Ophthalmological and Neurological Findings in Patients with Idiopathic Uveitis Associated with Retinal Vasculitis and the Relation with the HLA DR15 Allele.

PURPOSE: In 15 patients with idiopathic uveitis associated with retinal vasculitis, HLA DRB1 gene testing was performed to detect a possible association. 11 patients tested positive and 4 negative for the HLA DRB1 × 15 allele. The presence of the HLA DRB1 × 15 haplotype might be associated with a higher susceptibility to develop Multiple Sclerosis (MS). METHODS: In this case series, we describe the ophthalmological and neurological findings in 10 HLA DR15-positive patients and 4 HLA DR15-negative patients that had neurological workup, including Magnetic Resonance Imaging (MRI) of the brain. RESULTS: All patients had granulomatous ocular inflammation with either panuveitis or intermediate uveitis. MRI of the brain showed white matter lesions in 13 patients (9/10 and 4/4 respectively) of which 4 patients were eventually diagnosed with MS (3/10 and 1/4 respectively). CONCLUSION: Although the majority of tested patients was carrying at least one HLA DRB1-15 allele, there was no difference in ophthalmological and neurological findings in both groups.

Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome.

Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.

A rare presentation of a common carotid artery occlusion.

Background: A common carotid artery occlusion (CCAO) is very rare and the clinical features of CCAO have rarely been described. Since the blood supply of the eye and orbit is derived from the internal carotid artery, a CCAO may present with various ophthalmological symptoms, ranging from incidental findings to complete visual loss but also other neuro-ophthalmological abnormalities. Case report: A 61-year-old woman presented with acute monocular vision loss and an elevation deficit of the right eye. Fluorescein angiography showed delayed filling of both the retinal and choroidal vasculature, without occlusion/embolisms of the retinal arteries. Vascular imaging showed a right CCAO. Conclusion: CCAO has a variable presentation. In patients with acute unilateral visual loss a CCAO should be considered, especially when ocular motility deficits are present. Fluorescein angiography examination can aid in the localization and diagnosis of the vascular insult. Urgent referral for a systemic work-up is essential.

The use of optical coherence tomography angiography to measure changes in iris vasculature after strabismus surgery.

INTRODUCTION: Anterior segment ischemia (ASI) is a rare but potentially sight-threatening complication of strabismus surgery. Preoperative imaging of the iris vasculature may be appropriate in patients at high risk of ASI. In clinical practice, this is currently done through invasive fluoresceine or indocyanine green (ICG) angiography and in study context through laser speckle contrast imaging. The purpose of this study is to investigate the use of noninvasive optical coherence tomography angiography (OCTA) as a screening tool for ASI in strabismus surgery. METHODS: A prospective interventional trial was conducted from September until November 2021 at the Leuven University Hospitals. Patients scheduled for strabismus surgery to one or more rectus muscles underwent OCTA preoperatively and at day two postoperatively. The vascular density was calculated for all images with sufficient quality. Information on risk factors for ASI was collected. A two-sided t-test was used for pairwise comparison pre- and postoperatively. Filling defects were qualitatively assessed. RESULTS: Eighteen patients were included. In only seven muscles of five patients, images of sufficient quality on both image acquisition moments were suitable for statistical analysis. The mean age of these patients was 45.2 years and 40% were women. A mean vascular density of 53,099% preoperatively and a mean density of 50,782% postoperatively with a mean decrease of 2.316% (p = .318, 95% confidence interval [-2.886; 7.516]) was found. No filling defects were identified. DISCUSSION: The small final number of images contributing to statistical analysis shows that current application of the OCTA technique is hampered by poor image quality and poor repeatability. We identified difficulties in the image acquisition process and variable pupil size due to iris muscle contractions as the two main reasons. We believe that adjustments in the OCTA software such as pupil tracking and tracking of iris vasculature can largely overcome these limitations. Furthermore, there is a need for a normative database to allow good quantitative comparison and risk stratification. We conclude that OCTA could be suitable for screening in prevention of ASI with both qualitative and quantitative analysis if adjustments are made.

Optical coherence tomography as a prognostic tool for disability progression in MS: a systematic review.

Since multiple sclerosis (MS) is characterized by an unpredictable disease course, accurate prognosis and personalized treatment constitute an important challenge in clinical practice. We performed a qualitative systematic review to assess the predictive value of retinal layer measurement by spectral-domain optical coherence tomography (SD-OCT) in MS patients. Longitudinal MS cohort studies that determined the risk of clinical deterioration based on peripapillary retinal nerve fiber layer (pRNFL) and/or macular ganglion cell-inner plexiform layer (mGCIPL) atrophy were included. Our search strategy and selection process yielded eight articles in total. Of those, five studies only focused on patients with a relapsing-remitting disease pattern (RRMS). After correction for confounders such as disease duration, we found that (1) cross-sectional measurement of pRNFL thickness ≤ 88 µm; (2) cross-sectional measurement of mGCIPL thickness < 77 µm; (3) longitudinal measurement of pRNFL thinning > 1.5 µm/year; and (4) longitudinal measurement of mGCIPL thinning ≥ 1.0 µm/year is associated with an increased risk for disability progression in subsequent years. Longitudinal mGCIPL assessment consistently resulted in the highest risk estimates in our analysis. Within these studies, inclusion and exclusion criteria accounted for the retinal degeneration inherent to (acute) optic neuritis (ON). This small systematic review provides additional evidence that OCT-measured pRNFL and/or mGCIPL atrophy can predict disability progression in RRMS patients. We therefore recommend close clinical follow-up or initiation/change of treatment in RRMS patients with increased risk for clinical deterioration based on retinal layer thresholds, in particular when other poor prognostic signs co-occur.

Association between near viewing and acute acquired esotropia in children during tablet and smartphone use.

We investigated a possible association between the acute onset of esotropia and tablet or smartphone use in children. We characterized the clinical aspects of esotropia associated with tablet or smartphone use. The medical records of 10 children aged between 5 and 15 years old with presumably tablet or smartphone associated esotropia were reviewed regarding orthoptic examination and cycloplegic refraction. Legal guardians of the children were asked to fill in a questionnaire regarding tablet and smartphone use of their child. This questionnaire was also conducted in a control group of age-matched children. The results of this questionnaire were compared to search for possible determinants of tablet or smartphone associated esotropia. All 10 patients presented with a comitant esotropia ranging from 8 to 45 prism diopters with no significant difference between near and far. The mean age of onset was 9.8 years. Cycloplegic refraction showed a mild hyperopia in eight patients, a mild myopia in one patient and emmetropia in the other patient. All patients had near full refractive correction at the onset of esotropia. Diplopia was reduced after visual hygiene recommendations, however in six patients, strabismus surgery was needed. The working distance was significantly shorter in the 10 cases compared to the controls. In children with acute acquired esotropia, we found a statistically significant association with a smaller working distance during tablet or smartphone use compared to age-matched controls. We hypothesize that intensive near viewing can be a precipitating factor in this type of esotropia.

Extraocular muscle hypoplasia associated with Axenfeld-Rieger syndrome.

We describe a four-year-old girl with bilateral severe iris hypoplasia and secondary ocular hypertension. Genetic testing revealed a de novo deletion in the FOXC1 gene, establishing the diagnosis of Axenfeld-Rieger syndrome (ARS). The girl developed a gradually increasing exotropia, up to 95 prism diopters by the age of 3 years wherefore strabismus surgery was performed. Intra-operatively, only very rudimentary developed medial and lateral rectus muscles were found. This is the first observation of pronounced hypoplasia of both medial and lateral rectus muscles associated with ARS.

Two Cases Presenting With Unilateral Adduction Deficit Associated With Human Adenosine Deaminase 2 Deficiency.

Deficiency of human adenosine deaminase 2 (DADA2) is an auto-inflammatory inborn error of immunity caused by biallelic deleterious mutations in the gene encoding ADA2. The purpose of this article is to raise awareness among ophthalmologists and pediatricians to consider DADA2 as a possible diagnosis for patients with acute onset of diplopia. The authors describe two pediatric patients who presented with double vision due to uni-lateral adduction deficit, and discuss the importance of recognizing this clinically as an ophthalmologist. If a child presents with a sudden eye movement abnormality, ophthalmologists must be aware of the possibility of an ischemic insult due to an underlying genetic disorder (eg, DADA2), especially in patients with a positive familial history or associated clinical signs such as a personal history of characteristic skin lesions or paresis of other cranial nerves. Given the multi-organ involvement in this disorder, a multi-disciplinary approach is crucial to have a timely diagnosis and to treat this rare disorder appropriately. [J Pediatr Ophthalmol Strabismus. 2021;58(4):e22-e26.].

Insights into multiple sclerosis-associated uveitis: a scoping review.

PURPOSE: This paper is a scoping review of research on multiple sclerosis (MS)-associated uveitis to determine its epidemiology, pathophysiology, clinical features and treatment. METHODS: A comprehensive search of the medical databases MEDLINE (PubMed), EMBASE, Web of Science and Cochrane was carried out on 25 November 2019, to identify papers published between 1980 and 2019 that focus on patients with MS-associated uveitis. RESULTS: Based on large cohort studies (n ≥ 1000), the prevalence of uveitis in patients with MS is estimated to be 0.53-1.34% (mean = 0.83%), and MS is diagnosed in 0.52-3.20% (mean = 1.30%) of patients with uveitis. The condition is most frequent among middle-aged women. Patients usually complain of floaters and/or blurred vision, with bilateral intermediate uveitis (with retinal vasculitis) as the most frequent ophthalmological finding. Both MS and intermediate uveitis are associated with HLA-DRB1*15:01 and IL-2RA gene polymorphism rs2104286 A > G, suggesting a common genetic background. T cells, and possibly B cells, play an important role in both autoimmune disorders. Multiple sclerosis (MS)-related uveitis is classically treated as non-infectious uveitis, with corticosteroids as the first treatment step. Other treatments include immunosuppressants, cryotherapy, laser photocoagulation and vitrectomy. These treatment options have a limited, if any, effect on the course of MS and can be complicated by side-effects. As treatment strategies for MS have increased in the last decade, it would be interesting to evaluate the efficacy of these new treatments during the course of uveitis. Moreover, the correlation between retinal periphlebitis and MS could be established more accurately with the recently developed techniques of wide-field fluorescein angiography in a large cohort of MS patients. CONCLUSION: MS-associated uveitis is a rare, highly discussed pathology about which much is still unknown. Large epidemiological studies and extrapolation of new MS treatments to this condition are warranted.

Globe Subluxation following Long-Term High-Dose Steroid Treatment for Myasthenia Gravis.

This case report describes the unusual presentation of a globe subluxation following long-term high-dose oral steroid treatment for myasthenia gravis (MG). The patient presented initially with fluctuating vertical diplopia. Auto-antibodies against the acetylcholine receptor were weakly positive, confirming the diagnosis of MG. After initial treatment with pyridostigmine, the disease evolved to generalized MG. Plasmapheresis and high-dose steroids were started subsequently. As a side effect of this treatment the patient gained about 30 kg in weight and developed steroid myopathy and a prominent cushingoid facies with bilateral exophthalmos. A year after his initial diagnosis he experienced a spontaneous globe subluxation on the left eye. He was able to immediately reposition the globe manually himself. Four months later a new subluxation occurred. Because of these aforementioned severe side effects of the steroid treatment, the methylprednisolone was tapered and replaced by tacrolimus. After about 6 weeks the patient went into remission. We believe, that the spontaneous globe subluxations were caused by a weakness of the extraocular muscles in combination with a significant gain of intraorbital fat tissue, both induced by cumulative, excessive steroids. Steroids are often necessary in the treatment of MG; however, most of the time a high dose of 64 mg is not needed for ocular MG and especially the continuation of a dose of 58 mg or more for a long period is not recommended. Careful follow-up is obligatory to timely recognize side effects. In case of severe side effects or the need for long-term treatment, the use of other immunosuppressive therapies should be considered. Extra care and caution is recommended in patients who are anatomically predisposed with proptosis.

Acute bilateral serous retinal detachments with spontaneous resolution in a 6-year-old boy.

A healthy 6-year-old boy presented with acute bilateral vision loss, multiple serous retinal detachments between the vascular arcades and a thickened choroid. Spontaneous resolution occurred over several weeks. We hypothesize that the clinical constellation in our patient is suggestive of acute exudative polymorphous vitelliform maculopathy (AEPVM) or might be an atypical presentation of Vogt-Koyanagi-Harada (VKH) disease. We propose that it was caused by an autoimmune-mediated activation of inflammatory cells at the level of the choroid, induced by an unknown trigger.

Congenital bilateral folds in Descemet's membrane with high astigmatism.

We present the case of a boy with congenital bilateral folds in Descemet's membrane, causing high astigmatism and myopia. There are multiple causes of folds and tears in Descemet's membrane. In our case, the most likely origin is the mother's prolonged labor, although a severe car accident of the mother at the gestational age of 27 weeks as the cause of these folds cannot be entirely excluded.

Ophthalmic Outcome in a Belgian Cohort of Cystinosis Patients Treated with a Compounded Preparation of Cysteamine Eye Drops: Retrospective Analysis.

INTRODUCTION: Treatment of the anterior segment problems in cystinosis is challenging as oral cysteamine is ineffective in the treatment of corneal problems because of its avascular structure. Although cysteamine eye drops have been formulated to counter this issue, the stability of cysteamine in these off-licensed formulations and treatment compliance are major problems. The aim of this retrospective study was to determine the efficacy of a compounded preparation of aqueous 0.5% cysteamine eye drops in the management of corneal complications of cystinosis. METHODS: Data of patients attending the multidisciplinary cystinosis clinic at the University Hospitals Leuven, Belgium between January 2015 and December 2018 were analyzed. All cystinosis patients were treated with the compounded preparation of aqueous 0.5% cysteamine eye drops and oral cysteamine. RESULTS: A total of 12 patients were treated with the compounded preparation of aqueous 0.5% cysteamine eye drops, of whom 75% were aged > 18 years (n = 9). The mean instillation frequency of the cysteamine eye drops was 3.3 drops/eye per day, and the mean number of hospital visits was two per year. All patients showed photophobia, > 30% corneal infiltration, blepharospasm, eye pain and conjunctival hyperemia during the study period. None of these symptoms improved with treatment with aqueous compounded 0.5% cysteamine eye drops. The corneal cystine crystal score was ≥ 2 in all patients at the last  visit. CONCLUSION: Treatment with the compounded preparation of aqueous 0.5% cysteamine eye drops, combined with oral cysteamine, was not effective in reducing corneal cystine crystal deposition and other ocular symptoms in these patients with cystinosis. FUNDING: Recordati Rare Diseases.

Ocular Neuromyotonia: Case Reports and Literature Review.

Ocular neuromyotonia (ONM) is a rare eye movement disorder, presenting as a paroxysmal involuntary spasm of one or more extra-ocular muscles, that can persist for a few seconds up to several minutes. The phenomenon is caused by the contraction of an extra-ocular muscle, excited by a damaged nerve, which leads to delayed muscle relaxation. We present eight patients with this rare condition together with an overview of the literature on all published ONM cases. One of the presented cases is possibly secondary to hypovitaminosis D. This association has not been reported previously in the literature. A possible underlying mechanism is given.

Optical Coherence Tomography Angiography of Retinal Microvascular Changes Overlying Choroidal Nodules in Neurofibromatosis Type 1.

PURPOSE: To report 3 cases of neurofibromatosis type 1 (NF1) with choroidal nodules associated with retinal microvascular changes imaged with optical coherence tomography angiography (OCTA). METHODS: Small case series in 3 NF1 patients. OCTA examinations were performed by a trained examiner (J.J.) after pupillary dilation. A standard scan, centered over the macula measuring 6 × 6 mm and 3 × 3 mm was obtained according to the findings on standard color photography. Additional scans were obtained in the zones with microvascular abnormalities. The segmentation provided by the machine software was used. RESULTS: Corkscrew retinal vessels were observed in association with "placoid"-type choroidal nodules as shown by near-infrared reflectance imaging. In all cases, multiple lesions were found. They were second- or third-order tortuous vessels originating from the superior or inferior temporal veins. OCTA demonstrated that the tortuous venules were located in the superficial capillary plexus, and no abnormalities were found in the deep capillary plexus. DISCUSSION: Corkscrew retinal vessels are part of a spectrum of retinal microvascular alterations seen in association, sometimes overlying choroidal nodules in patients with NF1 and are visualized in the superficial capillary plexus on OCTA. We demonstrated with OCTA that they are not associated with flow loss or ischemia in the superficial and deep capillary plexus. The link between the underlying nodule remains unclear. Since neovascularization was described in choroidal ganglioneuroma, we hypothesize that corresponding secretory substances from Schwann cells, ganglion cells, or melanocytes in choroidal nodules might alter the retinal vasculature. CONCLUSION: We report on 3 cases of NF1 with choroidal nodules in association with retinal microvascular changes imaged with OCTA. OCTA demonstrated preservation of the blood flow in the deep and superficial capillary plexus of the retina. We hypothesize that angiogenic factors secreted by the underlying choroidal nodules could have an effect on the retinal vasculature. Further immunohistological studies in NF1 patients with choroidal nodules to detect angiogenic factors (such as VEGF) are necessary to confirm this hypothesis.

Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation.

BACKGROUND: Paraneoplastic melanocytic proliferation (bilateral diffuse uveal melanocytic proliferation, BDUMP) is a rare but devastating disease that causes progressive visual loss in patients who usually have an occult malignancy. Visual loss occurs as a result of paraneoplastic changes in the uveal tissue. METHODS: In a masked fashion, the serum of two patients with BDUMP was evaluated for the presence of cultured melanocyte elongation and proliferation (CMEP) factor using cultured human melanocytes. We evaluated the efficacy of plasmapheresis as a treatment modality early in the disease in conjunction with radiation and chemotherapy. RESULTS: The serum of the first case patient was investigated after plasmapheresis and did not demonstrate proliferation of cultured human melanocytes. The serum of the second case was evaluated prior to treatment with plasmapheresis and did induce this proliferation. These findings are in accordance with the diminution of CMEP factor after plasmapheresis. Treatment with plasmapheresis managed to stabilise the ocular disease progression in both patients. CONCLUSIONS: In the past, visual loss due to paraneoplastic melanocytic proliferation was considered progressive and irreversible. We treated two patients successfully with plasmapheresis and demonstrated a relation between CMEP factor in the serum of these patients and proliferation of cultured melanocytes.