1. Deep Brain Stimulation for Parkinson’s disease Overview and UpdatesBy
Hesham Abboud
Assistant lecturer of Neurology
Faculty of Medicine, University of Alexandria
Clinical fellow of Movement Disorders
Neurological Institute, Cleveland Clinic

2. DEFINITION
Deep Brain Stimulation (DBS) is a novel surgical technique that involves implantation of a stimulation electrode in the deep structures of the brain for the treatment of involuntary movements and other neuropsychiatric disorders.
The stimulation electrode provides continuous electrical stimulation at overactive brain structures resulting in a net inhibitory effect that is functionally equivalent to a reversible lesional surgery.

3. HISTORICAL BACKGROUND
Surgical treatment for movement disorders started as early as 1947 when the first pallidotomy was performed for the treatment of Huntington’s chorea.
In the fifties, thalamatomies were routienly performed for the treatment of Parkinson’s disease (PD) and essential tremors (ET).
With the introduction of levodopa in 1968, the interest in movement disorder surgery for PD decreased considerably.
The interest in lesional surgeries was regained again in the late eighties after the long years of levodopa experience unmasked the ugly face of dopaminergic treatment (dyskinesias and motor fluctuations). th

4. HISTORICAL BACKGROUND
Also in the eighties, the animal model for PD was developed (MPTP-injected monkeys). Animal studies showed that destruction of the subthalamic nucleus (STN) lead to dramatic and permanent improvement in parkinsonian symptoms.
lesional STN surgery in humans was complicated by the development of balism highlighting the need for non-lesional surgeries.
In 1993, professor Benabid in France introduced the concept of DBS for the treatment of movement disorders.
In 1997 DBS was approved for the treatment of ET followed by approval for PD in 2002 and dystonia in 2003.
In the present day, DBS surgery is considered the optimal treatment for advanced cases of PD, ET, and primary generalized dystonia. Thousands of procedures are done routinely each year in specialized DBS centers. It is also widely used for a wide spectrum of off-label indications.

5. DBS: components
Stimulator lead or macroelectrode implanted at the target to deliver the electrical stimulation. Each lead has four contacts.
Extension wire implanted subcutaneously behind the ear to connect the lead to the pulse generator.
Intermittent Pulse Generator (IPG): programmable pulse generator (battery) implanted SC below the clavicle.

6. DBS: components

7. DBS: components
Physician programmer
Patient access device

8. INDICATIONS/TARGETS FDA-approved indications Off-label indications
PD: STN, GPI, (VIM in special cases).
ET: VIM
Dystonia: GPI
Other movement disorders: MS tremors, rubral tremors, orthostatic tremors, tardive dystonia, tourette’s syndrome.
Psychiatric indications: depression, OCD, chronic pain.

9. DBS for PD Important rules
In patients with PD, DBS can improve all levodopa-responsive symptoms (bradykinesia, rigidity) and all tremors regardless of levodopa response.
DBS provides a continuous state of brain stimulation resembling continuous levodopa intake thus protects against motor fluctuation (wearing off, unpredictable off, on/off phenomenon, and dyskinesia).
STN DBS allows for medication reduction thus protects against medication side effects.

10. DBS for PD Important rules
DBS does not improve axial symptoms: gait, balance, and speech (except if levodopa-responsive or dyskinesia-related).
DBS does not improve non-motor symptoms of PD: cognitive, psychiatric, autonomic, fatigue, …etc.
DBS DOES NOT STOP THE PROGRESSION OF THE DISEASE.

11. DBS for PD: Indications
Medication-resistant tremors and tremor predominant PD.
Significant dyskinesia.
Motor fluctuations: wearing off, delayed on, on/off phenomenon.
Intolerance to medications (and significant medication side effects).
Other considerations: young age, work status, level of education, motivation, … etc.

12. DBS for PD Contraindications
Parkinson plus and secondary parkinsonism.
Lack of levodopa response (except in tremor predominant disease).
Dementia (and significant cognitive impairment…).
Significant psychiatric disorders (note that DBS for psychiatric disorders has different targets from those of PD).
Early and/or mild PD
Relative contraindications: surgical risk, severe non motor symptoms, severe dysartheria, unrealistic patient expectations, lack of family support, poor motivation.

13. DBS for PD Side effects Operative risks: Intracerebral bleeding.
Infection of the lead (intracranial), extension wire, or the IPG.
Immediate postoperative confusion.
Postoperative side effects (temporary or permanent):
Aggravation of executive dysfunction and reduction of verbal fluency.
Weight gain.
Depression / mania.
Aggravation of postural hypotension and other autonomic features (rare).
Stimulation-related side effects (reversible):
Capsular side effects: weakness, numbness, posturing, eye deviation, aggravation of dysartheria.
Thalamic side effects: numbness, hemihyposthesia.
Limbic side effects: depression, emotionality.
Midbrain: ophthalmoplegia.
Stimulation-induced dyskinesia (in some cases).

14. DBS for PD The role of neurology
Preoperative: screening and case selection.
Intra-operative: physiological targeting (mapping).
Postoperative: programming and medication management.

15. DBS for PD: Screening and case selection
The aim of the screening process is to ensure that the surgery will be carried out for an appropriate indication and exclude any contraindications for surgery.
Educating the patient and his/her family about the benefits, risks, and alternatives of DBS is an essential part of the screening process. Patient expectations, level of motivation, and family support should all be explored at this stage as well.
The process of screening and case selection is often carried out by a multi-disciplinary team consisting of neurologists, neurosurgeons, neuropsychologists, and psychiatrists. Each candidate is discussed in a periodical patient-management meeting and the decision for each case is made by the whole multidisciplinary team.

16. Center for Neurological Restoration (CNR) Cleveland Clinic

17. DBS for PD: screening and case selection
The process of screening includes the following:
Neurological evaluation: to confirm the diagnosis, exclude non idiopathic disease, and look at the indications for surgery.
Levodopa-response test: (on and off testing): comparing the UPDRS score in the worst off and the best on states.
Neurosurgical evaluation: to educate the patient about the surgery and exclude surgical contraindications (uncontrolled HTN, medical comorbidities, …etc.)
Neuropsychological testing: to exclude dementia, characterize the type and degree of MCI if any, and evaluate the risk for postoperative cognitive decline.
Psychiatric evaluation: to exclude (and treat) significant psychiatric disorders: anxiety, psychosis, depression, impulse control disorders (ICD), dopamine dysregulation syndrome.
MRI brain: to exclude structural lesions and causes of secondary parkinsonism.

18. DBS for PD: exclusion factors
We studied causes of excluding DBS candidates at the Center for Neurological Restoration of the Cleveland Clinic between 2006 and We found that 30% of all PD patients evaluated for DBS were excluded due to one or more of the following causes:
Cognitive causes: 32.7%
Early/mild PD: 29%
Psychiatric disorders: 21%
Suspected parkinson plus or 2ndry parkinsonism: 13%
PD with poor levodopa response: 11%
Unfeasible or unrealistic patient expectations: 10%
Predominant axial symptoms 6%
Medical/surgical comorbidities 6%
Abnormal brain imaging 3%
Abboud, H., Mehanna, R., Machado, et al. (2014), Comprehensive, Multidisciplinary Deep Brain Stimulation Screening for Parkinson Patients: No Room for “Short Cuts”. Movmnt Disords Clncl Practice. doi:  /mdc .

19. DBS Outcomes
Multiple studies have shown that DBS is superior to medical treatment for advanced PD.
The DBS for PD study group reported a 50% improvement of UPDRS III with stimulation on compared to medical therapy alone (37% for GPI).
They reported an improvement in the time spent with good mobility and no dyskinesia from 27% in medically-treated patients to 74% with DBS on (28% to 64% in GPI).
Studies comparing STN and GPI stimulation showed equal efficacy although medication reduction was achieved only with STN stimulation.
Deep Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson’s Disease. The Deep Brain Stimulation for Parkinson’s Disease Study Group. N Engl J Med 2001; 345:

20. Functional and QOL Outcomes
We looked at the effect of DBS on functional (UPDRS II) and QOL (EQ5D) outcomes in PD patients who underwent surgery at the Cleveland Clinic CNR between 2006 and 2011:
We found a statistically significant 4.3 point improvement in UPDRS II six months following surgery (P=0.0396).
We also found a statistically significant 0.06 point improvement in EQ5D index six months following surgery (P=0.002)
Abboud H, Floden D, Genc G, et al. Do Parkinson Patients with Mild Cognitive Impairment have different Immediate and Long-term DBS Outcomes? (2014), Poster Presentations. Mov. Disord., 29: S1–S571. doi:  /mds.25914

21. Global Patient Impression Scale
Abboud H, Floden D, Genc G, et al. Do Parkinson Patients with Mild Cognitive Impairment have different Immediate and Long-term DBS Outcomes? (2014), Poster Presentations. Mov. Disord., 29: S1–S571. doi:  /mds.25914

22. Cognitive Predictors of DBS outcomes
Dementia is a well-established DBS contraindication. However, little is known about the effect of MCI on outcome after DBS.
We studied the effect of different patterns of cognitive impairment on outcome after DBS.
We found that MCI per se doesn’t influence functional outcome after DBS but the types of impaired domains do.
Attention impairment predicted prolonged postoperative hospitalization (P=0.0015) and showed a trend towards occurrence of postoperative confusion.
There was a trend of association between visuospatial impairment and a worse UPDRS II at 6 months and between language impairment and a worse EQ5D index at 1 year postoperatively.
Memory and executive dysfunction had no effect on outcomes.
Abboud H, Floden D, Genc G, et al. Do Parkinson Patients with Mild Cognitive Impairment have different Immediate and Long-term DBS Outcomes? (2014), Poster Presentations. Mov. Disord., 29: S1–S571. doi:  /mds.25914

23. DBS and Body Weight
Clinical observation suggested a worse outcome after DBS in obese patients.
We studied the effect of preoperative BMI on functional and QOL outcomes following DBS.
After adjusting for the effect of the pre-op UPDRS II, a 1 unit increase in BMI resulted in a significant 0.49 point increase (worsening) in the 6-month post-op UPDRS II (P=0.033).
BMI had no effect on post-op EQ5D.
Unclear if this negative effect is related to further increase in body weight following surgery.
Obese patients are not optimal candidates for DBS and should be advised to reduce their weight prior to surgery.
Abboud H, Genc G, Thompson N, et al. Does Body Weight play a Role in Success of Deep Brain Stimulation for Parkinson’s Disease? In Progress

24. DBS for early PD?
In 2013 the EARLYSTIM study group published their controversial results in NEJM concluding that DBS is superior to medical therapy in early PD if associated with motor complications.
They randomized PD patients with motor complications within the 1st 3 years of diagnosis to medical therapy alone or medical therapy +DBS.
They found that DBS patients had statistically and clinically significant improvement in QOL (PDQ-39), UPDRS III, UPDRS II, UPDRS IV, and time spent with good mobility and no dyskinesia compared to patients in the medical arm.
Early PD is no longer considered a CAI to DBS if associated with early motor complications. s
Schuepbach WM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med (7):

25. DBS for PD: target selection
VIM
GPI
STN
Target - ++
Bradykinesia/rigidity
+++ +
Tremors
- (in PD)
Medication reduction
Dyskinesia
Cognitive decline
Speech decline
Bleeding
ET and other tremors
Dystonia
Depression (medial STN)
other indications

26. DBS for PD: target selection
Most PD cases are currently implanted in the STN.
PD patients with high risk for cognitive decline and those with predominant dyskinesia may be implanted in the GPI.
Patients with tremor-predominant PD may be implanted in the VIM especially if they have coexistent ET or are at risk for cognitive decline.

27. Operative considerations
Each candidate is admitted to the hospital one day before the operation for surgical preparation and routine blood work.
A head frame is inserted to the patient’s head then a CT scan is performed to provide landmarks for the surgeon. The CT image is then superimposed on the patient’s preoperative MRI for accurate anatomical targeting.
A burr hole is then made under brief general anesthesia to provide an inlet for introduction of the stimulating electrodes.
The patient is then awaken for the mapping part.

28. Intra-operative mapping
A microelectrode is inserted through a pre-calculated trajectory targeting the STN (or the GPI or VIM). The microelectrode records extracellular action potentials.
Each part of the brain has a specific waveform that can be recognized by well-trained neurophysiologists. The waveform of the target (e.g. STN) is recognized and is further divided into functional subdivisions via a process called recruitment or driving.
The microelectrode is then used to provide brief and limited electric stimulation (microstimulation) to ensure the absence of stimulation side effects.
This process is repeated again once or twice at different locations to choose the best trajectory and to establish a safety margin.
A macroelectrode is then inserted at the best trajectory and macrostimulation is tested for benefits and side effects. In case of satisfactory results, the macroelectrode is left in place and the patient is put back to sleep to connect the extension wire.
The IPG is inserted S.C below the clavicle (stage 2) either on the same day or few weeks later.

29. DBS SURGERY

30. DBS SURGERY

31. Postoperative considerations
The patient stays in the hospital for one day after stage 1 or a two-staged operation. The stimulator is left off for at least two weeks following surgery to allow time for the brain to heal. Some improvement in symptoms is usually seen before the stimulator is turned on due to a micro-lesion effect caused by micro- and macro- electrode passes.
The stimulator is turned on during the first programming session. Medications should not be altered after surgery until reaching the final programming parameters (usually reached within the first 3 to 4 programming sessions).

32. DBS programming
The IPG provides continuous low-voltage electrical stimulation with the following adjustable parameters: voltage, frequency, pulse width, and polarity.
Polarity refers to the configuration of the cathode (-) and the anode (+). The term monopolar stimulation refers to the state where the case is the positive and one of the 4 lead contacts is the negative. Bipolar stimulation is when one of the lead contacts is positive and another contact is negative.
Monopolar stimulation provides a wider area of stimulation: more efficacy but more potential for stimulation side effects. Bipolar stimulation provides a smaller area of stimulation but has less potential for side effects.

33. Monopolar versus bipolar stimulation

34. DBS programming
A monopolar review refers to the process of testing each contact of the lead to determine the thresholds for efficacy and side effects.
We start with contact zero and increase the voltage gradually with a 0.5 volts increments. We select the voltage that produces optimal effect and no side effects.
The pulse width is usually kept constant at 60 to 90 msec. and the frequency is usually kept at 130 Hertz (for PD). The pulse width and/or the frequency can be lowered in case of side effects (especially speech problems).
Contact zero is usually the closest to the internal capsule and the most prone to side effects. Contact 3 is the furthest but can be the least effective. Contact 1 or 2 are the ones usually used for their reasonable efficacy and often limited side effects.
If side effects persist despite parameter adjustment, bipolar review is performed and the best combination is used.
Monopolar and bipolar reviews are usually time consuming and can take up to six hours per session. They are only needed in the first 2 to 3 sessions following surgery or whenever there is loss of efficacy or development of side effects.
In case of satisfactory control, the patient should be seen once every 6 to 12 months for battery check.
The battery is usually changed every 4 to 5 years depending on the rate of consumption and the parameters used (high V, F, PW leads to less battery duration). Replacement is carried out by a simple outpatient procedure.

35. DBS: precautions
The following important precautions must be followed for any patient with an implanted deep brain stimulator:
DBS Patients cannot have an MRI (brain MRI with a small coil is an exception).
DBS patients cannot have diathermy.
Patients with a cardiac pacemaker can only have bipolar stimulation with an IPG implanted on the opposite side regardless of the side of implantation.
Medtronic company should be contacted before having any surgery or procedure.
Large magnetic fields can inadvertently turn the stimulator off: (security scanning machines, large microwaves, vending machines, … etc.).

36. How to build a local DBS program?
Case selection and screening:
We need well-trained neurologists experienced in differentiating idiopathic PD from plus/secondary syndromes and in UPDRS rating for the levodopa response test.
We need a protocol for cognitive evaluation (all patients with cognitive complaints, functional impairment, and/or an MMSE score less than 24 can be excluded. Patients without frank dementia should be referred for full neuropsychological evaluation).
Psychiatric symptoms should be treated before surgery. Patients with persistent and significant anxiety/depression should be excluded.
MRI brain with special emphasis on the basal ganglia.

37. How to build a local DBS program?
Postoperative:
We need well-trained neurologists experienced in DBS programming and post-DBS medication management.
Continuous and productive collaboration with the functional neurosurgeon is mandatory.
Collaboration with the Cleveland Clinic is possible.

38. Thank you