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What is the role of surgery in the

treatment of Parkinsons Disease


in 2016?
2016 Hope Parkinson Symposium
Ft. Myers, FL

February 12, 2016

Kelly D. Foote, M.D.


Professor of Neurosurgery
Co-Director, Center for Movement Disorders and Neurorestoration

Disclosures
Potential Conflicts of Interest
Medtronic: Grants for DBS research and Fellowship support, Consultant
Neuropace: Grants for DBS research, Neurosurgical Advisory Board Member
ANS-St. Jude: Grants for DBS research
Boston Scientific: Grants for DBS research
Functional Neuromodulation: Grants for DBS research

Grant Support

National Institutes of Health

National Parkinson Foundation

Parkinson Alliance

Michael J. Fox Foundation

McKnight Brain Institute

Discussion of non-FDA approved procedures:


Closed Loop (Adaptive) DBS
DBS for Tourette syndrome
Dual Lead DBS for multiple sclerosis tremor
Pedunculopontine nucleus DBS for gait disorder
DBS for early Alzheimers dementia
DBS for major depressive disorder

Its not the building, its the people:


The UF Center for Movement Disorders and Neurorestoration

Acknowledgement of key players:


The UF Center for Movement Disorders and Neurorestoration
Physical Therapy
Meredith Defranco, PT, PhD
Shankar Kulkarni, PT, PhD

Occupational Therapy
Lisa Warren, OT
Heather Simpson, Peds OT

Communcation and Swallowing


Disorders
Irene Shields, MA CCC-SLP
Emily Plowman, PhD
Karen Hegland, PhD
Jay Rosenbeck, PhD
Chris Sapienza, PhD

Neuropsychology
Dawn Bowers, PhD
Russ Bauer, PhD
Cate Price, PhD
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Neurology
Michael Okun, MD
Pam Zeilman, ARNP
Janet Romrell, PA-C
Ramon Rodriguez, MD
Irene Malaty, MD
Nick McFarland, MD
Aparna Shukla-Wagle, MD
Christopher Hess, PhD
Tetsuo Ashizawa, MD
Sub Subramony, MD

Neurosurgery
Kelly Foote, MD
Frank Bova, PhD
Pam Martin, BSN
Fran Anderson, Admin
Russel Moore, Computing

Psychiatry
Herbert Ward, MD
Sarah Fayad, MD

Scientists
Todd Golde, MD, PhD
David Vaillancourt, PhD
Chris Hass, PhD
Aysegul Gunduz, PhD
Karim Oweiss, PhD
Ben Giasson, PhD
Ron Mandel, PhD
Jada Lewis, PhD
Keith White, PhD
Ken Heilman, PhD
Brent Reynolds, PhD
Dennis Steindler, PhD
Catherine Striley, PhD
James Oliverio
Jill Sonke
William Shain, PhD

Brain Surgery

100 billion neurons

100 trillion connections (synapses)

MR DTI image of actual brain fiber pathways

Your brain controls everything


We can control your brain.

Parkinsons Disease

A complex, progressive and degenerative


neurological disorder that causes loss of
control over body movements.

Primary motor symptoms: TRAP


Tremor
Rigidity
Akinesia/Bradykinesia
Postural instability
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Mieux vaut avoir la maladie de


Parkinson que celle
d'Alzheimer, car il est
prfrable de renverser un
peu sa bire que d'oublier de
la boire.

University of Florida McKnight Brain Ins9tute Gainesville, Florida


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Parkinsons Disease

Key Statistics--Costs of the disease.


PD aicts over 1 million Americans
Average age of onset is 60 years
Cost: $25 billion/year
(Health related, disability, lost productivity)

U.S. PD patients spend $1000 to $6000 per


year on medications alone
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Distribution of individuals with Parkinsons disease by country, 2005 and


2030*
2005
100% = 4.1 million individuals

2030
100% = 8.7 million individuals
Others, 10%
Brazil, 4%

Others, 12%
Brazil, 4%
U.S. 8%

China, 57%

U.S. 7%
China, 48%
India, 8%

India, 8%
Europe, 14%
Europe, 20%
*Among individuals over 50 in the worlds ten most and Western Europes five most populous nations

(Dorsey et al, 2007)


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High price of health care

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Parkinsons Disease
Etiology is not entirely clear, but we are
learning more about the pathophysiology and
genetics of PD all the time
(genetic predisposition plus environment)

Motor symptoms arise when Substantia


Nigra degenerates
Dopamine producing neurons die
Reduced levels of dopamine lead to (most)
symptoms
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Parkinsons Disease Circuitry

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How do we treat PD?

Replace the dopamine


Works great
Limitations
Increasing dosages
Increasing side eects

Dyskinesias

Hallucinations
Wearing o

Unpredictability
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Pharmacology 101
Supratherapeutic = side effects / toxicity

Therapeutic Window

Blood
Level[
Drug]
Subtherapeutic = no effect
Dose

Time

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-KD Foote

Early Parkinsons Disease


Supratherapeutic = dyskinesias/hallucinations...

Blood
Level[
Dopa]

Therapeutic Window

Subtherapeutic = stiff, slow, tremor, freezing, dystonia, pain...


Dose

Dose

Dose

Time
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-KD Foote

Late Parkinsons Disease


Supratherapeutic = dyskinesias, hallucinations...

Blood
Level[
Dopa]

Therapeutic Window

Subtherapeutic = stiff, slow, tremor, freezing, dystonia, pain...


Dose

Dose

Dose

Time
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-KD Foote

Late Parkinsons Disease


Supratherapeutic = dyskinesias, hallucinations...

DBS

Therapeutic Window

Blood
Level[
Dopa] Subtherapeutic = stiff, slow, tremor, freezing, dystonia, pain...
Dose

Dose

Dose

Time
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-KD Foote

Late Parkinsons Disease


Supratherapeutic = dyskinesias, hallucinations...

DBS

Therapeutic Window

Blood
Level[
Dopa] Subtherapeutic = stiff, slow, tremor, freezing, dystonia, pain...
Dose

Dose

Dose

Time
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-KD Foote

What is DBS?
Deep
Brain
Stimulation

Okun, M.S. N Engl J Med. 2012 Oct 18;367(16):1529-38.

Virtual
Reality
Targeting

MicroElectrode
Recording

Smithsonian Magazine
- May 2014

ET Intra OP before 15 s
(no audio)

ET intra OP after 8 s
(no audio)

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10

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DBS for Tourette Syndrome


37 year old woman
Eye rolling, jaw cracking, head twists, fingertip tapping, hitting with the elbow,
copropraxia, growling, coprolalia, self injurious behavior, chronic OCD
Scheduled Stimulation Settings 16 seconds on, 120 seconds off

Baseline

Continuous

Scheduled

Medication Trials: Diazepam; lorazepam; clonidine hydrochloride; tizanidine hydrochloride;


risperidone; carbamazepine; pimozide; haloperidol lactate; divalproex sodium (Depakote);
fluvoxamine maleate; olanzapine; paroxetine hydrochloride; quetiapine fumarate; lithium
carbonate; acetaminophen, hydrocodone bitartrate (Vicodin); aripiprazole; quetiapine fumarate;
estazolam; fluoxetine hydrochloride; benztropine mesylate; ziprasidone hydrochloride;
clarithromycin (Biaxin XL); alprazolam; tramadol hydrochloride

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UF DBS Implants since 2002


N = 1022 Lead implantation procedures
(1132 Leads, 702 Patients)

Not uncommonly
unilateral procedures*

Predominantly
staged procedures*
Patient-tailored
procedures*

(7/2002 - 5/2015)
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SINGLE SURGEON SERIES


(KDF)

Parkinson Disease
Essential Tremor
Dystonia
Tremor (other)
OCD
Tourette Syndrome
Alzheimer's Disease
Parkinsonism
Alien Limb
XDP (Lubag)
Cluster Headache
Oculopalatal Myoclonus

My personal biases

STN
GPI
VIM
VO Thalamus
CM Thalamus
VC/VS
Fornix
PPN
Red Nucleus
Hypothalamus

Doctors sometimes do stupid things

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1000 DBS leads, patients from all over

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DBS Failure Experts


Dont publish an algorithm for the management of
DBS Failuresunless you want to become the DBS
Failure Referral Center

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Patients referred to UF after DBS


implantation at other centers
N = 390
(7/2002 - 5/2015)

Parkinson Disease
Essential Tremor
Dystonia
Tremor (other)
Tourette Syndrome
Parkinsonism
Tardive Syndromes

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DBS Failure Expert: a dubious honor


10 years and 390 referred
DBS Failure patients
(plus our own failures)
later

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> 70 DBS REVISION/REPLACEMENT PROCEDURES PERFORMED

DBS for Parkinson Dz

BEFORE DBS

AFTER DBS

(OFF MEDICATIONS)

(OFF MEDICATIONS)

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DBS for Young Onset PD


(with Severe Dystonia)

BEFORE DBS

AFTER DBS
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Patient Selection for PD DBS

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Looking to Spice up your Life?

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DBS Decision Making


DBS is not a life-saving or curative procedure.
DBS is elective brain surgery. Some might reasonably argue
that elective brain surgery should not even exist. Brain
surgery is risky.
The goal of DBS is to alleviate debilitating symptoms of brain
dysfunction, and thereby improve quality of life.
Success and failure should be patient defined. If a patients
answers to Are you glad you had DBS surgery? and Is
your life better? are not YES, then DBS has failed.
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Evaluation of DBS Candidates


Quantifying Risk:
Age, medical comorbidities, brain atrophy...
Existing deficits/susceptibility to deterioration:
progressive cognitive dysfunction, psychiatric disorder, speech/swallowing
difficulty, gait problems, unrealistic expectations.

Predicting Benefit:
What bothers you the most?
How likely is it that the symptoms that most adversely effect this patients
quality of life will be significantly improved by DBS therapy?

Tailoring Therapy:
Which DBS target/technique will minimize risk and maximize potential
benefit for this patient?
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Patient-Tailored DBS

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Expectation Management
Review each patients ranked list of most problematic
symptoms and have a frank discussion with the patient and
caregivers about which symptoms are likely to improve
with DBS and, perhaps more importantly, which are not.
For example: Parkinsonian gait and balance disorders
frequently do not improve with DBS
STN DBS commonly makes these symptoms worse*
GPI DBS has less adverse effect on ambulation, but does not typically
produce significant benefit in this domain*

Minimize anxiety by explaining the details of the operation


and prepare the patients and caregivers psychologically for
iterative programming, incomplete relief of symptoms, etc.
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The effect of deep brain stimulation randomized by site on balance in Parkinson's disease.
-St. George et. al. Movement Disorders, 29(7):949-53.

Patient-Tailored DBS
DBS for PD = Bilateral simultaneous STN
A preponderance of evidence now suggests that this monosynaptic
thought process will not produce the best global DBS outcomes

We have sufficient data to more effectively tailor our


DBS procedures to the needs of each individual
patient to optimize outcomes*
STN vs. GPI*
Unilateral vs. bilateral*
If bilateral, simultaneous vs. staged*
Awake vs. asleep with intraoperative imaging
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STN vs. GPI: Patient Tailored DBS

Okun and Foote, Archives of Neurology Vol 62, Apr 2005

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Movement Disorders Clinical Practice 2014 Apr 1;1(1):24-35.

DBS is more effective than


Best Medical Therapy for PD
N = 156, Prospective, randomized,
controlled trial
STN DBS compared to best medical
therapy (BMT)
QoL (PDQ-39) after 6 months was the
Primary Outcome Variable
DBS resulted in improvements of 24 to 38
percent in the PDQ-39 subscales for
mobility, ADLs, emotional well-being,
stigma, and bodily discomfort.
No change in PDQ-39 in BMT group.
SAEs: 13% for DBS, 4% for BMT
Overall AEs: 50% for DBS 64% for BMT
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DBS is more effective than


Best Medical Therapy for PD
N = 156, Prospective,
randomized, controlled trial
STN DBS compared to best
medical therapy (BMT) after 6
months
Mean change in PDQ-39 SI:
DBS: 9.5 BMT: 0
Mean change in UPDRS III:
DBS: 48 to 28 (41% improvement)
BMT: 47 to 46 (no change)

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DBS is more effective than


medical therapy for PD patients
with motor fluctuations
Weaver et. al.
(VA co-op study group)
JAMA 2009

N = 255, Prospective, randomized, controlled trial


STN or GPI DBS (60 each) compared to best medical therapy (134)
Motor diaries: DBS increased time on without troublesome
dyskinesia by 4.5 hours/day. Medical group zero increase.
Motor function, QOL improved with DBS. More adverse events.
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Lancet Neurol 2012; 11: 14049

N = 136, Prospective,
randomized, controlled trial
using St. Jude DBS hardware
STN DBS compared to sham
stimulation control group

Stimulation vs. Sham


effectively compares the
effect of STN stim to the
combined effects of
placebo and
microsubthalamotomy

Stim vs. Sham:


More ON time
More med reduction
More improved mood
Similar mild deterioration
in verbal fluency

DBS for PD, Expectations

What does DBS do for Parkinsons disease?


DBS does not cure Parkinsons disease
Most common indication: Motor Fluctuations

We expect DBS to keep PD patients at or near their current


best level of functioning much more of the time

Exceptional Indications for PD DBS:

Medication refractory tremor

Debilitating dyskinesia (extra involuntary movement)

Other, based on patient-tailored risk vs. benefit analysis

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Parkinsons Disease
Bottom Line
DBS is the best available treatment
for appropriately selected
Parkinsons patients with motor
fluctuations (better than medications).

Class 1 evidence from three large


prospective randomized controlled trials

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Better Bionics
Targeting (Imaging, software, technology)
Surgical technique (Countersinking)
DBS hardware
MRI compatibility, Current steering, High density electrode
arrays

Novel applications (Freezing of gait, Tourette, MS tremor,


OCD, major depression, addiction? obesity? Alzheimers?)

Closed loop Smart DBS


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Skin Complications

2010

85 Parkinsons disease patients underwent DBS surgery


(mean f/u 3 years)
21/85 patients (24.7%) developed 30 skin complications:
Time:
- 60% presented within the 1st year
- 40% greater than one year post implantation
Site:
- lead-cap site 37%
- connector site 33%
- IPG site 30%
6 out of 21 patients had recurrent skin complications
DBS systems were permanently explanted in 8 of 21 patients
Sixel-Dring et al.

Out of 30 skin complications:


- 8/30 (26%) infection of the site (culture confirmed)
- 3/30 (10%) no clear infection, but preceded by a local injury
- 19/30 (63%) no clear infection, just aseptic necrosis over the implant

Sixel-Dring et al.

Linhares et al. 2013. One-step tunneling of DBS extensionsa technical note.

Countersinking

Countersinking

Countersinking

Countersinking

Countersinking

Countersinking

Countersinking

Countersinking

Countersinking

Poor post-operative cosmesis


secondary to cap protrusion

Countersunk

Linhares et al. 2013. One-step tunneling of DBS extensionsa technical note.

connector groove

UF Scalp Erosion Experience

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Discomfort and patient dissatisfaction


secondary to cap (and connector) protrusion

Patients do care about this

As patients become more aware that there is an option


to have DBS surgery without bumps on their heads, they
will preferentially select centers that offer this

This method is better for patients: minimizes risk for


delayed scalp erosion, maximizes comfort, maximizes
patient satisfaction

This will predictably become a hallmark of quality DBS

Many complain about discomfort at the sites of hardware


protrusion and dissatisfaction with bumps

Closed Loop (adaptive)


Deep brain stimulation
What is closed loop DBS?
DBS systems that feature automated control
strategies that can adjust DBS parameters in real
time based on quantifiable, objective changes
(e.g. neurophysiologic, neurochemical, or
behavioral biomarkers)
Smart DBSa smart system is one that enables
a non-expert to achieve expert results
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Postural Instability

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Walking is complicated
Gait: a persons manner of walking
Balance: the ability to maintain equilibrium and
maintain upright posture

Postural Reflexes: automatic righting responses that


restore balance in response to a destabilizing force

Determinants of eective ambulation:


vestibular function, proprioception, vision
posture, fluidity of movement, muscle control
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Walking and Parkinsons disease

Rigidity, bradykinesia result in shuing gait

Dystonic symptoms or severe dyskinesia can result in


asymmetric, unsteady gait

Shuing gait combined with diminished postural reflexes can


result in festination

Compromised motor programs can result in gait initiation


diculty/freezing

Severe loss of postural reflexes results in very poor balance


in a subset (5-15%) of PD patients

Compromised frontal lobe function (attention, concentration,


judgment, impulse control) combined with any of the above
can lead to fallsespecially when multitasking
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Walking and Parkinsons disease

Rigidity, bradykinesia result in shuing gait

Dystonic symptoms or severe dyskinesia can result in


asymmetric, unsteady gait

Shuing gait combined with diminished postural reflexes can


result in festination

Compromised motor programs can result in gait initiation


diculty, freezing, retropulsion

Severe loss of postural reflexes results in very poor balance


in a subset (10-25%) of PD patients

Compromised frontal lobe function (attention, concentration,


judgment, impulse control) combined with any of the above
can lead to fallsespecially when multitasking
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N = 24, Prospective, randomized, doubleblind, controlled trial of bilateral STN vs


GPI DBS to assess effect on balance
Used quantitative measurement of
automatic postural response to assess
stability in various states (off/on DBS/
dopa)
Conclusion: Turning on the DBS current
improved APR stability for both STN and
GPI sites. However, there was a
detrimental DBS procedural effect for the
STN group, and this effect was greater
than the benefit of the stimulating current,
making overall APR stability functionally
worse after surgery for the STN group.

UF Parkinsonian
on-FOG Project
Levodopa-resistant freezing of gait (on-FoG) in PD is
highly disabling and difficult to treat
PD causes increased GABA-ergic (inhibitory) activity
in GPI, which inhibits the PPN
STN and GPI DBS ineffective, PPN DBS mixed results
We need a better understanding of the functional
neurocircuitry involved in human ambulation and FoG
MJ Fox Foundation Grant funded
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UF Parkinsonian
on-FOG Project
Implant 5 on-FoG patients with bilateral GPI and bilateral PPN
DBS leads (16 electrodes) and connect them to bilateral PC+S
IPGs (FDA IDE)
Record LFP activity at all electrodes during standardized
ambulation tasks in the gait lab
Determine electrophysiologic biomarkers associated with
freezing, provocation of freezing, and optimal ambulation
Develop appropriate closed-loop control algorithms that can be
tested with the Medtronic Nexus-D system coupled to the PC+S
(e.g. responsively deactivate GPI stim and deliver brief pulses to PPN)
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Closed loop conclusions


Closed loop DBS offers automated adjustment of stimulation
parameters to optimize clinical effect in real time
Promises increased effectiveness, efficiency/battery life,
patient-tailored adaptive therapy, and diminished
programming burden with more consistent outcomes
Current research is employing novel tools to decipher the
electrophysiological and electrochemical connectomes
associated with normal and pathological brain function
Closed loop DBS will be implemented in the near future, and
may represent a transformative change in neuromodulation
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Take Home Messages


The brain is an awesome, living supercomputer
We can control your brain
Parkinsons disease sucks
Dopamine (Sinemet) is good (mostly)
Motor fluctuations are treatable
(DBS is better than medications)
DBS is really cool
(It helps various brain malfunctions, and its increasingly safe
and effective)
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Take Home Messages


Multidisciplinary, patient specific risk-benefit
analysis is the best way to select patients for
DBSand plan their patient-tailored DBS surgery
Bionics are getting better and more
sophisticated
The future looks bright, and we have good
reason to expect safer, more effective treatments
for Parkinsons disease in the near future.
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THANK YOU
Contact Information:
foote@neurosurgery.ufl.edu

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