Convection Enhanced Delivery of Autologous Cerebral Spinal Fluid Improves MRI Visualizations of Basal Ganglion Nuclei During Deep Brain Stimulation Surgery
Phase: NA
Conditions: Parkinson Disease
Sponsor: Jeff Elias, MD

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
1 
 
 
 
Study Title 
Convection Enhanced Delivery of Autologous Cerebral Spinal Fluid 
Improves MRI Visualizations of Basal Ganglion Nuclei During Deep 
Brain Stimulation Surgery 
 
 
Indication Studied 
DBS (globus pallidum or subthalamus) for treatment of medication-
refractory Parkinson’s disease 
 
 
 
 
Protocol Version 
5.0 
 
 
Development 
Phase of Study 
Feasibility 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with acceptable 
Good Clinical Practices (GCP) and regulations. All required study 
documentation will be archived as required by regulatory authorities. 
 
 
Confidentiality 
This document is confidential and the property of the University of 
Virginia. No part of it may be transmitted, reproduced, published, or 
used by other persons without prior written authorization from the 
study sponsor. 
 
 
 
 
 
Principal  
Investigator 
 
Dr. William Jeffrey Elias 
Department of Neurological Surgery  
University of Virginia 
Box 800212 
Charlottesville, VA  22908 
(434) 924-0451    (434) 982-3806 fax 
 
 
 
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
2 
 
 
SIGNATURE PAGE 
  
 
 
INVESTIGATOR’S AGREEMENT 
 
I confirm that I have read this protocol and I agree to conduct the study as outlined herein.  I 
agree to conduct the study in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and that are consistent with Good Clinical Practices as outlined in ICH 
E6 and the applicable laws and regulations.  
 
 
 
 
 
 
Investigator: 
 
Signature 
 
Date 
 
 
 
 
 
Name 
 
 
 
 
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
3 
 
 
 
SYNOPSIS 
Title of Study:  Convection Enhanced Delivery of Autologous Cerebral Spinal Fluid Improves MRI 
Visualizations of Basal Ganglion Nuclei During Deep Brain Stimulation Surgery 
Investigator(s): W. Jeffrey Elias, MD 
Study center(s): University of Virginia Medical Center 
Phase of study: Feasibility 
Planned Study Initiation:  January 2018 
Objectives: The proposed study will evaluate safety foremost but also the distribution and initial 
effectiveness of infusion-enhanced, MRI-guided DBS for patients with medication-refractory, 
Parkinson’s disease.  
Primary: 
• 
To evaluate the incidence and severity of adverse events (AEs) associated with convection 
enhanced delivery of autologous CSF into the internal segment of the globus pallidus or subthalamic 
nucleus in patients with advanced PD who are undergoing DBS surgery. 
Secondary: 
• 
 To determine the volume of distribution (Vd) relative to the volume of infusion (Vi) for a 
convective infusion of autologous CSF into a deep brain nuclear region in humans 
• 
To determine the level of effectiveness or symptom response of infusion-enhanced, MRI-guided 
DBS.   
Methodology: Open-label, single-arm, quantitative study 
Number of subjects (planned): 4 
Diagnosis and main criteria for inclusion: Patients with Parkinson’s disease and medically-
refractory motor symptoms, who are already planned for MRI-guided DBS electrodes under general 
anesthesia. 
Investigational intervention: Unilateral infusion of 0.5 ml autologous CSF before DBS electrode 
insertion with MRI monitoring. 
Other study intervention(s): None 
Criteria for evaluation (i.e. endpoints): 
Efficacy:  
The primary efficacy assessment will be measured with the unmedicated UPDRS, motor subsection 
(part III) at 6 months in comparison to baseline. Additional efficacy endpoints will include standard, 
validated assessments of PD before and after DBS.  Standard clinical measures of PD will be 
obtained as per usual clinical protocol at pretreatment baseline and 6 months postoperatively. 
Safety: 
Safety will be assessed by incidence and severity of AEs, changes in physical examinations, 
neurological exams and the number of discontinuations due to AEs. 
Distribution: 
Distribution will be assessed using MRI imaging to calculate the volume of distribution of autologous 
CSF into the basal ganglia in relation to the volume infused.   
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
4 
 
TABLE OF CONTENTS 
 
1. 
LIST OF ABBREVIATIONS ................................................................................. 4 
2. 
BACKGROUND AND RATIONALE ..................................................................... 6 
2.1. 
Study Synopsis ................................................................................................. 6 
2.2. 
Disease Background ......................................................................................... 6 
2.3. 
Case Study ....................................................................................................... 7 
2.4. 
Part 1 Preclinical Animal Studies ...................................................................... 8 
2.5. 
Part 2 Preclinical Animal Studies .................................................................... 11 
3. 
STUDY OBJECTIVES ........................................................................................ 12 
3.1. 
Primary Objectives .......................................................................................... 12 
3.2. 
Secondary Objectives ..................................................................................... 12 
4. 
SUBJECT ELIGIBILITY ..................................................................................... 13 
4.1. 
Inclusion Criteria ............................................................................................. 13 
4.2. 
Exclusion Criteria ............................................................................................ 13 
5. 
TREATMENT PLAN ........................................................................................... 14 
5.1. 
Study Overview ............................................................................................... 14 
5.2. 
Treatment Assignment .................................................................................... 14 
5.3. 
DBS Surgery and Treatment Administration.................................................... 14 
5.4. 
Concomitant Medications/Treatments ............................................................. 17 
5.5. 
Duration of Study Participation ........................................................................ 18 
5.6. 
Discontinuation/Withdrawal from Study ........................................................... 18 
5.7. 
Subject Status Definitions ............................................................................... 18 
6. 
DEVICE INFORMATION .................................................................................... 19 
7. 
EVALUATION AND ASSESSMENTS ................................................................ 19 
7.1. 
Schedule of Events ......................................................................................... 19 
7.2. 
Study Assessments ........................................................................................ 20 
7.3. 
Final Study Visit .............................................................................................. 22 
7.4. 
Early Termination Visit .................................................................................... 22 
8. 
DATA ANALYSIS PLAN .................................................................................... 22 
8.1. 
Safety ............................................................................................................. 22 
8.2. 
Efficacy ........................................................................................................... 22 
8.3. 
Additional Evaluations ..................................................................................... 23 
8.4. 
Statistical Considerations and Sample Size .................................................... 23 
9. 
ADVERSE EVENT AND REPORTING ............................................................... 23 
9.1. 
Definitions ....................................................................................................... 24 
9.2. 
Attribution Assessment ................................................................................... 26 
9.3. 
IRB Reporting Requirements .......................................................................... 27 
9.4. 
Additional Reporting Requirements ................................................................. 27 
9.5. 
Expected adverse events ................................................................................ 28 
10. 
STUDY MANAGEMENT .................................................................................... 29 
10.1. Institutional Review Board (IRB) Approval and Consent ................................. 29 
10.2. Adherence to the Protocol ............................................................................... 29 
10.3. Emergency Modifications ................................................................................ 29 
10.4. Other Protocol Deviations/Violations ............................................................... 29 
10.5. Record Retention ............................................................................................ 30 
10.6. Obligations of Investigators ............................................................................. 30 
11. 
REFERENCES ................................................................................................... 31 
 
 
1. LIST OF ABBREVIATIONS 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
5 
 
 
Abbreviation or 
specialist term 
Explanation 
ACUC 
Animal Care and Use Committee 
AE 
Adverse Event 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CED 
Convection-Enhanced Delivery 
CFR 
Code Of Federal Regulations 
CNS 
Central Nervous System 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid  
CT 
Computed Tomography 
DBS 
Deep Brain Stimulation 
ECG 
Electrocardiogram 
FDA 
Food And Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
GPe 
External Globus Pallidum 
GPi 
Internal Globus Pallidum 
HCG 
Beta-Human Chorionic Gonadotropin 
HR 
Heart Rate 
h 
Hour 
I/E 
Inclusion Exclusion Criteria 
ICF 
Informed Consent Form 
ICH 
International Conference On Harmonization 
IRB 
Institutional Review Board 
IV 
Intravenous 
MRI 
Magnetic Resonance Imaging 
min 
Minute 
PD 
Parkinson’s Disease 
PK 
Pharmacokinetic 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
STN 
Subthalamic Nucleus 
UPDRS 
Unified Parkinson’s Disease Rating Scale 
UVA 
University of Virginia 
Vd 
Volume of distribution 
Vi 
Volume of infusion 
WOCBP 
Women of Childbearing Potential 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
6 
 
 
2. BACKGROUND AND RATIONALE 
 
2.1. Study Synopsis 
 
This will be a small feasibility study investigating the safety and feasibility of infusion-
enhanced, MRI-guided DBS electrode placement. We intend to enroll four (4) patients, 
with Parkinson’s disease and medically-refractory motor symptoms, who are already 
planned for MRI-guided DBS electrodes under general anesthesia. Only a single side 
(nondominant) will be investigated with the research infusion when bilateral DBS 
electrodes are planned. 
2.2. Disease Background 
 
MRI-guided surgery was initially developed in the 1990s for a more precise brain 
biopsy.1,7  Recently, image-guided DBS has been proposed as an alternative to 
traditional electrophysiologically-guided DBS for medically-refractory Parkinson’s 
disease.2,11,13-16,18  MRI-guided DBS can be performed under general anesthesia to avoid 
the discomfort of awake surgery and the need for prolonged unmedicated states. Clinical 
outcomes note improved off medication UPDRS motor scores by 60% and 49%, 
respectively which compares similarly to a recent meta-analysis of 34 studies estimating 
52% in PD with STN DBS.9 
 
True image-guided surgery adjusts to brain shifting during the procedure and the 
inherent registration errors that can be associated with image fusion techniques.4,8 
 
Contemporary MRI continues to improve so that small stereotactic targets, that previously 
required intraoperative confirmation of their location with recordings or clinical testing, 
can now be directly visualized, however there is still room for improvement. McClelland 
et. al. analyzed electrodes placed using frame-based stereotaxy and microelectrode 
recording guidance, and found that 40 of 52 electrodes required re-positioning based on 
electrophysiologic localization.10 Unfortunately one can’t determine whether this is from 
frame placement error, image fusion, MRI distortion, or stereotactic positioning error.   
The assessment of DBS electrode placement relative to a selected target 
location in stereotactic space is relatively simple, requiring only postoperative imaging to 
compare with the preoperative plan. Real-time image-guided DBS placement has only 
recently been realized with compatible skull-mounted frames and high-field MRI. Radial 
vector error during DBS for PD has been measured at 1.2 ± 0.65 and 0.8 ± 0.4 mm.12,16 
CT has also been used as a modality to guide asleep DBS surgeries although it is 
primarily used for image registration and confirmation of the placement as opposed to 
true image guided, localization during the procedure.  Burchiel et al reported similar 
accuracies, but clinical outcomes are not yet available.2 
Even with highly precise MRI-guided placement, the need for occasional 
electrode repositioning exists.16 This work was pursued on the assumption that improved 
resolution of these deep brain structures will aid stereotactic targeting, ultimately 
improving patient outcomes.  We are interested to investigate if the combined use of 
intraoperative MRI-guided electrode placement, with improved target visualization from 
infusions, will improve patient outcomes as determined from UPDRS. The potential 
applicability of this technique to humans has many issues.  First and foremost, the 
risk/benefit ratio must be favorable to ultimately consider infusion-enhanced, MRI-guided 
surgery as a valid surgical option.  We perceive the addition of a small volume infusion 
(<0.5 ml) of autologous CSF to be associated with low morbidity. The increased risk of 
micro-catheter insertion should be similar or less than the current electrophysiological 
mapping process that requires multiple, sharp microelectrode penetrations. The safest 
infusate to test intuitively would be autologous CSF which is easily and safely obtained by 
lumbar puncture from patients who are already under general anesthesia. 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
7 
 
 
Finally, the preclinical study described a proof-of-concept technique that mainly 
relies on the improved visualization of structures like the STN from T2 signal 
manipulation in the laboratory and clinic. Other structures like the internal segment of the 
globus pallidum or the ventral intermediate nucleus of the thalamus are better visualized 
with other MR sequences like inversion recovery or susceptibility-weighted images, 
respectively. In the future, we envision that infusion-enhanced MR imaging would be 
tailored to the desired brain target with target-specific sequences and infusates. For 
example, a choline-specific infusate could be designed to visualize the basal nucleus of 
Meynert if a neuroprotective or regenerative intervention were available for Alzheimer’s 
disease.  Imaging of all modalities will continue to improve with technology, but tailored 
intracerebral infusions may serve as an adjunct for improved visualization, not as a 
replacement for current imaging. 
 
2.3. Case Study 
 
A 59-year-old retired psychologist with Parkinsons disease presented for consideration of 
deep brain stimulation surgery. He underwent successful surgery consisting of bilateral 
subthalamic nucleus DBS with micro-electrode mapping and a staged pulse generator 
implantation. Unfortunately, he developed a pseudomonas infection involving the pulse 
generator, which required explantation of the pulse generator and the distal portion of the 
lead extensions. Despite ciprofloxacin therapy, he presented again two months later with 
evidence of infection at the cranial incision. Cerebral MRI with gadolinium revealed no 
intracranial abscess, however, there was hyperintense signal on T2 weighted images 
around the right DBS electrode tract to the subthalamus (Figure 1). The remainder of the 
DBS system was explanted, and the infection was cleared after several weeks of 
intravenous aztreonam therapy. A second bilateral subthalamic DBS system was 
eventually re-implanted one year after the first. 
 
Figure 1: (A) Patient who had a 
unilateral infection of a DBS electrode 
which led to increased signal 
differentiation between the 
surrounding white matter tracts and 
visualization of the STN nucleus 
which is not visible on the 
contralateral side. (B) Enlarged view 
of infected side.  STN: Subthalamic 
nucleus, GPi/GPe: internal and 
external globus pallidum.   
 
 
 
 
The presumed vasogenic edema around the infected electrode highlighted the 
boundaries of the right subthalamic nucleus and adjacent deep brain anatomy in contrast 
to the unaffected, contralateral, left side (Figure 1). This observation led to the premise of 
this study, where we believe that the extracellular space could be manipulated 
experimentally to improve MRI visualization. 
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
8 
 
2.4. Part 1 Preclinical Animal Studies 
 
2.4.1. 
Methods 
 
Following UVA Institutional Animal Care and Use Committee approval (ACUC # 3843-08-
10), Sus Scrofa Domestica (YorkShire) female pigs weighing approximately 25 pounds 
were acquired and acclimated in the vivarium facility for 3 days. The CED swine 
experiments were performed with 3T MRI utilizing a standard human head coil. 
 
Before surgery, the infusion apparatus was prepared. A PHD Ultra syringe pump 
(Harvard Apparatus, Holliston, MA, USA) was used with a 500 microliter, airtight, glass 
syringe. The syringe was connected to a series of four 60-inch extension sets (Medex 
Micro Bore, Product Code 536020, Smiths Medical, Dublin, OH, USA), each of which had 
0.4 ml priming volume. The extension sets were then connected to an EViTAR 
microcatheter.  (NexGen Medical Systems, Inc., Reno, NV, USA). In experiments where 
normal saline was infused, the system was primed with normal saline via a 3-way valve 
at an extension set connection point. Care was taken to ensure there were no air 
bubbles.  When CSF was infused, the priming was performed in the same manner after 
CSF had been obtained by lumbar puncture in the anesthetized animal. 
On the day of surgery anesthesia was induced, and a T2 3T MRI was obtained in 
three orthogonal directions (Siemens Trio with Numaris 4 B17 software, TR 6000, TE 93, 
2mm slice width, no gap, resolution 320x320). The mid-thalamic targets were identified 
on these pre-surgical MR images and then compared to a published swine stereotactic 
atlas.6,17 The coordinates for cannula placement were calculated and ranged in relation to 
the bregma: 0-3 mm anterior, 6-8 mm lateral, and 33-36 mm deep. 
The animal was then positioned in a custom, MRI-compatible, stereotactic head 
frame such that the bregma and lambda points were aligned in the same plane. The 
scalp was then shaved and prepped with betadine, opened in linear fashion with a 
scalpel, and a small burr hole was created in the skull. After the dura was opened, the 
outer cannula of the infusion catheter, with a stylet, was then connected to the 
stereotactic manipulator and advanced to the target minus 1 cm in vector length (the 
infusion cannula is 1cm longer than the outer cannula). The outer cannula was then 
affixed to the skull.  After removal of the stylet, the inner infusion microcatheter was then 
advanced through the outer cannula to the target.  The PHD Ultra syringe pump was kept 
in the MRI control room and the tubing was passed through the wall. Sagittal, axial, and 
coronal T2 images were then obtained to verify the placement of the micro-catheter.  
After MRI confirmation of the micro-catheter position, the infusion was instituted 
with rates between 1- 6 µL/min so that convective distribution would be achieved. MRI 
monitoring was obtained at consistent 15 minute intervals for a total of 90-120 minutes 
depending on the rate of infusion. The volume of distribution (Vd) was obtained by using 
the average diameter of the infusion front as measured from T2 signal changes. 
Following completion of micro-infusion experiments and MR imaging, the infusion 
catheter was removed and the scalp was sutured closed. Animals were recovered with 
direct observation for evidence of behavioral, neurologic, or gait dysfunction.   Necropsy 
was performed at either early (48 hours), subacute (1 week), or late (1 month) time 
points. The brains were formalin fixed for sectioning, gross inspection, and histology with 
immunohistochemistry by a certified neuropathologist. A total of seven animals were 
infused: five with normal saline and two with CSF.  The summary is shown below in Table 
1.  
 
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
9 
 
Table 1: Summary of Swine CED Experiments 
 
# 
Infusate 
Rate 
Observation/ Histology 
(Days) 
1 
NS 
1µl/min x 45min, then 
3 µ l/min for 45 min, 
then 6 µ l/min for 30 
min 
2 
2 
NS 
3 µl/min x 90 min 
28 
3 
NS 
5 µl/min x 90min 
7 
4 
NS 
5 µl/min x 90min 
28 
5 
NS 
5 µl/min x 90min 
7 
6 
CSF 
5 µl/min x 90min 
28 
7 
CSF 
5 µl/min x 90min 
7 
 
NS: Normal Saline, CSF: Cerebrospinal Fluid 
 
 
2.4.2. 
Results 
 
Volume of Distribution 
 
The Vd/Vi, measured from T2 weighted MRI sequences varied from 2 to 4.5 regardless of 
the infusate. The rate for CED (as opposed to diffusion) is generally accepted as greater 
than 0.05 µL per minute. These experiments infused between 1 to 6 µL per minute without 
noticeable differences in the Vd/Vi. Total volume of infusion was bounded by either MRI 
time for low flow rates (limited to 90 minutes), or by observing no further increase in the 
volume of distribution when a pial boundary was encountered, and this ranged from 90 to 
360 µL. 
 
MR Imaging 
 
All MRI assessments were made from T2 weighted sequences. The CED infusions of 
normal saline or CSF became apparent with increased T2 hyperintensity after 30-45 µL as 
infused.  By 90 µL, clear definition of nuclear structures began to develop. MRI changes in 
the infusion ceased when the infusion front reached the pial boundaries. CED infusions 
into the thalamus delineated the dorsomedial, ventral anterior, reticular, and centromedian 
nuclei – all of which were not apparent before the infusion (Figure 2). The enhanced 
appearance of the nuclear structures was consistent across animals with the ventral 
anterior and then the dorsomedial nucleus becoming the most apparent. Animal #7 had a 
post infusion scan performed 30 min after the completion of the infusion and the infusion 
effects persisted. Long term imaging was not performed. 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
10 
 
 
Figure 2: (A) axial view of animal #1 after 
360 µL infusion of saline demonstrating 
the reticular nucleus is lateral to the VA 
nucleus, (B) axial view of animal #4 after 
450 µL of saline, (C) coronal view of 
animal #6 after 450 µL CSF, and (D) axial 
time lapsed infusion of animal #3 at a rate 
5 µL / min.   The white matter tract medial 
to the VA nucleus, lateral to DM, and 
anterior to CM is readily apparent after 
infusion.   
 
 
 
Histology 
 
Histology was examined at either early (within 2 days), subacute (7 days), or late (28 days) 
time points for evidence of acute or latent infusion toxicity. All specimens were analyzed 
with Hematoxylin and Eosin stains. Animals infused with normal saline demonstrated mild 
neuronal effects with pyknotic neurons and axonal retractions – possibly attributed to the 
tonicity of the infusate (Figure 3).  Those infused with autologous CSF had no evidence 
of neuronal change at either time point: 7 and 28 days. 
 
Figure 3: Hematoxylin and Eosin stains 
after convective infusion with normal 
saline identifying pyknotic neuron (dashed 
arrow) and axonal retraction figures (solid 
arrow) in a saline infused thalamus.  
These findings were not present when 
CSF infusion was performed. 
 
 
 
 
 
 
 
 
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
11 
 
2.5. Part 2 Preclinical Animal Studies 
 
2.5.1. 
Purpose 
 
Following the Part 1 preclinical animal studies, and FDA review, further infusions were 
performed to validate that there was no toxicity related to the infusion of CSF.  A control 
site was included for comparison. The infusion catheter planned for the human trials was 
used in the Part 2 preclinical animal studies (SmartFlowTM K123605). 
 
2.5.2. 
Methods 
 
Following UVA Institutional Animal Care and Use Committee approval (ACUC # 3843-08-
16), Sus Scrofa Domestica (YorkShire) female pigs weighing approximately 25 pounds 
were acquired and acclimated in the vivarium facility for 3 days. 
On the day of surgery anesthesia was induced and a spinal tap was performed 
under fluoroscopic guidance.  Five milliliters of CSF were removed and saved for later to 
be infused.  The animal was then positioned in a custom stereotactic head frame such 
that the bregma and lambda points were aligned in the same plane. The scalp was then 
shaved and prepped with betadine, opened in linear fashion with a scalpel, and a small 
burr hole was created in the skull bilaterally 6mm lateral to the bregma. After the dura 
was opened, the infusion catheter (SmartFlowTM K123605) was advanced into the brain 
30mm in the right thalamus then retracted (control site).  It was then advanced 30mm in 
the left thalamus for the CSF infusion.   
The previously acquired CSF was used to prime the infusion system.  A Harvard 
Apparatus PHD Ultra infusion pump was used with a piece of extension tubing (Medex 
Micro Bore, Product Code 536020, Smiths Medical, Dublin, OH, USA) and a 500 
microliter airtight gas syringe.  The CSF was filtered with a 0.1 micron in-line filter while 
priming the system. CSF was then infused in the left thalamus at a rate of 5 microliters / 
min for a total volume of 450 microliters.  The infusion catheter was then withdrawn, the 
wound was closed, and the animal was taken to recovery. 
Nine animals in total were infused with autologous CSF.  Five animals underwent 
necropsy at 24 hours and 4 animals underwent necropsy at 28 days.  Necropsy was 
performed by removing the brain immediately following euthanasia via a craniectomy and 
placing the whole brain in 10% buffered formaldehyde. 
After a minimum of 2 weeks the formalin fixed brains were cut, H&E stained, and 
analyzed by an independent neuropathologist. 
 
2.5.3. 
Results 
 
Histology results are summarized below.  None of the CSF infusion sites had evidence of 
toxicity.  Distinct tracts were identified in eight of the nine brains.  In the brain where a 
tract was not identified, the thalamus was sectioned forty times in 5-micron thicknesses.  
After sectioning, slides were H&E stained then reviewed.  All tracts showed typical 
findings of catheter insertion into brain (microhemorrhage at 24 hours; gliosis and 
hemosiderin deposition at 1 month).  There was evidence of axonal injury in one acute 
animal control tract, consistent with severing of axons from the insertion of the CED 
catheter. The neuropathology report is attached as attachment 2.0. 
 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
12 
 
 
 
Animal # 
CSF Infusion 
Control 
Acute  
(24 hours) 
1 
No neuronal injury, 
distinct track identified 
Axonal swelling, 
distinct track identified 
 
4 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
5 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
8 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
9 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
 
 
 
Chronic  
(1 month) 
2 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
3 
No neuronal injury, no 
distinct track identified 
No neuronal injury, no 
distinct track identified 
 
6 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
7 
No neuronal injury, 
distinct track identified 
No neuronal injury, 
distinct track identified 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. STUDY OBJECTIVES 
 
The proposed study will evaluate safety foremost but also the distribution and initial effectiveness 
of infusion-enhanced, MRI-guided DBS for patients with medication-refractory, Parkinson’s 
disease.  
 
3.1. Primary Objectives 
 
Safety:  
 
Safety of the CSF infusion will be evaluated using a common description of clinical 
complications for patients treated in this study. Safety will be determined by an evaluation 
of the incidence and severity of infusion-related side effects and complications from the 
first treatment day visit through the 6-month post–treatment time point. All AEs will be 
reported and categorized by investigators as definitely, probably, possibly, unlikely, or 
unrelated to the CSF infusion, and/or Parkinson’s disease progression.    Safety will be 
assessed by incidence and severity of AEs, changes in physical examinations, 
neurological exams, and the number of discontinuations due to AEs 
 
3.2. Secondary Objectives  
 
Distribution:   

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
13 
 
 
The volume of distribution (Vd) will be determined immediately following the infusion (Vi) 
with intraoperative 1.5T MRI, T2-weighted sequences.  The distribution of the infusion by 
convective properties in a deep brain human nucleus (GPi or STN) will be determined by 
calculating the Vd/Vi ratio.   
 
Efficacy:  
 
The primary efficacy assessment will be measured with the unmedicated UPDRS, motor 
subsection (part III) at 6 months in comparison to baseline. Additional efficacy endpoints 
will include standard, validated assessments of PD before and after DBS.  Standard 
clinical measures of PD will be obtained as per usual clinical protocol at pretreatment 
baseline and 6 months postoperatively.  These DBS-related assessments include: 
 
• 
UPDRS in the off and on medication state  
• 
Levodopa medication equivalents (milligrams)  
• 
Neuropsychological assessment 
• 
PDQ-39  
 
4. SUBJECT ELIGIBILITY 
 
Patients with medically-refractory Parkinson’s disease who are planned for MRI-guided 
DBS surgery under general anesthesia are candidates for this protocol. They will be 
invited to participate in this study if they decide to have DBS surgery in the intraoperative 
MRI suite under general anesthesia. Patients who decide to have awake DBS surgery 
with clinical and electrophysiologic testing will not be eligible. The consenting process will 
occur in the outpatient clinic setting, and patients will have the opportunity to review the 
consent document at home with their families. A total of eight patients will be enrolled. 
 
4.1. Inclusion Criteria 
 
1. Men and women, age 30 years and older  
2. Subjects with advanced PD who are scheduled for MRI-guided DBS surgery under 
general anesthesia 
3. Subjects who are able and willing to give informed consent and able to attend clinic visits 
through 6 months 
4. The target nucleus, GPi or STN, is visible on MRI so that it can be targeted for the study 
infusion and then for MRI-guided DBS    
 
4.2. Exclusion Criteria 
1. DBS surgery planned in the awake condition with microelectrode recordings and clinical 
testing 
2. Spinal pathology not amenable to lumbar puncture 
3. Subjects who have had deep brain stimulation or a prior stereotactic ablation of the basal 
ganglia 
4. Legal incapacity or limited legal capacity as determined by the neuropsychologist  
5. Are participating or have participated in another clinical trial in the last 30 days 
6. Any illness that in the investigator's opinion preclude participation in this study. 
7. Subjects who are prisoners. 
8. Women who are pregnant. 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
14 
 
9. Subjects who do not speak English. (Questionnaires are validated in English and no 
other language.) 
5. TREATMENT PLAN  
 
5.1. Study Overview 
This will be an open-label, single-arm, pilot study investigating the safety and feasibility of infusion-enhanced, 
MRI-guided DBS electrode placement. We intend to enroll patients, with Parkinson’s disease and medically-
refractory motor symptoms, who are already planned for MRI-guided DBS electrodes under general 
anesthesia.  The hypothesis of the study is that a convective micro-infusion of autologous CSF will enhance 
the T2-weighted MRI visualization of the targeted nucleus during image-guided DBS surgery for Parkinson’s 
disease. We will record standard clinical measures of PD at baseline and 6 months following DBS surgery. The 
study will recruit patients at a rate of approximately one a month and will take less than two years to complete. 
5.2. Treatment Assignment 
All subjects will receive the CSF infusion during the DBS surgery. The DBS surgery will be performed on the 
targeted nucleus either bilaterally or unilaterally, as previously determined by a multidisciplinary team of 
neurology, neurosurgery, and neuropsychology. During unilateral DBS surgery, the targeted nucleus will be 
infused using CED. The nondominant side will be infused during a bilateral DBS procedure. 
5.3. DBS Surgery and Treatment Administration 
 
5.3.1. 
Pre-surgical evaluation 
 
Patients will undergo standard pre-surgical evaluations in preparation for surgery at the same time as their 
baseline assessment.  This will include preoperative visits with the neurosurgeon and anesthesia team at the 
Preanesthesia Evaluation and Testing Center (PETC). Patient history will be taken with regards to any recent 
changes in medical status and a review of current medications both prescription and over-the-counter will be 
obtained by a qualified sub-investigator. Patients taking aspirin, other non-steroidal anti-inflammatory 
medications and vitamin supplements that include vitamin E will have been counseled to stop taking these at 
least 7 days before surgery which is our standard clinical practice for DBS surgery. Routine labs, including 
complete blood count with platelets, blood chemistries, PT/PTT, pregnancy test for women of childbearing age 
and urinalysis will be obtained, as well as 12 lead electrocardiogram and plain film chest radiograph when 
indicated. Additional studies specific to certain medical conditions and/or to ensure patient safety may also be 
obtained. The results of this detailed assessment will be recorded in written form on case report forms and 
recorded in the patients electronic medical record. Subjects will be instructed to be NPO and hold their PD 
medications after midnight prior to the surgery. 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
15 
 
Table 2: Treatment day procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.3.2. 
Initial DBS surgery 
DBS 
surgery 
Presurgical admission 
 
 
 
Clinical practice 
 
General anesthesia 
Reference MRI for stereotactic planning 
Surgery for frontal burr hole      
Stereotactic insertion of guide cannula 
Infusion 
 
Lumbar puncture for 10 ml CSF 
 
 
Research 
 
Insertion of microcatheter to unilateral GPi or STN 
CED infusion of autologous CSF (<0.5 ml) 
MRI monitoring of infusion  
Completion  
DBS 
Replacement of microcatheter with DBS electrode 
 
Clinical practice 
 
Wound closure 
Implantation of pulse generator 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
16 
 
 
Patients will present to the pre-surgical area having not eaten since midnight and off all PD medications.  They 
will be checked in by the pre-surgical staff, which includes placement of an intravenous line, baseline vital 
signs, and medication reconciliation as standard of care.  After meeting with the anesthetic and surgical teams, 
the patient will be taken back to the operating room for general anesthesia and intubation. A lumbar puncture 
will be performed to obtain up to 10 ml of autologous CSF. This will be passed through a sterile 0.1 micron 
filter and maintained sterile.   
 
Patients will then undergo MRI-guided DBS surgery in the intraoperative MRI suite (IMRIS) according 
to standard practice.   Clinically, we utilize frameless stereotaxy (ClearPoint, MRI Interventions) for the surgery.  
A 1.5T reference MPRAGE MRI is acquired and then fused with preoperative 3T MRI of the designated target. 
GPi is optimally visualized with inversion recovery sequence and STN is best imaged with a T2 sequence.  
(The choice of stereotactic target, either globus pallidum or subthalamus, is a predetermined clinical decision 
made by a multidisciplinary team of neurology, neurosurgery, and neuropsychology.) The stereotactic 
trajectory is planned on a neuronavigation workstation by direct MRI visualization of the target nucleus: GPi or 
STN.    
 
The scalp is prepped and draped and local anesthetic is infiltrated into the frontal incision. The incision 
is opened and a pre-coronal, frontal burr hole is drilled corresponding to the designated entry point from the 
stereotactic coordinates. A closed-dura technique is utilized to minimize loss of CSF and brain shift. A scalp 
mounted stereotactic frame (MRI Interventions) is attached to the burr hole. The bore of the magnet is draped 
with sterile technique, and the patient is moved into the bore of the magnet for the stereotactic portion of the 
surgery that is MRI guided and monitored.  
  
5.3.3. 
Infusion Procedure 
 
Once the patient is positioned within the MRI, the dura is sharply punctured with a sharp, ceramic stylet, and 
the MR-compatible infusion catheter is inserted. A second MRI is obtained to confirm the catheter position. 
 
The research infusion of autologous CSF is initiated at 5 microliters/minute.  Serial MRI monitoring of 
the infusion is obtained with T2 weighted images at approximately 15 minute intervals until the target nucleus 
can be visualized or until a total of 500 microliters is administered. The research infusion could add up to an 
additional 100 minutes to the patient’s DBS surgery. MR imaging of the research infusion and then clinical 
assessment of the DBS electrode placement will be conducted on a 1.5T Siemens Espree system with 
continuous monitoring of both SAR and B1+rms values.   
 
A Medfusion 3500 syringe infusion pump with a 1.0 milliliter BD glass syringe will be used with 
extension tubing (Medex Micro Bore, Product Code 536020, Smiths Medical, Dublin, OH, USA). The infusion 
catheter will be the SmartFlowTM K123605 (MRI Interventions).   
   
5.3.4. 
Completion of DBS procedure  
 
The microcatheter is removed, and replaced with the DBS electrode. There is no intraoperative, 
macrostimulation testing of the DBS electrode as the patient is asleep and electrode position is based on MRI 
targeting. The electrode is anchored in place, and the wound is closed.  For bilateral cases, the contralateral 
(dominant side) DBS electrode will be inserted as per standard practice without the research infusion protocol. 
 
The second stage of the DBS procedure is then performed on the same day and under the same 
general anesthetic for placement of the implanted pulse generator. For this, the patient is repositioned in a 
supine fashion with their head slightly rotated away from the pulse generator site. The ipsilateral scalp, neck, 
and chest are prepped and draped. The cranial incision is reopened and a small counter incision is made 
behind the ear. A subcutaneous pocket is made at the clavicular level. The DBS lead extension is tunneled 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
17 
 
subcutaneously between the head and chest, such that the appropriate connections can be made from the 
DBS electrode to the lead extension and then to the pulse generator. Intraoperative lead impedance test is 
performed to confirm the electrical integrity of the system. The wounds are then copiously irrigated with 
antibiotic saline and closed. The patient is taken to the recovery area following extubation. Medications are 
reinstituted, and they are observed overnight on a neurosurgical ward for one or two nights. Postoperative MRI 
is obtained standard of care, and the DBS system is maintained off until programming in the clinic. At the 
University of Virginia, we routinely perform a postoperative MRI after DBS surgery to assess the final position 
of the electrode.  The imaging is conducted within the conditional limits set forth by the FDA for DBS systems.  
The final DBS system implanted will be assessed with MRI in one of two scenarios:  
 
DBS systems that are full-body eligible: 
 
Neurostimulator models 37612 Activa RC, 37603 Activa SC, 37601 Activa PC 
 
No pocket adaptor can be implanted with the DBS system. 
 
Fully-implanted leads (ie, leads that are internalized and capped) 
 
No open or short circuits 
 
DBS systems that are head-only eligible: 
 
Neurostimulator models 37602 Activa SC, 7428 Kinetra, 7426 Soletra 
 
Any DBS system that is implanted with a pocket adaptor 
 
Partially-implanted leads (ie, leads that are externalized) 
 
No open or short circuits 
 
 
 
5.3.5. 
DBS programming and outpatient follow-up 
 
The following is the standard clinical protocol for DBS programming in the outpatient setting:  The wound is 
assessed at seven to ten days and surgical clips are removed. The DBS pulse generator is turned on at one 
month. For this first programming session, all patients present without having taken their PD medications since 
midnight. Each of the four DBS contacts is tested by escalating the stimulation to either symptom response or 
the induction of stimulation-induced side effects. High frequency stimulation is used at either 130 or 180 Hz. 
The optimal electrode configuration is selected, and then the patient takes their routine oral PD medications. 
They are observed for an hour for potential side effects with stimulation plus medication. Standard neurologic 
measures and PD assessments are performed in the clinic during stimulation testing. These include testing for 
tremor, bradykinesia, and gait. The patient is observed for potential dyskinesia after taking their medications. 
Follow up programming visits are then scheduled for two and three months postoperatively. At this time, 
stimulation and medications will be titrated for an optimal symptoms response. A full UPDRS assessment in 
the on and off state will be obtained at six months.   
 
The patient and their caregiver will be trained in the management of the DBS device. They may have 
some ability to adjust the DBS amplitude within the parameters set by the neurologist. They will be able to 
interrogate their system at any time, and can disable the device in the event of an emergency. They will be 
instructed about the issues of an implanted pacemaker device, and to be cautious of strong magnetic fields.
 
 
 
As part of this research protocol, adverse events will be recorded during this first programming visit 
and each subsequent visit.   
 
5.4. Concomitant Medications/Treatments 
 
Prohibited Medications 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
18 
 
 
Patients taking aspirin, other non-steroidal anti-inflammatory medications and vitamin supplements that include 
vitamin E will have been counseled to stop taking these at least 7 days before surgery. These medicines are 
contraindicated for DBS surgery. 
 
Concomitant Medications 
 
All medications and other treatments taken by a subject beginning at the baseline visit and continuing 
throughout the subject’s participation in the study will be recorded on the Concomitant Medication CRF. 
Thereafter, Concomitant Medications information will not be collected or recorded in the eCRFs. The 
information documented will include the medication name, indication, dosage, and the dates of start and 
discontinuation. 
 
At each visit, the site will obtain a complete listing of all medications currently being taken by the 
subject. Any changes, additions or deletions in the administration of concomitant medications will be recorded 
on the Prior and Concomitant Medications CRF. This information will also be documented in the subjects 
electronic medical record. Subjects may receive medications to treat safety events and routine treatment for 
underlying medical conditions as deemed necessary by the Investigator.  
 
5.5. Duration of Study Participation 
 
Subjects who are enrolled will be followed for six months after their DBS surgery. The Screening and Baseline 
period is a maximum of 90 days before the surgery and CED infusion. The follow-up period is the first 6 
months post-DBS implantation.  Follow up clinic visits correspond with routine post DBS clinic follow up and 
does not include additional visits specific to this research.  
5.6. Discontinuation/Withdrawal from Study 
 
Subjects may withdraw or be discontinued from the study at any time for any of the following reasons: 
• 
Disease progression 
• 
Inter-current illness that prevents further treatment 
• 
Unacceptable adverse event(s) 
• 
Subject decides to withdraw from the study 
• 
Subject does not comply with study procedures (i.e. missed follow-up visits) 
• 
At the discretion of the investigator 
• 
Death 
5.7. Subject Status Definitions 
 
Enrolled: All subjects who sign an informed consent will be considered enrolled in the study. All subjects 
consented on the study will be assigned to the research study in EPIC. 
Screen Failure: A subject who is withdrawn or discontinues from the study prior to receiving DBS is considered 
a screen fail. Screen failures are not considered a study accrual and will be replaced. Note: The IRB defines 
any individual that has signed an informed consent as an enrollment in this study and so screen failures should 
be reported to the IRB with enrollment numbers. 
On-Study: A subject is considered on-study on the date when the study team has confirmed the subject has 
met all of the inclusion and none of the exclusion criteria, and the treating physician/surgeon or study PI has 
signed off on the confirmation. 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
19 
 
On-Treatment: A subject is considered on-treatment on the date that the DBS surgery is initiated. A subject 
who is withdrawn or discontinues from the study after receiving DBS surgery is considered a discontinuation 
and will not be replaced. 
On Follow-up: A subject is considered on follow-up on the date that the DBS surgery is completed.    
Off-Study: A subject is considered off-study if they are removed from the study for any of the reasons listed in 
Section 4.6, or if they have completed all study assessments through follow-up (6 Month follow-up visit). 
6. DEVICE INFORMATION 
 
 
Description 
 
The agent under investigation is an intracerebral infusion of autologous CSF.  The autologous CSF will be 
obtained via lumbar puncture and administered during the same procedure, so there is no need for storage of 
the CSF.   
 
Agent Preparation and Administration 
 
A lumbar puncture will be performed to obtain 10 ml of autologous CSF. This will be passed through a sterile 
0.1 micron filter and maintained sterile. A disposable, MRI-compatible frameless stereotactic system that is 
employed for MRI-guided DBS surgery under general anesthesia will be secured to the patient’s skull. Once 
the patient is positioned within the MRI, the dura is sharply punctured with a sharp, ceramic stylet, and the MR-
compatible infusion catheter is inserted.   
 
The research infusion of autologous CSF is initiated at 5 microliters/minute. Serial MRI monitoring of 
the infusion is obtained with T2 weighted images at 15 minute intervals until the target nucleus can be 
visualized or until a total of 500 microliters is administered. Any remaining CSF will be disposed of at the end 
of the procedure. 
 
A Medfusion 3500 syringe infusion pump with a 1.0 milliliter BD glass syringe will be used with 
extension tubing (Medex Micro Bore, Product Code 536020, Smiths Medical, Dublin, OH, USA). The infusion 
catheter will be the SmartFlowTM K123605 (MRI Interventions).   
 
 
7. EVALUATION AND ASSESSMENTS 
 
7.1. Schedule of Events 
 
The following table shows the standard of care and research assessments that will be performed throughout 
the study. 
 
 
 
 
Screening and 
Baseline* 
 
DBS 
Surgery 
One 
Month 
(± 
2weeks) 
6 
Months 
(± 1 
month) 
Informed Consent 
X 
 
 
 
Review study 
eligibility 
X 
 
 
 
Medical History 
X 
 
 
 
MRI  
X 
X 
 
 
Vital signs 
X 
X 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
20 
 
PDQ-39* 
X 
 
 
X 
Physical Exam 
X 
 
 
 
Neurological Exam 
X 
 
X 
X 
Clinical Labs  
X 
 
 
 
Lumbar Puncture 
and CED infusion 
 
X 
 
 
Neuropsychological 
Evaluation 
X 
 
 
X 
UPDRS  
X 
 
 
X 
Review of PD 
medications 
X 
 
 
X 
Adverse Event 
assessment 
 
X 
X 
X 
 
*Screening and Baseline assessments will be performed up to 90 days prior to DBS surgery.  Standard of care 
procedures completed within this period but prior to consent may be used for the purposes of the study.  The order of 
screening/baseline procedures will vary, but all tests required for eligibility must be complete prior to confirmation of 
eligibility.   
 
Please note that any assessments done as part of the patient’s standard care need not be performed by an 
investigator, as long as the assessor is qualified and regularly performs this type of assessment as part of their regular 
medical center duties.  The results of the standard tests and any abnormal findings will be reported back to the 
principal investigator to be evaluated and reported for the research. 
 
7.2. Study Assessments 
 
7.2.1. 
Medical History  
 
A medical history should be obtained during the screening/baseline visit to establish baseline medical condition 
for evaluation of AEs. Medical history includes clinically significant diseases, surgeries, history of cancer, brain 
injuries, and heart conditions. A start date (year), end date (year) and any medications or surgeries to treat the 
condition will be recorded. In addition, all medications (e.g., prescription drugs, over-the-counter drugs, 
herbal/homeopathic remedies, nutritional supplements) used by the patient at the time of the assessment for 
any reason will be collected at this time.  
7.2.2. 
MRI 
 
For the purpose of this study, MR Exams without contrast will be performed. The MR Imaging should include 
T1, T2, and DTI sequences. In addition, MR Images: DWI (including ADC maps, which allows differentiation 
between lesion cytotoxic edema-low ADC and vasogenic edema around the lesion-high ADC) will be obtained 
at baseline. 
 
7.2.3. 
Vital Signs 
 
Vital signs including respiratory rate, pulse rate, systolic blood pressure [SBP], and diastolic blood pressure 
[DBP] and body temperature, will be collected at Screening/Baseline assessment and during CED infusion. 
Vital signs will be continuously monitored during the DBS surgery. At the Screening/Baseline visit, it is 
recommended that vital signs be assessed in subjects who have been in a seated resting position for at least 3 
minutes. Transient changes in BP, HR, or RR may be expected. If a subject has symptoms that appear to be 
related to changes in BP, HR, or RR, all changes deemed by the Investigator to be of clinical importance 
should be reported as an AE. 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
21 
 
7.2.4. 
PDQ-39 Questionnaire 
 
A self reported Parkinson’s Disease Questionaire (PDQ-39) will be completed at Screening/Baseline as well as 
6 Months FU as a secondary measure of effectiveness.  
7.2.5. 
Physical Exam 
 
A full physical examination will be performed at the Screening/Baseline visit only. Physical examinations will 
include examination of the following body systems: general appearance (including height and body weight), 
skin, neck, HEENT (head, ears, eyes, nose and throat), heart (auscultation of heart sounds), lungs 
(auscultation of lung fields), abdomen palpation and auscultation of bowel sounds, lymph nodes, extremities, 
and nervous system. 
 
An abbreviated, symptom-directed physical exam will be performed at all other assessments. Any 
abnormal findings which were not noted at the baseline assessment must be reported as an AE.  
 
7.2.6. 
Neurological Exam 
 
A full neurological exam will be performed at the Screening/Baseline visit and at the 1 and 6 Month follow up 
visits for adverse event determination. Neurological examinations will include orientation, sensory (pain, 
position, vibration, and light touch), reflexes (biceps, triceps, knees, ankles and pathological). Coordination and 
balance will be tested by performing Finger to Nose, Heel to Shin, Rapid Alternating Movements, Heel-to-toe 
walking, and Romberg’s test assessments. In addition, motor, strength and gait testing will be performed. 
 
7.2.7. 
Laboratory Parameters 
Blood samples for clinical labs will be obtained at the Screening/Baseline visit to determine eligibility for DBS 
surgery.  The following clinical laboratory tests should be performed as per standard of care: 
Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
Total leukocyte count and differential 
• 
Platelet count 
 
Serum Chemistry 
• 
Aspartate aminotransferase (AST) 
• 
Alanine aminotransferase (ALT) 
• 
Gamma-glutamyl transferase (GGT) 
• 
Total bilirubin 
• 
Direct bilirubin 
• 
Alkaline phosphatase 
• 
Lactate dehydrogenase (LDH) 
• 
Creatinine 
• 
Blood urea nitrogen (BUN) 
• 
Blood glucose 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Calcium 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
22 
 
• 
Phosphorus 
 
Clotting Time 
• 
Prothrombin time (PT) 
• 
Partial Thromboplastin Time (PTT) 
 
Pregnancy Test 
 
7.2.8. 
Neuropsychological Assessment 
 
A standard neuropsychological assessment will be conducted prior to DBS surgery and will be repeated at the 
6 month follow up visit for potential cognitive and psychological effects of the surgery.  
 
 
7.2.9. 
Unified Parkinson’s Disease Rating Scale 
 
The Unified Parkinson’s Disease Rating Scale (UPDRS) will be performed at Screening/Baseline, and at the 6 
Month Follow Up visit to assess the patient’s motor symptoms. Each treated subject will be examined “off 
medication” and “on medication” by a qualified movement disorders specialist. 
 
7.3. Final Study Visit 
 
The final study visit will occur at the 6 Month Follow Up visit. All final efficacy assessments will be collected at 
this visit. Any ongoing adverse events will be followed at the routine annual clinic visit.   
7.4. Early Termination Visit 
 
In the event that a subject does not want to continue in the study until the 6 Month Follow Up visit, every effort 
will be made to complete a a visit where final AE determination will be made. Subjects may withdraw 
voluntarily from participation in the study at any time. The subject will continue to be monitored on an annual 
basis as part of routine clinical care. 
8. DATA ANALYSIS PLAN 
 
For this study, the Safety and Effectiveness assessment will be descriptive with no statistical endpoints.  The 
results will be examined and analyzed and used as a basis for determining the nature of future studies.  Formal 
hypothesis testing for efficacy is not proposed for this initial safety and preliminary efficacy trial.   
 
8.1. Safety 
 
The PI will evaluate all AE's that occur throughout the study and provide his assessment of the study safety 
profile as well as his recommendations for the study continuation.  All AEs will be communicated to the FDA as 
part of the annual reporting for this proposed IDE study.   
All AEs will be reported and categorized by investigators as definitely, probably, possibly, unlikely, or 
unrelated to the CSF infusion, and/or Parkinson’s disease progression. Standard Code of Federal Regulation 
definitions for Serious Adverse Events (SAEs) and Unanticipated Adverse Device Effects (UADEs) will be used 
in assessment of AEs. 
Primary safety endpoint for this study is the adverse event profile generated during the CED procedure 
through Month 6.   
 
8.2. Efficacy 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
23 
 
 
The primary efficacy endpoint will be focused on determining the degree of change in motor symptoms as 
measured from the un-medicated (off), UPDRS motor subsection (Part III) at 6 months in comparison to 
baseline by a movement disorder neurologist.   
8.3. Additional Evaluations  
 
Additional measures of safety will be obtained during the study.  These secondary measures of safety will 
include evaluations post-treatment which are compared to a baseline assessment.  These measures include: 
• 
Neuropsychological assessment for cognition, depression, and behavioral changes at scheduled visits   
• 
Adverse events 
• 
Physical exam 
• 
Neurological exam 
 
Secondary efficacy endpoints will include comparison of Baseline to post-treatment assessments for:  
• 
Levodopa equivalent medication usage (milligrams) 
• 
Quality of life assessment with PDQ-39 
 
8.4. Statistical Considerations and Sample Size  
 
This is an open-label feasiblity study of 4 subjects to be recruited from a single center.  In order to find 4 
eligible subjects suitable for treatment, up to 20 subjects may be consented and screened.  For this study, a 
statistical sample size analysis is not proposed.  All those subjects that were consented and then found not 
meeting study requirements will be considered screen failures.  
The Safety and Effectiveness assessment will be descriptive with no statistical endpoints.  The results 
will be examined and analyzed and used as a basis for determining the nature of future studies.  
 
9. ADVERSE EVENT AND REPORTING  
 
The adverse event collection interval for this study begins at the time of the lumbar puncture (start of 
investigational procedure) and ends at the 6 Month Follow up visit.  
 
After informed consent has been obtained, and prior to initiation of investigational intervention, only 
serious adverse events caused by a protocol-mandated intervention should be reported (e.g., serious adverse 
events related to invasive procedures such as blood draw). AEs reported between the time the patient signed 
the informed consent and the DBS surgery will be captured as concurrent medical history unless due to a 
protocol-related procedure. 
 
After initiation of investigational intervention, all adverse events will be reported according to the 
guidelines in the following sections. After this period, investigators should report any deaths, serious adverse 
events, or other adverse events of concern that are believed to be related to the investigational intervention. 
 
All adverse events, whether reported by the patient or noted by study personnel, should be recorded in 
the patient’s medical record. Adverse events should be assessed for seriousness, severity, attribute and 
expectedness by the Principal Investigator, or designee.  
AEs should be followed to resolution or stabilization, and reported as SAEs if they become serious. This also 
applies to subjects experiencing AEs that cause interruption or discontinuation of study intervention, or those 
experiencing AEs that are present at the end of their participation in the study. Such subjects should receive 
post-treatment follow-up as appropriate.  
 
If an ongoing AE changes in its severity or in its perceived relationship to study intervention, a new AE 
entry for the event should be completed. 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
24 
 
 
AE and SAE recording will continue until the End of Treatment visit is performed. SAEs considered 
related to the interventional procedure may be reported at any time, even after the patient’s final visit. 
 
9.1. Definitions 
 
Adverse Event 
 
An adverse event is any untoward medical occurrence in a subject who has received an investigational 
intervention, whether or not related to the investigational intervention(s). Medical conditions present before 
starting the investigational intervention will be considered adverse events only if they worsen after starting 
study treatment. Adverse events include unfavorable, harmful or pathological changes in the general condition 
of a subject; subjective or objective symptoms (spontaneously offered by the subject and/or observed by the 
Investigator or the study nurse); intercurrent events or exacerbation of pre-existing diseases which occurred 
after the administration of the study drug; clinically significant changes in laboratory abnormalities; or any 
undesirable and unintended effect of research occurring in human subjects as a result of the collection of 
identifiable private information under the research. 
Persistent or Recurrent Adverse Events 
 
A persistent adverse event is an event which extends continuously, without resolution, between assessments. 
This event should only be recorded once with the initial severity grade. If the severity of the event worsens, 
then the original event ends and a separate event is recorded at the greater grade.  
 
A recurrent adverse event is an event which resolves between assessments and subsequently recurs. This 
should be recorded as a separate event for each recurrence. 
Secondary Adverse Events 
 
In general, events occurring secondary to other events (e.g., cascade events or clinical sequelae) should be 
considered a single event identified by the primary cause. However, a secondary event should be listed as an 
independent event if it meets one of the following criteria: 
• 
severe  
• 
serious  
• 
separated in time from the primary event 
 
If it is not clear as to whether events are dependent, then record as separate adverse events. 
Abnormal Laboratory Values/Clinical Assessments 
 
It is the responsibility of the investigator, or designee, to review and document all laboratory findings and 
clinical assessments, which may include vital signs, physical exams and ECGs. Medical and scientific 
judgment should be exercised in deciding whether a laboratory abnormality or clinical finding should be 
classified as an adverse event. In general, an abnormal laboratory test result or clinical finding should be 
considered as an adverse event if it meets at least one of the following criteria: 
• 
Is associated with clinical symptoms 
• 
Results in a change in study treatment (e.g., treatment modification, interruption or discontinuation) 
• 
Requires a medical intervention or change in concomitant therapy  
• 
Clinically significant in the investigator’s judgment  

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
25 
 
 
Note that if a clinically significant laboratory abnormality or clinical finding is a sign of a disease or syndrome 
(e.g. elevated ALT) then this should be recorded as a single event identified by the diagnosis (hepatic failure).  
 
If a clinically significant laboratory abnormality is not a sign/symptom of another primary event, the abnormality 
itself should be recorded as an adverse event. The event should be described using a specific clinical term 
(“hyperkalemia”), if possible, or as test result above or below the normal range (e.g., "elevated Vitamin D," as 
opposed to "abnormal Vitamin D"). 
Death 
 
Death should be considered an outcome of an adverse event and not an independent adverse event. The 
event or condition that caused the death should be recorded as the adverse event with the outcome of death. If 
the cause of death is unknown and cannot be ascertained at the time of reporting, then the event should be 
reported as an “unexplained death”. If the cause of death later becomes available (e.g., after autopsy), 
“unexplained death” should be updated by the established cause of death.  
Preexisting Medical Conditions 
 
A preexisting medical condition is one that is present during the pre-study screening assessments. These 
conditions should be noted on the Medical History form. Preexisting medical conditions are not considered 
adverse events unless any of the following characteristics worsen following initiation of any study-related 
procedure: 
• 
frequency 
• 
severity 
• 
character  
If any of the above conditions apply, then this should be recorded as an adverse event. Remember to 
convey that this is a change in a preexisting condition when describing the event (e.g., “increased 
frequency of kidney stones”). 
Adverse Device Effect (ADE) 
 
An adverse device effect (ADE) is any untoward and unintended response to a medical device. This definition 
includes: 
• 
- any event resulting from insufficiencies or inadequacies in the instructions for use   or the deployment 
of the device, 
• 
- any event that is a result of a user error 
Serious Adverse Device Effect (SADE) 
 
A serious adverse device effect (SADE) is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event or that might have led to any of these consequences if 
suitable action had not been taken or intervention had not been made or if circumstances had been less 
opportune. 
Unanticipated Adverse Device Effect (UADE) 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
26 
 
Unanticipated adverse device effect (UADE) is any serious adverse event on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
Serious Adverse Event  
 
A serious adverse event or experience (SAE) is any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
• 
Fatal; 
• 
Life-threatening (places the subject at immediate risk of death from the event as it occurred); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization;* 
• 
Results in congenital anomaly/birth defect; 
• 
Results in a persistent or significant disability/incapacity; 
• 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition.  For reporting purposes, also consider the 
occurrences of pregnancy as an event which must be reported as an important medical event. 
*Hospitalization or prolonged hospitalization should be documented and reported as a serious adverse 
event, except if the hospitalization meets at least one of the following criteria: 
 
• 
The hospitalization is less than 24 hours without an admission 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for anticipated or protocol specified procedures 
such as administration of chemotherapy, central line insertion, metastasis interventional therapy, 
resection of primary tumor, or elective surgery) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria are met: 
 
The hospitalization was planned prior to the study or was scheduled during the study 
when elective surgery became necessary because of the expected normal 
progression of the disease.  
 
The patient has not suffered an adverse event. 
 
If the hospitalization meets any of these criteria, then it is not considered a serious adverse event. 
9.2. Attribution Assessment 
 
The Principal Investigator, or designee, will evaluate all AEs and assess their toxicity and attribution, if any, to 
study drug.  The following criteria will define the attribution: 
Definite:  The AE is clearly in relation to the investigational intervention. 
Probable: The AE is likely related to the investigational intervention. 
Possible: The AE may be related to the investigational intervention. 
Unlikely: The AE is doubtfully related to the investigational intervention. 
Unrelated: The AE is NOT related to the investigational intervention. 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
27 
 
9.3. IRB Reporting Requirements 
 
Serious and unexpected adverse events must be submitted to the site Institutional Review Board according to 
the participating site institutional policies. 
 
For the University of Virginia clinical site, the Principal Investigator (PI) or designee is responsible for reporting 
AEs and unanticipated problems to the UVA HSR-IRB according to the following guidelines.   
 
Table 1. IRB Reporting Requirements 
Type of Event 
To whom will it be 
reported: 
Time Frame for 
Reporting 
How reported? 
Any internal event resulting in 
death that is deemed 
DEFINITELY related to (caused 
by) study participation 
An internal event is one that 
occurs in a subject enrolled in a 
UVa protocol 
IRB-HSR 
Within 24 hours 
IRB Online and phone call 
 
www.irb.virginia.edu/ 
 
Internal, Serious, Unexpected 
adverse event  
 
See Oncore reporting 
requirement (sponsor's protocol 
section 10.5).  
 
IRB-HSR 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the event. 
 
Timeline includes 
submission of signed 
hardcopy of AE form. 
IRB Online 
 
www.irb.virginia.edu/ 
 
Unanticipated Problems that are 
not adverse events or protocol 
violations  
This would include a Data 
Breach.   
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the event.  
Unanticipated Problem report form.  
 
http://www.virginia.edu/vprgs/irb/HSR
_docs/Forms/Reporting_Requiremen
ts-Unanticipated_Problems.doc ) 
 
  
Protocol Violations 
 (The IRB-HSR only requires that
MAJOR violation be reported, 
unless otherwise required by you
sponsor, if applicable.) 
 
Or  
 
Enrollment Exceptions 
IRB-HSR 
 
 
Within 7 calendar days 
from the time the study 
team received 
knowledge of the event.  
 
Protocol Violation and Enrollment 
Exception Reporting Form 
 
 
http://www.virginia.edu/vprgs/irb/hsr_
forms.html 
 
Go to 3rd bullet from the bottom.  
Data Breach  
The UVa Corporate 
Compliance and 
Privacy Office, a 
 
 
ITC:  if breach 
involves  electronic 
data-  
 
 
UVa Police if 
breach includes 
such things as 
stolen computers.  
As soon as possible and 
no later than 24 hours 
from the time the 
incident is identified. 
 
As soon as possible and 
no later than 24 hours 
from the time the 
incident is identified. 
IMMEDIATELY.  
 
 
UVa Corporate Compliance and 
Privacy Office- Phone 924-9741 
 
 
 
ITC:  Information Security Incident 
Reporting procedure,  
http://www.itc.virginia.edu/security/re
porting.html 
 
Phone- (434) 924-7166 
 
 
9.4. Additional Reporting Requirements 
 
9.4.1. 
Reporting to the FDA 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
28 
 
The Sponsor for the study (the UVA PI or designee) is responsible for providing safety updates to the FDA per 
the following guidelines.  The reporting times refer to the time the study team received knowledge of the AE. 
Table 2. FDA Reporting Requirements 
Type of Event 
To whom 
will it be 
reported: 
Time Frame for 
Reporting 
How reported? 
Life-threatening and/or fatal unexpected 
events related or  
possibly related to the use of the 
investigational agent. 
FDA 
Within 7 calendar days of 
the study team learning of 
the event 
Form FDA 3500A (MedWatch) or 
narrative 
Serious, unexpected and related or possib
related adverse events 
FDA 
Within 15 calendar days 
after 
the 
study 
team 
receives knowledge of 
the event 
Form FDA 3500A (MedWatch) or 
narrative 
All adverse events 
FDA 
Annually 
IND annual report 
 
 
9.4.2. 
Data Safety Monitoring Plan 
 
The Principal Investigator will provide continuous monitoring of subject safety in this trial. 
9.5. Expected adverse events 
 
All events that are commonly seen in this patient population or in patients who have DBS may be reported as 
expected.  The patient will undergo two procedures during the course of this study that differ from the standard 
clinical practice of MRI-guided placement of DBS electrodes under general anesthesia. They are a lumbar 
puncture and an intracerebral infusion of autologous CSF.  Adverse events described here and in the informed 
consent may also be considered expected. 
 
 
Lumbar puncture 
 
Obtaining a lumbar puncture leads to the risk of complications of the lumber puncture which include bleeding, 
infection, nerve root damage, CSF leak, bowel or bladder incontinence, weakness, sensory loss, need for 
operation to repair CSF leak or evacuate hematoma.  Lumbar punctures are a standard procedure used for 
many indications; the risk of a complication is minimal.  Discomfort from the procedure should be minimal as 
the procedure is being performed while the patient is under general anesthesia.  Patients with known spinal 
pathology will be excluded to minimize the risk of complications associated with the lumbar puncture.  In the 
event that CSF cannot be obtained or the fluid obtained is excessively bloody, then the infusion procedure will 
be aborted and the DBS electrodes will be placed using standard techniques.  Patients will be fully informed of 
the risks of lumbar punctures during the consenting process.   
 
Intracerebral infusion 
 
The primary risk of the intracerebral infusion is that the infusion of autologous CSF will lead to neuronal 
damage. This risk is assessed to be minimal based on our preclinical animal studies demonstrating no acute 
and chronic histologic effects as a result of the infusion of CSF in swine. Our results are similar to other results 
in a rat model where albumin was infused and no damage was noted.3 In order to mitigate the risk for toxicity, 
we plan to limit the infusion to a maximum volume of 500 microliters of autologous CSF.  However, if 
unforeseen neuronal damage were to occur, there could be damage to the target structures and the 
surrounding structures leading to loss of sensation, worsening of movement disorders, and weakness. Patients 
will be fully informed of the risks of the CSF infusion during the consenting process.       

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
29 
 
 
Catheter insertion 
 
The insertion of the infusion catheter into the brain could also lead to brain injury from intracerebral bleeding or 
stroke. This risk should not be increased beyond that for routine DBS surgery as the microcatheter will be 
inserted through a guide cannula that is already positioned for the DBS electrode. Typically, the risk of a 
hemorrhagic complication from stereotactic insertion of an electrode is ~1%.5  Potentially, fewer DBS electrode 
passes will be required with the improved imaging leading to an overall reduced risk than traditional, awake 
DBS surgery where multiple microelectrodes are inserted to map the target nucleus. 
 
10. STUDY MANAGEMENT 
 
10.1. 
Institutional Review Board (IRB) Approval and Consent 
 
It is expected that the IRB will have the proper representation and function in accordance with federally 
mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to all ICH E6 principles and Good Clinical Practice (GCP), to 
ethical principles that have their origin in the Declaration of Helsinki. 
 
Before recruitment and enrollment onto this study, the subject will be given a full explanation of the 
study and will be given the opportunity to review the consent form. Each consent form must include all the 
relevant elements currently required by the FDA Regulations and local or state regulations. Once this essential 
information has been provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to participate in the study by 
signing an IRB-approved consent form. 
 
Prior to a subject’s participation in the trial, the written informed consent form should be signed and 
personally dated by the subject and by the person who conducted the informed consent discussion. 
10.2. 
Adherence to the Protocol 
 
Except for an emergency situation in which proper care for the protection, safety, and well-being of the study 
subject requires alternative treatment, the study shall be conducted exactly as described in the approved 
protocol.   
10.3. 
Emergency Modifications 
 
Investigators may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) 
to trial subjects without prior IRB-HSR approval/favorable opinion.   
 
For any such emergency modification implemented, a UVA IRB modification form must be completed 
by study Personnel within five (5) business days of making the change.   
 
10.4. 
Other Protocol Deviations/Violations 
 
Protocol Deviations: A protocol deviation is any unplanned variance from an IRB approved protocol that:  
 
• 
Is generally noted or recognized after it occurs 
• 
Has no substantive effect on the risks to research participants 
• 
Has no substantive effect on the scientific integrity of the research plan or the value of the data 
collected  
• 
Did not result from willful or knowing misconduct on the part of the investigator(s).  

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
30 
 
Study personnel will record the deviation, and report to any sponsor or data and safety monitoring committee 
in accordance with their policies.  Deviations should be summarized and reported to the IRB at the time of 
continuing review. 
Protocol Violations: An unplanned protocol variance is considered a violation if the variance: 
 
• 
Has harmed or increased the risk of harm to one or more research participants. 
• 
Has damaged the scientific integrity of the data collected for the study. 
• 
Results from willful or knowing misconduct on the part of the investigator(s). 
• 
Demonstrates serious or continuing noncompliance with federal regulations, State laws, or 
University policies. 
Violations should be reported by study personnel to the IRB within one (1) week of the investigator becoming 
aware of the event.  
10.5. 
Record Retention 
 
Study documentation includes all Case Report Forms, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB correspondence and approval, signed subject consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all reports and 
records necessary for the evaluation and reconstruction of the clinical research study. 
 
Government agency regulations and directives require that all study documentation pertaining to the 
conduct of a clinical trial must be retained by the study investigator.  In the case of a study with a drug seeking 
regulatory approval and marketing, these documents shall be retained for at least two years after the last 
approval of marketing application in an International Conference on Harmonization (ICH) region.  In all other 
cases, study documents should be kept on file until six years after the completion and final study report of this 
investigational study. 
 
10.6. 
Obligations of Investigators 
 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in accordance with Title 
21 of the Code of Federal Regulations, all applicable local regulatory laws and regulations and/or the 
Declaration of Helsinki.  The Principal Investigator is responsible for personally overseeing the treatment of all 
study subjects.  The Principal Investigator must assure that all study site personnel, including sub-investigators 
and other study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and guidelines 
regarding clinical trials both during and after study completion. It is the responsibility of the Principal 
Investigator to ensure that all study site personnel are aware that the study protocol and all data generated is 
confidential and should not be disclosed to third parties (with the exception of local and national regulatory 
bodies which require access for oversight purposes).  
 
The Principal Investigator will be responsible for assuring that all the required data will be collected 
and entered onto the Case Report Forms. Periodically, monitoring visits will be conducted and the Principal 
Investigator will provide access to his/her original records to permit verification of proper entry of data. At the 
completion of the study, all case report forms will be reviewed by the Principal Investigator and will require 
his/her final signature to verify the accuracy of the data. 
 
 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
31 
 
11. REFERENCES 
 
 
1. 
Black PM, Moriarty T, Alexander E, 3rd, Stieg P, Woodard EJ, Gleason PL, et al: Development and 
implementation of intraoperative magnetic resonance imaging and its neurosurgical applications. 
Neurosurgery 41:831-842; discussion 842-835, 1997 
2. 
Burchiel KJ, McCartney S, Lee A, Raslan AM: Accuracy of deep brain stimulation electrode 
placement using intraoperative computed tomography without microelectrode recording. J 
Neurosurg 119:301-306, 2013 
3. 
Ding D, Kanaly CW, Cummings TJ, Herndon JE, 2nd, Raghavan R, Sampson JH: Long-term safety 
of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321. 
Neurol Res 32:810-815, 2010 
4. 
Elias WJ, Fu KM, Frysinger RC: Cortical and subcortical brain shift during stereotactic procedures. J 
Neurosurg 107:983-988, 2007 
5. 
Elias WJ, Sansur CA, Frysinger RC: Sulcal and ventricular trajectories in stereotactic surgery. J 
Neurosurg 110:201-207, 2009 
6. 
Felix B, Leger ME, Albe-Fessard D, Marcilloux JC, Rampin O, Laplace JP: Stereotaxic atlas of the 
pig brain. Brain Res Bull 49:1-137, 1999 
7. 
Hall WA, Martin AJ, Liu H, Nussbaum ES, Maxwell RE, Truwit CL: Brain biopsy using high-field 
strength interventional magnetic resonance imaging. Neurosurgery 44:807-813; discussion 813-
804, 1999 
8. 
Ivan ME, Yarlagadda J, Saxena AP, Martin AJ, Starr PA, Sootsman WK, et al: Brain shift during bur 
hole-based procedures using interventional MRI. J Neurosurg 121:149-160, 2014 
9. 
Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, et al: Subthalamic nucleus 
deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord 21 Suppl 14:S290-
304, 2006 
10. 
McClelland S, 3rd, Ford B, Senatus PB, Winfield LM, Du YE, Pullman SL, et al: Subthalamic 
stimulation for Parkinson disease: determination of electrode location necessary for clinical efficacy. 
Neurosurg Focus 19:E12, 2005 
11. 
Mirzadeh Z, Chapple K, Lambert M, Evidente VG, Mahant P, Ospina MC, et al: Parkinson's disease 
outcomes after intraoperative CT-guided "asleep" deep brain stimulation in the globus pallidus 
internus. J Neurosurg 124:902-907, 2016 
12. 
Ostrem JL, Galifianakis NB, Markun LC, Grace JK, Martin AJ, Starr PA, et al: Clinical outcomes of 
PD patients having bilateral STN DBS using high-field interventional MR-imaging for lead placement. 
Clin Neurol Neurosurg 115:708-712, 2013 
13. 
Patel NK, Plaha P, Gill SS: Magnetic resonance imaging-directed method for functional 
neurosurgery using implantable guide tubes. Neurosurgery 61:358-365; discussion 365-356, 2007 
14. 
Sillay KA, Rusy D, Buyan-Dent L, Ninman NL, Vigen KK: Wide-bore 1.5 T MRI-guided deep brain 
stimulation surgery: initial experience and technique comparison. Clin Neurol Neurosurg 127:79-
85, 2014 
15. 
Starr PA, Markun LC, Larson PS, Volz MM, Martin AJ, Ostrem JL: Interventional MRI-guided deep 
brain stimulation in pediatric dystonia: first experience with the ClearPoint system. J Neurosurg 
Pediatr 14:400-408, 2014 
16. 
Starr PA, Martin AJ, Ostrem JL, Talke P, Levesque N, Larson PS: Subthalamic nucleus deep brain 
stimulator placement using high-field interventional magnetic resonance imaging and a skull-
mounted aiming device: technique and application accuracy. J Neurosurg 112:479-490, 2010 
17. 
Sudhyadhom A, Okun MS, Foote KD, Rahman M, Bova FJ: A Three-dimensional Deformable Brain 
Atlas for DBS Targeting. I. Methodology for Atlas Creation and Artifact Reduction. Open Neuroimag 
J 6:92-98, 2012 

CED of CSF in DBS for Parkinson’s 
PI: W. Jeffrey Elias MD 
Version/Date: Version 5.0, 10/08/2018 
32 
 
18. 
Vega RA, Holloway KL, Larson PS: Image-guided deep brain stimulation. Neurosurg Clin N Am 
25:159-172, 2014