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Рецензент: д.мед.н., проф. А.М. Петруня
1Харківська медична академія післядипломної освіти
Харьковская медицинская академия последипломного образования
61176, г. Харьков, ул.Корчагинцев, 58
Kharkov medical academy of Postgraduate Education
61176, Kharkov, 58 str.Korchahyntsev
2КЗ Сумська обласна клінічна лікарня
КУ Сумская областная клиническая больница
MI Sumy regional hospital
Introduction. Haemodynamics disturbances are characteristic of alcoholic toxic neuroretinopathy (ATN). The ophthalmodynamometry revealed regional arterial hypertension, which was the most severe in the central retinal artery . Rheoohthalmography showed vascular dystonia of hypertonic type with primary suffering of small caliber vessels and microcirculatory disoders [2,8,10]. But solitary investigations devoted to haemodynamics disturbances at ATN does not illuminate the entire spectrum of these disorders. 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 , and TNF-α contributes to endothelial dysfunction in vessels, damaging endothelial cells by amplifying the expression of adhesion molecules [3,14,16,17]. 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 . 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 . Polyoxidonium has a detoxificating, immunomodulating and membrane protecting activities. Antitoxic potential of polyoxidonium exceeds Neogemodez and Rheosorbilact . Doppler changes in arterial hemodynamics of the eye and orbit under the influence of treatment have not been studied previously.
Purpose. To investigate the changes of dopplerography indexes of arterial hemodynamics of the eye and orbit under the influence of combined detoxification therapy using polyoxidonium.
Material and methods. 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 )  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). 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 . 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. . 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 eye and orbit arteries blood flow was held by transorbital method by means of an ultrasound diagnostic device Toshiba “Aplio” (Japan). Colour and power Doppler imaging were used. The arteries were identified according to the anatomical localization and blood flow direction. 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 . 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 patterns of dopplerography changes of arterial blood flow at different stages of ATN were distinguished . At the stage of hyperemia the moderate decrease in arteries blood flow velocities was observed. CRA, PSCA, PLCA were characterized by 2,13, 2,99 and 1,59 times decrease in Vmin and corresponding 23,53%, 24,24% and 10,77% increase in RI respectively compared with age normal indexes. These changes in blood flow indexes could be consequences of initial occlusion of the arteries brunches of a small caliber. The peculiarity of the stage of swelling of ATN was the change in CRA blood flow waveforms, which had the form of “splashes”. Though Vmах was high enough (10,73±0,11 sm/s) the pulsation wave faded away quickly, and Vmin equaled merely 0,51±0,03 sm/s, and what is more in 13,8% cases reached zero level. At the stage of dystrophy further rise in РІ in ОА and PLCA compared with the stage of swelling was observed. It was probably connected with vessel wall elasticity reduction in consequence of sclerotic processes.
At the stage of hyperemia the significant increase in arteries blood flow velocities with decrease in PI and RI were observed both after conventional treatment and after treatment with CDT (Tab. 1). But in the subgroup 2A (with CDT) unlike the subgroup 1A OA blood flow velocities reached the levels in the control group. In 1 month after treatment in the subgroup 1A the deterioration of arterial haemodynamics indexes compared with after treatment levels was observed. The rise in PI and RI of all examined arteries as well as decrease in PSCA and PLCA blood flow velocities occurred. On the contrary, in in th e subgroup 2A the haemodynamics indexes kept being improved. The increase in arteries blood flow velocities as well as decrease in PI and RI in PSCA and PLCA were observed.
At the stage of swelling after treatment the significant increase in arteries blood flow velocities with decrease in PI and RI were observed both in the subgroup 1B and 2B (Tab. 2). In OA indexes of haemodynamics reached the levels in the control group. But in the subgroup 2B the parameters of CRA haemodynamics became closer to the levels in the control group and PI in PSCA was lower compared with the subgroup 1B. In 1 month after treatment in the subgroup 1B unlike the subgroup 2B the deterioration of arterial haemodynamics was observed. In CRA it was shown by the decrease in Vmin and the increase in PI and RI to the levels which were higher than before treatment. In PSCA it was shown by the decrease in Vmin and Vmed and the increase in PI and RI. In PLCA it was shown by the decrease in all blood flow velocities and the increase in PI and RI.
At the stage of dystrophy without AVS in SOV after treatment the significant increase in arteries blood flow velocities with decrease in PI and RI in OA and PLCA were observed both in the subgroup 1C– and 2C– without significant difference between those subgroups (Tab. 3). But such changes in CRA and PSCA were significant only in the subgroup 2C–. In 1 month after treatment in the subgroup 1С– the significant deterioration of arterial haemodynamics compared with one after treatment was observed. It was shown by the increase in PI and RI in all examined arteries, which became higher than before treatment, except from PI in OA which did not show significant difference from corresponding level before treatment. In the subgroup 2С– in 1 month after treatment the deterioration of arterial haemodynamics did not occur. Moreover in OA and PLCA the significant decrease in RI was observed, and in PLCA the significant decrease in PI was also determined. The last one might be owing to the improvement of functioning of arterial collateralization after CDT.
At the stage of dystrophy with AVS in SOV after treatment all examined arteries blood flow velocities increased both in the subgroup 1С+ and 2С+ in ОА and PLCA only (Tab. 4). But in the subgroup 1С+ it was followed by the increase in RI in ОА whereas in the subgroup 2С+ RI in PLCA decreased. In the subgroup 1С+ after treatment the significant increase in CRA PI was determined because of decrease in Vmed. Thus in the subgroup 1С+ the CRA “steal” syndrom was observed. In PSCA the haemodynamics indexes of arterial blood flow did not show significant difference with ones before treatment. In 1 month after treatment in the subgroup 1С+ the decrease in Vmed in PSCA and further decrease in Vmed in CRA with corresponding increase in CRA PI were determined. Thus in the subgroup 1С+ the CRA and PSCA “steal” syndrom was observed. Besides ОА, PSCA and PLCA showed significant decrease in Vmin, RI in ОА PSCA increased, RI in PLCA tended to rise, but the difference was not significant. It could indicate the progression of occlusion of minute caliber arteries and microcirculation blood vessels. In the subgroup 1С+ in 1 month after treatment in OA and CRA PI and RI showed significant decrease. It could indicate the continuing process of regeneration after the treatment was finished. PSCA and PLCA did not show any significant difference in arteries haemodynamics indexes during 1 month after treatment.
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. Thus in ATN treatment with CDT contributes to better cytokine imbalance correction in those materials (Tab. 5, 6). The dynamics of the cytokine status as well as visual function indexes under the influence of CDT at different stages of ATN were analyzed in detail in our previous publications .
The analysis of correlation between tear and serum TNFα and IL-4 levels and dopplerography indexes in the eye and orbit arteries (Tab. 7) 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. For example PSCA Vmed correlated only with serum TNFα (inverse relation); PSCA РІ correlated with tear TNFα (direct relation) and serum IL-4 (inverse relation); PLCA РІ correlated with tear but not serum TNFα (direct relation) and IL-4 (inverse relation).
The relationship between dopplerography indexes in the eye and orbit arteries and visual function indexes was studied (Tab. 8). The significant direct correlation between arteries 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 arteries blood flow velocities (inverse relation) as well as PI and RI (direct relation). There were solitary exceptions in particular PSCA Vmax and Vmed which did not disturb general tendency.
In ATN the inverse correlation between tear TNFα and visual acuity as well as direct correlation between tear IL-4 and visual acuity were established (for TNFα ρ=-0,839; for IL-4 ρ=0,689). The same was observed for colour vision index (for TNFα ρ=-0,867; for IL-4 ρ=0,759), SVF in white (for TNFα ρ=-0,759; for IL-4 ρ=0,724), red (for TNFα ρ=-0,716; for IL-4 ρ=0,666) and green (for TNFα ρ=-0,766; for IL-4 ρ=0,691), spatial contrast sensitivity (for TNFα ρ=-0,862; for IL-4 ρ=0,769). The direct correlation between the area of centro-cecal scotoma in white and serum TNFα was established (ρ=0,477) and the inverse direct correlation between the area of centro-cecal scotoma in white and serum IL-4 was observed (ρ=0,346) (Tab. 9) .
Thus the decrease in blood flow velocities of the arteries of the eye and orbit and the increase in PI and RI correlated with the deterioration of the visual functions as well as with the increase in proinflammatory cytokine TNFα and the decrease in anti-inflammatory cytokine IL-4 in tear and serum. On the other hand the increase in TNFα and the decrease in IL-4 in tear and serum showed significant correlation with visual function indexes . Thus cytokine imbalance deteriorates visual functions partly by means of vascular factor. As TNFα contributes to endothelial disfunction injuring endothelial cells [3,14,16,17], it could be one of the mechanisms of vascular changes. Those pathological endothelial changes require further investigation.
Conclusions. The efficacy of the combined detoxification therapy (СDT) using polyoxidonium (the patent of Ukraine for useful model № UA 71921u) in complex treatment of patients with ATN according to arterial hemodynamics indices, visual function parameters and cytokine imbalance at various stages of ATN was proved. The СDT had advantages compared with the conventional regimen at all stages of ATN.
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