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Рецензент: д.мед.н., проф. А.М. Петруня
УДК 617.736 - 005.98 - 02: 616.379 - 008. 64: 615. 37 - 073
ДУ ‹‹Інститут очних хвороб і тканинної терапії ім. В.П. Філатова НАМН України››
ГУ "Институт глазных болезней и тканевой терапии им. В.П.Филатова НАМН Украины" (Одесса)
SI “The Filatov Institute of Eye Diseases and Tissue Therapy of the National Academy of Medical Sciences of Ukraine” (Odessa)
Introduction. The diabetes (D) incidence in 2000 totalled near 170 million people (5% of the global population). Every year this figure grows by 5-7% and doubles biennially. The number of registered diabetes cases in Ukraine is about one million .
Manifestations of the disease on the fundus include diabetic retinopathy (DR) and diabetic macular edema (DME). This is DME that is the major cause of visual impairment in patients with type 2 diabetes [2,6].
In case of DME, high blood glucose level in the cells results in a disturbance of the osmotic and electrolyte balance, pericyte loss and endothelial dysfunction. In the system of blood-aqueous barrier, the blood vessel endothelium plays an important part in regulating platelet activity, prevents intravascular thrombosis and fibrin accumulation. Damage of the endothelium is an essential link in DME pathogenesis .
Laser coagulation is known to remain a major treatment for macular edema . However, in some patients, despite the adequate laser therapy, DME keeps progressing. Laser care aims at eliminating only those manifestations and complications of diabetic maculopathy which are direct causes of deteriorated vision; metabolic and haemocirculatory disorders underlying DME pathogenesis are not corrected .
On the other hand, laser coagulation often causes such complications as retinal and vitreous bleeding, disciform degeneration, retinal atrophy, recurrent and increased macular edema. This situation calls for search of medications which work on different links of diabetic macular edema and can promptly and effectively eliminate the edema.
Objectives: The study aims at determining the thickness of the retina of the macular area for complicated and diffuse (occlusive and non-occlusive) DME in patients with type 2 D after immune correcting therapies.
Materials and methods: The study involved type 2 diabetes patients with various diabetic macular edemas and enrolled the total of 64 patients (128 eyes), including 28 females (43.8%) and 36 males (56.3%) aged in average 58 (SD 10) - from 24 to 78. The average length of type 2 D was 9.3 years (SD 2.8), the minimum length being 6 years and the maximum 19 respectively. Visual acuity before the treatment fell into the range from 0.01 to 0.6, namely from 0.01 to 0.1 in 67 cases (52.3 %); from 0.1 to 0.2 in 24 cases (18.8%); from 0.2 to 0.3 in 18 cases (14.1%); from 0.3 to 0.4 in 10 cases (7.8%); from 0.4 to 0.5 in 6 cases (4.7%); from 0.5 to 0.6 in 3 cases (2.3%).
All the patients underwent a complex ophthalmologic examination, including visometry, refractometry, biomicroophthalmoscopy, optical coherent tomography, fluorescent angiography, as well as immunological tests included in the research plan. The study embraced cases of diffuse (occlusive and non-occlusive) and complicated (occlusive and non-occlusive) DME. There were 33 cases of diffuse occlusive DME, 35 cases of diffuse non-occlusive DME, 28 cases of complicated occlusive DME and 32 cases of complicated non-occlusive DME.
Analysis of OCT data relied on Mаcular Thickness Map protocol, and the scanning results were interpreted using Retinal Thickness/VolumeTabular and Retinal Thickness/Volume Change protocols. In all the patients fluorescent angiography served for differentiating DME types. We proposed using cytoflavin and cycloferon for complex treatment of type 2 D with various types of DME. The patients were divided into 2 groups – Group I including non-occlusive cases of diffuse and complicated DME and Group II made up of occlusive cases of diffuse and complicated DME. In the complex treatment of DME, Group I patients were prescribed cycloferon, whereas Group II patients were given both cycloferon and cytoflavin.
Cycloferon is a low-molecular interferon inducer, which underlies its broad spectrum of biological activity – antivirus, immune-modulating, anti-inflammatory, anti-proliferative and antitumor effects.
The drug induces high titres of alpha-, beta-, gamma-interferon in the organs and tissues which contain lymphoid elements (the intestinal mucosa, spleen, liver, lungs) and penetrates the blood-brain barrier. The immune-modulating effect of cycloferon manifests itself in activation of phagocytosis, natural killer cells, cytotoxic T-lymphocytes and correction of the immune status for immune-deficient conditions of various origins. The course of treatment includes 10 intra-muscular injections according to the base scheme with the single dose of 2.5 g.
Pharmacological effects of cytoflavin stem from the complex action of substances which form components of the drug, namely 1 ml of the solution comprises succinic acid 100 mg, niacinamide 10 mg, inosine 20 mg, riboflavin mononucleotide (riboflavin) 2 mg and such excipients as N-methylglucamine (meglumine), sodium hydroxide and water for injection. The drug stimulates breathing and energy production in the cells, improves oxygen uptake by the tissues, and restores scavenging enzymes activity. It activates intracellular protein synthesis, promotes disposal of glucose and aliphatic acids and re-synthesis of γ-aminobutyric acid (GABA) in the neurons by GABA shunt. All the occlusive DME patients were administered cytoflavin by intravenous drop infusion of the medication diluted with 100 – 200 ml of 5 – 10% glucose solution or 0.9% sodium chloride solution in the dose of 10 ml q.d. for 10 days.
Experimental data were processed using Statistica 10.0. The differences between the patient groups were analysed with the help of variance analysis, and p-value (p) was presented; in case of deviation of the null hypothesis paired differences were analysed using Newman-Keuls test for multiple differences. The data were presented as the average and the standard error of the mean (M±m). For evaluating the correlation between the type of edema and the optical result, χ² - Pearson's chi-squared test was applied. RIDIT analysis with calculation of 95% confidence interval served to compare the effectiveness of vision improvement depending on the DME type .
Results and discussion.
In all the patients with various types of DME prior to the treatment the clinical examination revealed edema of the macular area, presence of hard and soft exudates as well as of spot and linear hemorrhages in the peripheral retina and along the blood vessel branches. Biomicroscopy detected the optical section of the retina to be non-uniformly enlarged. The recommended drugs were well-tolerated by the patients, causing no allergic reactions, complications or any other adverse effects. After 20-day treatment the patients reported subjective improvement of vision. Objectively, ophthalmoscopy showed reduced macular edema, resolution of the soft exudates and haemorrhages in the peripheral retina.
The treatment by the combination of cycloferon and cytoflavin resulted in the positive dynamics of the condition of the retina. Analysis of the data obtained shows that in case of non-occlusive diffuse and complicated DME, there are statistically significant metrical differences between the values of macular thickness before the treatment and after it: up to 555±29
Fig.1 Change of macular thickness for diffuse and complicated (occlusive and non-occlusive) DME before and after treatment; 1- diffuse non-occlusive and complicated non-occlusive DME; 2- diffuse occlusive and complicated occlusive DME.
Analysis of other retinal areas showed that there is a tendency towards reduced macular thickness in the inner temporal quadrant in case of non-occlusive type of diffuse and complicated DME, which amounts to 526±18 µm and 518±20 µm before and after treatment, respectively, though this difference is not statistically significant. In case of occlusive diffuse and complicated DME, the macular thickness in the internal temporal quadrant was 512±19 µm before the treatment and dropped to 490±21 µm after it, which is already statistically significant (p=0.003). Further analysis showed that macular thickness in the upper-inner quadrant for non-occlusive diffuse and complicated DME amounted to 515±17 µm before immune correction and became equal to 497±18 µm after it. The similar tendency is observed for occlusive diffuse and complicated DME, in which case before the therapy the macular thickness was 501±18 µm and following the treatment 487±19 µm, correspondingly, which is not statistically significant. In the inner nasal quadrant, for non-occlusive diffuse and complicated DME, macular thickness was 518±18 µm prior to treatment and dropped to 485±18 µm (p=0.00002), statistically significant difference) after it, whereas for occlusive diffuse and complicated DME the decrease of macular thickness was from 508 ± 18 µm to 466 ± 18 µm after the therapy, which is also statistically significant (p=0.00002). In the lower inner quadrant macular thickness for non-occlusive diffuse and complicated DME before treatment was 525±17 µm and after immune correction lowered to 492±17µm; at the same time, for occlusive diffuse and complicated DME these values were 518±18 µm and 479±18 µm, respectively, which is statistically significant in both cases (p=0.00002). Further on, there is observed a tendency towards reduction of macular thickness in the outer temporal quadrant for cases of non-occlusive diffuse and complicated DME, which is 450 ± 15 µm before treatment and 427 ± 15 µm after it; for cases of occlusive diffuse and complicated DME macular thickness in this quadrant amounted to 443 ± 16 µm and 411 ± 16 µm before and after treatment, respectively, which is statistically significant (p=0.00002). Analysis of the results obtained for the upper outer quadrant for non-occlusive diffuse and complicated DME estimated the macular thickness to be 428 ± 17 µm before and 397 ± 17.5 µm after treatment, which is statistically significant (p=0.0001); for occlusive diffuse and complicated DME these values were evaluated at 420 ± 17 µm before and 401 ± 18 µm after therapy (p=0.01). In the outer nasal quadrant, for non-occlusive diffuse and complicated DME macular thickness was found to be 431 ± 15 µm prior to treatment and 396 ± 15 µm after it (p=0.00008); for occlusive diffuse and complicated DME (p=0.0002) these values were 426± 16 µm and 403± 16 µm, respectively. In the outer lower quadrant, macular thickness for non-occlusive diffuse and complicated DME amounted to 439 ± 15 µm before therapy and 412 ± 15 µm after it (p=0.0007); accordingly, for occlusive diffuse and complicated DME these values were evaluated at 432 ± 15 µm and 415± 16 µm, which is a statistically significant difference (p=0.01).
Due to the administered therapy for diffuse and complicated DME there was observed positive clinical and morphometric dynamics accompanied by improved vision in the majority of the patients.
Fig. 2 shows visual acuity for every patient before and after the treatment.
Fig. 2 Visual acuity for diffuse and complicated DME (occlusive and non-occlusive types) before and after therapy.
In this figure, blue dots signify the initial vision for each patient prior to the treatment, and the data are grouped from the lowest to the highest. The red dots mean vision after the necessary immune correction. As it is seen above, most patients experienced improvement of vision.
Analysis of significance of differences between diffuse and complicated DME (occlusive and non-occlusive types) and improvement of vision in the mentioned groups of patients confirms the fact of statistically significant correlation between the DME type and improved vision (c2 =22.8; р=0.0008). For instance, in case of diffuse non-occlusive DME increase of visual acuity by 0.1 and higher was achieved in 32 cases, which constitutes 91.4%; in three cases (8.6%) there were no significant changes observed. For diffuse occlusive DME improvement of vision by 0.1 and higher was recorded in 24 cases (72.2%). Effectiveness of vision improvement for complicated DME cases is considerably lower, especially for occlusive type – there were only 11 cases of improved vision, which is 40.7%, whereas for complicated non-occlusive DME improvement of vision was observed in 16 cases (50%). There is observed a clear correlation between DME type and vision improvement. For complicated DME the effectiveness of vision improvement is much lower in most patients (especially for complicated occlusive DME), while for diffuse DME it is considerably higher, and its highest value is observed for diffuse non-occlusive DME, which is statistically significant (p=0.0008).
Comparison of vision improvement effectiveness for diffuse and complicated (occlusive and non-occlusive) DME relied on RIDIT-estimation, which is illustrated in Fig. 3.
Fig. 3. Vision improvement effectiveness for diffuse and complicated (occlusive and non-occlusive) DME after the administered treatment.
In this case, the result of the therapy is depicted as an ordered category – from 1 to 3. Mean ridits for these types of DME are 0.63 for diffuse non-occlusive DME, 0.53 for diffuse non-occlusive DME, 0.42 for complicated non-occlusive DME and 0.38 for complicated occlusive DME, respectively. The figure shows effectiveness of vision improvement as the function of DME type. The higher the score of mean ridit is, the larger the number of high values of vision improvement in the patients group under the research is; in our case ‘3’ means improvement by 0.1 and higher. Therefore, it is seen from the figure that in case of diffuse non-occlusive DME effectiveness of vision improvement is statistically significantly (р=0.0001) higher than for complicated (occlusive and non-occlusive) DME, whereas diffuse non-occlusive and diffuse occlusive types are similar, though in terms of vision improvement effectiveness there is a statistically significant difference between these two DME types (р=0.0001).
1. Cycloferon and cytoflavin promote improvement of disease pattern in the complex therapy for patients with diffuse and complicated (occlusive and non-occlusive) DME, namely macular edema reduction, faster resolution of haemo- and plasmorrhagias and improved visual acuity after the administered treatment. There is a distinct correlation between DME type and vision improvement. For complicated DME vision improvement effectiveness is much lower in most patients, especially in case of complicated occlusive DME, which accounts for 40.7%, whereas for diffuse DME effectiveness of vision improvement is considerably higher, and its largest value is observed for diffuse non-occlusive DME (91.4%), which is statistically significant (p=0.0008).
2. Using the proposed combination of drugs in the complex therapy for patients with diffuse and complicated (occlusive and non-occlusive) DME resulted in reduced macular thickness. For non-occlusive type of diffuse and complicated DME this value was estimated to fall into the range 555 ± 29 µm before therapy and 522 ± 21 µm (p=0.000009) after it, while for occlusive diffuse and complicated DME these values were found to be 520 ± 24 µm and 476 ± 22 µm, respectively (p=0.000009).
3. Administration of cycloferon and cytoflavin in the complex therapy for type 2 diabetes patients with diffuse and complicated (occlusive and non-occlusive) DME can be considered viable and substantiated.
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