predecessors. End of Part C prior to crossover and at end of crossover: (1) CAPS. The Activa DBS system for Parkinson’s disease (Medtronic Neuromodulation. This system has FDA approval. (2) Ham-D. Implantation of the DBS system would have been performed according to standard surgical procedure for Brodmann Area 25WM (Cg25) DBS implantation. Inc. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?203 End of Part B (following onset of active when stable response achieved or after three months. having conducted many hundreds of DBS surgeries. The investigators have extensive experience in the use of this system. (3) Ham-A. (3) Ham-A. . unilateral DBS may demonstrate sufficient efficacy. The risk attending doing only unilateral DBS initially is that any effect may be too small to detect. In the future. and (4) Columbia Suicide Severity Rating Scale. Patient may have needed to undergo an additional surgery if the lead or leads is or are found not to be in the recommended location. Kennedy et  al.17. (2) Ham-D. Medtronic Neuromodulation has the only FDA-approved commercially available system in the United States. 2009. it has been implanted in many tens of thousands of patients worldwide since its first description of use in 1979 (Dieckmann 1979).. and (4) Columbia Suicide Risk screen.

At any rate.204 2 0 T hings to K now A bout D eep B rain S timulation S A M PL E S IZE EST I M AT I O N A N D J U ST I FI CAT I O N Subjects would have had a prior diagnosis of PTSD independent of their enrollment in the proposed research.05.1). This was based on the mean and standard deviation of the CAPS reported in the literature. Sample-size calculations performed on a mean of 70 on the CAPS having a variance of 13 (as extracted from published trials) and an effect size of 10 points demonstrated that 30 subjects would have been needed in order to have an 80% probability of detecting the difference of 10 points to a p < . such was the primary purpose of the proposed study. The latter would not have been involved in the proposed research. The mean and standard deviations for each sample were then plotted versus sample size (Figure 17. Numeric (computational) simulations were performed to estimate the effects of sample size on reasonable estimates of means and standard deviations. As can be seen. . One hundred samples at each of increasing sample size (2 to 100 in two subject increments) were randomly selected from the population. Mean CAPS Mean 150 100 50 0 0 20 40 60 Sample Size 80 100 80 100 Standard deviation 60 Std 40 20 0 0 20 40 60 Sample Size Figure 17. A sample size of 15 provides a reasonable estimate of the mean and variance of the population and should consequently allow a reasonable estimate of sample size for follow-on large scale studies. the distribution stabilizes at approximately 15 subjects (indicated by the arrow).1  Results of computer simulations calculating mean and standard deviations as a function of sample size. A population of 200 CAPS was created by random number generator according to a mean of 83 and a standard deviation of 17. All subjects would have exhausted all reasonable attempts at pharmacological and behavioral therapies as determined by their treating healthcare professionals.

These .g. the Departments of Neurology and Neurosurgery hold morbidity and mortality conferences to review any untoward events in the context of surgery. 2. A diagnosis of PTSD according to the CAPS and the Structured Interview for DSM–IV Diagnosis. 12. Subject recruitment. Ability to provide informed consent to participate in the research project. Ability to cooperate with the microelectrode recordings. Absences of TBI at the level of concussion or more severe trauma.” criteria 7. the presence of dementia). The research neurologists and psychiatrist would have been seen subjects at frequent intervals. Absence of concomitant medical or psychiatric disorders that significantly alter the benefit to risk ratio (e. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?205 H U M A N S U B J ECTS Recruitment and Informed Consent After having obtained IRB approval and an Investigational Device Exemption from the FDA. neurosurgeons. and psychiatrists not directly involved in the proposed research would have reviewed all subjects. investigators would have recruited subjects to participate in the study. Human Subjects’ Involvement and Characteristics Included would have been the following criteria: 1. With respect to the intraoperative studies. Exhaustion of all reasonable attempts at pharmacological and behavioral therapy as determined by the Safety and Monitoring Committee. The independent safety monitoring committee consisting of neurologists. Nonuse of aspirin or other agents that may inhibit platelet function for at least two weeks. 10. 7. 11. 5.17. (See “Development of Selection Criteria. The principal investigator answers directly to the IRB regarding the safe conduct of the proposed research. Absence of any structural abnormalities on brain MRI that could interfere with the performance of the surgery. 3.) 8. and analysis and storage would have been under the direct supervision of the principal investigator. including data security and sharing. 9.. 4. Nonuse of valproate for at least four weeks. Absence of cardiac pacemakers or defibrillators. data acquisition. Low suicide risk as defined by the Columbia Suicide Severity Rating Scale. Adequacy of Protection from Risks This includes recruitment and informed consent and protections against risks. 6. Absence of a history of depression that could reasonably require electroconvulsive therapy.

indeed. There are many patients who do not benefit from medications or behavioral therapies. provided confidence that DBS of the anterior cingulum may help in PTSD. Telephone numbers to contact staff on a 24-hour basis would have been provided to the subjects. because the very nature of innovative clinical research militates against any demonstration of the same clinical utility as that enjoyed by established DBS applications. and other similarly refractory psychiatric disorders. These patients find little hope or few alternatives to suffering and disability. Proof of that benefit was the purpose of the proposed research. Requiring that the former ensure the same level of certainty as the latter would thus make the former impossible. may benefit. depression. DBS has been proven effective in patients with obsessive-compulsive disorder. One scientific reviewer wrote that “even a few pilot human subject cases would have been useful to assess the likely clinical impact. This experience. the comments themselves recommend a false and. The Columbia Scale for Suicide Risk would have been applied at each visit. in general. Potential Benefits of Research to Subjects and Others The subjects may not have received any direct benefit from participation in the proposed research.206 2 0 T hings to K now A bout D eep B rain S timulation assessments would have included specific indicators of significant psychosocial stress and suicidal ideation or intent. a danger discussed by Fins (2008). impossible course of action. As it stands. a leading ethicist in the field of DBS . Data and Safety Monitoring Plan The independent safety and monitoring committee would have reviewed and approved each prospective surgical candidate and the progress of research not less than three times annually as described previously. The knowledge potentially gained may lead to future clinical trials that may prove the safety and efficacy of DBS for PTSD so that future patients and society. As such. the pilot data in the preliminary study section (DBS in other conditions) address research capabilities but not clinical applicability of DBS to PTSD. or they may have experienced improvement of their symptoms as a result of DBS. Importance of Knowledge To Be Gained PTSD may be severely disabling and may even threaten life. R ES P O N S E TO T H E PR O P O S A L Evidence to support reasonable expectations of clinical utility. combined with considerable scientific evidence. clinical utility is less certain in comparison to DBS’s application to other disorders where clinical utility is better documented.” Though the caution and keenly felt sense of responsibility evidenced by the reviewer’s comments are commendable.

by implication. because the suggested actions would be uninformative and thus not provide any basis to evaluate the proposal.17. Underpowered studies. According to the Bernoulli distribution. Now consider the situation in which the risk of a serious complication is 3% but it happens that one of the three cases has a serious complication that produces the false impression that the complication rate is 33%. The argument is that it is impossible to make an . as well as a type I error. Several experts in PTSD research have argued that pilot studies (and. and this result could lead one to the erroneous conclusion that DBS is only 33% effective. This being so. which one may define as the discovery of a difference where no difference exists. he would only compound the error. Also. The case series likely will be underpowered. The converse is even more striking: What if the actual risk of a serious complication is 10% and is therefore deemed unacceptable? The Bernoulli probability of the first three cases avoiding serious complication is 73%. Yet experience with the IRB has been to the contrary. There is a 19% chance that only one of the three would demonstrate a benefit. the purpose is to determine the appropriate sample size for the design of subsequent clinical trials. one would think an IRB would no doubt have a difficult time sanctioning a small case series that has a high probability of being underpowered. Statistical power and sample size are at issue here. Consider the situation in which a treatment is 70% effective and no reasonable alternatives exist. hence the pejorative connotation. risk committing a type II error. because it will prove statistically and scientifically uninformative and consequently unethical. the salient matter concerns the determination of the number of subjects sufficient for ensuring a reasonable probability (however this is defined) of demonstrating a meaningful effect (however this is defined). the pejorative connotation regarding the lack of demonstrated clinical utility of DBS for PTSD in the comment by the reviewer demonstrates a common misconception in which the absence of data is taken as negative data. there is a 3% chance that all three cases would not show a benefit. If the issue of feasibility is not in doubt. Does this mean that those who sit in judgment should conclude that it is appropriate to continue? Requiring that one perform an initial small case series raises certain ethical concerns. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?207 research. One reads between the lines of these comments to gather the impression that the reviewer who made them understands their inherently paradoxical character. small case series) should not be done (Leon and Davis 2009) if. rather than efficacy or safety. However. As a means of perhaps overcoming this paradox. Assume three cases would have been sufficient to reassure the reviewer described previously. Must the research be abandoned? Calculating the Bernoulli probability. the reviewer suggests that a small case series of some unstated number be obtained first. Were the reviewer to extrapolate from these cases that the treatment was ineffective. any reassurance the reviewer may feel in making this suggestion is false. which one may define as the failure to find a difference where one actually exists. which means that no reasonable statistical and scientific inferences can be drawn and that any data produced would prove useless in terms of assessing the value of a clinical trial. one finds that the chance of one of the three cases having a serious complication is 8%. in terms of statistical power and sample size. apparently investigators are encouraged to forge ahead with a full-fledged clinical trial to demonstrate efficacy and safety.

from anything less than a full-fledged clinical trial. A series of interim analyses based on repetitive assessments of sample size and variance in the primary outcome measures. Alpha inflation increases the risk of a spurious statistical significance. There exists no anatomical. However. Extensive reviews offered in the proposal demonstrate relatively consistent surgical risks regardless of disease or DBS target. Ablative surgery of the proposed target was not associated with . recommends itself as an expedient. which go on until such time as statistically sufficient sample size is reached. and it involves the question. As a full-fledged clinical trial places subjects at risk. The simulations were performed with the recognition that the population they constituted was not exactly the same as the population to be studied in the proposed research.1). The results from the initial 20 subjects could subsequently be used to calculate a reasonable sample size for future studies to demonstrate clinical efficacy. These numerical simulations were achieved by creating a population of subjects using effect sizes and variance in conformity with published studies of nonsurgical treatments. One cannot escape these paradoxes. The implications of underpowering for both a type I and a type II statistical error attend this second paradox every bit as much as they do the first.208 2 0 T hings to K now A bout D eep B rain S timulation accurate estimate of the probability of benefit and risk. physiological. one may only reach reasonable compromise regarding them. faced by proponents of full-fledged clinical trials. Yet such a statement and its connotation belie clinical experience. Thus there is the risk of a type II error. this risks such a conservative p value that there is little chance of demonstrating a statistically significant result. The histogram of the variability of the effects sizes and variances with different sample sizes becomes asymptotic at 15 subjects (Figure 17. A sample size of 20 (with 5 subjects added in case of some subjects not completing the study) would thus arguably represent the minimum from which could be made a reasonable estimate of the effect size and variance for the exact population under consideration. based on effect size and variance. or biochemical reason to suspect the target proposed would be any different in terms of the surgical risk of directing DBS for PTSD. This situation thus represents a paradox. Assessment of Risk Assessment of risk complements concerns and expectations of clinical utility.” though they failed to specify what they meant by use of such fraught terms. Prevention is attempted by increasingly conservative p values. thus leaving one with an unqualified impression of inappropriate risk. A second paradox follows on the heels of the first. Repetitive sampling without replacement of this population was conducted with increasing sample size. most investigators or reviewers (such as the one quoted earlier) would want some assurance as to the positive outcomes. It was in the spirit of attempting to forge such a compromise that the grant proposal submitted included numerical simulations of the effects of sample size on estimates of effect size and variance. Several reviewers referred to DBS as “highly invasive brain surgery. as to how they may calculate beforehand the sample size for the full-fledged studies. Yet such an expedient faces the risk of alpha inflation owing to multiple repeated analyses.

17. Maintaining that DBS is somehow more invasive in PTSD than it is in Parkinson’s disease or Essential tremor leaves unanswered the question as to how exactly one determines that it is so. perhaps contributes to this bias. whether for the same or a different target. particularly if that effect should happen to be adverse. Indeed. Though issues were thoroughly discussed in the grant proposals. If one considers it reasonable to generalize from DBS for other conditions and other targets. the risks are small. the risk of mortality for inpatient administration of chemotherapy is much higher than the risk of DBS (O’Brien et al. DBS in Parkinson’s disease and Essential tremor is thus “less” invasive by virtue of expectations for benefit. 1994) and carries a negative connotation consequent to the unique nature of surgical trials (Fins 2008). Surgical interventions are held in quite a different regard than are medical interventions. they are illusory from the patient’s standpoint. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?209 any greater risks than were other targets. Yet no matter how many degrees of separation there may be. one can draw from DBS-induced risks associated with the treatment of other disorders inferences as to the risk attending stimulation of the PTSD target. The reviewers apparently encountered difficulty in disentangling potential benefits from potential risks—difficulty that caused them to overestimate the latter. medications may be more invasive than DBS. while DBS for PTSD is “more” invasive by virtue of the uncertainty of benefit. however. 2009). The proximity of actor to effect influencing ethical positions is seen in the trolley car dilemma in which a person is standing at the switch of a railway where a trolley car is approaching out of control. If it were to be deemed inappropriate to generalize from DBS for other surgeries to DBS for PTSD. paralysis would result. then one must conclude that DBS for PTSD is no more invasive than is DBS with respect to such accepted indications as Parkinson’s disease and Essential tremor. then. The apparent proximity of cause to effect. One cannot exclude the possibility. From the patient’s perspective. Similarly. Even in the case of Parkinson’s disease. because any reasonable estimate of risk for PTSD DBS would be impossible to establish beforehand. Asch et al. they perhaps were not discussed with sufficient clarity. In view of the close observations the research subjects would be under in this case. It can only be that the invasiveness of DBS is conditional on the expectations of benefit. A trolley car experiences brake failure and goes . DBS for PTSD or any other condition is no more invasive than is chemotherapy in the treatment of certain cancers. One would thus consider it reasonable to generalize from DBS surgery in other targets and conditions to the DBS target for PTSD in assessing surgical risk. however. more degrees of separation obtain between physicians prescribing a medication and the complications that arise from it than between a surgeon and her actions (Fins 2008). that reviewer bias blunted any effect of reasoned argument. DBS produced fewer side effects than did best medical management (Weaver et  al. Yet such uncertainty always attends innovative (nonincremental) clinical trials. The Unique Nature of Surgical Clinical Trials The characterization of DBS for PTSD as highly invasive rests on Omission bias (Ritov and Baron 1990. even in such instances in which the latter are more dangerous. 2006).

The question becomes. an invasive procedure typically of the neck rather than the brain. however. in other words. then. The difference may lie in the fact that. The reviewers would have found no similar equivalence between endarterectomies and DBS. A  sixth individual observes this situation. unlike an endarterectomy.210 2 0 T hings to K now A bout D eep B rain S timulation hurtling down the tracks. However. most would not consider endarterectomy as “highly invasive and a risk for serious brain injury” (anonymous scientific reviewer). she could stop the runaway trolley and save the other five individuals downfield. Throwing the switch seems a less personal act than does shoving the man. Proximity of the actor to the consequence perhaps explains this tendency. however. Should she give that large man the fatal shove? Asked to put themselves in the place of the sixth individual. who wrote:  “My own review of the literature suggests that the psychiatric clinical trial are small and methodologically challenged. Such a rationale would be hard to construct for DBS and PTSD. respondents tend to show greater willingness to throw the switch than shove the man. The sixth individual no longer stands near a switch but on a bridge near a large man who holds a heavy bag. DBS requires that the surgeon operate directly on the brain. Patients undergoing endarterectomy. the posited theories of pathophysiology and DBS mechanisms were wrong (Montgomery 2011). She notices also that she stands near a switch that. a serious brain injury). is whether there exists any ethical distinction between adverse effects accompanying DBS and those accompanying endarterectomy. risk certain neurological complications (not the least of which being stroke. jeopardizing the lives of five individuals standing downfield. Certainly. but the patient undergoing this procedure might disagree.” The importance of a scientific rationale is amply demonstrated in the resurgent interest in DBS for Parkinson’s disease. the proximity of pathophysiological cause and therapeutic effect is operating in the subtext—a mechanistic rationale that links in lockstep a transition from cause to effect. whether the individual near the switch should throw it. Greater proximity between surgical actions and adverse events thus attends DBS. Along the siding downfield. Proximity of Pathophysiological Cause and Therapeutic Effect Although not specifically raised in the formal reviews. the endarterectomy procedure and any possible complications appear qualitatively equivalent to that of DBS. would send the trolley down a siding rather than into the five endangered individuals. This suggests that merely . In selected patients endarterectomy is considered reasonable. What remains unclear. To someone who does not know how the surgery is performed. The example of endarterectomy illustrates this problem of characterizing procedures as highly invasive. in which there did appear to be a direct mechanisms link between DBS mechanisms and Parkinson’s disease pathophysiology (Montgomery 2011). despite the fact that its complication rate is greater than that of DBS (Goldstein et al. A subsequent variation on the trolley car dilemma further complicates the issue. stand two individuals who would be struck by the trolley should the switch be thrown. The sixth individual realizes that were she to shove the man from the bridge and onto the tracks. 1997). Perhaps this rationale informs the reasoning of one reviewer. if thrown. despite the fact that throwing the switch results in double the deaths.

to paraphrase a quote attributed to Albert Einstein (Bell 1951). Rather the question is how clinical scientists and administrators deal with difficult surgical clinical trials.” The reviewer failed to appreciate the unique circumstances of the patient population for which the study was proposed. “the costly and invasive application of DBS may not be as attractive or cost efficient as other means of treatment. which. the cost of providing DBS for patients with PTSD would ultimately prove too high. a priori. e. S U M M A RY Whether DBS could be effective for PTSD or whether such a clinical trial should be undertaken is not the main point of this chapter. . Even clinical situations with extensive level-1 Evidence-Based Medicine support require investigators to exercise judgment (Montgomery and Turkstra 2003). In the interim. Judgment is needed even more in innovative clinical trials and other situations in which level-1 Evidence-Based Medicine does not exist. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?211 having some intuitive sense overcomes the sense of uncertainty (Johnson-Laird 2006). suffering and debilitation will continue unrelieved. improving compliance. This may owe to the fact that those who should be exercising it have received little education or training in how to do it effectively. to render any reasonable judgment. is nothing more than the common prejudice. but there is no telling when such a thing may come along. some rethinking may be in order. Expectations as to prior demonstrations of cost effectiveness and social utility also inform the recommendations made by the reviewers. potentially denying patients relief from severe suffering disability. it is not germane to the clinical trial. They object that. What are the means by which to effect such an education so as to improve evaluate proposals for innovative DBS clinical trials? Can this improvement be realized in a single grant application limited to 15 or 20 pages that is permitted but a single resubmission? One doubts that such an undertaking is possible. because the study would require several years to complete. “If the estimate of the applicable population is very small relative to the heterogeneous population of PTSD. The risk is that Omission bias and unsophistication regarding the statistical necessities of such trials may make it difficult to conduct such studies.17. In my opinion. At the very least. Refractory to alternatives.” one reviewer wrote. particularly those for psychiatric disorders. One is left to common intellectual heritage and experience and perhaps the “common sense” of the scientific community. reasoned judgment is often altogether lacking. One can hold out hope for a less invasive and expensive treatment.. these subjects look forward to few if any “other means of treatment” geared toward “improving compliance” or relieving “comorbid conditions. Clinical investigators and researchers should not worry about questions like: what is a reasonable price to pay for relieving a patient from incapacitating PTSD? There is no way.” Though resolution of these issues would be welcome. treatment of comorbid conditions.g.

Deep brain stimulation for refractory obsessive-compulsive disorder. Machamer JE. Kasai K. Gordon E.363(1511):3787–3800. Dieckmann G. et al. Psychological treatment of post-traumatic stress disorder (PTSD). Kotler M. 2008:75(Suppl. Am J Psychiatry 2004. et al. Outcome 3 to 5 years after moderate to severe traumatic brain injury. New York: McGraw-Hill. Burdick A. Omission bias and pertussis vaccination. autonomic. Goodman WK. Andrew M. Queen and Servant of the Sciences. 1979:85–93. Recognition and treatment of posttraumatic stress disorder. eds.174(10):1005–1009.161(3):515–524. 2004:138–151. Chen G. Harwood JE. Baron J. Alvarez RP. Philos Trans R Soc Lond B Biol Sci. and neuropsychological findings in veterans with traumatic brain injury and/or posttraumatic stress disorder.20(9):1178–1184. Fregni F. 2009. Delgado MR. Cochrane Database Syst Rev. Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind. Cohen H. Front Biosci (Landmark Ed). Powell JM.55(1):401–410. et al. et al. . 2009.55(1):389–400. An exploratory study of neuroimaging. Harwood JE. Neuroimage 2011. Drabant EM. et al. Med Decis Making 1994. Modern Concepts in Psychiatric Surgery. The role of the striatum in aversive learning and aversive prediction errors. Surgical innovation and ethical dilemmas:  precautions and proximity. Utility of the trauma symptom inventory for the assessment of post-traumatic stress symptoms in veterans with a history of psychological trauma and/or brain injury. 286(5):584–588.gov/downloads/AboutFDA/ReportsManuals Forms/Forms/UCM048334. Li J. et al. Microelectrode Recordings in Movement Disorders Surgery. Ramel W. Processing angry and neutral faces in post-traumatic stress disorder:  an event-related potentials study. Hershey JC. Neuroimage 2011. Brenner LA. Bryant RA. Amsterdam: Elsevier. et al. Yamasue H. Schiller D. Fins JJ. Voxel-based diffusion tensor analysis reveals aberrant anterior cingulum integrity in posttraumatic stress disorder due to terrorism. Davidson JR. Bodurka J.212 2 0 T hings to K now A bout D eep B rain S timulation R EFER ENCES Abe O. Cleve Clin J Med. 1951. Bahraini NH. Meyerson BA. Kaplan Z. Target selection using microelectrode recordings.pdf Felmingham KL. neurologic. Boggio PS. Bell ET. et al. Foote KD. Arch Phys Med Rehabil. eds. Mov Disord. 2007. Effect of repetitive TMS and fluoxetine on cognitive function in patients with Parkinson’s disease and concurrent depression. New York: Thieme Medical Press.. Phasic and sustained fear in humans elicits distinct patterns of brain activity. Ladley-O’Brien SE. Mathematics. Brenner LA.146:231–242. Bermpohl F.14(2):118–123.84(10):1449–1457. Ballantine HT.14:1880–1890. et  al. Bisson J. Asch DA. et al. Boulis NM. FDA FDA Form 3500A http://www. 2005. In: Israel Z. and neural responses during threat anticipation vary as a function of threat intensity and neuroticism.14(5):777–780. 2003. Rezai AR.3:CD003388. 6):S7–S12.174(4):347–352. Burchi K. Chronic mediothalamic stimulation for control of phobias. In: Hitchcock ER Jr. 2009. Neuroreport 2003. Kuo JR. et al. Baker KB. Dikmen SS. Mil Med. Psychiatry Research 2006. placebo-controlled study. 2008. JAMA. Experiential. Mil Med.fda.

et al. Giacobbe P. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. et al. Polosan M. . Kay H.2:403–405. Jensen J. Arch Phys Med Rehabil. Chard KM.17. 1999. Mathias JL. et  al. Menon D. Fox AS.32(3):516–543. Proc Natl Acad Sci USA 2010. et al. 1993. J Trauma Stress 2009. et al. J Head Trauma Rehabil. Cinalli FZ. Miotto EC. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. Direct activation of the ventral striatum in anticipation of aversive stimuli. De Salles AA. Jaafari N. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. 2010. Arch Phys Med Rehabil. Mallet L. et al. Johnson-Laird PN. Horner MD. Essential Neuromodulation.168(5):502–510. Moore WS. Montgomery EB Jr. Hare TA. In: Arle JE. J Psychiatr Res. Kennedy SH. McIntosh AR.20(8):799–806. Robertson JT. Brain Inj. Herskovits EH. Mayberg HS. Shelton SE. Adams R. J Int Neuropsychol Soc. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?213 Goldstein LB. et al. Rowe JB. Shils JL. 2011:451–463. Common data elements for posttraumatic stress disorder research.107:20582–20586. Enhancing clinical trial design of interventions for posttraumatic stress disorder. 2010.22:603–611. Crawley AP. Giacobbe P. Kalin NH. Harrison-Felix CL.68(6):862–868. Haacke EM. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years.40(6):1251–1257. Nature Neurosci. Complication rates for carotid endarterectomy. 2004. et al.359(20):2121–2134. Kosoyan HP.91(11):1641–1649. Gean AD. 2006. Arq Neuropsiquiatr. Deep Brain Stimulation Programming:  Principles and Practice. Lozano AM. Hutchison WD. N Engl J Med.58(10):796–804. Lozano AM. et al. 2008. Common data elements in radiologic imaging of traumatic brain injury. Neuropsychol Rev. Am J Psychiatry 2011. eds. Kaloupek DG. Erratum in: N Engl J Med. et al. Commentary on neuromodulation perspectives. Davis KD. New York: Oxford University Press. Common data elements for traumatic brain injury: recommendations from the interagency working group on demographics and clinical assessment. Amsterdam: Elsevier. Rizvi SJ. Neural activity associated with monitoring the oscillating threat value of a tarantula. Leon AC. et al. Harrington DE. Yu R. Serrao VT. et al. The bivalent side of the nucleus accumbens. Levita L. et  al.361(10):1027. Definition of mild traumatic brain injury. 2010. J Magn Reson Imaging 2010. Pain-related neurons in the human cingulate cortex. de Boussard C. Neuropsychological and information processing deficits following mild traumatic brain injury. Biol Psychiatry 2008:64:461–467. Davis LL. Montgomery EB Jr. Bigler ED. Edman G.224(2):345–351. New York: Oxford University Press. Is the spatial distribution of brain lesions associated with closed-head injury in children predictive of subsequent development of posttraumatic stress disorder? Radiology 2002.12(1):15–30. Beall JA. Symptoms and disability until 3 months after mild TBI. Mobbs D. 2010. Lundin A. Neuroimage 2009. Neuron 2003. et al. Cognitive deficits in patients with mild to moderate traumatic brain injury. Maas AI. Davatzikos C.8:86–87.10(2):286–297.91(11):1684–1691. Stroke 1997.28:889–890. Hamner MB: Neurocognitive functioning in posttraumatic stress disorder. Biol Psychiatry 2005. Duhaime AC. 2006. Langevin JP. Voss HU. How We Reason. et  al.44(3):1178–1187. et  al. 2002.44(16):1241–1245. Freed MC. 2009. Brain regions associated with the expression and contextual regulation of anxiety in primates. Gerring JP. 2010.

PLoS One 2009. Neurosurgery. Bilateral effects of unilateral subthalamic deep brain stimulation on Parkinson’s disease at 1  year. Arch Phys Med Rehabil. US Food and Drug Administration. Shackman AJ. Sehlmeyer C.17(1):41–46. Guthrie S. Omission and commission in judgment and choice. Program NCDE:  Adverse Event and Serious Adverse Events reporting form. learning. J Psychiatr Res. Welter ML. Stein MB.91(11):1633–1636.4(6):e5865. and neuroimaging characterization of posttraumatic stress disorder in survivors of a severe coalmining disaster in China. Med Care 1996. LaMantia TJ. Montgomery EB Jr. biological. Zwitserlood P.3:263–277. J Med Speech Lang Pathol. 2000. et  al. et al. Neylan TC. Am J Psychiatry 2009.11:ix–xii. Tan QR.15(3):474–478. et al. Jr. 2010.. discussion 309–310. Pain and emotion interactions in subregions of the cingulate gyrus.12(1):125–133. et al.d. 1991. Frank MJ. Robinson OJ. Dissociable responses to punishment in distinct striatal regions during reversal learning. DC:  US Food and Drug Administration. et al. Thurmond VA. Sahakian BJ. Ipser JC. Brailey K. Watts RL. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. et al.12:154–167. and memory in posttraumatic stress disorder. Baron J. Kosinski M. 1991.166(7):768–776. Lenoci M. Mov Disord. . et al. Montgomery EB Jr. Ware J. Schoning S. Nat Rev Neurosci. Exploring the convergence of posttraumatic stress disorder and mild traumatic brain injury. Borthwick A. Early detection of probable idiopathic Parkinson’s disease: I.106: 1039–1061. O’Brien ME.. Wang HH. 2009. Advancing integrated research in psychological health and traumatic brain injury:  common data elements. J Trauma Stress 2004. Baron J. Koller WC. Schupbach M.51(4):1459–1467. Washington. Neuroimage 2010. Vasterling JJ. Seedat S.. The integration of negative affect. McAllister TW. Mov Disord. Zhang ZJ. pain and cognitive control in the cingulate cortex. Nat Neurosci Rev. Development of a diagnostic test battery.27:76–105. Tversky A and Kahneman D: Loss aversion in riskless choice: a reference-dependent model.(1):CD002795. Br J Cancer 2006. n. 2011. 2003. 2000. Minsk E. Attention and memory dysfunction in posttraumatic stress disorder.6(7):533–544. et al. Lyons K. et  al. 2010. Walker HC. Rothlind J. J Behav Decis Making 1990. Constans JI. Vogt BA.. Reluctance to vaccinate: omission bias and ambiguity. Attention. Gleason T. Stein DJ. A  prospective application of a diagnostic test battery. Evidenced based medicine: let’s be reasonable. Keller SD. Slagter HA. Human fear conditioning and extinction in neuroimaging: a systematic review.15(3):467–473.34(3):220–233.44:385–392.95(12):1632–1636. Neuropsychology 1998.65(2):302– 309. Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology 2006. Psychopathological. Q J Econ. J Exp Soc Psychol. Early detection of probable idiopathic Parkinson’s disease:  II. Koller WC. Spranca M. Rigg A.66(12):1811–1816. 2005. Gargiulo M. Ritov I. Pharmacotherapy for post traumatic stress disorder (PTSD).214 2 0 T hings to K now A bout D eep B rain S timulation Montgomery EB Jr. et al. Mortality within 30  days of chemotherapy:  a clinical governance benchmarking issue for oncology patients. et  al. 2006. Cochrane Database Syst Rev. Hicks R. Solomons TV. Turkstra LS.

17.18:321–345. et al. JAMA. . Cereb Cortex. 1998. 2009. Widespread origin of the primate mesofrontal dopamine system. Could DBS Be Effective in the Treatment of Posttraumatic Stress Disorder?215 Weaver FM. Williams SM. Stern M.301(1):63–73. Follett K. Goldman-Rakic PS. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial.

as there was no subsequent need to discover North America. the paradigm is wrong. It solidified the paradigm of pharmacology as physiology:  that physiology and pathophysiology could be inferred from the neurochemistry reflected in the pharmacology (Montgomery 2004). the rational treatment of which involves replacing the dopamine effect. which was correlated with neuronal degeneration of the substantia nigra pars compacta. they are not mediated by dopamine (Hilker et al. Indeed. Benebid and colleagues were credited with the discovery in the same sense that Christopher Columbus was said to have discovered America. as has been said. It is remarkable that DBS has provided considerable evidence against theories of pathophysiology prevalent at the time DBS was discovered by Benebid and colleagues (1987). Suffice it to say at present its long history dates to Galen (130–200 ce) which derived from Aristotle’s physics (Aristotle 2001). Rather. 2003). In a similar manner. Whatever the effects of DBS on Parkinson’s disease. a paradigm shift followed the rational development of levodopa therapy upon demonstration that levodopa reverses catatonia in rodents treated with dopamine antagonists and that Parkinson’s disease is associated with a loss of dopamine. Christopher Columbus was the last man to discover North America [the Viking having preceded him]. (Actually. since the development of levodopa for the treatment of Parkinson’s disease.) The prevailing theory of Parkinson’s disease pathophysiology was that degeneration of the dopamine neurons in the substantia nigra pars compacta set in motion a sequence of events—describable as a series of one-dimensional push–pull . DBS has ushered in another narrative quite distinct from the notion of Parkinson’s disease as a dopamine deficiency. An explanation is beyond the scope of the present. and neurology generally. Unfortunately.18 Deep Brain Stimulation and Insights to Pathophysiology and Physiology W H Y D EEP B R A I N ST I M U L AT I O N I S R EM A R K A B LY EFFECT I V E Deep Brain Stimulation (DBS) is perhaps the most remarkable treatment for movement disorders specifically.

Deep Brain Stimulation and Insights to Pathophysiology and Physiology217 mechanics—that resulted in overactivity of the globus pallidus interna (globus pallidus interna) and subsequent suppression of the thalamus and motor cortex’s power to inhibit movement. globus pallidus interna influences may be more appropriately considered delayed excitation (Montgomery 2006). The second logical error is the Fallacy of Confirming the Consequence. should improve Parkinson’s disease symptoms” and b is “Parkinson’s disease symptoms are improved. T H E I M P O R TA N C E O F T H E PR E VA I L I N G PR ED I S P O S I N G   T H EO R I ES The key point from this discussion is that the preexisting theories of pathophysiology essentially determined the interpretation of the observations regarding mechanisms of action.18. freeing those centers to initiate movement (Montgomery 2012). however. DBS in the vicinity of the globus pallidus interna should worsen rather than improve Parkinson’s disease symptoms. For many neurons. a is “DBS in the vicinity of the globus pallidus interna reduces globus pallidus interna output. then. In this case a is “pallidotomy reduces globus pallidus interna output. The basis for this presumption was that the subthalamic nucleus neurons are overactive and drive the overactivity of the globus pallidus interna. which similarly improved the symptoms of Parkinson’s disease. The interpretation of the therapeutic mechanism of DBS in the vicinity of the globus pallidus interna actually followed on theories of the therapeutic mechanisms of pallidotomy. The first is the Fallacy of Psueudotransitivity. from which it is falsely . The therapeutic effects of DBS were interpreted in light of the prevailing theory. Contrary to prevailing theories dependent on the notion of globus pallidus interna regulation of the thalamus by inhibition. Research conducted in the context of DBS clearly demonstrates that DBS in the vicinity of the globus pallidus interna activates the output of the globus pallidus interna neurons to produce initial inhibition of the thalamic neurons. DBS in the vicinity of the subthalamic nucleus was similarly presumed to inhibit the subthalamic nucleus. initial inhibition was followed by rebound excitation. This extrapolation rests on a number of logical fallacies. In this case. then the false conclusion is that “reduced globus pallidus interna out” is the same as the mechanism of DBS in the vicinity of the globus pallidus interna.” c is “improves Parkinson’s disease. The therapeutic effects were thus attributed to high-frequency stimulation. which caused inhibition of globus pallidus interna neurons and “release” of the thalamus and motor cortex. Considerable evidence suggests that overactivity of the subthalamic nucleus neurons is neither a necessary nor a sufficient condition for Parkinson’s disease (Montgomery 2008). which may be expressed in the following form: If a implies c and b implies c then a implies b. The similarity of clinical benefit was taken as evidence of similar mechanisms. which is of the form if a implies b is true and b is true then a is true. which similar to pallidotomy.” As DBS in the vicinity of the globus pallidus interna does improve Parkinson’s disease symptoms. then b is true.” and b is the mechanism of DBS in the vicinity of the globus pallidus interna. According to the prevailing theory.

Extrapolation is different from interpolation. The latter defines a trend anchored by reference points at the beginning and the end. Yet the theory of globus pallidus interna overactivity in Parkinson’s disease has survived for more than 20  years. In the case of motor control. Humans prefer an intuitively appealing story to no story at all—indeed to the point that they easily overlook contrary evidence (Johnson-Laird 2006). Admittedly. The Henneman Size Principle argued that the orchestration of motor unit behavior owes to the biophysical properties of the lower motor neurons. Any theory whose explanations stop short invites extrapolation from the point at which the considered evidence leaves off before reaching the lower motor neurons. it is unsurprising that prior theorists felt no compunction to extend explanations of pathophysiology to the level of the motor unit. specifically the lower motor neuron in the brainstem and spinal cord that drive the muscles (comprising the motor unit) to produce the abnormal behavior. There must have been something about the theory that allowed it to persist despite the contrary evidence. having proponents to this day. The projection from the evidence is thus unconstrained and admits of a potentially infinite number of possible projections.218 2 0 T hings to K now A bout D eep B rain S timulation concluded that DBS in the vicinity of the globus pallidus interna reduces globus pallidus interna output. thereby relieving the basal ganglia. It is likewise impossible to predict the exact pattern of muscle synergies underlying abnormal movement. It is impossible to infer the exact muscular synergy from observation. . The problem of extrapolation for an incomplete theoretical explanation is also reflected in the so-called Inverse Problem. In the case of the pathophysiology of Parkinson’s disease. there is only a single end that is fixed by evidence. activity in the motor cortex. AVO I D I N G T H E I N T U I T I V E A PPE A L BY I N S I ST I N G O N  A  C O M PL E T E E X PL A N AT I O N The problem with intuitively appealing theories is that they seem reasonable in that their understandability offers some comfort and thus possibly occasions complacency. Its underlying one-dimensional push–pull dynamics have been popular since Aristotle’s notion of contraries (Aristotle 2001). such as degeneration of the dopamine neurons in the substantia nigra pars compacta. In this case. the explanation offered by the theory must extend from the pathoetiological events. were contradicted by numerous observations made virtually since the theory of globus pallidus interna overactivity was described (Montgomery 2007). With extrapolation. Critical and forceful confrontation with all the facts and insistence on a complete understanding offer an antidote. It may well be that the theory of globus pallidus interna overactivity was intuitively appealing. and the basal ganglia. any movement trajectory effected by sequences of joint rotations may be effected by a variety of different muscular synergies. One may infer only the movement trajectory. which directly lead to the early theories regarding the mechanisms of action of DBS in the vicinity of the globus pallidus interna. to the end effector organs. The theory of the mechanisms of action of pallidotomy. the range of possible interpolations are constrained by the anchors at each end.

The question arises as to how many scientific reports contain a theory-differential diagnosis. takes hold of the first.D I F F ER EN T I A L D I AG N O S I S P O S S I B L E The notion of theory-differential diagnosis is analogous to the differential diagnosis physicians and healthcare professionals construct in light of a patient’s constellation of symptoms and signs. And the human mind. Deep Brain Stimulation and Insights to Pathophysiology and Physiology219 as well as the motor cortex. it will be impossible to know the therapeutic mechanisms. which implies the presence of underlying dynamics over different bandwidths. of the responsibility to account for motor unit control. Indeed. that is. There are multiple levels of motor unit orchestration over numerous time scales. EN T ER TA I N I N G T H E W I D EST T H EO RY. and c implies d and b and c are found false and d is true. consistent array of alternative theories. for example. Until there is some complete better theory of the pathophysiology of Parkinson’s disease and similar disorders. A  good clinician will entertain the widest range of diagnostic possibilities reasonable and give each its due consideration. As Tolstoy noted. which is the Fallacy of Confirming the Consequence. leaping to a single diagnosis risks commission the Fallacy of Limited Alternatives. Any theories that do not must be recognized as incomplete. which may be expressed in the following form: “If a. It is not simply a matter of neglecting an actual diagnosis. the .18. Any theory of basal ganglia pathophysiology must therefore account for changes at all levels of motor unit control. At the next level are synergies between agonists and antagonists. then a must be true. An unwise clinician jumps to a conclusion of a single diagnosis and therefore risks misdiagnosis. There now is evidence that the motor unit recruitment order is affected in Parkinson’s disease and normalized by high-frequency DBS (Montgomery 2013). of which each separately may appear as a cause. this can be seen when b and c are removed and one is left with if a implies d is true and d is true then a is true. But the need to seek causes has been put into the soul of man. b. It is now clear that all these levels of motor unit control are affected by Parkinson’s disease (Montgomery 2013). a reasonable. At the lowest level is the order of motor unit recruitment. At the next level is the time course of motor unit activations. Researchers may at most be able to demonstrate those mechanisms that are not therapeutic—by demonstrating a failure of any particular mechanism to correlate with the presence of disease symptoms. without grasping in their countlessness and complexity the conditions of phenomena.” The falsity of b and c has no impact on the truth or falsity of a. and at the final level is control of sets of agonist–antagonists over multiple joints. W H AT I S K N OW N A B O U T D B S M EC H A N I S M S O F   T H ER A PEU T I C ACT I O N? What is known about the therapeutic mechanisms of action? The honest answer is: nothing. However. “The totality of causes of phenomena is inaccessible to the human mind. most comprehensible approximation and says: here is the cause” (Pevear and Volokhonsky 2007).

Now one may demonstrate that even in the face of high correlations. 2. For example. 2009). epiphenomenal to the effect. numerically there will be a correlation. The utility of this approach lies in its being able to disprove necessary or sufficient conditions. condition A is neither necessary nor sufficient. If there is one example out of a multitude where condition A was present without the presence of the effect.220 2 0 T hings to K now A bout D eep B rain S timulation complexity and interconnectedness of the basal ganglia-thalamic-cortical system (and others) commonly means that clear exclusion of any particular mechanism is highly problematic. condition B may be sufficient: The effect will occur if condition B is present. Even attempts to quantify degrees of correlation are highly problematic and often require assumptions unmet in experimental conditions. some other condition is necessary in conjunction with condition A to produce the effect. The condition A may be necessary but it may not be sufficient. Condition A is. In the case of subthalamic nucleus. It does not matter how many times the effect was paired with the presence of condition A. 1986. However. Application of the technique of necessary and sufficient conditions may be implemented by defining some condition A and then identifying or creating circumstances in which condition A is present and others in which it is absent before looking at the presence or absence of the effect. It does not matter how many other times the effect was associated with the presence of condition A. in other words. It is only necessary to demonstrate a single example of the effect in the absence of condition A to demonstrate that condition A is not a necessary condition. if one assumes that one has reference data to determine whether the activity is increased. Yet despite the high correlation. one need only demonstrate a single case in which the effect was present without condition A to demonstrate that condition A is not a sufficient condition. The incidence of condition A with the presence of effect will produce a high correlation. 4-tetrahydropyridine demonstrate unchanged globus pallidus interna and subthalamic nucleus discharge frequencies in the presence of parkinsonism (Montgomery et al. there may be a multitude of occasions where condition A was associated with the effect but only one where there was not association. One may nonetheless assert that condition A is not a sufficient condition. Similarly. 3. testing whether high-frequency neuronal activity of globus pallidus interna and subthalamic nucleus neurons is causal to Parkinson’s disease requires creation or identification of situations in which globus pallidus interna or subthalamic nucleus neurons are increased and situations in which they are found not to be increased in the presence of parkinsonism. . Similarly. Studies in nonhuman primates before and after induction of parkinsonism using the neurotoxin n-methyl-4-phenyl-1. a specific condition A may be necessary for an effect. Condition B may not be necessary. Another approach is captured by the philosophical notion of necessary and sufficient conditions. condition A may be excluded as a necessary condition. meaning that the effect may be present in the absence of condition B. For example. recordings in patients with Parkinson’s disease and patients with epilepsy demonstrated no significant differences in the distribution of discharge frequencies or in the coefficients of variation of the discharge frequencies (Montgomery 2008). the effect is not possible without the presence of the condition A. In other words. It is clear that increased globus pallidus interna or subthalamic nucleus neuronal discharge frequencies are not a necessary condition. Wang et al.

it is necessary to demonstrate the absence of parkinsonism in the presence of increased globus pallidus interna and subthalamic nucleus neuronal activities.18. particularly in the basal ganglia. which accounts for the suppression of neuronal activities within such DBS targets as globus pallidus interna and subthalamic neurons. The presence of increased globus pallidus interna and subthalamic nucleus neuronal activities is clearly not a sufficient condition. it has been learned that the axons themselves (particularly the nodes of Ranvier). The logical conclusion is that in those circumstances associated with increased globus pallidus interna and subthalamic nucleus neuronal activities in the presence of parkinsonism. There may be reduced neuronal action potentials when recording within the DBS structure. then DBS at those frequencies may be tested for their effect on the parkinsonian symptoms. even if they cannot be attributed a causal role. The logical conclusion is that the increased beta oscillations are epiphenomenal. To emphasize the notion of local inhibition as a . One immediate effect of the orthodromic action potentials is the release of neurotransmistters from the presynaptic terminals. Yet increased output from the neurons of that structure continues. DBS activates neurons to produce orthodromically and antidromically conducted action potentials. a significant number of patients experienced parkinsonian symptoms without an increase in beta oscillations. Increased beta oscillations is therefore not a necessary condition. increased beta oscillations is not a sufficient condition (Huang et al. and in those circumstances parkinsonism improved (Montgomery 2006). it actually makes some symptoms better. It has also been learned that DBS activates neuronal elements. Finally. The orthodromically conducted potentials may end locally for local axons or project to downstream structures in terms of efferent axons. the neuronal cell body (soma). it is not possible to state which types of brain responses are the therapeutic mechanisms. In some studies. DBS is associated with local release of GABA. axon terminals having the lowest threshold. and dendrites have higher threshold. then. Because the pathophysiological mechanisms of disorders of the basal ganglia are unknown in most cases. at least not directly. the increased activities were epiphenomenal rather than causal to parkinsonism. If one assumes that beta oscillations may be increased by DBS at the beta frequencies. Deep Brain Stimulation and Insights to Pathophysiology and Physiology221 In order to determine whether increase neuronal activities in globus pallidus interna or subthalamic nucleus is a sufficient condition. The same analysis may be applied to the notion of increased beta (10 Hz to 30 Hz) oscillations in parkinsonism. Much has been learned about brain responses. however. It has been learned that DBS does not inhibit neurons. which typically causes inhibition in the postsynaptic neuron. DBS may be used to drive the globus pallidus interna and subthalamic nucleus neurons at a high rate. Some studies have demonstrated that stimulation in the beta frequencies do not worsen parkinsonism. 2014). Because gamma amino butyric acid (GABA) is the most common neurotransmitter. Interpretation of this suppression of local neurons due to increased release of GABA in the target is problematic. At least for those symptoms. Action potentials may be generated in axons that are in transit. particularly in the form of generating action potentials. because these same neurons that are inhibited may nonetheless continue to generate action potentials in the axons of these same neurons (McIntyre and Grill 1999). Demonstrating that increased beta oscillations in the absence of parkinsonism is more problematic.

222 2 0 T hings to K now A bout D eep B rain S timulation therapeutic mechanism is therefore inappropriate. display postinhibitory rebound excitation. In the case of cortical neurons activated by . Action potentials conducted orthodromically generated by antidromic action potentials that reach the axon collateral may activate neurons innervated by the axon collaterals. particularly in the output of basal ganglia nuclei. The event that is causal is unknown. that is. presumably by depolarizing axons passing to or by the subthalamic nucleus. for example. Local effects may include the effects of the DBS pulse on glial cells and the local microvasculature. It is now clear in a nonhuman primate model and humans that DBS in the vicinity of the subthalamic produces antidromic activation of cortical neurons. These include the effects of neurotransmitters from presynaptic terminals within the electrical field generated by the DBS pulse and the presynaptic terminals of efferent axons from the vicinity of the electrical field—the effects of the globus pallidus interna DBS pulse on the thalamic neurons described previously. which generates postsynaptic effects on neurons that receive inputs from such thalamic neurons as cortical neurons. Action potentials in axons exiting the DBS structure go on to cause changes in neuronal activities in downstream structures. These effects are referred to as first-order effects. However. Because GABA is the most common neurotransmitter. effects on the local neuronal elements. demonstrates a reduction in thalamic action potentials approximately 3 ms after a globus pallidus interna DBS pulse. the possibility of coincident depolarizations—one from the antidromic action potential and others from the usual synaptic inputs to the parent neuron—may represent a source of Hebbian learning and may underlie some of the long-term or plastic changes observed clinically with DBS. because there is a relatively massive discharge in the dendrites by retrograde propagation of the action potential. which for many thalamic neurons results in a net increase in thalamic neuronal activities in response to DBS in the vicinity of the globus pallidus interna (Montgomery 2006). The release GABA onto thalamic neurons in response to globus pallidus interna DBS. particularly axon terminals and axons in the vicinity of the DBS pulse. this is not entirely true: Many neurons. because the output of the structure is the same as if the neuronal activities within the structure were increased. One might think that these effects can be predicted by the neurotransmitter released by the presynaptic terminals of the DBS structure efferent axons terminating in the downstream structure. Axon collaterals are typically local. Second-order effects include the effects of neurotransmitter release from the axons excited by the first-order effect. for example. Also. such as the basal ganglia relay nucleus of the thalamus. This inhibition is followed by a remarkable rebound excitation. produces postinhibitory rebound excitation. Recording in the ventral lateral pars oralis nucleus of the thalamus. These include the orthodromic and antidromic response described previously. the predicted effect is inhibition of downstream structures. Antidromically generated action potentials may propagate backward up the axon to the neurons of origin. The antidromic action potentials may greatly change the excitability of the parent neuron by depolarizing the neuron soma and dendrites. whether locally or outside the DBS target. for example. Antidromically conducted action potentials can reach a branch point with subsequent orthodromic conduction to other neurons. Second-order effects generate third-order effects.

perhaps owing to disruption of synchronization of descending neuronal activities. This statement does not exclude a role of the subthalamic nucleus in speech. plays no role. C L A I M S W I T H O U T VA L I D I T Y Any physiological or behavioral change associated with DBS of a particular structure cannot be attributed to the structure stimulated. Similarly. C L A I M S W I T H O U T STA N D I N G. however. the effects of DBS in the vicinity of the subthalamic nucleus on speech may owe to any number of other effects discussed previously. One cannot state. Again. this is not to say that neuronal inhibition. One cannot infer DBS mechanisms from such neurometabolic imaging as Positron Emission Tomography and functional Magnetic Resonance Imaging. Rather. because they may explain why some symptoms take time to respond. which has a typical latency of several seconds. It says only that such changes are not evidence of inhibition. which depend on the temporal dynamics of the blood oxygen dependent response. The temporal dynamics of the multiordered responses are far too rapid (on the order of milliseconds) to be revealed in the blood oxygen dependent response. there is not solely a monotonic increase or decrease in neuronal activities that remain the same when DBS is started. Indeed. The limitations as to inferences from DBS-related research. the axon collaterals of these neurons excite neighboring cortical neurons. at least in the subthalamic nucleus on one side in response to DBS in the vicinity of the other subthalamic nucleus. Yet this is not the same as saying that the tremor was inhibited. particularly through the release of GABA in response to DBS. engendering complicated interactions between all of these effects and ongoing DBS pulses when delivered continuously for therapy. Many of the effects are also related to antidromic action potentials. This may account for the changes seen once DBS is discontinued—the reduction in globus pallidus interna neuronal activity following excitation by a train of DBS pulses in the vicinity of the subthalamic nucleus. any physiological or behavioral change associated with DBS of a particular structure cannot be attributed to its effects on downstream structures for the same aforementioned reasons. reduction of tremor may be achieved by activation to the corticospinal tract.18. It simply states that the DBS effect cannot be taken as evidence for such a role. One can anticipate fourth and higher orders of effects as the third-order effects percolate and reverberate through the neural networks. for example. For example. Evidence suggests that neurometabolic imaging is relatively insensitive to antidromic effects (Logothetis and Wandell 2004). for example. The component in the complex evolution of response that proves therapeutic is unknown. These late effects may not be trivial. Reduction of a symptom or the appearance of a new deficit with DBS cannot be attributed to inhibition or the inhibition of inhibition. DBS-related activities percolate and reverberate throughout the neural networks over time. There is a complex evolution in the neuronal responses. in addition to those described here. that the effects of DBS in the vicinity of the subthalamic nucleus on speech reflects a specific role of the subthalamic nucleus in speech. Deep Brain Stimulation and Insights to Pathophysiology and Physiology223 antidromic action potentials. include all the limitations associated neurophysiological research .

Watts RL. The epistemology of deep brain stimulation and neuronal pathophysiology. Montgomery EB Jr. 1987. 2001. Logothetis NK.14(2):120–125. Annu Rev Physiol. Huang H. S U M M A RY DBS has presented a remarkable opportunity to study the human brain in a manner previously impossible. New  York:  Modern Library. Deep brain stimulation of the subthalamic nucleus does not increase the striatal dopamine concentration in parkinsonian humans. 2013:258–280. Montgomery EB Jr.66:735–769. The brain responses to DBS are multiple and multifaceted. high-frequency reentrant. McIntyre CC. Appl Neurophysiol. Excitation of central nervous system neurons by nonuniform electric fields. non-linear oscillators embedded in scale-free basal ganglia-thalamic-cortical networks mediating function and deep brain stimulation effects. The ability to power the DBS on and off at will provided remarkable experimental control. 1999.. Montgomery EB Jr. Ghaemi M.117(12):2691–2702. Johnson-Laird PN. 2003. Front Integr Neurosci.. Trevor AJ. Parkinsonism Relat Disord. Alterations in basal ganglia physiology following MPTP in monkeys.29(2):203–206. Castagnoli N. Benabid AL. Biophys J. Nonlinear Studies 2004. Montgomery EB Jr. et al. et al. The Handbook of Parkinson’s Disease. McKeon. 2007. Effects of deep brain stimulation frequency on bradykinesia of Parkinson’s disease. R. Subthalamic nucleus neuronal activity in Parkinson’s disease and epilepsy subjects. Care in designing and interpreting DBS-related experiments is critical. .11:385–421. Montgomery EB Jr.76(2):878–888. et al.13(8):455–465. et al. Mov Disord. 2004. The Basic Works of Aristotle. New York: Oxford University Press. Lyons KE. Montgomery EB Jr.18(1):41–48. Interpreting the BOLD signal. Its therapeutic benefit in Parkinson’s disease is independent of dopamine and thus provides a contrasting perspective in which to study pathophysiology and physiology.224 2 0 T hings to K now A bout D eep B rain S timulation in general. Pollak P. Effects of GPi stimulation on human thalamic neuronal activity. Neurophysiology. Hilker R. Basal ganglia physiology and pathophysiology:  a reappraisal. Delitto A. 2012. Buchholz SR. 2006. How We Reason. Montgomery EB Jr. Grill WM. ed. Dynamically coupled. 2008. Wandell BA. Interpretation of the mechanisms underlying phenomena affected by DBS is thus highly problematic. R EFER ENCES Aristotle. Addressing these issues is beyond the scope of this chapter and have been discussed elsewhere (Montgomery 2012). Parkinsonism Relat Disord. 2006. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Voges J. Clin Neurophysiol. because the potential insights are well worth it. In: Pahwa R. Louveau A. 2014.6:78. eds. Mov Disord. Boca Raton.50(1–6):344–346. FL: CRC Press. Montgomery EB Jr. In: Markey SP.

Baker KB. 828. Neurophysiological changes in the basal ganglia in mild parkinsonism: a study in the non-human primate model of Parkinson’s disease. 1986:679–682. Deep Brain Stimulation and Insights to Pathophysiology and Physiology225 eds. Jensen A. A Neurotoxin Producing a Parkinsonian Syndrome. New York: Vintage Books. 2009 Neuroscience Meeting Planner. Academic Press. Pevear R. Chicago: Society for Neuroscience.9. Program No. Volokhonsky L. 2007. London. et al. Wang Z.18. 2009. Online. War and Peace. .

among others. Yet though DBS is considered standard and accepted therapy for many disorders. and perhaps even moral. a small percentage of eligible patients are actually referred for it. upon having undergone the surgery. it contains no legal opinions or advice. No doubt the vast majority of physicians and healthcare professionals would agree that they are under an ethical. A growing number of clinical research studies have demonstrated effectiveness in depression. and other movement disorders. If one accepts the premise that the mission of those who practice medicine is to relieve suffering. Indeed. matters. she may have difficulty acknowledging that a problem exists. What is worse. albeit regrettable. their referrals often come only after years of unnecessary suffering. Considered in the aggregate. W H Y A R E N OT M O R E PAT I EN TS U N D ER G O I N G T H E PR O C ED U R E? As discussed at various points in other chapters. as morals relate to what is right or wrong.19 Ethical Issues of Deep Brain Stimulation Though this chapter contains references to laws and legal decisions. as well as Obsessive-Compulsive Disorder. If one does not accept that such is the case. patients with DBS commonly wonder. they represent a failure of the healthcare delivery system. Essential tremor. why it took their physician so long to refer them. and Alzheimer’s disease. Legal subjects are discussed for the sole purpose of illuminating ethical concerns. which refers to principles that apply to how people should act. then failure to provide such a moral good as the relief brought by DBS becomes an ethical issue. I F D EEP B R A I N ST I M U L AT I O N I S SO EFFECT I V E. dystonia. Because law regulates relations among citizens. Deep Brain Stimulation (DBS) is remarkably effective and safe for many patients with Parkinson’s disease. Perhaps it is a moral failure as well. epilepsy. such delays may seem small. Considered individually. Every physician and healthcare professional must navigate in their practice the ethical and moral terrain of medicine. it fulfills a function similar to the function fulfilled by ethics. If ethics concerns the manner in which one must conduct oneself in order to accomplish a moral good. then failure to do so is an ethical failure. all physicians and . however. obligation to relieve suffering. For this reason. good or harm.

it is not at all clear how conducive implicit ethics are to the ethical practice of medicine. The same question was given a twist and posed again. They may serve strictly as post hoc rationales rather than deliberate and critical assessments and formulations. As an individual gains language skills and the capacity for conceptual understanding. the development of implicit ethical and moral notions is attended by explanations.19. They were asked whether they believed it was appropriate for a physician to lie to an insurance company if it meant getting necessary care for the patient covered. arterial revascularization (56. they said. Absent context. and they express greater distress when they see that a cookie jar has been broken in order to steal its contents than they do when they see that it has been broken by accident. Children ages 2 and 3 years express distress with ethical or behavioral transgressions regardless of whether their setting is supervised or unsupervised (Kochanska and Aksan 2006). however. Each student was asked to imagine that the patient in question was his or her mother. All students gave the same response: As telling a lie is never good. The question is how well they fulfill their ethical obligations.com/features/slideshow/public/ethical-dilemmas). each of the 30 students in attendance responded to a question put to them the first day of class. intravenous pain medication and . whether explanations actually serve to supplant the implicit developed. however. Also. It is unclear. Whether a physician should lie to an insurance company depends on whether the insurance company was a good or bad one. individuals have certain ethical and moral notions established in their minds. the physician must not lie. By the time they reach the age at which they pursue studies in medical and healthcare professions. The students’ responses stand in contrast to those offered by physicians in one survey.medscape. In one medical ethics course offered to undergraduates at a small liberal arts college. The approaches developed in philosophy can guide or at least illuminate the issues and questions involved in ethical practice. The answers some students gave to the new version of the question changed. These tend to develop implicitly. However. of whom a mere 17% believed “it was acceptable to overstate or falsify a patient’s condition when submitting claim seeking prior authorization” (http:// www. Another survey. perhaps to the point of some body of principles. showed that physicians were willing to use deception in the coronary bypass surgery (57. E T H I CA L PR I N C I PL ES A N D M O R A L T H EO R I ES I N B R I EF Nearly every individual leaves infancy with some ethical and moral notions. Likely informing the students’ initial response was a prima facie ethical truth that it is bad to lie. usually in response to consequences of some act committed by the individual in question. they imitate their mothers in scripted contexts of teaching some precept. the case no doubt invites such a conclusion. It simply is insufficient to allow physicians and healthcare professionals to merely continue with the ad hoc folk ethics gained during childhood.2%). Ethical Issues of Deep Brain Stimulation227 healthcare professionals are ethicists.7%). Critical approaches to ethics has been a subject of scholarly analysis for millennia and are embodied in the formal discipline of philosophy.

Of course. and for physicians spending less time in clinical practice. there was no need to codify them. More senior medical students—namely. Rates were highest for physicians practicing in predominantly managed care markets. and regulating large corporations’ delivery of .1%) vignettes. These include rules against fraternizing with nonallopathic physicians. and emergent psychiatric referral (32. will fail to serve them in the increasing rarified air of current healthcare delivery. and expectations. Their untutored native conceptions. neither the Hippocratic Oath nor the Declaration of Geneva are any help. and other similar incidents put to rest to any conviction that a competent physician’s actions are ethical on their face. Physician ratings of the justifiability of deception varied by perspective and vignette. though they may prove useful in ordinary interactions. For the codification of ethics. The point is that a medical or healthcare professional student does not enter professional school as a blank slate (tabula rasa) upon whom may be inscribed ethical precepts.5%). those who have arrived at the clinical years of medical school and thus face ethical issues of greater contextualization—performed worse than beginning students in measures of ethical sensitivity (Akabayashi et al. (Freeman et al. There was little willingness to use deception for cosmetic rhinoplasty (2. 2004).228 2 0 T hings to K now A bout D eep B rain S timulation nutrition (47. predispositions. The dichotomy between “gut” and “brain” ethics exists within individual physicians. current medical ethics. because sound ethics guide competent physicians’ actions by definition. with the Declaration of Geneva adopted by the General Assembly of the World Medical Association. regulating relationships to government-sponsored health care. If anything. 1999. screening mammography (34. Evidence exists that challenges the notion that adequate contextualization resolves an ethical dilemma by revealing the appropriate solution. Rather they bring with them many presumptions. Indeed. and 1948. the Willow Brook School scandal. p. That this is the case renders the instruction of medical students tremendously difficult.8%). the growing cynicism resulting from the rapid changes in the delivery of health care following the introduction of the Health Maintenance Organization Act of 1973 and the Employee Retirement Income Security Act of 1974 in the United States has served to aggravate the situation. early serious opposition to the development and codification of specific biomedical ethical principles came from those who insisted that. 2263) The difference between the question posed in the first survey and the question posed in the second turns on context:  the second provides it and the first offers none.5%). for clinically severe vignettes. First. restricting rights of pharmacists. emerged with the formulation of the Hippocratic Oath and have remained unchanged in spirit through 1847. It is altogether unclear that postgraduate medical education emphasizes ethics to an extent sufficient to compensate for the relative ineffectiveness of such education in medical school. the Tuskegee Syphilis Study. What did change with subsequent versions of the Codes of Ethics of the American Medical Association are rules for governance of the profession. as they pertain to the physician–patient relationship. This is the case for two reasons. with the advent of the various Codes of Ethics of the American Medical Association. That which is practiced presents an example of an ethics proceeding “from the gut” rather than the brain. Both surveys nonetheless suggest a dichotomy between that which is practiced and that which is preached.

It then follows that there must be some procedure of ethics to strike the appropriate balance. as well as remarkable advances in medical technology that challenged established notions of personhood. Thus the two ethical principles are in conflict. Indeed. along with the balkanization of a formerly collegial loose affiliation of physicians. The term “malfeasance” is taken in its ethical context (Beauchamp and Childress 2013) to mean any case of harm regardless of the intent and is not meant in the legal sense of failure to act in accordance of the standards of practice. initially developed by Thomas Aquinas (Summa Theologica. because it involves the need for a specification typically in the context not relevant or germane to research or direct issues of personhood. . They require. Patient autonomy in the context of biomedical ethics. The second reason for the lack of aid offered by the Hippocratic Oath and the Declaration of Geneva in codifying ethics derives from the first reason. Consequently. but they have certainly changed the field in which these rules play out. specification or context (Beauchamp and Childress 2013). Counterbalancing the malfeasance (harm) of surgery is providing benefit. performing surgery presents a harm. In DBS. may not have changed the rules implicit in the aforementioned ethics. This second reason is that ethical questions cannot be settled in the abstract. at least as they relate to the relationship between a patient and physician or healthcare professional. even revolutionary. and risks inherent in surgery. nonmalfeasance (do not harm). cost. For example. and justice are inherently unworthy. the issue having been deemed by them a fait accompli dating back to Hippocrates. that is the pain. these codes enshrine patient care as the ultimate arbiter of professional conduct. rather. Scholars in ethics have shown little interest in the responsibility physicians and healthcare professionals have to patients. Yet in some contexts they may come into conflict.19. providing or even referring for surgery without assuring adequate postoperative DBS programming could be said to violate the Principle of Double Effect and consequently creating the harm (surgery) as an ends in itself rather than a means to benefit (DBS programming). Few reasonable individuals would argue that the principles of beneficence (do good). The purpose is to simply the discussion so that one does not have a variety of types of malfeasance conditioned on difficult notions of intent. It is unclear whether these codes remain relevant in the current system of healthcare delivery. Interest in biomedical ethics stemmed primarily from many human research scandals. One technique is the Principle of Double Effect. 1274). changes that have occurred in the delivery of health care. for example. clearly a violation of the principle of nonmalfeasance. Productive discussion of these principles thus requires contextualization for the purpose of deconstructing the ethical question in order to understand their dynamics. The ascendency of Health Maintenance Organizations and other systems that restrict access to care. The context surrounding biomedical ethics is different from the context surrounding everyday medicine. Ethical Issues of Deep Brain Stimulation229 health care. autonomy (respect the patient). Applying biomedical ethics to everyday medicine is therefore difficult. the ethical guidelines regarding the ethical relationship between patient and physician and healthcare professional essentially have not changed despite the remarkable. One of the precepts of the Principle of Double Effect is that the harm must not be the end in itself but rather a means to achieve the end of beneficence.

such as being poor with limited insurance options. Nonmalfeasance indicates the obligation physicians and healthcare professionals have to act solely in ways that avoid harming patients or at least mitigate the harm by beneficence as described in the Principle of Double Effect. In the context of everyday medicine. whether current laws or contracts manage or enforce a physician or healthcare professional’s duty to a patient rather than some other interest. 211 [2000]). is unclear. The best action is that which most fully discharges one’s duty. Recent experience has shown that absent any legal or contractual constraints. (4) deontology. libertarianism may lapse into anarchy. such his family’s class status or the specific nature of the condition affecting him. for example. 530 U. not an issue of medical malpractice. (2) libertarianism. and false . and (4) justice. Utilitarianism privileges those actions that promote the greatest good. Ethical principles may nonetheless guide one’s decisions in the DBS context as well. competing interests—deployment of a state-of-the-art weapon system whose financing impoverishes citizens it protects. Egalitarianism holds that desirable or undesirable consequences of human action (individual or collective) must exclude factors beyond the actor’s control. Libertarianism privileges those actions that maximize personal liberty. deontology privileges moral duty over all other duties. Particularly challenging to utilitarianism is any situation in which there arise incommensurable. Four general moral theories are subsumed under the ethical principle of justice: (1) egalitarianism. Herdrich. Finally. undesirable consequences may follow. Beneficence indicates the obligation physicians and healthcare professionals are under to act solely in ways that conduce to the patient’s good. according to Beauchamp and Childress (2013). US Supreme Court decisions make questions of bringing a law suit against an health maintenance organizations on the basis of denial of coverage for medical treatment a contractual issue. (3) nonmalfeasance.230 2 0 T hings to K now A bout D eep B rain S timulation is enshrined as a specific and inalienable right in research ethics. At any rate. This chapter applies four ethical principles borrowed from biomedical ethics: (1) autonomy. Autonomy indicates the respect physicians and healthcare professionals must show for patients. however.S. Even diagnostic tests threaten harm: False negatives may encourage complacency. and consequently not subject to jurisdiction in state courts. (3) utilitarianism. such as shareholder. as would be the case if the result of denial of coverage actually resulted in malpractice (Pegram v. one example of which is a patient’s right with respect to medical decisions. laws reflect the fact that patient autonomy enjoys no such status. A physician or healthcare professional is simply obliged to act in beneficent and nonmalfeasant ways. Should libertarianism become hegemonic. Whether a patient becomes a recipient of a physician or healthcare professional’s beneficence or nonmalfeasance should not depend on lottery. (2) beneficence. B EN EFI C EN C E V ER S U S N O N M A L FE AS A N C E The balance of beneficence (benefit) versus the risk of harm (violating nonmalfeasance) is central to nearly every decision made in medicine.

A decision cannot go unmade. it is difficult to argue a lack of harmful intent behind the commission of a present harmful act. All but the most jaded physicians and healthcare professional experience a sense of wanting to help and a sense of pride in being able to doing so. Nonmalfeasance must occur in temporal proximity to the beneficence. This condition relates to intention. engenders risk of countertransference. a motivation other than financial must exist. and any indecision already casts a lot: indecision is a choice not to do something.” as the saying goes. To choose a mechanism that has attending it risks of greater harm is to make the incremental greater harm an end. The mechanism to produce the beneficence is the same as the mechanism that risks malfeasance. Ethical Issues of Deep Brain Stimulation231 positives may lead to inappropriate treatment. Even randomized control trials. patients or their surrogates in fact must compare incommensurables when consulting physicians and healthcare professionals. Clearly. they could be separately manipulable. As such. There are a number of corollaries that help to demonstrate an absence of harmful or malfeasant intent. more—remunerative careers. Balancing beneficence and nonmalfeasance is made more difficult by the fact that the language of risk is often different from the language of benefit. implicit or otherwise. Were they separate. Issues related to mammography in relatively young women who face no increased genetic risk. by the choice of mechanism. one must not intend to commit harm (malfeasance). indeed. are powerless in this situation (Montgomery and Turkstra. Consequently. Nonetheless. despite any distant future benefit the act might bring about. and vice versa. a nonmalfeasant mechanism must not admit of a more beneficent alternative. Though proponents of algorithmic medicine may insist otherwise. for example offering DBS lead implantation surgery without assurance of postoperative programming. Neither are physicians and healthcare professionals. One then may act with beneficence without acting with nonmalfeasance. it is the inverse of the Freudian notion of transference. an act must be means to a beneficent end. C O U N T ER T R A N S FER EN C E AS A G U I D E TO PH YS I C I A N A N D H E A LT H CA R E PR O FES S I O N A L ACT I O N S Physicians and healthcare professionals’ emotional investment. a physician or healthcare professional’s self-esteem is also subject to the beneficence or malfeasance inherent in any medical decision. Any direct comparison thus becomes a comparison of incommensurables—“apples and oranges. 2003). the Principle of Double Effect offers guidelines for balancing beneficence with nonmalfeasance. play potential benefit of early detection against the consequence of a false positive. Countertransference occurs when physicians and healthcare professionals impose their emotions on patients. Their doing so may lead to unnecessary biopsies or worse. 1274). To accord with nonmalfeasance.19. for example. which have become synonymous with Evidence-Based Medicine. because individuals in the medical and healthcare professionals always have before them the option of pursuing other equally—or. First described by Thomas Aquinas (Summa Theologica. Finally. patients are not widgets. In other words. in which a patient .

When transference is recognized. according to him. as it is the patient who continues to suffer from lack of treatment by the physician. a patient must also confront possible effects of Omission bias in the person of her physician or healthcare professional. bridging the respective motivations of patient and physician or healthcare provider on one hand. the beneficence and nonmalfeasance for the physician and healthcare professional. In these examples a physician or healthcare professional transfers to a patient his notion of a sound balance of beneficence and nonmalfeasance. for example. In addition to accepting surgical risk. or in a situation in which a physician or healthcare professional refrains—or refuses—to mention the potential use of a treatment believed by him to fail to balance beneficence and nonmalfeasence for a patient’s sake. and healthcare professionals are comforted by the knowledge that they did no harm. informed consent. First. One finds additional examples of countertransference in a situation in which a physician or healthcare professional tells a patient or his surrogate that the patient’s symptoms do not warrant such a therapy as DBS. Doing so requires translation of his notion of a balance between beneficence and nonmalfeasance to notion that. it helps a patient. In the case of medical treatments. thus placing physicians or healthcare professionals at a distance from the . it is important to recognize and manage any potential biases. If such a belief prompts a definite act. A patient placed in this predicament has arguably suffered an injustice. because it may align a patient and a physician or healthcare professional’s respective interests. which suggests the errors of omission are somehow less onerous than errors of commission. countertransference of a desire to help may be tremendously powerful. helps others. “Do no harm” (Primum non nocere). transferring the respective biases of the latter to the former on the other. a patient or her surrogate should hold. surgical therapies differ according to proximity of an actor to an action. An individual motivated by the untimely death of a loved one to become a physician or healthcare professional. blaming a physician or healthcare professional is symptomatic of the patient’s own underlying fears that then can be recognized and treated. though she was unable to help her loved one. Perhaps the most pernicious and widespread bias on the physician side of the medical–surgical divide is expressed in the imperative. countertransference may likewise prove helpful. as well as its derivative. however. as in an equation. The bias of the physician and healthcare professional not to act becomes a burden on the patient. This is the case for two reasons. Omission bias is particularly strong in considerations of surgical therapies. Second. Refraining from action thus becomes the preferable option in situations in which all things are equal or in which some things are indeterminate. Yet just as there is no ready calculus to compare. Consequently. One is left wondering. the chain of events typically extends over a longer time frame and follows an indirect route to the effect. In a sense. there prevails the perception that surgical therapies carry greater risks than do nonsurgical treatments. it may violate the autonomy of the patient in question. whether it is preferable for the individual acting (the physician and healthcare professional) or the individual acted on (the patient). Whether implicit or explicit. as well double-edged. there is none to compare the beneficence and nonmalfeasance that a patient or her surrogate would hold. notwithstanding the fact that the magnitude of complications attending chemotherapy and other medical therapies may be as great or greater.232 2 0 T hings to K now A bout D eep B rain S timulation projects her feelings onto a physician or healthcare professional. Within limits.

stand two unsuspecting bystanders who will be struck and killed if the car is diverted. believing that it would be better to sacrifice two persons to save five. which was introduced in print by philosopher Philippa Foot (1978). which do not follow directly from any actions on the part of the medical physician. The runaway trolley car dilemma. Direct responsibility for one death most readers apparently find more difficult to accept than indirect responsibility for five. which follow directly from a physician’s recommendation. they would sacrifice five lives to spare one. As discussed in ­chapter 17. Whether the mice lived or died depended on the decision of the individual. the price was 10 euros. illustrates this issue of proximity of actor to action. Downfield from it stand five unsuspecting individuals in danger of being struck and killed. In the case of the single individual who must purchase the lives of the mice. are most often immediate. Between the car and the five unsuspecting bystanders is a siding. In the majority of instances. involves the same trolley car bearing down on the same five people. A runaway trolley car barrels down a track. Adverse events consequent of surgery. and all the mice were euthanized. The two individuals were required to negotiate an exchange of euros for the lives of the mice. is more personal and therefore more salient than are the consequences of untreated disease.19. Omission bias also plagues DBS clinical research. the action is direct. who is large enough to stop the car. In the second case. most readers imagining themselves in the situation would throw the switch. but it also involves an extremely large man who wears a heavy backpack and stands on a bridge over the tracks. A variation on the runaway trolley car scenario. which intervenes between the actor and the action. and owe perceptibly to the actor. A reader is invited to imagine that she is standing on the bridge next to the man wearing the backpack. most readers would not push the large man off the bridge. An experiment in which a group of surplus mice were to be euthanized presents another example (Falk and Szech 2013). In another circumstance. In other words. first elaborated by Judith Jarvis Thomson (1985). two individuals decide the fate of the mice. Nearly half the individuals paid it. on the other hand. Ethical Issues of Deep Brain Stimulation233 effects of a medication prescribed by them. Responsibility is therefore diffused and the relationship less direct between actor and the action. The argument advanced here is that one possible reason for the reluctance of medical physicians (as opposed to surgeons) to recommend DBS is related to Omission bias. however. the Institutional Review Board (IRB) did not approve a 20-subject pilot clinical trial of DBS in the vicinity of the anterior cingulum for the treatment of medically and . she does have the strength to push the man with the backpack. Experiment participants were given money with which to purchase mice from euthanasia and allow them to live out their lives. In one circumstance. As Foot reveals. As Thomson reveals. Again a possible explanation for the inability to reach an agreement owes to the proximity of the actor to the action. The adverse consequences of surgery. Timely throwing of a switch will divert the car to a siding. It has been suggested that the dramatic change in response from the first scenario to the second owes to the presence of the switch. though she is too small to stop the runaway trolley by leaping on the track below. they were unable to reach an agreement. On this siding. She is invited to imagine also that. direct. one person was given 20 euros and another person custody of the mice.

presupposes that good may be quantified in such a way as to permit comparison. an approach informed by a deontological commitment to patient sovereignty is unfeasible. which is unwise because it invites abuse. if the results proved favorable. because it allows patients to dictate their care without regard to any effect on others. However. but there would be no hope of a result in which anyone may have confidence. 3 patients or 20. Ultimately the physicians’ and healthcare professionals’ problem. Physicians and healthcare professionals must therefore balance the two. and there is no way that operating on three to five patients would have answered that question. it often is necessary to expose the patient to the risk of adverse effects. Further. notwithstanding the fact that patients with this disorder suffer greatly. Though the IRB was told that a study of three to five patients would be uninterpretable. the arbitrating value system becomes the issue. B EN EFI C EN C E V ER S U S N O N M A L FE AS A N C E A N D   AU TO N O M Y As discussed previously. Yet because the balance that must be struck is between estimations of the value of the benefit and an estimation of the value of the harm. The risk to a patient would be just the same as the risk of each of 1. what good is to be . The reason for the disapproval in the IRB’s recommendation was the request that the surgery be performed on three to five patients and. In the effort to provide relief from disease or some similar good. which deems an action that maximizes benefit and minimizes risk a good. A patient may demand treatment that effectively denies benefit to others. One may take a deontological position and insist that a patient (or a physician) retains the right to determine the values of the potential benefit and harm. permission would be requested to enroll up to 20 subjects.000 patients.234 2 0 T hings to K now A bout D eep B rain S timulation behaviorally refractory Posttraumatic Stress Disorder. An approach informed by a utilitarian commitment. in part. based on the first three to five subjects. it maintained its position. Omission bias has been made the patients’ problem. an opposing approach informed by a deontological commitment to the special status of the physician encourages defaulting to a physician’s judgment. it would be illogical and irrational. to determine what the risk to the individual is. This is unfair. beneficence and nonmalfeasance are often opposed. I believe that Omission bias keeps effective treatment from patients who have no other hope. as the Tuskegee Syphilis Study and the Willow Brook School scandal amply attest. and have no other options. The disapproval had nothing to do with the risks and potential benefits themselves or with the appropriateness of the rationale. The IRB must have surmised that the risk of the research summed over the 20 patients with severe intractable Posttraumatic Stress Disorder exceeded the potential benefit. However. because it draws inordinately on limited resources. The whole point of the research is. and it keeps DBS therapies from advancing further in order to help patients with severe neurological and psychiatric disorders who otherwise have no hope. if the IRB was to make a decision on the remaining 15 to 17 subjects in the original estimate of 20 patients. The initial three to five patients would thus face risks of DBS surgery. for example. each face the same individual risk. Yet. face increased suicide risk. By the same token.

then all must be denied DBS. If physicians and healthcare professionals were made surrogates of the insurance company. In other words. prognosis. and cost. DBS comes at a price. Ethical Issues of Deep Brain Stimulation235 maximized—that of the patient or those who have a competing interest such as paying for the care? Such a utilitarian approach in providing Medicaid in Oregon was attempted. then all must be.19. whether in a direct way as a caregiver or an indirect way as an insurance underwriter or a provider of services to the disabled. their personal liberty is not at risk. the system failed to gain the necessary support from the US Federal government. Ultimately. as members of the same insurance plan. their opinions would hold more sway. as taxpayers. those funded received care. Admittedly. Their opinion holds no more sway than the opinion of any insurance plan member or taxpayer. and was abandoned. in other words. Insurance companies could jeopardize the liberty of the physicians and healthcare professionals. and however far down the priority list the money went. Yet in another respect it demands that the individual surrender a degree of liberty. physicians and healthcare professionals are not afforded any privileged position. Yet throughout medicine’s long history. An approach informed by an egalitarian commitment. they may object on the basis of malfeasance—that is unreasonable expenditure of resources. DBS delivers relief. a physician or healthcare professional’s moral stance may be excluded only for purpose of academic discussion. If one person is to be denied a treatment such as DBS. Even in this case. An approach informed by a libertarian commitment treats maximization of individual liberty as the paramount concern. perhaps from fear that it was contrary to the American with Disabilities Act. diseases were ranked on a number of utilitarian criteria such as age. The libertarian approach necessitates a contractual obligation that does not necessarily turn on the physician’s or healthcare professional’s moral stance. . Because physicians or healthcare professionals pay neither the costs of the treatment nor any later expenses. providing the treatment admits of little downside. but it also reaches those who care for a patient. preference for a libertarian commitment over a deontological brackets the sense of morals on the part of physicians and healthcare professionals. considerable deference has been paid to patients or their surrogates. which forces them to bear the cost of treatment. In that case. If one is allowed DBS. underwrite the patient’s insurance or. The benefit clearly reaches a patient. then from a physician or healthcare professional’s perspective. If a patient paid the total cost of the treatment as well as any later foreseen or unforeseen expenses directly or indirectly. does not fit the issue because it holds that a chosen formula must apply without discrimination to everyone. in the real world it remains a significant factor in diagnoses and decisions. by imposing on them capitated care. meanwhile. such the class into which they are borne or the diseases that befall them. If physicians and healthcare professionals were to not only treat a patient but also. subsidize the patient’s treatment. In this case the benefit is the liberty that comes with relief from a disability. the care afforded patients should not depend on luck. A fixed sum of funds were applied. and meeting that price requires money that may have been otherwise devoted to other purposes. and in doing so increases in one respect the liberty of the individual relieved. that is. Of course. having the freedom to spend funds on something of desire rather than of necessity like treatment.

Autonomy for medical care means treating a patient as the end (or goal) of efforts. Autonomy does not solely concern the issue of whether patients or their surrogates should decide a medical issue. Respect is important even in situations in which choice is not an issue. The practical point of this discussion is that physicians and healthcare professionals cannot know a potential benefit’s value. Showing respect for a patient helps to disentangle a patient’s interests from the interest of a physician or healthcare professional. Is a physician obliged to inform patients about the possibility of DBS? If such an obligation exists and a physician fails to live up to it. Autonomy does not necessarily mean that every patient who wants DBS has a right to receive it. “Why did my physician wait so long to recommend DBS?” Some patients resort to referring themselves in order to gain access to DBS. it also involves respect for patients—respect that extends beyond their right to choice. Patients in Great Britain had a right to veto a physician’s . It places the patient at the center of intentions. Any attempt to a physician or healthcare professional’s valuation for a patient’s instances the “hard” paternalism described by Beauchamp and Childress (2013) and is unethical. Congress alone may do so. would appear to be one of veto power rather than legislative. the President of the United States cannot pass laws. which in turn implies an obligation on the part of physicians and healthcare professionals to address the issues valued by the patient or surrogate. it implies a respect for patients. only patients can know to the first approximation. Autonomy is not simply about a patient’s right to decide acceptable treatments. Likewise.236 2 0 T hings to K now A bout D eep B rain S timulation To do so would be to place physicians and healthcare professionals at a conflict of interest with their patients that. a patient has the right to refuse a treatment recommended by a physician but may lack a right to treatments not recommended by a physician. physicians and healthcare professionals cannot evaluate the risks that patients or their surrogates are willing to face against the benefit’s value. on the evaluations of the patient’s insurance underwriters. Rather. Such respect protects both patient and physician or healthcare professional from the possible ill effects of countertransference. This right. The task of placing value on benefits and risks falls to a patient or her surrogate and. Physicians and healthcare professionals are in a position to know and communicate possible benefits and risks but are in no position to place a value on them. however. is that physician acting unethically? These questions admit of no clear answers. Central to this question is the notion of autonomy. For example. The president may sign (enact) or veto the laws passed by Congress. AU TO N O M Y A N D I N FO R M ED C O N S EN T Patients who successfully underwent DBS frequently ask. would outrage any patient or patient surrogate. Autonomy as it relates to a patient’s rights to refuse treatment are clear and well established by case law. These situations raise the question about the ethics of failing to inform patients as to the potential for DBS. Similarly. contractually. were it to become known.

or autonomy. Patients. which requires that prospective subjects are informed about all reasonable alternatives. Laws to this effect presume that a physician is the final arbiter of medically indicated or warranted treatments (Coggon 2007). Rather. such as the Tuskegee Syphilis Study. Informed consent in the clinic seems to have escaped. A physician and healthcare professional thus have rights analogous to those enjoyed by Congress. for example— and may therefore conceal them from patients by failing to mention them. However. It does not appear that there is any material difference with respect to beneficence. such as Parkinson’s disease. It is not so clear in other countries. This situation was true in research as well as in the clinic. It was the scandals involving medical research. physicians and healthcare professionals are under no obligation to offer treatments they are not inclined to offer. if provided to a patient would lead him to refuse to participate in the research establishes the standard for what is reasonable. an act that exposes the guilty physician or healthcare professional to legal action. If it were research. meanwhile. The difference is the apparent obligation to informed consent that necessitated disclosure of all alternatives that would be material to a reasonable patient in the context of research rather than the clinic is historical. Assuming in a particular context. It is likely that the relationship of physician and healthcare professional was “soft” paternalism (Beauchamp and Childress 2013)  where physicians and healthcare professionals determined themselves what were reasonable alternatives (see previous discussion of countertransference). The question is whether there is any a different set of ethics that apply in the research situation that does not apply in the clinic. physicians did not offer patients antibiotic treatment. function as chief executives. that resulted in the presidential commission that established the rules for informed consent. one expects that a physician or healthcare professional tasked with enrolling subjects in a clinical trial of a medication for a disorder that is treatable by DBS. the physician would have a legal obligation to mention DBS. and to treat a subject in such a circumstance would be to commit battery. avoid harm. One sees readily how a physician and healthcare professional may abuse such discretionary power. could be chosen by that patient. the situation is clinical and not research. she effectively denies patients their right to those treatments. The necessity to explicitly stipulate the nature of informed consent and taking that out of the hands of physicians and healthcare professionals in the context of research was necessary to prevent the potential for self-interest on the part . it is not clear that it is typical for physicians to have the same obligation in the clinic. The situation is different in research. if presented to a reasonable patient. In the Tuskegee Syphilis Study. In this case. reserving unto themselves veto power. and respect the patient regardless of whether the relationship involves research or clinical care. To fail to do so would be to invalidate a patient’s informed consent. However. Just as the Congress is under no obligation to pass laws the president would like to see enacted.19. Ethical Issues of Deep Brain Stimulation237 recommendations but no right to request or expect that a physician recommend specific treatments. would be required to inform the subject that DBS may be an alternative to participation. In doing so. DBS is an option that. A  physician and healthcare professional may have moral objections to certain treatments—birth control or abortion. Neither physicians nor healthcare professionals are empowered to determine what is reasonable. nonmalfeasance. information that. The presumption is that the physician and healthcare professional have the obligation to do good.

The patient brought a lawsuit against the insurance plan claiming that the insurance plan created an inappropriate inducement for the physician to withhold the ultrasound. Thus it is clear that many (if not most) physicians and healthcare professionals have conflicts of interest little different from those of the researcher. a physician refused to perform an abdominal ultrasound on a patient with abdominal pain that subsequently became a ruptured appendix. One finds perhaps the most visible instantiation of patient autonomy in the legal process of obtaining informed consent. The physician was in a group practice that was rewarded physicians for minimizing care. he would elect not to proceed with a proposed treatment. As a means of mitigating a charge of battery. 211 [2000]). if a reasonable patient knew of them.S. A charge of battery most likely does not apply because no bodily transgression had occurred. For the researcher. Interestingly.238 2 0 T hings to K now A bout D eep B rain S timulation of physicians and healthcare professionals to create a conflict of interest. Whether a proposed treatment injures a patient does not matter. Among them is the requirement that a patient or his surrogate be informed of reasonable alternatives. notwithstanding the fact that the patient in question would have been much better off with the treatment the physician or healthcare professional failed to mention. informed consent presents clear and extensive requirements. Clearly. The US Supreme Court held that the insurance company could not be held liable. whether an experimental treatment will help or not is not known at the time of consent. autonomy was as murky a right in 1985 as it is today. One route to autonomy lies through the right to bodily security. there is the potential of research funding and fame. alternatives that. In routine medical care it is presumed that a physician or healthcare professional has no conflict of interest and their recommendations are directed solely to the patient’s benefit. where financial gain may run counter to the patient’s best interests. The reasonable conclusion would be that physicians and healthcare professionals in the clinic should be held to the same standards of informed consent as the research. Touching another person without her permission constitutes battery. Indeed. The issue becomes whether not treating the patient—by refraining from recommending DBS or some other way—may reasonably be considered an act of omission. . namely. The value comes from learning whether the treatment is a benefit or not. In the case of Pegram v. the fact that battery is an act of commission—someone must do something—renders the designation somewhat problematic. as shown by Shultz (1985). such satisfaction is the only action that can counterbalance the harm the patient is exposed to in order to fulfill the Principle of Double Effect. powerful conflicts of interest. it may well be that the research participant will never benefit other than from the satisfaction that may come from contributing to the greater good of all through the increase in knowledge. financial gain or loss based on the physician’s and healthcare professional’s recommendations immediately places the physician and healthcare professional at a conflict of interest. For example. It appears that autonomy is not a right in itself but a derivative of other rights (Shultz 1985). However. which is illegal and unethical. Herdrich (530 U. The belief that physicians or healthcare professionals act in patients’ best interest perhaps explains the British law that grants them wide berth to determine which treatments to offer. a surgeon who operates on a patient unable to give consent commits battery. However. In the modern system of healthcare delivery in the United States.

2d 1087 [R. However. which carries with it an obligation to inform the patient of DBS or another alternative. a patient continues on a treatment that. It indicated that few cases address this issue. In the aforementioned case. the commission also mentioned the 2006 case. In assessing any alleged lapse in upholding standards. The issue of failure to inform in the absence of battery (bodily transgression) falls within the domain of medical malfeasance or malpractice which is different from the notion of malfeasance in the ethical principle of nonmalfeasance. then the recognition that a patient has not achieved the desired improvement obliges a physician to discuss DBS and other alternatives. Riley v. for example. A physician’s discussing DBS or other treatment options with a patient reflects descriptive ethics if it reflects a . does not prompt the necessity to recommend another treatment. that would necessitate a discussion of permission. The commission stated that no federal or state statute directly addresses the duty of a physician or healthcare professional to report an incidental finding to patients or their surrogates. If in a context in which there occurs no bodily transgression most physicians and healthcare professionals fail to mention treatments. (900 A. The commission went on to discuss whether failure to report the incidental finding constitutes malpractice. This subjects a physician who fails to inform a patient of alternative treatments to the standards of malpractice law. in which a Rhode Island court found a neurologist who deemed an incidental finding as posing no danger free of any obligation to report it. Ethics that reflect an ideal for behavior other than any behavior exhibited by a majority of individuals are said to be normative. Such at least is my impression. thus raising the question of whether failure to improve eo ipso constitutes a type of finding similar to the incidental finding discussed earlier. similar situation may illuminate the issue.I. then failing to mention these treatments does not amount to malpractice. Constituting an exception is a case in which a patient experiences failure of a medication she had long been taking. If her physician recommends no new or altered treatment. Stone. because it remains unchanged. findings and codes of conduct governing professional organizations and societies. then the issue of informed consent may not arise. If one assumes that the analogy is appropriate. because failing to do so would represent bodily transgression. courts usually look to experts. and it found malfeasance in reports of incidental findings that would have prevented harm or altered the course of future disease. 2006]). such as DBS. The Presidential Commission for the Study of Bioethical Issues (2013) reviewed the issues associated with incidental findings that resulted from various tests and procedures—a benign meningioma appearing on a CT scan. with “malpractice” defined as a departure from the standards of practice expected of similar physicians and healthcare professionals under similar circumstances.19. who admittedly is not an attorney and wishes to avoid being understood as rendering legal opinions. A second. D ESC R I P T I V E V ER S U S N O R M AT I V E E T H I C S Ethics that reflect the behavior of a majority of individuals are said to be descriptive. Ethical Issues of Deep Brain Stimulation239 One may argue that an institution must require full disclosure of alternatives prior to use of a medication or any other treatment recommendation.

Some studies have demonstrated that prospective payment based on diagnosis have not altered the quality of health. then the average length of stay approximates the median: half of the patients required shorter than average length of stays and half required longer than average length of stays. then a reasonable inference. it pressures a physician to discharge a patient before the length of stay is reached. however. descriptive ethics would hold that failing to present DBS as a treatment option is entirely ethical. This outcome leads one to wonder further whether length of stays associated with specific DRGs depended on physicians and healthcare professionals’ perceptions of the methods of calculation. patients are typically assigned to a Diagnosis-Related Group (DRG). which rests on descriptive ethics. Descriptive ethics would enshrine the vice as the standard. which is interested in limiting expenditures. If fewer than 50% of all patients involved stay longer than the DRG length of stay. By definition. If one assumes a normal distribution of lengths of stays in the database. a hospital should have as many patients whose stays are longer than a DRG length of stay as it does patients whose stays are shorter. The converse holds true as well. Unfortunately. a society may have a vice that is so common as to be thought a virtue. DRG length of stays were calculated according to the average length of stay divided by the number of cases in the database studied after removing the outliers (Office of Inspector General 2001). A hospital thus receives the same reimbursement regardless of its actual expenses. the physician discharging all or most of her patients prior to the length of stay has a high risk . According to a rational analysis of the length of stays for a specific DRG. and the amount of reimbursement paid to a hospital is based on the average length of stay associated with a specific DRG. Indeed. which would otherwise raise issues of informed consent and battery. render this finding highly suspect. The DRG system appears reasonable from the perspective of the US government. For example. is that many patients have received inappropriate and unnecessary care. The issue of whether to discuss DBS appears to fall within the domain of standard of care. Indeed. Justification for doing so rests on the assumption that losses incurred as a result of any patient’s hospitalization exceeding the DRG length of stay would be compensated by early discharges of other patients belonging to the same DRG group. a DRG length of stay may appear quite different to a clinician than it does to a hospital administrator. then an inordinate number of them received insufficient care. Having become an administrative target for the clinician. If the patients whose stays are shorter are fewer than 50% of all patients involved. statistically speaking. A physician’s discussing DBS or other treatment options with a patient reflects normative ethics if it observes the prohibition against battery. In a context in which most physicians do not discuss DBS. Descriptive ethics and codes of conduct that rest on them can produce perverse consequences. as discussed previously. Medicare significantly altered its reimbursement to hospitals from a fee-for-service arrangement to a prospective payment based on diagnosis. According to their diagnosis. Certain methodological and statistical considerations. the large increase in hospital readmissions following the introduction of prospective payments based on DRGs suggest that the participating patients received suboptimal care.240 2 0 T hings to K now A bout D eep B rain S timulation typical tendency among physicians regardless of whether it happens in a context of initiating a treatment change.

then the issue becomes that of enforcing the obligation. indicates that expectations do not reflect exceptional care. is critical. and healthcare provider systems are concerned. they cannot establish a standard for excellence. A  consensus of actual practice. For example. then. a patient who requires a 9-day stay. a DRG length of stay. Most evidence suggests.19. If the standard of care represents the average practice of physician colleagues. physicians and healthcare professionals practice should be governed by standards of care implicitly derived from reasonable consensus practices of peers. professional and governmental guidelines for practice carry a disclaimer concerning any binding rules and any guarantees of patient outcomes. and their peers who lack adequate time and resources tend to be rated as unexceptional. whose basis lies in database of 5 days and whose range is 1 to 9 days. This tendency is reinforced by insurance companies who limit the number of days approved for hospitalization to the DRG length of stay. . most restrictions relate to acts of commission rather than omission. The practical strength of the guidelines also stems from their use by insurers in reimbursement. which would not be outside the range. E XC EL L EN C E: A M AT T ER O F PER SO N A L C H O I C E Every physician and healthcare professional wishes to provide excellent care. Ethical Issues of Deep Brain Stimulation241 of discharging patients prematurely. Because standards of care are reflective of descriptive ethics. Whether they are obliged to provide it is another matter. Many. however. In the former instance. they dictate best practices and compel physicians and healthcare professionals to engage in them. a distribution of the nature and quality of practice ranges from the exceptional to unexceptional. then it describes the central tendency—the mean or average. for example. As discussed previously. If they are. but stays 5 days presumably faces much more possible harm than does a patient who requires a 6-day stay but stays 5 days. that physicians substantially vary their practice. if not most. A median or mean is meaningless in itself. For example. comes to mean something quite different if the range becomes 4 to 6 days. insurance. Physicians and healthcare professionals with adequate time and resources tend to be rated as exceptional. Rather they reflect the quality of care given by physicians and healthcare professionals whose time and resources are limited. Such standards do not simply reflect consensus practices. Such standards reflect descriptive ethics and therefore fail to establish any obligation to provide excellent care. or should faith be placed solely in physicians’ and healthcare professionals’ good will? As far as law. Yet the fidelity with which they are followed remains unclear. Standards are reflective of normative ethics that must supersede descriptive ethics. If the variability in practice was slight. rather. variance or distribution of data. Should there be any means of enforcement in place. Professional organizations have long upheld established therapeutic guidelines and algorithms for excellent care. Rather. and likely due to differences other than differences in patients within each practice. the standard of care is easily construed. A physician or healthcare professional who practices exceptional medicine therefore would not be practicing according to the standards of care.

though it also called for further clinical trials. 2011). Evidence-Based Medicine has become synonymous with prospective randomized clinical trials. In addition to supportive clinical studies. 2006). expert opinion and case studies are ignored or seriously devalued. the US Food and Drug Administration has approved DBS for Obsessive-Compulsive Disorder under a Humanitarian Device Exemption. 2005). To wonder why a minority of patients who need and would benefit from DBS are referred for it is to do more than engage in idle speculation. Thus. The potential for Evidence-Based Medicine to establish standards of practice presents an interesting dilemma. The issue of DBS for treating Obsessive-Compulsive disorder is a bit clearer. One of the fundamental aspects of medical malpractice is a departure from professional standards. dystonia (Albanese et  al. and Parkinson’s disease (Pahwa et al. in an environment in which Evidence-Based Medicine is hegemonic. Increased use of professional guidelines have affected their use in court cases. EPI ST EM I C I S S U ES I N D EEP B R A I N ST I M U L AT I O N AC C EP TA N C E The clinical studies documented throughout this book attest to DBS’s remarkable effectiveness. Critics claimed that. and other conditions affecting the cerebellum or its pathways. It may be . because they were neither randomized nor blinded. these studies have had their findings challenged. the issue of actual recommendation remains unclear. have shown that DBS succeeded to provide benefit where all medication alternatives had failed. In the past. Another professional organization held that DBS is an experimental treatment for Tourette’s syndrome (Steeves et al. hypoxia. Thus even appeal to expert testimony in a malpractice case may prove problematic when Evidence-Based Medicine is introduced. Other studies. these standards have been descriptive rather than normative. particularly those that appear lax in light of patient protections or that betray motivations inordinately favorable to the profession. 2009). Contrary to its original description. Rigorous randomized control trials that directly compared best medical therapy to DBS for Parkinson’s disease have demonstrated the superiority of DBS (Weaver et al. One professional organization held DBS to be recommended for the treatment of Tourette’s syndrome. (Muller-Vahl et al. Courts also may refuse to follow guidelines. treat professional guidelines as prima facie evidence of “prudent and diligent medical practice” (Guillod 2010). meanwhile. the findings failed to substantiate DBS’s superiority. 2006). These same critics went on to suggest that the experts could better used medication solely by engaging in a randomized clinical trial. 2012). as well as for hyperkinetic disorders from a wide variety of etiologies. Though many clinical cases have shown DBS benefit for cerebellar outflow tremor for anoxia. Practice guidelines list DBS as an effective treatment for Essential tremor (Zesiewicz et  al. Hubris alone supported them.242 2 0 T hings to K now A bout D eep B rain S timulation The issue thus becomes whether compliance with professional guidelines affect medical liability. Conducted by experts in pharmacological management thereby mitigating the lack of pharmacological optimized control groups. The standard in some cases rests on actions of a “prudent and diligent medical practitioner.” Courts and juries. not of randomized controlled trial design. multiple sclerosis.

Unfortunately. Inc. Ethical Issues of Deep Brain Stimulation243 that. In Beaumont Spine Pain and Sports Medicine Clinic. a referring physician must adhere to the ethical principles of beneficence and nonmalfeasance. It is possible. may or may not be directed at pathoetiologies. then.] would not have died. From the standpoint of pathophysiology (altered physiological mechanisms consequent to a cause). to affect the pathophysiology by intervening at subsequent steps in the pathophysiological process. he would act in a way that is devoid of beneficence. The individual who gave that testimony stated that the referring physician should have known of [the surgeon’s] history through the TBME [Texan Board of Medical Examiners] newsletter. demonstrated replacement of dopamine in the striatum notwithstanding. Pathoetiologies are therefore not synonymous with pathophysiology. Texas’s Ninth District Court of Appeals affirmed expert testimony given in an earlier trial. which must be directed at pathophysiology. stem cells become fetal dopamine cells. Failure to realize this principle may engender undue bias in favor of dopamine-based therapies that may end up harming patients. . v. Whether stem cell transplantation would share the same fate as fetal dopamine cell transplantation is unclear. Loss of dopamine neurons results in a cascade of effects that describes the pathophysiology. Swan. Symptomatic treatments. This conclusion admits of a corollary: Multiple etiologies may result in the same pathophysiological mechanisms. it is not true. in addition to the reasons discussed here. Fetal dopamine cells fail to provide meaningful relief. DBS somehow fails to accord with physicians’ notions of pathophysiology. the published court cases involving malpractice by [the surgeon]. which in turn result in a single clinical syndrome. Yet this is true from the standpoint of pathoetiology (cause of the pathology). Yet were he to refer a patient who is unlikely to gain reasonable expected benefit. [The expert] opined that [the referring physician] breached the standard of care by referring [the patient] to [the surgeon] because [the referring physician] failed to ascertain [the surgeon’s] qualifications. on the other hand.19. DBS does not accomplish this. and that if [the referring physician] had not referred [the patient] to [the surgeon]. [the patient . The fact that Parkinson’s disease is often viewed as a dopamine deficiency. and [the surgeon’s] loss of privileges at two hospitals. information on the TBME website about complaints concerning [the surgeon]. . PH YS I C I A N S’ R ES P O N S I B I L I T Y TO N EU R O S U R G EO N S When referring a patient to a neurosurgeon for DBS. The notion of Parkinson’s disease as a dopamine deficiency derives in part from the recognition that Parkinson’s disease is associated with degeneration of the dopamine neurons of the substantia nigra pars compacta. . Stem cell transplantation to restore dopamine neurons. appears to have captured physicians’ and healthcare professionals’ imaginations. may lead some physicians to think that the only sensible treatments are those that directly restore the dopamine effect. He must also refrain from referring a patient to a surgeon whom a court has deemed incompetent or impaired. for example.

Because a referring physician and a surgeon shared responsibility with respect to malfeasance. see also St. the issue of referral presents problems. One anchored in descriptivist ethics would suffer from the problems discussed previously. for example. . whether considerations of beneficence admit of any idea of sufficiency rather than exceptional. Stealth Detection.and CT-based targeting)—do not provide sufficient accuracy (Nestor et al. no pet. the anterior and posterior commissures (reference points for MRI. a surgeon is wedded to her usual technique. referring to any lesser means the referring physician has failed to provide beneficence. 517 [Tex. ruling that “[t]‌he theory of joint enterprise imputes liability to one who. Yet the court recognized a principle of joint responsibility. Inc. favor one technique over another for specific reasons. L. because scans fail to distinguish. The resulting situation would be untenable. Contrary to the prevailing notion. is so closely connected to the wrongdoer that it justifies the imposition of vicarious liability” (David L. It is therefore quite difficult for surgeons to reach equipoise when participating in trials that may require them to perform a surgery whose technique they believe inferior to their own. They would establish the ways in which a neurosurgeon must perform DBS. A survey in the literature reveals a tremendous variety of methods—everything from recording neuronal activity to using temporarily implanted microelectrodes to identify the optimal target prior to inserting a permanent DBS lead. If. Joseph Hosp.]. she essentially selects the surgical technique. the target is neither the subthalamic nucleus nor the globus pallidus interna. There was.  Smith & Assocs. A proper trial would require that a single physician randomize the patient to one of several different techniques. A  meta-analysis of this sort requires that one identify the proper target and then select navigation methods capable of revealing differences between the target and adjacent untargeted regions (Montgomery 2014). The same holds true for surgeons who provide routine surgical care.3d 513. Wolff. App. the obligation to beneficence involves referring a patient to the greatest surgeon. shared responsibility for violating the principle of nonmalfeasance. because many patients would go unseen and untreated. If. In a sense. Should the shared responsibility for beneficence become open-ended. 878 [Tex. Certain visible markers—for example. The potential of inducting principles from observations of practices in the hope of generating subsequent normative guidelines is thus highly problematic. Yet the ways in which DBS surgeries are performed vary significantly.W. 2002]. v. The paucity of randomized controlled clinical trials of surgical techniques owes to surgeons’ unique situation (Fins 2008). in other words.W. One is unable to use MRI and CT to discover sensorimotor regions from other adjacent brain tissue. One must ask.. When a physician refers a patient to a specific surgeon. it is the sensorimotor region of those nuclei (Montgomery 2014).—Dallas 2010.3d 873. One may engage in a meta-analysis of issues concerning the accurate placement of DBS leads. they may also share a responsibility for beneficence. No easy answer presents itself. v. for example. noting that joint enterprise is a theory of vicarious liability). rather.. Normative ethics alone point a way to an answer. however.244 2 0 T hings to K now A bout D eep B rain S timulation This case’s circumstances were extreme. 94 S. Most surgeons.L. although he did no wrong. 327 S. 2014).P. and there exists no accrediting body to credential surgeons who perform surgical techniques in ways faithful to normative standards.

1999. both those who receive DBS and those who do not. Coggon J. Cleve Clin J Med.13(5):433–444. Science 2013. Weinfurt KP. Childress JR. Surgical innovation and ethical dilemmas:  precautions and proximity. Falk A. Yet these principles may well be informed by nonprofessional past experiences. Szech N. it remains a most pressing one. Oxford: Basil Blackwell. Aksan N.159(19):2263–2270. Albanese A. BMC Med Ethics 2004. and if one assumes that surgery without microelectrode recordings offers a lower probability of benefit and higher risk of adverse effects with DBS. Varied and principled understanding of autonomy in English law. 2006. Morals and markets. J Pers.19. New  York:  Oxford University Press.2007. Principles of Biomedical Ethics. The development of a brief and objective method for evaluating moral sensitivity and reasoning in medical students.340(6133):707–711.15(3):235–255. 2013. et al. et al. Though referring physicians and healthcare professionals may be unaccustomed to this duty. Slingsby BT. Beauchamp TL.72(3):133–136. Health Care Analysis. A duty to behave ethically falls to all individuals charged with caring for patients. discussion 136–137. The Problem of Abortion and the Doctrine of the Double Effect in Virtues and Vices. Ethical Issues of Deep Brain Stimulation245 a surgeon does not perform microelectrode recordings. Rathore SS. . This consideration is best accomplished by way of a systematic deconstruction of the ethical and moral theories undergirding those principles. Fins JJ. but whether she remains free of her conscience is another matter. Eur J Neurol. Freeman VG. The unique circumstances surrounding DBS requires careful consideration of a physician’s and healthcare professional’s presumptive ethics. particularly if one feels obligated to ensure access to all who might benefit. Lying for patients: physician deception of third-party payers. Kai I. S U M M A RY Relatively few good candidates are referred for DBS. 6):S7–S12. The referring physician in question may be free of legal culpability.75(Suppl. This situation raises important ethical questions. Arch Intern Med. ORL J Otorhinolaryngol Relat Spec. A systematic review on the diagnosis and treatment of primary (idiopathic) dystonia and dystonia plus syndromes: report of an EFNS/MDS-ES Task Force.5:E1. 1978.74(6):1587–1617. Foot P. Kochanska G. Guillod O. 2010. Barnes MP. then a physician referring to that surgeon fails to act in a spirit of beneficence and nonmalfeasance. 2006. et  al. Children’s conscience and self-regulation. Most physicians and healthcare professionals observe certain ethical principles in their practice. R EFER ENCES Akabayashi A. 2008. Clinical guidelines and professional liability:  a short comment from the legal side. Bhatia KP.

Gorman D. Coordinate-based lead location does not predict Parkinson’s disease deep brain stimulation outcome. Presidental Commission for the Study of Bioethical Issues. and transcranial magnetic stimulation. Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review):  report of the Quality Standards Subcommittee of the American Academy of Neurology. 2000. et al. Intraoperative Neurophysiological Monitoring for Deep Brain Stimulation:  Principles. . DC: Centers for Medicare & Medicaid Services.9(4):e93524. Canadian guidelines for the evidence-based treatment of tic disorders:  behavioural therapy. Zesiewicz TA. 530 U. Muller-Vahl KR. Factor SA. 2014. Butson CR.66(7):983–995. J Neurosurg. EB. et al. et al. PLoS One 2014. New  York:  Oxford University Press. Thomson JJ. Steeves T. Turkstra LS. Neurology 2006. The trolley problem. Stern M. Nestor KA. Part IV: deep brain stimulation. Argued February 23.95:219–299. Montgomery EB Jr. Practice parameter:  therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology.S. Montgomery Jr.94:1395–1415.120(6):1497–1498.301(1):63–73. Yale Law J.  Herdrich.246 2 0 T hings to K now A bout D eep B rain S timulation Montgomery EB Jr. Anticipate and communicate:  ethical management of incidental and secondary findings in the clinical. J Med Speech Lang Pathol 2003. Pahwa R. Washington. Can J Psychiatry 2012. Pegram v. DC:  US Department of Health & Human Services. Eur Child Adolesc Psychiatry 2011. European clinical guidelines for Tourette syndrome and other tic disorders. 98-1949.20(4):209–217. Louis ED. 2001.11:ix–xii. From informed consent to patient choice: a new protected interest. Cavanna AE. Weaver FM. et  al. Decided June 12. Follett K. deep brain stimulation. Neurology 2005. JAMA. et al. 1985. 2009. Washington. Yale Law J.57(3):144–151. Practice and Cases. Medicare hospital prospective payment system: How DRG rates are calculated and updated. et al. Letter to the editor: deep brain stimulation without microelectrode recording. research. McKinlay BD. Cath DC. Elble R.64(12):2008–2020. Jones JD. 211 (2000) No. Evidenced based medicine: let’s be reasonable. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. 2014. Lyons KE. United States Supreme Court. Office of Inspector General. 2013. 1985. and direct-to-consumer contexts. Shultz MM. 2000.

Currently underway are a variety of clinical trials for the treatment of neurological and psychiatric disorders. Its presence was limited to a single educational course devoted to postoperative programming. A  recent article’s authors surveyed patients who underwent DBS and found that a large number had to fight aggressively to obtain it. as flooding the brain with dopamine. they are neither message nor information. 2013). memory disorders in Alzheimer’s disease (Laxton et al. epilepsy (Lee et al. panel talks. These include depression (Lozano et al. 2010).gov/) reveals that many more conditions are under consideration for DBS. whether by drugs or fetal dopamine cell transplants. the brain processes and conveys information electronically. and anorexia nervosa (Lipsman et al. Likewise. medical. there is nothing inherent in the electrons that would predict a computer. and ethical (see ­chapter 19)—are entrenched and pervasive. 2012). Review of the clinical trials registry at the National Institutes of Health (http:// www. or posters on DBS. This chapter examines some conceptual prejudices that dampen appreciation of DBS as a therapy and hinder development of future DBS therapies. . Neurotransmitters and neuromodulators are analogous to electrons that traverse computer circuitry. does not in itself cure Parkinson’s disease. While a computer cannot function without electrons. One finds evidence for this lack of interest in the fact that the 2014 meeting of the American Academy of Neurology featured no plenary sessions.20 The Future of Deep Brain Stimulation C U R R EN T C L I N I CA L T R I A L S Although Deep Brain Stimulation (DBS) provides remarkable benefit—greater benefit than that provided by best medical therapy in many cases—its future is uncertain because the neurological community appears uninterested in it. As an electrical device. cluster headache (Seijo et al. It will be shown that these prejudices—scientific.clinicaltrials. there is nothing inherent in dopamine that would automatically determine the nature of Parkinson’s disease. Neurotransmitters and neuromodulators are simply the messenger. That anyone would be surprised by what appears to be a large list of potential DBS therapies offers some sense of the challenge confronting DBS. 2012). 2011).

To argue that any given neurotransmitter or neuromodulator is the source of the function or behavior is to commit the logical error of confusing the actor for the action. It would be illogical to say those actions originated with the actor rather than the script. Similarly. that when world experts carefully diagnosed a set of patients as having idiopathic Parkinson’s disease who subsequently evidenced no dopamine depletion in neuroimaging. then one wonders as to what is specific to a location such that the application of dopamine produces a specific effect. Information and misinformation alike are encoded in the patterns of electrical impulses received by neurons that are electronically processed and relayed to the next neurons. most modern computers do require electrons. Indeed. which results in misinformation. Yet a computer’s function does not solely depend on electrons. This statement is analogous to saying that DBS is another means to affect electrons. a new disease was invented on the spot: Symptoms without Evidence of Dopamine Depletion (SWEDDs). Parkinson’s disease is not a dopamine-deficient state. nothing specific to the dopamine molecule leads in one circumstance to schizophrenia (assuming the theory of excess dopamine). Neurological and psychiatric disorders owe no more to relative excess or deficiency of neurotransmitters and neuromodulators than computer failure owes to an excess or deficiency of electrons.248 2 0 T hings to K now A bout D eep B rain S timulation I hold that the vast majority of neurological and psychiatric disorders owe to abnormalities of normal information processing. One may also have the same actor perform many different actions. Nothing specific to the actor determines the actions to any significant extent. The notion of idiopathic Parkinson’s disease as a dopamine-deficient state presents a useful example. So entrenched has it become. Dopamine in all these circumstances retains the exact same molecular structure. One may argue that dopamine’s action and site of application combine to produce a specific effect. the absence of dopamine has become the sine qua non for Parkinson’s disease. Yet their symptoms continued unabated. If one were to accept the premise that dopamine’s action following from its structure and site of application determine the effect. DBS has been said to be another means of affecting neurotransmitters. This naïve notion and others like it will only hamper future development of DBS. in fact. Flooding their circuitry with static electricity will likewise cause them to fail. An actor follows a script that prompts her to certain actions. Depriving them of electrons by powering them off will cause them to fail. given the fact that the specifier does not reside in the dopamine molecule. The specifier cannot be in the individual neurons. because it is doubtful that the neurons have sufficient uniqueness to specify certain behaviors. dopamine imaging of patients who underwent fetal dopamine cells showed repletion of dopamine. and to relief of depression in yet another. This conclusion rests on the fact that repletion of dopamine in the basal ganglia by fetal dopamine cell transplants or other techniques failed to reverse the symptoms of Parkinson’s disease. it does not solve it. Appropriate electrical stimulation of the brain thus ought to affect— and hopefully improve—nearly every disorder of the central nervous system. Indeed. one may replace the actor in question with another yet observe the same actions. Admittedly. Such an argument simply translates the problem. These patients who show no evidence of dopamine depletion after transplant— are they to be denied the diagnosis of idiopathic Parkinson’s disease and instead . to excessive movement in another (such as levodopa induced dyskinesia).

something that escapes properties of dopamine alone causes the symptoms and disabilities of idiopathic Parkinson’s disease. The symptoms of an excess were the opposite of the symptoms associated with deficiency. Prior to the Germ theory. or follow intuitively from. One finds examples of this in attitudes related to approaches to medical treatment that have no obvious connection to. Arikha 2007). The development of the Germ theory. To someone beholden to the pharmacology-asphysiology paradigm. DBS as an electrophysiological treatment will win acceptance only with tremendous difficulty. Remarkable diagnostic skills notwithstanding. and radiology dramatically changed diagnoses (or so it would seem). To return to the previous analogy: dopamine is the actor. phlegm. fire. dynamics of disease were thus oppositional (push–pull) and one-dimensional. Osler practiced many forms of medicine developed early in the first millennium by the physician Galen. The diagnostician considered not only a patient’s symptoms. four humors—blood. and yellow bile—control the body. a pathophysiology. Indeed. histological pathology. the whole world looks like a nail. the season. Understood as excesses or deficiencies. Summer months in swampy areas suggested certain intuitions. Osler deduced his choices for treatment. Sir William Osler perhaps owes his remarkable success as a physician and educator to his diagnostic acumen and the fact that throughout his career he worked as a pathologist and frequently conducted postmortem examinations on his own patients (Bliss 1999). A pathophysiology that posits an excess of a humor dictated therapeutic efforts to reduce that humor by such treatments as bloodletting and cupping. Galen’s conception of pathophysiology of disease rested on metaphysical concepts advanced by Aristotle metaphysics. earth. for example in the pharmacology of the four Galenic humors (Galen 130–200 ce) that determine behavior (physiology. Evidence-Based Medicine (EBM) based on randomized control trials (RCTs) has been touted as critical to efficient and effective medical care. The predisposition to think that it does or should instances the pharmacology-asphysiology paradigm. Yet there has been . which testifies to its power. the origin of which dates to classical antiquity. DBS appears unimpressive. “When all one has is a hammer. Abraham Maslow wrote. and water—and the excess or deficiency of each with respect to the others produces various diseases. Reasoning from Galenic pathophysiology to the individual patient.” The problem of the pharmacology-as-physiology paradigm may be appreciated in light of this observation. These humors Galen patterned after Aristotle’s four elements—air. Within this dominant paradigm. According to Galen. but his lifestyle. the script for Parkinson’s disease is written elsewhere. Dopamine replacement does not recapitulate physiology. histological pathology. and radiology. The Future of Deep Brain Stimulation249 called SWEDDs? Again. The pharmacology-as-physiology paradigm has a long history.20. black bile. diagnosis was primarily intuitive. Pathophysiology continues to have an important place in selecting treatments. and the environment as well. A PPR EC I AT I N G PAT H O PH YS I O LO GY D E T ER M I N ES T R E AT M EN T The practice of medicine has always been a curious mix of intuition and deduction.

Despite considerable contrary evidence. DBS was seen as a form of pallidotomy and thus borrowed from the interest in pallidotomy. That which seems reasonable from a folk notion of pathophysiology clashes with a statistical sense. Most physicians do not profess to be statisticians. The acceptance of DBS for Parkinson’s disease is a case in point. women under 50 years of age forgo mammograms (US Preventative Services Task Force 2009) and that elderly men should forgo having their prostate specific antigen levels studied (US Preventative Services Task Force 2009) have found little purchase with physicians. The resurgence of pallidotomy did not owe to new surgical technologies. the greater the probability of a happy outcome. which holds that excessive neuronal activity in the globus pallidus interna consequent to the loss of dopamine in the basal ganglia is causal to Parkinsonism. Their reluctance appears to result not from any epistemic reservations about EBM. Acceptance of DBS was driven by a resurgence of interest in pallidotomy in the late 1980s. Nothing in the structure of a RCT requires pathophysiological justification or relevance. If an RCT demonstrated statistically significant benefit over placebo to ingesting pulverized kitchen sink. thereby exposing these women to unnecessary procedures with their risks. Equating the mechanisms of pallidotomy with high-frequency stimulation of the globus pallidus interna rests on an error in reasoning known as the Fallacy of Pseudotransitivity. The recommendation for women under age 50 to forego mammograms is based on the fact that there may be many false positives because of the relative low prior probabilities of women with breast cancer under 50  years of age. which enables a transference of the justification from pallidotomy to pallidal DBS.250 2 0 T hings to K now A bout D eep B rain S timulation considerable difficulty in persuading physicians to accept EBM. because EBM is based on RCTs. The Fallacy of Pseudotransitivity may be expressed in the following form: If a implies c and b implies c then a implies b. Nor did it owe to a sudden recognition of the need for pallidotomy. then the logic of EBM demands that pulverized kitchen sink be offered as a therapy. Resurgent interest in pallidotomy likely owes to the advent of the Globus Pallidus Interna Rate theory of pathophysiology. The resulting fallacy is that stroke (a) implies curare (b). specifically Bayes theorem. That EBM fails to resonate with physicians perhaps owes to the fact that theories of pathophysiology are ultimately irrelevant to EBM. In the case of pallidotomy and DBS. the fallacy takes the following form: Pallidal DBS (a) improves Parkinsonism (c) and pallidotomy (b) improves Parkinsonism (c) therefore pallidal DBS (a) implies pallidotomy (b). It has been clear since the early 1970s that long-term successful management with medications was problematic for a great many patients. Disregard for these recommendations makes perfect sense:  The earlier cancer is detected. Yet every physician and healthcare professional is in truth a statistician. the Globus Pallidus Interna Rate theory positing over activity of the globus pallidus interna endures and provided intuitive justification for pallidotomy. The recommendation that unless a genetic or other kind of risk is present. many of the leaders in the resurgence continued to use ventriculography for targeting. . The fallacy becomes clearer in the following analogy: Stroke (a) causes weakness (c) and curare (b) causes weakness (c). Rather. Indeed. Whether they are good or bad statisticians is the question. EBM appears simply to fail to resonate with them. The reasoning is false.

At the next level. nothing justifies the notion. Targeting the globus pallidus interna and subthalamic nucleus “made sense” in view of the Globus Pallidus Interna Rate theory. Most movements may involve multiple rotations of a specific joint and rotations about multiple joints. and carefully rotate the joint to the desired angle (Montgomery 2013). 2011. Admittedly. The pathophysiological notions that neurological and psychiatric disorders are related to various structures’ excessive activity and that high-frequency DBS inhibits this activity figured prominently in the development of DBS of the subgenu cingulum for the treatment of depression resistant to medication and behavioral therapy. The dynamics involved in reaching for a cup offers a useful example. The effects of disease—Parkinson’s disease. One finds a useful example in the situation of Parkinson’s disease. The first direct studies clearly demonstrated that DBS of the globus pallidus interna or the subthalamic nucleus activated action potentials in the efferent neurons (Baker et  al. for example—must likewise be complex. 2014). some sites in the refractory patients showed increased blood flow and some reduced blood flow. there must occur orderly recruitment of motor units of individual muscles. (A motor unit consists of muscle fibers innervated by a single lower motor neuron in the brainstem and spinal cord. Based on the presupposition that high-frequency DBS inhibits. DY N A M I C S Dynamics refers to changes in a state over time. each requiring the first two levels of orchestration and also imposing higher levels of organization. brake. The Future of Deep Brain Stimulation251 Other than fallacious reasoning.) As the force required for rotating joints to produce the desired task is reached. was picked as the target and was successful. 2005). 2002. that high-frequency DBS inhibits excessive neuronal activity. The critical question becomes whether current notions of pathophysiology constrain the range of possible future DBS therapies (Montgomery 2013). Montgomery 2006. it is clear that stimulation in any site within the basal ganglia–thalamic-cortical system improves Parkinsonism (Huang et al. motor units are organized into bursts of activities between the muscles agonistic and antagonistic to the joint rotation in order to accelerate. Walker et al. which demonstrated increased blood flow. much of which amounted to “chasing lesions”: Previously lesioned structures subsequently underwent stimulation. 2012). Whether DBS of those targets associated with decreased blood flow likewise would have improved is unknown. because abnormal multisegmented movements still are possible. The abovementioned dynamics of a normal multisegmented limb movement are very complex. However.20. The complexity of the dynamics is far greater than that suggested by the simple role . the prior precedent of surgical ablations for neurological and psychiatric disorders was a boon to the early development of DBS. the subgenu cingulum. In comparisons to responding patients. Helen Mayberg and colleagues compared Positron Emission Tomography regional blood flow of patients responsive to medication therapy for depression to those of patients who were refractory (Mayberg et al. At the first level of analysis. small motor units are recruited first and larger motor units follow. which inference from a comparison to pallidotomy otherwise supports.

one of contraries. “even things which are not simple but complex follow the same principle. “may be generalized into ‘excess and defect. but the opposite state has not received a name. The ontological status as reciprocal presupposes the nature of the interactions among the ontological entities—interactions that are clearly one-dimensional and antagonistic. What is in tune must come from what is not in tune. but into the corresponding opposite” (Aristotle 2001). fire. the question is whether to ascribe a unique physics or metaphysics to every possible condition along the continuum. Hegel’s . and vice versa. Most observations vary in a continuous manner rather than according to a dichotomous presence or absence. as Aristotle termed it. Arikha argues rather persuasively that many current medical therapies for neurological and psychiatric disorders continue to adhere to the one-dimensional push–pull paradigm of Galen. air. Galen extrapolated Aristotle’s four elements and the one-dimensional dynamics within each element to his humoral theory of disease.W. This theory held that abnormal overactivity of the cholinergic system and underactivity of the dopaminergic system were causal to Parkinsonism. As beautifully discussed by Noga Arikha (2007). A popular current theory holds that overactivity of low beta oscillators (10–20 Hz) are causal to Parkinsonism. Given this. The physical world consists of reciprocally related dichotomized elements.F. It is unrealistic to think that the Globus Pallidus Interna theory or another simple theory of physiology or pathophysiology merits consideration as adequate. What characterizes a body is the position along the single dimension of each element. One place to search is in the physics of Aristotle. which. The relation between the objects dichotomized thusly is reciprocal or.252 2 0 T hings to K now A bout D eep B rain S timulation posited for the globus pallidus interna. which posited overactivity of the globus pallidus interna as causal to Parkinsonism. The fact that it has been considered adequate merely serves to underscore how simplistic the requirements of any theory under current perspectives are where anatomy and pharmacology serve as metaphors for physiology. or to state that all conditions along a continuum is some amalgam of the two conditions that constitute the extremes.’ ” “The same holds true of other things also. the tuned passes into untunedness—and not into any untunedness.” he continued. This theory. Aristotle (2001) wrote. the only readily discernible condition are the extremes. The one-dimensional push–pull dynamics posited by current theories appears reasonable. namely that of acting to permit or prevent movements in a one-dimensional system. In a continuum. posits a push–pull system whose single dimension is the amount of low beta oscillations. in which all bodies were some admixture of a finite set of different atoms. like its predecessors. Closer to the present one finds a second instance of one-dimensional push–pull dynamics paradigm in nineteenth-century German philosopher G. Prior to Globus Pallidus Interna Rate theory. and water. The ancient Greeks also held that all bodies were some admixture of the four elements: earth. One notes that this differs little from the early notion of atomistic theories of the ancient Greeks. Aristotle posited contraries. Evidence of one-dimensional push–pull dynamics is not difficult to discover if one knows where to look. so we fail to notice the fact. which could risk an infinite number of conditions. It is not difficult to understand the motivation behind Aristotle’s positing contraries. because virtually all theories posit one-dimensional push–pull systems (Montgomery 2012). there was the Acetylcholine/ Dopamine Imbalance theory.

003 of a second. which is clearly a positive reaction to a direct and positive cause. even if it results in a number of systems. destruction of pyramidal fibers causing the negative symptom paralysis. . Though the combinatorial mechanisms of Hegel’s dialectics are not as quantitative as they were for the ancient Greeks. . DBS’s mechanisms of action are complex. Illustrative of this point is the fact that 100-pps DBS typically fails to improve the symptoms of Parkinson’s disease. it continues also to sow confusion. According to Hughlings Jackson. The difference in the interstimulus pulse interval between the two is approximately 3 ms or 0. Demonstration of the power of neurology’s notion of positive and negative symptoms may be seen in the opinion of Francis Martin Rouse Walshe. one has to wonder about inferences to physiological mechanisms based on pharmacological observations or any observation . It is as though an individual’s frontal lobe. This requirement continues to hold true for the modern approach to neurological and psychiatric disorders. the contraries require an embodiment. This being the case. makes an intentional value judgment to repress antisocial activities. (quoted in Phillips 1974) For the ancient Greeks. then excessive activity must occur in some other structure previously suppressed by the frontal lobe.] So with beriberi. a famous British neurologist. which has helped to shape current concepts of neurological disorders. The extrapolation of one-dimensional push–pull systems may be observed in the work of John Hughlings Jackson. and consequently unbalances activity of other centers causing positive the symptom spasticity. to recall in this connection a famous axiom of Hughlings Jackson with regard to cerebral disease. D EEP B R A I N ST I M U L AT I O N: A N U N E X PECT ED SE A OF CHANGE Whatever their nature. If the frontal lobes lose their ability to function but the antisocial behavior is regarded as a positive symptom. absence of vitamine cannot be an adequate cause of polyneuritis. then the behavior must represent excessive function elsewhere. DBS mechanisms of action operate on time scales that pharmacological therapies cannot approach. because the frontal lobe has lost its ability to influence social behavior. Paralysis is an example of absence of function. Because Hughlings Jackson’s theory continues to influence current neurological thinking. Hegel argued that all knowledge is a synthesis of thesis and antithesis.20. He said that negative or destructive lesions could not cause positive symptoms. Of beriberi—neuropathy now clearly known to be a deficiency of thiamine—Walshe wrote:  It is not too far-fetched. Seizure and involuntary movement are examples of excessive function. symptoms and signs owe to excess or defect of function. but might allow of their development—in other words two factors were concerned in the production of spastic paralysis. perhaps. whereas 130-pps DBS succeeds. The Future of Deep Brain Stimulation253 dialectics. [. they are nonetheless organized according to a one-dimensional push–pull scheme. If a patient becomes self-centered and heedless of social norms after part of her brain suffers damage. rather than the individual herself.

whereas the thalamus in patients in persistent vegetative states was not. One may test this claim by attempting to explain how these theories explain the complex time course of muscular actions necessary to produce movement. however. Demonstrated spontaneous arousal of patients in minimally conscious states argues for the relative preservation of mechanisms for arousal and attention that might be supported by DBS. The concept of DBS suppression of pathologically overactive regions of the brain. became the proofs of concept for subsequent DBS. None of the major theories proposed since the 1970s—the Acetylcholine/Dopamine Imbalance theory. followed on the research of Dr. Nicholas Schiff and colleagues. neurochemistry. is limited. The dynamics of these theories may at best be described as related solely to steady-state dynamics. One may argue that the concept rested on the now untenable assumption that DBS inhibits excessive activity. The success of surgical ablations for neurological disorders. for example. or the Indirect/Direct/Hyperdirect Imbalance theory. which operate on extremely short dynamical time scales—the millisecond time scale at which therapeutic DBS appears to operate. Schiff and colleagues (2007) demonstrated a proof of this concept. Alternative means to proofs -of-concepts are necessary. Future possible targets for DBS may follow from improved understanding of DBS mechanisms and the mechanisms of physiology and pathophysiology. it is not proof of it. The plausibility of subgenu cingulum DBS followed from the presumption that high-frequency DBS inhibits activity. They also demonstrated that the thalamus of patients in minimally conscious states was intact. the Low-beta Oscillator theory. for example—begin to approach the necessary dynamics. One wonders how inferences about physiology and pathophysiology from pharmacology. Positron Emission Tomography imaging demonstrated that subgenu cingulum of patients who were refractory to current treatment of depression had higher metabolic activity in the subgenu cingulum.254 2 0 T hings to K now A bout D eep B rain S timulation based on dynamics that are far slower. Proofs of clinical efficacy and safety are currently underway. despite the fact that the concepts themselves were ill founded. and anatomy may inform actual physiology and pathophysiology. The . the proof of concept worked even if for the wrong reason. Such a hypothesis clearly would not follow from the notion of DBS’s inhibitory effect. Proofs of concept require a concept to be proven. became the rationale for a proof of concept for the pilot studies of DBS for depression. and how they relate to the physiology and pathophysiology. for example. They actually demonstrated that the arousal of a patient in a minimally conscious state is consistent with the hypothesis. Fortunately. All that remained was to find an overactive region of the brain. for example. the Globus Pallidus Interna Rate theory. FA I LU R E O F I M AG I N AT I O N Any novel DBS therapy must arise out of research—as proofs of concept initially and then as proofs of clinical efficacy and safety. even altered movement observed in movement disorders. who demonstrated that in nonhuman primates the intralaminar nuclei of the thalamus were important to maintaining attention. The range of surgical ablative treatments replaceable by DBS. The remarkable development of the proof of concept that DBS of the intralaminar nuclei of the thalamus for minimally conscious states. for example. such as functional Magnetic Resonance Imaging.

In an attempt to prevent such hegemony. then a is true. which describe a particular progression: established hypotheses persist. Someone with only a hammer would understandably be suspicious and perhaps unfairly critical of the hypothesis advanced by someone to whom the world appears to be a screw. The idea behind Kuhn’s incommensurability echoes the idea behind Maslow’s observation that the whole world appears as a nail to an individual equipped only with a hammer. Politics. The lapse in logic lies in the fact that b may be true for any number of reasons. The best ally of a researcher who attends to logic is another researcher who attempts to prove an alternative hypothesis. this practice has since been abandoned. psychological. A hypothesis may only be disproven. Though many critics may dispute the philosophical underpinnings of Thomas Kuhn’s (1963) The Structure of Scientific Revolutions. no one may dispute the accuracy of the historical observations contained in that text. To suggest that because an experiment’s results are consistent with a hypothesis they prove that hypothesis is to commit an error in reasoning known as the Fallacy of Confirming the Consequence. by the power of incumbency with it hegemony of resources. not only in terms of potential clinical impact but also in terms of possible eventual testable hypotheses and an extended range of DBS therapies. Needless to say. Whether such encouragement is forthcoming becomes the question. The Structure of Scientific Revolutions (Kuhn 1963) was received as more of a political. This fallacy takes the following form: If a implies b is true and b is true. The potential untoward effect due to dominance of one perspective was recognized as early as the Middle Ages by members of many Italian universities. or sociological than a scientific work. psychology. and psychology. T H E I N C O M PL E T EN ES S O F T H E SC I EN T I FI C M E T H O D Introduced by the Englishman Francis Bacon (1561–1626). and sociology do admittedly play roles in decisions as to which theories are protected and advanced. an advocate for a prevailing theory would be made departmental chairman. the Scientific Method observes a particular sequence. Much to its author’s dismay. tested by demonstrating . Every researcher thus should encourage researchers with reasonable alternative hypotheses to pursue them. Though Schiff and colleagues demonstrated that the arousal of a patient in a minimally conscious state is consistent with but not proof of their hypothesis. The Future of Deep Brain Stimulation255 success is nonetheless an important development. but an explanation need not rest solely on them. while an advocate of popular alternative theory would be made vice-chairman. Kuhn’s concept of incommensurability suggests that proponents of one theory often cannot grasp another and.20. it cannot be proven. their finding does not rule out their hypothesis. Many scientists have rejected outright Kuhn’s historical analyses. until some overwhelming intervening crisis forces a change. A hypothesis is generated. the difference between antagonistic perspectives cannot be adjudicated by science alone and naturally opens the way for politics. This offers an important lesson. Any confidence one may have about a hypothesis that is consistent with subsequent demonstration of its predictions thus depends on the degree to which one may be certain that all other reasonable explanations have been excluded. sociology. Confidence that a is true rests solely on the fact that b is be true if and only if a is true. consequently.

pathophysiological mechanisms addressed by DBS. Deduction does not result in any new knowledge. early in DBS. The Scientific Method is deductive in the sense that a hypothesis is used to derive a set of particulars. for example. Designing experiments to succeed. The variable X in this case also stands for reduced globus pallidus interna output. Yet no one designs experiments to fail. These complex systems may also give rise to metastable states and transitions between metastable states. opens the door to the Fallacy of Confirming the Consequence. however. It merely preserves knowledge already contained (or thought to be contained) in the hypothesis. These offer a basis for understanding behavior—the . the risk is that it will be taken as right. because they appear foreign to most scientific discussions. She thus established the following analogy: Curare is to myasthenia as anticholinesterases for curare poisoning are to X for myasthenia gravis. As curare poisoning is alleviated with application of anticholinesterases. Subsequent research demonstrated the hypothesis to be correct. The Scientific Method reveals nothing about hypotheses’ origins. or physiological mechanisms that may be used by DBS. The presumption of truth is applied if the predictions succeeded. One may argue that hypothesis generation often proceeds by metaphor. which are critical to new knowledge. and revised should the predictions fail. If an unreasonable hypothesis is not proven wrong. Analogies derived from pharmacology. Mary Walker. It seems logical to think that scientific advancement depends on an adequate understanding of hypothesis generation. a set of expected observations based on a hypothesis and an exact experimental context. The variable X in this case also stands for anticholinesterases. so might also myasthenia gravis be alleviated with application of anticholinesterases. An analogy must be at least as complex as the phenomenon its hypothesis attempts to explain. Because analogies generate hypotheses. which continues to inform criticisms of alternative explanations. neurochemistry. there appeared the following metaphor:  Pallidotomy improvement in Parkinson’s disease is to pallidal DBS improvement in Parkinson’s disease as reduced globus pallidus output from pallidotomy is to X in pallidal DBS. Antithetical to the one-dimensional push–pull dynamics characteristic of most current theories of basal ganglia physiology and pathophysiology.256 2 0 T hings to K now A bout D eep B rain S timulation its predictions. and anatomy will not advance the understanding of DBS. on the other hand. they generate only hypotheses. that is. When such metaphors are taken as evidence. noted that patients with myasthenia gravis exhibit weakness similar to the weakness exhibited by patients with curare poisoning. Complex Systems theory may provide a sufficiently complex analogy. Yet these concerns are often dismissed as happenstance or a matter for psychologists. The Scientific Method was instrumental in the establishment of the Royal Society in 1660 and the British Association for the Advancement of Science in 1831. Thanks to recent advances in physics and mathematics. understands that the Scientific Method works only when experiments fail. One who understands the Fallacy of Confirming the Consequence. For example. science may be impeded. It is important to note that metaphors do not generate evidence. complex systems often involve highly nonlinear interactions. the presumed mechanism of action. the task becomes that of determining those analogies that will generate hypotheses amenable to advancing the field of DBS.

Of the basal ganglia-thalamic-cortical system. then. A  hypothetical DBS pulse train. it also normalizes the information transmitted to the motor units. Therefore. The radio must select a desired signal from all signals received. Eliminated from this theory is any notion of intention. one changes the information to misinformation—“01000100 01000010 01010010” or “DBR. one may say that the system self-organizes into a series of transitions (bifurcations) that produce normal movement and that.” Simply by changing the 8th. whose antenna picks up of a multitude of radio signals. It is simply to demonstrate how misinformation may be created and corrected. in other words. The Globus Pallidus Interna Rate theory. though motor units receive information. Patients with Parkinson’s disease maintain an ability to move. increases the signal-to-noise ratio. To the degree that DBS normalizes movement. for example. It becomes important. misinformation. The radio’s oscillators interacts (resonates) with a desired radio signal frequency to amplify it above other signals in order to render it audible. A second pulse train. and then back to a system that produces tremor when returning to rest. It accomplishes this by setting an oscillator within the radio to the same frequency as the desired signal. The orchestration relies on information from the central nervous system. Offering a useful example is the varying precise orchestration of motor unit recruitment over multiple muscles and multiple joints.20. A significant advantage to self-organizing dynamics in complex systems is the ability to discard anthropomorphic notions of “intentionality” that characterize current theories of brain function.” Adding the DBS pulse train to the “DBR” pulse train restores the original “ECS” pulse train. the organization is such that symptoms manifest.” contains variation in the order of zeroes and ones and may encode unique information. for example. Originally lost in the noise created by the other radio signals. A LT ER N AT I V E C O N C EP T I O N An alternative to one-dimensional push–pull systems mediated by relative excesses and deficiencies of neurotransmitters or low-beta oscillations is consideration of a disease as misinformation (Montgomery 2013). as a consequence of disease. to consider the ways DBS may improve the information transmitted to motor units to normalize behavior. yet contains no information. In this case. from a state that produces Parkinsonian tremor at rest to a state during action in which the behaviors do not self-organize to produce tremor. The DBS pulse train contains no information. that is.” in Ryle 2002). The radio’s oscillator. for example. contains “00000010000000010000001” (0 is the time between pulses and 1 is the pulse). The theory thus invites a “ghost in the machine” criticism (see “Descartes’ Myth. and 24th bit from a 1 to a 0. The abovementioned mechanism may be explained by way of analogy to an amplitude modulated radio. This is not to suggest that this is how DBS actually works. One may regard DBS as an oscillator (in the radio) that interacts with oscillators in the basal ganglia-thalamic-cortical system . The Future of Deep Brain Stimulation257 transition. holds that the globus pallidus interna intends to halt inappropriate movement and that the frontal lobe intends to suppress antisocial behaviors. it is abnormal. 16th. the information is the ASCII binary code for “ECS. a desired radio signal is amplified by the radio’s oscillator above the noise. “01000101 01000011 01010011.

et al. 2006. 1999. Giacobbe P. William Osler: A Life in Medicine. Clin Neurophysiol. Bliss M. Passions and Tempers: A History of the Humours. 1963.117(12):2691–2702. Lee KJ. Montgomery EB Jr. the DBS signal amplifies the neural signal above the noise created by disease to restore the information contained in the neural signal (Montgomery 2013). Montgomery EB Jr. Subthalamic nucleus deep brain stimulus evoked potentials:  physiological and therapeutic implications. et al. New York: Oxford University Press. . J Neurosurg. Effects of deep brain stimulation frequency on bradykinesia of Parkinson’s disease. Hamani C.45(5):651–660. New  York:  Modern Library. however. Woodside DB. Voon V. 2001. 2014. Neuron 2005.90(6):379–385. Effects of GPi stimulation on human thalamic neuronal activity. Mayberg HS. et al. Stereotact Funct Neurosurg. There appears to be no reason to believe that virtually any neurological and psychiatric disorder will fail to improve with DBS. The future success of DBS. 2007. In interacting with them. Montgomery EB Jr. Ann Neurol. McAndrews MP. Huang H.29(2):203–206.116(2):315–322. Laxton AW. R.” It has been demonstrated that the brain often fares better without information than it does with misinformation. Giacobbe P. ed. Aristotle. Lozano AM. Mov Disord. the physiology and pathophysiology of the nervous system.17(5):969–983. Deep brain stimulation for treatment-resistant depression. McKeon. R EFER ENCES Arikha N. Indeed. Baker KB. Lancet 2013. the therapeutic mechanism of pallidotomy and other surgical ablations reduces misinformation to no information. Further research is needed in order to confront presumptions inimical to the fundamentals of DBS and. Long-term outcome of anterior thalamic nucleus stimulation for intractable epilepsy. Lipsman N. 2012. Subcallosal cingulate deep brain stimulation for treatment-refractory anorexia nervosa:  a phase 1 pilot trial. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. Watts RL. the DBS pulse train may overwrite the misinformation with information—“01000100 01000010 01010010” to “00000010000000010000001. Alternatively. The Structure of Scientific Revolutions. et al. Cho CB. S U M M A RY DBS’s remarkable therapeutic benefits have been demonstrated. is anything but assured.381(9875):1361–1370. et  al. Mov Disord. Tang-Wai DF. Chicago: University of Chicago Press.258 2 0 T hings to K now A bout D eep B rain S timulation (in the transmission from the radio station). 2010. ultimately. 2002. New York: HarperCollins Publishers. Shon YM. Rezai AR. Kuhn TS. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. The Basic Works of Aristotle.68(4):521–534. 2012. Lozano AM.

2013:258–280. Screening for prostrate cancer.uspreventiveservicestaskforce. The Handbook of Parkinson’s Disease. Seijo F. 1974. Ryle G. Giacino JT. Behavioural improvements with thalamic stimulation after severe traumatic brain injury.27(7):864–873. Mov Disord. Boca Raton. 2012.20:457–481. The epistemology of deep brain stimulation and neuronal pathophysiology. Lozano B. Ann Intern Med. Neurophysiology. Walker HC. Gonzalez CL. Short latency activation of cortex during clinically effective subthalamic deep brain stimulation for Parkinson’s disease. Francis Martin Rouse Walshe. Huang H. MD:  US Preventative Services Task Force. Lyons KE.htm. Cephalalgia. 2009.105(3):1112–1121. et al. Activation of subthalamic neurons by contralateral subthalamic deep brain stimulation in Parkinson disease. Walker HC. 1885–1973. J Neurophysiol. eds. The Concept of Mind. Saiz A. Kalmar K. Montgomery EB Jr. Schiff ND. Schrandt CJ. Screening for breast cancer: US Preventive Services Task Force recommendation statement. Nature 2007. 2012. 2011.151(10):716–726. org/prostatecancerscreening/prostatefinalrs. Rockville. http://www. US Preventative Services Task. Chicago: University of Chicago Press.31(16):1634–1641. Neuromodulation of the posterolateral hypothalamus for the treatment of chronic refractory cluster headache: experience in five patients with a modified anatomical target. In: Pahwa R. 2012. et  al. . Phillips CG. FL: CRC Press. Biogr Mem Fellows R Soc. et al. Front Integr Neurosci.6:78. Watts RL.448(7153):600–603. 2002. 2011. US Preventative Services Task.20. The Future of Deep Brain Stimulation259 Montgomery EB Jr. et al.

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131 Americans with Disabilities Act. as DBS target.. 230 ethical principle of. 135–138 Antonello. 163 Antipsychotic medications. DBS and. 109 tissue activation volume constraints to reduce. 247 American Board of Neurology and Psychiatry. 163 Autonomy beneficence  versus nonmalfeasance and. 254 Action potentials. 12. 23 ADHD (attention deficit hyperactivity disorder). 60–61 reporting protocols for. 139–140 Autoimmune disorders. 187. 181 Anterior-medial region of the globus pallidus interna. 191–192 Anterior limb of the internal capsule. 216. 178. Thomas. 38. 231 Arikha. 221–222 Activities of daily living (ADLs). 172. in Tourette’s syndrome patients. 8 American Medical Association. 127 Acetylcholine/Dopamine Imbalance theory. 202 of selective peripheral denervation for dystonia. 234–236 description of. 95–96. 102 Ataxia. 89 Atrial fibrillation. 89–90 in postoperative patients with Parkinson’s disease. 249. 131. 92 Attention deficit hyperactivity disorder (ADHD) in Tourette’s syndrome patients. 106 Acanthocytosis. 140.INDEX Abetalipoproteinemia. C. 124–125 Affordable Care Act of  2010. 123 Allopathic medicine. 247 Anterior cingulate cortex role in PTSD. 235 Anorexia nervosa. E. 163 Anti-NMDA receptor encephalitis. chorea secondary to. 37–38. 135–138 Alzheimer’s disease. 97–98 in DBS for Parkinson’s disease. 152 Abnormal dopamine metabolism. 229. DBS production of. 228 American Psychiatric Association. 252. 97. 252 Ashworth scale. as DBS target. 247 American Academy of Neurology. for Tourette’s syndrome. 200 in Tourette’s syndrome. 127–128 Anticonvulsants. Noga. for Tourette’s syndrome. 131. 139–140 Adverse effects in DBS for dystonia. 158. 252 Aristotle. 123–124. 110 Aquinas. 49 in postoperative patients with Essential tremor. 27–29 peak-dose dyskinesias as. 70 Alpha agonist medications. 179–181 .

106.. 66 British Association for the Advancement of Science. 128 Cerebellar outflow tremor. 145–155 appropriate measures. 127 Chorea secondary to pantothenate kinase-associated neurodegeneration. 152 postoperative programming. 195. J. 156 Chorea gravidarum. 196–199. 216 Beneficence description of. for PTSD research. See also Ethical issues Blepharospasm. L. 201–202. 102 Cervical dystonia. 139 CBT (cognitive-behavioral therapy). v.. 83 for hyperkinetic disorders. 67. 123. 97. 147–150 DBS targets. 150–151 symptom-specific  versus disease-specific. 151 selection criteria. E. 229–230. 80. 45. D. 111. 116 California Verbal Learning Test. 95. 243–244 Behavioral intervention. A. See Clinician Administered PTSD Scale (CAPS) INDEX Capsulotomy. 138. 189. 236 Bacon. A. 102. 131–132 Childress. See also Posttraumatic stress disorder (PTSD) Clinician Administered PTSD Scale (CAPS). Swan. Francis. 229 nonmalfeasance  versus. 2. 230. 192 Botulinum toxin for dystonia. 97. for Tourette’s syndrome.262 Autonomy (Cont. 256 Bromocriptine. response to. 124 Centromedian-parafascicular nucleus. 182 Cognitive impairment drug-induced. 108 for Essential tremor. 158 Burke-Marsden-Fahn Rating Scales.. 136. 126. 151 from multiple sclerosis. S. 2. 104 Boggio. 204 Cluster headaches. 195 Bernard. as DBS target. 145–147 from postanoxic and posttraumatic tremor.. P. L. hyperkinetic disorders from. 230 malfeasance  versus. 163 Chorea secondary to acanthocytosis. 138. T. 127 Chronic tics. 117. 133 with Tourette’s syndrome. 247–249. 49 Cavanna. Claude. 38 Benebid. 163 Cochrane Database of Systematic Review. 236–239 respect for patients in. 247 Cocaine use. 234–236 Benton Visual Form Discrimination. as DBS target in Parkinson’s disease. 34–35. 236 Chorea-acanthocytosis. 109–110 Children with dystonia. 164 Bilateral DBS systems. Inc. 97. 132 Clinical trials for DBS. 199 Cell Theory.) informed consent and. 123 Beauchamp.. 98. R. 43 Bryden. balance of. 236 Beaumont Spine Pain and Sports Medicine Clinic. 111. 152–153 Cerebral palsy. 199 CAPS (Clinician Administered PTSD Scale). 166 Bradykinesia. 138 Belmont Report. 104. 178 Catecholamine-o-methyltransferase (COMT) inhibitors. 51 . 135 Beta-ketotheolase deficiency. 97. dystonia-choreoathetotic. 230. 255 Basal ganglia-thalamic-cortical system. 199 Cognitive-behavioral therapy (CBT).. 203 Biomedical ethics. 151–152 “off-label” DBS use for. 230–231.

197–198 Common Data Elements in Radiologic Imaging of Traumatic Brain Injury. patients assigned to. 39. 230 Depression DBS surgery and. 15–16 when all else fails. 239–241 Diagnosis-Related Group (DRG). 172 Descriptive ethics. 30 Countertransference. 39 Cost-benefit of DBS surgery. 18–19 pathophysiology importance.INDEX263 as Parkinson’s disease medication side effect. 8–10 healthcare system limitations and. 251 self-limiting. 198–199 Combat Exposure Scale. 255–257 Deep brain stimulation (DBS). 57 Dementia. normative ethics versus. 253–254 dynamics. 198–199 Common Data Elements for TBI. 254–255 scientific method incompleteness. 1–13 ethical issues. 91 Disease-based treatments. 138 Controlled Oral Word Association Test. 91 COMT (catecholamine-o-methyltransferase) inhibitors. 97. Rene. 46 Deep Brain Stimulation Programming: Principles and Practice (Montgomery). fallacy of. 217. 191 Declaration of Geneva. 140 electroconvulsive therapy (ECT) for. 16–17 pathoetiology and pathophysiology conflation. 249–251 proofs of concept. 44 Deontology. 72 Descartes. for Tourette’s syndrome.”  163 Cranial dystonia. Richard. 197 Comorbidities in Tourette’s syndrome patients. 255–256 Contingency management. 256–257 Computed Tomography scans. 126 Columbia Suicide Risk screen. General Assembly of the World Medical Association. 240–241 Diagnostic and Statistical Manual of Mental Disorders (DSM. 89 in posttraumatic stress disorder. 49–50 in Parkinson’s disease patients least acceptable for DBS. overview of. for Parkinson’s disease. 247–259 alternative conception. 195. 228–229 Deep brain stimulation (DBS). in atypical Parkinson’s disease. 195. 50–51 in postoperative patients with Tourette’s syndrome. 251–253 pathophysiology determining treatment. 84. 6–7 revolutionary nature of. 131–132 Diathermy. 179 in postoperative Essential tremor patients. 2 . 49 Confirmation bias. 7–8 mechanics of. 3–6 for neurological and psychiatric disease symptom control. 1–3 neurosurgical treatment versus. 199 Common Data Elements Interagency Steering Committee. 24. 10–12 Deep brain stimulation (DBS). 102–103 Davidson. 140 Confirming the Consequence. 45. 14–15 Deep Brain Stimulation for Parkinson’s Disease Study Group. American Psychiatric Association). future of. 257–258 clinical trials. 188 regional blood flow in. 247–249 complex mechanisms of action. purpose of. 117. 26. 51. 14–21 dynamics. 231–234 “Crack dancing. 199 Core Assessment Program for Surgical Intervention Therapies in Parkinson’s disease. 139–140 Complex Systems theory.

69–70 in obsessive compulsive disorder (OCD). 97. 228 Epilepsy. 101–103 severity. 251–253 overview. 111–112 Dystonic tremor. postoperative care of patients with. 46–47 in postoperative patients with Essential tremor. 42–43 Essential tremor. 179 Efficacy. 94–95 Dystonia. 131–132 Duration of effect. 79 Double Effect. 49 tardive. 40 DSM (Diagnostic and Statistical Manual of Mental Disorders.264 Dopamine agonists. 87–93 adverse effects. 115–121 DBS-induced plasticity.  See also Hyperkinetic disorders DBS battery failure and. 165 Dopamine depleting agents. 97–98 DBS efficacy. 70–73 DBS efficacy. 45. 1–2 levodopa-induced. 165 Dopamine transporter ligand imaging-single photon emission computerized tomography (SPECT). 94–100 causal mechanisms. 103–106 tolerability. of DBS. 16–17 Dyskinesias. 69–70 DBS in practice guidelines for. 99 diagnosis. 46–49 Dynamics complexity of. 76 Emergency situations. 242 DBS nature of. 172. 87–89 in Tourette’s syndrome. 120–121 epistemological considerations. 152 ECT (electroconvulsive therapy). American Psychiatric Association).  See also Parkinson’s disease in dystonia. 181–182 peak-dose. 127 Drug-induced parkinsonism. 179 Embarrassment. 102 Dystonia patients least acceptable for DBS. 124–125 Egalitarianism. 247 Essential tremor. 11–12 time dimension of. 96 FDA Humanitarian Device Exemption for. 118–120 programming problems. 112 primary  versus secondary. 117–118 overview. 127. 116–117 Dystonia-choreoathetotic cerebral palsy. 220. 156. 70–73 DBS safety and effectiveness. 127 peak-dose. postoperative care of patients with. 111 spontaneous remission potential. patients assigned to. 127 DBS in practice guidelines for. 161 primary and secondary. 96–97 DBS in globus pallidus interna for. 66–67 FDA approved DBS for. 96–97 in Essential tremor. 103. in Essential tremor. 115–116 INDEX programming approaches. 172. 89–90 . 67–69 DBS risks. 66–73 DBS adverse effects. 30. 106–111 overview. 240–241 Drug-induced dyskinesia. 135–137. 101–114 alternative therapy failure. 229–231. 62–64. 164 Dystonia. 98–99 decision for DBS. 1 tremor-predominant idiopathic Parkinson’s disease  versus. 95–96 children with. Principle of (Aquinas). 163. 101 postoperative programming provision. 62–63 drug-induced. 242 DBS targets. 238 DRG (Diagnosis-Related Group). 230 Electroconvulsive therapy (ECT). 133 DBS adverse effects. 49. 91–92 Employee Retirement Income Security Act of  1974.

198–199 . 174. 134 Exposure and response prevention. 123 Globus pallidus interna. 216. 74–86 candidate selection responsibilities. 31–32 descriptive  versus normative ethics. 87 efficacy. 95–96. 223 Gait and balance involvement. 90–91 Essential tremor patients least acceptable for DBS. as DBS target. 221–222 General Assembly of the World Medical Association. and health care provider in Parkinson’s disease. 75–84 diagnosis. 95 Glasgow Coma Scale. 189–190. 91–92 medication adjustments. 179 countertransference. 249. 194 Global perspective measures of patient. Food and Drug Administration). 70 fMRI (functional Magnetic Resonance Imaging). 234–236 comorbidities as exclusion basis. 226–227 epistemic issues in DBS acceptance. 106 Habit-reversal therapy. 228 Generalized torsion dystonia. 217 Globus Pallidus Interna Rate theory. 236–239 in neurosurgery referrals. 158. 148–149 context of. 152 Freud. 231 Friedman’s Analysis of Variance. 189 Fixed dystonia. in Parkinson’s disease. 172. 231–234 in DBS for Parkinson’s disease. 192. 1. 84 challenges of. 15. 41 physicians' responsibility to neurosurgeons. 205–206 principles and theories overview. P. 192. as DBS target. 107 Guanidinoacetate methyl-transferase deficiency. 172. 132. 96. 252 Galvani. 87–89 emergencies. 179–181. 254. 23 Galen. 74–75 selection criteria. choosing. 8–10 in patient selection. for Tourette’s syndrome. 11 Gamma amino butyric acid (GABA) neurotransmitter. 227–230 European Society for the Study of Tourette’s Syndrome. Food and Drug Administration (FDA) Fins. 97. 241–242 informed consent. Luigi.. Philippa. 77–80 exhaustion of less invasive therapies. 32–34. caregiver. 84 tolerability. 106 Failure to inform. 32. 5 Omission bias. 257 Glutaric aciduria type I. 234–239 beneficence  versus nonmalfeasance. Sigmund. 38. 82 Functional assessments. 250–252. 243–245 in postoperative care. 38. for Tourette’s syndrome. 115 in posttraumatic stress disorder research. 80–83 overview. Joseph. 242–243 excellence. 233 Fragile-X-Associated Tremor. 105 Flexnerian revolution in medicine. 138 Fahr’s disease. 23 Functional Magnetic Resonance Imaging (fMRI). 99 overview. 83–84 Ethical issues. 239 FDA (U. 138 Hamilton Anxiety Scale (Ham-A). 75–77 postoperative care availability. 106 Greene.S. 1. 23 Globus pallidus externa.INDEX265 availability of.S. 239–241 efficacy  versus prevalence. 223 Foot.  See U. 226–246 American Medical Association Code of Ethics. 104–106 Germ Theory. 230–231. 228 autonomy.

123 Intrathecal and intraventricular baclofen. I. postoperative care methods on. 228–229 Hohen and Yahr scale. 56–57 impedance effects. 98 Medtronic Neuromodulation. 156. See Implanted pulse generator (IPG) Italian Movement Disorders Association. 227–228 Internet. postoperative. 7 Intracerebral hemorrhage.. 205 understanding choices for. 2. from FDA. 127. 133 from FDA. 238 physician ethical dilemmas with.. 2 for PTSD DBS research. W. 189 PTSD DBS study disapproved by. 165 Hyperkinetic disorders. 202 for DBS for obsessive-compulsive disorder. 152 Homocystinuria. 122. 203 programming adjustments to. 173 for primary dystonia. 51 Indirect/Direct/Hyperdirect Imbalance theory. 106 Humanitarian Device Exemption for children with dystonia. 92. 218 Investigational Device Exemption (IDE). 120 Hegel. 7–8 Health Maintenance Organization Act of  1974. research on. 180 Institutional Review Board (IRB) adverse event definition and policies of. 89 infection risk with replacement. 58–60 status checking. 62–63 Impulse control. F. 198–199 Hariz.266 Hamilton Depression Inventory (Ham-D). 145. 162 Pegram v. 8. 92 in patients with obsessive compulsive disorder. G. 252–253 Hemiballismus. 233–234 Insurance “off-label” use deemed experimental by. 40–44 Implanted pulse generator (IPG) DBS benefits dependent on. See also Ethical issues Huntington’s disease. 179. as DBS target. 98 in patients with Essential tremor. 2 on “off-label” use of devices. DBS surgery and. 124 Healthcare system limitations. 163–167 Hyperthyoidism. M. 254 Infections. Herdrich (2000). to FDA. 127. 94 Human subjects. 110 Inverse Problem. 145. 161–163 overview. 89. 183 informed consent and. 158 Informed consent autonomy and. 156–170 DBS for. 163 psychological impact on judgments of. 218 Hippocrates. 161. 125–126 Intralaminar nuclei of thalamus. 159–161 “off-label” uses of FDA-approved devices. 2 epistemic status. 156 Henneman Size Principle. 98 Inferior thalamic peduncle. 173. 145. as DBS target. 38. 156–158 selection criteria. 1 for obsessive-compulsive disorder. 81 . 182 in patients with Tourette’s syndrome. 70–71 Intracranial hemorrhage in patients with dystonia. 171. 23 Holmes' tremor. 190 Hippocratic Oath. 228 Hebbian learning. 161 Investigational New Drug Application (IND). 181 INDEX Information Theoretic entropy (Shannon). tremor and. 71–72. 71. 78 Idiopathic Parkinson’s disease diagnosis. 161 IPG (implanted pulse generator). 236–239 Institutional Review Board (IRB) supervision for.

103 Neuron Doctrine. 255 Massed negative practice. 251 Medicare. as DBS target in Parkinson’s disease. 12. 49 Montgomery. 2. tardive dystonia from.. HMO denial of coverage as. 230 Life Stressor Checklist. 117–118 Kyphoscoliosis. 193. K. balance of. 247 Neurodegenerative disorders with metabolic disease. in Essential tremor diagnosis.. 230 MAO-B (monoamine oxidase type B) inhibitors. W. 79 Libertarianism. 150–151 Multisystem atrophy (MSA). 91. 151–152 DBS nonspecific risks and. 25.. 138 Mayberg. 203 Meige syndrome. 58. 181 Motor cortex. 182 National Institutes of Health. 28. 106 Misinformation. 131 Justice.. 104 Mereological fallacy. 173. 40 Myoclonus-dystonia disorders.INDEX267 Jackson. 133 Levodopa equivalents. 229 Malpractice. 2–3 Mitochondrial disorders. 123 Metabolic disease. 255 Kupsch. 254 Lupus anticoagulant syndrome. 164 Magnetic Resonance Imaging (MRI). 2. in Parkinson’s disease. 97. 28 Leckman. Immanuel. 8–10 peak-dose efficacy of. 120 Low-beta Oscillator theory. E. Thomas. 110 Movement Disorders (Watts et al. 146.).. 230 Kant. 40 Kuhn. 106 Mitochondrial encephalopathy. in idiopathic Parkinson’s disease. to improve DBS response in dystonia.. 57 Morishita. Jr. neurological disorders resulting from. 161 overview. 152 Kuff’s disease. 105 Lead misplacement. Abraham. neurodegenerative disorders with. 152 . 253 Jankovic. F. 148 Expanded Disability Status Scale for. for Tourette’s syndrome. F. 198–199 Long-term depression (LTD). 49 Maslow. Helen. 249. 160–161 dystonia from. 43–45 for Segawa disease and tyrosine hydroxylase deficiency. 162 Klinefelter syndrome. 45.. 152 Monoamine oxidase type B (MAO-B) inhibitors. 97 National Institute for Health and Clinical Excellence (UK). 47–49 response to. 67. 32 Motta. repeat surgery and. 149.. 46 Levodopa treatment dyskinesia from.” 103–104 Kim. John Hughlings. 57 Multiple sclerosis cerebellar outflow tremor in. 120 Long-term potentiation (LTP). T. reimbursement policies of. to improve DBS response in dystonia. 30 Medtronic Neuromodulation. 106 Neuroleptics. 45. A. 125 Klein v. 107 unresponsiveness to. J. 124 Neuropathies. 191 Malfeasance  versus beneficence. 240 Medication reduction with DBS. Biscup (1996). 180 Kaplan-Meier “survival curves. B.

171–185 autonomy. 31 medication reduction with DBS. 216 DBS in practice guidelines for. See also Obsessive compulsive disorder (OCD) adverse effects of treatments. 243. 94. 1–2. 102 for Tourette’s syndrome. 141–142. 239–241. 252 healthcare-related DBS issues. 182 DBS status for. 24–26 DBS targets. DBS versus. 2. 145–146 for hyperkinetic disorders. 156 Parkinson’s disease. 249 Pallidotomy. in PTSD. 123 DBS effectiveness measures. 230–231. 161–163 for secondary dystonia. 181–182 DBS programming. 147. 181 Obsessive compulsive disorder (OCD). 243–245 Neurosurgical treatment. 106 NINDS Common Data Elements program. ethical principle of. 40 Normative ethics. 176–177 DBS efficacy. 6–7 Neurotransmitters. 106. 202 Nonmalfeasance. 22–24 DBS effect unrelated to dopamine. 7 pharmacoeconomic considerations. 31–32 FDA approved DBS for. 30 . 147 One-dimensional push-pull dynamics paradigm. 171–172 selection criteria. 181 FDA Humanitarian Device Exemption for. 1 Globus Pallidus Interna Rate theory and. 98–99. 122–123 Omission bias “Do no harm” imperative and. 252–253 Organic acidemia. 234–236 Nonsurgical management means. 158 in PTSD. 234 psychological and emotional factors under. 188 Pantothenate kinase-associated neurodegeneration. physicians’ responsibility to. 34–35. 95–96. 141 INDEX as patients' problem. 242 lack of perspective and context. 250 Panic disorder. 22–36. 179–181 burden of. 139–140 “Off-label” DBS use for cerebellar outflow tremor. 131. 106 Osler. 218. 27–29 as basal-ganglia-thalamic-cortical system disorder. 5 DBS studies. beneficence versus. 173–176 DBS targets. 16. 24 Nieman Pick C disease. 30 epistemological and ethical DBS factors. 248–250 duration of benefit with DBS. 135. 67. 216. 157. 218. 209 as therapeutic nihilism. 99. 182–183 in Tourette’s syndrome patients. 177–179 overview. as DBS target. 218–219 patients suitable for DBS with. 32–35 dopamine deficiency as focus. 190 Tourette’s syndrome selection criteria affected by.268 Neurosurgeons. 183 DBS safety. 127 Pantothenate kinease deficiency. 45–50 Normal pressure hydrocephalus. Sir William. 242 DBS program evaluation based on improvements in. DBS mechanism of action  versus. 30 pathophysiology of. 232 non-surgery alternative preferred because of. 123. 16 New England Journal of Medicine. 244 Nucleus accumbens. 135.

251. 152 Physicians’ responsibility to neurosurgeons. 37–38 patient-selection context. 216–217 DBS therapeutic action. 188 DBS implantation. DBS-induced. 18–19 prevailing predisposing theories. 238 PET (Positron Emission Tomography). 243–245 Physiology insights. 49 Peak-dose efficacy. 217–218 theory-differential diagnoses. See Pathophysiology and physiology insights Piedad. 254 Pharmacology as physiology paradigm. 186–215 anterior cingulate cortex role in. 56–65 adverse effects. as DBS target. 223–224 pathoetiology and. 219–223 importance of. 152 Posterior lateral globus pallidus interna. 50–51 toleration of surgery. 152 Posttraumatic stress disorder (PTSD). 52–53 preexising cognitive impairment. 57–58 programming or medication adjustments. 39 postoperative care plans. 51–52 overview. 62–64 ensuring benefits and minimizing risks. 40–44 overview. 254 Postanoxic tremor. 123–124 Posterior limb of the internal capsule. 123 Patients. 205–206 Institutional Review Board (IRB) disapproval of DBS study on. See also Omission bias Pathoetiology. 123 Postoperative management. 120–121 Polycythemia vera. 191–192 background and significance. 15–16 intuitive appeal  versus complex explanations. 192 outcomes measure. J. 219 Patient Protection and Affordable Care Act of  2010. 223. 189–190