Only rEMS was preferred as the initial step

Order to augment the effect of the rEMS, sub-tenon aPRP injection was added.

Served as control group, and existing systemic disorder(s) were consulted and treated accordingly.

Deep Retinal Capillary Ischemia

Paracentral Acute Middle Maculopathy

Acute Macular Neuroretinopathy

Retinal electromagnetic stimulation A high-frequency repetitive electromagnetic stimulation protocol has been defined in the literature and was applied in groups 1 and group 2 via a novel device developed specifically for ophthalmic usage (Magnovision-TM, Bioretina Biyoteknoloji AŞ, Ankara,Turkey). The patients underwent 10 consecutive sessions of rEMS application. Parameters for the treatment were 42 hertz frequency/min, 30 minutes of duration and mild operating cycle. The power of the electromagnetic field was 2000 milligauss, which is a very low dose and within the safety limits of World Health Organisation. In group 2, sub-tenon aPRP injections were also performed immediately after the first, fifth, and tenth sessions of rEMS application.

Electromagnetic stimulation

About 20 ml of blood was drawn from the patient's antecubital vein and inserted into two 10-ml vacutainer tubes that contain trisodium citrate (T-LAB PRP Kit, T-Biyoteknoloji, Bursa, TURKEY). These tubes were placed in a refrigerated (+4 °C) centrifuge (Nüve NF 1200R, Nüve Laboratuar Teknolojileri, Ankara, TURKEY) and spun at 2500 rpm (580×g) for 8 min within 30 min of collection. Three different layers formed in the tubes: red blood cells at the bottom, platelet-rich plasma in the middle, and platelet-poor plasma in the top layer. A total of 1.5 ml of the middle layer (which mainly contained platelets) was withdrawn by syringe and immediately injected into the sub-tenon space of each eye after topical anesthesia with proparacaine hydrochloride (Alcaine, Alcon, USA) drops.

Platelet rich plasma

Ankara University Biotechnology Institute

Management of Deep Retinal Capillary Ischemia by Electromagnetic Stimulation and Platelet- Rich Plasma

The vessel densities (in %) of deep capillary plexus were measured with "AngioAnalytic" feature of the OCTA device. To compare the percentage of the vessel densities precisely during follow-up, the "Link-B Scans" button on the screen was activated so that the exact same segmentation planes of the DCP could be compared. The OCTA device automatically calculated and displayed the vessel density maps as follow-up sequences (Angio Retina multiscan view) and trend analysis.

Number of readable letters after glasses correction

Umut Arslan

Principle investigator, MD

Ankara Universitesi Teknokent

The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125 mg twice/daily, the target dose will be 25mg twice daily (50 mg/day) and participants will take 50 mg/day carvedilol for 6 months.Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.

REM Sleep Behavior Disorder

Pre-motor Parkinson Disease

Symptomatic Parkinson Disease

At the end of Baseline visit, carvedilol 3.125 twice daily will be initiated and maintained for 1 week, increased to 6.25twice daily (dispensed at week 1visit), to 12.5mg twice daily (dispensed at week 2) and a max dose of 25mg twice daily (dispensed at week 4 visit), as tolerated. A subject that cannot tolerate at least a 25 mg daily dose will be excluded from the study. Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose. The project will include a washout period at study end.

Carvedilol

Cedars Sinai Medical Center

Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease

The Effect of Adrenergic Blocker Therapy on Cardiac and Striatal Transporter Uptake in Pre-Motor and Symptomatic Parkinson's Disease

123I-MIBG reuptake will be measured by early and late Heart to Mediastinal ratio (H/M) and Washout ratio (WR) which will be calculated using the following formula: [(early heart counts/pixel - early mediastinum counts/pixel) - (late heart counts/pixel decay-corrected - late mediastinum counts/pixel decay-corrected)]/(early heart counts/pixel - early mediastinum counts/pixel). Care will be taken to exclude lung or liver from the myocardial and large vessels and lung from the mediastinum region of interest. MIBG abnormality cutoffs will be set for values of late H/M <2.2 and WR >30%.

Safety will be monitored collecting the type and frequency of adverse events, including clinical symptoms, changes in vital signs, clinical laboratory measures and EKG abnormalities.

Twenty-four-hour Holter monitoring of all patients will be conducted at two points during the study: 1) After MIBG and prior to the administration of the study drug and 2) within one week of the end of the six-month treatment trial. Two-channel Holter recordings will obtained and analyzed on a commercially available scanner in the cardiac laboratory at Cedars Sinai Medical Center, according to published guidelines.

The Movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS) Part III will be administered at baseline and 26 weeks after study medication titration. Each item of the MDS-UPDRS has a possible rating from 0 to 4, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe.Clinical scales will be performed OFF medication in those subjects that might be receiving dopaminergic drugs

RBD questionnaire (RBDSQ) changes from Screening at 26 weeks after study drug titration

University of Pennsylvania Smell Identification Test (UPSIT) changes from screening at 26 weeks after study medication titration

Functional constipation will be assessed at screening and at 26 weeks after study medication titration using a questionnaire based on modified ROME III diagnostic criteria, which focuses on symptoms including straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction or blockage, manual maneuvers to facilitate evacuation, and two or fewer bowel movements per week. This questionnaire is based on a six item self-report measures with a three point summated rating scale. The total score has a range of 0 to 12, with scores > 4 identifying functional constipation.

Color vision changes will be assessed using HRR Pseudochromatic Plates from screening at 26 weeks after study medication titration

DaT/SPECT uptake at baseline will be quantified at baseline and 26 weeks after study medication titration

The NMSS measures non-motor symptoms over the previous month. Each symptom is scored with respect to: Severity: 0 = None, 1 = Mild; 2 = Moderate; 3 = Severe and Frequency: 1 = Rarely (<1/wk); 2 = Often (1/wk); 3 = Frequent (several times per week); 4 = Very Frequent (daily or all the time).

The SCOPA-AUT scale consists of 25 items assessing autonomic symptoms in the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction.

Peripheral IR will be defined by testing for fasting plasma insulin (FPI), fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) from baseline at 26 weeks after study medication titration. HOMA index will be calculated by the formula: HOMA-IR = (FPI x FPG)/405. [A cutoff HOMA index of 2.0, equivalent to <50% sensitivity, will be used to define IR. Subjects were considered to have IR if they either had a HOMA≥2.0 and/or HbA1c≥5.7.

Measures of insulin sensitivity in neuronal-origin enriched plasma EVs (central IR) will be used to test the association of changes in such sensitivity to changes in MIBG uptake and clinical scores from baseline to 26 weeks after carvedilol titration. For that purpose, plasma samples will be collected and stored and -80oC to allow for isolation of neuronal origin EVs at the completion of the study.

Michele Tagliati, MD

Professor of Neurology, Director of Movement Disorders

Treatment: carvedilol titration; Experimental treatment with carvedilol will be offered at stabilized medical treatment. The dosage of carvedilol will be gradually increased from the initial recommended starting dose of 3.125mg twice daily and will be doubled every week according to patient tolerability, as measured by subjective complaints, arterial blood pressure and heart rate. The target dose will be 25mg twice daily (50 mg/day). Subjects that cannot tolerate the 50 mg daily dose, will be offered to continue at the 25 mg daily dose.

ganglion cysts/tyrosine

Management of Deep Retinal Capillary Ischemia by Electromagnetic Stimulation and Platelet- Rich Plasma

Adrenergic Blockers for Cardiac Changes in Early Parkinson's Disease

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