Deep Brain Stimulation for Dystonia and Other Disorders: The Ten Things You Really Need to Know

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Michael S. Okun, M.D., Kelly D. Foote, M.D.
University of Florida McKnight Brain Institute, Gainesville, FL
Website: http://mdc.mbi.ufl.edu

Introduction-
Deep brain stimulation (DBS) is a promising technology that has provided symptomatic relief of many symptoms of Parkinson’s disease, dystonia, tremor, tics, and various other “movement” disorders(1-6). At the University of Florida we have a long tradition of treating patients with brain lesion therapy and DBS. Because of our experience we see a large referral population of patients who are primarily interested in a surgical solution. At our institition, we consider only a small number of patients referred to be excellent candidates for DBS(7). Recent FDA approval of DBS for Parkinson’s disease (PD), essential tremor, and dystonia has made these procedures widely available in the United States, but they are also available worldwide. The procedure, including screening, implantation, and follow-up requires advanced training, specialty expertise, and a commitment of an interdisciplinary team to the care of implanted patients. Patients interested in DBS can receive the therapy from over 200 centers in North America, and many others around the world (but only a few offer dystonia surgery because of FDA and IRB restrictions), however there is reason to be cautious before considering DBS. Patients should be careful when deciding where to receive the therapy for a number of important reasons. This article will focus on 10 important issues (in the form of questions) regarding the potential use of DBS. The content of this article aims to provide a useful framework for patients, general neurologists and practitioners to screen appropriate dystonia DBS candidates.

1- What is Deep Brain Stimulation?
DBS is a relatively new procedure that utilizes a lead that is implanted into “deep” brain structures. It may be used in place of or in conjunction with lesioning procedures such as pallidotomy or thalamotomy(8) (burning a hole in structures in the brain that control movement). Patients with PD, tremor, dystonia, or OCD/Tourette who are medically refractory to standard therapies, and who have no cognitive difficulties or “minimal” cognitive dysfunction, and who are otherwise healthy may qualify. The currently used lead is FDA approved and manufactured by the Medtronic corporation. It has four electrode contacts (quadrapolar), and depending on the disorder and/or the target, one may use variable sized contacts with different spacing arrangements (Figure 1). Each contact can be activated utilizing monopolar or bipolar stimulation, and multiple settings can be adjusted for individual patient needs. These settings include the pulse width (how long the stimulation is), frequency (how often the stimulation is delivered), and amplitude (how much stimulation) of stimulation. The DBS lead is placed into a brain target, and is attached to a connector wire and a programmable pulse generator (Figure 1). The pulse generator or neurostimulator is placed below the clavicle. The pulse generator is connected to the DBS lead by an attachment wire that travels across the posterior aspect of the neck and skull.

2- Who is a Candidate for Deep Brain Stimulation?
Careful patient selection is the first and perhaps the most important step for success of DBS. There are no standardized criteria for choosing candidates, and criteria may differ depending on the targeted symptom or disorder. We will discuss the important aspects of patient selection that should be considered in PD, essential tremor, dystonia, and OCD/Tourette.
PD, which is a slowly progressive neurodegenerative disorder (cardinal manifestations- resting tremor, bradykinesia, rigidity, gait disorder), presents many challenges for the practitioner who is considering offering DBS. Although there are no set criteria for surgical candidacy, recently we developed and validated a screening questionnaire for this purpose. The Florida Surgical Questionnaire for PD(7) or FLASQ-PD is a 5-section questionnaire that includes: (A) criteria for the diagnosis of “probable” idiopathic PD, (B) potential contraindications to PD surgery, (C) general patient characteristics, (D) favorable/unfavorable characteristics, and (E) medication trial information subscores. The scoring system was designed to assign higher scores to better surgical candidates. The highest/best possible FLASQ-PD score is 34 with 0 red flags, and the lowest/worse possible FLASQ-PD score is 0 with 8 red flags. A red flag is a sign or symptom that would automatically put a patient at high risk for a complication of surgery. A score of approximately 25 without red flags indicates a potentially good surgical candidate. This questionnaire can be filled out and scored by your general neurologist, general practitioner, or other qualified health professional. Potential candidates who score well on this questionnaire will require medical optimization with a movement disorders specialist (if possible), a neurosurgery consultation, a special MRI for targeting, and a full neuropsychological evaluation. Some patients may additionally require a speech and swallowing evaluation, and psychiatric evaluation for treatment of active affective disorders.
In general the best PD surgical candidates have idiopathic PD (not parkinsonism which includes other diagnoses such as multiple system atrophy, progressive supranuclear palsy, Lewy body disease, corticobasal degeneration), tend to be younger (below age 69, but may be older), have a great response to medication (at least 30% improvement, but preferably higher), be medication refractory to symptoms (wearing off of medications prior to the next dose, on-off fluctuations, dyskinesias, etc.), and have no or little cognitive dysfunction. Perhaps the most controversial aspect of patient selection often involves defining unacceptable cognitive dysfunction, especially since many PD patients suffer from frontal and memory deficits, but are quite functional in their daily lives. A general rule is that PD patients with a lot of memory or cognitive problems, and those who get disoriented frequently are poor candidates and can be made worse from surgery.
In ET, patients suffer from postural (holding the hands and arms in a fixed position) and action tremor (tremor when they attempt tasks) which often disrupts the simple but important daily tasks such as handwriting or drinking. ET candidates for DBS must have medication refractory tremor defined as having failed maximal titrations and preferably combinations of a beta blocker, primidone, and possibly a benzodiazepine. There are other medications that have been found effective in some patients with ET and these may be tried as well. The tremor must be interfering with the quality of life to consider surgery. There are no available questionnaires to screen for good ET surgical candidates, however the same interdisciplinary workup is necessary (as was discussed in PD), and it is important that the tremor be diagnosed correctly as ET can be confused with other tremor subtypes. Again, the most difficult criteria to interpret for the ET surgical candidate is the neuropsychological screening data, especially since it has recently been appreciated that ET can be associated with frontal lobe and memory dysfunction(9, 10).
Other disorders which may be addressed by DBS have been less studied in terms of selection criteria. In general the best dystonia (a twisting disease where agonist and antagonist muscles co-contract and leave the sufferer in abnormal postures which may be worsened by action) surgical candidates suffer from generalized disease (multiple body regions) which may or may not be the result of an identified genetic defect. This criteria is a generality based on a limited experience, however as more reports of DBS for focal dystonia emerge, the criteria may be expanded. So far at the University of Florida we have been successful with other more focal dystonias. Secondary dystonia, or dystonia due to other causes such as trauma, toxin, birth defect, or metabolic disorder seems to be less responsive to DBS, although the best surgical target remains to be defined for these cases, and there has been some successes reported. The dystonic patients need to fail maximal doses of appropriate medications and preferably combinations of medications including anticholinergics, muscle relaxants, and benzodiazepines, and should also undergo the same workup as for PD patients. It is helpful in dystonia if the operation is performed before abnormal joint postures become fixed or contracted. Patients with generalized dystonia may be normal on detailed neuropsychological testing, although recently it has been shown that they may suffer from impairments in complex learning(11, 12). It remains unknown whether the neuropsychological profile in dystonia patients effects surgical outcome.
DBS for OCD or Tourette remain investigational at this time. All potential candidates should be refractory to standard medical therapies, and informed consent should be obtained from an institutional review board before offering the procedure. The profile of the best candidates with these and similar syndromes remains unknown, although all candidates should undergo the same vigorous testing described above, and should be medication refractory. We are currently testing patients with refractory OCD under a National Institutes of Health grant, but the results are not yet available.
Since the optimal dystonia candidate remains to be defined, it is in the best interest of the dystonia patient to seek a medical expert in the area and an experienced center for evaluation. Medication and botulinum toxin refractory cervical dystonia as well as craniofacial dystonia may be addressed by DBS in select cases.
3- Why Everyone is Not a Candidate?
Though almost every patient who visits our practice, particularly those with PD are excited about DBS, and want to know how and when they can share in this “new hope”, most are not candidates. In a study examining 174 PD patients referred for surgery at the University of Florida, less than 10% were acceptable candidates(7). It turns out that based on our experience and the experience of many other groups, we have learned that the perceived benefit of DBS mirrors that which patients see and read about. This perceived patient benefit often equates to cure. Patients are bombarded with stories and video-clips of dramatic successes, but often are not briefed on the reality of reasonable perceived benefits. It is for this reason that we have introduced a mneumonic device (Table 1) which we teach patients prior to and at subsequent programming sessions after surgery. The “DBS Rules” (Table 1) help our PD patients to understand the importance of perceived benefits from surgery. This program allows us to ensure the success not only of the implanting team, but of each individual patient. We similarly educate our patients with other movement disorders as to perceived benefits of surgery.
Patients with other parkinsonian syndromes besides idiopathic PD, either do not benefit, or may worsen from surgical therapy. Though these patients may represent groups most devastated by their movement disorders they should not be offered DBS surgery at this time.
Cognitive problems associated with PD can be a contraindication to surgery, but in other disorders such as tremor, dystonia, OCD, and tic these have been less well investigated and it is unclear their effects on surgical candidacy. Additionally, those patients who have significant thinking and memory problems may have a difficult time tolerating awake surgery, a difficult post-operative course, delayed recovery, confusion, and may ultimately worsen their overall cognitive status (author observations).
The Hippocratic aphorism of “do no harm,” applies to DBS, especially in light of the high ratio of the number of patients desiring surgery versus the low number of appropriate surgical candidates.

4- How Do We Accomplish Large Population Screening?
If 10% or less of a population of patients at any given time, such as those suffering from PD, qualify for a surgery(7) that may have a dramatic impact on their quality of life, how do we effectively screen these patients. We have answered this question at our center for PD, and in surrounding practices in the state of Florida by disseminating the FLASQ-PD surgical questionnaire. It is a simple tool designed for general neurologists, practitioners, or qualified health care providers to make quick decisions as to suitable candidates to refer for surgery. The questionnaire is also suggestible, meaning that if you do not achieve a high enough score for surgery, you may attempt to modify factors that can later improve your score on a follow-up administration of the survey. There are no such tools available at this time for the other disorders, however a reasonable standard would be to refer patients to an experienced movement disorders neurologist if their symptoms are medically refractory, and they are not demented.
5- Should Patients See a Movement Disorders Neurologist for Medical Optimization Prior to Surgery?
If there was ever a trip that was worth making, seeing the movement disorders neurologist prior to DBS implantation may be the most valuable use of time and resources an individual patient and family can make. Accurate diagnosis, medical optimization, and discussion of a plan of care, particularly for chronic progressive diseases like PD, will lay the foundation for future successes, whether medical or surgical. Also, it should be understood that in most cases surgery will not alleviate the need for medications, and continuing medical management (another myth propagated by media and internet sources). The majority of patients we see in our movement disorders neurology practice, after careful assessment have an unfavorable risk to benefit ratio for surgery at least at the initial assessment. This ratio may of course improve with optimization of therapy. Of the group of reasonable surgical candidates, as many as 20-25% will decide either not to have surgery or to delay surgery because of successful medical optimization.
Movement disorders neurologists have the important task of making the careful determination that an individual patient is medically refractory, and often will need to evaluate patients on standardized scales. If this task is difficult and time consuming for a movement disorders neurologist, you can imagine how difficult it may be for the general neurologist or practitioner. Although there are many skilled and licensed health care providers, in general there is no substitute for the training of a movement disorders neurologist when considering such an important decision. The other advantage of the movement disorders neurologist is the time devoted to determining especially in PD patients, which symptoms will respond to therapy and which symptoms will not. This is crucial for each individual patient (for example the patient who wants his or her balance back from the surgery; but after evaluation the movement disorders neurologist he or she learns the balance symptom is unlikely to improve following surgery).
6- What Kind of Commitment Does DBS Require From the Patient, Family, and the Implanting Center?
Each patient who receives DBS for the treatment of a movement disorder has knowingly or unknowingly made a huge emotional and physical commitment. Not only has the patient devoted a large amount of time, energy, and travel for pre-operative screening and appointments, but there is an even larger commitment post-operatively. There will often be a need for follow-up brain scans, device checks, and post-operative care. There will be multiple DBS device adjustments especially during the first six months, and continuous management of medications. There is now additional information available for patients and practitioners, that have been published as part of the North American Survey, undertaken by the DBS society(13). This survey which included more than 4000 DBS procedures indicated that there was a significant number of post-operative visits necessary for DBS programming, especially in the first 6 months following the procedure. The battery life may be as short as 6-8 months in some disorders (e.g. dystonia), or as long as 5-6 years in others (e.g. essential tremor). There may not be adequate local expertise for follow-up programming or device related complications and this may require the patient to travel long distances for each visit. Patients who receive DBS should be prepared to make a large commitment of time, energy, emotional, and financial resources. There will be a new ongoing relationship for every patient who decides to become “bionic,” whether there is local DBS programming support or not.

7- Should All Centers Perform Deep Brain Stimulation, and Should Care be Regionalized? The Need for Well Trained Interdisciplinary Teams
A recent large survey of DBS centers revealed that the majority of implanters feel that a well-trained interdisciplinary team is necessary for this type of surgery(14). In the United States DBS has been FDA approved for the treatment of many disorders, and therefore unlike 5 years ago, any licensed neurosurgeon may perform the procedure. Additionally, there are no standard requirements for a center performing DBS surgery, and there is currently no standard procedure. Therefore, there is a wide range of quality of service especially involving patient selection, pre-operative screening, the operative procedure, and post-operative follow-up. Since there are no specific adopted guidelines for setting up a DBS program we suggest the following elements as important for the short and long term success of DBS in any center. The center must have a substantial commitment to an interdisciplinary team expert in the medical management of both movement disorders and movement disorders surgery. Patients often require access to ancillary services, and an experienced PD center can provide these services thereby potentially improving the overall risk benefit ratio prior to surgery and minimizing errors in medical decision making. We believe the most important element of a successful center is a fellowship trained movement disorders neurologist (or equivalent) to perform screening and medical optimization. Another crucial element for patient success is a well organized and well trained team to perform neuropsychological screening, neurosurgical screening, psychiatric screening, and advanced imaging. In our center we utilize a movement disorders trained neuropsychologist, neurosurgeon, and psychiatrist. It helps tremendously if the neurosurgeon has done specific fellowship training in stereotaxic surgery and movement disorders surgery, beyond a weekend “refresher course,” and has significant experience and/or training with DBS devices. The neurosurgeon should have at his or her disposal either a neurologist or electrophysiologist to perform detailed microelectrode recording to ensure proper lead placement. This point cannot be emphasized enough as correct placement is usually measured in millimeters, and no amount of expert programming can make up for a poorly placed lead. Additionally, most excellent centers prefer a neurologist in the operating room to test the lead and look for side effects and benefits of stimulation. Once the lead is in place there needs to be a team including an experienced neurologist, neurosurgeon, and dedicated programming nurse available to the patient, often on short notice, for adjustments and medication changes. This team needs to be prepared to deal with device failures, and to treat the individual needs of each patient.

8- Why Does Deep Brain Stimulation Work?
The mechanism of action for DBS remains unknown. DBS may act by reversibly suppressing or normalizing neuronal (brain cell) activity through the activation of inhibitory interneurons (brain cells). DBS may also act by creating an “informational lesion” within the motor and non-motor circuitry of the systems in the brain responsible for movement disorders. Alternatively other complex neurological mechanisms such as depolarization block, interruption of cell bursting, or normalizing irregular and abnormally bursting brain cell patterns may all serve as possible mechanisms(6, 15). It has been suggested that DBS may inhibit brain cells and excite brain fibers(6). Its effects on neurotransmitters or chemicals in the brain remain unknown. Disrupting one or more of the “basal ganglia” circuits seems to mysteriously lead to dramatic improvements in symptoms despite the fact we are uncertain of the mechanism.

9- What are the Risks of Deep Brain Stimulation?
DBS, like any brain surgery, has significant risks(16-18). The most serious and worrisome risk occurs during the surgical procedure when “probes” called microelectrodes are inserted into the brain to determine the best target location. If a microelectrode, or alternatively the DBS lead, punctures a blood vessel it can lead to a stroke or stroke-like syndrome which may result in weakness, numbness, sensory loss, visual difficulties, or a host of other neurological problems. Additionally, patients with cognitive dysfunction may worsen following DBS, and the surgery may affect one of many mood and cognitive circuits leading to changes such as depression, laughter, memory problems, or other psychiatric and/or behavioral features. Additionally, there is a chance the lead may migrate, or the electrode, connecting wire, or impulse generator may break and need to be replaced. Any time a foreign body is implanted into a human there is a risk for infection, both at the skin level, and in the brain. The batteries in the device will have to be changed requiring additional surgery, with the average time to battery replacement differing based on the underlying disorder, as well as the stimulation settings. As with all surgical procedures, there is a small chance of infection, and death from the procedure. Batteries may need to be replaced more frequently in dystonia, although there has been a recent discovery of new settings that may conserve battery life for some patients (low frequency stimulation).
Perhaps the biggest risk of surgery is that for patients and families the surgery will not meet perceived expectations. It is for this reason that we strongly suggest an in depth consultation with a movement disorders neurologist. This discussion should address individual symptoms and be as specific as possible. We offer in depth counseling to help educate them and alter their perceptions to more closely match what is known about anticipated benefits of surgery.

10- What is the Future for Deep Brain Stimulation?
DBS has provided dramatic improvements in quality of life for patients with PD, tremor, dystonia, and other movement and basal ganglia related brain disorders. As the technology is refined we will learn to improve our treatment of “motor (tremor, stiffness, slowness, balance, gait),” as well as “non-motor (mood, cognitive, and behavioral)” symptoms, perhaps in combination with other therapies. Additionally, we will need to improve on our ability to select the best possible candidates and those who have the most favorable risk-benefit ratios. In the next 5-10 years we will need to become more sensitive to the unrealistic hope of some patients and families. We will additionally need to better educate them about who is a candidate, and what they can expect and anticipate from a surgical approach to their problems. There will be rechargeable devices in the foreseeable future, as well as devices that will work on a closed-loop circuit, meaning they will automatically turn on when needed (like a cardiac defibrillator). Finally, we will adapt this technology to be used for other promising therapies such as viral vectors, gene therapies, stem cell therapies, and the instillation of other factors which may aid in the survival of brain cells. Since many of these diseases are neurodegenerative, and many have multiple motor and non-motor manifestations, we can reasonably expect that DBS will be used in combination with other promising therapies and technologies. Now that DBS is an accepted therapy, we the practitioners will have to accept the responsibility of delivering the highest quality of care to the patients and families who need it the most. It will be important for us to proceed with caution, and realize that just like any choice in life, DBS is not for everyone.
**This article was adapted by the authors from previous works on the UFMDC website
About the Author:
Michael S. Okun, MD, Co-Director of the Movement Disorders Center, neurologist and movement disorders expert, received his B.A. in History from Florida State University, and his M.D. from the University of Florida where he graduated with Honors. Dr. Okun went on to complete an internship at the University of Florida and a residency in Neurology. He then completed two fellowships at Emory University, one in movement disorders and a second in microelectrode recording and surgical treatments for movement disorders. He was recruited back to the University of Florida in 2002 to create the University of Florida Movement Disorders Center. The Center, which he co-directs, has over 20 interdisciplinary researchers in all areas of Parkinson’s disease and movement disorders. The center is unique in that it provides interdisciplinary care for patients, as well as important bench and translational research.
Dr. Okun currently serves as the National Medical Director for the National Parkinson Foundation.
Dr. Okun is supported by grants from the National Institutes of Health and the Michael J. Fox Foundation for Parkinson’s Disease Research. His main area of focus is on programmable brain implants for Parkinson’s disease, tremor, dystonia, complex movement disorders, and behavioral disorders such as Obsessive Compulsive Disease. Dr. Okun, and the team at the University of Florida, also have three NIH projects exploring the cognitive, behavioral, and mood effects of brain stimulation.
Dr. Okun is also a faculty member in the Department of History at the University of Florida, and, in addition to founding and administrating the History of Medicine lecture series, he teaches an undergraduate/junior honors course on the History of Medicine. Additionally, he has recently published a book of prose and poetry about the medical school experience, Lessons from the Bedside.

MOVEMENT DISORDERS CENTER
AT THE
UNIVERSITY OF FLORIDA

What steps do I take to become a patient at the UF Movement Disorders Center?

1. Contact your physician. This can be your family doctor, your internal medicine physician, your neurologist, or any physician who feels you may have a movement disorder.

2. Have your physician’s office fill out a referral form or fax your demographic information . They can obtain a referral form by calling 352-273-5566; ask for Rachelle Stephen. Rachelle is the UF MDC scheduler and can respond to any questions you may have about the Movement Disorders Center.

3. Ask your doctor’s office to fax your demographic information//referral form and attach a copy of your insurance card and your medical records; then fax this information to 352-273-5575, to the attention of Rachelle Stephen.

4. If you don’t hear from us within a week, please contact your referring physician’s office to be sure they sent us the requested information. Once this has been verified, then call 352-273-5566 to see about your appointment.

Thank you for your interest!

Rachelle Stephen
Movement Disorders Center
University of Florida
McKnight Brain Institute
PO Box 100236
Gainesville, FL 32610-0236
TEL: 352-273-5566
FAX: 352-273-5575

References

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7. Okun MS, Fernandez H.H., Pedraza, O. Development and Initial Validation of a Screening Tool for Parkinson’s Disease Surgical Candidates. Neurology 2004:In press.

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11. Ghilardi MF, Carbon M, Silvestri G, Dhawan V, Tagliati M, Bressman S, et al. Impaired sequence learning in carriers of the DYT1 dystonia mutation. Ann Neurol 2003;54(1):102-109.

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13. Ondo W, Bronte-Stewart, H., DBS Study Group. The North American Survey of Placement and Adjustment Techniques for Deep Brain Stimulation. Neurology 2004;62(7, Supplement 5):A393.

14. Prehn AW, Vawter, R.G., De Vries R.G., et.al. Practical and Ethical Challenges in Surgical Trials: Perspectives of Parkinson’s Disease Researchers. Neurology 2004;62(7, Supplement 5):A393.

15. McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol 2004;21(1):40-50.

16. Kondziolka D, Whiting D, Germanwala A, Oh M. Hardware-related complications after placement of thalamic deep brain stimulator systems. Stereotact Funct Neurosurg 2002;79(3-4):228-233.

17. Umemura A, Jaggi JL, Hurtig HI, Siderowf AD, Colcher A, Stern MB, et al. Deep brain stimulation for movement disorders: morbidity and mortality in 109 patients. J Neurosurg 2003;98(4):779-784.

18. Beric A, Kelly PJ, Rezai A, Sterio D, Mogilner A, Zonenshayn M, et al. Complications of deep brain stimulation surgery. Stereotact Funct Neurosurg 2001;77(1-4):73-78.

My mom and I wanted to thank you for hosting such a great symposium this year. This was our third year and we are looking forward to next years. E. Mathews