Deep Brain Stimulation Surgery for Movement Disorders

Objective:

The objective of this protocol is to provide DBS surgery and to collect physiology and
efficacy data related to DBS therapy and motor and cognitive function in people with
medically refractory Parkinson s disease (PD), dystonia, and essential tremor (ET). All
treatment under this protocol will be based on the current standard of care for DBS surgery.

Study Population:

Patients 18 years and older with medically refractory PD, dystonia and/or ET may participate
in this study.

Study Design

The treatment that is rendered in this protocol is standard of care for PD, dystonia, and ET.
Patients confirmed to have medically refractory PD, dystonia or ET will be offered DBS. The
therapeutic goal of this procedure is to implant chronically stimulating macroelectrodes in
the basal ganglia or thalamic nuclei in order to alleviate the symptoms of PD, dystonia or
ET. Pre- and post-operative imaging will be used to precisely localize electrode locations
within the brain and will be correlated with measures of clinical efficacy and recorded
intra-operative neural activity. Intra-operative microelectrode recordings, as well as micro-
and macroelectrode electrical stimulation, will be used to confirm positioning of electrode
leads. Intra-operative electrode recordings will also be used to investigate the
neurophysiological mechanisms of deep brain stimulation and to explore the neural circuits
underlying motor and cognitive processing in the basal ganglia. Intraoperative physiology
will be used for clinical and research purposes. Patients will be followed for 3 months after
the surgical procedure to determine effectiveness of DBS treatment.

Outcome Measures:

The primary goal of this protocol is to determine the physiology and efficacy of DBS surgery
for movement disorders. Efficacy outcome measures include the change in motor symptoms, as
measured by the UPDRS III scale, the Burke-Fahn-Marsden (BFM) dystonia rating scale, and the
Tremor Rating Scale before and 3 months after treatment. Secondary measures include 1) levels
of effective drug therapy before and after surgery; 2) change in behavior and performance of
activities of daily living; 3) complications of therapy as measured by the UPDRS I, II, and
IV scales before and after surgery and the SF-12 score; 4) radiographic correlation of DBS
electrode position and clinical changes; and 5) neurophysiological mechanisms of DBS and
motor and cognitive function in the basal ganglia.

- INCLUSION CRITERIA:

To be eligible for entry into the study, candidates must meet all the following criteria:

Be 18 years of age or older.

Able to provide informed consent.

Have a clinical diagnosis of idiopathic PD, primary dystonia, or ET:

- The diagnosis of idiopathic PD will be based on the UK Brain Bank Criteria, and
confirmed by the Movement Disorders Neurologists in the NIH Parkinson Clinic

- The diagnosis of primary (generalized or segmental), hemidystonia, or cervical
dystonia will be confirmed on clinical examination in the NIH Movement Disorders
Clinic

- The diagnosis of ET will be confirmed on clinical examination in the NIH Movement
Disorders Clinic (the diagnosis of ET will be based on bilateral, largely symmetric
postural or kinetic tremor involving hands and forearms that is visible and
persistent. Additional or isolated tremor in head may be present but there should be
the absence of abnormal posturing).

History of appropriate response to dopaminergic medication, with at least a 30% improvement
in motor UPDRS with L-DOPA by history or in-clinic testing, for the PD patients OR:

Patients with tremor-dominant PD that do not respond to dopaminergic therapy and that
exhibit a tremor score of at least 2 for tremor severity on at least one side of the body
on the motor UPDRS examination.

Unsatisfactory clinical response to maximal medical management (with trials of both higher
and lower doses of drugs), including:

- good benefit from dopaminergic medication but associated with insufficient duration of
action or unacceptable side-effects OR

- intractable disabling motor fluctuations (severe off periods, dyskinesias, or freezing
spells) OR

- intractable symptoms of ET or dystonia impacting at least 2 activities of daily
living.

Agree to undergo DBS if indicated to treat medically refractory movement disorder.

EXCLUSION CRITERIA:

Candidates will be excluded if they meet any of the following criteria:

Clinically significant medical disease that would increase the risk of developing pre or
postoperative complications, including but not limited to uncontrolled systemic
hypertension with values above 170/100; active heart disease needing immediate
intervention; active respiratory disease needing immediate intervention; uncorrected
coagulation abnormalities or need for therapeutic anticoagulation which cannot be
interrupted; current or pre-existing life-threatening respiratory disease, such as
respiratory failure or ARDS.

Intellectual impairment as determined by a score of less than 70 on the estimated General
Ability Index (GAI), a composite score of the Wechsler Adult Intelligence test 4th Edition
(WAIS-IV), which would render the participant unable to provide informed consent or to
comply with the study procedures (equivalent to FSIQ less than 70).

Evidence of secondary or atypical parkinsonism/dystonia/tremor as suggested by:

- History of CVA, exposure to toxins, neuroleptics, or encephalitis

- Neurologic signs of upper motor neuron or cerebellar involvement, supranuclear gaze
palsy, or orthostatic hypotension.

- MR-imaging with evidence indicative of secondary disease such as iron deposits in
putamen, tumor, or stroke, which could cause the movement disorder.

- Features atypical of idiopathic Parkinson s disease.

Dementia as evidenced by formal neuropsychological evaluation, Mattis Dementia Rating Scale
(DRS-2) score, and clinical evaluations.

Depression or evidenced by self-report on the Beck Depression Inventory-2 (score above 20).

Unable to undergo MR-imaging because of implanted pacemakers, medication pumps, aneurysm
clips, metallic prostheses (including metal pins and rods, heart valves or cochlear
implants), shrapnel fragments, permanent eye liner or small metal fragments in the eye that
welders and other metal workers may have, or if candidates are uncomfortable in small
closed spaces (have claustrophobia), or cannot lie comfortably on their back for up to one
hour.

Pregnant women.

Patients with tremor-dominant PD with Scans Without Evidence of Dopaminergic Effect (SWEDD)
will be excluded based on clinical and historic information, including DaT functional
imaging obtained during routine clinical evaluation of PD as needed.