Download Spencer K. Hutto, M.D. Department of Neurology, Emory University

Spencer K. Hutto, M.D.
Department of Neurology, Emory University
Journal Club
August 19, 2016
Speaker Disclosure
• I have no potential conflicts of interest to report
• No one is even paying me to talk to you today; this is of
my own free will without coercion (sort of)
Study Question
• Do patients with early Parkinson’s Disease benefit from
neurostimulation?
• Early:
• Younger patient age (mean roughly 52-53 years old)
• Decreased overall duration of disease (mean 7.5 years)
• Decreased duration of motor complications (mean 1.7 years)
• Neurostimulation has traditionally been used for patient’s with
advanced Parkinson’s disease
• In seminal article, mean age 60-61 years old, mean duration of disease
of 11.1-13.8 years, and on levodopa for 13-14 years
Authors and Potential Sources of Bias
• Medtronic provided some degree of funding (major
supplier of DBS hardware)
• Majority of authors associated with Medtronic (receipt of
lecture fees, payment for educational programs, travel
support, grant support, consulting fees) as well as the
broader pharmaceutical industry
BACKGROUND
Background
• Parkinson’s Disease
• Clinical syndrome of bradykinesia, rigidity, tremor, and shuffling gait
produced by depletion of dopaminergic neurons in the substantia
nigra pars compacta projecting to the striatum of the basal ganglia
• Sinemet (carbidopa/levodopa) typically works well early in
the disease course though later complicated by motor
fluctuations (on/off phenomenon, dyskinesias)
• DBS is a surgical therapeutic option usually reserved for
advanced cases
Deep Brain Stimulation – How It Works
• Nobody knows for sure (McIntyre and Hahn 2010)
• Originally thought to be due to direct effect of electrodes
on the local circuitry rather than an alteration to the
network itself (cortico-basal ganglia-thalamo-cortical)
• Paradigm now shifting to electrode-induced network
changes
• Induces changes to the way groups of neurons fire (rate, oscillatory
pattern [regular/irregular], burst patterns)
• PD associated with beta activity within the basal ganglia, likely as result
of the striatum’s impaired ability in the low dopamine state to filter out
beta activity from the motor cortex (anti-Parkinsonian meds improve this
defect)
• STN stimulation produces effects on the hyper-direct pathway as well to
regulate the overall network from a cortical perspective
Deep Brain Stimulation - Procedure
• Electrodes implanted in the STN or the GPi with
assistance of MRI, microelectrode recording, and exam
• Greater mean decrease in anti-Parkinsonian medications with STN
implants in comparison to GPi implants; dyskinesias only improved
owing to effect of medication reduction
• STN also an area where multiple motor loops of the network converge
on a single focused area with separation from non-motor loops; smaller
in size than the GPi, requiring less energy demands on the generator
• GPi implantation may provide better control over dyskinesias
independent of medication changes
• No significant difference between the rate of complications for STN
vs GPi implantation
• Multidisciplinary team required for effective implantation
(neurology, neurosurgery, neuropsychiatry,
neuroradiology, neurocritical care)
Rationale for Deep Brain Stimulation
• Waning temporal effectiveness of medical therapy
• Surgery effectively targets the GPi/STN, improving
bradykinesia and reducing dyskinesias frequently
associated with Sinemet
• The DBS device is programmable (VA-NIH) in terms of
voltage, pulse width, and stimulation frequency (within
limits of maximal charge-density)
• Must weigh against risks associated with implantation:
infection, hemorrhage, failure of generator/leads
• Must also consider the cost:
• £468,528 per quality-adjusted life year during the 1st year following
implantation, £45,189 by year 5, and £70,537 by year 10
METHODS
Patient Inclusion Criteria
• Ages 18 to 60
• Improvement of motor signs by at least 50% with dopaminergic
•
•
•
•
•
medications (UPDRS*-III)
Disease duration of 4 years or more
Scores of more than 6 for ADLs in the worst condition despite
medication treatment (UPDRS*-II)
Disease severity on medication rating below stage 3 (Hoehn
and Yahr scale)
Fluctuations or dyskinesia present for 3 years or less
Mild-to-moderate impairment in social and occupational
functioning (Social and Occupational Functioning Assessment
Scale)
* Unified Parkinson’s Disease Rating Scale
Patient Exclusion Criteria
• Necessity of determining whether or not patients had
typical Parkinson’s disease
• Disease duration less than 4 years
• Conditions that may impact conduction of study:
• Dementia
• Major depression with suicidal thoughts
• Acute Psychosis
• Any other major medical or psychological problem that would
interfere with the conduction of study protocol (exact meaning not
specified by article)
Study Design
• Randomized, multicenter, parallel-group, prospective
design with centralized data collection and analysis for
two year period
• Randomized to neurostimulation and medical therapy vs.
medical therapy alone
• Neurostimulation group underwent bilateral stereotactic
surgery of the STN within 6 weeks of randomization
• Implantations of electrodes (model 3380, Medtronic) and a pulse
generator (Kinetra or Soletra, Medtronic)
Study Design
• Regular assessments – baseline, 5, 12, and 24 months
• Preoperative and postoperative standardized video
assessments by experts (with exception of rigidity)
• Adjustments to medication and stimulation performed at
follow-up according to pre-defined standards
Outcome Measures
• Primary end point: between group difference in mean
change in quality of life from baseline to 2 years (PDQ-39)
• Secondary end points (tested sequentially if primary end
point found to be significant):
• ADLs (UPDRS-II score)
• Severity of motor signs (UPDRS-III score)
• Severity of treatment-related complications (UPDRS-IV score)
• Time with good mobility and no troublesome dyskinesia (patient
diary)
• Several additional minor secondary outcomes recorded
Adverse Events
• Defined as any events leading to death, disability, or
prolonged or new hospitalization with serious health
impairment
RESULTS
Definitions
• Intention-to-treat population – analysis of the entire
patient population completing randomization, regardless
of if they drop-out or cross-over, with last values carried
forward
• Per-protocol population – analysis of only those patients
completing the study in the portion they were originally
randomized to
Patient Characteristics
• 392 patients assessed; 251 enrolled
• 124 assigned to neurostimulation group (120 implanted and
completed study)
• 127 to the medical-therapy group (123 completed study)
• No significant differences in baseline patient
characteristics
• 25 patients with major protocol deviations
• PDQ-39 assessment outside the window, absence of motor
fluctuations or dyskinesia, insufficient exposure to treatment, death
during study period
Primary Outcome on Quality of Life
• Neurostimulation
• Intention to treat – improved by 26%
• Per-protocol – improved by 27%
• Medical therapy alone
• Intention to treat - declined by 1%
• Per-protocol – stable at 0% change
QoL: PDQ-39
• Maximum effect
achieved at 5 months
• All subcomponents
show improvement in
favor of
neurostimulation with
exceptions of social
support and
communication
(roughly same as
medical therapy)
Major Secondary End Points
• Severity of motor signs off-medication (UPDRS-III)
• Neurostimulation: 53% improvement
• Medical therapy: 4% improvement
• Mean difference between groups: 16.4 points on UPDRS-III scale
• Levodopa-induced complications (UPDRS-IV)
• Neurostimulation: 61% improvement
• Medical therapy: 13% decline
• Mean difference between groups: 4.1 points on UPDRS-IV scale
Major Secondary End Points
• ADLs in the worse condition (UPDRS-II)
• Neurostimulation: 30% improvement
• Medical therapy: 12% decline
• Mean difference between groups: 6.2 points on UPDRS-II scale
• Notably no significant difference when queried on ADLs in the best
condition (minor secondary end point)
• Time with good mobility and no troublesome dyskinesia
• Neurostimulation: 20% improvement
• Medical therapy: 2% improvement
• Mean difference between groups: 1.9 hours
Selected Minor Secondary End Points
• Levodopa-equivalent Daily Dose
• Neurostimulation: 39% reduction
• Medical therapy: 21% increase
• Mean difference between groups: 609 mg
• No significant differences noted on cognitive assessments
(Mattis Dementia Rating Scale or UPDRS-I)
• Positive effects noted on mood for the neurostimulation
group per the Montgomery and Asberg Depression Raing
Scale (administered by examiner) and Beck Depression
Invenotry II (patient completed)
Adverse Events
• Increase in serious adverse events with neurostimulation
• Other serious adverse events related to medicine decreased with
neurostimulation
• Suicide (2 neurostimulation, 1 medical therapy)
• Depression more frequent in the neurostimulation group
• Motor problems, impulse control disorders, and psychotic
manifestations more common in the medical therapy
group
DISCUSSION
Author’s Discussion
• Findings of the study were clinically relevant as:
• 26% statistically significant improvement in the primary outcome,
felt to represent clinically significant outcome as well
• Similar to improvement noticed in prior study on patients with advanced
PD (25% improvement)
• Patients benefited with neurostimulation even while medication was
still effective
• Felt secondary to the benefit seen in the neurostimulation group as
opposed to any deterioration in the medical therapy group
Author’s Discussion
• More frequent adverse events in the neurostimulation
group, principally due to an increase in mild adverse
events
• Frequency of suicidal behavior high but no significant difference
between groups
• Strengths of study:
• Strict standards for interventions
• Small number of withdrawals
• Consistency between results of intention-to-treat and per-protocol
analyses
CRITICAL APPRAISAL
Validity
• Randomization:
• Patient’s were randomized though allocation difficult to conceal in
the setting of surgery as the intervention
• Patient’s were analyzed via both intention-to-treat and
per-protocol methods with comparisons made between
analyses
• Follow-up was nearly complete for the patient population
(only 8 patients did not complete the study out of 251
[3.2%])
• Per-protocol analysis included 116 patients in the
neurostimulation group (8 fewer) and 110 in the medicaltherapy group (17 fewer) for a total of 25 major protocol
deviations
Validity
• Evaluators were blinded while reviewing the standardized
video encounters
• With that noted, it was impossible to blind the patients (due to
surgery)
• Patients otherwise received equal treatment in terms of
medical therapy according to strict guidelines with outside
review of adherence to protocol
• No major differences in baseline patient characteristics at
the start of the trial
Conclusions
• Notable and extensive conflicts of interest in many of the study
investigators
• Interesting study question though faced with difficulties related
to cost and durability of equipment
• Study conducted in a highly regulated fashion in the best way
possible given limitations of surgical intervention and inability to
blind patients
• Methods of intervention effect evaluated by current gold standards
utilized for Parkinson’s disease interventions (PDQ-39, UPDRS)
• Difficult to know exactly how clinically significant QoL findings
were
• Significant benefits achievable with comparable degree of
adverse events experienced when DBS studied for advanced
PD
Implications
• Probably would not push for early DBS placement in my
patients with Parkinson Disease due to following:
• High cost per QALYs early in device placement with risk for declining
cost effectiveness in future
• QoL benefit only truly known for the first two years; with that said, the
primary outcome trend after the two years was toward worsening QoL
with stability noted for the medication group
• Study subject to potential patient bias given the main outcome
measure is a patient completed questionnaire in the setting of a nonpatient blinded study
• With that said, I may be inclined to consider it with the following
reservations:
•
•
•
•
Early development of Sinemet-induced side effects
Potential candidacy for future DBS placement
Patient’s ability to mitigate financial/energy/time drains
Possibility for durability of equipment with understanding that
surgically-related complications and need for re-operation may arise
Future Directions
• Additional research certainly necessary in terms of DBS
durability, its effectiveness, and effect on QoL over time
• Cost/benefit analysis of earlier implantation given milder
symptoms in the patients enrolled in this study
• Research directed at bilateral implantation as centers
today predominantly implant unilaterally
• Additional DBS studies related to its effect on mood
Resources
• Anderson WS, Lenz FA. Surgery Insight: deep brain stimulation for movement
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disorders. Nature Clinical Practice Neurology Nat Clin Pract Neurol.
2006;2(6):310-320. doi:10.1038/ncpneuro0193.
Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain
stimulation for Parkinson’s disease. N Engl J Med 2006;355:896-908.
Mcintosh E, Gray A, Daniels J, et al. Cost-utility analysis of deep brain stimulation
surgery plus best medical therapy versus best medical therapy in patients with
Parkinson's: Economic evaluation alongside the PD SURG trial. Movement
Disorders. 2016;31(8):1173-1182. doi:10.1002/mds.26423.
Mcintyre CC, Hahn PJ. Network perspectives on the mechanisms of deep brain
stimulation. Neurobiology of Disease. 2010;38(3):329-337.
doi:10.1016/j.nbd.2009.09.022.
Okun MS, Zeilman PR. Parkinson's Disease: Guide to Deep Brain Stimulation
Therapy. Parkinson's Disease: Guide to Deep Brain Stimulation Therapy. 2014.
Schuepbach W, Rau J, Knudsen K, et al. Neurostimulation for Parkinson’s
Disease with Early Motor Complications. N Engl J Med 2013; 368:610-622.
Tarsy D. Surgical Treatment of Parkinson Disease. UpToDate.
http://www.uptodate.com/contents/surgical-treatment-of-parkinson-disease.
Published May 19, 2015. Accessed August 14, 2016.
Acknowledgements
• Jorge Juncos, M.D. – Faculty Advisor
• Mary Beth Ramsey, M.D. – Senior Advisor
• David Pearce, M.D. – Chief of Education