A Data Collection and Analysis Pilot Study to Indicate Preliminary Characterisation of the Electromyogram Signal in Relation to Needle Position With Respect to the Extraocular Muscles, as Observed During Electromyogram Needle Guided Treatment of Strabismus in Adults
Conditions: Strabismus
Sponsor: Liverpool University Hospitals NHS Foundation Trust

 
 
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Eye Muscle Needle Electromyogram (EMu) Pilot Study 
Protocol 
A data collection and analysis pilot study to indicate preliminary 
characterisation of the electromyogram signal in relation to needle 
position with respect to the extraocular muscles, as observed during 
electromyogram needle guided treatment of strabismus in adults 
V1.8, 21st November 2018 
 
 
 
MAIN SPONSOR: Royal Liverpool and Broadgreen University Hospitals NHS Trust (RLBUHT) 
FUNDERS: Medical Physics & Clinical Engineering, RLBUHT 
STUDY COORDINATION CENTRE: Royal Liverpool Hospital, RLBUHT 
IRAS Project ID:  249119 
 
 
Study Team 
Chief Investigator: 
Dr Tristan Payne, Clinical Scientist, Royal Liverpool Hospital 
Co‐investigators: 
Mr Ali Yagan, Consultant Ophthalmologist, Manchester Royal Eye Hospital (MREH), 
Manchester University NHS Foundation Trust 
Ms Elisabeth Nichol, Orthoptist, Manchester Royal Eye Hospital 
Statistician: 
Dr Antonio Eleuteri, Statistician, Royal Liverpool Hospital 
Study Manager: 
Dr Tristan Payne, Clinical Scientist, Royal Liverpool Hospital 
 
 

 
 
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Study Coordination Centre 
For general queries, supply of Study documentation, and collection of data, please contact: 
Study Coordinator: 
Dr Tristan Payne 
Address:  
 
Medical Physics & Clinical Engineering 
 
 
 
Royal Liverpool Hospital 
 
 
 
Royal Liverpool & Broadgreen University Hospitals NHS Trust 
 
 
 
Duncan Building, 1st Floor 
 
 
 
Prescot Street 
 
 
 
Liverpool L7 8XP 
Tel:  
 
 
0151 706 4223 
Fax: 
 
 
0151 706 5803 
E‐mail:   
 
tristan.payne@nhs.net 
Clinical Queries 
Clinical queries should be directed to Dr Payne who will direct the query to the appropriate person. 
Sponsor 
The Royal Liverpool and Broadgreen University Hospitals NHS Trust is the research Sponsor for this Study. 
For further information regarding the sponsorship conditions, please contact: 
Heather Rogers 
RD&I Governance Manager 
4th Floor Linda McCartney 
Royal Liverpool Hospital  
Prescot St 
Liverpool L7 8XP 
Tel: 0151 706 3320 
Fax: 0151 706 3703 
Email: RGT@rlbuht.nhs.uk 
Funder 
The research is funded by Medical Physics & Clinical Engineering, RLBUHT. 
 
 

 
 
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STUDY SUMMARY 
This protocol describes the EMu Pilot Study and provides information about procedures for entering 
participants. Every care was taken in its drafting, but corrections or amendments may be necessary. 
These will be circulated to investigators in the Study. Problems relating to this Study should be referred, in 
the first instance, to the Chief Investigator. 
This study will adhere to the principles outlined in the NHS Research Governance Framework for Health 
and Social Care (2nd edition) and Good Scientific Practice (Version 1). It will be conducted in compliance 
with the protocol, the Data Protection Act and other regulatory requirements as appropriate. 
GLOSSARY OF ABBREVIATIONS 
HRA 
Health Research Authority 
REC 
Research Ethics Committee 
EMG 
Electromyogram 
EOM 
Extraocular muscle 
BTX 
Botulinum toxin 
 
KEYWORDS 
Extraocular muscle, electromyogram, monopolar, needle guidance, Botulinum toxin, strabismus 
TITLE  
A data collection and analysis pilot study to indicate preliminary characterisation of the electromyogram 
signal in relation to needle position with respect to the extraocular muscles, as observed during 
electromyogram needle guided treatment of strabismus in adults 
DESIGN  
A cross-sectional observational pilot study 
AIMS 
Gain more knowledge of the electromyogram acquired during electromyogram (EMG) needle guided 
treatment of strabismus, indicate the feasibility of improving the technology and inform a larger study to 
provide evidence to underpin the development of such new technology. 
OUTCOME MEASURES  
Primary 
• 
The change in the EMG signal as the needle approaches, and enters, the target extraocular muscle. 

 
 
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Secondary 
• 
Clinician’s score of the step change from baseline EMG to ‘active’ EMG level heard immediately 
prior to delivery of Botulinum toxin (BTX); 
• 
Clinician’s score of their confidence in accurate needle placement; 
• 
Clinician’s score of overall quality of the EMG signal heard during the procedure; 
• 
Change in patient’s angle of deviation following treatment. 
POPULATION ELIGIBILITY 
Adults undergoing planned, routine EMG needle guided BTX injection into either lateral or medial rectus 
muscle for the treatment of strabismus. 
DURATION 
Up to 20 weeks. 
 
 
 

 
 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ......................................................................................................................................... 7 
1.1 
BACKGROUND ................................................................................................................................... 7 
1.2 
RATIONALE FOR CURRENT STUDY ..................................................................................................... 9 
2 
STUDY OBJECTIVES .................................................................................................................................. 10 
3 
STUDY DESIGN ......................................................................................................................................... 10 
3.1 
MATERIALS ...................................................................................................................................... 10 
3.2 
METHOD .......................................................................................................................................... 10 
3.3 
LOCATION ........................................................................................................................................ 12 
3.4 
PERSONNEL ...................................................................................................................................... 13 
3.5 
STUDY OUTCOME MEASURES .......................................................................................................... 13 
4 
PARTICIPANT ENTRY ................................................................................................................................ 13 
4.1 
PRE‐REGISTRATION EVALUATIONS .................................................................................................. 13 
4.2 
INCLUSION CRITERIA ........................................................................................................................ 13 
4.3 
EXCLUSION CRITERIA ....................................................................................................................... 13 
4.4 
WITHDRAWAL CRITERIA .................................................................................................................. 14 
5 
ADVERSE EVENTS ..................................................................................................................................... 14 
5.1 
DEFINITIONS .................................................................................................................................... 14 
5.2 
REPORTING PROCEDURES ............................................................................................................... 14 
6 
ASSESSMENT AND FOLLOW‐UP ............................................................................................................... 15 
7 
STATISTICS AND DATA ANALYSIS ............................................................................................................. 15 
8 
REGULATORY AND QUALITY ISSUES ........................................................................................................ 16 
8.1 
SAFETY ............................................................................................................................................. 16 
8.2 
ETHICS APPROVAL ........................................................................................................................... 16 
8.3 
CONSENT ......................................................................................................................................... 16 
8.4 
CONFIDENTIALITY ............................................................................................................................ 17 
8.5 
INDEMNITY ...................................................................................................................................... 18 
8.6 
SPONSOR ......................................................................................................................................... 18 
8.7 
FUNDING.......................................................................................................................................... 18 

 
 
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8.8 
AUDITS ............................................................................................................................................. 18 
8.9 
REGULATORY APPROVAL ................................................................................................................. 18 
8.10 
LOCAL APPROVAL ............................................................................................................................ 18 
8.11 
COMMUNICATION PLAN ................................................................................................................. 18 
8.12 
PROTOCOL AMENDMENTS .............................................................................................................. 19 
8.13 
STUDY EVALUATION ........................................................................................................................ 19 
8.14 
RISKS TO COMPLETION OF STUDY ................................................................................................... 20 
8.15 
QUALITY PLAN ................................................................................................................................. 20 
9 
STUDY MANAGEMENT ............................................................................................................................. 21 
9.1 
RESOURCES ...................................................................................................................................... 21 
9.2 
TIMESCALES ..................................................................................................................................... 21 
9.3 
COSTS ............................................................................................................................................... 22 
10 
END OF STUDY ..................................................................................................................................... 22 
11 
ARCHIVING ........................................................................................................................................... 22 
12 
PUBLICATION POLICY ........................................................................................................................... 22 
13 
REFERENCES ......................................................................................................................................... 22 
14 
VERSION CONTROL .............................................................................................................................. 23 
15 
APPENDICES ......................................................................................................................................... 26 
15.1 
APPENDIX 1: EMG SIGNAL CAPTURE SYSTEM ................................................................................. 26 
15.2 
APPENDIX 2: DETAILED METHOD .................................................................................................... 28 
 
 
 

 
 
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1 INTRODUCTION 
1.1 
BACKGROUND 
1.1.1 
Strabismus, Botulinum toxin and EMG 
Strabismus is an ocular condition caused by unbalanced contraction of EOMs, specifically the medial or 
lateral rectus muscle.  There are several functional consequences of the condition, and significant negative 
psychosocial effects that reduce quality of life (Durnian et al., 2011).  In some cases, strabismus is treated 
with injections of BTX to temporarily inhibit the medial or lateral rectus muscle responsible for the 
excessive deviation of the globe, thus straightening the gaze. 
The EOMs are histologically unique, being the only muscles in humans containing both slow fibres and fast-
twitch fibres.  Consequently, the motor unit potentials generated by EOMs are also unique, being of much 
lower amplitude and duration, and with a higher firing rate when compared to peripheral skeletal muscles 
(Björk, 1952). 
Due to the deep location of the rectus muscles, the needle used to deliver BTX cannot be easily guided 
without assistance.  The unique electrical activity of the EOMs described above is harnessed in combination 
with EMG needle guidance to help ensure the toxin is delivered correctly. 
1.1.2 
Current practice 
An early publication described the application of EMG needle guidance in treating strabismus with BTX, 
whereby a needle electrode was used to pick up the EMG activity at the injection site, and by amplifying 
and playing the EMG signal through a loudspeaker, the clinician could learn to identify the correct location 
from the sounds.   In this paper, Scott (1981) states “one learns to differentiate the low amplitude distant 
signal from the high amplitude and crackling sound when the centre of the muscle is reached”.  The sound 
is also described as “rain on a tin roof” (Childers, 2003), and the increase in EMG volume together with the 
change in sound are discerned by the clinician as the patient gazes in the direction of the dystonic muscle 
into which the BTX is injected, thus activating the muscle. 
Practice commonly observed today has not changed in the intervening 37 years.  Today, as then, the sound 
is provided by a simple device that amplifies the EMG signal at the tip of the needle through with the BTX 
will pass when it is injected, and plays it through a loudspeaker.  Devices today may also provide an 
indication of the signal level and/or the waveform morphology. 
1.1.3 
Existing research 
There is very little research exploring the technology described above, and how it may be improved in the 
context of strabismus.  Techniques with potential for improving EMG guidance include: 
- 
Visualisation of the waveform.  Kim et al. (2011) published a method of displaying the EMG 

 
 
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waveform to the clinician during delivery of BTX to treat strabismus.  Kim et al. suggest displaying 
the waveform delivers an increase in accuracy and decrease in procedure time, although do not 
detail how this was achieved or measured. 
- 
Motor unit potential rise time.  Ajax et al. (1998) used a threshold applied to the motor unit 
potential rise time to determine correct positioning within limb muscles.  They showed an 
improvement in localisation of the needle under EMG guidance compared to anatomic localisation. 
- 
High-pass filtering to remove noise.  Brown et al. (2010) performed experiments with rotator cuff 
muscles, and related signals from needle electrodes to signals from surface electrodes.  They found 
that there was still good correlation between the two signals even when low frequency 
components of the surface signal below 240 Hz were removed.  If, by extension, this applies to 
EOMs that contain even higher frequency components, then high-pass filtering may reduce 
interference without degrading the information from the target muscle.   
- 
Measuring parameters of the EMG spectrum.  Early research by Trimble et al. (1973) characterised 
the spectrum of an averaged extraocular motor unit potential, and found a peak around 900 Hz, in 
contrast to a high prevalence of much lower frequencies in skeletal muscles.  Despite this evidence, 
Hunter et al. (1996), in a study of only 23 patients, did not find correlation between effectiveness of 
strabismus treatment and three basic parameters of the spectrum: tallest peak, peak frequency and 
total power.  This may be due to the different electrode types used – Trimble et al. used coaxial 
electrodes capable of detecting more localised EMG than the monopolar electrode used by Hunter 
et al.  However, recent unpublished evidence gathered at Medical Physics and Clinical Engineering, 
Royal Liverpool Hospital, using thread electrodes does suggest high frequency components of the 
EMG signal relate to EOM activity. 
- 
Interference analysis.  Werdelin et al. (2011) used bipolar electrodes with previously reported turn 
amplitude analysis (TAA) to guide BTX injections for the treatment of torticollis.  The injection was 
performed subsequently to the analysis, suggesting TAA may not be achievable in the case of 
monopolar needle EMG. 
- 
Signal decomposition.  Decomposition of the EMG signal may allow single motor unit activity to be 
detected and characterised.  Although reported using concentric (bipolar) needle electrodes (Pham 
et al., 2014), this technique may be useful in the analysis of monopolar EMG signals. 
The publications above indicate possible improvements to the technology; however, the evidence is sparse 
and inconclusive in the context of EMG needle guided treatment of strabismus. 
Specifically, while the EMG of individual motor units is well characterised, when monopolar needles of the 
type used in EMG guided BTX injections are used, the EMG signal represents the contribution of many 
motor units, and is not so readily interpreted. 

 
 
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1.2 
RATIONALE FOR CURRENT STUDY 
The rather imprecise “rain on a tin roof” identification of the EMG signal described above for what is a 
precise procedure – the medial and lateral rectus muscles are around 2.5 mm to 4.7 mm in diameter – will 
arguably negatively impact on treatment efficacy and repeatability.  There may also be an increase in the 
likelihood of side effects such as ptosis and vertical deviation when the toxin spreads beyond the target 
muscle.  When the needle is guided with direct observation into the muscle belly, the number of cases of 
ptosis is as low as 1 in 32 cases (Wan et al., 2011), suggesting the higher rates generally observed with EMG 
guidance are due to suboptimal positioning of the needle.  Furthermore, if more toxin is used where 
injection takes place distal to the optimum location, the result may be an increase in antibody formation 
and reduced response to the toxin.  It is also difficult to teach the effective use of EMG needle guidance 
where such descriptive interpretation is involved. 
The need for improvement was confirmed during recent research of consensus needs of a group of 
clinicians (Payne, 2016), which distilled specific needs relating to EMG needle guidance in this context.  Four 
of these are particularly challenging and of interest for this study: 
1) Isolating the EOM EMG signal by reducing contamination from other muscles; 
2) Displaying the confidence that the needle is within the EOM; 
3) Indicating the proximity of the needle to the EOM; 
4) Providing a signal quality score. 
Clinicians ranked the first two as higher priority than the third and fourth.  Note that all are dependent 
upon learning more about the EMG signal characteristics that are affected by distance of the needle to the 
target muscle. 
Despite the need, commercially available handheld EMG monitors of the type typically used to guide 
injections in this context do not appear to assist the clinician by isolating the extraocular EMG signal from 
interfering EMG signals, nor do they process the EMG signal to provide additional information such as 
confidence of location or proximity to the EOM.  This presents a potential opportunity to develop the 
technology and deliver benefits to patients with improved treatment efficacy. 
Considering this clear need for improvement, there is currently little evidence to support development of 
the EMG guidance technology used to treat strabismus with BTX.  Detailed analysis of extraocular muscle 
EMG obtained using a monopolar needle electrode is needed to identify feasible approaches in improving 
EMG needle guidance. 
This pilot study is an exciting opportunity to gain more knowledge and explore the hypothesis that there is 
a relationship between characteristics of the EOM EMG signal and the proximity of the needle to the rectus 
muscle belly.  This knowledge may then be used to develop a new needle guidance technology, potentially 
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2 STUDY OBJECTIVES 
The principal objective is to identify any signal characteristics that could potentially be indicative of the 
location of the EMG needle with respect to the target muscle. 
A secondary objective is to indicate the value of developing the technology of EMG needle guidance in this 
application, and inform the design of any future research. 
3 STUDY DESIGN 
This is a cross-sectional observational study. 
3.1 
MATERIALS 
The key equipment and software required are: 
• 
EMG Signal Capture System, comprising: 
o A USB powered bio-signal acquisition device to capture the EMG signal; 
o A buffer device to allow the EMG signal to be detected; 
o A USB camera (webcam) to record audio and video of the procedure; 
o An office laptop to drive the signal acquisition device and camera; 
o Acquisition software to capture the EMG signal and event markers; 
• 
R software environment for statistical computing and graphics. 
• 
MATLAB software environment for data analysis and software development. 
Further details of the EMG signal capture system, including specification analysis, are in APPENDIX 1: EMG 
SIGNAL CAPTURE SYSTEM. 
3.2 
METHOD 
The study involves recording data during routine treatment of strabismus using EMG guided needle 
injection of BTX.  The current procedure involves amplifying the EMG signal detected at the needle, which 
is used by the clinician to guide the needle.  The pilot study will record this EMG signal onto computer, in 
addition to some other data available during or after the procedure.  The data to be captured is: 
Data 
Detail 
Justification 
EMG signal 
EMG signal throughout procedure, from just 
prior to initial contact of needle with conjunctiva 
through to final withdrawal of needle from 
conjunctiva following delivery of BTX 
To facilitate processing and 
analysis of EMG waveform 
Needle event 
markers 
The points in the recording when: the needle 
contacted the conjunctiva; where the needle is 
considered by the clinician to be ‘on target’; 
when BTX was delivered; and when the needle 
To help distinguish ‘on target’ 
and ‘off target’ regions of the 
EMG waveform 

 
 
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was withdrawn 
Audio / video 
recording 
An audio and video recording of the procedure 
showing needle position and patient’s eye 
position 
To help distinguish ‘on target’ 
and ‘off target’ regions of the 
EMG waveform 
Clinical scores 
Post-procedure, the clinician’s score of: 
• 
The step change from baseline EMG to 
‘active’ EMG level heard immediately prior 
to delivery of BTX, from 1 to 5: 
1 – No significant step change heard; 
2 – Possible step change heard, not at all 
clear; 
3 – Unambiguous step change but not 
clear; 
4 – Somewhat clear step change heard; 
5 – Very clear step change heard. 
• 
Confidence in accurate needle placement, as 
a percentage; 
• 
Overall quality of the EMG signal heard 
during the procedure, from 1 to 5: 
1 – Signal not present 
2 – Poor quality 
3 – Adequate quality 
4 – Good quality 
5 – Excellent quality 
To help evaluate signal 
processing and statistical 
analysis outcomes 
Patient / 
procedure meta-
data 
• 
Patient age 
• 
Units of BTX injected 
• 
The target muscle (lateral or medial, left of 
right) 
• 
Any known contraindications to optimal EMG 
needle guidance, e.g. scar tissue around the 
target muscle 
• 
Whether: 
o The patient is repeat or ‘routine’, where 
no follow-up is planned and the patient 
has been seen at least once before for 
the same treatment; or 
o The patient is ‘new’, and has not 
previously received BTX for the 
treatment of strabismus by Mr Yagan. 
• 
Approximate distance between the centre of 
the reference skin electrode and the needle 
insertion point 
• 
The outcome of the routine skin electrode 
impedance check 
To include potential 
characteristics for statistical 
analysis and help identify 
potential causes of outliers 
Patient pre-
Typically measured in units of prism dioptres 
To allow comparison of signal 

 
 
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treatment angle 
of deviation 
characteristics with the amount 
of improvement in deviation, 
and help evaluate signal 
processing and statistical 
analysis outcomes 
 
There will also be follow-up for each patient, within four weeks, but typically around two to three weeks 
following treatment.  This is current practice for new patients and is an additional requirement for repeat 
patients.  The data recorded during the follow-up is: 
Data 
Detail 
Justification 
Patient post-
treatment angle of 
deviation 
Typically measured 
in units of prism 
dioptres 
To allow comparison of signal characteristics with the 
amount of improvement in deviation, and help evaluate 
signal processing and statistical analysis outcomes 
 
Once the data has been captured, processing and statistical pattern recognition of the recorded data will 
address the study objectives. 
Duration: up to 20 weeks.  Mr Yagan’s clinic takes place every two weeks and each list includes 
approximately seven patients.  If five successful recordings are made per clinic, 25 recordings will be made 
over a period of 10 weeks; allowing an additional four weeks for follow-up and four weeks contingency 
equates to 20 weeks.  Data processing and analysis will take place once the study has ended.  See Section 
9.2 for a Gantt chart. 
Subjects: Signals will be recorded from 25 adult patients receiving treatment for strabismus with EMG 
guided injection of BTX. 
3.3 
LOCATION 
All recording will take place at: 
Manchester Royal Eye Hospital 
Oxford Road 
Manchester M13 9WL. 
Data processing and analysis will take place at: 
Medical Physics & Clinical Engineering 
Royal Liverpool Hospital 
Royal Liverpool & Broadgreen University Hospitals NHS Trust 
Duncan Building, 1st Floor 
Prescot Street 

 
 
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Liverpool L7 8XP. 
3.4 
PERSONNEL 
The procedure being observed will be carried out by Mr Yagan.  There are no training needs identified for 
this protocol. 
Pre-treatment and post-treatment angle of deviation measurements and other patient data as required by 
the Method will be provided by an orthoptist.  There are no training needs identified for this protocol. 
The data recording will be carried out by Dr Payne.  There are no training needs identified for this protocol.  
Data analysis will be carried out by Dr Antonio Eleuteri. There are no training needs identified for this 
protocol. 
 
3.5 
STUDY OUTCOME MEASURES 
3.5.1 
Primary 
• 
The change in the EMG signal as the needle approaches, and enters, the target extraocular muscle. 
3.5.2 
Secondary 
• 
Clinician’s score of the step change from baseline EMG to ‘active’ EMG level heard immediately 
prior to delivery of BTX; 
• 
Clinician’s score of their confidence in accurate needle placement; 
• 
Clinician’s score of overall quality of the EMG signal heard during the procedure; 
• 
Change in patient’s angle of deviation following treatment. 
4 PARTICIPANT ENTRY 
4.1 
PRE‐REGISTRATION EVALUATIONS 
None, since this is an observational study. 
4.2 
INCLUSION CRITERIA 
i. 
Adults undergoing planned, routine EMG needle guided BTX injection into either lateral or medial 
rectus muscle for the treatment of strabismus. 
ii. 
Patients being treated by Mr Yagan.  This criterion will optimise consistency of recorded data, 
especially clinician’s opinion of needle placement and EMG signal quality. 
4.3 
EXCLUSION CRITERIA 
Patients with Chronic progressive external ophthalmoplegia (CPEO) are excluded; a highly attenuated EMG 
signal is expected. 

 
 
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4.4 
WITHDRAWAL CRITERIA 
Should the injection not be delivered for any reason, the participant will be withdrawn from the study. 
5 ADVERSE EVENTS 
5.1 
DEFINITIONS 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject. 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect that: 
• 
Results in death 
• 
Is life‐threatening – refers to an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were more 
severe 
• 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
Medical judgement should be exercised in deciding whether an AE is serious in other situations. Important 
AEs that are not immediately life‐threatening or do not result in death or hospitalisation but may jeopardise 
the subject or may require intervention to prevent one of the other outcomes listed in the definition above, 
should also be considered serious. 
Potential Adverse Events: 
i. 
EMG recording system interferes with existing EMG monitor used to guide the needle, 
preventing delivery of treatment.  In this case, the EMG recording system will be immediately 
disconnected from the EMG monitor and the procedure resumed. 
Potential Serious Adverse Events: none identified. 
5.2 
REPORTING PROCEDURES 
All adverse events should be reported. Depending on the nature of the event the reporting procedures 
below should be followed. Any questions concerning adverse event reporting should be directed to the 
Chief Investigator in the first instance. 
5.2.1 
Non serious AEs 
All such events, whether expected or not, should be recorded. 
5.2.2 
Serious AEs 

 
 
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An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  However, 
hospitalisations for elective treatment of a pre‐existing condition do not need reporting as SAEs. 
All SAEs should be reported to the North West – GM South REC where in the opinion of the Chief 
Investigator, the event was: 
• 
‘related’, i.e. resulted from the administration of any of the research procedures; and 
• 
‘unexpected’, i.e. an event that is not listed in the protocol as an expected occurrence 
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief Investigator 
becoming aware of the event, using the NRES SAE form for non‐IMP studies. The Chief Investigator must also 
notify the Sponsor of all SAEs. 
Local investigators should report any SAEs as required by their Local Research Ethics Committee, Sponsor 
and/or Research & Development Office. 
Contact details for reporting SAEs 
Fax: 0151 706 5803, attention Tristan Payne 
Please send SAE forms to:  
Medical Physics & Clinical Engineering 
Royal Liverpool Hospital 
Royal Liverpool & Broadgreen University Hospitals NHS Trust 
Duncan Building, 1st Floor 
Prescot Street 
Liverpool L7 8XP 
Tel: 0151 706 4223 (Mon to Fri 09.00 – 17.00) 
6 ASSESSMENT AND FOLLOW‐UP 
Follow-up for each patient is as set out in the Method (Section 3.2). 
7 STATISTICS AND DATA ANALYSIS 
EOM EMG signals will be characterised by time series analysis methods [14]: 
- 
Plotting 
- 
Estimation of autocorrelation function 
- 
Estimation of spectral density (to separate short-term and seasonal effects) 
- 
Model identification (information criteria) 
- 
Model fit (ARMA processes) 
Regression analysis techniques [15] will be employed to assess the relationships between EMG signal 

 
 
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characteristics (to be defined) and position of needle with respect to target location in EOM.  
An ordinal logistic regression model will be designed to estimate the expected value of the scores 
conditional on signal characteristics. 
Given the expected sample size of 25 subjects, it’s possible to empirically assess the maximum number of 
signal characteristics that can be used in the model formulation as 1/10th of the sample size [15], i.e. 2 
parameters (assuming an even spread of the scores across the subjects). 
Wald statistics and the Akaike Information Criterion will be used to assess the goodness of the fit, and 
discrimination and calibration measures of accuracy of the model will be estimated by bootstrap 
resampling. 
8 REGULATORY AND QUALITY ISSUES 
8.1 
SAFETY 
Risks to the patient and users of the EMG Capture System have been controlled through application of 
Medical Physics and Clinical Engineering’s Risk Management Procedure CD1451, which complies with BS EN 
ISO 14971:2012 – Risk Management for Medical Devices. 
8.2 
ETHICS APPROVAL 
The Chief Investigator has obtained approval from the North West – Liverpool East Research Ethics 
Committee and Health Research Authority (HRA) approval. The study will be submitted to each proposed 
research site for Confirmation of Capacity and Capability. The study will be conducted in accordance with 
the recommendations for physicians involved in research on human subjects adopted by the 18th World 
Medical Assembly, Helsinki 1964 and later revisions. 
The approving body will be kept informed as in Section 8.11. 
The ethical considerations of the project are viewed as minimal for the following reasons: 
• 
The study is non-interventional; 
• 
There is low impact on study participants, including a small change to procedure, an additional 
person present during the procedure and in some cases an additional follow-up visit; 
• 
There are no after-effects of participation; 
• 
The participant is not required to interact for the purposes of the study. 
8.3 
CONSENT 
Before the clinic session, an orthoptist will review the patient records for eligibility to enter the study.  
Patients are seen by the orthoptist prior to the procedure as part of standard care.  During this pre-procedure 
appointment, if the patient is eligible to participate in the study, the study will be explained to them and 

 
 
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they will be invited to take part.  They will be offered the Participant Information Sheet to read while they 
wait for the procedure, and will have at least 15 minutes to decide if they wish to take part.  Before the 
clinical procedure, the ophthalmologist Principal Investigator will address any questions or concerns, and if 
they wish to take part, obtain signed consent from the participant.  The Chief Investigator will securely hold 
a copy of the consent forms.  The right of the participant to refuse to participate without giving reasons 
shall be respected. 
After the participant has entered the study, the ophthalmologist remains free to deviate from the protocol 
at any stage if he feels it is in the participant’s best interest, but the reasons for doing so should be 
recorded. In these cases, the participants remain within the study for the purposes of follow‐up and data 
analysis.  
All participants are free to withdraw at any time from the study without giving reasons and without 
prejudicing further treatment.  If a participant withdraws their consent to take part in the study, their 
personally-identifiable data will be securely deleted; any anonymous data already collected will be retained. 
8.4 
CONFIDENTIALITY 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and 
will abide by the General Data Protection Regulation. 
All patient data including identifiable audio / video recordings will be recorded directly onto an encrypted 
laptop drive during the clinic.  After each clinic, the laptop and encrypted data stored on it will be 
physically transported by the Chief Investigator from Manchester Royal Eye Hospital to Royal Liverpool 
Hospital for processing and statistical analysis.  The data will be transferred from the laptop to the local 
NHS computer network as soon as practicable after the clinic, and the data immediately removed from the 
laptop encrypted drive. 
All data will be held by Medical Physics and Clinical Engineering, Royal Liverpool Hospital on secure, 
password protected and firewalled network facilities provided by the department.  Security arrangements 
include nightly backups and access controls to restrict access to those who need it.  Analysis will be carried 
out within Medical Physics and Clinical Engineering, Royal Liverpool Hospital, by the Chief Investigator (Dr 
Payne) and the Statistician (Dr Eleuteri).  Personal, identifiable data will only be used for this study, and all 
steps reasonably necessary will be taken to ensure such data will only be disclosed to those involved in the 
study that have a need in relation to this study. 
Within three months of the end of the study, following analysis of the data, all personal identifiable data 
will be destroyed.  Video recordings will be deleted, and any identifiable or pseudonymous participant 
identifiers will be removed.  All deleted data will also be removed from any backups.  The remaining 
anonymous data will be stored securely for three years, after which it will be destroyed; similarly, it will be 
removed from any backups.  The anonymous data will be held for this period as it may contribute to a 
further, larger study if this pilot study indicates that additional research is required.  This may reduce the 

 
 
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number of participants required in subsequent research. 
The data custodian will be Dr Tristan Payne, Royal Liverpool Hospital. 
8.5 
INDEMNITY 
This study is covered by NHS indemnity. 
8.6 
SPONSOR 
The Royal Liverpool and Broadgreen University Hospitals NHS Trust will act as Sponsor for this study. It is 
recognised that as an employee of the Trust, the Chief Investigator has been delegated specific duties, as 
detailed in the Sponsorship Approval letter. 
8.7 
FUNDING 
Medical Physics and Clinical Engineering, Royal Liverpool Hospital are funding direct costs and Royal 
Liverpool staff opportunity costs. 
8.8 
AUDITS 
The study may be subject to inspection and audit by Royal Liverpool and Broadgreen University Hospitals 
NHS Trust  under their remit as sponsor and other regulatory bodies to ensure adherence to GCP and the 
NHS Research Governance Framework for Health and Social Care (2nd edition). 
8.9 
REGULATORY APPROVAL 
The study is not required to be registered with the MHRA as it is not a clinical investigation of a new 
medical device. 
8.10 LOCAL APPROVAL 
Local approval will be sought from Royal Liverpool Hospital and Manchester Royal Eye Hospital Research & 
Development departments following local procedures. 
8.11 COMMUNICATION PLAN 
Stakeholders will be kept informed by the Chief Investigator as follows: 
Activity 
Principal 
Investigator 
at 
Manchester 
Royal Eye 
Hospital 
Royal Liverpool 
R&D (Sponsor) 
Manchester Royal 
Eye Hospital R&D 
Health Research 
Authority 
Study protocol 
Consult 
Seek approval 
Seek approval 
Seek approval 

 
 
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Non-substantial 
deviations1 from 
protocol 
Consult 
Inform 
Inform 
Inform at end of 
study 
Substantial deviations 
from protocol 
There will be no intentional substantial deviations from the protocol.  
Substantial changes must be made by approved amendment to the protocol.   
Any unintentional substantial deviations will result in the study being 
suspended while the Ethics Committee is informed and a protocol 
amendment made if appropriate. 
Non-substantial 
changes2 of any 
documentation already 
approved by the Ethics 
Committee 
Inform 
Inform 
Inform 
Inform 
Substantial changes3 
(amendments) of any 
documentation already 
approved by the Ethics 
Committee 
Consult 
Seek approval 
Seek approval 
Seek approval 
Premature ending of the 
study 
Consult 
Inform 
Inform 
Inform 
Planned end of study 
Inform 
Inform 
Inform 
Inform 
Outcome of study 
Inform 
Inform 
Inform 
Inform 
 
8.12 PROTOCOL AMENDMENTS 
Amendments to this protocol will be subject to approval as set out in the Communication Plan (Section 
8.11). 
The protocol version (m.n) will be updated in the event of any change after version 1.0, the first externally 
communicated.  Minor changes will be identified by increase to n, while major version updates will be 
identified by an increase to m. 
8.13 STUDY EVALUATION 
Following completion of the study, the study will be evaluated by reflecting on the process and outputs as 
an opportunity for learning and future improvement.  The Chief Investigator is responsible for carrying out 
                                                          
 
1 Not affecting the rights, safety and well-being of human subjects and not related to the study objectives or 
endpoints 
2 e.g. minor logistical or administrative changes, telephone numbers, renewal of insurance 
3 Affecting patient’s rights, safety and well-being, or the scientific integrity of the study 

 
 
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the evaluation, which will ideally take the form of a reflective meeting with those involved. 
8.14 RISKS TO COMPLETION OF STUDY 
Impact 
High Sponsorship cannot be 
agreed 
 
 
Medium 
EMG Capture System is 
not suitable for the 
intended environment 
Patients are not 
recruited at anticipated 
rate due to lower than 
expected throughput of 
clinic, or fewer patients 
consent to recording of 
data 
 
Low  
 
 
 
 
Low 
Medium 
High 
 
 
Probability 
 
Mitigating actions are: 
• 
Sponsorship cannot be agreed: sponsorship to be sought at earliest opportunity from Royal 
Liverpool Hospital. 
• 
Patients are not recruited at anticipated rate: three week contingency included in time scales. 
• 
EMG Capture System is not suitable for the intended environment: the system will be tested in the 
intended environment before the first patient is recruited to identify any use or environmental 
issues. 
8.15 QUALITY PLAN 
In developing the EMG Capture System, a design lifecycle process will be followed using Medical Physics & 
Clinical Engineering Quality Management System procedures and templates where available, including: 
i. 
Requirements Analysis, capturing the needs of this study on the EMG Capture System. 
ii. 
Requirements Specification, capturing the technical and quality requirements of the EMG Capture 
System. 
iii. 
Design, capturing the choice of components to the EMG Capture System. 
iv. 
Build. 

 
 
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v. 
Design Verification, testing the technical performance of the solution. 
vi. 
Design Validation 
Risks will be managed by following the Department’s Risk Management Procedure, as discussed in Section 
8.1. 
The project will be managed as described in this protocol. 
9 STUDY MANAGEMENT 
9.1 
RESOURCES 
At Manchester Royal Eye Hospital, required practical provisions are: 
• 
Access to the clinical procedure room for the duration of the clinic; 
• 
Space to accommodate the EMG Signal Capture System, camera and researcher operating the 
system; 
• 
Provision for follow-up assessment of patients. 
At Liverpool Royal Hospital, provisions are made for: 
• 
Data processing and pattern recognition software, as required; 
• 
Secure storage of data. 
The day‐to‐day management of the study will be coordinated by the Chief Investigator at the Royal Liverpool 
Hospital. 
9.2 
TIMESCALES 
 
Milestones: 

 
 
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All approvals in place – study ready to start 
20/12/2018 
Begin patient recruitment and data recording 
10/01/2019 
Last patient follow-up 
17/04/2019 
 
9.3 
COSTS 
Direct costs 
 
  BIOPAC MP45 device and software 
£2014 
  R and MATLAB software (free / license in-hand) 
£0 
  Travel  
£200 
  Contingency 
£500 
  TOTAL Direct Costs:  
£2714 
Opportunity costs 
 
  Clinical Engineer (Tristan Payne) 0.1 FTE 8a for 12 
months 
£6000 
  Statistician (Antonio Eleuteri) 8c for 1 week 
 
£1600 
TOTAL:  
£10,314 
 
All above direct and opportunity costs will be met by Medical Physics & Clinical Engineering, Royal Liverpool 
Hospital. 
10 END OF STUDY 
The study will formally end when the follow-up has been completed for the last participant.  At the end of 
the study, a Project Evaluation will be carried out, as discussed in Section 8.13. 
11 ARCHIVING 
All appropriate documentation will be archived by the Chief Investigator and stored securely in Medical 
Physics & Clinical Engineering for a minimum of five years after the completion of the study.  Anonymous 
participant data will be retained as set out in Section 8.4. 
12 PUBLICATION POLICY 
The results will be reported internally and used to decide if further research in the area is justified. 
The results may be disseminated to the scientific community via an appropriate journal publication and/or 
a conference presentation, authored by the investigators and statistician, with acknowledgement given to 
any other people supporting the research at either site. 
13 REFERENCES 
[1] 
J. M. Durnian, C. P. Noonan, and I. B. Marsh, ‘The psychosocial effects of adult strabismus: a review’, 

 
 
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Br. J. Ophthalmol., vol. 95, no. 4, pp. 450–453, Apr. 2011. 
[2] 
A. B. Scott, ‘Botulinum toxin injection of eye muscles to correct strabismus.’, Trans. Am. Ophthalmol. 
Soc., vol. 79, pp. 734–770, 1981. 
[3] 
M. K. Childers, ‘The importance of electromyographic guidance and electrical stimulation for injection 
of botulinum toxin’, Phys. Med. Rehabil. Clin. N. Am., vol. 14, no. 4, pp. 781–792, Nov. 2003. 
[4] 
X.-M. Wan, R.-X. Chu, and H.-Q. Gong, ‘Minimally invasive botulinum toxin type A injection from the 
ocular surface to extraocular muscles’, Int. J. Ophthalmol., vol. 4, no. 2, pp. 179–181, Apr. 2011. 
[5] 
T. G. Payne, ‘Redevelopment of a CE marked needle guidance device for the treatment of strabismus 
(MSc Thesis)’, King’s College London, 2016. 
[6] 
Å. Björk, ‘Electrical activity of human extrinsic eye muscles’, Experientia, vol. 8, no. 6, pp. 226–227, 
Jun. 1952. 
[7] 
J. Kim et al., ‘Development of an assistance system for the Botox procedure of patients with 
strabismus’, in 2011 4th International Conference on Biomedical Engineering and Informatics (BMEI), 
2011, vol. 2, pp. 1086–1088. 
[8] 
T. Ajax, M. A. Ross, and R. L. Rodnitzky, ‘The role of electromyography in guiding botulinum toxin 
injections for focal dystonia and spasticity’, Neurorehabil. Neural Repair, vol. 12, no. 1, pp. 1–4, 1998. 
[9] 
S. H. M. Brown, R. L. Brookham, and C. R. Dickerson, ‘High-pass filtering surface EMG in an attempt to 
better represent the signals detected at the intramuscular level’, Muscle Nerve, vol. 41, no. 2, pp. 
234–239, Feb. 2010. 
[10] J. L. Trimble, B. L. Zuber, and S. N. Trimble, ‘A Spectral Analysis of Single Motor Unit Potentials from 
Human Extraocular Muscle’, IEEE Trans. Biomed. Eng., vol. BME-20, no. 2, pp. 148–151, Mar. 1973. 
[11] D. G. Hunter, T. Nguyen, S. N. Patel, and M. X. Repka, ‘Automated analysis of electromyographic 
(EMG) recordings during botulinum injections’, J. Pediatr. Ophthalmol. Strabismus, vol. 33, no. 5, pp. 
241–246, Oct. 1996. 
[12] L. Werdelin et al., ‘The utility of EMG interference pattern analysis in botulinum toxin treatment of 
torticollis: A randomised, controlled and blinded study’, Clin. Neurophysiol., vol. 122, no. 11, pp. 
2305–2309, Nov. 2011. 
[13] T. T. Pham, A. J. Fuglevand, A. L. McEwan, and P. H. W. Leong, ‘Unsupervised discrimination of motor 
unit action potentials using spectrograms’, in 2014 36th Annual International Conference of the IEEE 
Engineering in Medicine and Biology Society, 2014, pp. 1–4. 
[14]   W. N. Venables, B. D. Ripley, Modern Applied Statistics with S. 4th Edition. Springer. 2002. 
[15]   F. E. Harrell Jr., Regression Modeling Strategies. Springer. 2001. 
 
14 VERSION CONTROL 
Version 
No. 
Date 
Issued 
Author(s) 
Change Description 
0.4 
17/01/2018 AE 
Added statistical and data analysis section. Added references. 
0.5 
18/01/2018 TP 
Added full title, clarified data collected in Methods section, 
added section 8.15 Quality Plan, various minor changes 
1.0 
08/02/2018 TP 
Added follow-up. 
1.1 
27/03/2018 TP 
Added CPEO Exclusion Criterion (Section 4.3).  Added inter 
electrode distance and impedance test meta data (Section 
3.2).  Refined Quality Plan (Section 8.15).  Revised timescales 

 
 
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(Section 9.2).  Data archiving changed to minimum 5 years 
(Section 11). 
1.2 
02/05/2018 TP 
Replaced Royal Liverpool Hospital with full RLBUHT name.  
Corrected Sponsor details (page 3).  Corrected version control 
(Section 8.12) 
1.3 
02/05/2018 TP 
Replaced indemnity with NHS indemnity (Section 8.5).  
Replaced sponsor as RLBUHT (Section 8.6 and 8.8). 
1.4 
10/05/2018 TP 
Removed MREH as source of funding (page 1 and 2, Section 
8.7).  Study title revised to specify “data collection and 
analysis” instead of observational.  Revised timescales 
(Section 9.2). 
1.5 
12/07/2018 TP 
Minor clarifications to organisation and contact details; 
minor grammar corrections; Section 3.2, follow-up specified 
within four weeks; Section 8.11 added MREH PI as 
stakeholder; Section 8.12 added approval of amendments 
communication plan; Section 8.15 added Design Validation; 
Appendix 1 Section 15.1 revised Recording System diagram to 
include Buffer and replaced BSLCBL8 with SS2LB cable, PSU 
not removed from laptop before patient connection, system 
tested for electrical safety; Section 15.2.2 added stage to 
bypass buffer and isolate MP45 for impedance check; Section 
8.4 reworded to clarify data protection, analysis and 
reference to new GDPR; Section 12 added internal report and 
conference presentation; Study Outcome Measures 
rewritten, Section 3.5; Consent, Section 8.3, reworded to 
clarify procedure and handling of consent withdrawal, 3 year 
data storage; Archiving Section 11 revised; title: EMG 
expanded; Introduction Section 1 rearranged for clarity; 
Objectives Section 2 rewritten to main plus secondary 
objective; Materials Section 3.1 updated with buffer; Ethics 
approval Section 8.2 corrected reference to anonymous data 
and added follow-up visit; Costs Section 9.3 minor correction; 
Personnel Section 3.4 reference to orthoptist in place of Ms 
Nichol; Inclusion Criteria Section 4.2 reference to Allergan 
removed. 
1.6 
25/07/2018 TP and AE 
Minor changes; Method Section 3.2 clarified scoring; 
Statistics and Data Analysis Section 7 replaced binary class 
label with scoring and ordinal logistics regression model 
1.7 
06/09/2018 TP 
Minor changes: removed reference to BOTOX®, replaced with 
BTX; Ethics Section 8.2 specified REC name; detailed 
procedure Section 15.2.2 revised to include Buffer Box 
ByPass following review of Risk Log. 
1.8 
21/11/2018 TP 
Revised Timescales Section 9.2 to reflect progress to date and 
added milestones table. 

 
 
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15 APPENDICES 
15.1 APPENDIX 1: EMG SIGNAL CAPTURE SYSTEM 
 
Figure 1 - EMG Signal Capture System Schematic 

 
 
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Equipment: 
• 
EMG-3 is existing EMG monitor (Royal Liverpool Hospital, UK) 
• 
SS2LB is input connection adapter (BIOPAC Systems, Inc., CA, USA) 
• 
MP45 is 2 channel data acquisition device, USB powered (BIOPAC Systems, Inc., CA, USA) 
• 
Buffer is custom made device (MPCE) 
• 
Camera is standard webcam, e.g. HD 720P VIVEO (Trust International B.V., The Netherlands)  
• 
Laptop is standard office laptop, e.g. B590 (Lenovo, Hong Kong) 
• 
PSU is standard laptop mains adapter/charger for above laptop 
NOTES: 
• 
EMG-3 will be positioned on a trolley close to the patient’s head as is current practice; the EMG 
Capture System (SS2LB, MP45, buffer and Laptop) will be located on the same trolley, or a second 
trolley positioned adjacent to the first. 
• 
EMG cables are to be bundled (twisted/plaited/clipped) where possible, especially between EMG-3 
and SS2LB, to reduce possibility of inducing additional noise. 
• 
All cables are to be coiled where possible and the system cabling kept tidy to reduce the risk from 
slips or blunders. 
• 
All recorded data will be stored in encrypted format, either on the laptop or on a memory stick. 
SYSTEM SPECIFICATIONS ANALYSIS: 
Specification Representative 
Requirement 
EMG Signal Capture System 
Outcome 
Electrical 
Safety 
Meets or 
exceeds CE 
marked 
Medical Device 
standards 
MP45 complies with IEC 60601-1 Medical Electrical 
Equipment General Requirements for Basic Safety and 
Essential Performance 
 
MP45 complies with IEC 60601-1-2 Medical electrical 
equipment. General requirements for basic safety and 
essential performance. Collateral Standard. 
Electromagnetic disturbances. Requirements and tests. 
 
MP45 is CE marked for compliance with the Low 
Voltage and Electromagnetic Compatibility directives. 
 
System tested for Electrical Safety to IEC 60601-1 
standard 
Requirement 
met 
Input 
impedance 
> 10 MOhm 
SS2LB has input impedance of 11 MOhm (DC), 2 MOhm 
(differential) and 1 GOhm (a.c. 50 Hz) 
Requirement 
met 
Input 
voltage 
> 10 uV 
MP45 has input range adjustable from ± 200 μV to ± 2 V 
Requirement 
met 

 
 
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Sampling 
frequency 
> 10 kSps 
(samples per 
sec) 
MP45 records max rate  48 kSps per channel 
Requirement 
met 
Input 
bandwidth 
>5 kHz 
MP45 provides adjustable lowpass filter, highest setting 
8 kHz 
Requirement 
met 
Resolution 
0.01 uV 
MP45 digitises using 16 bit, resulting in resolution of 
0.006 uV at 400uV p-p 
Requirement 
met 
 
15.2 APPENDIX 2: DETAILED METHOD 
15.2.1 Preparation 
Before the patient is moved into the clinical procedure room: 
i. 
The EMG signal capture system is installed in the clinical room and connected to the EMG monitor. 
ii. 
The researcher operating the EMG signal capture system ensures that EMG cables between the 
EMG monitor and the capture system are bundled together where possible to reduce induced 
interference; 
iii. 
A brief test is carried out to verify the EMG signal capture system operates as expected; 
iv. 
Anonymous details of the patient and treatment as set out in Section 3.2 are recorded at this point, 
or post-procedure. 
15.2.2 EMG Signal Capture 
After the patient is brought into the clinical procedure room: 
i. 
The power supply from the MP45 to the Buffer Box is disconnected at the MP45; this is to reduce 
the chance of a falsely positive impedance test. 
ii. 
The patient is prepared for treatment in the usual way, including connections to the EMG monitor 
and check of skin electrode impedance using the EMG-3 monitor while holding down the Bypass 
switch on the Buffer Box. 
iii. 
The camera is positioned to capture the eye being treated only; 
iv. 
The power supply from the MP45 to the Buffer Box is reconnected and the Bypass switch is 
confirmed to be released. 
v. 
Prior to contact between the needle and the conjunctiva, the EMG signal capture system is 
triggered to begin recording EMG and the video/audio recording is started; 
vi. 
During the procedure, the timing of events in Section 3.2 is recorded. 
vii. 
The patient is disconnected from the recording system. 
15.2.3 Post-Procedure 
i. 
Information from the clinicians regarding the procedure and EMG signal heard is captured.