Rainer Guthoff

Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography

Objective: The aim of this non-interventional study was to characterize retinal layer pathology in Susac syndrome (SuS), a disease with presumably autoimmune-mediated microvessel occlusions in the retina, brain, and inner ear, in comparison to the most important differential diagnosis multiple sclerosis (MS). Methods: Seventeen patients with SuS and 17 age- and sex-matched patients with relapsing-remitting MS (RRMS) and healthy controls (HC) were prospectively investigated by spectral-domain optical coherence tomography (OCT) including intraretinal layer segmentation in a multicenter study. Patients with SuS additionally received retinal fluorescein angiography (FA) and automated perimetry. Results: Patchy thinning of the retinal nerve fiber layer, ganglion cell layer, inner plexiform layer, inner nuclear layer, and outer plexiform layer compared to corresponding sectors in RRMS and HC eyes (p < 0.003 for SuS vs RRMS and HC) was observed in 23/34 (68%) SuS eyes, particularly in temporal quadrants. The outer nuclear layer (ONL) and photoreceptor layers (PRL) were not affected. FA performed in 15/17 patients with SuS was negative for disease-specific branch retinal artery occlusions in all but 1 eye at the time of OCT examination and revealed no additional vascular abnormalities, even in severely damaged OCT areas. In a subset of patients with SuS, associations of visual field data with distinct retinal layers were observed. Conclusion: Distinct OCT patterns of scattered, scar-like intraretinal pathology in SuS eyes, sparing the ONL and PRL, suggest a retinal, but not choroidal, vascular pathomechanism and clearly differentiate SuS from RRMS. Depending on the disease stage, OCT and FA provide specific complementary diagnostic information in SuS.

Diagnostic criteria for Susac syndrome.

Background Susac syndrome is characterised by the triad of encephalopathy with or without focal neurological signs, branch retinal artery occlusions and hearing loss. Establishment of the diagnosis is often delayed because the triad is complete only in a minority of patients at disease onset. This leads to a critical delay in the initiation of appropriate treatment. Our objective was to establish criteria for diagnosis of either definite or probable Susac syndrome. Method The establishment of diagnostic criteria was based on the following three steps: (1) Definition of a reference group of 32 patients with an unambiguous diagnosis of Susac syndrome as assessed by all interdisciplinary experts of the European Susac Consortium (EuSaC) team (EuSaC cohort); (2) selection of diagnostic criteria, based on common clinical and paraclinical findings in the EuSaC cohort and on a review of the literature; and (3) validation of the proposed criteria in the previously published cohort of all Susac cases reported until 2012. Results Integrating the clinical presentation and paraclinical findings, we propose formal criteria and recommend a diagnostic workup to facilitate the diagnosis of Susac syndrome. More than 90% of the cases in the literature fulfilled the proposed criteria for probable or definite Susac syndrome. We surmise that more patients could have been diagnosed with the recommended diagnostic workup. Conclusions We propose diagnostic criteria for Susac syndrome that may help both experts and physicians not familiar with Susac syndrome to make a correct diagnosis and to prevent delayed treatment initiation.

Subtle retinal pathology in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is characterized by neuro‐ophthalmological abnormalities beyond disturbed oculomotor control such as decreased visual acuity and disturbed visual evoked potentials. Here we report retinal alterations in a cohort of 24 patients with clinically definite (n = 20) or probable (n = 4) ALS as compared to matched controls. High‐resolution spectral domain optical coherence tomography with retinal segmentation revealed a subtle reduction in the macular thickness and the retinal nerve fiber layer (RNFL) as well as a marked thinning of the inner nuclear layer (INL). Our data indicate an unprecedented retinal damage pattern and suggest neurodegeneration beyond the motor system in this disease.

Corneal confocal microscopy in chronic inflammatory demyelinating polyneuropathy

There is an unmet need for better diagnostic tools to further delineate clinical subsets of heterogeneous chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) to facilitate treatment decisions. Corneal confocal microscopy (CCM) is a noninvasive and reproducible nerve imaging technique. This study evaluates the potential of CCM as a diagnostic surrogate in CIDP and MMN.

Age-related macular degeneration and coronary heart disease: evaluation of genetic and environmental associations.

An association between coronary heart disease (CHD) and age-related macular degeneration (AMD) has long been postulated but results from epidemiological case-control studies, and genetic analyses have been ambiguous. In this study we illuminate the association between AMD and CHD with respect to genetic and environmental risk factors, age of disease onset and AMD subgroups. AMD patients (n = 1036) and age-matched control subjects (n = 412) between 68 and 95 years of age were included in the case-control study. A medical history of CHD, cerebral stroke and arterial hypertension was determined for each individual. The assessment of interacting factors included the current use of systemic medications and smoking habits. Analysis of AMD associated genetic variants included frequent polymorphisms at the complement factor H (CFH, MIM 134370) gene (rs1061170 [p.Y402H], rs800292 [p.I62V]), the complement factor H-related 3 (CFHR3, MIM 605336)/complement factor H-related 1 (CFHR1, MIM 134371) locus (rs6677604; proxy for ΔCFHR3/CFHR1; r(2) = 0.97) as well as the age-related maculopathy susceptibility 2 (ARMS2, MIM 611313) gene (rs10490924 [p.A69S]). Logistic regression identified a significant positive association of AMD with AMD-risk variants in CFH, ARMS2, and smoking ≥ 20 packs/year. A history of CHD and the current use of antihyperuricemic agents were inversely associated with the disease. Significantly fewer patients with rs6677604 nonrisk genotype A/A regularly used statins. ARMS2:p.A69S risk variant was significantly associated with exsudative AMD. AMD patients with risk variants at rs1061170 (CFH:p.Y402H) and ARMS2 and smokers (≥20 packs/year) were significantly earlier affected by AMD than those carrying the non-risk variants at each locus. Our data support three major conclusions. First, the age of AMD onset is significantly influenced by genetic and environmental risk factors. Second, in support of previous reports we also show that the ARMS2 rs10490924:T allele is significantly linked to exsudative AMD. And finally, a self-reported history of CHD was inversely associated with AMD in this study. Novel therapeutic strategies aiming at preventing the development of AMD may considerably differ from those that have been developed to treat cardiovascular disorders as both common disorders likely underlie different pathomechanisms.

Congenital cystic eye.

BackgroundCongenital cystic eye is a rare ocular and orbital malformation describing an intraorbital cavity lined by neuroglial tissue. Clinical and histopathologic findings of a 3-year-old boy with a congenital cystic eye are presented.MethodsA 4-year-old otherwise healthy boy with anophthalmia of the right eye was referred because of progressive volume enlargement of his congenital cystic lesion of the right orbit. Imaging techniques revealed a hyperintense cystic tumor with calcifications of the wall. There was no evidence of a globe, no communication to the intracranial space and a normal bony orbit. The mass was excised and a 20-mm silicone orbital implant inserted.ResultsMicroscopic examination of the cyst revealed irregularly shaped layers of fibrovascular tissue lined by neuroglial tissue with calcified bodies and positive immunohistochemical staining for glial fibrillary acid protein (GFAP), neuron-specific enolase (NSE) and neurofilament protein (NF). No structures like cornea, lens, retinal pigmented epithelium or rosettes were identified.ConclusionsCongenital cystic eye is a primary developmental abnormality of the globe caused by an invaginational arrest of the primary optic vesicle between the 2-mm and 7-mm stages of fetal development. The luminal neuroglial tissue contains dystrophic calcified bodies and degenerated primitive nerve fibers. The enlargement of the cyst may be due to fluid produced by glial tissue. The differential diagnoses for cystic anomalies without epithelial lining include microphthalmia with cyst, microphthalmia with cystic teratoma, ectopic brain tissue and meningoencephalocele.

Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial

Importance Anti–vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; Pu2009=u2009.53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.

Retinal pathology in idiopathic moyamoya angiopathy detected by optical coherence tomography.

Objective: To investigate whether patients with moyamoya angiopathy without obvious retinal pathologies such as retinal infarctions or the congenital morning glory anomaly may have subtle subclinical retinal changes. Methods: In this cross-sectional study, spectral domain optical coherence tomography was used to analyze the retinal morphology of 25 patients with idiopathic moyamoya angiopathy and 25 age- and sex-matched healthy controls. We analyzed the retinal vasculature with blue laser autofluorescence, lipofuscin deposits with MultiColor confocal scanning laser ophthalmoscopy, and the optic nerve head (ONH) volume with a custom postprocessing algorithm. In addition to the total retinal thickness, semiautomated segmentation was used for segmentation of retinal layers in macular cross scans, macular volume scans, and peripapillary ring scans. Results: The main finding was a pronounced reduction of the ONH volume in moyamoya angiopathy compared with controls (0.76 ± 0.45 mm3 and 1.47 ± 0.50 mm3, respectively; p < 0.0001), which was associated with a less pronounced reduction of the retinal nerve fiber layer in macular volume scans (0.97 ± 0.11 mm3 and 1.10 ± 0.10 mm3, respectively; p < 0.001). Autofluorescence and MultiColor confocal scanning laser ophthalmoscopy images revealed no pathologies except for one branch retinal artery occlusion. Conclusion: Our results indicate that even patients with moyamoya angiopathy who do not have obvious retinal abnormalities have retinal abnormalities. These can be detected by spectral domain optical coherence tomography, and the association of ONH abnormalities with the vascular changes may suggest that idiopathic moyamoya angiography is a systemic disease involving abnormalities of the early mesodermal development.

Acetazolamide therapy in a case of fingolimod-associated macular edema: early benefits and long-term limitations

UNLABELLEDnFingolimod is a potent drug in relapsing forms of multiple sclerosis. Visual impairment due to fingolimod-associated macular edema (FAME) usually leads to discontinuation of fingolimod therapy.nnnMETHODSnWe report on a 24-year old woman with bilateral FAME.nnnRESULTSnWe continued fingolimod and added oral acetazolamide, which led to recovery of visual acuity and regression of macular edema. However, fingolimod had to be discontinued when fluorescein angiography revealed an enlarged foveal avascular zone.nnnDISCUSSION AND CONCLUSIONnOral acetazolamide might be a treatment option for FAME, while ischemic conversion may be limiting. Ophthalmologic assessments are mandatory for follow-up when fingolimod therapy is continued after onset of FAME.

Long-term course in type 2 idiopathic macular telangiectasia

IntroductionTo study the long-term course in patients with idiopathic macular telangiectasia and report the effect of anti VEGF and laser treatment.MethodsA retrospective case series of 19 patients/38 eyes with symptomatic type 2 idiopathic macular telangiectasia was performed. Six eyes received intravitreal injections of bevacizumab (1–3 injections), four eyes received focal laser treatment. Follow up examinations comprised visual acuity, biomicroscopy, fluorescein angiography and assessment of macular morphology and thickness by time and spectral-domain optical coherence tomography (OCT).ResultsMean follow-up time was 81xa0months (range 15–188xa0months) – the median added up to 80xa0months. Visual outcome at final visit varied substantially (20/200–20/20). On average visual acuity decreased 1,2 lines (range −0,5 to 6) by 3xa0years, 2 lines (range −0,5 to 7) by 5xa0years and 4,1 lines (range 0 to 12) by 10xa0years. Development of choroidal neovascularisation was observed in only one eye. There was no significant difference in visual acuity between eyes receiving no treatment, intravitreal bevacizumab or laser treatment after 3 and 5xa0years. Morphological studies by OCT revealed typical changes with retinal atrophy and intraretinal cysts. Visual acuity correlated with the eccentricity of the main manifestation–visual preservation was associated with mainly extrafoveal disease manifestation.DiscussionType 2 idiopathic macular telangiectasia is a chronic, often slowly progressing macular disease leading to retinal atrophy and visual impairment over decades. Thorough knowledge about the long term course of this disease is necessary to evaluate possible therapeutic options in the long run.