High-accuracy Augmented Reality Guidance for Intracranial Drain Placement Using a Standalone Head-worn Navigation System
Phase: NA
Conditions: Intracranial Hypertension
Sponsor: Universitair Ziekenhuis Brussel

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Protocol title: Augmented Reality-Assisted 
Neurosurgical Drain placement (ARANED)  
 
Protocol identification number: 2018 - 447 
 
Principal investigator and study coordinator: 
 
Johnny Duerinck 
 
Neurosurgery Department  
 
UZ Brussel 
 
Laarbeeklaan 101  
 
1090 Brussels, Belgium 
 
Academic Study Sponsor  
 
UZ Brussel  
 
Laarbeeklaan 101  
 
1090 Brussels, Belgium 
 
 
 
 
 
 
 
 
 
 
9/01/2019 
Protocol approval 
21/06/2019 
Amendment 1 
 
 
Protocol version number: 2 / 26 December, 2018 
Amendment 1 version number: 1 / 21 June, 2019 
 
 
 

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Contact information 
Prof. Dr. Johnny Duerinck 
Neurosurgery Department  
UZ Brussel 
Laarbeeklaan 101  
1090 Brussels, Belgium 
Tel.: +32 (0)2 477 5514 
Fax: +32 (0)2 477 5570 
E-mail: johnny.duerinck@uzbrussel.be 
 
Dr. Frederick Van Gestel 
Neurosurgery Department  
UZ Brussel 
Laarbeeklaan 101  
1090 Brussels, Belgium 
Tel.: +32 (0)2 474 9705 
Fax: +32 (0)2 477 5570 
E-mail: frederick.vangestel@uzbrussel.be
 
 
Medical investigators  
 
 
Study Coordinator: Prof. Dr. Johnny Duerinck 
Tel.: +32 (0)2 477 5514 
Fax:  +32 (0)2 477 5570 
E-mail: johnny.duerinck@uzbrussel.be 
 
Co-investigator 1: Dr. Frederick Van Gestel 
Tel.: +32 (0)2 474 9705 
Fax: +32 (0)2 477 5570 
E-mail: frederick.vangestel@uzbrussel.be 
 
Co-investigator 2: Prof. Dr. Thierry Scheerlinck 
Tel.: +32 (0)2 477 3448 
Fax: +32 (0)2 477 6505 
E-mail: thierry.scheerlinck@uzbrussel.be 
 
 
Statistician 
 
Prof. Ronald Buyl 
Tel.: +32 (0)2 477 4438 
E-mail: ronald.buyl@vub.be 
 
 
Co-investigators that will not deal with medical data 
 
Co-investigator 3: Shirley Elprama 
Tel.: +32 (0)483 45 02 68 
E-mail: shirley.elprama@vub.be 
 
Co-investigator 4: Anouk Verhellen 
Tel.: / 
E-mail: / 
 
Co-investigator 5: Prof. Dr. An Jacobs 
Tel.: +32 (0)486 45 19 54 
E-mail: an.jacobs@vub.be 
 
 

 
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Study synopsis 
Protocol - full title 
Augmented Reality-Assisted Neurosurgical Drain placement 
Protocol 
acronym 
- 
short title 
 ARANED 
Version and date of 
final protocol 
Date: 26/12/2018 
Version:  2 
Version and date of 
protocol amendments 
Date: 21/06/2019 
Version: 1 
Study sponsor 
Name: UZ Brussel  
Address: Laarbeeklaan 101, B-1090 Brussels, Belgium 
Sites 
and 
research 
groups participating in 
the study 
Site: UZ Brussel  
Research groups: (Vrije Universiteit Brussel) 
• 
C4N-NEUR 
• 
BEFY-ORTHO 
• 
ETRO 
Principal investigator – 
promoter 
 
Name: Prof. Dr. Johnny Duerinck 
Telephone: +32 (0)2 477 5514 
Email: johnny.duerinck@uzbrussel.be 
Co-investigators 
Name: Dr. Frederick Van Gestel 
Telephone: +32 (0)2 474 9705 
Email: frederick.vangestel@uzbrussel.be 
 
Name: Prof. Dr. Thierry Scheerlinck 
  
Telephone: +32 (0)2 477 3448 
Email: thierry.scheerlinck@uzbrussel.be  
 
 

 
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Background 
The Augmented Reality-Assisted Neurosurgical Drain placement (ARANED) 
study is part of a larger project called Surgical Augmented Reality Assistance 
(SARA). The goal of the SARA project is to assess the added value of augmented 
reality (AR) during surgery in terms of usability, relevance and (surrogate) 
outcomes (measuring for accuracy, usefulness, gain in time, patient safety and 
physician comfort). To this end, a series of experiments is defined, 
complementary to each other, and involving a variety of medical specialties, 
focusing on cranial and spinal neurosurgery and orthopedic surgery. The use of 
the AR device with associated software will first be assessed with several 
preclinical experiments based on geometric models, anthropomorphic models 
and cadavers.  
Clinical testing within the scope of the SARA project will be limited to class II pilot 
studies, and all procedures will take place in specific settings where the safety of 
the human subjects cannot be compromised. Completion of larger-scale clinical 
randomized trials are beyond the scope of this project. 
 
ARANED focuses on neurosurgical drain placement. Drain placement is an often-
used procedure for patients with increased intracranial pressure (intracranial 
hypertension; ICH) or with intracranial hemorrhage (intraparenchymal 
hemorrhage (IPH) or chronic subdural hematoma (CSDH)), with the goal to 
drain cerebrospinal fluid (CSF) or blood, respectively, as well as to measure 
pressure in the specific compartment the drain is positioned in.  To drain CSF, a 
so-called external ventricular drain (EVD) is placed. The placement of any 
intracranial drain is almost always performed freehand, following inspection and 
planning on CT images of the patient. For EVD placement additional, literature-
defined landmarks are employed, however, these are not patient-specific. As 
detailed below, these procedures and their accuracy have been studied 
extensively in literature, making them a suitable subject for clinical testing.  
 
AR-assisted placement of EVD and intra-hematoma drains (using a head-
mounted display (HMD) – the Microsoft HoloLens - with proprietary software) 
will be performed in the context of the ARANED trial. Beside geometric and 
clinically relevant (e.g. clinically used accuracy scale) outcome variables, 
surgeon experience (intuitiveness, ergonomics, quickness) will be evaluated, 
and used as a feedback to the technical developments behind the study. User 
experience can be influenced by several factors, such as the efficiency of the 
workflow, ergonomics (regarding both the head-mounted display (HMD) 
itself as well as the use of the device and the software), the ease of data flow, 
etc. Wherever possible, feedback from the clinical experiences will be used to 
support further technical developments. This way, exploration of advanced 
topics beyond pure accuracy measures becomes possible, including but not 
limited to: 
• 
Inattentional blindness (confusion between real and virtual world),  
• 
The use of historical images (i.e. updating preoperative images to 
better reflect the current situation)  
• 
Marker-free navigational tracking 
• 
Different points-of-view for multiple surgeons 
• 
Telepresence 
• 
… 

 
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Participants to include 
Adult patients requiring external ventricular drain (EVD) placement. The 
current clinical status does not prevent the patient from undergoing the 
standard treatment for the abovementioned condition(s). The patient or his 
legal representative received a detailed verbal explanation of the study 
treatment, after which they had the chance to ask any questions. The patient 
or his legal representative read the informed consent (IC) document after 
which it was signed in duplicate. 
Study design 
In order to assess the accuracy of AR in drain placement surgery with the clinical 
feasibility in mind, we will sequentially recruit 10-15 patients. Prior to enrollment 
of these patients, the surgeons will have a brief adjustment period in which the 
holographic information will not be displayed on the patient but elsewhere in the 
field of view of the surgeon (unregistered), to adjust to the HoloLens and the use 
of the AR navigation interface while still adhering to the conventional drain 
placement methods. For the following 10-15 patients the AR overlay will be 
registered to and displayed on top of the patient, showing the relevant anatomy 
in its supposed actual location (giving the impression of “see-through vision”). This 
conversion not only assures optimal patient safety, but also allows us to 
investigate and improve upon the concurrently developed AR user-interface. 
 
Thus, a clinical experiment will be set up where current practice is compared to 
AR guidance. Minimal invasive drain placement in the CSF-space (ventricle) will 
be performed in standard fashion, but with the aid of a 3D model of the patient 
and the specific compartment to be targeted displayed in the field of view of the 
surgeon, either without registration to the patient (i.e. next to the patient serving 
as an in-room 3D visualization), or with registration to the patient (i.e. on top of 
the patient providing the surgeon with the impression of “see-through vision”). 
Results from these drain placements (accuracy being measured using clinical 
scales) will be compared to historical controls from literature and from our center. 
Primary 
objective/endpoint 
To demonstrate the feasibility and added value of an AR based (neuro)navigation 
system implemented on the HoloLens aimed towards external ventricular drain 
(EVD) placement in critical care settings. EVD placement accuracy will be 
assessed using the Kakarla scale, ranging from good (grade I) to poor (grade III) 
placement. We will implement a comparative analysis of the clinical outcome data 
to normal ranges based on historical values obtained from literature and from our 
center. 
Secondary 
objectives/endpoints 
• 
Improvement 
of 
user 
experience 
(intuitiveness, 
ergonomics, 
quickness; using the questionnaires in Appendix B) 
• 
Decrease of duration of procedure compared to same procedure 
performed without AR (based on historical values of procedure time, 
recorded at our institution) 
• 
Decrease of difference in outcome (accuracy scale) and of difference 
in duration of procedure between surgeons of different expertise 
levels compared to same intervention without AR (flattening of the 
learning curve) 
• 
Improvement of clinical outcome measures with AR-assisted surgery 
compared to standard practice (using the scales in Appendix C) 
• 
Improvement of pathology-specific clinical outcome measures: 
 
o 
Revision rate 
o 
Complication rate 
o 
Velocity of the decrease in ICP 
o 
Evolution of midline shift 

 
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Exploratory 
objectives/endpoints 
• 
Explore development and optimization of an efficient and ergonomic 
workflow in a well-structured pipeline (pipeline from imaging to display 
of holograms) 
• 
Explore and describe necessity for continuous implementation of 
technical advances improving the AR experience, such as: 
o 
Correcting for inattentional blindness (confusion between real 
and virtual world), 
o 
Correcting for the use of historical images (i.e. updating 
preoperative images to better reflect the current situation), 
o 
Implementing marker-free navigational tracking, 
o 
Exploring cooperation by offering different points-of-view for 
multiple surgeons, 
o 
Explore assistance of these interventions by using 
telepresence, 
• 
… 
Safety monitoring 
All data from every single patient will be collected in a unique electronic Case 
Report Form (eCRF) which perfectly matches the source documents (e.g. 
study charts at the hospital). It is the investigator's responsibility to ensure 
completion and to review and approve all eCRF data. Thus, accuracy and 
authenticity of all data entered on the eCRFs is guaranteed by the investigator. 
Adverse events, both related and unrelated to study treatment, will be 
monitored on an ongoing basis and their frequencies reported semi-annually. 
Clinical outcome data will be tabulated and compared to historical values from 
literature as well as normal ranges for the institution, based on retrospective 
review of historical clinical data from the institution. 
Statistical 
design 
& 
sample size 
This is a class II, single-arm, clinical pilot study investigating feasibility, safety 
and efficacy of a proprietary software solution for augmented reality-display, 
and registration and tracking of patient-specific anatomic models on the 
Microsoft HoloLens, with the aim to provide guidance during external 
ventricular drain placement. The protocol will enroll 10-15 patients over the 
course of one year.    
Investigational product 
SARA consortium-developed proprietary software solution for Microsoft 
HoloLens 
Study period 
• 
Recruitment Start Date (FPI): 01/01/2019 
• 
Estimated recruitment End Date (LPI): 30/06/2020 
• 
End of study: the first follow-up appointment of the last patient to 
receive study treatment, or death of the last patient in this trial 
(whichever comes first). 
 

 
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Table of contents 
1 
Introduction and background 
9 
1.1 
Context of the project 
9 
1.2 
State of the art: navigation in surgery 
9 
1.2.1 Neuronavigation 
9 
1.2.2 AR navigation 
10 
1.2.3 HoloLens in surgery 
11 
1.3 
State of the art: drain placement 
13 
2 
Study Design 
15 
3 
Patient selection criteria 
16 
4 
Treatment plan 
17 
4.1 
HoloLens application 
17 
4.1.1 Pre-operative phase 
17 
4.1.2 Operative phase 
17 
4.1.3 Post-operative phase & follow-up 
18 
4.2 
Clinical evaluation, imaging & follow-up 
18 
4.3 
Concomitant therapy 
19 
4.4 
Life Style Guidelines 
19 
5 
Statistical design 
20 
5.1 
Objective & endpoints 
20 
5.2 
Sample size calculation 
20 
5.3 
Accrual 
21 
5.4 
Statistical analysis 
21 
6 
Patient registration procedure 
22 
7 
Forms and procedures for collecting data 
23 
7.1 
Case Report Forms / Electronic Data Record 
23 
7.2 
Record Retention 
23 
7.3 
Study Monitoring 
23 
7.4 
GDPR-compliancy 
23 
8 
Reporting adverse events 
24 
8.1 
Safety Monitoring 
24 
8.1.1 Adverse events 
24 
8.1.1.1 
Definition of an adverse event 
24 
8.1.1.2 
Hospitalization 
25 
8.1.2 Severity Assessment 
26 
8.1.3 Causality Assessment 
27 
8.1.4 Withdrawal due to adverse events 
27 
8.2 
Reporting period 
27 

 
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8.2.1 Reporting Requirements 
27 
9 
Quality assurance 
28 
9.1 
Intellectual quality assurance 
28 
9.2 
Technical quality assurance 
28 
10 Ethical considerations 
28 
10.1 
Patient protection 
28 
10.2 
Subject identification & anonymization 
28 
10.3 
Informed consent 
29 
11 Trial sponsorship and financing 
30 
12 Trial insurance 
30 
13 Intellectual property and publication policy 
30 
  
 
Table of appendices 
Appendix A: List of abbreviations 
31 
Appendix B: User experience questionnaires 
32 
Appendix C: Clinical follow-up scales 
37 
Appendix D: Declaration of Helsinki 
40 
Appendix E: References 
41 
 
 

 
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1 Introduction and background 
1.1 
Context of the project 
Extensive knowledge of surgical anatomy has always been the cornerstone of successful surgical 
or non-surgical invasive procedures. Due to limited imaging possibilities in the early days of surgery, 
large incisions were often made in order to expose as much normal anatomy as possible for 
orientation purposes. This most often led to longer and more extensive interventions that were 
difficult to perform for the surgeon, had steeper learning curves, but also led to more patient 
discomfort and higher likelihood of complications. Limited-access procedures where no relevant 
anatomy is exposed for orientation, such as cranial drain placement, relied on (and currently still do) 
predefined external anatomical landmarks, most often without adaptation to the patient’s specific 
situation.  
The advent of 3D imaging modalities has vastly improved pre-operative planning. Surgeons have 
become very adept at interpreting these slice-based imaging modalities, which are typically 
presented in an axial, coronal and sagittal fashion. Based on these, the physician produces a mental 
image of the 3D anatomy. Alternatively, a 3D reconstruction is displayed on a screen during the 
intervention. For orientation, the surgeon uses his knowledge of anatomy but also occasionally 
glances at the screen. The problem is that the images are uncorrelated to the actual patient and that 
the surgeon continually has to mentally align the anatomy from the imaging modalities with the 
patient before him.  This puts an unnecessary cognitive load on the surgeon, for one, and secondly, 
often extensive surgical exploration looking for anatomical landmarks still has to be performed for 
orientation during the surgical intervention. 
Augmented reality (AR) may increase the accuracy [1] and safety [2] of the surgery, allow for more 
minimally invasive surgical approaches and reduce the duration and cost of interventions. AR may 
also prove beneficial for surgeons in training [3], as it provides realistic 3D visualizations of normal 
and pathological anatomy which can be manipulated and inspected from all angles. 
The Augmented Reality-Assisted Neurosurgical Drain placement (ARANED) study is part of a 
larger project called Surgical Augmented Reality Assistance (SARA). SARA took shape as a 
project by the interaction between a group of people with relevant expertise and interested in the 
potential of this novel technology, as well as clinicians (the end-users) expressing a clear clinical 
need. The project aims to investigate the feasibility of using AR for pre-operative planning, per-
operative visualization and navigational support, and assess its impact on surgical training. Clinical 
validation of the technical solutions is a crucial step in assessing the real-world accuracy and 
usefulness of the augmented reality holographic information provided to the surgeons. 
 
1.2 
State of the art: navigation in surgery 
1.2.1 
Neuronavigation  
Current neuronavigation uses optical or electromagnetic tracking technology to establish and 
maintain correspondence between preoperative imaging and the patient with high accuracy [4–6]. A 
tracked reference frame is fixed to the patient’s anatomy, and registered to the preoperative imaging. 
From then on, imaging can be easily viewed in the corresponding plane by placing a tracked pointer 
on the patient anatomy. The advent of neuronavigation has facilitated minimally invasive surgery, 
relying on imaging instead of direct sight. Various "(neuro)navigation systems" have been 
commercialized [7]. They are not often used for routine interventions due to a number of inherent 
limitations: 
• 
Bulkiness of devices – An additional computer system, external tracking camera and multiple 
screens are needed, taking up space in the operating theatre 
• 
Setting up the system and patient registration are time-consuming and error-prone 

 
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• 
The need to mentally transpose the 2D or 3D images on an external screen to the actual 
patient puts a significant cognitive load on the surgeon (Figure 1). Moreover, a pointer device 
is held inside the patient’s anatomy (for example against the brain tissue) while the surgeon 
looks elsewhere (at the screen). This interrupts workflow, but can also be dangerous. 
• 
The control over what imaging data is displayed on the screen is too limited for the surgeon, 
who cannot touch the screen directly due to sterility constraints. 
• 
The outside-in tracking by an external tracking device (infrared (IR) camera) often creates a 
‘line of sight’ problem. When the line of sight is blocked, the workflow breaks. 
• 
Navigation mostly makes use of ‘historical images’: the imaging information is not updated 
as surgery progresses, even though anatomy alters during surgery. 
 
Although it is possible to present the anatomical images in a virtual world, it is still constrained by a 
screen (Figure 1), only linking the virtual world and the patient by means of a tracked pointer. AR 
aims at blending this virtual world with the actual world in a more ergonomic way, addressing many 
of the limitations of current neuronavigation. AR using a head-mounted display (HMD) is not yet 
applied in (neuro)surgical practice but is receiving increased attention lately. 
 
 
Figure 1. Current situation: the surgeon looks at an external display (left). With AR, the image could be 
projected directly on a relevant surface (right) (adapted from [8]) 
1.2.2 
AR navigation 
Neurosurgery was one of the first and is currently the most popular surgical specialty where AR is 
used [9].  In most cases presented in literature until now, the augmented data is presented into the 
surgical microscope, as an overlay on top of the magnified view of the surgical site [10–15]. AR 
microscopic surgery is until now the only AR application in surgery which has been 
commercialized.  Such AR systems don’t require a pointer device, as it is the focal point of the 
microscope that is navigated. As the operating microscope is used for many neurosurgical 
interventions, the surgeon is also very familiar with its use which adds to ergonomics. However, AR 
microscopic surgery suffers from many similar issues as neuronavigation as described earlier and 
the microscope itself is not practical for all phases of surgery or for procedures that would otherwise 
not require a surgical microscope. 
Besides AR on the surgical microscope, hand-held cameras have also been used. In this case, the 
captured images together with the AR overlays are displayed on a screen in the OR [16–19]. Such 
systems can be more conveniently used in all steps of the surgery, from skin incision to tumor 
resection. However, the positioning of these cameras is not straightforward, and they still require the 
surgeon to look away from the surgical field to a screen.  

 
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To overcome this problem, several research groups explored the use of mobile devices such as 
smartphones and tablets, that immediately display the AR overlays while looking at the patient [20–
24]. This, however, forces the surgeon to put down his/her instruments in order to pick up the device. 
Secondly, even though in a more practical fashion, the information is still observed on a screen.  
Others have proposed AR systems where a projector is used to display the virtual elements on top 
of the real world [1]. Whereas such systems allow to maintain direct vision of the patient and 
operating field, allow for intuitive visualization and potentially resolve the eye-hand coordination 
problem, they suffer from a major parallax error which increases with the depth of the anatomical 
structures. 
The only approach that does not suffer from any of these limitations, is the use of smartglasses and 
other HMDs which either project an AR enhanced camera view [25] on the glasses (potentially with 
unacceptable lag for use during surgery) or come with transparent “see-through” glasses. The great 
advantage of using such HMDs, next to ergonomics, is that the surgeon’s head can be tracked to 
adapt the point of view. This still requires an external tracking camera in most instances, however, 
as most smartglasses do not possess accelerometers or an inside-out tracking mechanism.  
Most available literature on the use of smartglasses or similar HMDs in surgery remains experimental 
in nature – not clinical – or proposes systems not truly augmenting the perceived world [26–28]. Only 
one recent clinical report has examined the clinical application of smart glasses for surgical 
navigation [29] (using a customized version of the Epson Moverio to allow for external tracking). 
1.2.3 
HoloLens in surgery 
The HoloLens, developed by Microsoft Corporation, is the first device of its kind. It combines an HMD 
with an integrated full-powered, untethered computer and a multitude of sensors that can register 
the real world around it, and also track the position of the device itself (and thus of the wearer’s head) 
using accelerometers, gyroscopes and an inside-out tracking system. So far, only four reports on 
the use of the Microsoft HoloLens in surgery have been published in medical scientific literature. The 
first consists of a report on a phantom study in the field of vascular surgery, but does not assess any 
clinical validation [30]. The second and third, by Incekara et al. [31] and Li et al. [32], are both a first 
attempt in validating the use of an HMD (the Microsoft HoloLens) in a clinical neurosurgical setting. 
These prospective studies provide an estimate of the feasibility and accuracy of HMDs in tumor 
incision planning and external ventricular drain (EVD) placement, respectively, but have some 
shortcomings: the authors only used generic open-source software for 3D model creation and 
visualization and thus did not have a customized user interface for hologram manipulation nor a 
method for automated registration. They also attest to insufficient accuracy. This is due to the fact 
that they did not develop a customized application to optimize accuracy of placement and stability of 
the hologram relative to the physical world but rather made use of the HoloLens’ built-in SLAM 
(Simultaneous Localization And Mapping) algorithm.   
The fourth publication is by our own research group. This work came about as the result of ongoing 
collaboration between UZ Brussels and VUB-ETRO. An application for AR based neuronavigation 
with the HoloLens was developed in the context of a master thesis by Ir. T. Frantz. This application, 
which is Unity-based, provides the technology necessary for each of the components in the SARA 
project, ranging from 3D model generation over user interface, automated segmentation and 
registration to validation.  
As shown in Figure 2, our system has previously been used in the OR for testing purposes and proof-
of-concept demonstration. 

 
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Figure 2. Holographic semi-transparent overlay of patient anatomy in current interface 
 
In the experimental setup using phantom models, Frantz et al. [33] showed a mean perceived drift 
between the virtual object and physical object of no more than 1.41 ± 1.08 mm when using an 
optimized version of the Vuforia tracking software development kit (Table 1-1). 
 
Table 1-1. Change in mean perceived drift for each measurement angle (from Frantz et al) 
 
It was also demonstrated that a test person is able to pinpoint a predefined point on the physical 
object (only visible on the virtual object) within 5mm in 93% of cases, comparing favorably to 
literature (Table 1-2). This is also clinically highly relevant when a cranial burr hole needs to be made, 
for example. It was thus demonstrated that our system is as precise as current neuronavigation 
methods and can be used for initial clinical testing. 
 
Table 1-2. Comparison of published surface localization results (from Frantz et al) 
 

 
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1.3 
State of the art: drain placement  
Drain placement is an often-used procedure for patients with increased intracranial pressure 
(intracranial hypertension; ICH) or with intracranial hemorrhage (intraparenchymal hemorrhage 
(IPH) or chronic subdural hematoma (CSDH)), with the goal to drain cerebrospinal fluid (CSF) 
or blood, respectively, as well as to measure pressure in the specific compartment it is positioned 
in.  To drain CSF, an EVD is placed. In current practice, the minimally invasive placement of any 
intracranial drain is most often performed freehand, after inspection of and planning on CT images 
of the patient. For EVD placement additional, literature-defined landmarks are employed. These 
landmarks are not patient-specific, and literature even dictates to follow them even in the presence 
of anatomy-altering pathology [34]. As detailed below, these procedures and their accuracy have 
been studied extensively in literature, making them a suitable subject for clinical testing. Since all of 
these procedures are currently always performed in a “blind” fashion (i.e. without visual feedback, 
relying on either anatomical landmarks and standard angles in the case of EVD placement or on the 
uncorrelated CT-images and measurements made on these in the case of hematoma drainage), 
they provide the ideal context for demonstrating the added value of an AR-based visualization 
system for neuronavigation. 
For EVD placement, an accuracy scale for drain placement in the CSF spaces has been described 
in literature [35,36], given below in Table 2-1. To promote conformity within our clinical assessment 
and to be able to lump patients together for statistical analysis, we will subdivide this accuracy scale 
into three tiers (right column). 
Grade 
Description 
Assessment 
1 
Appropriately placed catheter in the 
ipsilateral frontal horn including tip of the 
3rd ventricle 
Good 
placement 
2 
Suboptimal placement in the contralateral 
frontal horn, corpus callosum or 
interhemispheric fissure 
Suboptimal 
placement 
3 
Placement in other brain parenchyma or 
other fluid filled spaces 
Poor 
placement 
Table 2-1. Accuracy scale for EVD placement in the CSF spaces as described by Kakarla et al. [35] 
Accuracy rates according to this scale have been reported in literature to be between 77 and 79% 
for good placement, between 10 and 14% for suboptimal placement and between 7 and 13% for 
poor placement using the freehand technique [35,36]. Multiple passes were reported in 5,4% of the 
EVD placements [36]. Similar studies have been performed when using guides or image guidance 
[35,36]. In literature, the overall complication rate (covering drain-related infections, post-placement 
hemorrhage and malplacement of the ventricular drain) ranges from 14,2 to 16,1% [36,37]. 
Hemorrhage has been reported to range from 1,8 to 33% [35,37,38], and reported infection rates 
range from 5,4% to 10,2% [36,37]. Kakarla et al. reported a mortality rate of 0,6% [35]. 
 
 

 
~ 14 ~ 
 
For intra-hematoma drain placement for IPH, a scale defined for the MISTIE trial [39] is used (Table 
2-2): 
Assessment 
Description 
Good 
placement 
Placed along the entire longitudinal axis of the 
hematoma with the fenestrated segment in the 
epicenter of the clot, circumferentially surrounded by 
the hematoma 
Suboptimal 
placement 
Over- or undershooting the target position or in 
eccentric location, yet fully engaging the IPH and 
suitable for dosing 
Poor 
placement 
Not engaging the IPH (i.e. catheter perforations not 
in contact with the clot), not allowing safe/effective 
dosing, hence requiring replacement 
Table 2-2. Accuracy scale for drain placement in an IPH 
Literature reports that for IPH drainage using catheters, 58% of drains is in good position, 28% is 
suboptimally placed (but sufficient for drainage and intra-hematoma administration of specific drugs), 
and 14% is poorly placed (requiring repositioning) [40]. The overall complication rate goes up to 
33,3% [41,42] and Barrett et al. also reported a mortality rate of 13,3% [42]. 
For twist-drill drainage of CSDH, [43] no specific scale has been described so far. For consistency 
with the abovementioned scales, we suggest the following classification (Table 2-3): 
Assessment 
Description 
Good 
placement 
Drain positioned in the hematoma in the subdural 
space 
Suboptimal 
placement 
Placement in the subdural space but not in the 
hematoma 
Poor 
placement 
Incorrect placement of the drain: subcutaneous 
placement, epidural placement or intraparenchymal 
placement of the drain 
Table 2-3. Accuracy scale for drain placement in a CSDH 
No data on the accuracy of twist-drill drain placement is currently available in literature, but the overall 
complication rate has been reported to range from 3 to 26,9%, recurrence rate from 10 to 33% and 
mortality rate from 2,9 to 11,4% [43,44]. Sindou et al. also reported insufficient evacuations in 3,3 to 
5,7% of the cases [43], and Weigel et al. reported a cure rate (full autonomy after surgery) in up to 
88,2% of the patients [44]. 
In this study we aim to demonstrate that AR-assistance in EVD placement surgery increases the 
accuracy and clinical results, flattens the learning curve for these procedures and increases surgeon 
comfort by making the procedure more visual in nature. For accuracy testing, the clinically validated 
accuracy scales will be used to compare outcomes to historical values from literature, but also 
historical values from retrospective review of drain placement procedures performed previously at 
UZ Brussel. 

 
~ 15 ~ 
 
2 Study Design 
In order to assess the accuracy of AR in EVD placement surgery with the clinical feasibility in mind, 
we will sequentially recruit 10-15 patients. Adequate accuracy of registered-hologram drain 
placement has been demonstrated in our phantom trials, that will be continued concurrently with the 
clinical trial in order to optimize any technical issues, the user interface and the user experience, and 
to demonstrate learning-curve effect in a safe manner. Thanks to Li et al [32], the preliminary work 
to demonstrate the efficacy and safety of the use of the HoloLens for clinical drain placement has 
already been done. Prior to enrollment of these patients, the surgeons will have a brief adjustment 
period in which the holographic information will not be displayed on the patient but elsewhere in the 
field of view of the surgeon (unregistered), to adjust to the HoloLens and the use of the AR navigation 
interface while still adhering to the conventional drain placement methods. For the following 10-15 
patients the AR overlay will be registered to and displayed on top of the patient, showing the relevant 
anatomy in its supposed actual location (giving the impression of “see-through vision”). This 
conversion not only assures optimal patient safety, but also allows us to investigate and improve 
upon the concurrently developed AR user-interface. 
Thus, a clinical experiment will be set up where current practice is compared to AR guidance. Minimal 
invasive drain placement in the CSF-space (ventricle) will be performed in standard fashion, but with 
the aid of a 3D model of the patient and the specific compartment to be targeted displayed in the 
field of view of the surgeon, either without registration to the patient (i.e. next to the patient serving 
as an in-room 3D visualization), or with registration to the patient (i.e. on top of the patient providing 
the surgeon with the impression of “see-through vision”). Results from these drain placements 
(accuracy being measured using clinical scales) will be compared to historical controls from literature 
and from our center. 
In order to optimize image processing from a technical point of view (optimization of segmentation 
procedure), but also for the mentioned concurrent phantom trials we will also (aside from the imaging 
data from the prospectively included patients) use imaging (CT and MRI) data, obtained 
retrospectively and fully anonymized, from 20 randomly selected patients.   
 

 
~ 16 ~ 
 
3 Patient selection criteria 
Patients must meet all of the following recruitment criteria to be eligible for enrolment into the trial: 
1. Diagnosis of any intracranial pathology requiring external ventricular drain placement. 
2. Age ≥18 years. 
3. The patient or his/her legal representative must be able to understand the planned study 
treatment after receiving a detailed verbal explanation, after which they had the chance to 
ask any remaining questions. 
4. No contraindication for evaluation by CT. 
5. Baseline CT is performed maximum 1 week before initiation of treatment (usually even 
performed at the moment of diagnosis, immediately prior to the intervention). 
6. Current clinical status does not prevent the patient from undergoing the standard treatment 
for the abovementioned condition(s); standard inclusion and exclusion criteria for surgery in 
general will be applied. 
7. Willingness and ability to comply with scheduled visits, treatment plans and other study 
procedures. 
8. The patient or his/her legal representative signed and dated the informed consent (IC) 
document indicating that the patient (or legal representative) has been informed of all the 
pertinent aspects of the trial.  

 
~ 17 ~ 
 
4 Treatment plan 
4.1 
HoloLens application 
4.1.1 
Pre-operative phase  
The patient will be screened for eligibility as mentioned above. Further screening assessments will 
include anamnesis, documentation of the medical history, clinical examination (including vital 
parameters) and baseline CT-imaging of the brain. If the patient is deemed eligible for inclusion, 
information on the trial will be provided to the patient. If the patient agrees to participate in the trial, 
a signed IC document will be obtained. 
Upon inclusion, standard procedures for clinical management of patients requiring drain placement 
will apply. Baseline imaging of the brain is performed pre-operatively, as is common practice for 
these procedures. The obtained imaging material (as anonymized DICOM images) will be prepared 
for transfer to HoloLens (segmentation, 3D modelling and subsampling) using proprietary software 
developed by the SARA-consortium. Planning of the intervention itself will be performed either on a 
planning station (a computer equipped with the beforementioned software) or on the HoloLens itself, 
using the 3D models as guidance (see Part 10 for ethical considerations). This concludes all 
preparations required for the intra-operative application of the HoloLens. 
4.1.2 
Operative phase  
The procedure itself will take place in a standardized fashion, performed by surgeons (in this case 
neurosurgeons or neurosurgeons in training) of different expertise levels (but always with adequate 
expertise and clearance to perform this procedure, as is current clinical practice). Surgical technique 
for the procedure is described below. The main difference is the use of the HoloLens as an AR 
device for visual aid during the procedure, which will not alter the operational workflow. The HoloLens 
will only be used immediately before and during the planned surgical procedures.  
Surgical technique 
The patient is installed on the operating table in the supine position. Patients will be sedated. The 
entry point is decided by the surgeon (usually at Kocher’s point), based on the pathology at hand, 
pre-existing anatomical knowledge and knowledge of anatomical landmarks, but also surgical 
planning information based on the preoperative CT scan, as well as the augmented reality-displayed 
surgical trajectory. The entry point is then marked on the skin (after local shaving if necessary) and 
the patient undergoes standard surgical prepping (disinfection) and draping. A stab incision is made 
at the entry point, after which the hand drill is placed against the skull and a drill trajectory is made 
in the skull, following the predefined trajectory that the drain should follow. This trajectory is based, 
again, on the pathology at hand, pre-existing anatomical knowledge and knowledge of anatomical 
landmarks and trajectories, surgical planning information based on the preoperative CT scan, and, 
importantly, the augmented reality-displayed surgical trajectory. The drain is then placed through the 
drill hole and advanced until the predefined depth (decided upon based on the surgical planning). 
After placement, flow of CSF or blood (depending on the pathology) through the drain is checked, 
after which it is secured to the skin with suture thread and connected to a drainage system.  
Analysis 
The following measures pertaining to the surgical experience will be recorded during and after the 
surgical procedures: 
- 
Duration of the surgical procedure (in minutes) 
- 
Number of passes of the drain before correct placement 
- 
Surgeon’s estimate of success of placement (using the graded scale detailed below) 
- 
Surgeon experience (detailed questionnaire available in Appendix B) 
 

 
~ 18 ~ 
 
4.1.3 
Post-operative phase & follow-up 
Within 24h after surgery the patient will undergo a CT-scan to assess the position of the newly-
placed drain. The primary endpoint, accuracy of drain placement evaluated on the immediate 
postoperative CT and graded according to clinical relevance, will be evaluated using the 
abovementioned Kakarla scale (Table 2-1). 
 
In the further post-operative period, the patient’s status will be monitored as it would be for every 
patient undergoing standard treatment for the abovementioned pathologies: in the immediate post-
operative phase the patient is monitored in the Intensive Care Unit (ICU). In the following days the 
patient may undergo additional imaging of the brain if deemed necessary, and his/her clinical status 
will be continuously monitored, as is common practice. Based on the clinical evolution, the drain may 
or may not be removed, and the patient may or may not be transferred to the neurosurgical ward. 
As soon as the patient is deemed adequately fit, he/she will be discharged from the hospital and a 
first follow-up appointment will be planned after 6 weeks. At this appointment the patient’s clinical 
status and cranial imaging status will be assessed one final time, after which the patient has 
completed his/her participation in the trial.  
 
4.2 
Clinical evaluation, imaging & follow-up 
Patients will be clinically monitored in accordance with standard of care for patients requiring EVD 
placement. We do not intend to do extensive research concerning the pathology, but rather want to 
get a notion of the possible difference in outcome related to the use of the HoloLens. The evaluations 
mentioned in this chapter will therefore be limited to the regular standard of care and only data 
obtained until the first follow-up appointment will be used for the trial. The schedule and types of 
assessments are presented in Table 4. The schedule is flexible as long as changes do not, in the 
opinion of the investigator, expose the patient to undue risk or induce bias in the evaluation of the 
endpoints. Data from the specified assessments will be collected in the electronic Case Report 
Form (eCRF).    
Table 4. Protocol related procedures and assessments. The bold line indicates the end of the patient’s 
participation in the trial.  
 
Assessments outlined in Table 4 include the following components: 
• 
Prior medical history – diagnosis, prior and/or current treatments, history of other diseases (active 
or resolved), concomitant illnesses, and demographics. 
Protocol related 
procedures and 
assessments 
Screening 
Surgery 
Post-operative 
period 
Hospital 
discharge 
Follow-up 
 
≤ Day 0 
Day 0 
 
Weekly 
 
 
Signed IC 
X 
 
 
 
 
Prior medical history 
X 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
Clinical follow-up scales 
X 
X 
X 
X 
X 
Adverse events monitoring 
X  
 
 
X 
X 
Concomitant therapy 
X  
 
 
X 
X 
Other assessments 
CT-scan 
X 
X  
within 24h 
following 
surgery 
(X)  
when deemed 
necessary for 
clinical reasons 
 
X 
Study treatment 
Surgery using HoloLens 
 
X 
 
 
 
Survival status 
X 

 
~ 19 ~ 
 
• 
Physical examination – examination of major body systems (especially neurological evaluation), 
body weight and height (at screen only), vital parameters (i.e. temperature, blood pressure, and 
heart rate) and clinical follow-up scores (GCS, mRS, NIHSS, MGS; Appendix C). 
• 
Adverse Events – Adverse events that are recorded in this trial are medical or surgical 
complications. Nature of the complication, date of appearance, relationship to the surgical 
procedure/trial intervention, offered treatment and outcome will be recorded. Patients will be 
followed for adverse events during the study until at least the first follow-up appointment, or until 
all serious adverse events have resolved or are determined to be “chronic” or “stable”, whichever 
is later. Serious adverse events should be monitored and reported from the time that the patient 
is included in the study (cfr. Part 8).  
• 
Concomitant therapy – concomitant medications and treatments will be recorded from the time 
that the patient is included, during the study, and up until the first follow-up appointment. 
• 
CT-scan – CT imaging of the brain: 
o Signs of increased intracranial pressure of any cause (e.g. trauma, anoxia, …), requiring 
placement of an EVD (e.g. GCS ≤ 8) 
o Hematoma volume and evolution, evolution of midline shift 
• 
Survival status – information on the patient’s post-operative survival will be collected for all 
patients until the first follow-up appointment. 
 
4.3 
Concomitant therapy 
The use of the HoloLens does not interfere with the patients’ (medicinal) therapy. Medical treatment 
will therefore be continued or adjusted based on the requirements for the planned surgical 
procedure. This includes the standard post-operative care and follow-up.  
All concomitant medications and blood products, as well as interventions (e.g. analgesic use or 
paracentesis) received by patients until the end of study inclusion will be recorded on the eCRF. 
 
4.4 
Life Style Guidelines 
The use of the HoloLens does not interfere with the patients’ life style. Lifestyle adjustments will 
therefore only be adjusted if necessary based on the requirements for the planned surgical 
procedure. This includes the standard period of post-operative care and follow-up. 
 
 

 
~ 20 ~ 
 
5 Statistical design 
This is a class II, single-arm, clinical pilot study investigating feasibility, safety and efficacy of a 
proprietary software solution for augmented reality-display, and registration and tracking of patient-
specific anatomic models on the Microsoft HoloLens (further referenced to in this paragraph as “the 
experimental treatment”) in patients requiring EVD placement. 
A patient is considered evaluable if he has signed informed consent and has undergone the 
HoloLens-assisted surgical intervention. Primary endpoint is accuracy according to the 
abovementioned Kakarla scale and can be evaluated within 24 hours after surgery. Patients will be 
encouraged to complete follow-up (which does not differ from standard follow-up for these 
pathologies) in order to evaluate the secondary endpoints (clinical outcome, cfr below) but will remain 
evaluable in the context of the trial even if planned follow-up has not been completed.  
 
5.1 
Objective & endpoints 
We wish to demonstrate the feasibility and added value of an AR based (neuro)navigation system 
implemented on the HoloLens for guidance during EVD placement. EVD placement accuracy will be 
assessed using the Kakarla scale, ranging from good (grade I) to poor (grade III) placement. These 
clinical outcome data will be compared to normal ranges based on historical values obtained from 
literature and from our institution. 
 
Secondary endpoints: 
• 
Improvement of user experience (intuitiveness, ergonomics, quickness; using the 
questionnaires in Appendix B). 
• 
Decrease of duration of procedure compared to same procedure performed without AR 
(based on historical values of procedure time, recorded at our institution) 
• 
Decrease of difference in outcome (accuracy scale) and of difference in duration of 
procedure between surgeons of different expertise levels compared to same intervention 
without AR (flattening of the learning curve) 
• 
Improvement of clinical outcome measures with AR-assisted surgery compared to 
standard practice (using the scales in Appendix C) 
• 
Improvement of pathology-specific clinical outcome measures: 
 
• 
Revision rate 
• 
Complication rate 
• 
Velocity of the decrease in ICP 
• 
Evolution of midline shift 
 
Exploratory endpoints: 
• 
Explore development and optimization of an efficient and ergonomic workflow in a well-
structured pipeline (pipeline from imaging to display of holograms) 
• 
Explore and describe necessity for continuous implementation of technical advances 
improving the AR experience, such as: 
• 
Correcting for inattentional blindness (confusion between real and virtual world), 
• 
Correcting for the use of historical images (i.e. updating preoperative images to 
better reflect the current situation), 
• 
Implementing marker-free navigational tracking, 
• 
Exploring cooperation by offering different points-of-view for multiple surgeons, 
• 
Explore assistance of these interventions by using telepresence, 
• 
… 
 
5.2 
Sample size calculation 
When aiming to objectively demonstrate an accuracy improvement of EVD placement obtained 
through AR guidance in comparison to the freehand technique, we’d aim for 95% correct placement 

 
~ 21 ~ 
 
as is the case for guidance using conventional neuronavigation systems. Testing against the null 
hypothesis EVD placement accuracy of 70-80% with current freehand techniques, thus would be the 
alternating hypothesis accuracy of 95% using AR guidance. Given a significance level (i.e. the 
probability of rejecting H0 when it is true) of 5% (alpha=0,05) and power (i.e. 1-beta, the probability 
of confirming the added value) of 80% (beta=0,20), minimally 67 patients would be needed.  
However, given the purpose of the current study being the evaluation of the system’s feasibility for 
intraoperative use in a critical care setting, this number will be limited to 10-15 patients, as is common 
practice for such studies. Following positive results, this trial may be followed by such a larger, 
randomized controlled trial. Dropout is expected to be unlikely, since the surgery is planned unrelated 
to the study and will not be cancelled under normal circumstances. 
 
5.3 
Accrual  
Patients will be enrolled in a consecutive fashion over the course of one year. Patient inclusion can 
only take place in case one of the mentioned medical investigators is present to ensure correct 
adherence to study protocol. We will account for all of the patients registered in the study. The 
number of patients who were not evaluable, who died or withdrew before treatment began will be 
specified. The number of patients lost to follow-up will be given. 
 
5.4 
Statistical analysis  
Dichotomized comparisons will be used to compare drain placement accuracy performed with versus 
without surgical AR assistance. Results obtained from the Kakarla scale after surgery with the AR 
guidance will be tabulated and compared to historical values obtained from literature and from our 
institution. These historical values are based on previous research in drain placement (without the 
use of AR guidance), and will be matched with the cases of the current study.  
To achieve these dichotomized comparisons, we will use cut-offs within the accuracy scale to define 
different benchmarks of good versus bad drain placement. The cut-off can be placed at either side 
of the ‘suboptimal placement’-category (cfr. Part 1), depending on the degree of accuracy we wish 
to pursue: a comparison with the cut-off above this category will analyze the improvement of perfect 
placement, whereas the cut-off below this category will analyze acceptable drain placement in 
general. Given the eventual alternating hypothesis of increased placement accuracy related to the 
use of AR guidance, along with the small expected sample size, these comparisons will be performed 
through one-sided Fisher’s exact tests. 
 
 
 
 

 
~ 22 ~ 
 
6 Patient registration procedure 
Prior to undergoing any study-specific procedure, patients must read the patient information 
brochure and sign the current Institutional Review Board (IRB)-approved IC form (see Part 10.3 
for the procedure during emergency situations). Screening procedures can then take place as listed 
in Part 4. Subjects meeting the eligibility criteria for study participation will start experimental 
treatment as soon as is estimated possible by the investigator.  
Patient withdrawal 
A patient may withdraw from the trial at any time at their own request, or they may be withdrawn at 
any time at the discretion of the investigator or sponsor for safety, behavioral, or administrative 
reasons. Unless the subject specifically withdraws his consent for use of the obtained data, the 
patient will remain evaluable within the trial if he has undergone the AR-assisted surgical procedure 
since the primary endpoint and some secondary endpoints are based on results that are obtained 
immediately after the surgical intervention.  
If a subject does not return for the scheduled follow-up visit, every effort should however be made to 
contact the subject and to document subject outcome, if possible. If the subject withdraws consent, 
no further evaluations should be performed and no attempts should be made to collect additional 
data, and the data obtained until that point will not be used in the final analysis.  
A patient may be withdrawn from the trial in case the surgical intervention cannot be performed for 
any reason (for example sudden unexpected adverse event preceding the surgery and precluding 
it), or in case of withdrawal of patient consent 
 
 

 
~ 23 ~ 
 
7 Forms and procedures for collecting data 
7.1 
Case Report Forms / Electronic Data Record 
As used in this protocol, the term eCRF should be understood to refer to an electronic data record 
(Excel and Microsoft Access file). This eCRF will be completed for each included subject. The 
completed original eCRF is the sole property of the study sponsor (UZ Brussel) and will not be made 
available in any form to third parties, appropriate regulatory authorities, without written permission of 
the UZ Brussel. 
It is the investigator's responsibility to ensure completion and to review and approve all eCRF data. 
At all times, the investigator has final personal responsibility for the accuracy and authenticity of all 
data entered on the eCRFs.  
Subject source documents are the physician's subject records maintained at the trial site. In most 
cases, the source documents will be the hospital's or the physician's chart or a study chart. The 
source documents must match the information collected on the eCRF. 
 
7.2 
Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating subjects (sufficient information to link records, e.g. 
eCRFs and hospital records), all original signed IC forms, copies of all eCRFs, source documents, 
and detailed records of treatment disposition. The records should be retained by the investigator 
according to local regulations during a period of 20 years. 
 
7.3 
 Study Monitoring  
This study will be initiated as a single center study. During the conduct of this study at a single site 
(UZ Brussel), the sponsor will monitor for the completeness and accuracy of the eCRF content. 
 
7.4 
GDPR-compliancy  
In accordance with the recent installment of the General Data Protection Regulation (GDPR) on 
the 25th of May 2018, following measures will be taken: 
- 
All personal data of the participating patients will be processed by the PI of this study or 
anyone working directly under his supervision. 
- 
To ensure protection of all personal data during processing, a Data Protection Officer 
(DPO) (dpo@vub.be) will be appointed. 
- 
The gathered data will only be used to investigate the endpoints mentioned in this protocol 
under 5.1 Objective & endpoints. As mentioned before, a patient may withdraw his consent 
for the use of any previously obtained data at any time. This withdrawal requires no 
justification from the patient, nor will it have any influence on the quality of the provided care. 
- 
The only investigators with access to personal data are investigators with a medical 
background (physicians) and physicians caring for the patient. All other involved parties and 
investigators will only be able to view anonymized data (see Part 10). 
- 
There will be no transfer of personal data to any other countries. 
- 
All personal data will be retained as explained above in Part 7.2. 

 
~ 24 ~ 
 
8 Reporting adverse events  
8.1 
Safety Monitoring 
Adverse events will be monitored on an ongoing basis and their frequencies reported semi-annually. 
The worst event for each patient will be described. Both events related and unrelated to treatment 
will be captured. Clinical outcome data will be tabulated and compared to normal ranges for the 
institution, based on historical values obtained at the institution. 
8.1.1 
Adverse events 
All observed or volunteered adverse events regardless of suspected causal relationship to the 
investigational product(s) or intervention will be reported as described in the following sections. For 
all adverse events, the investigator must pursue and obtain information adequate both to determine 
the outcome of the adverse event and to assess whether it meets the criteria for classification as a 
serious adverse event (cfr. below) requiring immediate notification to the study sponsor / IRB / 
Internal Ethics Committee (IEC). For all adverse events, sufficient information should be obtained 
by the investigator to determine the causality of the adverse event. The investigator is required to 
assess causality. For adverse events with a causal relationship to the investigational product, follow-
up by the investigator is required until the event or its sequelae resolve or stabilize at a level 
acceptable to the investigator. 
As the use of the HoloLens has no direct impact on the workflow of the standard surgical procedure, 
we do not expect it to cause any adverse events whatsoever. We expect general surgery-related 
complications as they would happen in the standard of care for the abovementioned pathologies, 
but none of these complications are directly linked to the use of the device. 
8.1.1.1 
Definition of an adverse event 
An adverse event is defined as any untoward medical occurrence or experience in a patient or clinical 
investigation subject which occurs following the application of the study treatment regardless of the 
causal relationship. Examples of adverse events include but are not limited to: 
• 
Abnormal test findings; 
• 
Clinically significant symptoms and signs; 
• 
Changes in physical examination findings; 
• 
… 
A serious adverse event is defined as any undesirable experience occurring to a patient, whether or 
not considered related to the protocol treatment. Worsening of signs and symptoms should be 
reported as adverse events in the appropriate section of the eCRF. Disease progression should not 
be reported as adverse event. 
Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows: 
• 
Test result is associated with accompanying symptoms, and/or 
• 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• 
Test result leads to discontinuation from the trial, significant additional therapy, and/or 
• 
Test result is considered to be an adverse event by the investigator or sponsor. 

 
~ 25 ~ 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute 
an adverse event. Any abnormal test result that is determined to be an error does not require 
reporting as an adverse event. 
Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
• 
Results in death; 
• 
Is life-threatening (immediate risk of death); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Is an important medical event. Medical and scientific judgment should be exercised in 
determining whether an event is an important medical event. An important medical event may 
not be immediately life-threatening and/or result in death or hospitalization. However, if it is 
determined that the event may jeopardize the patient and may require intervention to prevent 
one of the other outcomes listed in the definition above, the important medical event should be 
reported as serious. An example of such events is intensive treatment in an emergency room or 
at home for convulsions that do not result in hospitalization.  
Progression of the pathology during the study (including signs and symptoms of progression) should 
not be reported as an adverse event unless the outcome is fatal during the trial or within the safety 
reporting period. Hospitalizations due to signs and symptoms of disease progression should not be 
reported as serious adverse events. If the pathology has a fatal outcome during the trial or within the 
safety reporting period, then the event leading to death must be recorded as a serious adverse event. 
8.1.1.2 
Hospitalization 
Adverse events reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) to a 
healthcare facility meets these criteria. Admission also includes transfer within the hospital to an 
acute/ICU (e.g. from the psychiatric wing to a medical floor, medical floor to a coronary care unit, 
neurological floor to a tuberculosis unit). 
Hospitalization does not include the following: 
• 
Rehabilitation facilities; 
• 
Hospice facilities; 
• 
Respite care (e.g. caregiver relief); 
• 
Skilled nursing facilities; 
• 
Nursing homes; 
• 
Routine emergency room admissions. 
For same-day surgeries (outpatient/ambulatory procedures), hospitalization or prolongation of 
hospitalization in the absence of a precipitating, clinical adverse event is not in itself a serious 
adverse event. Examples include: 
• 
Admission for treatment of a pre-existing condition not associated with the development of a new 
adverse event or with a worsening of the pre-existing condition (e.g. for work-up of persistent 
pre-treatment lab abnormality, for single treatment-responsive seizure in a patient with known 
epilepsy); 
• 
Social admission (e.g. patient has no place to sleep);  

 
~ 26 ~ 
 
• 
Administrative admission (e.g. for yearly physical exam);  
• 
Protocol-specified admission during a clinical trial (e.g. for a procedure required by the trial 
protocol); 
• 
Optional admission not associated with a precipitating clinical adverse event (e.g. for elective 
cosmetic surgery); 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline documentation 
for the entire protocol and/or for the individual patient; 
• 
Admission exclusively for the administration of blood products; 
• 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events. However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event. For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event. 
8.1.2 
Severity Assessment 
Complications will be classified as medical (infection, electrolyte disturbance, etc.) or surgical. The 
investigator will use the following definitions of severity as defined by the Clavien-Dindo classification 
[45] to describe the maximum intensity of the adverse event (Table 5). The grade reported in the 
adverse event eCRF must be consistent with the description of the Clavien-Dindo grade included in 
the narrative section of the serious adverse event report. 
 
Table 5. Classification of Postoperative Complications (Clavien-Dindo) 
Grade 
Definition 
Grade I 
Any deviation from the normal postoperative course without the need for pharmacological 
treatment or surgical, endoscopic and radiological interventions. 
 
Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgesics, diuretics, 
electrolytes, and physiotherapy. This grade also includes wound infections opened at the 
bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for grade I 
complications.  
 
Blood transfusions and total parenteral nutrition are also included. 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
Grade IIIa 
Intervention not under general anesthesia 
Grade IIIb 
Intervention under general anesthesia 
Grade IV 
Life-threatening complication (including CNS complications)* requiring IC/ICU-management 
Grade IVa 
single organ dysfunction (including dialysis) 
Grade IVb 
multiorgan dysfunction 
Grade V 
Death of a patient 
Suffix “d” 
If the patient suffers from a complication at the time of discharge, the suffix “d” (for “disability”) is 
added to the respective grade of complication. This label indicates the need for a follow-up to 
fully evaluate the complication. 
*Brain hemorrhage, ischemic stroke, subarachnoid hemorrhage, but excluding transient ischemic attacks. 
CNS, central nervous system; IC, intermediate care; ICU, intensive care unit 
Table 5. Classification of Postoperative Complications (Clavien-Dindo) 
Note the distinction between the severity and the seriousness of an adverse event. A severe event 
is not necessarily a serious event. For example, a headache may be severe (interferes significantly 
with subject's usual function) but would not be classified as serious unless it met one of the criteria 
for serious adverse events, listed above. 

 
~ 27 ~ 
 
8.1.3 
Causality Assessment 
The investigator’s assessment of causality must be provided for all adverse events (serious and non-
serious). An investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the investigational product caused or contributed to an adverse event. If 
the investigator’s final determination of causality is unknown and the investigator does not know 
whether or not investigational product caused the event, then the event will be handled as “related 
to investigational product” for reporting purposes. If the investigator's causality assessment is 
"unknown but not related to investigational product", this should be clearly documented on trial 
records. In addition, if the investigator determines a serious adverse event is associated with trial 
procedures, the investigator must record this causal relationship in the source documents and eCRF, 
as appropriate, and report such an assessment in accordance with the serious adverse event 
reporting requirements, if applicable. 
8.1.4 
Withdrawal due to adverse events 
Withdrawal due to adverse events should be distinguished from withdrawal due to insufficient 
treatment results, according to the definition of adverse event noted earlier, and recorded on the 
appropriate adverse event eCRF page. When a patient withdraws due to a serious adverse event, 
the serious adverse event must be reported in accordance with the reporting requirements defined 
below. 
 
8.2 Reporting period 
Serious adverse events require immediate notification beginning from the time that the patient is 
included in the study, through and including the first follow-up appointment. Any serious adverse 
event occurring any time after the reporting period must be promptly reported if a causal relationship 
to the investigational product is suspected. Adverse events (serious and non-serious) should be 
recorded on the eCRF from the time the patient is included in the study until the first follow-up 
appointment. Death must be reported if it occurs during the serious adverse event reporting period, 
irrespective of any intervening treatment.  
8.2.1 
Reporting Requirements 
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial patient. In addition, each trial patient will be questioned about 
adverse events.  
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse event. 
If a serious adverse event occurs, expedited reporting will follow local and international regulations, 
as appropriate. Adverse event reporting to regulatory authorities will be carried out in accordance 
with applicable Belgian regulations.  
All adverse events will be reported on the adverse event page(s) of the eCRF. It should be noted 
that the form for collection of serious adverse event information is not the same as the adverse event 
eCRF. Where the same data are collected, the forms must be completed in a consistent manner. 
For example, the same adverse event term should be used on both forms. Adverse events should 
be reported using concise medical terminology on the eCRFs as well as on the form for collection of 
serious adverse event information.  
 

 
~ 28 ~ 
 
9 Quality assurance 
9.1 
Intellectual quality assurance 
The quality of all presented data will be thoroughly monitored and reviewed by both the principal 
investigator and sponsor. In addition, several focus groups, involving both academic peers 
(neurosurgeons, orthopedic surgeons, anesthetists, …) and industrial partners (Microsoft, 
Materialise, …), as well as an independent data monitoring committee will be employed to review all 
provided results, thusly ensuring a high level of quality.  
 
9.2 
Technical quality assurance 
Post-hoc video analysis of the intra-operative footage obtained from the HoloLens’ RGB camera 
and, if applicable, external cameras that implement a spectator view of the augmented situation, will 
be performed in order to assess proper functionality of the system as well as to detect whether the 
measured results correspond with the user’s perceived performance. These results provide further 
feedback information for the HoloLens software, supplementary to the comparative and user 
experience analyses.  
Additionally, this intra-operative footage will be applied for the development of a mixed reality 
interface, thus improving on the augmented reality interface we currently use. Through machine 
learning the computer will be able to recognize certain operative steps and instruments used by the 
surgeon, after which it can interact with the situation at hand. This will enhance the synergy between 
the surgeon and the software, making an even greater improvement of accuracy possible. 
 
10 Ethical considerations 
10.1 Patient protection 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles for 
Medical Research Involving Human Subject (Appendix D), adopted by the General Assembly of the 
World Medical Association (1996). In addition, the trial will be performed in accordance with the 
protocol, International Organization for Standardization Good Clinical Practice (GCP) guidelines 
[46], and applicable local regulatory requirements and laws. 
 
10.2 Subject identification & anonymization 
Upon inclusion in the trial, patients will be issued a study code. eCRFs for specific patients will only 
use the code as will the study database, which is password protected. The only investigators with 
access to specific patient data are investigators with a medical background (physicians) and 
physicians caring for the patient. All other involved parties and investigators will only be able to view 
anonymized data.  
The obtained imaging information (in DICOM format) will be also anonymized and coded as it will be 
used for further manipulation into holograms. Video information will be anonymized if it is to be 
viewed by anyone other than the trial investigators with a medical background (physicians) or 
physicians caring for the patient. 
In order to optimize image processing from a technical point of view (optimization of segmentation 
procedure), but also for phantom trials (concurrently performed and used for evaluation and 
optimization of the procedures in this trial in a non-invasive fashion) we will use imaging (CT and 
MRI) data, obtained retrospectively and fully anonymized, from 20 randomly selected patients.   
 

 
~ 29 ~ 
 
10.3 Informed consent 
The IC form must be agreed to by the IRB/IEC and must comply with the International Organization 
for Standardization GCP, local regulatory requirements, and legal requirements. The IC form used 
in this study, and any changes made during the course of the study, must be prospectively approved 
by the IRB/IEC before use. 
The investigator must ensure that each trial subject, or his/her legally acceptable representative, is 
fully informed about the nature and objectives of the trial and possible risks associated with 
participation. The investigator will try to obtain written IC from each subject or the subject's legally 
acceptable representative before any study-specific activity is performed. The investigator will retain 
a copy of each subject's signed consent form. 
In emergency situations, however, the study treatment must be started as soon as possible after the 
patient is admitted to the hospital. In these situations, the patient is usually unable to decide for him-
/herself whether or not to take part in the study. Waiting until the legal representative arrives to inform 
him/her of the study and obtain his/her consent for the participation of the patient he/she represents 
would mean the normal urgent care has to be provided and the investigational treatment can no 
longer be offered under these conditions. Since a patient’s participation will most likely benefit the 
progress of his/her clinical situation under these specific conditions, we will therefore implement the 
investigational treatment both without the consent of the patient and without the consent of the legal 
representative, in accordance with the provisions of Chapter VI of the Law of May 2004 related to 
experiments on humans. 
The consent of the legal representative will be obtained as soon as possible and the patient’s consent 
will be asked once the improvement in his/her clinical situation allows him/her to be informed 
correctly of the objectives and procedures of the study and to agree to them. If the patient (or legal 
representative) does not give his/her consent, the previously obtained data cannot be used for further 
analysis. All decisions and informed consent procedures during this emergency situation will be well 
documented, dated (date & time) and signed by the investigator in charge. 
 

 
~ 30 ~ 
 
11 Trial sponsorship and financing 
The sponsor of this study is C4N-NEUR and BEFY-ORTHO of UZ Brussel, Laarbeeklaan 101, 1090 
Brussel, Belgium. A grant from both Imec-icon and VLAIO was obtained for the duration of the study.  
 
12 Trial insurance 
The sponsor of this study, UZ Brussel will offer insurance coverage for all the study participants in 
accordance with the Belgian law. 
 
13 Intellectual property and publication policy 
All data resulting from this study are the intellectual property of the study sponsor (UZ Brussel, 
represented by the principal investigator). No data from this study can be used for any purpose 
without the written consent of the study sponsor. The study sponsor stays the owner of the author's 
rights of all reports (partial or final) made up by the investigators in the context of this study. 
The industrial partners recognize the right of the investigators to use data resulting from this study 
for educational purposes, for communications at congresses and for scientific publications. The 
sponsor of this study and the industrial partners will exchange ideas prior to each publication or 
public announcement and discuss results. The role of the industrial partners will stay advisory at any 
moment. The investigators commit themselves to restrain from any form of publication, 
announcement or press-release concerning results emerging from this study, without previous 
consultation with the industrial partners.  
We aim to present results at major international conferences (EANS annual meeting, CNS annual 
meeting, AANS annual meeting, WFNS annual meeting) and publish the mature results in an 
international neurosurgery journal (preferably the Journal of Neurosurgery, World Neurosurgery, 
Operative Neurosurgery, Neurosurgery or the International Journal of Computer Assisted Radiology 
and Surgery). The article will be submitted at the latest two years after completion of the trial. 
First author for all publications emerging from this protocol will be the first co-investigator of this trial 
listed in the beginning of the protocol. The principal investigator will be senior author for publication. 
Any other authors and order of the author string will be determined by the principal investigator and 
based on the significance of the contributions of each co-author (contribution of each author will be 
specifically mentioned). 

 
~ 31 ~ 
 
Appendix A: List of abbreviations 
 
 
 
 
AR 
Augmented Reality 
eCRF 
Electronic Case Report Form 
CSDH 
Chronic Subdural Hematoma 
CSF 
Cerebrospinal Fluid  
CT 
Computed Tomography 
DPO 
Data Protection Officer 
EVD 
External Ventricular Drain 
FPI 
First Patient In 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HMD 
Head-Mounted Display 
IC 
Informed Consent 
ICH 
Intracranial Hypertension 
ICU 
Intensive Care Unit 
IEC 
Internal Ethics Committee  
IPH 
Intraparenchymal Hemorrhage 
IR 
Infrared  
IRB 
Institutional Review Board 
LPI 
Last Patient In 
OR 
Operating Room 
SARA 
Surgical Augmented Reality Assistance 

 
~ 32 ~ 
 
Appendix B: User experience questionnaires 
 
1. Utaut-model: measuring the likelihood of technology-acceptance (Venkatesh et al. [47]) 
 
 
The following items are answered on a 5-point Likert scale ranging from strongly disagree to 
strongly agree. 
 
Strongly 
disagree 
 
 
 
Strongly  
agree 
 
 
 
 
 
1 
2 
3 
4 
5 
 
Performance expectancy 
▪ 
I would find the system useful in my job. 
▪ 
Using the system enables me to accomplish tasks more quickly. 
▪ 
Using the system increases my productivity. 
▪ 
If I use the system, I will increase my chances of getting a raise. 
 
Effort expectancy 
▪ 
My interaction with the system would be clear and understandable. 
▪ 
It would be easy for me to become skillful at using the system. 
▪ 
I would find the system easy to use. 
▪ 
Learning to operate the system is easy for me. 
 
Social influence 
▪ 
People who influence my behavior think that I should use the system. 
▪ 
People who are important to me think that I should use the system. 
▪ 
The senior management of this business has been helpful in the use of the system. 
▪ 
In general, the organization has supported the use of the system. 
 
Facilitating conditions 
▪ 
I have the resources necessary to use the system. 
▪ 
I have the knowledge necessary to use the system. 
▪ 
The system is not compatible with other systems I use. 
▪ 
A specific person (or group) is available for assistance with system difficulties 
 
Behavioral intention (adapted from [47]) 
▪ 
I intend to use the system as soon as it becomes available in the hospital. 
▪ 
I predict I would use the system as soon as it becomes available in the hospital. 
▪ 
I plan to use the system as soon as it becomes available in the hospital. 
 
 
Gender 
▪ 
Female 
▪ 
Male 
 
Age: I am ____ years old 
 
Experience 
▪ 
Neurosurgical resident, year  ___ 
▪ 
Certified neurosurgeon, since ______ 
  
 
 

 
~ 33 ~ 
 
2. System usability scale (Brooke [48]) 
 
 
 
 
 
 

 
~ 34 ~ 
 
3. Socio-demographic details 
 
Gender: 
Male / female 
Year of birth: 
   
Profession: 
  
 
Please indicate your dominant hand. 
O Right 
O Left 
O No preference 
Are you currently wearing glasses/contact 
lenses? 
  
O No 
O Yes, I wear glasses. 
O Yes, I wear contact lenses. 
Do you wear glasses/contact lenses during 
surgery? 
  
O No 
O Yes, I wear glasses. 
O Yes, I wear contact lenses. 
Have you previously participated in a similar 
study? 
O Yes 
O No 
Surgical experience 
How much surgical experience do you 
possess? 
O Little / I’m still in training 
O Intermediate 
O Extensive 
Please indicate the estimated amount of 
surgeries you have performed (semi-) 
independently. 
O < 25 
O 25 – 50   
O 50 – 100 
O 100 – 500 
O 500 – 1000  
O > 1000 
How many surgeries do you perform on a 
weekly basis? 
O ………… surgeries per week 
  
 
 
 
 
4. Subjective measures related to comfort (adapted from Tanagho et al. [49]) 
 
Do you experience one of the following discomforts? To what extent (x = somewhat; xx = quite a 
lot; xxx = extensively)? 
 
Yes 
No 
Eye strain 
 
 
Headache 
 
 
Dizziness 
 
 
Disorientation 
 
 
Physical discomfort 
 
 
Poor visualization 
 
 
 
 
 

 
~ 35 ~ 
 
5. Cognitive workload: NASA-TLX (Task Load Index; Hart et al. [50])  
 
 
 
 
 

 
~ 36 ~ 
 
6. Various subjective measures (created by Imec-SMIT or adapted from [47] and [51]) 
 
 
The following items are answered on a 5-point Likert scale ranging from strongly disagree to 
strongly agree. 
 
Strongly 
disagree 
 
 
 
Strongly  
agree 
 
 
 
 
 
1 
2 
3 
4 
5 
 
▪ 
I feel comfortable working with this system. 
 
▪ 
I can use the system in an intuitive way. 
 
▪ 
I was able to finish the task efficiently (adapted from Kumcu et al. [51]). 
 
▪ 
I felt in control over the system (adapted from Kumcu et al. [51]). 
 
▪ 
I believe this system might have a negative influence on the safety of the patient during 
surgery (adapted from Kumcu et al. [51]). 
 
▪ 
The system allows me to work accurately.  
 
▪ 
I could complete a certain task using this system without anybody present to provide me 
with step-by-step guidance on what I need to do (adapted from Venkatesh et al. [47]). 
 
 
If you have any additional remarks or feedback, please leave them in the box below. In case more 
writing space is needed, please use the backside of this document (from Kumcu et al. [51]). 
 
  
 
  

 
~ 37 ~ 
 
Appendix C: Clinical follow-up scales 
 
1. Intracranial hypertension & intraparenchymal hemorrhage 
 
Glasgow Coma Scale 
Behavior 
Response 
Score 
Eye opening 
response 
Spontaneously 
4 
To speech 
3 
 
To pain 
2 
 
No response 
1 
Best verbal 
response 
Oriented to time, place, and person 
5 
Confused 
4 
 
Inappropriate words 
3 
 
Incomprehensible sounds 
2 
 
No response 
1 
Best motor 
response 
Obeys commands 
6 
Moves to localized pain 
5 
 
Flexion withdrawal from pain 
4 
 
Abnormal flexion (decorticate) 
3 
 
Abnormal extension (decerebrate) 
2 
 
No response 
1 
Total score: 
Best response 
15 
 
Comatose patient 
8 or less 
 
Totally unresponsive 
3 
 
 
 
Modified Rankin Scale 
Description 
Score 
No symptoms at all 
0 
No significant disability despite symptoms; able to carry out all usual duties 
and activities 
 
1 
Slight disability; unable to carry out all previous activities, but able to look 
after own affairs without assistance 
 
2 
Moderate disability; requiring some help, but able to walk without assistance 
3 
Moderately severe disability; unable to walk without assistance and unable 
to attend to own bodily needs without assistance 
 
4 
Severe disability; bedridden, incontinent and requiring constant nursing care 
and attention 
 
5 
Dead 
6 

 
~ 38 ~ 
 
2. Intraparenchymal hemorrhage 
 
National Institutes of Health Stroke Scale 
Instructions 
Scale definition 
Score 
1a. Level of Consciousness (LOC) 
Alert; keenly responsive 
0 
Arousable by minor stimulation 
1 
 
Obtunded  
2 
 
Unresponsive or reflex response 
3 
1b. LOC Questions (Month & Age) 
Answers both questions correctly 
0 
Answers one question correctly 
1 
 
Answers neither question correctly 
2 
1c. LOC Commands (Open/close eye 
& Grip/release non-paretic hand) 
Performs both tasks correctly 
0 
Performs one task correctly 
1 
 
Performs neither task correctly 
2 
2. Best Gaze (Horizontal eye 
movements) 
Normal 
0 
Partial gaze palsy 
1 
 
Total gaze paresis 
2 
3. Visual 
No visual loss 
0 
Partial hemianopia 
1 
 
Complete hemianopia 
2 
 
Bilateral hemianopia 
3 
4. Facial Palsy 
Normal  
0 
Minor paralysis  
1 
 
Partial paralysis  
2 
 
Complete paralysis 
3 
5. Motor Arm (score both sides 
separately) 
No drift 
0 
Drift  
1 
 
Some effort against gravity  
2 
 
No effort against gravity  
3 
 
No movement.  
4 
 
Amputation or joint fusion  
N/A 
6. Motor Leg (score both sides 
separately) 
No drift 
0 
Drift  
1 
 
Some effort against gravity  
2 
 
No effort against gravity  
3 
 
No movement.  
4 
 
Amputation or joint fusion  
N/A 
7. Limb Ataxia 
Absent 
0 
Present in one limb 
1 
 
Present in two limbs 
2 
 
Amputation or joint fusion 
N/A 

 
~ 39 ~ 
 
8. Sensory 
Normal  
0 
Mild-to-moderate sensory loss 
1 
 
Severe to total sensory loss 
2 
9. Best Language 
No aphasia; normal.  
0 
Mild-to-moderate aphasia  
1 
 
Severe aphasia 
2 
 
Mute, global aphasia 
3 
10. Dysarthria 
Normal 
0 
Mild-to-moderate dysarthria 
1 
 
Severe dysarthria 
2 
 
Intubated or other physical barrier 
N/A 
11. Extinction and Inattention 
No abnormality  
0 
One of the sensory modalities 
1 
 
Profound hemi-inattention 
2 
Total score: 
No stroke 
0 
 
Minor stroke 
1 – 4 
 
Moderate stroke 
5 – 15 
 
Moderate to severe stroke 
16 – 20 
 
Severe stroke 
21 – 42 
 
 
 
3. Chronic subdural hematoma 
 
Markwalder Grading Scale 
Description 
Score 
Patient neurologically normal 
0 
Patient alert and oriented; mild symptoms such as headache; absent or mild 
neurological deficit, such as reflex asymmetry 
 
1 
Patient drowsy or disoriented with variable neurological deficit, such as 
hemiparesis 
 
2 
Patient stuporous but responding appropriately to noxious stimuli; severe 
focal signs such as hemiplegia 
3 
Patient comatose with absent motor responses to painful stimuli; 
decerebrate or decorticate posturing 
4 
 

 
~ 40 ~ 
 
Appendix D: Declaration of Helsinki 
 
At the time this protocol was issued, the full document was available on the World Health 
Organization website at http://www.who.int/bulletin/archives/79%284%29373.pdf 
 
 

 
~ 41 ~ 
 
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