# Presentation: 381752

## Parkinson’s Disease

- Fran Weaver, PhD
- Deputy Director,
- Center for Management of Complex Chronic Care;
- Research Director, SCI QUERI;
- Career Scientist Awardee
- Hines VA Hospital
- Research Associate Professor
- Department of Neurology &
- Institute for Healthcare Studies
- Northwestern University

## Parkinson’s Disease (PD)

- Neurodegenerative disorder
- Progressive loss of substantia nigra dopaminergic neurons; loss of 70% before one is symptomatic, >90% loss at death
- Common cause of disability
- Incidence = 4.9-26/100,000
- Prevalence = 18-418/100,000
- Approx 60,000 new cases per year in U.S.
- VA – over 45,000 cases estimated

## Etiology

- Increasing age (rare in those < 50; early or young onset)
- 2 times more common in men than women
- May be more common in whites
- 1.4 to 3.5 more often to occur in families with relatives with PD (more common in siblings than children – early environmental factors or recessively inherited genes?)
- Environmental factors (pesticides, rural residence)
- Head trauma? Infection?
- Caffeine and smoking have been found to be protective

## Diagnosing PD

- No test or lab result available
- Cardinal symptoms: tremor, bradykinesia (slowed movements), rigidity, postural abnormalities (e.g., shuffling gait and balance problems)
- Patient is responsive to levodopa
- Recent work suggesting early loss of taste may be predictive of future PD

## PD Characteristics

- A movement disorder (walking, balance, freezing, handwriting); a progressive, bilateral disease
- Many non-motor problems also occur over time
- Speech, swallowing
- Depression, anxiety, compulsive behaviors (gambling, etc)
- Dementia, psychosis
- Autonomic problems (thermoregulatory dysfunction – e.g., low BP)
- Sleep related problems (insomnia, excessive daytime sleepiness, sleep apnea)
- May be a function of the disease and/or treatment

## PD System of Care - VA

- 6 Parkinson’s disease research, education and clinical care (PADRECC) centers (2000) – regional care centers
- National VA Parkinson’s Disease Consortium (2003)
- Consortium Center Network (2006) – 41 centers with movement disorders clinics and links to PADRECCs
- Neurology clinics in other VA facilities

## Treatment Options

- No Cure – address the symptoms
- Medication
- Physical therapy (exercise, Tai Chi, music)
- Surgery
- Stem cell transplantation & gene therapy

## Medications

- Dopaminergic Therapy: Levodopa – converts to dopamine (that is being lost) – introduced in 1960s, still primary treatment for PD – common side-effect after continual use - Dyskinesias
- COMT inhibitors: to enhance and prolong dopaminergic response (taken with Ldopa)
- Dopamine agonists: directly activate DA receptors

## Surgery

- Ablative surgery – pallidotomy, thalamotomy
- Deep brain stimulation – a functional lesion (modifiable, reversible)
- various sites in the brain:
- Thalamus
- Subthalamic nucleus
- Globus pallidum

## Why is Surgery Important?

- L-dopa is effective in early stages of disease
- Within 5-10 years of therapy, most patients begin to experience complications of therapy
- Longer periods in ‘off’ state (impaired movement, slowness)
- Dyskinesias
- Motor fluctuation
- On/off, end of dose wearing off

## Ablative Surgery

- Create a lesion on one or both sides of brain (pallidotomy, thalamotomy)
- Addresses motor symptoms; particularly side effects of l-dopa (dyskinesias)
- Significant side effects/adverse events, particularly for bilateral surgery
- Permanent (unable to reverse or modify)

## Deep Brain Stimulation

- Has become the surgical treatment of choice for PD
- Create a functional lesion using electrical stimulation
- Two primary “targets” for DBS
- Globus pallidus (GPi)
- Subthalamic nucleus (STN)

## DBS System

## Deep Brain Stimulation

- STN and GPi DBS are both effective for the reduction of PD symptoms
- STN DBS has become surgical treatment of choice
- Considered superior to GPi DBS
- Typically allows reduction of PD meds
- Primarily Level IV and anecdotal evidence, one small RCT, suggest similar outcomes

## A Meta-Analysis of Studies of Deep Brain Stimulation for the Treatment of Parkinson’s Disease

- To determine whether DBS of STN is more effective than DBS of GPi for treatment of symptoms of Parkinson’s Disease

- Weaver F., et al.  Deep brain stimulation in Parkinson disease: a metaanalysis of
- patient outcomes.  J Neurosurg 2005;103:956-967.

## Methods

- Medline Search
- Mesh terms: Parkinson’s disease, subthalamic nucleus, globus pallidum, deep brain stimulation
- Supplemented with bibliography published as part of FDA consideration of approval of DBS for PD
- Reviewed references of articles identified for additional articles/abstracts
- Attempted to contact authors for data elements not included in published work

## Methods

- Criteria for inclusion in meta-analysis: Bilateral DBS of STN and/or GPi
- Outcome measured as motor function in off medications/on stimulation state
- UPDRS subscale before and after surgery
- Other outcomes of interest:  ADL subscale of UPDRS, levadopa equivalents pre- and post surgery
- Develop a coding system for key variables
- Sample size, patient demographic information, definition of treatment and control groups, mean, standard deviation, standard error in order to calculate an effect size for each study’s findings

## Results

- 65 published studies/abstracts identified
- 20 studies excluded
- 		6 reported elsewhere
- 		5 did not report UPDRS motor scores
- 		6 reported only pre or post scores
- 		1 included both unilateral and bilateral
- 		   cases combined
- 		2 involved only unilateral DBS

## Results: STN DBS

- 30 studies
- 1995-2003
- 13% conducted in USA
- 565 patients (range 1-96)
- Patient demographics
- Mean age =  57.8 yrs
- 66% male

## Results: GPi DBS

- 13 studies
- 1997-2002
- 15% conducted in USA
- 136 subjects (range 3-38)
- Patient demographics
- Mean age =  55.0 yrs
- 69% male

## Motor Function – UPDRS III (on stimulation/off medications)

- STN Studies
- Mean Baseline score = **51.9****+**
- Mean Follow-up score = **22.8**
- % improvement = **54.3%**** **(range 27.5-80%)
- GPi Studies
- Mean Baseline score = **52.2**
- Mean Follow-up score = **32.5**
- % improvement = **40.1%**** **(range 10.5-68.1%)
- + Higher score, worse impairment

## Motor Score Effect Sizes

- STN studies
- Overall ES = 2.59 (95% CI 2.33-2.91), p<.001
- Q statistic* = 92.9, p<0.001
- GPi studies
- Overall ES=2.04 (95% CI 1.5-2.58), p<.05
- Q statistic = 32.57, p<.0021
- *tells you whether ES’s across studies are homogeneous or not (ours are not)

## ADLs Effect Sizes

- STN studies
- Baseline ADL=27.9; follow-up=14.8; 47%
- Overall ES = 1.81 (95% CI 1.62-2.0), p<.05
- Gpi studies
- Baseline ADL=28; follow-up=17.2; 39%
- Overall ES = 1.48 (95% CI 1.14-1.81), p<.05

## Medication Use (l-dopa equivalents)

- STN Studies
- Baseline dose = **1185 mg **_**+**_** 537.3**
- Follow-up dose = **632.4 mg **_**+**_** 429.9**
- % change = **- 46.7%**
- GPi Studies
- Baseline dose = **1045 mg + 461.6**
- Follow-up dose = **1057 mg + 482.0**
- % change = **+ 1.2%**

## Conclusions

- Both groups had significant improvement in motor function following DBS
- Following surgery, on average STN subjects were able to reduce their PD medication use by approximately half while GPi subjects experienced no change in medication dose
- Few Gpi studies and results not uniform

## Limitations of Existing Work

- Small sample sizes
- Non-randomized designs
- Significant selection bias
- Unclear patient inclusion criteria
- Unknown effect of surgeon experience
- Unable to determine whether certain patient characteristics (e.g., age) were related to outcomes

## Deep Brain Stimulation

- Many significant questions remain
- Is surgery more effective than medication therapy?
- Is STN the “best” target when other outcomes (e.g., nonmotor) and adverse events (e.g., cognitive) are considered?
- Do certain patients or certain symptoms respond better to DBS in one site vs. the other?
- Is medication reduction desirable?

## CSP#468: A Comparison of Best Medical Therapy and Deep Brain Stimulation of the Subthalamic Nucleus and Globus Pallidus for the Treatment of Parkinson’s Disease

*Principal Investigator*
- Kenneth A Follett, M.D., Ph.D.
- University of Nebraska
- Omaha, Nebraska
*Co-Principal Investigators*
- Frances M. Weaver, Ph.D.
- Hines VA Hospital & Northwestern University
*&*
- Matthew Stern, M.D.
- University of Pennsylvania Health System
- Philadelphia, PA & Philadelphia VAMC

## Randomized trial comparing best medical therapy to DBS and comparing STN DBS to GPi DBS
Funded by 
Department of Veterans Affairs 
National Institute of Neurological Disorders and Stroke
Medtronic Neurological
Thirteen centers recruited 316 patients (6 PADRECCs*, 6 University sites)
Follow-up to 3 years

- Funded by
- Department of Veterans Affairs
- National Institute of Neurological Disorders and Stroke
- Medtronic Neurological
- Thirteen centers recruited 316 patients (6 PADRECCs*, 6 University sites)
- Follow-up to 3 years

- CSP #468

- *Portland & Seattle were a joint PADRECC site, thus 7 VAs

## Study Design & Randomization 

- Enrollment criteria: PD, impaired 3+hrs/days, no prior PD surgery, cognitively intact, no dementia/psychosis

**Enrollment**

**N = 316**

- 3 & 6 month assessment

- 1,3,6,12,18,24 & 36 mo

- 1,3,6,12,18,24 & 36 mo

## Primary Outcome Measures 

- At 6 months, BMT v. DBS
- Time in the “on” state without troubling dyskinesias (using patient diaries)
- Represents outcome with functional significance for patients
- At 2 and 3 years post-surgery, GPi v. STN
- Motor function “on stim/off meds” (UPDRS III -motor subscale)
- “Standard” outcome measure for studies of surgery for PD

## Secondary Outcome Measures

- Functional Status
- Hoehn & Yahr
- Schwab & England
- Timed ‘stand-walk-sit’ test
- UPDRS
- Sections I, II and IV (instrumental & functional adl’s, side effects; self-report)
- Section III (motor subscale; observation)
- Blinded and unblinded assessments

## Secondary Outcome Measures

- Quality of Life
- Short-Form 36 (SF-36)
- Parkinson’s Disease Questionnaire 39 (PDQ-39)
- Quality of Well Being scale
- Health Care Use
- Medication use

## Secondary Outcome Measures

- Neuropsychological status
- Attention
- Language
- Learning and Memory
- Reasoning/executive function
- Mood

## Secondary Outcomes

- Operative technique
- Simultaneous bilateral electrode implant
- Simultaneous or staged battery implant
- DBS lead location
- Radiographic (CT or MRI) target
- Actual target (i.e., after intraop adjustment of target location)
- Independent review of postop MRI
- Number of microelectrode passes
- Operative complications, need for reoperation

## Secondary Outcomes

- DBS programming and stimulation parameters
- Hours stimulation system used
- Person doing programming
- Physician, nurse, electrophysiologist
- Time spent programming
- Settings at visit completion
- Amplitude, pulse width, frequency, contacts
- Frequency of self-adjustment using hand-held controller

## Secondary Outcomes

- Adverse events (AE)
- Serious Adverse events (SAE) – resulting in prolonged hospitalization, ER visit or hospitalization, and/or death
- Surgery-related (e.g., hemorrhage, wound dehiscence)
- Device-related (e.g., wire break)
- Disease progression (new or worsening symptoms such as rigidity, tremor, poor balance)
- Other (e.g., cardiac event, fracture)

## Checks and Balances	

- Executive committee (inc. PIs, some site investigators, selected CSP staff, NINDS program officer and Medtronic rep)
- Data Monitoring group – independent group, views outcomes data to monitor patient safety issues
- Human Rights Committee
- Monitoring through visit sites quarterly
- Electronic data entry/corrections

## CSP #468

- The largest clinical trial of surgery for PD
- Expected to be a “landmark” study
- Will clarify the role of DBS for the treatment of PD
- Will facilitate safe and effective use of DBS for PD
- Will provide level 1 evidence
- Will allow us to assess the effects of DBS by patient characteristics (e.g., age, gender)

## Baseline Data – Phase I

- N = 316 enrolled
-  134 randomized to BMT
-  124 to immediate DBS
-  68 (27%) were age 70 +
-  187 were less than 70 years old
- 58% were veterans
- Additional 42 enrolled in DBS for Phase II; 16 patients from BMT dropped out before DBS phase

## Demographics (Phase I)

|  | BMT (n=134)
Mean (sd) or % | DBS (n=121)
Mean (sd) or % |
| --- | --- | --- |
| Age  | 62.9 (9.0) | 63.0 (8.7) |
| Male | 82.1% | 81.0% |
| VA patient | 59.7% | 60.3% |
| Years since PD diagnosis  | 13.2 (5.9) | 11.5 (5.6)* |
| White | 95.5% | 96.7% |
| Married | 70.9% | 66.1% |
| Living with family | 76.1% | 81.8% |
| Has personal caregiver help | 44.8% | 47.1% |
| Family history of PD | 23.9% | 26.4% |

## Motor Diary Results

## Status	

- Phase II data collection scheduled to end Oct. 2008
- Primary paper (BMT v. DBS) in draft, target journal: NEJM
- STN v. GPi paper scheduled for early 2009
- Many papers on secondary outcomes planned

## Recent Developments

- NEJM (2006; Deuschl et al)
- Pairwise randomization to bilateral DBS v. medical management, n=156 (all subjects less than age 75)
- PDQ-39: outcome favored DBS (64%), outcome favored medical tx (36%)
- UPDRS III: outcome favored DBS (71%), outcome favored medical tx (27%)
- Motor diary: good on time increased by 5.4 hrs (DBS) vs. 0.6 hours (medical tx)

## Differences

- Larger sample, true RCT
- Comparison of surgical target (STN v. GPi)
- Inclusion of older patients (27% between ages 70 and 83)

## Long Term Impact of DBS

- 3-5 years out, motor function improvements are stable (e.g., tremor)
- Axial symptoms: speech, postural stability, gait decline (disease progression)
- Cognitive issues (several studies have found significant negative psychological effects of STN surgery)

## Costs of Surgery

- Estimated that annual management cost of PD is $6000 ($4500 for meds alone)
- Device (electrodes, extension wires, pulse generator) = $20,000 (2003 dollars)
- Surgical costs (pre-op, surgery, post-op) = $52,200 (2002 dollars)
- Ongoing costs of medications, adverse events, battery replacement (every 2-5 yrs)

## Cost-effectiveness of Surgical Target

- IIR planned for December
- Obtain VA, Medicare and possibly private sector use and cost data
- Include quality of well-being data
- Subanalysis of medical vs. surgical management (only 6 mos, attempt to project costs beyond)

## Where is the Field Going?

- New medications
- New surgical targets
- Gene therapy/stem cells
- Neuroprotection: the mechanisms and strategies used to protect against neuronal injury or degeneration in the Central Nervous System (CNS). The goal is to limit neuronal dysfunction/death and attempt to maintain the highest possible integrity of cellular interactions in the brain resulting in an undisturbed neural function
- Cure