The Role of Surgery in Parkinson's Disease in 2016

7/24/2019 The Role of Surgery in Parkinson's Disease in 2016

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What is the role of surgery in the

treatment of Parkinsons Diseasein 2016?

Kelly D. Foote, M.D.Professor of Neurosurgery

Co-Director, Center for Movement Disorders and Neurorestoration

2016 Hope Parkinson SymposiumFt. Myers, FL February 12, 2016


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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


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Its not the building, its the people:

The UF Center for Movement Disorders and Neurorestoration


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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

Neurology

Michael Okun, MD

Pam Zeilman, ARNP

Janet Romrell, PA-C

Ramon Rodriguez, MD

Irene Malaty, MD

Nick McFarland, MDAparnaShukla-Wagle, MD

Christopher Hess, PhD

Tetsuo Ashizawa, MD

Sub Subramony, MD

Neurosurgery

Kelly Foote, MD

Frank Bova, PhDPam Martin, BSN

Fran Anderson, Admin

RusselMoore, 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


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Brain Surgery!


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100 billion neurons

100 trillion connections (synapses)


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MR DTI image of actual brain fiber pathways


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Your brain controls everything

We can control your brain.


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Parkinsons Disease

! A complex, progressive and degenerativeneurological disorder that causes loss ofcontrol over body movements.

! Primary motor symptoms: TRAP

!Tremor

!Rigidity

!Akinesia/Bradykinesia

!Postural instability

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!"#$%&'#() +, -.+/0 1 234"#56( 7&0#" 8"'9(:(% 1 ;0#"%'$#..%< -.+/0

Mieux vaut avoir la maladie de

Parkinson que celle

d'Alzheimer, car il estprfrable de renverser un

peu sa bire que d'oublier de

la boire.

=>


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Parkinsons Disease

! Key Statistics--Costs of the disease.

! PD a"icts 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 peryear on medications alone

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Distribution of individuals with Parkinsons disease by country, 2005 and2030*

(Dorsey et al, 2007)

*Among individuals over 50 in the worlds ten most and Western Europes five most populous nations

2005100% = 4.1 million individuals 2030100% = 8.7 million individuals

China, 48%

Europe, 14%

China, 57%Others, 12%

Brazil, 4%

U.S. 8%

India, 8%

Europe, 20%

India, 8%

U.S. 7%

Brazil, 4%

Others, 10%


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High price of health care

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Parkinsons Disease

! Etiology is not entirely clear, but we arelearning more about the pathophysiology andgenetics of PD all the time

! (genetic predisposition plus environment)

! Motor symptoms arise when SubstantiaNigra degenerates

! Dopamine producing neurons die

! Reduced levels of dopaminelead 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 e#ects

! Dyskinesias! Hallucinations

! Wearing o#

!

Unpredictability18


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DoseTime

Blood

Level[

Drug]

Supratherapeutic = side effects / toxicity

Subtherapeut ic = no effect

Therapeutic Window

Pharmacology 101

19 -KD Foote


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Dose

Time

Blood

Level[

Dopa]

Dose Dose

Supratherapeutic = dyskinesias/hallucinat ions...

Subtherapeutic = st iff, slow, tremor, freezing, dystonia, pain...

Therapeutic Window

EarlyParkinsonsDisease

20 -KD Foote


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Dose

Time

Blood

Level[

Dopa]

Dose Dose

Therapeutic Window

LateParkinsons Disease

Supratherapeutic = dyskinesias, hallucinations...

21 -KD Foote



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Dose

Time

Blood

Level[

Dopa]

Dose Dose

Therapeutic Window



22

DBS

-KD Foote



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Dose

Time

Blood

Level[

Dopa]

Dose Dose

Therapeutic Window



23

DBS

-KD Foote



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What is DBS?

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

Deep

BrainStimulation


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Virtual

RealityTargeting


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Micro-

ElectrodeRecording


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Smithsonian Magazine- May 2014


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ET intra OP after 8 s

(no audio)

ET Intra OP before 15 s

(no audio)


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DBS for Tourette Syndrome


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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

37 year old womanEye 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

DBS for Tourette Syndrome


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1538


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UF DBS Implants since 2002

N = 1022 Lead implantation procedures

(1132 Leads, 702 Patients)

Parkinson DiseaseEssential TremorDystoniaTremor (other)

OCDTourette SyndromeAlzheimer's DiseaseParkinsonismAlien LimbXDP (Lubag)Cluster HeadacheOculopalatal Myoclonus

STNGPIVIM

VO ThalamusCM ThalamusVC/VSFornixPPNRed NucleusHypothalamus

SINGLE SURGEON SERIES(KDF)

(7/2002 - 5/2015)

Predominantly

staged procedures*

Not uncommonly

unilateral procedures*

Patient-tailored

procedures*

My personal biases


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Doctors sometimes do stupid things

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1000 DBS leads, patients from all over

41

S


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DBS Failure Experts

Dont publish an algorithm for the management ofDBS Failuresunless you want to become the DBS

Failure Referral Center!

Patients referred to UF after DBS


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Patients referred to UF after DBSim lantation at other centers

Parkinson Disease

Essential TremorDystoniaTremor (other)

Tourette SyndromeParkinsonism

Tardive Syndromes

N = 390(7/2002 - 5/2015)


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DBS Failure Expert: a dubious honor

10 years and 390 referred

DBS Failure patients

(plus our own failures)

later!

> 70 DBS REVISION/REPLACEMENT PROCEDURES PERFORMED


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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 D i i M ki


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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 DBSis 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.

E l ti f DBS C did t


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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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E t ti M t


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Expectation Management

Review each patients ranked list of most problematicsymptomsand 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 balancedisordersfrequently 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 anxietyby explaining the details of the operation

and prepare the patients and caregivers psychologically for

iterative programming, incomplete relief of symptoms, etc.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.

P ti t T il d DBS


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Patient-Tailored DBS

DBS for PD = Bilateral simultaneous STN A preponderance of evidence now suggests that this monosynaptic

thought processwill not produce the best global DBS outcomes

We have sufficient data to more effectively tailor our

DBS procedures to the needs of each individual

patientto optimize outcomes*

STN vs. GPI*

Unilateral vs. bilateral* If bilateral, simultaneous vs. staged*

Awake vs. asleep with intraoperative imaging

STN GPI P ti t T il d DBS


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STN vs. GPI: Patient Tailored DBS

Okun and Foote,Archives of NeurologyVol 62, Apr 2005

Movement Disorders Clinical Practice2014 Apr 1;1(1):24-35.


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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

DBS is more effective than

Best Medical Therapy for PD


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Best Medical Therapy for PDN = 156, Prospective,randomized, controlled trial

STN DBS compared to best

medical therapy (BMT) after 6months

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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N = 255, Prospective, randomized, controlled trial

STN or GPI DBS (60 each) compared to best medical therapy (134)

Motor diaries: DBSincreased time on without troublesomedyskinesia by 4.5 hours/day. Medicalgroup zero increase.

Motor function, QOL improved with DBS. More adverse events.


medical therapy for PD patientswith motor fluctuations

Weaver et. al.

(VA co-op study group)

JAMA 2009


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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

S i i S


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Stim vs. Sham:

More ON timeMore med reduction

More improved mood

Similar mild deteriorationin verbal fluency

Stimulation vs. Shameffectively compares theeffect of STN stim to thecombined effects ofplacebo and

microsubthalamotomy

DBS for PD E pectations


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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 currentbest 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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P ki Di


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Parkinsons Disease

Bottom Line! DBS is the best available treatment

for appropriately selectedParkinsons patients with motor

fluctuations(better than medications).

! Class 1 evidencefrom three largeprospective randomized controlled trials

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Better Bionics


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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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89.%) :;1 < 7.%&*=

>?;!" /%0(.)0* 8/2345= [email protected]+/.-


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N10 +:


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S()F%&.*.0 %AM >B?


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Countersinking

Countersinking


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Countersinking

Countersinking


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Countersinking


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Countersinking


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Countersinking


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Countersinking


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Countersinking


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Countersinking


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Countersinking

Poor post-operative cosmesis


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Poor post operative cosmesis

secondary to cap protrusion

Countersunk


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S()F%&.*.0 %AM >B?


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G+)).G0+& 6&++@.

UF Scalp Erosion Experience


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UF Scalp Erosion Experience

Discomfort and patient dissatisfaction


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Discomfort and patient dissatisfaction

secondary to cap (and connector) protrusion

Patients do care about this Many complain about discomfort at the sites of hardware

protrusion and dissatisfaction with bumps

As patients become more aware that there is an optionto have DBS surgery without bumps on their heads, theywill preferentially select centers that offer this

This method is better for patients: minimizes risk fordelayed scalp erosion, maximizes comfort, maximizespatient satisfaction

This will predictably become a hallmark of quality DBS

Closed Loop (adaptive)


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Deep brain stimulation

What is closed loop DBS?

DBS systems that feature automated control

strategies that can adjust DBS parameters in realtime 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

Postural Instability


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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 andmaintain upright posture

! Postural Reflexes: automatic righting responses thatrestore balance in response to a destabilizing force

! Determinants of e#ective ambulation:

! vestibular function, proprioception, vision

! posture, fluidity of movement, muscle control

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Walking and Parkinsons disease


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! Rigidity, bradykinesia result in shu"ing gait

! Dystonic symptoms or severe dyskinesia can result inasymmetric, unsteady gait

! Shu"ing gait combined with diminished postural reflexes canresult in festination

! Compromised motor programs can result in gait initiationdi%culty/freezing

! Severe loss of postural reflexes results invery poor balance

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

! Compromised frontal lobe function (attention, concentration,judgment, impulse control) combined with any of the abovecan lead tofallsespecially when multitasking

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! Rigidity, bradykinesiaresult in shu"ing gait

! Dystonic symptoms or severe dyskinesiacan result inasymmetric, unsteady gait

! Shu"ing gait combined with diminished postural reflexes canresult in festination

! Compromised motor programscan result in gait initiationdi%culty, freezing, retropulsion

! Severe loss of postural reflexesresults invery poor balance

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

! Compromised frontal lobe function(attention, concentration,judgment, impulse control) combined with any of the abovecan lead tofallsespecially when multitasking

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N = 24, Prospective, randomized, double-blind, controlled trial of bilateral STN vsGPI DBSto assess effect on balance

Used quantitative measurement ofautomatic postural responseto assessstability in various states (off/on DBS/dopa)

Conclusion:Turning on the DBS currentimproved APR stability for both STN andGPI sites. However, there was adetrimental DBS procedural effect for theSTN group, and this effect was greaterthan the benefit of the stimulating current,making overall APR stability functionallyworse after surgery for the STN group.

UF Parkinsonian


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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 functionalneurocircuitry involved in human ambulation and FoG

MJ Fox Foundation Grant funded

UF Parkinsonian


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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 standardizedambulation 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)

Closed loop conclusions


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p

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

Take Home Messages


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The brainis an awesome, livingsupercomputer We can control your brain

Parkinsons disease sucks

Dopamine(Sinemet)is good (mostly) Motor fluctuationsare treatable

(DBS is better than medications)

DBS is really cool (It helps various brain malfunctions, and its increasingly safe

and effective)

Take Home Messages


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Multidisciplinary, patient specific risk-benefitanalysisis the best way to select patients for

DBSand plan their patient-tailored DBS surgery

Bionicsare getting better and more

sophisticated

The future looks bright, and we have goodreason to expect safer, more effective treatments

for Parkinsons disease in the near future.

THANK YOU


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THANK YOU

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Documents

The Role of Surgery in Parkinson's Disease in 2016