Combined Deep Brain Stimulation for Parkinson's Disease

OBJECTIVE:

1. Determine if bilateral Pedunculo-Pontine Nucleus (PPN) Deep Brain Stimulation (DBS)
will improve gait and balance problems in Parkinson Disease (PD) patients whose other
disease features have responded to bilateral subthalamic nucleus (STN) DBS and
medications

2. Determine if bilateral PPN DBS will improve swallowing function in Parkinson Disease
patients treated with bilateral STN DBS and medication

3. Obtain electrophysiological data related to PPN

4. Obtain data related to the physiological relationship of the STN and PPN

STUDY POPULATION:

Three (3) subjects with clinically diagnosed PD who have undergone bilateral STN DBS at
least one year prior to enrollment, who continue to have gait and balance disturbance.

DESIGN:

Pilot study of 3 patients with clinically diagnosed PD who have undergone bilateral STN DBS
at least one year prior to enrollment. Baseline evaluation will include neurologic clinical
evaluation, postural and gait physiologic and clinical assessment, brain imaging, and video
swallow evaluation. The patients will undergo the surgical procedure (bilateral PPN DBS
implant) in the Clinical Center (CC). Electrode recordings will be obtained from the implant
site within the first week post-operatively from an externalized lead, then the second
surgical stage (pulse generator implant) will take place, also in the Clinical Center. The
patients will undergo programming to optimal parameters and appropriate follow-up, and the
outcome measures will be assessed at 1 week and 1, 3, 6 and 12 months post-surgery.
Recruitment will be staggered and at least 4 weeks will be required between different
patients beginning the study. Recruitment will be halted if major unexpected side-effects
occur causing concern about the welfare of patients.

This study is to serve as the basis for an extended, larger study, which would be properly
powered to answer the clinical research questions. The efficacy criterion for translation
into a larger study will be 30% improvement in the primary outcome in 2 out of the 3
patients. In addition, we will obtain valuable and for the most part novel data regarding
the electrophysiologic properties of the PPN and the complex interactions between basal
ganglia (BG) components in the parkinsonian state and the response to DBS. The data obtained
in this study will inform the design, selection and treatment paradigms in future larger
studies.

OUTCOME MEASURES:

Primary:

- Change in the amount of time needed to complete a standardized timed up and go (TUG)
study at 6 months post-surgery on stimulation

- Change in the amount of time needed to complete a standardized timed up and go (TUG)
study at 6 months post-surgery on stimulation, compared to off stimulation.

Secondary:

- Change in time needed to complete the TUG study at 1, 3 and 12 months post-surgery on
stimulation

- UPDRS part III score and UPDRS part III points 27-30 at 1, 3, 6 and 12 months on
stimulation

- Parkinson's Disease Questionnaire (PDQ 31) quality of life questionnaire at 6 months

- Change in static and dynamic posturography outcome parameters at 1, 3, 6 and 12 months
on stimulation

- Number of adverse events during the follow-up period

- Change in timed and non-timed variables of swallowing function at 6 months

- Recorded physiologic function of PPN with STN stimulator off and on at rest and during
gait

- Changes in the patient global impression of change at 1, 3, 6, and 12 months. All the
outcome measures are assessed on best medical therapy..

-INCLUSION CRITERIA:

i. Greater than 22 years of age

ii. Successful bilateral STN DBS implants for at least 1 year

iii. At least 30% improvement in the motor UPDRS following STN therapy, by history and
record review

iv. Improved UPDRS and self assessment questionnaire following STN DBS by at least 20%, by
history and record review.

v. Good STN DBS placement assessed with imaging (CT scan, MRI or fused CT-MRI imaging)

vii. Persistent gait disturbance as ascertained by abnormal performance on the
time-up-and-go test compared to age-matched controls as well as preoperative evaluation
with posturography and quantitative gait assessment (values compared to normal age-matched
controls) at least 30% difference from age-matched controls on either measure.

vii. Persistent speech and swallowing problems as measured by a minimum score of I in
items 5 and 7 of the UPDRS

viii. Evaluation by an independent movement disorders specialist who will confirm gait
disturbance in the presence of STN stimulation.

EXCLUSION CRITERIA:

i. Pregnant or nursing women

ii. Cognitively impaired subjects as determined by pre-operative neuropsychology
evaluation, including Mattis Dementia Rating Scale (DRS). Patients scoring below 70 on the
Mattis DRS will be excluded.

iii. Depressed subjects as determined by the neuropsychology screen, including Beck
Depression Inventory. Patients scoring above 20 on the Beck inventory will be excluded.

iv. Patients with uncontrolled co-existing medical conditions: uncontrolled systemic
hypertension with values above 170/100; heart disease needing intervention; respiratory
disease needing intervention; uncorrected coagulation abnormalities or need for
therapeutic anticoagulation which cannot be interrupted; any condition that would render
the patient unable to safely cooperate with the study tests as judged by the screening
physician.

v. Patients with metal objects in their body that are not MRI compatible, excluding the
previous STN DBS hardware

vi. Patients who have a history of seizures, require repeated magnetic resonance imaging
(MRI) scans or have had a cranial neurosurgical procedure since receiving an STN implant.