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Trial registered on ANZCTR


Registration number
ACTRN12614000319673
Ethics application status
Approved
Date submitted
11/03/2014
Date registered
25/03/2014
Date last updated
12/05/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Evaluation and comparison of Autonomic Nervous System function with neurophysiological interventions such as pupillometry and Mangina Test in patients with Myasthenia Gravis and healthy subjects
Scientific title
Evaluation of the cholinergic hypothesis with neurophysiological interventions such as Pupillometry and Mangina-Test in Myasthenia Gravis patients (MG)
Secondary ID [1] 284242 0
‘Nil known’
Universal Trial Number (UTN)
U1111-1154-3871
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
patients with Myasthenia Gravis 291354 0
Condition category
Condition code
Neurological 291717 291717 0 0
Other neurological disorders
Musculoskeletal 291758 291758 0 0
Other muscular and skeletal disorders
Other 291759 291759 0 0
Conditions of unknown or disputed aetiology (such as chronic fatigue syndrome/myalgic encephalomyelitis)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All subjects underwent pupillometric measurements. All participants were assessed on a single occasion only. Pupillary measurements were taken with a monocular and fully automated system.Participants remained for 2 min in darkness, and 5 flashes were administered afterwards (inter-stimulus interval was 30sec). Stimulus duration was 20 msec, and the luminance 24.6 cd/m2. Each eye was tested separately. The flash was placed at a distance of 30 cm from the eye.
Intervention code [1] 288949 0
Diagnosis / Prognosis
Comparator / control treatment
The original psychophysical paper-and-pencil version of the Mangina-Test was used. The Mangina-Test was administered according to the steps described in the Manual for the Mangina Diagnostic Tool of Visual Perception. This test is composed of 44 simple and 44 complex original geometrical visual stimuli, presented with an increasing degree of difficulty. One simple and one complex stimulus are presented simultaneously. The task consists of exactly identifying and tracing completely with a fine marker the simple stimulus which is masked within a complex configuration of stimuli varying in direction, spatial orientation, size, dimension, and shape in a limited span of time.
Control group
Active

Outcomes
Primary outcome [1] 291661 0
Two pupillometric indices Maximum Velocity of Constriction (VCmax) and Maximum Acceleration of Constriction (ACmax) are governed mainly by the action of the Parasympathetic Nervous System, through Acetylcholine. The Myasthenic patients showed decreased VCmax and ACmax compared to healthy controls and significant decreased scores in the Mangina-Test as compared to healthy controls. Accordingly, the results of this study demonstrate that the Central Nervous System is affected and that MG has central cholinergic effects manifested by cognitive dysfunction.
Timepoint [1] 291661 0
Assessed at time of pupillometric measurements and the original psychophysical paper-and-pencil version of the Mangina-Test were performed on the participants.
Secondary outcome [1] 307251 0
From the pupillometric results we assumed that the iris sphincter smooth muscle is affected in Myasthenia Gravis patients
Timepoint [1] 307251 0
Assessed at time of pupillometric measurements and the original psychophysical paper-and-pencil version of the Mangina-Test were performed on the participants

Eligibility
Key inclusion criteria
All patients were diagnosed with MG (mean time from the diagnosis was until the beginning of the study 2.9+/-0.2 years) using the established and diagnosis criteria. Specifically, their diagnosis was based on one hand on the clinical symptoms (fatigue during the day, etc), and on the other hand, on the laboratory findings (presence of positive antibodies for the AchR, positive response at the repeated stimuli test). Apart from these, MG patients showed an improvement of the muscle strength following the intake of edrophonium chloride and reacted positively to Mestinon. It was a key inclusion criterion that participants previously showed an improvement of the muscle strength following the intake of edrophonium chloride and reacted positively to Mestinon because from this we were sure that the Myasthenia Gravis Diagnosis was correct.
All patients were free of any other neurological, ophthalmological, physical or mental disease and their visual acuity, corrected or not, were 20/20. Moreover, they had symmetrical pupils and no past history of ocular operations or diseases affecting the pupil and were not being treated at that time with anticholinergics, steroids, sympathomimetics, beta-blockers or other agents affecting the Pupil Light Reflex (PLR). Also, the basic precondition for participation was a mini mental score greater than or equal to 22. All measurements were performed between 09.00 and 10.00 hours after the participants had had a full eight-hour sleep.
Minimum age
34 Years
Maximum age
69 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
If MG patients do not show an improvement of the muscle strength following the intake of edrophonium chloride and reacted positively to Mestinon.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Data were analyzed with Statistical Package for Social Sciences (SPSS, Chicago, Illinois, USA), version 20.0 software for Windows. The number of participants needed to achieve study objectives was determined with G*power analysis. The Kolmogorov-Smirnov test was used to examine the normality of the distribution. Changes of variables within the groups at baseline and the end of the study were evaluated by a One-Way ANOVA with group being the independent variable. The significance level was p<0.05. Finally, the Pearson correlation was calculated between each pair of pupillometric parameters for each patient group and for the total group of the healthy people. Moreover, the correlation of each pupillometric parameter with age was also estimated.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/01/2013
Actual
17/01/2013
Date of last participant enrolment
Anticipated
26/06/2013
Actual
26/06/2013
Date of last data collection
Anticipated
Actual
Sample size
Target
66
Accrual to date
Final
Recruitment outside Australia
Country [1] 5888 0
Greece
State/province [1] 5888 0
Thessaloniki

Funding & Sponsors
Funding source category [1] 288873 0
Self funded/Unfunded
Name [1] 288873 0
Antonia Kaltsatou
Country [1] 288873 0
Greece
Primary sponsor type
Individual
Name
Antonia Kaltsatou
Address
AHEPA University Hospital of Thessaloniki
1 Kyriakidi Street, Thessaloniki, 54636, Greece
Country
Greece
Secondary sponsor category [1] 287567 0
Individual
Name [1] 287567 0
Dimitris Fotiou
Address [1] 287567 0
Dimitris Fotiou
1 Kyriakidi Street, Thessaloniki, 54636, Greece
Country [1] 287567 0
Greece

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290702 0
the Ethical Committee of the AHEPA University Hospital based on the Helsinki Declaration
Ethics committee address [1] 290702 0
1 Kyriakidi Street, Thessaloniki, 54636
Ethics committee country [1] 290702 0
Date submitted for ethics approval [1] 290702 0
Approval date [1] 290702 0
03/01/2013
Ethics approval number [1] 290702 0

Summary
Brief summary
Many studies have demonstrated that the central cholinergic system is important in mediating cognitive processes of learning and memory. Nonetheless, many studies have supported the hypothesis of Central Nervous System cholinergic involvement in Myasthenia Gravis.More specifically, there is some evidence that Myasthenia Gravis has central cholinergic effects manifested by cognitive dysfunction. Hence, the aim of this study was to investigate with established psychophysiological methods such as pupillometry and concomitantly with the Mangina-Test, the hypothesis of Central Nervous System cholinergic involvement in patients with Myasthenia Gravis. All participants were informed about the study procedure and provided written informed consent and all the experiments were approved by the Ethical Committee of the AHEPA University Hospital based on the Helsinki Declaration.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 46858 0
Dr Antonia Kaltsatou
Address 46858 0
Aristotle University of Thessaloniki,
AHEPA Hospital,
1 Kyriakidi Street,
Thessaloniki, PC 54636
Country 46858 0
Greece
Phone 46858 0
+306938767967
Fax 46858 0
Email 46858 0
[email protected]/ [email protected]
Contact person for public queries
Name 46859 0
Antonia Kaltsatou
Address 46859 0
22, Dim. Gounari Str
PC 54621
Thessaloni, GREECE

Aristotle University of Thessaloniki,
AHEPA Hospital,
1 Kyriakidi Street,
Thessaloniki, PC 54636
Country 46859 0
Greece
Phone 46859 0
+306938767967
Fax 46859 0
Email 46859 0
[email protected]/ [email protected]
Contact person for scientific queries
Name 46860 0
Antonia Kaltsatou
Address 46860 0
22, Dim. Gounari Str
PC 54621
Thessaloni, GREECE

Aristotle University of Thessaloniki,
AHEPA Hospital,
1 Kyriakidi Street,
Thessaloniki, PC 54636
Country 46860 0
Greece
Phone 46860 0
+306938767967
Fax 46860 0
Email 46860 0
[email protected]/ [email protected]

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