Zaid Shalchi

Circulating Nucleic Acids and Diabetic Complications

Abstract:  Diabetes mellitus is a major health problem across the world. Diabetic retinopathy (DR) and nephropathy are two of the major complications of diabetes. DR is the leading cause of blindness and diabetic nephropathy is the leading cause of end‐stage renal failure. We have examined the potential value of circulating nucleic acids in the detection and monitoring of these two complications of diabetes. mRNA for nephrin was significantly higher in all diabetics compared to healthy controls and it was significantly higher in normoalbuminuric patients compared to healthy controls. This may indicate progression to microalbuminuric stage. Circulating rhodopsin mRNA was detectable in healthy subjects and in diabetic patients. It was significantly raised in diabetic patients with retinopathy. Higher rhodopsin mRNA in diabetic patients without retinopathy suggests that some of them may go on to develop it or already have it subclinically. Circulating nucleic acids have the potential to be noninvasive molecular tests for diabetic complications.

Twenty-year follow-up of a randomized prospective clinical trial of excimer laser photorefractive keratectomy

PURPOSE To investigate the 20-year efficacy and safety of photorefractive keratectomy (PRK). DESIGN Long-term observational case series. METHODS In the setting of a university hospital, a study population of 42 patients (42 eyes) who had, as part of a randomized prospective trial, undergone PRK 20 years previously were studied. All had received -3.0 or -6.0 diopter (D) corrections with either 5.0 or 6.0 mm optical zones or a multizone treatment. The mean preoperative spherical equivalent refractive error (SEQ) was -5.13 D (range, -2.75 to -8.0 D). The outcome measures included visual acuity, refractive error, corneal topography and axial length. RESULTS Between 1 and 20 years there was an increase in mean myopic SEQ of -0.54 D (P < 0.02). In patients younger than 40 years of age at time of correction, this increase was -0.92 D (P < 0.002) with an accompanying increase in variance (P < 0.02), whereas in those older than 40 it was -0.08D (P = 0.8). In female patients the change was -0.69D (P < 0.01), while in males it was -0.26D (P = 0.6). The efficacy index at 20 years was 0.49, and the safety index was 0.97. Corrected distance visual acuity improved between 1 and 20 years (P < 0.01); 93% of corneas were clear at 20 years; 3 eyes had trace haze. There was an improvement in haze scores between 1 and 20 years (P < 0.02). Cornea power remained unchanged between 6 months and 20 years (P = 0.4). Axial length increased by a mean of 0.84 mm (P < 0.0001). There was no ectasia. CONCLUSIONS There was a slight but significant increase in myopic SEQ after PRK between 1 and 20 years, particularly in those under 40 at the time of treatment and in female patients. Corneal power remained unchanged, but axial length increased. The procedure was safe, with no long-term sight-threatening complications and with improvements in corrected distance visual acuity and corneal transparency with time.

Retina-Specific mRNA in the Assessment of Diabetic Retinopathy

In a previous study we demonstrated the presence and diagnostic usefulness of circulating rhodopsin mRNA in the assessment of diabetic retinopathy (DR). In the present study we investigated three further retina‐specific markers in blood to determine their suitability as markers of DR. The markers were RPE65, retinoschisin, and melanopsin. Whole blood was collected from diabetic patients and healthy controls into PAXgene Blood RNA tubes and RNA was extracted using the PAXgene Blood RNA System. Quantitative real‐time PCR was used to quantify mRNA for RPE65, retinoschisin, and melanopsin. β‐actin mRNA was used for normalization. RPE65, retinoschisin, and β‐actin mRNA were detected in 100% of subjects; melanopsin was not detected in either controls or diabetic patients. Circulating RPE65 mRNA concentration was 63% higher in diabetic patients than in healthy individuals (P= 0.019), whereas retinoschisin showed no change between the two groups. Compared with healthy controls, circulating RPE65 mRNA concentration was higher in diabetics with no retinopathy (30%; P= NS), background DR (93%; P= 0.01), preproliferative DR (20%; P= NS), and proliferative DR (107%; P= 0.004). Compared with diabetics with no retinopathy, levels of RPE65 mRNA were also significantly higher (60%) in the presence of proliferative DR (P= 0.029). In contrast, levels of retinoschisin mRNA were lower in background DR (34%; P= 0.033), preproliferative DR (43%; P= 0.026), and proliferative DR (47%; P= 0.038) compared to that in diabetics without retinopathy. We conclude that not all retina‐specific mRNA species are detectable in circulation (e.g., melanopsin). This may be related to differences in expression levels for the individual markers. Both RPE65 and retinoschisin were detectable and demonstrated contrasting trends in diabetics with and without retinopathy. In combination with rhodopsin, RPE65, and retinoschisin, mRNA may offer a useful tool in developing a blood test for DR.

Spectral domain optical coherence tomography findings in long-term silicone oil-related visual loss.

Purpose: To investigate spectral domain optical coherence tomography findings in long-term silicone oil–related visual loss. Methods: Four symptomatic patients were reviewed 4 years to 9 years after vitrectomy with silicone oil tamponade for macula-on retinal detachment. Three lost vision with oil in situ, with one at the time of oil removal. Eleven control eyes with good vision were included. Patients underwent assessment of best-corrected visual acuity, contrast sensitivity, Farnsworth-Munsell 100 Hue testing, static perimetry, and spectral domain optical coherence tomography imaging of the macula and disk. Results: Long-term best-corrected visual acuity was significantly reduced in affected eyes (range, 0.44–1.02), as was contrast sensitivity (0.75–1.35) and color discrimination (Farnsworth-Munsell-100 Hue score, 151–390). Static perimetry showed a central scotoma in all affected eyes. Optical coherence tomography revealed microcystic macular changes in the inner nuclear layer of all affected eyes associated with severe loss of the papillofoveal retinal nerve fiber layer. In one patient, serial optical coherence tomography images showed development of microcystic macular changes 18 months after oil removal. Control eyes lacked these features, except two asymptomatic eyes that showed microcystic changes on optical coherence tomography with a corresponding paracentral scotoma. Conclusion: We have demonstrated microcystic macular changes in the inner nuclear layer of affected eyes, as well as focal severe loss of the papillofoveal projection. These changes share significant morphologic features reported in multiple sclerosis–associated optic neuritis and Leber hereditary optic neuropathy.

Macular spectral domain optical coherence tomography findings in Tanzanian endemic optic neuropathy.

Bilateral optic neuropathy in Dar es Salaam is now considered endemic and is estimated to affect 0.3-2.4% of young adults. The condition is characterized by a subacute bilateral loss of central vision of unknown aetiology. Findings of spectral domain optical coherence tomography have not previously been reported for these patients. All patients diagnosed with endemic optic neuropathy over a 2-year period at the Muhimbili National Hospital underwent spectral domain optical coherence tomography macular imaging. Scans were graded qualitatively for severity of retinal nerve fibre layer loss as well as the presence of microcystic macular changes, which have not previously been described in this condition. Of the 128 patients included (54.7% male; median age 20 years), severe retinal nerve fibre layer loss was found in 185 eyes (74.0%). There was full concordance in retinal nerve fibre layer thickness between the two eyes in 113 (91.1%) patients. Microcystic macular spaces were found in 16 (12.5%) patients and were bilateral in nine (7.0%) individuals. These changes were typically more prominent in the nasal than the temporal macula, predominantly involving the inner nuclear layer, and often occurred in an annular configuration that was evident on en face infra-red imaging, though not discernible on colour fundus photography or clinically. All patients with microcystic macular changes had severe thinning of the retinal nerve fibre layer (P = 0.02). Four patients in whom cystic spaces were demonstrated had sequential scans, and there was no detectable alteration in the configuration of these changes over a period of up to 16 months. This is the first study to document optical coherence tomography findings in endemic optic neuropathy. We have observed symmetrical severe loss of the caeco-central projection (papillomacular bundle) with otherwise well-preserved macular architecture. Also, we have observed microcystic retinal changes in a significant proportion of patients, which were associated with severe retinal nerve fibre layer loss. Similar changes have recently been reported from optical coherence tomography images of patients with multiple sclerosis, relapsing isolated optic neuritis, dominant optic atrophy, Lebers hereditary optic neuropathy and a patient with a chronic compressive optic neuropathy, supporting the hypothesis that this may be a non-specific phenomenon secondary to ganglion cell death. The correspondence of the changes to an annulus discernible on infra-red en face imaging, but not using other conventional retinal imaging techniques highlights the potential usefulness of this modality.

Spectral Domain Optical Coherence Tomography Findings in a Case Series of Patients with Bilateral Diffuse Uveal Melanocytic Proliferation

Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic disorder characterized by bilateral serous retinal detachment with degeneration of the retinal pigment epithelium (RPE). The condition commonly occurs in females with gynecological carcinoma or males with lung malignancy, although several other cancer sites have been described. Furthermore, the condition may occur as the first sign of yet undiscovered malignancy. Our understanding of BDUMP has increased significantly in the last 5 years. Affected patients have recently been shown to possess cultured melanocyte elongation and proliferation (CMEP) factor in the IgG fraction of the serum, explaining the efficacy of plasma exchange in the treatment of the condition. Furthermore, BDUMP-associated dermal and conjunctival melanocytic proliferations have been shown to have minimal malignant potential. Although several authors have reported histological retinal findings in BDUMP, these may be complicated by preparation artifact. We present, for the first time to our knowledge, a mini case series of spectral domain optical coherence tomography (OCT) findings in BDUMP. CASE REPORTS

Risk factors for visual impairment in patients with sickle cell disease in London.

Purpose Dramatically improved health care in recent years has increased the life expectancy of patients with sickle cell disease (SCD) as well as the prognosis for its ocular complications. We sought to identify risk factors for visual impairment in patients with SCD in London 4 decades after Goldbergs seminal studies. Methods Patients 16 years and older with SCD (genotypes HbSS, HbSC, HbSβ-thalassemia) attending hematology and ophthalmology services were offered ocular examination. Retinopathy was graded according to the Goldberg classification. Visual impairment was defined as corrected distance visual acuity of 20/40 or poorer. Results In total, 182 eyes of 182 patients (mean ± SD age, 37.2 ± 12.8 years; female, 65.9%) were included. Women were significantly older than men (mean ± SD age, 38.8 ± 13.1 vs 34.2 ± 11.8 years; p = 0.0174). There was no difference in mean age of each genotype group (p>0.15). Risk factors for sight-threatening proliferative sickle retinopathy (PSR) were age over 35 years (odds ratio [OR] 2.01; 95% confidence interval [CI] 1.05-3.89; p = 0.0359) and HbSC genotype (OR 4.06; 95% CI 2.07-7.98; p<0.0001). Although visual impairment was related to the presence of sight-threatening PSR (OR 7.23; 95% CI 1.50-35.0; p = 0.0138), it was not related to hemoglobin genotype (p>0.50). Conclusions We present the largest study of ocular findings in SCD in the United Kingdom. Sight-threatening PSR is a risk factor for visual impairment, but hemoglobin genotype status is not.

Bilateral descemet membrane detachment following cataract surgery.

Descemet membrane detachment (DMD) is a sight-threatening complication that has been reported after diverse surgical procedures. Unilateral DMD typically arises as the result of engagement of the Descemet membrane during intraocular surgery. We report an unusual case of bi latera l DMD occurring spontaneously several weeks after sequential uncomplicated phacoemulsification cataract extraction. We review previously reported cases and propose that these eyes share an underlying weakness of Descemet membrane attachment.

Re: Abegg et al.: Microcystic macular edema: retrograde maculopathy caused by optic neuropathy (Ophthalmology 2014;121:142-9)

Dear Editor: The study by Abegg et al adds significantly to the evidence that the optical coherence tomography microcystic macular changes first described by Gelfand et al in the context of multiple sclerosis are not specific for demyelinating disease, but occur in other optic neuropathies. In their study, they found such changes in compressive, vascular, and hereditary optic neuropathies. We recently published a study of optical coherence tomography findings in 128 patients with another optic neuropathy (Tanzanian endemic optic neuropathy), and found that 12.5% of affected individuals imaged at a single center displayed the same microcystic changes. All of these patients also had severe nerve fiber layer loss in the cecocentral projection (suggesting that this may be a necessary condition for developing microcystic changes in this context) and the changes were frequently in an annular configuration, evident in en face infrared fundus images. We feel that the term “retrograde maculopathy” is highly appropriate and would support its adoption for these changes because it seems likely that this represents a retrograde degeneration that can follow the loss of retinal ganglion cells from a variety of causes. Whether it is akin to retrograde trans-synaptic degeneration seen elsewhere in the central nervous system remains to be established. As the range of etiologies grows wider, identifying common features (and potentially excluding those features unique to each disorder), together with longitudinal optical coherence tomography data, could shed light on underlying homeostatic processes in the retina, including those that, when perturbed, cause these changes to develop in some individuals and not in others. OMAR A. MAHROO, PHD, FRCOphth ZAID SHALCHI, MRCP JOHN KISIMBI, MD, MMed ANNA J. SANYIWA, MD, MPH MOIN D. MOHAMED, PhD, FRCOphth GORDON T. PLANT, MD, FRCP Department of Ophthalmology, St Thomas’ Hospital, London, UK; Department of Ophthalmology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania

‘Dilatation’ and ‘dilation’: trends in use on both sides of the Atlantic

The synonyms ‘dilation’ and ‘dilatation’ are used frequently in ophthalmology and other disciplines. The first recorded examples of early forms of the two words in English date from the end of the 14th century.1 ‘Dilatation’ is etymologically more sound,2 preserving the Latin dilatatio (corresponding to the verb dilatare , with the stem dilatat , from which the word ‘dilate’ also derives), but ‘dilation’ could be justified by arguing that –tion is a live suffix in English and so can be added to the verb ‘dilate’ to give ‘dilation’.2 We examined trends in usage in medical and wider English-language literature using three open access digital databases: the PubMed database (http://www.pubmed.com) provides data for citations per year; the Google Scholar search engine (http://scholar.google.com) searches more widely, including non-medical literature and patents; and the Google Books Ngram Viewer (http://books.google.com/ngrams) searches corpora of several million digitised books, taken from over 40 university libraries, stretching …