DBS for Movement Disorders Approved indications: Essential tremor - - PowerPoint PPT Presentation

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Deep Brain Stimulation for Multiple Movement Disorders

Jill Ostrem, MD Carlin and Ellen Wiegner Endowed Professor of Neurology Division Chief and Medical Director UCSF Movement Disorder and Neuromodulation Center

Disclosures

• Consultant: AbbVie, Adamas, Neurocrine, Acadia
• Educational grant support: Medtronic, Allergan, Boston

Scientific, AbbVie

• Clinical trial support: Boston Scientific, Cala Health, Medtronic,

Biogen

DBS for Movement Disorders

Approved indications:

• Essential tremor
• Parkinson’s disease
• Isolated dystonia

Off label indications:

• Tardive dystonia
• Secondary dystonia
• Tourette syndrome
• Orthostatic tremor
• Holmes tremor
• Musician’s dystonia

DBS Stimulation Therapy

* The negative electrode exerts the therapeutic effect

Unipolar

1 2 3

• ff
• ff

(-)

• ff

(+) positive

Rate (Hertz)

number of pulses per second

Pulse Width (sec)

duration of each stimulus

Amplitude

intensity of stimulation

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1987 1993 1995 1997 1998 2002 2003 2009 2010 2015 2016 2017 2018 2019 History of DBS Landmarks and Current Approved Indications

First DBS implanted ET ET PD tremor Advanced PD Dystonia Epilepsy Boston MICC steering Abbott steering OCD Tremor ET+PD OCD (HDE) Dystonia (HDE) Advanced PD FDA >4 yrs PD Boston MICC Abbott steering US Approvals European Approvals Boston steering

Main findings: DBS better than medical therapy alone:

• Decreased OFF time

(4.6 hours/day)

• Improved quality of life

measures

Major Randomized Parkinson’s Disease Trials Comparing DBS to Medical Therapy

Who is a Candidate for DBS? (Increased Benefit)

Most Candidates:

• Moderate/advanced PD disease
• Levodopa-responsive
• Experiencing motor fluctuations
• Experiencing dyskinesia
• “Failed” good control with medical treatments

Who is a Candidate for DBS? (Increased Benefit)

Minority: Overall milder disease, but:

• Severe rest tremor resistant to levodopa
• Painful off-medication state dystonia
• Severe dyskinesia with low doses levodopa
• Disability preventing employment

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Who are not good DBS candidates? (Increased Risk)

• Significant psychiatric illness
• Psychosis
• Depression
• Significant cognitive impairment
• Awake surgery, requires patient input
• Complex, long-term therapy
• Worsening of cognition after surgery, even if motor

symptoms improve?

• Significant medical co-morbidities
• Unrealistic goals and expectations

Realistic Expectations from DBS

Identify your patient specific PD symptoms you hope DBS will improve:

• Tremor
• Slow movement
• Stiffness
• Dyskinesia
• Falls/balance
• Painful dystonia
• Depression/Anxiety
• Hallucinations
• Poor Speech
• Poor Sleep
• Freezing
• Unexpected Off time
• Medication side effects
• Poor dexterity
• Motor fluctuations
• Fatigue

Are these symptoms DBS responsive? How levodopa responsive are these symptoms? Tremor and/or dyskinesia in the top 3? 

Parkinson’s Disease Candidacy for DBS

Off Medications On Medications

• Optimization of medications
• Detailed motor testing (on and off medications)
• Neuropsychological testing
• Psychiatric evaluation (in some cases)
• Pre-operative Brain MRI
• Genetic testing?

Charles, P.D. et al. Neurology 2002;59:932-934

Age Cut Off?

• Historically over 70

years not considered candidates for DBS

• Now a more individual

approach is applied

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Alternative Diagnoses- Poor DBS Responders

Multiple System Atrophy

• MSA-P, MSA-C, MSA-A
• RBD
• Parkinsonian signs
• Sometimes “head drop”
• Stridor
• Poor levodopa response
• Autonomic problems

Digestive, BP, erectile dysfunction

• Synucleanopathy

Progressive Supranuclear Palsy

• Often no rest tremor
• Early dementia
• Early Falls
• Gaze palsy
• Poor levodopa response
• Tauopathy

Cortical Basal Syndrome

• Can be very asymmetric

signs and symptoms

• Problems with skilled

movements - apraxia/alien limb

• Cognitive impairment
• Poor levodopa response
• T

auopathy

Personalized Parkinson’s Disease DBS

One or both sides?

Which surgical method?

Need for multi-disciplinary team approach! Awake Asleep

New Generation DBS Systems

• Three commercial DBS companies in the US with FDA approved systems
• Smaller profile, longer-lasting, re-chargeable neurostimulators
• Delivering constant current stimulation
• Segmented steering or current shaping leads
• Improved physician and patient interfaces
• Some MRI conditional devices
• Some offer personalized closed-loop adaptive stimulation platforms
• STN and GPi DBS
• ffer similar overall

motoric and quality

• f life improvement
• STN DBS allows for

greater medication reduction

• Some evidence for

more cognitive and mood issues with STN

• One study

secondary endpoint showed STN greater improvement in UPDRS III off meds score

Which Target? Major Randomized Parkinson’s Disease Clinical Trials STN Verses GPi DBS

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Ramirez-Zamora, Ostrem; JAMA Neurology 2018 Typical Progression and Clinical Course Typical Progression and Clinical Course

• Fahn. Ann NY Acad Sci. 2003;991:1-14.

3 8 15 20

Years

Onset Diagnosis Therapy Preclinical Phase Honeymoon Period Motor Complication Period Resistant Symptoms Cognitive Decline

• 2 to -6

How Early Should We Offer DBS in PD ?

DBS Therapy

• 2 year long German trial
• 251 PD with early motor complications (starting 4 mo to 3 years earlier)
• Divided patients to DBS plus medication OR medication alone
• Primary objective was measurement of quality of life
• DBS group improved quality of life scores by ~8 points
• Best medical therapy worsened by 0.2 points
• DBS superior in motor disability, activities of daily living, levodopa-related

complications and time with good mobility – DBS improves quality of life

“Early Stim Trail”

Schuepbach W. et al New label language

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DBS for Essential Tremor

Who is a Candidate? Failed control with ET meds

• Propranolol
• Primadone
• Others?

Disability from tremor Most DBS surgery for ET still done awake

• Largest (N=127 pts) prospective,

controlled trial of Vim DBS for ET

• DBS system- Constant-current, non

directional lead

• Unilateral and bilateral leads
• 60% improvement in tremor score
• Also significant improvement in QoL,

depression symptoms, and ADL scores

Deep Brain Stimulation for ET

• Unilateral stimulation can sometimes treat axial tremor
• Bilateral stimulation results in higher risk for ataxia and

balance issues or dysarthric speech

• Loss of stimulation effect over time may be due to tolerance
• r disease progression
• Turning stim off at night may result in less “tolerance” to

stim – but controversial

• Posterior Subthalamic Area (PSA) target for proximal tremor

phenotype or refractory VIM DBS tremor being explored

DBS for Isolated Dystonia

Candidacy: 1. Failed reasonable, medication treatment (Artane, Baclofen, benzodiazepine) 2. Failed botulinum toxin injections for focal dystonia 3. Negative trial of levodopa (R/O DRD) 4. Significant disability or pain 5. Absence of significant dementia or depression 6. Absence of significant surgical risk factors 7. Realistic expectations 8. Risk/benefit acceptable

Age at surgery: 11 yo female, 4 year duration of disease, DYT1

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Class I Evidence for use of GPi DBS in Isolated Generalized and Segmental Dystonia

Randomized sham- stimulation control design

25

GPI DBS Long-term Outcomes DYT1

N=47

Mean improvement in BFMDRS-MS score Markun L, et al. Neurosurgery 71:325–330, 2012

Neurology 2017;88:25-35

Improvement (36mo) BFMDRS m - 70% TWSTRS t - 67% N=20

DYT1 Segmental Dystonia

Baseline

3 Years after Bilateral STN DBS

17 yo male, 6 year duration of dystonia Medications: None Previous medication trials:

• Botulinum toxin injections both arms
• Sinemet and Artane no benefit

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Class I Evidence for Use of GPi DBS in Cervical Dystonia

Improvement in dystonia after 6 mo of Gpi DBS

Use of GPi DBS in Cranial Dystonia – Meige Syndrome

Cranial dystonia can improve but usually not as much compared to

• ther body regions

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Non-responders: n=8/40, 20%

Variability in Outcomes

y = -3.05x + 94.45 ρ = -0.71 10 20 30 40 50 60 70 80 90 100 5 10 15 20 25 Percent improvement in BFMDRS-MS at final follow-up

Duration of Disease (years)

Disease duration (x-axis) correlates with percent improvement in BFMDRS-MS (y-axis) at final follow-up. Each square represents a patient (1-14). Patients with fixed skeletal deformities (3, 4, 6, and 14) are indicated by a square with an “x.” Markun L, et al. Neurosurgery 71:325–330, 2012

Generalized dystonia - disease duration correlates with outcomes

UCSF experience – DYT1+

Shorter disease duration predicts better outcome (GPI DBS)

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Acquired Dystonia - Less Responsive to DBS

• 13 patients, 24% mean improvement, variable

Secondary/Combined Dystonia

• Generally poor responders
• How to identify new target with abnormal anatomy?

Witt J, Starr P, Ostrem J. Stereotact Funct 2013

Neurodegeneration with Brain Iron Accumulation (NBIA), GPi DBS

Pre-Op 12 Months Post-Op Age at surgery: 13 yo male

• Can show some

improvement, but not as much as isolated cases

• Does not help other

neurological signs – spasticity, dysarthria

Tardive Dystonia Syndromes

Typically respond well to GPi DBS

• Similar to primary/isolated dystonia

Sako W, Goto S, Shimazu H, et al. (N=5)

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Tourette’s Syndrome

Kurlan N Engl J Med. 2010 Dec 9;363(24):2332-8.

DBS for Tourette’s Syndrome

Age (current): 13 yo female

• Next DBS indication?
• Midline intralaminar nuclei of the thalamus to treat TS in the 1950’s
• In 1999, Vandewalle proposed centromedian nucleus (CM) nucleus and

substantial periventriculari (SPV) DBS to treat TS

• Suppress excitatory feedback projections to motor and limbic parts of striatum to

decrease tics and improve behaviors disorders

• Young female with severe Tourettte’s

syndrome and mild OCD.

• Symptoms worsened despite TS meds.
• Presented with 3 week history of

quadraparesis, sensory loss, and urinary symptoms.

• Cervical MRI: Cervical cord contusion
• Botulinum toxin injections not very helpful.
• Patient had emergent anteriomedical GPi DBS.
• With rapid titration of DBS settings, did well.
• One year later, “good power in all 4 limbs”, mild

sensory issues in the right leg, Yale Global Tic Severity Score from 83 to 37.

DBS for Tourette’s Syndrome

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DBS and Holmes Tremor

• GPi > VIM DBS
• 78% improvement in FTM

tremor rating scale

DBS for Orthostatic Tremor

Pre DBS Post Bilateral VIM DBS

• Rare syndrome – unsteadiness when standing due to high-frequency (13-18HZ) tremor in legs
• Symptoms improve with walking
• Medical treatment: benzodiazepine, gabapentin – often not helpful

DBS for Orthostatic Tremor

• 17 patients
• Primary end point was the composite

activities of daily living/instrumental activities of daily living score.

• 21.6% improvement in the composite

activities of daily living/instrumental activities of daily living score, which gradually attenuated (12.5%).

DBS for Musician’s Dystonia

C+2- 1.7V 60us 150Hz Left VIM DBS 61 yo male with right hand dystonia tremor and accomplished musician

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Tuning the Brain. Andres Lozano. The Scientist Nov 2013 Issue.

Driven by high prevalence of neurological / psychiatric disorders, massive unmet medical needs in treatment options, robust R&D investments and technology developments Expanding DBS indications: Epilepsy, Tourette’s Syndrome, Depression, Addiction, PTSD, Chronic Pain, Obesity, Anorexia, Alzheimer’s Disease and Dementia, Tinnitus, Traumatic Brain Injury, Minimally Conscious State, Stroke Recovery, Headache

Future DBS Indications?

Chronic Brain Recordings to Identify Markers of Disease

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ECoG DBS PC+S

Philip Starr Lab Cora De Hemptinne Ro’ee Gilron Doris Wang

• Activa PC+S / RC+S allow for chronic brain

sensing and therapeutic stimulation

– DBS lead the GPi or STN – ECOG strip covering M1 or PFC

sensor 1: DBS 5Hz sensor 2-3: movement kinematics Sensor 4: HRV INS PCS sensing tablet Telemetry antennas For both PCS and INS

Studying the Brain in a ‘Naturalistic’ Environment

Brain signals recorded at the patient’s house

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Identification of Potential Biomarkers

dyskinesia bradykinesia tremor FOG Depression anxiety

• Chronic brain recordings allow us to begin to identify cortical and

subcortical signals that correlate with signs in movement disorders

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Conceptual Framework for Future DBS

• Move past the “point and shoot” DBS

method with chronic stimulation

• Identify the abnormality in oscillatory

synchronization in a network

• Determine best location/frequency to

reduce that synchronization for specific signs

• DBS with neural interfaces that both

sense and deliver adjustable stimulation automatically

UCSF Movement Disorders

Neurosurgery Philip Starr, MD, PhD Paul S. Larson, MD Doris Wang, MD, PhD Daniel Lim, MD, PhD Krzysztof Bankiewicz, MD, PhD Coralie De Hemptinne, PhD Ro’ee Gilron, PhD Whitney Chen, PhD Sheila Rajagopalan Joncarmen Mergenthaler Neuropsychology Caroline Racine Belkoura, PhD Nursing Monica Volz, FNP, MS Susan Heath, MS, RN Gina Bringas-Cinco, RN Annie Li Wong, NP Rigzin Lama, RN Neurology Jill Ostrem, MD Nicholas Galifianakis, MD Caroline Tanner, MD, PhD Marta San Luciano, MD Maya Katz, MD Ian Bledsoe, MD,MS Robert White, MD, PhD James Maas, MD, PHD Chadwick Christine, MD Michael Aminoff, MD Robert Edwards, MD, PhD Ken Nakamura, MD, PhD Alexandra Nelson, MD, PhD Michael Geschwind, MD Cameron Dietiker, MD Nijee Luthra, MD, PhD Ethan Brown, MD Samuel Goldman, MD Psychiatry Andrea Seritan, MD Fellows Jennifer Choi, MD Melissa Heiry, MD Fay Gao, MD Lauren Spiegel, MD Research /Support Staff Sarah Wang, PhD Janet Allen Yasmeen Gonzalez Christine Jiunti Jeverly Calaunan Kathleen Comyns, MPH Cheryl Meng, MPH Farah Kauser, PhD Danilo Romero Vy Nguyen Enrique Esteinou Jana Guenther Raisa Syed Darel Obonna Kanchi Mehta Kian Bageri Social Work Monica Eisenhardt, LCSW Samuel Yee Chaplin Judith Long Physical Therapy Nancy Byl, PT, PhD Heather Bhide, PT

Clinical Appointments: 415-353-2311