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

Not Applicable

Completed

• Conditions: Paracentral Acute Middle Maculopathy; Acute Macular Neuroretinopathy; Deep Retinal Capillary Ischemia
• Interventions: Device: Electromagnetic stimulation; Biological: Platelet rich plasma

• Registration Number: NCT04242719
• Lead Sponsor: Ankara Universitesi Teknokent

Brief Summary

To investigate the efficacy of retinal electromagnetic stimulation and sub-tenon autologous platelet rich plasma in the treatment of deep retinal capillary ischemia.

Detailed Description

Deep retinal capillary ischemia (DRCI) is a recently described entity in patients presenting with an acute-onset paracentral scotoma. Subclinical macular lesions of DRCI were formerly best visualized on near-infrared reflectance imaging. The development of optical coherence tomography angiography (OCTA) has facilitated studies of the retinal capillary structures. The multiplanar superficial capillary plexus is located in the inner plexiform layer (IPL) and contains synapses between bipolar and ganglion cells as well as amacrine cells. The deep capillary plexus (DCP) is located in the outer plexiform layer (OPL), which is thinner than the IPL. The DCP is composed of synapses of photoreceptors, bipolar cells, and horizontal cells. This area is also at the border of the oxygen diffusion from the choroid. It is likely that the oxygen coming from the choroid has been completely consumed by the photoreceptors because of the low partial pressure of oxygen level in the outer nuclear layer (ONL). The DCP supplies both the bipolar cells and the synaptic structure of the OPL and Henle fibers.

Deep retinal capillary ischemia is an ischemic event in the middle and deep layers of the retina due to various systemic or local vascular pathologies. It is obvious in the intraretinal hyper-reflective bandlike zone located superior or inferior to the OPL conjointly on in a structural cross-sectional B-scan of the spectral domain optical coherence tomography (SD-OCT) examination along with an acute-onset paracentral scotoma and subjective complaints of the patient. Ophthalmologists often face a significant diagnostic challenge because of a lack of noticeable changes in the appearance of the retina.

DRCI has two different appearances on B-scan SD-OCT exams according to the level of the involved DCP. If the hyper-reflective bandlike zone is located on the outer plexiform layer-inner nuclear layer (OPL-INL) junction, then it is termed "Paracentral Acute Middle Maculopathy (PAMM)" or type-1 deep retinal capillary ischemia. If the hyper-reflective band is seen on the OPL-ONL junction, then it is termed as type-2 deep retinal capillary ischemia. This might be a new variant of "Acute Macular Neuroretinopathy (AMN)". These intraretinal hyperreflective zones are seen as patchy areas of various patterns on en-face OCT image, and atrophic areas in the inner and the outer nuclear layer respectively are developed in the late stage of the diseases. The pathophysiologic features of DCP ischemia is considered to be ischemic hypoxia leading to cell death with swelling of the middle retinal tissues. This may lead to severe vision loss and permanent paracentral scotoma depending on the underlying cause and depth of ischemia. It can also be observed by slowing metabolic activity in photoreceptors and neural retina. The metabolic slowdown is defined as a dormant phase in photoreceptors and OFF mode in the neural retina.

The retinal deep capillary plexus is a single monoplanar capillary plexus located in the OPL. It has the lowest vessel density-this is a significant finding that might be used to evaluate retinal vascular diseases accurately. For this reason, the changes in the percentage of the vessel density in DCP during the follow-up were preferred as an assessment parameter of the treatment modalities used in this prospective clinical study.

Platelets are anucleated cells that contain many types of growth factors including platelet-derived growth factor(PDGF), transforming growth factor-β(TGF-β), vascular endothelial growth factor(VEGF), and epidermal growth factor(EGF) in alpha granules. Thus, the supplementation of growth medium with autologous platelet-rich plasma (aPRP) could be desirable for clinical applications and could lead to some functional improvement.

High-frequency repetitive electromagnetic stimulation (rEMS) has promising therapeutic potential in ischemic neurological patients. The rationale of rEMS is that it modulates neural excitability and increases neural plasticity; thus, it improves the functional outcome. These neuroprotective effects of rEMS are dependent on the increase in the level of brain-derived neurotrophic factor (BDNF), VEGF, and increased tyrosine kinase A, B, and C (TrkA, TrkB, and TrkC) receptor activation. Therefore, high-frequency rEMS might be a promising therapeutic strategy for ischemic retinal disorders such as DRCI.

There is no known and proven specific treatment for DRCI to date except for systemic check-ups and treatment of the underlying diseases or predisposing factors. The aim of this preliminary clinical study is to investigate the efficacy of high-frequency rEMS alone or in combination with sub-tenon fresh aPRP as a treatment modality in the treatment of DRCI. To the best of our knowledge, this is the first prospective clinical trial on this subject in the ophthalmic literature.

Study Timeline

• Study Start: 2018-01-01
• Primary Completion: 2019-01-30
• Study Completion: 2019-02-28
• Status Verified: 2020-01
• Study First Submitted: 2020-01-20
• Study First Submitted QC: 2020-01-23
• Last Update Submitted: 2020-01-23
• Study First Posted: 2020-01-27
• Last Update Posted: 2020-01-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

Inclusion Criteria

• Patients complaining of blurred vision and/or acute-onset paracentral scotoma during the last month without any visible fundus change along with typical SD-OCT and OCTA findings.

Exclusion Criteria

• The presence of noticeable changes in the fundus examination,
• Any optic media opacity that may cause artefacts on OCTA images and interfere with quantitative measurements of the DCP vessel density,
• Complaining of paracentral scotoma lasting more than 1 month (in order to exclude chronic changes in the retinal tissue),
• Presence of atrophic changes in INL or ONL on cross-sectional B-scan SD-OCT

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Combined with electromagnetic stimulation and PRP	Platelet rich plasma	Order to augment the effect of the rEMS, sub-tenon aPRP injection was added.
Only electromagnetic stimulation	Electromagnetic stimulation	Only rEMS was preferred as the initial step
Combined with electromagnetic stimulation and PRP	Electromagnetic stimulation	Order to augment the effect of the rEMS, sub-tenon aPRP injection was added.

Primary Outcome Measures

Name	Time	Method
Deep retinal capillary vessel density	Change from baseline deep reinal capillary vessel density at 1 month.	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.
Best corrected visual acuity	Change from baseline best corrected visual acuity at 1 month.	Number of readable letters after glasses correction

Trial Locations

Locations (1)

Ankara University Biotechnology Institute; 🇹🇷 Ankara, Türkiye, Turkey