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Ravina, B., Tanner, C., DiEuliis, D., Eberly, S., Flagg, E., Galpern, W.R., Fahn, S., Goetz, C.G., Grate, S., Kurlan, R., Lang, A.E., Marek, K., Kieburtz, K., Oakes, D., Elliott, R., Shoulson, I., Parkinson Study Group LAPBS-PD Investigators.. A Longitudinal Program for Biomarker Development in Parkinson’s Disease: A Feasibility Study. , Movement Disorders, 24(14): 2081-90Movement Disorders, 24(14): 2081-90

Background of the Study

When it comes to Parkinson's disease (PD), patient follow-up is crucial to provide longterm data that can help to predict symptoms of PD and develop therapies to treat or prevent them. Longterm data is also valuable for developing PD biomarkers, specific biological traits used to indicate PD severity or progression. Unfortunately, few studies have attempted to monitor patients for more than five years, since it is costly and difficult to maintain the follow-up of any participant study group.

To address these setbacks, a nonprofit association of researchers known as the Parkinson’s Study Group (PSG) developed the Longitudinal and Biomarker Studies in Parkinson’s Disease (LABS-PD), a program designed to re-recruit groups of PD patients from earlier studies and evaluate them through their disease in order to:


       
  • Provide longterm data on the course of PD symptoms
       

  •    
  • Develop biomarkers that measure risk for and progression of PD.
       


Accordingly, an initial feasibility study conducted by PSG researchers and published in the Movement Disorders Journal (Vol. 24, Issue 14), establishes that LABS-PD is a promising strategy to assess PD study groups over time and to provide a platform for biomarker development.

Purpose of the Study

 The purpose of this study was to test the program’s feasibility by evaluating patient enrollment and biomarker sampling in the first LABS-PD study groups.



LABS-PD Participants and Study Groups:

The first participant study groups formed in LABS-PD were:


       
  1.  A large group of PD patients

       

  2.    
  3.  A second group of control subjects including:

       



       
  • Healthy controls: Participants who do not have PD.

       

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  • Disease controls: Participants with other neurological disorders that resemble PD.

       


Study Methods

 In executing the study, researchers used the following methods:

Firstly, in order to create the program’s first study groups, researchers enrolled participants by: 


       
  • Inviting patients and research sites from PRECEPT (a former PD drug trial) to participate in PostCEPT—the firstPD study group in LABS-PD

  •    
  • Inviting healthy and disease controls to join the control group for the Prognostic Biomarkers (PROBE) study, a LABS-PD study that collects four different patient biological samples in order to analyze their potential as PD biomarkers.


Next, in order to obtain patient medical data and track the natural course of PD, researchers used the following methods to follow up on PostCEPT patients: 


       
  • Researchers met with patients annually and at 3-year intervals to evaluate progression of motor and non-motor symptoms of PD and changes in cognition and behavior

       

  •    
  • FOUND Study: Researchers invited patients to participate in the Follow-up of Persons with Neurologic Diseases (FOUND) study, a LABS-PD clinical study that conducts mail and telephone follow-up to update: patient diagnosis, medications, hallucinations, fatigue, sleep disorders, use of health care services, available social supports, and the economic impact of Parkinson’s.


 Afterwards, to provide a biological database to help study and develop PD biomarkers, researchers established three means to collect PostCEPT biological samples and patient data:


       
  1. Blood Samples: Patients were invited to donate blood samples to a DNA repository, where their cell samples were prepped and preserved to provide a source of DNA.

       

  2.    
  3. Imaging Study: Patients were invited to continue the PRECEPT drug trial’s DAT imaging study, where patients received a series of brain imaging scans to monitor dopamine-related damage.

       

  4.    
  5. PROBE Study: Patients were invited to participate in the LABS-PD Prognostic Biomarkers (PROBE) study, where researchers collected four different patient biological samples to analyze their potential as PD biomarkers.

       


Lastly, in order to manage LABS-PD data and link patient data from earlier studies (ex. PRECEPT) to patient data collected during LABS-PD, researchers used the following methods:


       
  • Researchers developed a unique identifier system that provides each patient with a special ID so that s/he can be tracked across multiple studies without being personally identified

       

  •    
  • Researchers created the PD-DOC website (a public-access website of clinical, environmental, and biological patient data) so that new LABS-PD data can be readily stored and accessed.

       


Study Results

In response to the program’s feasibility, this study suggests that LABS-PD is a promising strategy to assess PD study groups longterm and to support the development of PD biomarkers. This suggestion was based on statistical analyses evaluating enrollment in the first LABS-PD study groups and participation in the program’s clinical studies and biomarker sampling procedures.

In terms of LABS-PD study group enrollment, researchers found that:


       
  • Over two-thirds, 67% (537 of 806), of all PRECEPT patients were recaptured for the PostCEPT study group

       

  •    
  • Over 100 subjects (54 healthy controls, 53 disease controls) were recruited for the Prognostic Biomarkers (PROBE) control study group.

       


According to these results, researchers determined that LABS-PD is a feasible way to offer patients the opportunity for longterm study participation and to enroll participants for the purpose of developing PD biomarkers. Moreover, after comparing data from PRECEPT to PostCEPT enrollment, researchers discovered no significant difference between patients who enrolled in PostCEPT and patients who did not enroll in PostCEPT. This  discovery suggests that enrollment was not based on demographic differences (ex. age, gender, and race) or on the severity of PD symptoms. 



Furthermore, in terms of participation in LABS-PD clinical studies and biomarker sampling procedures, researchers found that:


       
  • Blood Samples: 72% of PostCEPT patients have donated blood samples to the DNA repository.

       

  •    
  • Imaging Study: 95% of PostCEPT patients have received follow-up imaging scans under the DAT imaging study.

       

  •    
  • PROBE Study: 100% of PROBE participants (102 PostCEPT patients, 107 control subjects) have completed biomarker processing for all four biological samples.

       

  •    
  • FOUND Study: 51 of 55 PostCEPT sites—and 92% (454 of 489) of their patients—have agreed to participate in the Follow-up of Persons with Neurological Diseases (FOUND) study.


 According to these findings, researchers concluded that LABS-PD is a feasible strategy to provide longterm patient data and to collect a variety of patient biological samples for biomarker study.

Study Discussion & Implications

The concept of LABS-PD is significant because it represents the potential to attain longterm patient data, which is critical to understanding Parkinson’s and how the disease evolves in patients. Such a milestone in understanding of the nature of PD would enable researchers to predict complications of the disease and develop therapies to prevent them. Overall, the study indicates that the LABS-PD program is a feasible strategy to support the longterm assessment of PD study groups and to provide a foundation for biomarker development. Based on the study results and the success of the initial LABS-PD efforts, researchers recommend that the program is put into full operation; continuing to enroll additional study groups to increase patient diversity and continuing to identify promising biomarkers that will track the course of PD.



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Chaturvedi A, Butson CR, Lempka SF, Cooper SE, McIntyre CC.. Patient-specific models of deep brain stimulation: Influence of field model complexity on neural activation predictions.. , Brain Stimul. 2010 Apr;3(2):65-77.Brain Stimul. 2010 Apr;3(2):65-77.

The purpose of this article was to evaluate different DBS STN settings as created by a computer based model in order to predict patient specific optimal settings for the best possible motor improvement.  The authors utilized various imaging and recording devices to evaluate five different models that produced stimulation from the DBS.  They also focused on the different types of brain tissue that surrounds the stimulator to evaluate possible causes of adverse events from possible spread of the stimulation.  This study was very detailed in the methodology used and recommended that continued work needs to be completed to better understand this therapy for People with Parkinson's (PWP) in order to avoid oversimplification of stimulator settings, maximize stimulation benefit, and minimize adverse events.  This study highlights that even though DBS STN has been around for years clinicians, researchers, patients, and families are still learning about this treatment option and improving upon techniques of the past in order to provide the best treatment possible.

Click here to go to Pub Med Abstract.

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Vitek JL, Lyons KE, Bakay R, Benabid AL, Deuschl G, Hallett M, Kurlan R, Pancrazio JJ, Rezai A, Walter BL, Lang AE. Mov Disord. 2010 Jun 11.. Standard guidelines for publication of deep brain stimulation studies in Parkinson's disease. ,

The purpose of this article was to provide standardized guidance for researchers and clinicians when creating and publishing studies that involve DBS.  One of the largest difficulties in current DBS research is that it is difficult to compare the strengths and weaknesses of studies as there is no consensus on how the treatment works, programming, surgical site, measures used to evaluate change, times to complete assessments, lead locations, length of time when measuring “off” or “on” DBS parameters, etc.  With studies having so many differences in how they complete the procedure and how outcomes were measured makes it difficult for the field to move forward on improving the technique in order to maximize efficacy. Notable suggestions by the group were for researchers to look at the typical PD motor issues but also to include evaluation of non-motor difficulties and issues related to quality of life.  They also recommended utilization of a multi-disciplinary team to evaluate participants pre and post stimulation as well as guidelines to reporting complications and adverse events.  The authors made a great point in the importance of reporting adverse events in studies not to be punitive to the authors or the study but so other researchers and clinicians can learn from each other in determining risks and efficacy of this procedure so that the individuals that undergo this procedure are fully informed in their decision to undergo this treatment.  Lastly, an easy to follow check list was provided in the article for those planning a study or preparing a manuscript for publication.

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Chan DT, Zhu XL, Yeung JH, Mok VC, Wong E, Lau C, Wong R, Lau C, Poon WS.. Complications of deep brain stimulation: a collective review.. , Asian Journal of Surgery 2009 Oct; 32(4):258-63.Asian Journal of Surgery 2009 Oct; 32(4):258-63.

The purpose of this article was to discuss what these authors have learned from completing the DBS surgery as well as to discuss the possible complications as well as what can be done to prevent such difficulties while moving forward with this treatment.  The authors reviewed their cases from 1997-2008 and broke the complications into those related to the surgery, the hardware, or the stimulation and provided discussion of each as follows: 



The surgery: 


       
  • One complication during the surgery involved having to move the DBS electrode to determine the best placement which increased the risk of hemorrhages.  In their patient group, less than 1% experienced a hemorrhage.  They suggested that the best way to prevent such complication was to extensively plan the surgery, utilize imaging techniques, and continue to develop surgical equipment that minimized the invasive nature of the surgery. 



       
  • Another complication from the surgery involves poor positioning of the electrode for a variety of reasons that reduced the efficacy of the treatment.  Prevention techniques for this complication include intraoperative recording of brain activity as well as improved surgical devices that keep the electrode placed in the correct position.  Approximately 2% of their patients experienced this complication.




The hardware:


       
  • The authors found that approximately 10% of their patients had electrodes that fractured, short circuited, or moved from their original placement site.  Reasons included improper tightening of the devices that hold the electrode in place as well as not enough tightening in other areas.  One patient experienced a fall that also led to the electrode moving from the original site.  Prevention techniques include improvement in the surgical devices as well as improved education and experience of the surgeons as they completed more and more of the surgeries.



       
  • Infection is a concern for any surgery involving placement of a foreign body/device into one’s body.  DBS surgery is no different and this study found approximately 10% of the patients experienced an infection related to the surgery and electrode placement.  The infections were usually detected very early and all of the patients that had infections had the implants removed.  The authors suggest that prevention of infections by taking precautions before the surgery is of utmost importance (e.g. antibiotics, antiseptic shampoo, etc.).




The stimulation:


       
  • A common stimulator complication is stimulation of surrounding tissues of the STN or GPi that cause a variety of motor and non-motor complications (e.g. speech, blinking, cognitive, psychiatric, weight gain, etc.).  Prevention techniques include changing stimulator settings and monitoring of patient’s condition for such complications.  Additionally, making sure that the patients are good surgical candidates and that they do not have pre-existing conditions (e.g. psychiatric or cognitive) that would worsen the chance of complications after the surgery.



       
  • Patients with DBS also have to be cautious and alert about having the stimulator and undergoing other medical procedures that may interfere with or cause damage to the stimulator or surrounding areas (specifics mentioned were radiofrequency and monopolar diathermy used in some dental procedures).  Prevention possibilities include that patients be given a card or other way of identifying that they have DBS as well as that they receive education on the importance of letting their medical professionals know about their surgical history. 




In general regarding prevention of complications in DBS, many studies, including this one, strongly suggest using a multidisciplinary approach with a team dedicated to the treatment of movement disorders is very beneficial in order to minimize complications and maximize efficacy of DBS.

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McIntyre CC, Frankenmolle AM, Wu J, Noecker AM, Alberts JL.. Customizing deep brain stimulation to the patient using computational models.. , Conf Proc IEEE Eng Med Biol Soc. 2009; 2009:4228-9.Conf Proc IEEE Eng Med Biol Soc. 2009; 2009:4228-9.

The purpose of this article was to compare DBS STN stimulator settings on cognitive and motor tasks in people with Parkinson’s disease (PWP) that were created on either a clinician’s skill and experience or settings generated by a computerized model.  One problem with DBS stimulator settings is that there are 1000’s of possible settings and it is not feasible (time or discomfort) for clinicians or PWPs to go through all of the possibilities in order to find the “perfect” setting.  Therefore, it would be ideal to find the least invasive and most efficient method to set stimulator parameters for the best possible motor improvement and minimization of cognitive dysfunction for PWP.



The study found that utilizing the computer based model resulted in less power used by the stimulator and the same amount of improvement in motor scores as found in the model created by the clinician.  When they looked specifically at the cognitive tasks they found no difference between the two models when tasks were easy.  However, as complexity increased, when the computer generated stimulator settings were used, the PWP did better than when the settings were generated by clinicians alone.  The authors suggest that the difference was caused by the DBS stimulation spreading to areas adjacent to the motor portion of the STN, which then disrupts the full potential of one’s cognitive abilities.  A goal of the computer based model would then be to prevent spreading of the DBS stimulation to areas that are involved in cognitive functions while at the same time stimulating areas to maximize motoric treatment efficacy.  The authors suggest that based on their results, the computer based models should be used to supplement the stimulator parameter selection along with the clinician in order to best optimize the efficacy of the DBS STN.

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Resnick AS, Foote KD, Rodriguez RL, Malaty IA, Moll JL, Carden DL, Krock NE, Medley MM, Burdick A, Haq IU, Okun MS.. The number and nature of emergency department encounters in patients with deep brain stimulators.. , 2010 Jan; 257(1):122-312010 Jan; 257(1):122-31

The purpose of this article was to look at reasons why people who have DBS go to the emergency room as well as to provide education and guidance on how to best treat those patients.  The most common type of patient that presented to the ER was a male in his mid 50’s with either unilateral or bilateral implantation. Four main disease groups were looked at including Parkinson’s disease, essential tremor, dystonia, and other (multiple sclerosis, obsessive-compulsive disorder, or other tremor).  Approximately one forth of the Parkinson’s disease group utilized the ER and most commonly went for evaluation of mental status changes (changes in one’s cognitive abilities).  Other reasons were headache, infection related as well as not related to the hardware, pain, and passing out.  It was not surprising that the main reason for PD patients to go to the ER was neurological in nature as that is a common effect of the disease itself.  The amount of time that had passed since their surgery ranged quite a bit from 1 day post-op to 48 months post-op.  The authors also looked to see if the ER visit was related to the DBS surgery or hardware and found that about half of the time the reason was not related to the procedure or resultant hardware for the PD patients.  The study also provided easy to follow treatment algorithms (see article for specifics) for patients presenting to the ER that has DBS, regardless of the disease state.  The researchers conclude that as DBS continues to be a successful treatment for movement disorders, as well as other neurological conditions, that our health care systems need to be better educated and prepared for that DBS patient walking through the door regardless if that reason is DBS related or not.

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Stefani A, Roberto C, Livia B, Mariangela P, Alberto C, Salvatore G, Fabio P, Andrea R, Cesare I, Francesco M, Antonella P. (2009). Non-motor functions in parkinsonian patients implanted in the pedunculopontine nucleus: Focus on sleep and cognitive domains.. , J Neurol Sci. 2009 Sep 16. [Epub ahead of print].J Neurol Sci. 2009 Sep 16. [Epub ahead of print].

This is a follow-up article from an earlier study (see citation below) that looked at the efficacy of bilateral deep brain stimulation of both the Subthalamic Nucleus (STN) and the Pedunculopontine (PPN; another target under evaluation for the surgical treatment of PD).  The researchers initially wanted to look at the efficacy of both targets combined on motor functioning in the person with Parkinson ’s disease (PWP).  Their findings suggested that both targets were effective in reducing motor difficulties but more so for DBS-STN (STN 54% vs. PPN 32% improvement).  The follow-up study focused on how this dual-targeted treatment affects various non-motor functions in the PWP, specifically sleep and cognition.  The authors found that all six of the patients were classified as poor sleepers but with the PPN and STN in specific settings, patients had an increase in the quality of nighttime sleep as compared to DBS-STN settings alone.  Patients also reported less “restlessness, psychosis, and daytime sleepiness.”  In regard to cognitive functioning, the patients were found to have better working memory, executive functioning, response times, and delayed memory with various settings of the PPN as compared to when the PPN stimulator settings were off.  Metabolism changes in various frontal lobe brain areas were also found and discussed (we would refer the reader to the article for those details).  The authors purported that although the DBS-PPN was not as efficacious as the DBS-STN for motor improvement, it did have less cognitive side effects, which suggests it may be used as an alternative for patients that do not qualify for STN due to existing cognitive deficits.  They noted that research must continue to look into how the DBS works in various sites in the brain as well as maximizing the PWP’s quality of life as well as reduction in motor difficulties.





Original study:  Alessandro Stefani, Andres M. Lozano, Antonella Peppe, Paolo Stanzione, Salvatore Galati, Domenicantonio Tropepi, Mariangela Pierantozzi, Livia Brusa, Eugenio Scarnati, and Paolo Mazzone (2007).  Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease.  Brain (2007), 130, 1596-1607.



http://brain.oxfordjournals.org/cgi/reprint/130/6/1596 or http://www.ncbi.nlm.nih.gov/pubmed/17251240?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2

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Smeding HM, Speelman JD, Huizenga HM, Schuurman PR, Schmand B. . Predictors of cognitive and psychosocial outcome after STN DBS in Parkinson Disease.. , 2009 May 21. [Epub ahead of print]2009 May 21. [Epub ahead of print]

The purpose of this article was to look at the effects of DBS STN on cognition, mood, and quality of life in people with Parkinson's disease (PWP) as well as to evaluate any predictive factors for such changes.    The researchers tested two groups, one that had PD without DBS and another that had PD and underwent DBS STN surgery.  Each group was tested at baseline and then 12 months later.  No significant differences were found at baseline testing between the two groups on cognitive testing.  Twelve months after surgery, the DBS STN group showed improvement in their motor scores as well as a reduction in usage of levodopa.  In regard to the cognitive testing the DBS group showed decline, as compared to the control group, in the areas of verbal fluency (naming items as fast as one can that are from a category or that start with a letter; this finding is common), immediate and delayed memory, a Stroop task (a difficult task requiring naming the color of ink that a word is printed in, while ignoring the word itself), reading speed, and visuospatial reasoning.  Regarding the mood and behavior questionnaires, they found that the DBS STN group had more improvement in their quality of life as compared to the control group regardless of whether or not they experienced change in cognitive functioning.  It is notable that although there was a decline noted in scores on research measures, not all of the PWP that experienced change were able to detect a difference in their everyday lives.  As the findings of cognitive decline after DBS STN has been mixed, the authors suggest replication of this study, and continued attention is needed to this area.



The researchers also wanted to examine possible predictors of cognitive decline and quality of life in PWP.  They found that those PWP who had impaired attention, advanced age, and did not respond well to levodopa at baseline were more likely to experience cognitive decline after DBS STN.  They also found that how the PWP responded to levodopa prior to surgery was the best predictor of improvement in quality of life after surgery.



The authors concluded that DBS STN is an efficacious treatment for improved motor symptoms of PD as well as quality of life in the PWP.  However, the treatment has been found to have adverse effects that PWP need to know about before undergoing such treatment.  They discuss that physicians should also pay attention to premorbid factors before surgical intervention that may help predict who is more likely to have such adverse cognitive events after the surgery.

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Richardson RM, Ostrem JL, Starr PA. Surgical repositioning of misplaced subthalamic electrodes in Parkinson's disease: location of effective and ineffective leads.. , 2009;87(5):297-303. Epub 2009 Jul 292009;87(5):297-303. Epub 2009 Jul 29

The purpose of this article was to look at repositioning lead placements in people with Parkinson’s disease (PWP) that experienced suboptimal results after their initial DBS surgery.  It is notable that the researchers had patients from within their own practice as well as from other practices, suggesting that suboptimal surgical results happen at various facilities and more importantly that those suboptimal results should be individually reviewed in order to improve the effects of the DBS as well as reduce adverse events for such patients.   It should be noted that none of the patients in this study had surgical complications at either the initial or repositioning surgery that explained the suboptimal results.   We would refer the reader to the article for detailed and specific locations of each patient's initial lead as well as where the revised lead was placed (typically 2-5mm change towards the central zone of the dorsolateral STN).  All 8 of the PWP that underwent revision experienced improvement in their motor and nonmotor symptoms observed after the initial surgery and none reported any adverse events (improvements included general motor symptoms, gait, tremor, dystonia, depression, dysarthria, freezing of gait, and rigidity).



There continues to be mixed findings regarding the best lead placement site for DBS in PWP and this article contributes to that debate.  It is promising, that there is a large research study soon to come out that may best address the lack of consensus.  Although the debate continues, articles such as this remain important because there are individuals out there that are having suboptimal results from their initial surgery that may feel that there is nothing else to be done for them.  Research should and will continue regarding the best neuroanatomical lead placement sites but we cannot forget or ignore those PWP that are out there that did not benefit as much from the surgery as hoped.  This article is a great example that one option, lead repositioning, was appropriate for specific patients and those patients showed improvement after the second surgery.

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Kim HJ, Paek SH, Kim JY, Lee JY, Lim YH, Kim MR, Kim DG, Jeon BS.. Chronic subthalamic deep brain stimulation improves pain in Parkinson disease.. , Dec; 255(12):1889-94. Epub 2009 Jan 22Dec; 255(12):1889-94. Epub 2009 Jan 22

The purpose of this article was to look at pain in a subset of PWP before and after DBS STN. The article cites a prevalence rate of “40-78%” of the general group of PWP experiencing pain.  Approximately 80% of the PWP in this study reported pain in multiple areas of the body preoperatively.  The majority of the patients reported here had bilateral STN but a few had unilateral STN for specific reasons mentioned in the article.  Three months after surgery, the majority of those patients that were experiencing pain endorsed improvement (87%) in regard to their pain.  The authors found that dystonic pain was the most improved and back pain was the least reduced of the pain complaints.  It should be noted that not all patients had improvement in their pain and other patients developed pain where none existed prior to the DBS STN (24%).  After 6 months, most of the patients that had experienced a reduction in pain continued to report such reduction.  The authors also postulated ideas why DBS STN would reduce pain including reduced muscle tone, possible basal ganglia involvement, and other neuroanatomical possibilities.  More research needs to be done on pain in PWP to better understand how a treatment option for improved motor control may also be beneficial in reduction in yet another non-motor symptom of PD.  The authors also suggest that pain and DBS STN needs to be looked at longitudinally versus at a single point in time to best represent pain control or reduction in this group of people.

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Okun MS, Fernandez HH, Wu SS, Kirsch-Darrow L, Bowers D, Bova F, Suelter M, Jacobson CE 4th, Wang X, Gordon CW Jr, Zeilman P, Romrell J, Martin P, Ward H, Rodriguez RL, Foote KD. . Cognition and mood in Parkinson's disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: The COMPARE Trial.. , March 13, 2009March 13, 2009

The purpose of this article was to compare the effects of DBS-STN vs. DBS-GPi, in regard to mood and cognition.  The authors looked at various settings and stimulation parameters of both devices with patients off medication so they could evaluate the stimulators alone.  Patients were also given various cognitive and mood measures prior to surgery and then again 7 months after surgery.  It is notable that 7 patients did not continue the study after surgery due to adverse events (could not tolerate protocol, hemorrhage, and pneumonia related death [one]).  We would refer the reader to the supplementary tables in the article for more specific information about adverse events for those that remained in the study, although most were mild and did not last long.  However, the authors noted that the STN group had more adverse events than the GPi group.  



Generally, this article showed that there were few differences in mood and cognition between STN and GPi when both groups were at their optimal settings.  They concluded that the verbal fluency finding (naming as many words that start with a specified letter as fast as one can) likely is a result of the surgery as the effect was still there when the stimulator was not on for the DBS-STN group.   The authors also discussed that their findings suggest that the target of DBS may best be done based on individual patient characteristics (e.g. cognitive issue, behavioral concern, medication reduction, etc.).  It also showed different stimulator settings and areas that should be avoided in individuals with specific complaints (e.g. less energetic, less happy, etc.), which is very beneficial information for those doing the placement as well as the programming of the devices in improving the care and quality of life of individuals with DBS STN or GPi.

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Ellis TM, Foote KD, Fernandez HH, Sudhyadhom A, Rodriguez RL, Zeilman P, Jacobson CE 4th, Okun MS. (2008).. Reoperation for suboptimal outcomes after deep brain stimulation surgery.. , Neurosurgery. 2008 Oct;63(4):754-60; discussion 760-1.Neurosurgery. 2008 Oct;63(4):754-60; discussion 760-1.

The purpose of this article was to look at and learn from a group of patients (PD, Essential Tremor, or dystonia) that had suboptimal motoric results after their DBS surgery.  They discussed that one reason for poor results after surgery is suboptimally placed leads (even 2-3mm off target has been shown to affect results).  These authors looked at a group of patients that underwent reoperation with revision or replacement of the leads.  It should be noted that the group of patients from this study had their original surgery at a variety of sites, including that of the authors, which suggests that lead difficulties are possible regardless of where the surgery takes place or how careful the team is in placing the leads.  The authors suggested various precautions and techniques for movement disorder multidisciplinary teams to minimize such lead problems.  As DBS is a relatively new surgery for movement disorders, there will continue to be different surgical techniques used and implantation sites completed on various patients.  Researchers and clinicians need to continue to monitor and report their data to each other in order to come up with the best practice to successfully treat patients with movement disorders.



After reoperation the majority of the patients in this study had improvement in motor complaints and multiple areas of quality of life.  As can be seen with any DBS surgery, there were some adverse events noted with reoperation for 3 of the patients (infection, lead fracture, and wound closure difficulty due to thin skin).  The authors concluded that reoperation showed benefit for these patients.  They also discussed the strong need to have multidisciplinary teams create policies and guidelines for selection of patients that are good candidates for reoperation so that the subsequent surgery can be successful.

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Kirsch-Darrow L, Mikos A, Bowers D. (2008). Does deep brain stimulation induce apathy in Parkinson's disease?. , 2008 May 1;13:5316-222008 May 1;13:5316-22

This article is a review of the literature regarding apathy, a non-motor symptom, of PD, particularly looking at its relationship to DBS.   The authors define apathy as “a primary lack of motivation...[with] behavioral, cognitive, and emotional symptoms.”  Estimates of the prevalence of apathy ranged from 38-51% of PD patients (not specific to DBS) and can be distinguished from depression (a condition that has some symptom overlap).  The authors posed several hypotheses of what areas of the brain may be affected when someone is apathetic as well as what may be causing such changes (e.g. activation from the electrode that is possibly spreading to non-motor areas).



The authors of this manuscript found 7 studies that met their criteria for review and discussed each in detail regarding the strengths and weaknesses of each study.   The studies had mixed results regarding how much change occurred in apathy after DBS-STN, but it is notable that none of the studies found apathy to be improved after surgery.  Also, one of the more sound studies found that when comparing two surgical groups (one with PD and one without PD – the control group) the PD group had increases in apathy and the control group did not. 



The authors also suggested areas for future research to address when looking at apathy, such as looking at medication reduction, electrode placement, stimulation sites (GPi vs. STN), presurgical patient characteristics, and cognitive changes in relationship to changes in apathy.  They also brought up the need to use control groups, adequate apathy assessment tools/measures, and clinically significant statistical measures.  Their stated goal with this article was to support advancement in quality research that helps to better understand and treat PWP.

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Nègre-Pagès L, Regragui W, Bouhassira D, Grandjean H, Rascol O; DoPaMiP Study Group. Chronic pain in Parkinson's disease: the cross-sectional French DoPaMiP survey.. , 2008 Jul 30; 23(10):1361-92008 Jul 30; 23(10):1361-9

This article looked at chronic pain in Parkinson’s disease.  It should be noted that the patients involved did not have DBS.  The authors defined pain in two ways, 1. Pain related to PD and 2. Pain not related to PD.  Also, chronic pain has been defined by the International Association for the Study of Pain (IASP) as having unpleasant sensory and emotional experiences with actual or potential tissue damage that lasts for more than 3 months. Pain was assessed by various questionnaires as was depression, sleep quality, and quality of life in patients with PD as compared to a medical group without PD.  The authors found that the PD group had more severe depression, anxiety, and sleep disturbances than the medical group without PD.  Sixty-one percent of the PD patients met the criteria for chronic pain compared to 58.2% of the medical group.  However, when they “controlled for”/ took into account osteoarthritis in both groups (which is a common cause of pain for the general public), the PD group was twice as likely to suffer from chronic pain as the medical group.  Of the PWP and chronic pain, about 60% had pain due to their PD (aggravated osteoarthritis, dystonia, neuropathic pain, akathisia, which is a sense of discomfort or restlessness, and “deep ache, myalgia, cramps, stiffness, or discomfort”).  



This research also found that PWP having chronic pain due to their PD tended to be younger, have an earlier onset of PD, tend not to use analgesic medications for pain, and had a more severe case of PD on multiple medical measures than the other groups.  Additionally, PWP with chronic pain related to PD reported lower quality of life when compared to PD patients without pain or those with pain not related to their PD.   The authors stated that pain appears to be another component of PD because the group with chronic pain due to PD was noticeably different than the group with chronic pain that is not attributable to PD.  The authors also discussed possible neurotransmitters that may be involved in pain related to PD. Thus, it is evident that pain is a part of the PD experience, but it continues to be under recognized and understudied in this population. The understanding of pain deserves more attention and research for the PD population as a whole as well as for the PD patient with DBS to improve treatment of this disease and to improve the quality. 



(The full article was available free online at the time of this writing through the pubmed link below. Click on the red MDS button at the bottom of the abstract.  This should take you to the Movement Disorder Society website and you can click on the PDF or HTML option.  This appears to be a monthly special review of this article, which suggests it may not be available indefinitely.)

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Mehta SH, Morgan JC, Sethi KD. (2008), Sleep disorders associated with Parkinson's disease: role of dopamine, epidemiology, and clinical scales of assessment.. Sleep and PWP. , CNS Spectr. 2008 Mar;13 (3 Suppl 4):6-11.CNS Spectr. 2008 Mar;13 (3 Suppl 4):6-11.

(The full article was available free online at the time of this writing through the pubmed link below.  Click on the "CNS Spectrum" button towards the top right of the page and you should be automatically forwarded to the article.)



This article reviews some general information about sleep in PWP.  The authors briefly reviewed the relatively high prevalence of sleeping difficulties within the PD community (approximately 2 out of 3 patients).    They went into great detail about the many different possible causes of sleep disorders in PD as well as the role that various neurotransmitters (including dopamine) play in one’s sleep/waking cycle and in the sleep difficulties a person may experience.  The authors also discussed that different medications used to treat PD may also contribute to some of the sleeping difficulties (insomnia or sedation) for PWP.  Not only did the authors discuss some of the nighttime sleeping problems (frequent nighttime waking, sleep apnea, etc.) they also brought up that excessive daytime sleepiness occurs in approximately 15-50% of PWP.  The authors listed several tools that clinicians use to measure sleeping difficulties and went through the pros and cons of each measure. Lastly, there was mention of a few studies that have shown that DBS STN has improved total sleeping time, reduced patient self-report of sleeping trouble, and decrease of dystonia upon waking for PWP who have undergone that treatment.  As many will agree, more research needs to be done in the areas of non-motor symptoms (such as sleep disturbance) for PWP.  These authors suggested looking at different dopamine receptors and the role they play in sleep as well as improving research tools and education for patients, clinicians, and family members as they continue  to learn more about and treat symptoms of PD.

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Moreau C, Defebvre L, Destée A, Bleuse S, Clement F, Blatt JL, Krystkowiak P, Devos D. (2008). Surgical Treatment of PD. , STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology. 2008 Apr 16 [Epub ahead of print]STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology. 2008 Apr 16 [Epub ahead of print]

The purpose of this study was to look at the parameters of DBS-STN settings when PWP have severe gait disturbance or episodes of freezing.  The goal of this study was to evaluate if making setting changes would reduce such disturbances.  All of the patients who participated had undergone DBS STN within 5 years of the worsening of their motor difficulties and had experienced initial improvement after the surgery.  The results of this study suggested that a two step approach to the stimulation parameters may be the best method for controlling the severe gait disturbances and freezing episodes that can be seen in advanced Parkinson’s disease.  They suggested that initially a higher stimulator frequency setting (130 Hz) is beneficial with “typical voltage” for optimal motor control but after motor disturbances worsen with time a lower stimulator frequency setting (60 Hz) with higher voltage may show more promise.  The authors also offered multiple hypotheses as to why such stimulator changes may be beneficial (e.g. surrounding structures, changes in the STN with disease progression).  Further research on stimulator settings was recommended to fully evaluate this treatment option’s efficacy for controlling motor dysfunction in PWP.

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Melamed E, Ziv I, Djaldetti R. (2007). Management of motor complications in advanced Parkinson's disease.. , Mov Disord. 2007 Sep; 22 Suppl. 17:S379-84.Mov Disord. 2007 Sep; 22 Suppl. 17:S379-84.

This article is a summary of the progression of motor complications seen in the early and later stages of Parkinson’s disease as well as how best to manage those symptoms.  As discussed in the literature, levodopa is the most common treatment for PD, but approximately 2-5 years after the treatment is initiated the patient often experiences reduced efficacy of the drug and develops adverse motor complications (e.g. “dyskinesias and dystonias”).  As the disease progresses and the medications lose efficacy, most PWP will begin to experience “wearing off” phenomenon and increases in the daily need for levodopa.  The authors discussed various specific motor phenomenons (on/off, wearing off, delayed on, no-on) that can occur when taking levodopa (we refer the reader to the article for more discussion of the specific phenomenon, these can also be found in the DBS-STN glossary). 



In the article there was discussion about the underlying mechanisms for the motor complications/fluctuations that the PWP may experience.  It is notable that these mechanisms are not fully understood.  Researchers are continuously attempting to better understand these processes as well as create better therapies for the PWP to avoid motor complications or reduced responses to the medication.  The authors discussed 2 general hypotheses (central and peripheral) to explain these motor fluctuations. The central mechanism hypothesis suggests that due to disease progression there are changes in the brain (reduced receptors, less sensitive receptors, and poor conversion of the drug in the system) that do not allow the medications to work as effectively as they once did.  The peripheral mechanism hypothesis purports that the drug itself may cause changes in the stomach, which affects how much of the drug is available for the brain. 



Lastly, the authors gave specific guidelines for medical professionals to manage motor fluctuations related to levodopa.  The authors also gave suggestions on how best to improve absorption of levodopa that can be done within the patient’s home (e.g. taking the medication before meals, avoid protein filled meals, not to lie down after ingesting the medication, etc.).  Furthermore, they discussed other medical techniques that have shown promise, including surgical interventions (e.g., e.g. thalamotomy, pallidotomy, DBS, and stem cells).  This article, like many before it, concludes simply that more research needs to be done on these approaches to best understand and treat motor complications from PD.



**We at DBS-STN do not offer any medical advice in regard to how to take your medications.  Any changes in one’s medication regimen should be done only under the advice of your physician.  Any questions regarding how best to manage your motor complications should be discussed with your physician.

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Ludwig J, Remien P, Guballa C, Binder A, Binder S, Schattschneider J, Herzog J, Volkmann J, Deuschl G, Wasner G, Baron R.. Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson's disease.. , J Neurol Neurosurg Psychiatry. 2007 Jul;78(7):742-5. Epub 2007 Mar 19J Neurol Neurosurg Psychiatry. 2007 Jul;78(7):742-5. Epub 2007 Mar 19

This is a European study that looked at the effect of stimulator or medicinal treatment of PD on the autonomic nervous system (ANS; e.g. system in the body that controls heart rate, blood pressure, bladder control, temperature, etc.) of PWP.  The authors looked at PWP with and without DBS as well as at different times of stimulation and medication administration (e.g. immediately after taking it, off vs. on times, etc.).    The individuals that underwent DBS-STN were approximately 1-2 years out from the surgery and had significant improvement in their motor symptoms as well as a reduction in the amount of levodopa needed after surgery.   The authors found that select ANS functions (enhanced blood flow to the skin, bladder functioning) were positively affected by DBS-STN but in general that the stimulator did not affect blood pressure or cardiac functioning.  They also found that levodopa negatively affected select ANS functions (lowered heart rate, lowered blood pressure, increased temperature, decreased blood flow to the skin), which in turn increased problems with orthostatic hypotension (getting dizzy with positional change).  The researchers concluded that DBS-STN resulted in improvement in motor functioning, lowered need for PD medications after surgery, and that the symptoms of ANS dysfunction were reduced as compared to the non-stimulated PWP.

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Farris S, Vitek J, Giroux ML. (2008), . Deep brain stimulation hardware complications: The role of electrode impedance and current measurements.. , Mov Disord. 2008 Jan 9 [Epub ahead of print]Mov Disord. 2008 Jan 9 [Epub ahead of print]

The authors of this study began by discussing the improvement of motor symptoms from DBS.  However, as we know, this procedure may undergo changes in the level of motor control across time.  They discussed that there may be various reasons that DBS changes in efficacy across time, including the hardware of the device itself.  In a related finding by these authors, they looked at 466 patients across 7 years and found a rate of 8.1% of those patients had changes in their motor functioning as a direct result of hardware problems (e.g. battery failure, problems with the wires, or misplaced electrodes).   They discussed the role of hardware complications as being very important as more and more people are undergoing this procedure and sadly there is little guidance from the manufacturers in regard to technical manuals and there are no strict clinical guidelines to follow in regard to hardware/patient management.  The goal of their current study was to follow 4 patients that had hardware complications and how they were best managed for long term efficacy of DBS.   The authors went into a great deal of specific stimulator settings (we refer the reader back to the original article for specifics as it is beneficial to read the entire article for related information past the scope of this review) and findings for each patient including a kink in a lead wire, wire fracture, internal wire abnormality, and gap in the wire insulation.  It is notable that the patients had their DBS for less than 5 years and after finding hardware problems were treated by either stimulator parameter changes or surgery with resultant returned improvement in their motor symptoms.  The authors noted that there are various reasons why a PWP may undergo changes in symptoms related to their PD (e.g. disease progression, hardware failures, medication changes, comorbid illnesses, etc.) but when their patients experienced an acute change in “significant tremor” they found hardware issues best explained these changes.  They also noted that it is important to carefully look at the pattern of change in patients, including were there any preceding events that may have caused change (e.g. battery replacement, falls, etc.), what is the time course (e.g. acute or gradual), are the symptoms unilateral or bilateral, do the symptoms change with head or body positioning, is there an unusually short length of time before battery replacement (e.g. short in the wires), and what specific symptoms are increasing (e.g. tremor, paresthesia, surge sensations, etc.).  The authors concluded that there should be various clinical protocols in place for medical management of PWP.  As there are limited resources in this area for clinicians, the authors whom provide a great deal of patient care for PWPs, provided a “clinical pathway for DBS hardware monitoring” in an attempt to improve the medical management for other clinicians that may be struggling with similar hardware issues with their patients as well.

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Wider C, Pollo C, Bloch J, Burkhard PR, Vingerhoets FJ. (2007). Long-term outcome of 50 consecutive Parkinson's disease patients treated with subthalamic deep brain stimulation.. , Parkinsonism Relat Disord. 2007 Sep 5 [Epub ahead of print]Parkinsonism Relat Disord. 2007 Sep 5 [Epub ahead of print]

The authors of this study from Switzerland present the long term data (5 year follow-up) of 50 patients with Parkinson’s disease that underwent DBS-STN. It is notable that the patients in this study, as compared to others in the literature, were older (age = 64.9). All patient data was evaluated and 34% of the original 50 patients had died by the five year mark. The causes of death were infection (not directly related to the surgery), cancer, heart attack, embolism, anaphylactic shock, and suicide. All of the patients that died had good motor outcome from their surgery and did not generally differ from the remaining participants. The remaining patients also had improvement with their motor functioning with the stimulator on in the areas of dyskinesias, reduced “off” time, and tremor. Specific details regarding changes (good and bad) were included in the article. The results were less positive in regards to motor testing without medication, suggesting that disease progression continues and that the stimulator may not be as protective as originally thought. For many of the patients, there was also a reduced need for medications throughout the 5 years as compared to what they took prior to the surgery. It is notable that almost 30% of the patients did not take any PD medication after their surgery. The authors found that patients required more stimulation changes immediately after surgery than they did within the five years and the stimulation voltage increased across time. Patients typically had battery changes around 4 years after surgery. Adverse events immediately after the surgery included acute confusion (22%), seizure (2%), and hyperventilation during surgery (2%). Later adverse events were also well documented in the article and included; orthopedic injury (48%; fractures/arthritis; thought to be due to PD vs. the surgery itself), dementia (30%), depression (22%), misplacement of electrodes (8%), infection (8%), and seizure (2%). It should be noted that there was no specific discussion of speech testing or change within this study, which is important as other studies are finding changes in that area. The authors concluded that DBS-STN was beneficial and efficacious in motor testing at the 5 year follow-up but that the disease still progressed and caused patient symptoms to worsen over time. This study is important for patient’s considering as well as have undergone the DBS-STN procedure to allow the PWP to make informed choices about their medical conditions. Studies from the United States will soon be coming up, which will be interesting to see if similar results are found.

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