Malay Glaucoma Eye Study II Navigation, Mobility and Reading Ability in Primary Glaucoma

Objectives General objective: to develop, validate and evaluate the effectiveness of navigation, physical activities and reading abilities (the new rehabilitation protocols) in Malay adults with primary glaucoma.

Specific objectives:

1. To identify problems with navigation, physical activities and reading in Malay adults with primary glaucoma
2. To develop and validate the new rehabilitation protocols for patients with primary glaucoma
3. To evaluate the effectiveness of the new rehabilitation protocols in improving the quality of life of primary glaucoma patients
4. To evaluate the mean changes of total antioxidant level pre- and post-intervention with the new rehabilitation protocols in primary glaucoma patients
5. To evaluate the changes of ocular parameters pre- and post-intervention with the new rehabilitation protocols in primary glaucoma patients Research design

This research project will be divided into 3 phases with different research designs:

Phase 1: case control study on factors affecting navigation, physical activities and reading between primary glaucoma patients and age matched controls.

Phase 2: development and validation study on new rehabilitation program for navigation, physical activities and reading.

Phase 3: randomized control trial study to evaluate the effectiveness of rehabilitation program and exercise on clinical parameters, quality of life and oxidative stress of primary glaucoma patients.

Study area

1. Glaucoma clinic for patient recruitment, assessment and follow up in:

Hospital Universiti Sains Malaysia (HUSM), Kota Bharu, Kelantan, Malaysia Hospital Raja Perempuan Zainab II (HRPZII), Kota Bharu, Kelantan, Malaysia Hospital Sultanah Bahiyah (HSB), Alor Setar, Kedah, Malaysia Hospital Melaka, Melaka, Malaysia

1. Occupational rehabilitation, Rehabilitation Unit for visual rehabilitation program in:

Hospital Universiti Sains Malaysia (HUSM) Kota Bharu, Kelantan, Malaysia Hospital Raja Perempuan Zainab II, Kota Bharu, Kelantan, Malaysia Hospital Sultanah Bahiyah, Alor Setar, Kedah, Malaysia Hospital Melaka, Melaka, Malaysia Study population Reference population: Primary glaucoma patients-primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) Target population: Primary glaucoma patients (POAG and PACG) who attended glaucoma clinic in HUSM, HRPZII, HSB and Hospital Melaka Source population: Patients aged 40 to 70 years old diagnosed with POAG or PACG who are attending the glaucoma clinic, HUSM, HRPZII, HSB and Hospital Melaka from June 2020 until February 2020.

Sampling frame: Glaucoma database in eye clinic of HUSM, HRPZII, HSB and Hospital Melaka Sampling method and subject recruitment The sampling method is based on the specific objective and phases of the study For objective 1: a simple random sampling will be used. For objective 2: convenience sampling.

For objective 3, 4 and 5: randomized Controlled Trial will be conducted. Using block randomization method with sequentially numbered in opaque sealed envelopes (SNOSE), the eligible patients will be randomized into:

Group A: Intervention group Group B: Non-intervention group Primary investigators (Postgraduate students) will be blinded.

Operational definition Primary Open Angle Glaucoma (POAG): A chronic, progressive optic neuropathies that characterised by structural changes in the optic nerve head and/ or with visual field defect without identifiable causes (Asia Pacific Glaucoma guidelines, 2008).

Primary Angle Closure Glaucoma (PACG): An eye with an occludable drainage angle and features indicating that trabecular obstruction by the peripheral iris has occurred, such as peripheral anterior synechiae, elevated intraocular pressure and optic neuropathy (Foster et al., 2002).

Target Intraocular pressure: Target intraocular pressure throughout this study is dependent on severity of the disease based on threshold IOP (Sihota et al., 2018). In this study, target intraocular pressure will be personalized accordingly.

Lens status: Phakic is defined as patients with an intact natural lens without visually significant cataract. A person with visually significant cataract was defined by having, in either eye: any LOCS II grading of ≥2, best-corrected visual acuity of <6/12 in the cataractous eye, cataract as primary cause of vision impairment in that eye, and patient report that general vision was fair, poor, very poor, or blind (Ritcher et al, 2009). Pseudophakic refers to patients who have underwent lens extraction procedure with implantation of artificial intraocular lens for more than 3 months prior to recruitment.

Compliance to treatment: Patients who adhere and persistent to instillation of topical intraocular pressure lowering medications as recommended by their physician throughout follow up (Robin et al, 2011). Adherence is defined as less than 3 times missed their medication in a week. Persistence is defined as continuously on prescribed medication for more than 3 months.

Visual rehabilitation: The process of treatment and education that helps individuals who are visually disabled to attain maximum function, a sense of wellbeing, a personally satisfying level of independence, and optimum quality of life (American Optometric Association, 2004).

Reading speed: rate at which a person reads written text (printed or electronic) in a specific unit of time (Muñoz B et al, 2000).

In this study, the definition of reading speed will differ according to the task of reading and the reading material.

1. Reading speed in reading the Bahasa Malaysia reading chart: number of words read per minute
2. Reading the newspaper print and pharmacy label print: time taken to finish a reading task in minute
3. Reading book: number of pages read per hour/day Eye movement during reading: movement of the eye between the start of first saccade and the end of final saccade during the reading (Muñoz B et al, 2000).

Head movement during reading: all head movement during reading including of modulatory-velocity component with eye saccades and constant-velocity component independent of eye saccades (Muñoz B et al, 2000).

Quality of life: The term "quality of life (QoL)" is defined by the World Health Organization as individuals' perception of their position in life in the context of culture and value systems in which they live in relation to their goals, expectations, standards and concerns (World Health Group, 1995). Total scoring and each domain score of Bahasa Malaysia version GlauQoL -36 questionnaires will be used to determine the QoL. It has been translated and validated and piloted in 96 samples. All 36 translated questions were retained as the Cronbach alpha was found to be 0.85 (Chandramohan et al, 2015).

Depression: a feeling of depressed mood or loss of interest with at least five out of nine symptoms present for a diagnosis of major depression. The mGDS 14 questionnaire was used in this study to assess depression among primary glaucoma patients.

Bump: body contact above the knee, excluding the hands-on adjacent objects. Stumble: a change in posture or gait due to contact with an object below the knee.

Data collection method

This study will be divided into three phases:

1. Phase 1: identification factor affecting navigation, physical activities \& reading
2. Phase 2: development and validation of rehabilitation for navigation, physical activities \& reading
3. Phase 3: evaluation of the effectiveness of rehabilitation on clinical parameters, quality of life and oxidative stress Phase 1 A case control study will be conducted involving POAG and PACG patients with different severity according to Esterman binocular visual field. An age-matched control subjects will also be recruited. We estimated a sample size of 40 glaucoma subjects and 40 age-matched controls. Selected patients must be physical and mentally fit. Simple random sampling will be applied to patients who attend ophthalmology clinic for other ophthalmological conditions except for glaucoma especially those who were on follow-up for dry eye, non-visually significant cataract, pseudophakic patients. Patients that fulfil the inclusion and exclusion criteria will be selected during their follow up. These patients will be grouped as controls.

Ocular examination: Baseline examination will be conducted in all subjects including visual acuity assessment, contrast sensitivity, stereoacuity and Esterman binocular visual field.

Navigation \& physical activities: A stimulated area will be created using the existing facility in occupation rehabilitation unit, HUSM. Similar set up will be conducted in HRPZII, Hospital Sultanah Bahiyah and Hospital Melaka. Glaucoma patients and age-matched control subjects will be asked to navigate in the stimulated area and several areas will be equipped with closed circuit television (CCTV).

A predefined obstacle course navigation will be used to measure mobility performance among glaucoma and control groups. Subjects will be instructed to walk through the course as quickly and safely as possible while avoiding all obstacles in their path. The course will be constructed in a maze form, 30m length in total and seeded with obstacles made with styrofoam that represent objects in a patient's home environment. The illumination along the path range from 100 to 300 lux. Before walking through the course, participants will be given instructions and directions to ensure that they understood the path.

Mobility performance will be assessed by the time required to complete the obstacle course and the number of mobility incidents, which included bumps, stumbles, and orientation problems. A bump will be defined as a body contact above the knee, excluding the hands. A stumble will be defined as a change in posture or gait due to contact with an object below the knee. An orientation problem will be defined as a change in direction that was not consistent with the instructions. A trained observer will be following the participants closely behind to record time and bumps. Surveillance system comprising video camera to record the activities will be implemented as well. Errors are quantified on a 3 point scale, where errors were scored as 1 point if the subject made contact with an obstacle but was able to correct in ≤ 5 sec, 2 points if the subject took 5-15 sec to correct errors, and 3 points if the subject took > 15 sec to self-correct or required the assistance of one of the research assistants to correct the error. Travel time will be converted into walking speed (meters per second) by dividing the distance of established travel path by the time to complete the course. The converted measure permits a direct comparison of mobility performance across other routes and studies.

Special exercise: A special exercise will be designed that is safe for person with constricted visual field; combination of isometric and aerobic exercise. IOP will be taken at baseline and at certain phases of the exercise. If there is an increase of more than 20% from baseline IOP at certain phase of the exercise, that phase will be excluded or replaced accordingly.

Reading: Subject will be asked to read at 40cm (reading distance) with the reading material on a special pedestal. Reading materials include:

1. Universiti Teknologi Mara -Malay related words (UiTM-MrW)
2. Universiti Teknologi Mara- Malay unrelated words (UiTM-MuW)
3. Different sizes of text of common reading materials (Bahasa Malaysia):

• Pharmacy label print (0.131° print)
• Newspaper print size (0.26° print)
• Small newspaper headline/heading size (0.525° print)
• Large newspaper headline size (1.71° print)

1. A book in Bahasa Malaysia will be selected Reading speed will be assessed using Matlab version 8.3 programme. Eye and head trackers will be used (Polhemus Visiontrak Desktop 300) to document the head and eye movement. Reading will be done in a fix light intensity (500-600lux). A rehabilitation reading regime with or without low vision aid will be designed.

Phase 2

From phase 1 findings, a special rehabilitation device and programme will be designed for:

1. Navigation and mobility
2. Exercise
3. Reading A user friendly and inexpensive device and program with minimal usage of low vision aid will be designed and piloted for 30 glaucoma patients and 30 controls. Simple random sampling will be applied on the patients and control subjects recruited for phase 1 study. An advertisement is also attached here(phase 2).

Devices will include wearable body sensor vibrator and special smartphone apps for recognition of objects. The control subject will be using the special glasses (available in the department) that simulated constricted visual field. For the pilot study, the effectiveness will be considered based on the evaluation conducted for phase 1. The recruited subjects will be asked to practice according to the rehabilitation protocol for 2 weeks. Improvement will be made based on the outcome of the pilot study.

Validation process:

After development or modification of the program, the recruited subjects will be trained and asked to perform it at home for two weeks. They will be provided with a dairy (to ensure that they have conducted it daily). They will be seen after two weeks and the rehabilitation method will be assessed using specific questionnaire. Tentative questionnaire is attached here.

Navigation and physical activities- Any step of the program will be eliminated from the program if it is deemed dangerous (20% of the subjects reported bumping, stumbling, fall or near fall), difficult to manoeuvre (20% of the subjects have difficulty or expressed difficulty in performing the step) and impractical (20% of the subjects expressed infrequent of performing the step at home). Assessment will be made based on simple questionnaire, which will be made once the rehabilitation program has been developed.

Exercise - IOP will be obtained from the patients before and 10min after performing each important step of the exercise using tonometer. If any step of the exercise cause elevation of IOP of more than 2mmHg from the baseline IOP will be eliminated and replaced (if deem necessary). Patients will also be asked on the feasibility and practicality using the questionnaire.

Reading- if the reading material (book) is found to difficult, the material will be replaced. Any new movement of the eye or head that is scored difficult to manoeuvre or impractical will be removed. A questionnaire with Likert score scoring will be developed after completion of phase 1.

Definition of acceptable rehabilitation regime are as below:

Navigation and physical activities- reduction of at least 40% of bumping or stumbling to objects or fall in simulated area. An increase of 40% of total step per day based on accelerometer.

Exercise - An increase of 30% of based on accelerometer. Reading -An increase of 20% of reading task and reading speed.

Phase 3

A randomized single blinded control trial study will be conducted using the newly developed rehabilitation programme from phase 2. A known case of POAG and PACG patients who are compliance to treatment and follow up will be selected. Patients involved in phase 1 will not be recruited into this study. A total of 300 patients will be involved (100-navigation and mobility, 100- exercise and 100-reading). Based on the most recent reliable Humphrey visual field, only those who has more than 10 degree from fixation using Estermann binocular analysis will be selected. Other selection includes best corrected visual acuity of 6/60 on the better seeing eye, pseudophakic or phakic (without visually significant cataract) and without history of surgical intervention 3 months prior to recruitment. Those with severe hearing impairment, physical disabilities such as stroke, limbs amputation, macular and retinal pathology, and on low vision aids will be excluded. Using block randomization method with sequentially numbered in opaque sealed envelopes (SNOSE), the eligible patients will be randomized into:

Group A: Intervention group Group B: Non-intervention group In both groups, their usual topical treatment will be continued. They will be advised to be compliance to the existing treatment. This study will take 6 months to complete.

Baseline assessment An introductory session will be conducted to all selected subjects. The purpose of the study will be explained, and compliance will be emphasized. Venesection will be conducted and 3cc of blood will be obtained. The blood will be kept in the plain bottles and analysed for the level of total anti-oxidant capacity (TAC).

Patients (in group A \& B) will be given the GlauQol-36 and mGDS-14 questionnaire in Bahasa Malaysia (Appendix A \& B) and be given adequate time to read and answer the questionnaire. If the patient does not understand the questionnaire, they can obtain clarification from the primary investigators (SMCM \& NS). The GlauQoL-36 questionnaire consists of 36 questions grouped into 7 domains (daily life, driving, psychological well-being, self-image, anxiety, burden of treatment and confidence in healthcare). Each question was given 4- and 5- point on the Likert scale. The total score from each domain was summed and the score calculated. The mGDS-14 questionnaire consists of 14 questions. It has a yes/no answer and is scored 1 or 0 for each question. Patients with the score of 8 and above are considered depressed.

Accelerometer will be given to the patients with the instruction to wear it all day long except for sleeping and bathing. A baseline reading speed, visual span, eye and head movement will be obtained in those involved in reading rehabilitation program using the reading charts, newspaper and pharmacy label print. These assessments will be conducted twice; before the rehabilitation program and after 6 months of the program. Reading materials in Bahasa Malaysia (a book to read) will also be given. Clinical parameters including IOP and ONH imaging to assess the RNFL thickness and ONH parameters will also be conducted.

Rehabilitation regime

A.Navigation \& mobility:

The rehabilitation sessions will be conducted in the Rehabilitation Medicine Unit of HUSM, HRPZII and Hospital Melaka provided by the Occupational Therapy division. The patient is expected and encouraged to come with a carer (who live together with the patient) during the early part of the sessions. After randomization, patients in the group A will be assessed using modified Barthell index, the patient's limitations in daily activities with special attention to the components related to restricted visual field. An introductory session will be conducted by the occupational rehabilitation therapist (baseline), patients will be asked to practice it at home.

Depending on the respective limitations the patient will be taught of ways to get around the problems, emphasizing on the Visual Perception and Sensory Motor Ability as outlined by the Chessington Occupational Therapy Neurological Assessment Battery to maximize function, health and wellbeing. A set of realistic goals will be established together with the patient whether using the restorative or compensatory methods to promote motivation and enhance confidence. Restorative method includes restorative visual field training, optokinetic training and and search task training focussed at improving the loss in visual field or disability arises from the loss of patient's eye field. Interventions involve compensation which are strategies to minimize mismatch in the patient's ability with task difficulty; and substitution which can include environmental modifications to enhance vision such as adjustment of lighting. Subsequent sessions will involve consolidation of the concepts with supervised practices comprising indoor and outdoor activities to enhance patients' understanding and confidence and encourage participation.

Rehabilitation education and activities include:

1. Dressing Light closet to improve acuity. Hang matching clothes together. Pin socks together when placing them in the washer so they will stay matched.
2. Feeding Provide high contrast. Ensure that plates contrast with table surface. Avoid patterned table clothes. Arrange food on the plate in a clockwise fashion and orient the person to the arrangement.
3. Personal hygiene and grooming activities Reduce clutter in bathroom and kitchen cabinets. Use high contrast bathmat and minified mirrors
4. Communication and environmental hardware adaptations Use talking watches or clocks to tell time and high contrast doorknobs.
5. Functional mobility Mobility is eased with the clearing of pathways and the minimizing of clutter and furniture. Lighting in hallways and entryways is also needed. The person with constricted visual field needs to optimize visual scanning abilities by learning to turn and position the head frequently when mobile or participating in an activity.
6. Scanning activity or search task While focusing on a point central to the visual axis, the patient is asked to arrange wooden cubes forming vertical and horizontal lines one at a time. The instruction will be given to arrange from left to right, then right to left, top to bottom and lastly bottom to the top. Patient's visual field is estimated and described to the patient. Patient is advised on the 'danger area' outside the visual field that can pose various risks to the patient.
7. Room orientation and memory This is applied to a small area such as a bedroom or a toilet. The patient is asked to stand inside a simulated room in the Rehabilitation Unit and describe the names of the objects that he/she can see. Emphasizing on the location of the objects and their directions from the patient (right, left, in front, behind), patient is trained to systematically orientate himself in the room relative to those objects. Certain objects are highlighted to the patient as a precaution to avoid stumbles and falls. For safety, cleaning supplies should be placed separately from food supplies.
8. Orientation and mobility This activity covers a larger area that the patient will be in which is the patient's home. Patient will be instructed regarding room familiarisation according to the house's structure as described by patient's carer with the help of a drawing. For example, the patient is taught to memorize the number of steps needed to be made to get to the toilet from his room, and in what direction.
9. Reading (this is not part of the reading rehabilitation) Patient will be taught to label the things that are of importance to them at home to aid recognition, for example bottles of spice. The letters should be of appropriate size deemed legible by the patient according to the patient's field of view, and of high contrast. For patients on medications, they are advised to use medication organizer to get them organized.
10. Eye-hand coordination To enhance hand-eye coordination, a pegboard is used as a form of exercise for the patient. Patient is asked to match coloured pegs into its corresponding holes according to a reference template. This training also allows the patient to get used to the extent of field of view that he possesses.
11. Optokinetic training programme This programme is built based on the knowledge that eye and body movements are coordinated by the same parts of the brain, which is important in maintaining stability and balance. Repeated training helps to re-teach the body of its responsible actions, by the means of precise eye movements. This is done via optokinetic eye programme to accelerate physical and mental fitness. Fortunately, the high functional adaptability of the brain permits positive training and learning as the person ages.

Occupational therapist will conduct a home visit if necessary. A diary will be given to assess their compliance. Reassessment will be done for every 2 weeks for 2 months and every month for the next 2 months. Another home visit will be conducted if the patients show poor understanding or compliance during the re-assessment evaluation.

Patients in group B will also be given a diary to record their activities. In both groups, their usual topical treatment will be continued. They will be advised to be compliance to the existing treatment.

1. Special exercise:

An instruction course will be conducted and a CD (with step by step exercise demonstration) will be given to the patients in group A. They will be asked to come for another session in 2 weeks. Then they will be asked to conduct the exercise for at least three times a week. Exercise diary and accelerometer will also be given to patients of both groups.

1. Reading regime:

A briefing will be given to all the patients involved in this regime. Patients in both groups will be asked to complete a reading task (reading the given book) a day; number of pages completed in an hour per day, and time taken to complete a page in the given book. They will be asked to record the time they have completed the task in their reading diary. Any extra reading task will also be recorded this include reading Quran and newspaper.

Final assessment At 6 months post recruitment, patients in group A and B will be asked to complete the Malay version of Glau-QOL 36 and MGD14. Accelerometer reading will also be documented. The number of pages read for the given task will be compiled. The reading diary will be evaluated. Reading speed will be calculated daily and the mean reading speed will be used for analysis. Another venesection will be conducted to examine the level of TAC. Clinical assessment including IOP, RNFL thickness and ONH parameters will be conducted.

Serum TAC analysis Level of TAC analysis will be conducted using using QuantiChromTM Antioxidant Assay Kit (DTAC-100). It will be centrifuged 10 min at 14000 rpm, the plasma will be used as sample for calculation of total antioxidant capacity (TAC). Plasma can be stored in a freeze at -80°C in the laboratory (stable for 1 month) for future analysis if required. After preparing the reagent provided from the test kit (DTAC-100), patient plasma will be mixed with the diluted reagent in a plate which will be read at optical density of 570nm. The result obtained will be plotted against the standard concentration and a standard curve is obtained. By using the graph plotted and a formula provided in the test kit, the serum TAC will be calculated. Serum total antioxidant capacity will be calculated at baseline and at six months post recruitment.

Data Entry and Statistical Analysis The data entry and analysis will be performed by using Statistical Package for the Social Sciences (SPSS) version 22 licensed to USM. For numerical data, paired t-test will be used to compare the changes at baseline and 6 months post intervention. Multivariate analysis will also be conducted