There are currently over 260 different genetic mutations known to cause retinitis pigmentosa. Genetic inheritance can be autosomal dominant (AD), autosomal recessive (AR), X-linked, mitochondrial, mosaicism, or sporadic patterns . Thus, the prognosis is usually quite heterogeneous. Acquired factors such as nutrition, smoking, anemia, pregnancy, as well as long-term exposure to ultraviolet and blue light also affect the course of the disease[2–4]. Autosomal dominant inheritance shows the slowest progression with an average annual loss of 5% photoreceptors [20, 21]. X-linked inheritance shows the fastest progression with an average annual loss of 15% of photoreceptors [21, 22].
Knowledge about which genetic mutation affects the progression is increasing due to widespread genetic testing. The annual progression rate of retinitis pigmentosa was reported to be 5% in RHO gene mutation that was inherited as AD, and 15% in RPGR gene mutation inherited as X-linked [20–22]. The photoreceptors have cilia tubule functions that provide the transport of opsin and rhodopsin and can be impaired by X-linked mutations—they can be distinguished by the presence of widespread lipofuscin deposits in the fundus examination. The ciliopathy gene mutations have three-fold faster progression than non-ciliopathy mutations . Retinitis pigmentosa progresses with an average of 10% annual photoreceptor loss when AD, AR, X-linked, and mitochondrial inheritance patterns are collectively evaluated [6, 24, 25]. In our study, the annual photoreceptor loss rate was found to be 9.3% on average in the RP group without interventional procedures (Group 3, natural course) similar to the literature.
The visual function begins with the photochemical conversion of light energy, which comes from the objects and focuses on the retina with conversion to electrical signals. Photochemical conversion occurs in the sensorial unit and microenvironment consisting of a choriocapillaris-retina pigment epithelium-photoreceptor trio. The retina pigment epithelium is the unit center where the synthesized peptide growth factors (GFs) regulate photochemical reactions. These include the oxidative phosphorylation and energy cycle of glucose in the blood; transport of vitamin A, minerals, anions, cations, and necessary coenzymes; the synthesis of opsin-rhodopsin and necessary peptides in the visual cycle; and the removal of metabolic waste that occurs in RPE [26–29].
The growth factors, peptides, and fragments required for these functions are encoded by over 260 genes in RPE. Mutations in any of these genes leads to progressive vision loss and progressive degeneration of the sensorial unit . In particular, mutations that affect the conversion of glucose to adenosine triphosphate (ATP) lead to a condition in photoreceptor cells called sleep mode or dormant phase [30, 31]. Cells in this state have more solid plasma—they are live but metabolically inactive. The photoreceptors in the dormant phase can be metabolically reactive if neurotrophins and GFs can be delivered the microenvironment of the sensorial unit . Neurotrophins and GFs are key molecules in the cellular energy cycle . Prolonged dormant phase or conditions impairing sensorial unit homeostasis eventually lead to apoptosis and cell loss . RPE forms the outer blood-retinal barrier with its tight connections. Defects in the external blood retinal barrier due to apoptosis disrupt the immune-protected state in the retina and lead to low-density inflammation in the sensory unit. Neuro-inflammation accelerates the apoptosis process and sensorial unit loss .
Platelet-rich plasma is a good source of growth factors. Platelets have more than 30 GFs and cytokines in α-granules such as neurotrophic growth factor (NGF), neural factor (NF), brain derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF), transforming growth factor (TGF-β), vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), etc. These peptides regulate the energy cycle at the cellular level, local capillary blood flow, neurogenesis, and cellular metabolism [8–10]. Anti-inflammatory effects of PRP are also associated with soluble cytokines .
Our previous clinical and prospective study showed that subtenon injection of aPRP significantly increased the visual functions [10, 11]. Clinical and preclinical studies showed that the half-life of GFs in tissue derived from PRP is 4–6 months [36–38]. Our clinical observations are similar. Here, we investigated the effects of three loading doses with a 2-week interval and 2 boosters with 6-month interval of subtenon aPRP injections on photoreceptor loss (measured by EZW on SD-OCT) during the one-year follow-up. The photoreceptor loss rates during the follow-up period were 9.3% in the natural course group (group 3) and 3% in the only aPRP group (group 2). These results suggest that subtenon aPRP injection can decrease the photoreceptor loss rate by approximately three-fold.
The growth factors applied into the subtenon region reach the suprachoroidal area through the scleral pores. GFs in the choroidal matrix reach the subretinal area through Trk receptors. Tyrosine kinase receptors are commonly found around the limbus, extraocular muscle insertions, and the optic nerve . Molecules smaller than 75 kD can pass through the sclera via passive transport to the suprachroidal space . BDNF and IGF are key growth factors in PRP and are larger than 75 kD .
Repetitive electromagnetic stimulation increases the affinity and synthesis of Trk growth factor receptors on neural tissues [11–14]. rEMS also provides electromagnetic iontophoresis effect by changing the electrical charges of the scleral pores and the peptides. Electrical or electromagnetic iontophoresis accelerates passing the large molecules such as BDNF and IGF through the sclera [15–17]. rEMS creates hyperpolarization-depolarization waves in neurons, which increases neuro-transmission and capillary blood flow . In Group 1, rEMS was applied along with aPRP, and we found the change in mean EZW rate to be 0.7% at the end of one-year versus baseline. This result suggests that rEMS increases the effects of aPRP. The combined use of rEMS and aPRP has synergistic effects to prevent photoreceptor loss and reactivate the photoreceptor cells in sleep (dormant) mode. The electromagnetic field used here is far below the safety limits set by the World Health Organization .
In our study, ellipsoid zone widths and FDPI ratios in visual field showed similar changes. This proves that the visual field is related to the number of photoreceptors. The visual field is a subjective test and can be influenced by many parameters such as refractive error, media opacity, illumination intensity, the patient's current attention, learning curve etc . The visual field test gives indirect data about the number and functions of photoreceptors. EZW is an objective parameter in tracking the number of photoreceptors, it is not affected by subjective situations. We believe that EZW can be used for diagnosis and follow-up as a substitute for visual field and electroretinography in most cases. In our opinion, EZW should be the gold standard diagnostic-follow-up criterion for RP.
In contrast to the visual field, the central visual acuity is affected too late in RP. Apoptosis occurring in photoreceptors in the periphery leads to Müller cell hypertrophy and ectopic synaptogenesis in the central 19-degree area. Due to the paracrine effects of Müller cells, the cone cells are not affected by apoptosis for a long time. Consequently, BCVA can remain stable for a long time . In our study, BCVA in all three groups did not change during an average of 13 months follow-up.
Local and systemic adverse events related to rEMS and/or aPRP were not detected during the one-year follow-up. Patients did not describe any uncomfortable condition except for temporary light sensitivity (which may last several days due to aPRP injection) and headache (which may last several hours due to rEMS application).
This retrospective clinical study has some limitations. The annual progression rate of retinitis pigmentosa varies depending on the type of genetic mutation. However, this issue was not analyzed here because the genetic mutation analysis of each patient could not be performed. Inflammatory findings were observed in some genetic mutation types of RP or in some stages of the disease. There were no measurements such as a laser flare meter regarding how aPRP or combined procedures affect the inflammatory response. The progression rate of each genetic type and the effects of interventional procedures on inflammation are additional research topics.