[Pharmacological prevention of fibrosis in dacryosurgery]. / Medikamentoznaya profilaktika fibrotizatsii v dakriokhirurgii.

Chronic inflammatory process in the lacrimal drainage system is the main etiological factor leading to dacryostenosis and consequent obliteration - partial and total nasolacrimal duct obstruction. Prevention of this process is an urgent problem in dacryology. Currently, there is very little research on the development and use of conservative methods for treating dacryostenosis using anti-inflammatory, as well as anti-fibrotic drugs. In this regard, the main method of treating lacrimal drainage obstruction is dacryocystorhinostomy. However, the problem of recurrence after this operation has not been resolved. The causes of recurrence can be cicatricial healing of dacryocystorhinostomy ostium, canalicular obstruction, formation of granulations and synechiae in its area. Surgical methods of recurrence prevention are associated with possible complications, and there is conflicting data on the feasibility of their use. Based on this, the development of pharmacological methods for the prevention of fibrosis in dacryology is promising, among which the antitumor antibiotic Mitomycin C is the most studied. However, there are no specific scientifically substantiated recommendations for the use of this drug, and the data on its effectiveness vary. This has prompted researchers to look for and study alternative anti-fibrotic agents, such as antitumor drugs, glucocorticoids, hyaluronic acid, small molecule, biological, immunological and genetically engineered drugs, as well as nanoparticles. This review presents the current data on the efficacy and prospects of the use of these drugs in dacryology.

[Long-term changes in morphological and functional parameters of the optic nerve in patients with various genetic variants of hereditary optic neuropathies]. / Dolgosrochnaya dinamika morfofunktsional'nykh pokazatelei zritel'nogo nerva u patsientov s razlichnymi geneticheskimi variantami nasledstvennykh opticheskikh neiropatii.

Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON) are degenerative diseases of the optic nerve caused by mutations in nuclear or mitochondrial DNA (nDNA, mtDNA). The clinical picture of these diseases is similar, but there are some differences in how the visual functions change in patients with different molecular genetic variants of hereditary optic neuropathies (HON). PURPOSE: This study evaluates the long-term changes in morphological and functional parameters in patients with different genetic variants of HON. MATERIAL AND METHODS: The study included 84 patients (165 eyes) with a genetically confirmed LHON or ARON diagnosis. The patients underwent best-corrected visual acuity (VA) test, color vision (CV) examination, computerized perimetry using the program for low vision assessment, optical coherence tomography (OCT). RESULTS: Over the course of the follow-up (60 months or longer) HON patients were revealed to have higher VA in c.152A>G and m.14484T>C mutations compared to mutations m.11778G>A and m.3460G>A. The final VA 0.5 or higher in patients with c.152A>G and m.14484T>C mutations in 54 and 71% of cases, and only in 6 and 13% of cases - with m.11778G>A and m.3460G>A mutations. Direct correlation was determined between minimal VA in the first year after disease onset and the final VA (K=0.67; p<0.001). In all patients with the investigated mutations CV recovered slightly quicker than VA. CONCLUSION: HON associated with c.152A>G and m.14484T>C mutations have better prognosis compared to LHON caused by m.11778G>A and m.3460G>A mutations. Vision recovery prognosis is worse in patients who had significant decrease of visual acuity at the disease onset. OCT findings reveal preservation of visual functions in all mutations.

[Rare pathogenic nucleotide variants of mitochondrial DNA associated with Leber's hereditary optic neuropathy]. / Redkie patogennye nukleotidnye varianty mitokhondrial'noi DNK, assotsiirovannye s nasledstvennoi opticheskoi neiropatiei Lebera.

Patients with Leber Hereditary Optic Neuropathy (LHON) in most cases have one of the three most common mutations: m.11778G>A in the ND4 gene, m.3460G>A in the ND1 gene, or m.14484T>C in the ND6 gene. According to the international Mitomap database, in addition to these three most common mutations, there are 16 other primary mutations that are even more rare. There are nucleotide substitutions that are classified as candidate or conditionally pathogenic mutations. Their involvement in the disease development is not proven due to insufficient research. Moreover, in many publications, the authors describe new primary and potential mitochondrial DNA mutations associated with LHON, which are not yet included in the genetic data bases. This makes it possible to expand the diagnostic spectrum during genetic testing in the future. The advancements in genetic diagnostic technologies allow confirmation of the clinical diagnosis of LHON. The importance of genetic verification of the disease is determined by the existing problem of differential diagnosis of hereditary optic neuropathies with optic neuropathies of a different origin.

[Optic neuropathies as an interdisciplinary subject of research]. / Opticheskie neiropatii kak predmet mezhdistsiplinarnogo izucheniya.

Despite the wide range of clinical, instrumental and laboratory methods used in modern ophthalmology, the problem of diagnosing optic neuropathy and identifying its etiology remains relevant. A complex multidisciplinary approach involving various specialists is required in the differential diagnosis of immune-mediated optic neuritis, for example in multiple sclerosis, neuromyelitis optica spectrum disorder, and MOG-associated diseases. Of special interest is differential diagnosis of optic neuropathy in demyelinating diseases of the central nervous system, hereditary optic neuropathies and ischemic optic neuropathy. The article presents a summary of scientific and practical results of differential diagnosis of optic neuropathies with various etiologies. Timely diagnosis and early therapy start reduces the degree of disability in patients with optic neuropathies of different etiologies.

[Autosomal recessive optic neuropathies: genetic variants, clinical manifestations]. / Autosomno-retsessivnye opticheskie neiropatii: geneticheskie varianty, klinicheskie proyavleniya.

Hereditary optic neuropathies (HON) - a group of neurodegenerative diseases characterized by primary loss of structure and function of the retinal ganglion cells and subsequent death of their axons, development of partial optic nerve atrophy. Autosomal dominant optic neuropathy and Leber`s hereditary optic neuropathy until recently were considered the most common genetic hereditary optic neuropathies, while autosomal recessive optic neuropathies (ARON) were described as rare types of HON, usually accompanying severe syndromic pathologies. In the 2000s it has become clear that ARON occur significantly more often, are underestimated, and their clinical variability is poorly studied. Despite the fact that non-syndromic ARON are less common than syndromic optic neuropathies, their contribution to the development of isolated hereditary optic neuropathies should be considered. This article presents a literature review on non-syndromic ARON developing as a result of mutations in the ACO2, MCAT, WFS1, RTN4IP1, TMEM126A, NDUFS2, DNAJC30 genes.

[Leber's hereditary optic neuropathy clinical features in patients with mitochondrial DNA m.13513G>A candidate mutation]. / Klinicheskie osobennosti nasledstvennoi opticheskoi neiropatii Lebera u patsientov s kandidatnoi mutatsiei m.13513G>A v mitokhondrial'noi DNK.

Leber's hereditary optic neuropathy (LHON) is caused by primary mtDNA by both primary mtDNA mutations and new mtDNA mutations. The last ones, when detected in several independent LHON families, receive candidate status. The description of new LHON-associated mtDNA mutation is relevant. PURPOSE: To determine the LHON clinical features in patients with the m.13513G>A mutation and to estimate the patients' proportion with this pathogenic variant in the LHON patients' sample. MATERIAL AND METHODS: The study included 5 LHON patients, associated with m.13513G>A mutation in the ND5 gene in the heteroplasmic state. A standard examination was performed, including color blindness test, visual fields test, spectral optical coherence tomography. RESULTS: LHON, associated with m.13513G>A in the heteroplasmic state in the range of 25-60%, is characterized by visual impairment without additional neurological or other extraocular symptoms. Visual recovery to 0.3-1.0 presents in all patients; the visual recovery onset occurs between 12 and 20 months from the disease manifestation. The decrease of the central scotoma size and its density and the color vision improvement are also observed as well as the average retinal nerve fibers layer and ganglion cell complex thickness decrease. The m.13513G>A mutation frequency is 5% in 100 LHON patients' sample and 22.5% in 22 LHON patients with rare and candidate mtDNA mutations. CONCLUSION: The m.13513G>A mutation can be considered as primary LHON mutation. The list of pathogenic variants recommended for testing LHON can include this mutation. The m.13513 G>A mutation determines the mild LHON course and good visual functions prognosis in these patients.

[Metabolic disorders in hereditary optic neuropathies]. / Metabolicheskie narusheniya pri nasledstvennykh opticheskikh neiropatiyakh.

Folate metabolism disorders are known to have a potential involvement in the pathophysiology of mitochondrial diseases. Many researchers suggest that profound systemic folate deficiency may contribute to mitochondrial folate deficiency. Folic acid metabolism is closely related to vitamin B12 and homocysteine. Considering that hereditary optic neuropathies (HON) are mitochondrial diseases, it is important to study the folate status, the content of vitamin B12 and homocysteine in patients with this pathology. OBJECTIVE: To compare the content of folic acid, vitamin B12 and homocysteine in the blood serum of patients with Leber's hereditary optic neuropathy (LHON) and autosomal recessive optic neuropathy (ARON), optic neuropathy of other genesis, and the comparison group. MATERIAL AND METHODS: The study involved 58 patients with LHON and ARON, the control group of 49 patients with ischemic, inflammatory, traumatic and compressive optic neuropathies, and the comparison group of 20 healthy volunteers. RESULTS: A decrease in blood folic acid levels was revealed (4.0±1.6 ng/mL) in patients with HON compared to the control group (p=1.3·10-8) and the comparison group (p=1·10-17). The content of vitamin B12 in patients with HON was 380.8±168.1 pg/mL, which was significantly lower than in the comparison group (p=0.0001). The homocysteine content was 14.1±5.6 µmol/L in patients with HON, which was significantly higher than in the control group (p=0.0007) and the comparison group (p=0.000003). At the same time, an increase in homocysteine level of more than 10 µmol/L was revealed in 75% of patients with HON. Similar metabolic disorders were found in groups with various mutations in mitochondrial and nuclear DNA. CONCLUSION: Patients with HON showed marked decrease in the levels of folic acid and vitamin B12, as well as hyperhomocysteinemia. It is very important to identify the causes of metabolic disorders in order to determine the role of folate deficiency in the development of HON, as well as the possibility of its pharmacological treatment.

[Electrophysiological and psychophysical studies in assessment of visual functions in patients with hereditary optic neuropathy]. / Elektrofiziologicheskie i psikhofizicheskie issledovaniya v otsenke zritel'nykh funktsii pri nasledstvennoi opticheskoi neiropatii.

PURPOSE: To study the capabilities of electrophysiological and psychophysical examination methods for assessment of the functional state of ganglion cells, retina and optic nerve in patients with hereditary optic neuropathy (HON). MATERIAL AND METHODS: The study included 60 patients (118 eyes) with a genetically confirmed diagnosis of HON. All study patients underwent visual field test (VFT), spectral optical coherence tomography (OCT), flash and pattern visual evoked potentials (VEP) (Flash-VEP, FVEP; Pattern-VEP, PVEP), photopic electroretinography with photonegative response (PhNR) registration and the color vision test. In 24 patients (46 eyes), these parameters were assessed before the start of treatment and one year later. The treatment involved the mitochondria-targeted antioxidant SkQ1 - plastoquinonyl-decyl-triphenylphosphonium bromide (PDTP) in the form of eye drops. RESULTS: The main PVEP components for 1.0° and 0.3° were registered in 20% and in 14% of patient eyes with HON and high visual functions, respectively. After one year of PDTP use, a significant decrease in P100 peak latency was found only in the group with disease duration of ≤1.5 years as of the time of treatment start (p<0.05). Significant differences were observed in the PhNR amplitude (p<0.004) between patients of the main and the control groups, as well as in the PhNR amplitude between patients with visual acuity of ≤0.1 and ≥0.13 (p<0.01). Patients with high visual functions were found to have a correlation between the PhNR amplitude, GCC thickness and the global loss index (GLV). CONCLUSION: Along with VFT, OCT and color vision tests, electrophysiological studies are one of the main methods of examining patients with HON. After one year of PDTP use, there was a significant decrease in the FVEP P2 peak latency in the group with a disease duration of ≤1.5 years as of the time of treatment start. The PhNR amplitude in patients with high visual functions was found to correlate with structural changes in the ganglion cell layer and the retinal nerve fiber layer.

[Evaluation of therapeutic sensitivity of retinal ganglion cells to targeted peptide bioregulator in culture]. / Otsenka terapevticheskoi chuvstvitel'nosti ganglioznykh kletok setchatki v kul'ture k targetnomu peptidnomu bioreguliatoru.

PURPOSE: To study how therapeutically sensitive retinal cell culture is to the peptide bioregulator isolated from cattle retina (Retinalamin) in models of glaucomatous optic neuropathy (GON). MATERIAL AND METHODS: The cells were isolated from the retinae separated from newborn mice. Cell sheets were disaggregated and transformed into a suspension. Removal of the off-target cell population was done by adding antibodies to deplete the cells with CD48 marker, and magnetic microbeads that attach to them. Selection of ganglion cells and obtainment of its enriched fraction was done by immunomagnetic separation. To assess the toxicity of Retinalamin, a cytotoxic test was performed on the culture of skin fibroblasts with sequential dilution of the drug into concentrations of 5.0-0.009 mg/mL. The cells were seeded at 5000 per plate well and exposed to the drug for 24 hours. To study the excitotoxic damage, the first group of plate wells with retinal cells had solution of sodium glutamate added in concentration of 20 mM, Retinalamin was added into the second group of wells in concentration of 1.25 mg/mL; both substances were added into the third group of wells. The control group consisted of intact plate wells. The cells were exposed to substances for 24 hours. Cell vitality was then evaluated using colorimetry. Optic density was measured using an automatic photometer with detection wavelength of λ=490 nm. RESULTS: The cell culture achieved by immunomagnetic separation is mixed and consists of ganglion and glial cells. Retinalamin does not display significant cytotoxicity in any of the studied concentrations. The excitotoxic damage caused significant decrease of the amount of viable cells in the culture (9% of the control wells). The concomitant addition of glutamate and 1.25 mg/mL Retinalamin resulted in a 51.6% increase in the amount of viable cells. The intergroup differences were statistically significant by Student's t-test. CONCLUSION: Retinalamin is not cytotoxic. The concomitant addition of glutamate and Retinalamin reliably decreases the toxic action of glutamate on isolated retinal cells.

[Hereditary optic neuropathy associated with demyelinating diseases of the central nervous system]. / Nasledstvennaya opticheskaya neiropatiya v sochetanii s demieliniziruyushchimi zabolevaniyami tsentral'noi nervnoi sistemy.

Demyelinating optic neuritis and hereditary optic neuropathy (HON) take a leading place among the diseases, the leading clinical syndrome of which is bilateral optic neuropathy with a simultaneous or sequential significant decrease in visual acuity. Optic neuritis can occur at the onset or be one of the syndromes within multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOGAD). HON are a group of neurodegenerative diseases, among which the most common variants are Leber's hereditary optic neuropathy (LHON), associated with mitochondrial DNA (mtDNA) mutations, and autosomal recessive optic neuropathy (ARON), caused by nuclear DNA (nDNA) mutations in DNAJC30. There are phenotypes of LHON «plus¼, one of which is the association of HON and CNS demyelination in the same patient. In such cases, the diagnosis of each of these diseases causes significant difficulties, due to the fact that in some cases there are clinical and radiological coincidences between demyelinating and hereditary mitochondrial diseases.