The clinical variability of maternally inherited diabetes and deafness is associated with the degree of heteroplasmy in blood leukocytes.

CONTEXT: Maternally inherited diabetes and deafness (MIDD) is a rare form of diabetes with a matrilineal transmission, sensorineural hearing loss, and macular pattern dystrophy due to an A to G transition at position 3243 of mitochondrial DNA (mtDNA) (m.3243A>G). The phenotypic heterogeneity of MIDD may be the consequence of different levels of mutated mtDNA among mitochondria in a given tissue. OBJECTIVE: The aim of the present study was thus to ascertain the correlation between the severity of the phenotype in patients with MIDD and the level of heteroplasmy in the blood leukocytes. PARTICIPANTS: The GEDIAM prospective multicenter register was initiated in 1995. Eighty-nine Europid patients from this register, with MIDD and the mtDNA 3243A>G mutation, were included. Patients with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) or with mitochondrial diabetes related to other mutations or to deletions of mtDNA were excluded. RESULTS: A significant negative correlation was found between levels of heteroplasmy and age of the patients at the time of sampling for molecular analysis, age at the diagnosis of diabetes, and body mass index. After adjustment for age at sampling for molecular study and gender, the correlation between heteroplasmy levels and age at the diagnosis of diabetes was no more significant. The two other correlations remained significant. A significant positive correlation between levels of heteroplasmy and HbA(1c) was also found and remained significant after adjustment for age at molecular sampling and gender. CONCLUSIONS: These results support the hypothesis that heteroplasmy levels are at least one of the determinants of the severity of the phenotype in MIDD.

Macular pattern dystrophy in MIDD: long-term follow-up.

A case of maternally inherited diabetes and deafness (MIDD)-associated macular pattern dystrophy with a 15-year follow-up is reported. On initial examination at age 37, visual acuity was normal, but chorioretinal atrophy at the posterior pole was already present in both eyes. At age 52, visual acuity remained normal in the right eye and was only slightly decreased in the left eye despite notable extension of the areas of chorioretinal atrophy in that eye. No evidence of diabetic retinopathy was present at any time. This case shows that visual acuity can remain stable in the long term despite extensive lesions of macular pattern dystrophy.

Retinal and renal complications in patients with a mutation of mitochondrial DNA at position 3,243 (maternally inherited diabetes and deafness). A case-control study.

AIMS/HYPOTHESIS: We assessed the prevalence and determinants of retinal and renal complications in patients with maternally inherited diabetes and deafness (MIDD). METHODS: This was a multicentre prospective study comparing the prevalence of retinopathy and renal disease in 74 patients with MIDD and 134 control patients matched for sex, age and clinical presentation at onset of diabetes, duration of diabetes and current treatment. Comparisons were adjusted for HbA(1c) and hypertension. RESULTS: In MIDD patients, HbA(1c) (7.6 +/- 1.6 vs 8.5 +/- 2.0%, p < 0.002), systolic blood pressure (126.6 +/- 16.2 vs 133.1 +/- 17.3 mmHg, p < 0.007) and prevalence of hypertension (33.8 vs 64.2%, p < 0.0001) were lower than in control patients. Prevalence of diabetic retinopathy was 3.7-fold lower in MIDD patients (6/74, 8 vs 40/134, 29.6%, p < 0.0001). Differences between groups remained significant after adjustment for hypertension, systolic blood pressure and HbA(1c). In MIDD, urinary albumin excretion (314.8 vs 80.1 mg/24 h, p = 0.035) and creatinine plasma levels (103.5 vs 82.2 micromol/l, p = 0.0178) were higher and GFR was lower. Impaired renal function (GFR <60 ml/min) was four- to sixfold more frequent in MIDD. Differences between MIDD and control diabetic patients further increased when adjusted for HbA(1c) and systolic blood pressure (p < 0.0001). Adjustment for treatment with an ACE inhibitor or angiotensin II receptor antagonist did not modify the results. CONCLUSIONS/INTERPRETATION: This study indicates that diabetic retinopathy is less prevalent in MIDD than in control diabetes. This suggests that retinal alterations due to mitochondrial disease may have a protective role. By contrast, nephropathy is far more frequent in MIDD, suggesting the presence of a specific renal disease independent of diabetic nephropathy.

OPHDIAT: a telemedical network screening system for diabetic retinopathy in the Ile-de-France.

OBJECTIVE: International and national guidelines recommend an annual funduscopic examination for all diabetic patients, but such annual fundus examinations are not sufficiently performed in France. Non-mydriatic fundus photography is a valid method of evaluation for diabetic retinopathy (DR) and a viable alternative to ophthalmoscopy. After two pilot studies demonstrated the feasibility of telemedical screening for diabetic retinopathy in both hospital and primary-care settings, we developed a regional telemedical network, OPHDIAT, designed to facilitate access to regular annual evaluations of patients with diabetes while saving medical time. MATERIALS AND METHODS: OPHDIAT comprises peripheral screening centres equipped with non-mydriatic cameras, where fundus photographs are taken by technicians linked by telemedicine to a reference centre, where ophthalmologists grade the images. Currently in the Ile-de-France region, 16 screening centres are linked through a central server to an ophthalmologic reading centre and includes 11 centres located in the diabetes departments of 11 hospitals, one diabetic retinopathy screening centre located in northern Paris, three in healthcare centres and one in a prison. RESULTS: During the 28-month evaluation period, 15,307 DR screening examinations were performed. Retinal photographs of at least one eye could not be graded in 1332 patients (9.7%) and diabetic retinopathy was detected in 3350 patients (23.4%). After the screening examination, 3478 patients (25.2%) were referred to an ophthalmologist for either DR, cataract and/or non-gradable photographs. CONCLUSION: Fundus photography combined with telemedicine has the potential to improve the regular annual evaluation for diabetic retinopathy. The organization of the network around a central reading centre serves to guarantee quality control.

OPHDIAT: quality-assurance programme plan and performance of the network.

AIMS: There is a need for evaluation of screening and grading services for diabetic retinopathy (DR) in compliance with quality-assurance (QA) standards. We describe the screening/grading QA programme set up for OPHDIAT over the 2005-2006 period. METHODS: Screening and grading objectives, evaluation criteria and minimum acceptable QA standards were set. To ensure the quality of DR photos, the proportion of nongradable photos in at least one eye had to be less than 10%. To ensure grading accuracy, intergrading agreement had to be greater than 90%. Grader-generated reports had to be available in less than 48 h for more than 80% photos. Readers had to grade 500 to 3000 photos per year. RESULTS: Sixteen screening centres were opened between June 2004 and December 2006, and 14,769 patients were screened. Percentages of nongradable photos were consistently below the QA requirement (less than 10%). Overall, 800 photos were graded a second time by a reader blinded to original grading; agreement between graders ranged from 92 to 99%. More than 90% of grader-generated reports were produced within 48 h. The number of readings by each grader nearly achieved the QA standard. CONCLUSION: QA for DR telescreening should be a continuous process to provide performance feedback, thus guaranteeing a high standard for delivered results. Almost all of the predetermined QA standards in OPHDIAT for screening and grading were met. Besides the quality/sensitivity of the screening/grading modalities, it is important to evaluate at-risk patients so that they can be treated efficiently; this should be addressed in a global QA programme.

[A new grading system from color fundus photographs for screening for diabetic retinopathy]. / Classification simplifiée de la rétinopathie diabétique adaptée au dépistage par photographies du fond d'oeil.

AIM: Fundus photographs using a nonmydriatic digital camera are the reference method for diabetic retinopathy screening today. The aim of this study was to validate a simplified diabetic retinopathy classification, adapted for diabetic retinopathy screening, including all diabetic retinopathy severity scales. PATIENTS AND METHODS: One hundred and twenty-one diabetic patients had three digital color fundus photographs taken, which were graded by four independent ophthalmologists according to the proposed screening classification, and a reference examination (nine field fundus photographs and optical coherence tomography examination of the macula). RESULTS: The proposed diabetic retinopathy screening classification was easy to use, as it was based on a visual comparison between the three digital color fundus photographs and standard retinal photographs. This classification provided the diagnosis of severe levels of diabetic retinopathy with high sensitivity and accurate specificity (100% and 50%-58%,respectively, for a moderate nonproliferative diabetic retinopathy level or higher on the screening examination) and the diagnosis of macular edema with a high sensitivity and specificity (96%-97% and 89%-91%, respectively). The results of the screening examination using this classification were highly reproducible (weighted k for interobserver agreement: 0.78-0.93). CONCLUSION: These results suggest that this new simplified classification is accurate. The screening method should not be used above the threshold level of mild nonproliferative diabetic retinopathy. Thus, from the moderate nonproliferative level (inclusive), a complete fundus examination should be undertaken. Severe levels of diabetic retinopathy will be referred to an ophthalmologist without delay for laser treatment.

Evaluation of the effect of JPEG and JPEG2000 image compression on the detection of diabetic retinopathy.

AIMS: To compare the effect of classic Joint Photographic Experts Group (JPEG) and JPEG2000 compression algorithms on detection of diabetic retinopathy (DR) lesions. METHODS: In total, 45 colour fundus photographs obtained with a digital nonmydriatic fundus camera were saved in uncompressed Tagged Interchanged Files Format (TIFF) format (1.26 MB). They were graded jointly by two retinal specialists at a 1 month interval for soft exudates, hard exudates, macular oedema, newvessels, intraretinal microvascular abnormalities (IRMA), and retinal haemorrhages and/or microaneurysms. They were compressed to 118, 58, 41, and 27 KB by both algorithms and 24 KB by classic JPEG, placed in random order and graded again jointly by the two retina specialists. Subjective image quality was graded, and sensitivity, specificity, positive and negative predictive values, and kappa statistic were calculated for all lesions at all compression ratios. RESULTS: Compression to 118 KB showed no effect on image quality and kappa values were high (0.94-1). Image degradation became important at 27 KB for both algorithms. At high compression levels, IRMA and HMA detection were most affected with JPEG2000 performing slightly better than classic JPEG. CONCLUSION: Performance of classic JPEG and JPEG2000 algorithms is equivalent when compressing digital images of DR lesions from 1.26 MB to 118 KB and 58 KB. Higher compression ratios show slightly better results with JPEG2000 compression, but may be insufficient for screening purposes.

Advanced glycation end products can induce glial reaction and neuronal degeneration in retinal explants.

BACKGROUND/AIMS: Neuronal degeneration has been reported to occur in diabetic retinopathy before the onset of detectable microvascular abnormalities. To investigate whether advanced glycation end products (AGE) could be directly responsible for retinal neurodegeneration, retinal explants were incubated with glycated bovine serum albumin (BSA). METHODS: Retinal explants obtained from non-diabetic adult rats were incubated 4 days with or without 200 mug/ml glycated BSA. Neural apoptosis was quantified by terminal dUTP nick end labelling (TUNEL) binding and immunostaining with anti-cleaved caspase-3 antibody. Expression of glial fibrillary acidic protein (GFAP) was localised by immunofluorescence. RESULTS: TUNEL and cleaved caspase-3 positive cells increased significantly by 2.2-fold and 2.5-fold in retinal explants incubated in glycated BSA (p<0.05), respectively. The ganglion cell layer was the most sensitive retinal layer to the glycated BSA. Neuronal degeneration was confirmed by the increased GFAP labelling in Müller glial cells from retinal explants treated with glycated BSA. CONCLUSION: These results suggest that AGE could induce retinal neurodegeneration in the absence of blood perfusion. Cells in the ganglion cell layer appeared to be the most sensitive as in diabetic retinopathy and its animal models. AGE toxicity could therefore contribute to the early pathological mechanisms of diabetic retinopathy.

[Optic neuropathy associated with primary antiphospholipid syndrome]. / Neuropathie optique associée à un syndrome primaire des anti-phospholipides.

We describe a 45-year-old male patient with an atypical unilateral optic neuropathy who was diagnosed with primary antiphospholipid syndrome. The initially poor vision lasting several months completely recovered and long-term oral anticoagulation therapy prevented potential further systemic thrombotic complications.

Spontaneous resolution of vitreomacular traction associated with diabetic macular edema.

PURPOSE: Little information is available about the natural history of vitreomacular traction (VMT) associated with diabetic macular edema. A few cases of spontaneous resolution of VMT associated with diabetic macular edema have been described, but have not been documented by optical coherence tomography (OCT). The authors report the spontaneous resolution of VMT associated with diabetic macular edema 1 month after the end of panretinal photocoagulation therapy (PRP). CASE REPORT: A 66-year-old woman presented with complicated proliferative diabetic retinopathy and diabetic macular edema associated with VMT, documented by OCT, in the right eye. Left eye examination showed complete PRP and ischemic maculopathy. PRP was immediately realized in the right eye in regard to the presence of complicated proliferative diabetic retinopathy. RESULTS: One month after the end of PRP, right eye visual acuity improved. OCT examination showed complete release of foveal posterior hyaloid traction, and significant reduction in foveal thickness. The follow-up was 1 year. At the end of follow-up, visual acuity slightly improved again; only a small residual foveal retinal thickening remained. CONCLUSIONS: The authors report spontaneous resolution of VMT associated with diabetic macular edema, probably facilitated by PRP, with concurrent reduction of macular thickness and visual improvement. As spontaneous resolution may occur in some eyes with diabetic macular edema associated with VMT, a period of observation after the end of the PRP may be considered prior to vitrectomy.

Tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with unilateral neuroretinitis: a case report.

PURPOSE: To report a case of tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with unusual unilateral neuroretinitis. METHODS: An 11-year-old girl who developed anterior uveitis 3 months after acute tubulointerstitial nephritis, without any etiologic factors for either nephritis or uveitis, is presented. RESULTS: Several days after the anterior uveitis, the patient presented with unilateral optic disk edema associated with a serous retinal detachment of the posterior pole, never previously described in TINU syndrome, leading to the formation of perifoveal intraretinal exudates. CONCLUSIONS: In spite of these posterior lesions, clinical course confirmed the previously reported favorable visual outcome of TINU syndrome treated with corticosteroids. It appeared that ocular impairment in TINU syndrome could be more diffuse and more extensive than previously described. As well as the whole uveal tract, the retina and the optic nerve may also be the ocular targets of the idiopathic inflammatory response in TINU syndrome.

Tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with unilateral neuroretinitis: a case report.

PURPOSE: To report a case of tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with unusual unilateral neuroretinitis. METHODS: An 11-year-old girl who developed anterior uveitis 3 months after acute tubulointerstitial nephritis, without any etiologic factors for either nephritis or uveitis, is presented. RESULTS: Several days after the anterior uveitis, the patient presented with unilateral optic disk edema associated with a serous retinal detachment of the posterior pole, never previously described in TINU syndrome, leading to the formation of perifoveal intraretinal exudates. CONCLUSIONS: In spite of these posterior lesions, clinical course confirmed the previously reported favorable visual outcome of TINU syndrome treated with corticosteroids. It appeared that ocular impairment in TINU syndrome could be more diffuse and more extensive than previously described. As well as the whole uveal tract, the retina and the optic nerve may also be the ocular targets of the idiopathic inflammatory response in TINU syndrome. (Eur J Ophthalmol 2004; 14: 334-7).