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Резюме Резюме Summary Рецензент: д.мед.н., проф. А.М. Петруня УДК 617.731-002-005:616-099-085 КЗ Сумська обласна клінічна лікарня КУ Сумская областная клиническая больница MI Sumy regional hospital
daria_petrushenko@ukr.net
Introduction. In alcoholic toxic neuroretinopathy (ATN) haemodynamics disturbances are observed. Reoophthalmography revealed vessel distonia of Rheoohthalmography showed vascular dystonia of hypertonic type with primary suffering of small caliber vessels and microcirculatory disoders [2,9]. The study of bulbar conjunctiva in chronic alcoholism showed severe microcirculatory disturbances: the spasm of arterioles and the dilatation of venules, reduction of the number of functioning capillaries with appearance of avascular zones and net structure of vessels which was a sign of arteriolar-venular anastomosis. The deceleration or stasis of blood flow, II-III degree sludge syndrome in venules, capillaries and solitary arterioles were determined. The severe perivascular edema and microhemorrhages were observed. The changes in microcirculation in bulbar conjunctiva and eye fundus were analogous [4,14]. The changed of Зміни haemodynamics indexes of venous blood flow are insufficiently explored. The latest pathogenesis model of alcoholic optic neuroretinopathy is a theory of mitochondrial catastrophe by Sadun А. А.. According to this theory toxical influence of alcohol results in mitochondrial oxidative phosphorylation dissociation with consequence of ATP deficiency and at last apoptose promotors delivarence. ATP deficiency results in axonal transport disturbances causing energetic depletion in distal parts of axons. But the author emphasizes that the theory can not explain why the clinical manifestation of mitochondrial optic neuropathies is on the principle “everything or nothing” with acute visual function loss. He supposes the influence of additional factor which causes the threshold pathological changes for starting of the desease [16]. In ATN this factor might be the decompensation of hemodynamics of the eye and orbit. TNF-α is one of the key proinflammatory cytokines. It stimulates the production of other proinflammatory cytokines, including IL -1β, IL-6, IL-8. Pathomorphological studies have shown that chronic alcohol intoxication is characterized by desquamation of the endothelium [5], and TNF-α contributes to endothelial dysfunction in vessels, damaging endothelial cells by amplifying the expression of adhesion molecules [3,11,15]. Thus, TNF-α may course the pathological changes which are characteristic for ATN. IL-4 is an anti-inflammatory cytokine produced by T-cells class Th2, inhibit synthesis of proinflammatory cytokines [13]. Since Th-lymphocytes mainly produce TNF-α and Th2- lymphocytes mainly produce IL-4 one can judge the value of Th1 and Th2 activity and thus the functional of local and general immune status examining the level of TNF-α and IL-4 [7]. Polyoxidonium has a detoxificating, immunomodulating and membrane protecting activities. Antitoxic potential of polyoxidonium exceeds Neogemodez and Rheosorbilact [10]. To investigate the changes of dopplerography indexes of venous hemodynamics of the eye and orbit under the influence of combined detoxification therapy using polyoxidonium. The study involved 158 male patients (316 eyes) with ATN aged from 30 to 60 years abused alcohol for 10-20 years. The group 1 included 87 patients with ATN (174 eyes) who received conventional treatment (parabulbar injections of dexamethasone and emoxipine, vitamins B, antioxidants, detoxifying agents, drugs that improve blood circulation, antihypoxants, biostimulators). Patients of the group 2 (71 patients, 142 eyes) received the combined detoxification therapy (CDT) using Polyoxidonium intravenously and by intranasal electrophoresis in a daily dose of 6 mg every other day in an amount of 5 (the Patent of Ukraine № 71921U, valid from 25.07.12) in addition to the conventional treatment. Patients were divided into subgroups according to the stages of pathogenetic classification of optic nerve edema of any origin proposed by Zhaboyedov G. D., Skrypnik R. L. (1992 ) [6] according to ophthalmoscopy: A – the stage of hyperemia, B – the stage of swelling, C – the stage of dystrophy. In the same way as it was done by Zhaboyedov G. D., Skrypnik R. L. in point of diabetic optic neuropathy the pathogenetic stages of ischemia and glial atrophy in ATN were joined into the stage of dystrophy. As significant differences in indexes of the blood flow were observed depending on whether signs of arterio-venous shunt (AVS) in the superior orbital vein (SOV) at the stage of dystrophy existed or not the patients at the stage of dystrophy ATN were divided into two subgroups C– and C +. The one-way ANOVA showed a significant adequacy of the distribution of ATN patients among subgroups: 1A, 1B, 1C–, 1C +, 2A, 2B, 2C–, 2C+ (p<0,05). The control group (group 0) consisted of 30 relatively healthy men (60 eyes) of the same age range. The control group included 30 almost healthy male volunteers (60 eyes) of the same age range. According to the one-way ANOVA all the subgroups did not vary in age, which averaged 46,0±0,61 years. All patients were examined before treatment, after treatment and in a month after treatment. The ophthalmological examination included visometry, refractometry, biomicroscopy, computer perimetry, chromoperimetry, colour vision examination, visocontrastometry, biomicroophthalmoscopy using the Goldmann lens. The computer perimetry was performed using the visual field analyzer “Peritest 300” (Russia). The relative area of the visual field with normal perception of light stimuli and the relative area of centrocaecal scotoma were calculated. Chromoperimetry was performed using Forster perimeter. The summarized vision field (SVF) in red and green were determined. The colour vision was examined by Rabkin Y. B. method. In order to estimate the colour vision the index of the colour vision was proposed. The index is a percentage of the number of tables which the patient reads to the total number of the main tables without demonstrational ones which is 25. The visocontrastometry was performed using the atlas of test images by V. V. Volkov et al. [1]. The average spatial contrast sensitivity (SCS) of those in 16 areas of the visual field in percentage of the age norm was determined. The investigation of the blood flow in superior orbital vein (SOV), central retinal vein (CRV), vorticose veins (VV) was held by transorbital method by means of an ultrasound diagnostic device Toshiba “Aplio” (Japan). Colour and power Doppler imaging were used. The veins were identified according to the anatomical localization and blood flow direction. The dopplerography indexes of hemodynamics of SOV were determined in superior-medial part of the orbit at 3,5–4,0 sm depth from the corneal apex more proximal than the inferior orbital vein might flow into it forming of sinus venosus ophthalmicus. The following haemodynamics parameters were evaluated: Vmax – maximal systolic flow velocity; Vmed – mean flow velocity; Vmin – the end-diastolic (minimal) velocity; PI – pulsatility index; RI – resistivity index. The orbital artery (OA), the central retinal artery (CRA), the posterior short (PSCA) and long ciliary arteries (PLCA) were examined [8]. TNFα and IL-4 in tear and serum were measured by ELISA using test systems "Cytokine" (St. Petersburg, Russia) by means of ELISA analyzer-photometer Immuno-Chem-2100 (High Technology, Inc., USA).The statistical analysis was performed by means of the program “SPSS 15.0 for Windows”. Results. The investigation of dopplerography hemodynamics indexes of eye and orbit veins before treatment revealed the patterns of the venous hemodynamics at different stages of ATN. Pre-treatment values of hemodynamics indexes at all stages of the ATN in the group 2 did not show significant difference from those in the group 1 and the same patterns were observed. At the stage of hyperemia before treatment the increase in venous blood flow velocities was established (Tab. 1). It could be one of compensatory mechanisms. It was followed by significant increase in RI of the veins (in VOS – 1,19 times higher than in the control group, in CRV – 1,87 times, in VV – 1,3 times) and increase in РІ in CRV and VV (1,75 and 1,29 times higher than in the control group respectively), which was probably caused by the reduction of elasticity of the vessel wall in consequence of its toxic injury. But the stage of hyperemia ATN was obviously characterized by effectiveness of compensatory mechanisms as visual acuity kept high enough (in the subgroup 1А – 0,88±0,01, in the subgroup 2А – 0,87±0,02) (Tab. 2). The most significant changes of visual functions were centro-cecal scotoma in white enlargement (in the subgroup 1А – 4,93 times higher than in the control group, in the subgroup 2А – 4,99 times), decrease in SVF in red (in the subgroup 1А – 2,57 times less than in the control group, in the subgroup 2А – 2,61 times) and in green (in the subgroup 1А – 3,29 times less than in the control group, in the subgroup 2A – 3,53 times), though all examined indexes of visual function showed significant difference from the control. The most remarkable feature of the stage of swelling was the decrease in blood flow velocities in SOV and CRV compared with the control group (Vmed was 1,17 and 1,34 times lower than in the control group respectively) (Tab. 1). On the other hand, the stage of swelling was distinguished by sharp decrease in visual acuity (in the subgroup 1В it equaled 0,24±0,02 vs 0,88±0,01 in the subgroup 1А, in the subgroup 2B – 0,21±0,02 vs 0,87±0,02 in the subgroup 2А) (Pic. 1) Picture 1. Changes in visual acuity at different stages of ATN. Difference with control group was significant at all stages of ATN, р<0,05 Difference between subgroups was significant, р<0,05
The difference of the stage of dystrophy ATN was the appearance of the signs of arterio-venous shunt (AVS) including the increase in veins Vmax with nearly stable Vmed and Vmin (Tab. 1). In 77,27% cases in the subgroup 1С (the subgroup 1С–) and 79,95% cases in the subgroup 2С (the subgroup 2С–) the dopplerography did not show the signs of AVS in SOV. In SOV the uniform significant decrease in blood flow velocities compared with the control group was determined instead without ane significant differences with the stage of swelling. In 22,73% cases in the subgroup 1С (the subgroup 1С+) та 21,05% cases in the subgroup 2С (the subgroup 2С+) the signs of AVS in SOV were determined including the increase in Vmed in SOV on the account of systolic component. At the same time the signs of AVS in CRV and VV were more remarkable than if there were no signs of AVS in SOV (Vmax in CRV was 1,32 times higher than in the control group if there were signs of AVS in CRV vs 1,08 times if there were no signs of AVS in SOV, in VV – 1,42 times higher vs 1,24 times). The appearance of the signs of AVS in SOV can be regarded as a sign of more severe or long-term pathological changes in the hemodynamics. At the stage of dystrophy without AVS in SOV not sharp but significant decrease in colour vision index, SVF in red and average SCS was observed compared with the stage of swelling. The area of centro-cecal scotoma decreased which probably reflected prevalence of dystrophic changes over edema in the macula and optic nerve (Tab. 2). At the stage of dystrophy with AVS in SOV the significant decrease in the colour vision index and average SCS compared with the stage of dystrophy without AVS in SOV was observed. It proved the right chronological sequence of stages we have chosen. The correlation between dopplerography indexes in the eye and orbit veins and visual function indexes was studied (Tab. 3). The significant direct correlation between veins blood flow velocities and visual acuity, colour vision index, SVF in white, green and red, spatial contrast sensitivity was observed. The significant inverse correlation between PI and RI and above mentioned visual function indexes was shown. The area of centro-cecal scotoma in white showed significant correlation with veins blood flow velocities (inverse relation) as well as PI and RI (direct relation). There were solitary exceptions in particular SOV and VV Vmax and Vmed which did not disturb general tendency. After treatment the significant improvement of hemodynamic indexes of venous blood flow in the eye and orbit was observed both in the subgroups with conventional treatment and in the subgroups with additional CDT. But at the stages of swelling and dystrophy the patients who received CDT in addition to conventional treatment had significant advantages in Doppler indexes of the blood flow. At the stage of hyperemia the raised indexes of venous blood flow showed significant decrease without any significant difference between subgroups received conventional treatment and treatment with additional CDT (Tab. 4). At the stage of swelling the decreased venous blood flow velocities showed significant increase, PI and RI in SOV decreased independent of the regimen of treatment. But in the subgroup which received the conventional treatment PI in CRV and VV as well as RI in CRV increased (Tab. 5). At the stage of dystrophy without AVS in SOV after treatment with CDT the significant increase in all venous blood flow velocities was distinguished, moreover in VV PI and RI decreased while after conventional treatment mostly Vmax increased (Tab. 6). At the stage of dystrophy with AVS in SOV conventional treatment resulted in the increase in VV Vmax, which obviously indicated shunt blood flow enhancement (Tab. 7). In addition after the conventional treatment RI in all examined veins significantly increased. After treatment with CDT the significant increase in venous blood flow velocities was distinguished and in VV PI decreased. In 1 month after treatment at the stages of swelling and dystrophy ATN in the subgroups which received the conventional treatment the deterioration of hemodynamic indexes of venous blood flow in the eye and orbit was observed. It could be evidence of the continuing toxic influence. At the stage of swelling the rise in РІ and RI in CRV and VV was observed which probably indicated arterio-venous shunts formation as a consequence of progressed occlusion of the microcirculatory blood stream (Tab. 5). At the stage of dystrophy without AVS in SOV further increase in Vmax of veins with corresponding increase in PI was shown (Tab. 6). At the stage of dystrophy with AVS in SOV there was increase in RI of the veins (Tab. 7). Instead, in the subgroups which received additional CDT at the stages of swelling and dystrophy ATN the improvement of dopplerographic indexes of venous blood flow was observed. PI and RI decreased which might be due to continuing processes of regeneration (Tab. 4, 5, 6, 7). In ATN the imbalance of proinflammatory and anti-inflammatory cytokines in tear and serum was observed. It was shown by the increase in proinflammatory cytokine TNFα and the decrease in anti-inflammatory cytokine IL-4 in those materials at all stages of ATN (Tab. 8, 9). In tear (Tab. 8) after the conventional treatment (the group 1) at all stages of ATN the significant decrease in both TNFα and IL-4 was observed. In 1 month after the conventional treatment some significant increase in tear TNFα and IL-4 was observed but the levels of those cytokines were still lower than before treatment. The only exception was the subgroup 1С+ (the stage of dystrophy with AVS in SOV), in which in 1 month after treatment TNFα rose to the level which did not show significant difference with the level before treatment and IL-4 decreased. As a result in 1 month after the conventional treatment there were no significant changes of cytokines imbalance at all stages of ATN except for the subgroup 1С+, in which this imbalance rose. In serum (Tab. 9) after the conventional treatment the significant decrease in TNFα was observed without any difference in the levels of IL-4. Thus some decrease in cytokines imbalance was observed. But in 1 month after treatment TNFα rose to the level which at the stages of hyperemia and swelling was lower than before treatment and at the stage of dystrophy did not show significant difference with the last one. At the same time IL-4 did not change. Thus in 1 month after the conventional treatment the cytokines imbalance in serum rose and at the stage of dystrophy riched one before treatment. After the treatment with CDT (the group 2) at all stages of ATN both in tear and serum proinflammatory cytokine TNFα decreased and was significantly lower than after the conventional treatment with simultaneous increase in anti-inflammatory cytokine IL-4. In 1 month after the treatment with CDT tear TNFα did not show significant change at the stages of hyperemia and swelling and rose at the stage of dystrophy but it was lower than in the group 1. Simultaneously IL-4 significantly increased at all stages of ATN. Thus after the treatment with CDT at the stages of hyperemia and swelling the cytokine imbalance decreased and at the stage of dystrophy did not change compared with one after treatment. In serum in 1 month after the treatment with CDT there were no any significant changes in TNFα and IL-4 change compared with ones after treatment, therefore the imbalance of cytokines did not change. Thus in the group treated with CDT the levels TNFα were lower and the levels of IL-4 were higher both in tear and serum after treatment and in 1 month after its finish at all stages of ATN. Hence in ATN treatment with CDT contributes to better cytokine imbalance correction in those materials. The analysis of correlation between tear and serum TNFα and IL-4 levels and dopplerography indexes in the eye and orbit veins (Tab. 10) showed significant inverse correlation between levels of proinflammatory cytokine TNFα in examined materials and blood flow velocities and significant direct correlation between levels of this cytokine and PI and RI. On the contrary, significant direct correlation between levels of anti-inflammatory cytokine IL-4 in examined materials and blood flow velocities and significant inverse correlation between levels of this cytokine and PI and RI were observed. There were solitary exceptions which did not disturb general particularities namely CRV Vmax and VV Vmed did not correlate with serum TNFα. Thus the decrease in venous blood flow velocities in the eye and orbit and the increase in PI and RI showed significant correlation with the deterioration of the visual function indexes as well as with the increase in proinflammatory cytokine TNFα and the decrease in anti-inflammatory cytokine IL-4 in tear and serum. Hence the negative impact of cytokine imbalance on the visual functions of the patients could be partly mediated by the vascular factor. Conclusions
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