1. Deep Brain Stimulation
Punit Agrawal, DO
Movement Disorder Division
Department of Neurology
The Ohio State University

2. This lecture reviews DBS patient selection and management with a focus on approved FDA indication for Movement Disorders
No conflicts of interests to disclose

3. FDA Approved Indications
Essential Tremor
FDA approved in 1997
Parkinson’s disease
FDA approved in 2002
Dystonia
FDA approved (HDE*) in 2003
Obsessive Compulsive Disorder
FDA approved (HDE**) in 2009
Medicare and Insurance reimbursed for FDA approved indications
*Humanitarian Device: Authorized by Federal (U.S.A) law for the use as an aid in the management of chronic, intractable (drug refractory) primary dystonia, including generalized and segmental dystonia, hemidystonia, and cervical dystonia, for individuals 7 years of age and older.
**Humanitarian Device: Authorized by Federal (U.S.A) law for use as an adjunct to medications and as alternative to anterior capsulotomy for treatment of chronic, severe, treatment-resistant obsessive-compulsive disorder (OCD) in adult patients who have failed at least three selective serotonin reuptake inhibitors (SSRIs). The effectiveness of this device for this use has not been demonstrated.

4. > 80,000 DBS Implants worldwide >3000 published articles on DBS
Offers hope to severely impaired patients when symptoms are intractable despite optimal medication and other available therapies.
> 22 years of safety
> 80,000 DBS Implants worldwide
>3000 published articles on DBS
With proper patient selection, there is improvement seen with:
Standard scales/measures of disease
Quality of life measures
Co-morbid conditions
Medication intake
Chronic care costs

5. DBS Target Sites for Movement Disorders
Vim Thalamus: Essential Tremor
Subthalamic Nucleus: Parkinson’s disease and Dystonia
Globus Pallidus: Parkinson’s disease and Dystonia

6. Movement Disorders Patient Evaluation
Movement Disorder Neurology
Evaluate medications and disease
Levodopa ON-OFF assessment in Parkinson’s disease
Neurosurgery
Discuss surgery, implantable devices, risks
MRI of the brain
Neuropsychological testing
Review and Discussion at Patient Management Meeting
Team recommendation

7. Approach to Improve Outcomes
Multidisciplinary Team:
Neurology, neurosurgery, psychiatry, psychology, physical medicine and rehabilitation, neuroradiology, neuroanesthesia, PT/OT/ST, social worker/case manager.
Proper Patient Selection
Patient screening for appropriate candidates for DBS therapy and education
Realistic and proper expectations from DBS therapy
Psychosocial assessment

8. Poor Candidates for DBS
Significant dementia or cognitive impairment
Neuropsychological compromise
Untreated depression, anxiety, psychosis, or other co-morbid psychiatric illness
Unable to cooperate during surgical procedure
Unable to cooperate during programming visits
Unrealistic expectations of outcomes
Co-existing medical problems that significantly increase risks of surgery
Uncontrolled heart disease, lung disease, cerebrovascular disease, uncontrolled hypertension, or diabetes.
Significant structural abnormalities detected by brain MRI that would pose higher risk of brain surgery
Additional features suggesting poor candidates for parkinsonism
Minimal or absent response to levodopa
Atypical Parkinsonian syndromes 8

9. DBS for Tremor Severe debilitating medication refractory tremor
Propranolol Primidone Keppra
Neurontin Anticholinergic PD medications
Resting Tremor > Postural Tremor > Intention Tremor
Expectations: Improve quality of life and that it may not completely eliminate all tremor
Target: VIM thalamic DBS

10. Tremor Outcomes with VIM Thalamic DBS
- Essential tremor: 60-80% improvement
MS, traumatic brain injury and cerebellar tremor: 50% improvement
Medtronic Inc. conducted a series of clinical studies to demonstrate the safety and effectiveness of ActivaTM Tremor Control Therapy for the treatment of essential tremor and tremor-dominant Parkinson's disease.
The studies were prospective controlled trials and randomized, double-blind assessments were used to further evaluate the efficacy of the therapy.
For patients with essential tremor, tremor suppression, activities of daily living, and the patient and physician perception of disability were assessed using the Tremor Rating Scale (TRS).
The control group, shown as a solid line, had NO stimulation, and the treatment group, shown as a dashed line, received stimulation.
Results from the clinical trials show a clinically and statistically significant suppression of tremor: p=0.008 on the Wilcoxon Rank Sum Test which compares treatment and control group results. N=19 patients and Mean Follow-up=20.3 months.15
15 Medtronic Global Clinical Study Series 25

11. DBS for Parkinson’s Disease
Multiple prospective randomized controlled trials have demonstrated benefits
Tremor
Rigidity and bradykinesia similar to levodopa
Reduced motor fluctuations including less dyskinesia and improved “ON” time.
Reduction in medications
Reduction in maintenance cost of disease
10-20% of individuals with Parkinson’s disease may be candidates for DBS therapy*
Brain Targets: STN / GPi / VIM
Aspects important with regards to patient education and expectations
Not a cure and does not stop disease progression.
Does not reverse disease.
Does not prevent dementia.
May be minimally helpful for gait trouble, imbalance, or posture changes.
Excluding tremor, minimal help of symptoms not responsive to levodopa.
Does not help non-motor symptoms.
*AAN Guideline Summary for Patients and their Families: Medical and Surgical Treatment for
Motor Fluctuations and Dyskinesia in Parkinson Disease, 2006

12. PD with DBS Off verse On

13. Good PD Candidates Clear diagnosis of idiopathic Parkinson’s disease
Atypical Parkinson’s or Parkinson’s like syndromes do not improve with surgery
Good response to levodopa with levodopa challenge showing at least 33% improved UPDRS motor score
Issues include one or more of the following
1) Significant Motor fluctuations and/or disabling dyskinesia
2) Disabling tremor despite optimal medication treatment:
Levodopa Ropinirole/Pramipexole
Selegiline/rasagiline Benzodiazepines
Amantadine Parsitan/benztropine/trihexyphenidyl
3) Medication Intolerance
Stable cognition (absence of significant dementia)
Realistic expectations and good family support
No co-morbid psychiatric/behavioral problem
Greater than 5 years of disease duration
Patient with 3 or more hours of “off” time per day
Patients on 5 or more doses/day of levodopa
Patients who require polypharmacy (3 or more drug classes)
Patients with side effects (cognitive,hypotension,nausea)
Tremor predominant that is bothering to patient
“How many hours a day do your symptoms bother you?”

14. “ON” Time Without Dyskinesias Improves from 27% to 74%
DBS Improvement in PD
“ON” Time Without Dyskinesias Improves from 27% to 74%
27%
19%
49% 7%
74%*
23%
In the prospective, randomised, double-bind, crossover multi-center study conducted by the Deep-Brain Stimulation for Parkinson's Disease Study Group, 96 patients with advanced, drug-refractory PD underwent bilateral stimulation of the STN with Activa® Therapy.
Patients completed a home diary documenting their motor status during the 2 days before each visit. Three motor states were identified: poor mobility (‘Off’), good mobility without dyskinesia (‘On’ without dyskinesia), and good mobility with dyskinesia (‘On’ with dyskinesia).
Assessments of the percentage of time with good mobility and without dyskinesia (‘On’ without dyskinesia) during the waking time increased from 27% at baseline to 74% at six months, a 3-fold gain. This was paralleled by a decrease in the percentage of time with poor mobility (‘Off’ state), from 49% to 19%.
Deep-Brain Stimulation for Parkinson's Disease Study Group. “Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.” N Engl J Med 2001; 345: 956–63.
PD = Parkinson’s disease; STN = subthalamic nucleus; DBS = deep-brain stimulation
Before Surgery
(n=96)
6 Months After Surgery Bilateral STN Activa® Implant
(n=91)
‘ON’ with Dyskinesia
‘ON’ without Dyskinesia
‘OFF’
* The Deep-Brain Stimulation for Parkinson’s Disease Study Group. Deep-brain stimulation of the subthalamic nucleus for the pars interna of the globus pallidus in Parkinson’s disease. N Eng J Med. 2001;345:

15. PD Motor Symptoms Improvement Maintained After 5 Years
In a 5-year study, DBS significantly improved OFF-medication assessments of tremor, rigidity, and akinesia/bradykinesia
OFF-Medication Motor Score Improvements*
6-month
1-year
3 years
5 years
Tremor
79%
75%
83%
Rigidity
58%
73%
74%
71%
Akinesia
42%
63%
52%
49%
*Results for STN

16. Economic Benefits of DBS
Cost Analysis in PD: Multiple comparisons of medical resource use before and after DBS show that DBS significantly reduces the cost of care
Notes - When considering all treatments costs, STN-DBS pays off from the second year as motor symptoms improve significantly and antiparkinsonian medications are reduced 2
References
Fraix V, Houeto JL, Lagrange C, et al. Clinical and economic results of bilateral subthalamic nucleus stimulation in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2006;77(4):443-9
Meissner W, Schreiter D, Volkmann J, Trottenberg T, Schneider GH, Sturm V et al. Deep brain stimulation in late stage Parkinson's disease: a retrospective cost analysis in Germany. J Neurol 2005; 252:
Impact of Deep Brain Stimulation (DBS) of the sub-thalamic nucleus (STN) on health-related quality of life (HRQOL) and healthcare resource use in advanced parkinsonian patients. 2003
Tomaszewski KJ, Holloway RG. Deep brain stimulation in the treatment of Parkinson's disease: a cost-effectiveness analysis. Neurology 2001; 57:
Spottke EA, Volkmann J, Lorenz D, et al. J Neurol 2002; 249:
DBS reduces the daily dosage of levodopa and dopamine agonists, significantly reducing drug costs by 12 months (Spottke et al, 2002) 16

17. DBS for Dystonia Most effective for primary dystonia
 Generalized, segmental, hemi-dystonia, and focal dystonia including cervical dystonia
DYT -1
Secondary dystonia such as those caused by trauma or metabolic disorders can be less responsive to DBS therapy with inconsistent results
Those with structural lesions can worsen
Tardive dystonia are exceptions with often good response
Significantly impairment of normal activities and quality of life
Failed maximal combinations of medication trials:
- Muscle relaxants - Benzodiazepines
- Anticholinergics - Levodopa
Failure of botulinum toxin therapy or the dystonia affects too large of an area for this modality of treatment 
Ages 7 and older
Targets
Globus pallidus internus (Gpi)
Thalamus
Vop,Voa
Outcome 23-91% improvement

18. Double blind, class I study
40 pts with GPi DBS randomized to Stimulation or Sham for 3 months
At 3 months, all patients received open label active stimulation until the 6-month outcome measure
Stim ON: 15.8±14.1points Sham: 1.4±3.8 points (P<0.001)
BFMDRS score reduction

19. OCD Candidates for DBS The most severely disabled patients
5 years of disease
Multiple medication and behavioral therapy resistant
Predominant contamination behaviors
Requires multidisciplinary team for patient selection including psychiatry, psychology, neuropsychology, neurosurgery, and ethics.

20. DBS for Obsessive Compulsive Disorder
60% of Patients with severe end stage OCD were responders with DBS
Improvement in OCD scores (YBOCS), Quality of life (GAF)
And depression (HAM-D) Led to new indication for depression
FDA approval US-HDE 2009

21. DBS for OCD Clinical Trial:
The most severely disabled patients
5 years of disease, multiple medication resistant, 20 in-patient admissions
Results-- 60% of patients were significantly improved
Decreased obsessions, compulsion, improved functioning,
Improved self care, social and occupational functioning, Quality of life, functioning, working, dating, getting married, living independently

22. Surgical Procedure Brain imaging Computerized guidance Micro-robotics
Electrical recording of brain function
mm precision

23. Direct targeting RN
STN
SNr

24. Anatomical Atlas morphing and Targeting

25. Physiological Mapping
Microelectrode recording (MER)
microstimulation
Macrostimulation with DBS electrode

26. Intraoperative mapping

27. Intra-operative DBS Testing

28. Potential Complications/Risks
Hemorrhage (inherent in any stereotactic procedure); may be silent or symptomatic
Transient confusion
Infection (typically occurs at neurostimulator site in chest when it does occur)
Device related
Stimulation related
Usually can be minimized or eliminated by adjusting stimulation settings
Reversible paresthesia, dysarthria, muscle contraction 28

29. Overview of Programming
Anode/Cathode
Variables
Contacts – 4 for each electrode
Amplitude
Rate
Pulse Width
Monopolar vs Bipolar
Constant Current vs Constant Voltage
Soft Start
Impedance
Battery Status

30. DBS Lead Electrode Selection1 2 3
Lead Electrodes 3
(+) positive
off
off 3
off 2
off 2
(+) 1
(-) 1
(-)
off
off
Unipolar
Bipolar
* The negative electrode exerts the therapeutic effect

31. Monopolar vs Bipolar
Bipolar stimulation can limit the spread and is beneficial to shaping field of stimulation

32. Stimulation Parameters
Pulse Width (sec) duration of each stimulus
Amplitude (Volts) intensity of stimulation
Rate
(Hertz) number of pulses per second

33. Movement Disorder DBS Management
DBS programming goal
Deliver the therapy to the brain target of interest with avoiding stimulation of surrounding structures
Typically, initial programming of DBS is weeks after DBS electrode implant
Subsequent programming can be every 2-8 weeks for the first 3 months, and then every 3-6 months thereafter
Commonly takes 6 months to obtain the best settings
Many patients will require concurrent medication adjustments

34. Systematic Approach: Initial Programming
Identify patients prominent symptoms and review expectation of DBS.
Inspect and palpate hardware
Monopolar review – should be done with every initial programming and when side effects suspected:
With constant rate (130) and pulse width (90) assess individual contacts with monopolar settings with regards to threshold of stimulation and apparent improvement of symptoms while slowly increasing the amplitude
Useful to identify anatomy and position within the target nuclei
Useful for future programming sessions and trouble shooting
Trial of bipolar vs monopolar if low threshold
Check impedances and battery
Educate patient on use of patient programmer and/or recharger if applicable

35. Systematic Approach: Subsequent DBS Programming
Identify any problems or side effects related to DBS
Inspect and palpate hardware
Check impedances, battery and for activations
Adjust DBS parameters: common strategy is to make one parameter change with little adjustments to other parameters.
Adjust amplitude with little or no change in rate or pulse width
Adjust rate with little or no change to amplitude or pulse width
Adjust pulse width with little or no change to amplitude or rate
Change bipolar and assess for threshold with resetting at tolerable level
For PD, best to program with patients in the “Off” state
If PD, have patient take typical dose of PD medications and wait for medications to have taken effect
Adjust medication if indicated

36. DBS Common Settings PW (µs) Rate (Hz) 60-90 130-185 90-120 100-185
Settings for different indications and target
PW (µs)
Rate (Hz)
STN – PD
60-90
GPi - PD
90-120
VIM Tremor
GPi Dystonia
60-145

37. Programming StrategiesET
Settings of best tremor control with no side effects.
Some devices allow for patient programming
Turn off DBS at night PD
May need a few programming sessions with planned increases over time
Monitor dyskinesia as reducing medications preferred over reducing stimulation if no other side effects
Realistic expectations
Keep stimulator on all day and night
Dystonia
May take several months for dystonia to see response
Programming may take a few years

38. DBS Problem Solving
No improvement
Contracture/slurred speech
Persistent numbness
Double vision
Visual disturbances
Dyskinesia
Autonomic symptoms
Review anatomical location of stimulation with monopolar review
“No improvement” –
Reassess programming parameters
Repeat monopolar review without medications if applicable
Review patient’s pre-operative symptoms (including video if available for comparison)
Review expectations
Inspect evaluate hardware/lead placement.

39. Regional STN Anatomy Target is the dorsal-lateral portion of STN
Medial lemniscus – posterior
Stimulation can cause intolerable paresthesia
Internal Capsule – anterior, lateral and ventral
Stimulation can cause tonic contracture
CN III – medial caudal
Stimulation can cause diplopia
Hypothalamus – medial rostral
Stimulation can cause autonomic symptoms
Ventral Medial STN
Stimulation can cause mood changes
IC = internal capsule
STN = subthalamic nucleus
ML = medial lemniscus
RN = red nucleus

40. Regional VIM Anatomy Internal Capsule – ventral and lateral
Stimulation can cause tonic contracture
Ventral Caudal (Vc) thalamus (sensory relay) – posterior
Stimulation can cause intolerable paresthesia
Ventral Oralis Posterior (Vop) thalamus – anterior
Stimulation may cause no effect on tremor
Vo = ventral oral (pallidal relay)
Vim = ventral intermediate (cerebellar relay)
Vc = ventral caudal (principle somatosensory nucleus)
IC = internal capsule

41. Regional GPi Anatomy Internal Capsule - posterior
Stimulation can cause tonic contracture
Optic Tract – ventral
Stimulation can cause visual disturbances
GP = globus pallidus
IC = internal capsule
OT = optic tract

42. Long term Maintenance
No MRI other than of the head with use of specific restrictions.
Avoid activities that cause excessive torque on the neck
Awareness of electromagnetic fields that can cause DBS devices to turn on/off.
Battery drain – monitor battery status
Watch for signs of skin breakdown or irritation around DBS hardware, and inspect for signs of disconnections or lead wire migration
Check and reset activations with each programming session, and check impedance levels.
If concern for device failure, check unit if on/off, number of activations, battery status, hardware malfunction (imaging), and impedances