Post-COVID simultaneous onset of Graves' disease and ocular myasthenia gravis in a patient with a complex ocular motility impairment.

A 74-years-old man experienced severe diplopia one month after recovery from an uncomplicated SARS-CoV-2 infection. Neurological examination was normal whereas ophthalmological examination showed bilateral exophthalmos with a complex ocular motility disorder characterized by a pseudo-internuclear ophthalmoplegia after fatigue associated to impairment of elevation and infraduction. Antibodies against TSH and acetylcholine receptors were positive; subsequent hormonal tests, ultrasonography of thyroid gland, single fiber electromyography and orbit MRI confirmed the diagnosis of concomitant Graves Disease (GD) and Myasthenia Gravis (MG). The coexistence between MG and GD is not rare but simultaneous onset after viral infection is very unsual. The complex ocular disorder simulated a deficit of the oculomotor nerve nuclei, and on clinical examination it posed some problems in the diagnosis. We suggest that recent SARS-COV-2 infection may have triggered a complex autoimmune response.

Childhood-Onset Leber Hereditary Optic Neuropathy-Clinical and Prognostic Insights.

PURPOSE: To investigate the clinical and molecular genetic features of childhood-onset Leber hereditary optic neuropathy (LHON) to gain a better understanding of the factors influencing the visual outcome in this atypical form of the disease. DESIGN: Retrospective cohort study. METHODS: We retrospectively included 2 cohorts of patients with LHON with onset of visual loss before the age of 12 years from Italy and the United Kingdom. Ophthalmologic evaluation, including best-corrected visual acuity, orthoptic evaluation, slit-lamp biomicroscopy, visual field testing, and optical coherence tomography, was considered. Patients were classified based on both the age of onset and the pattern of visual loss. RESULTS: A total of 68 patients were stratified based on the age of onset of visual loss: group 1 (<3 years): 14 patients (20.6%); group 2 (≥3 to <9 years): 27 patients (39.7%); and group 3 (≥9 to ≤12 years): 27 patients (39.7%). Patients in group 2 achieved a better visual outcome than those in group 3. Patients in groups 1 and 2 had better mean deviation on visual field testing than those in group 3. The mean ganglion cell layer thickness on optical coherence tomography in group 2 was higher than those in groups 1 and 3. Patients were also categorized based on the pattern of visual loss as follows: Subacute Bilateral: 54 patients (66.7%); Insidious Bilateral: 14 patients (17.3%); Unilateral: 9 patients (11.1%); and Subclinical Bilateral: 4 patients (4.9%). CONCLUSIONS: Children who lose vision from LHON before the age of 9 years have a better visual prognosis than those who become affected in later years, likely representing a "form frustre" of the disease.

MOG-IgG positive optic neuritis after SARS-CoV-2 infection.

BACKGROUND: Many neurologic complications have been described after severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) including atypical cases of optic neuritis (ON), positive to myelin oligodendrocyte glycoprotein (MOG) IgG. OBJECTIVE: To report a case of MOG-IgG-associated ON and discuss why SARS-CoV-2 infection could be a potential trigger. METHODS: Retrospective single case report. RESULTS: We report a case of ON with positive MOG-IgG developed 15 days after presentation of SARS-CoV-2 infection. CONCLUSION: This report suggests that SARS-CoV-2 infection may have triggered autoantibodies production against MOG leading to ON.

Author Correction: Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Calcium mishandling in absence of primary mitochondrial dysfunction drives cellular pathology in Wolfram Syndrome.

Wolfram syndrome (WS) is a recessive multisystem disorder defined by the association of diabetes mellitus and optic atrophy, reminiscent of mitochondrial diseases. The role played by mitochondria remains elusive, with contradictory results on the occurrence of mitochondrial dysfunction. We evaluated 13 recessive WS patients by deep clinical phenotyping, including optical coherence tomography (OCT), serum lactic acid at rest and after standardized exercise, brain Magnetic Resonance Imaging, and brain and muscle Magnetic Resonance Spectroscopy (MRS). Finally, we investigated mitochondrial bioenergetics, network morphology, and calcium handling in patient-derived fibroblasts. Our results do not support a primary mitochondrial dysfunction in WS patients, as suggested by MRS studies, OCT pattern of retinal nerve fiber layer loss, and, in fibroblasts, by mitochondrial bioenergetics and network morphology results. However, we clearly found calcium mishandling between endoplasmic reticulum (ER) and mitochondria, which, under specific metabolic conditions of increased energy requirements and in selected tissue or cell types, may turn into a secondary mitochondrial dysfunction. Critically, we showed that Wolframin (WFS1) protein is enriched at mitochondrial-associated ER membranes and that in patient-derived fibroblasts WFS1 protein is completely absent. These findings support a loss-of-function pathogenic mechanism for missense mutations in WFS1, ultimately leading to defective calcium influx within mitochondria.

The Tadpole Pupil: Case Series With Review of the Literature and New Considerations.

Tadpole pupil is a rare phenomenon in which segmental spasm of the iris dilator muscle results in a tadpole-shaped pupil. The pupillary distortion is usually unilateral, lasts several minutes, and can recur in clusters. Any segment of the iris can be affected; thus, for some patients, a different-shaped tadpole pupil is noticed from episode to episode. Tadpole pupil most commonly appears spontaneously in young women. Tadpole pupil is not associated with any systemic disorders, but an ipsilateral Horner syndrome is noted in 46% of patients. In this article, we have reviewed the existing literature of tadpole pupil, compiling all the published cases in a table and reporting four additional cases to re-examine the clinical profile of this disorder and to consider the different purported mechanisms as means to understand its possible etiology and treatment. The common denominator in the pathophysiology of tadpole pupil is a focal excessive contraction (segmental spasm) of the iris dilator muscle. Based on various proposed pathophysiologic mechanism of tadpole pupil, we can consider potential forms of treatment.

Functional Changes of Retinal Ganglion Cells and Visual Pathways in Patients with Chronic Leber's Hereditary Optic Neuropathy during One Year of Follow-up.

PURPOSE: To assess changes of retinal ganglion cells (RGCs) and visual pathways' function in patients with Leber's hereditary optic neuropathy (LHON) during 12 months of follow-up of the chronic phase. DESIGN: Retrospective case series. PARTICIPANTS: Twenty-two patients with LHON (mean age, 36.3±9.3 years) in the "chronic phase" of the disease, providing 42 eyes (LHON group) with different pathogenic mitochondrial DNA mutations (group 11778: 21 eyes; group 3460: 4 eyes; group 14484: 13 eyes; and group 14568: 4 eyes) were enrolled. Twenty-five age-similar healthy participants, providing 25 eyes, served as controls. METHODS: Pattern electroretinogram (PERG) and visual evoked potentials (VEP), in response to 60' and 15' checks visual stimuli, were recorded at baseline in all subjects and after 6 and 12 months of follow-up in patients with LHON. At baseline, in all LHON eyes for each PERG and VEP parameter (amplitude and implicit time), the 95% confidence limit (CL) of test-retest variability was calculated. The PERG and VEP mean values observed in LHON eyes were compared (1-way analysis of variance [ANOVA]) with those of controls. During the follow-up, the PERG and VEP differences observed with respect to baseline were evaluated by ANOVA. MAIN OUTCOME MEASURES: Changes of individual and mean absolute values of 60' and 15' PERG amplitude and VEP amplitude and implicit time at each time point compared with baseline values in the LHON group. RESULTS: At baseline, mean values of PERG and VEP parameters detected in the LHON group were significantly (P < 0.01) different with respect to control values. In the LHON group, at 6 and 12 months of follow-up, the majority of eyes showed unmodified (within 95% CL) PERG and VEP values, and mean absolute values of these measures were not significantly (P > 0.01) different from baseline values. CONCLUSIONS: In our untreated patients with chronic LHON, with different specific pathogenic mutations, RGCs and visual pathways function were not significantly modified during 12 months of follow-up. This should be considered in the disease natural history when attempts for treatments are proposed in chronic LHON.

The Photopic Negative Response: An Objective Measure of Retinal Ganglion Cell Function in Patients With Leber's Hereditary Optic Neuropathy.

Purpose: The photopic negative response (PhNR) is a slow negative component of a flash photopic full-field ERG that has been shown to be specific for retinal ganglion cell (RGC) activity. Direct evaluation of RGC function is desirable in patients with Leber's hereditary optic neuropathy (LHON) in which the loss of central acuity can make it difficult to monitor patients with standard metrics. The purpose of this study was to evaluate the use of PhNR as an objective noninvasive clinical metric in LHON. Methods: Full-field photopic ERG recordings were collected in subjects with the mt.11778G>A/ND4 LHON mutation using a red on blue stimulus. The PhNR was identified using a computer-based automated detection system, and data were manually examined to remove movement artifacts. Results: The PhNR amplitude was compared between controls (n = 13), carriers (n = 17), and affected (n = 6). Mean PhNR amplitude decreased significantly across groups (P < 0.0001). Post hoc Tukey's test revealed a significant decrease in PhNR amplitude between carriers and controls (P < 0.05) and between carriers and affected (P < 0.01). Conclusions: We are able to demonstrate that the PhNR amplitude is significantly decreased in patients affected by LHON compared to carriers in a well-described pedigree. Surprisingly, there was also a decrease in PhNR in carriers, suggesting potential subclinical RGC dysfunction in some carriers. This is important in patients affected with LHON who typically have a dense central scotoma. The PhNR may be a useful objective outcome measure for future clinical trials.

Natural History of Conversion of Leber's Hereditary Optic Neuropathy: A Prospective Case Series.

PURPOSE: To illustrate the natural history of Leber's hereditary optic neuropathy (LHON). DESIGN: Prospective observational case series. PARTICIPANTS: The Soave-Brazil pedigree of m.11778G>A/ND4 mitochondrial DNA LHON mutation. METHODS: A prospectively acquired database of the Soave-Brazil pedigree was reviewed. Data from 285 individuals were included in the database over a 15-year period. The pedigree was reviewed for unaffected mutation carriers who converted to affected status, 6 patients with LHON were identified. The medical records were reviewed 1 year preconversion to 1 year postconversion for visual acuity (logarithm of the minimum angle of resolution [logMAR]), Humphrey Visual Field (HVF) mean deviation (MD), and retinal nerve fiber layer (RNFL) thickness, as measured by Cirrus (Carl Zeiss, Oberkochen, Germany) optic coherence tomography (OCT). The RNFL thickness values were normalized for age. Visual acuity, HVF, and processed RNFL data from each of the 12 eyes were then sorted into 2-month time periods relative to the date of conversion, within which they were averaged. MAIN OUTCOME MEASURES: The main outcome measures were visual acuity, HVF MD, and RNFL thickness. RESULTS: Decreased visual acuity preceded conversion by up to 2 months and then declined up to 8 months postconversion. Decrease in HVF MD occurred at least 4 months preceding conversion, after which values decreased until plateau at 6 to 8 months. Average RNFL thickness was above normal baseline thickness in all 4 quadrants as measured by OCT at the time of conversion. Increase in RNFL thickness preceded conversion as early as 4 to 6 months, peaked at conversion, and decreased until individual plateaus. The temporal quadrant was first to be involved, then the inferior and superior quadrants, and the nasal quadrant showed the latest and least changes. CONCLUSIONS: Subclinical changes preceded the date of conversion and may reflect the complicated nature of identifying the date of conversion in LHON. Early increases in RNFL preceding conversion suggest that structural changes precede clinically significant vision loss. Asynchronous quadrant involvement supports a previously published mathematical model. The natural history of LHON is not a subacute process, as previously believed, but progresses more slowly, taking up to 8 months to plateau.

Multifocal VEP provide electrophysiological evidence of predominant dysfunction of the optic nerve fibers derived from the central retina in Leber's hereditary optic neuropathy.

PURPOSE: To differentiate the bioelectrical cortical responses driven by axons from central and mid-peripheral retina in Leber's hereditary optic neuropathy (LHON) by using multifocal visual evoked potentials (mfVEP). METHODS: Seventeen genetically confirmed LHON patients (33.35 ± 8.4 years, 17 eyes) and 22 age-matched controls (C) (38.2 ± 6.0 years, 22 eyes) were studied by mfVEP and optical coherence tomography. MfVEP P1 implicit time (P1 IT, ms) and response amplitude density of the N1-P1 components (N1-P1 RAD, nV/deg(2)) of the second order binary kernel were measured for five concentric retinal areas between the fovea and mid-periphery: 0-20 degrees (R1 to R5). RESULTS: Mean mfVEP P1 ITs and N1-P1 RADs at all five foveal eccentricities were significantly different (p < 0.01) in LHON when compared to controls. In both groups, mean mfVEP responses obtained from R1 to R5 showed a progressive shortening of P1 ITs (linear fitting, LHON: r = -0.95; C: r = -0.98) and decrease of N1-P1 RADs (exponential fitting, LHON: r (2) = 0.94; C: r (2) = 0.93). The slope of the linear fitting between mean mfVEP P1 ITs in the two groups was about three times greater in LHON than in controls (LHON: y = -13.33x +182.03; C: y = -4.528x +108.1). MfVEP P1 ITs detected in R1 and R2 (0-5 degrees) were significantly correlated (p < 0.01) with the reduction of retinal nerve fiber layer thickness of the temporal quadrant. CONCLUSIONS: MfVEP identifies abnormal neural conduction along the visual pathways in LHON, discriminating a predominant involvement of axons driving responses from the central retina when compared to those serving the mid-peripheral retina.

Early macular retinal ganglion cell loss in dominant optic atrophy: genotype-phenotype correlation.

PURPOSE: To assess the peripapillary retinal nerve fiber and macular retinal ganglion cell (RGC) loss in patients with dominant optic atrophy (DOA) stratified by OPA1 mutation type. DESIGN: Cross-sectional study. METHODS: We studied 39 patients from 28 pedigrees with DOA harboring heterozygous mutations in the OPA1 gene along with 45 age-matched healthy subjects. The retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) of patients with DOA were evaluated by optical coherence tomography (OCT) and compared to those of controls. Patients' eyes were divided into 4 groups based on increasing severity of visual loss (DOA1 to DOA4) and were stratified by OPA1 mutation type. RESULTS: The average thicknesses of the RNFL and GC-IPL were smaller in patients with DOA than in healthy controls (P < 0.0001). RNFL analysis showed a significant reduction of the average, superior and inferior quadrants thicknesses in the DOA4 group compared to the DOA1 group (P = 0.001, P = 0.002 and P = 0.001, respectively). GC-IPL analysis showed a significant thinning in the superotemporal and superior sectors in the patients with DOA2 compared to those with DOA1 (P = 0.046 and P = 0.04, respectively). Stratifying by mutation type, average, superior and nasal RNFL thinning was significantly more severe in missense mutations and had a presumed dominant-negative effect compared to mutations causing haploinsufficiency. CONCLUSIONS: The present study demonstrates that in DOA, loss of macular RGCs is the earliest pathologic event, better reflected by GC-IPL measurements, whereas RNFL thickness is a measure of spared axons in late stages of the disease. Thus, mild cases (DOA2) show significant macular RGC loss as opposed to substantial maintenance of RNFL thickness, which is significantly decreased only in severe cases (DOA4). A clear genotype/phenotype correlation emerged, stratifying OCT measures by OPA1 mutation type, missense mutations being the most severe.

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.

Retinal function and neural conduction along the visual pathways in affected and unaffected carriers with Leber's hereditary optic neuropathy.

PURPOSE: We assessed retinal ganglion cell (RGC) function, and established a correlation between the neural conduction along the visual pathways and the retinal involvement in Leber's hereditary optic neuropathy (LHON). METHODS: A total of 39 individuals carrying a LHON mutation (mean age, 33.35 ± 8.4 years), LHON-unaffected (LU, 22 eyes) or LHON-affected (LA, 17 eyes), underwent visual acuity and visual field examinations. A total of 22 age-similar normal subjects (mean age, 38.2 ± 6.0 years) served as controls. In all subjects, simultaneous pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded in response to 60-minute (60') and 15-minute (15') checkerboard stimuli. RESULTS: When compared to controls, LU eyes did not show any statistically significant difference in 60' and 15' VEP P100 implicit times (ITs), VEP N75-P100 amplitudes, and 60' PERG P50 ITs, whereas 15' PERG P50-N95 amplitudes were significantly (P < 0.01) reduced. When compared to control and LU eyes, LA eyes showed significant differences in PERG and VEP ITs, and amplitudes with both stimulations (60' and 15' checks). No significant correlations between PERG and VEP parameters were found in LU eyes, while in LA eyes, PERG P50 and VEP P100 ITs correlated significantly only when using 60' checks. CONCLUSIONS: The LHON-unaffected eyes showed a retinal dysfunction detected by abnormal PERG responses that was not associated with changes along the visual pathways assessed by normal VEP responses. In LA eyes, the impaired neural conduction recorded by VEPs in response to larger (60' VEP responses) and smaller (15' VEP responses) checks were associated and not associated, respectively, with the detected retinal dysfunction.

Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a maternally inherited blinding disorder, which in over 90% of cases is due to one of three primary mitochondrial DNA (mtDNA) point mutations (m.11778G>A, m.3460G>A and m.14484T>C, respectively in MT-ND4, MT-ND1 and MT-ND6 genes). However, the spectrum of mtDNA mutations causing the remaining 10% of cases is only partially and often poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: In order to improve such a list of pathological variants, we completely sequenced the mitochondrial genomes of suspected LHON patients from Italy, France and Germany, lacking the three primary common mutations. Phylogenetic and conservation analyses were performed. Sixteen mitochondrial genomes were found to harbor at least one of the following nine rare LHON pathogenic mutations in genes MT-ND1 (m.3700G>A/p.A132T, m.3733G>A-C/p.E143K-Q, m.4171C>A/p.L289M), MT-ND4L (m.10663T>C/p.V65A) and MT-ND6 (m.14459G>A/p.A72V, m.14495A>G/p.M64I, m.14482C>A/p.L60S, and m.14568C>T/p.G36S). Phylogenetic analyses revealed that these substitutions were due to independent events on different haplogroups, whereas interspecies comparisons showed that they affected conserved amino acid residues or domains in the ND subunit genes of complex I. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that these nine substitutions are all primary LHON mutations. Therefore, despite their relative low frequency, they should be routinely tested for in all LHON patients lacking the three common mutations. Moreover, our sequence analysis confirms the major role of haplogroups J1c and J2b (over 35% in our probands versus 6% in the general population of Western Europe) and other putative synergistic mtDNA variants in LHON expression.

Retinal nerve fiber layer thickness in dominant optic atrophy measurements by optical coherence tomography and correlation with age.

PURPOSE: To measure the retinal nerve fiber layer (RNFL) thickness by means of optical coherence tomography (OCT) in patients with dominant optic atrophy (DOA). DESIGN: Cross-sectional study. PARTICIPANTS: Thirty-three patients from 15 pedigrees with DOA harboring heterozygous mutations in the OPA1 gene and 43 healthy subjects were enrolled. METHODS: The RNFLs of DOA patients were studied by OCT and compared with those of 43 healthy subjects matched for age and optic nerve head (ONH) size. MAIN OUTCOME MEASURES: Retinal nerve fiber layer thickness. RESULTS: Dominant optic atrophy patients revealed a significant RNFL thickness reduction in all quadrants, with a preferential involvement of the temporal and inferior sectors. The progressive decline of RNFL thickness with age was similar to that observed in healthy subjects and was more evident in the 2 quadrants with higher residual amounts of fibers, that is, the superior and the inferior. The temporal quadrant was profoundly depleted of fiber so that the further rate of loss of microns per year is close to zero, whereas the nasal quadrant was spared the most by neurodegeneration. CONCLUSIONS: The present findings, taken in conjunction with the authors' previous description of small ONH size in DOA, strongly suggest that patients with this disease are born with fewer optic nerve axons and support the hypothesis that subsequent visual loss depends on further age-related loss of fibers, which also occurs in controls. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

OPA1 mutations associated with dominant optic atrophy influence optic nerve head size.

PURPOSE: To analyze the influence of OPA1 gene mutations on the optic nerve head (ONH) morphology in patients with dominant optic atrophy (DOA). DESIGN: Cross-sectional study. PARTICIPANTS: Twenty-eight patients with DOA from 11 pedigrees, which were positive for the presence of OPA1 gene mutations, and 56 age-matched control subjects, were enrolled. METHODS: The ONH of DOA patients was studied by optical coherence tomography and compared with an age-matched control group of 56 individuals. MAIN OUTCOME MEASURES: ONH area, and vertical and horizontal diameters. RESULTS: The ONH analysis of DOA patients showed a significantly smaller optic disc area (P<0.0001), vertical (P = 0.018), and horizontal (P<0.0001) disc diameters, compared with controls. Stratification of the results for the single OPA1 mutation revealed normal ONH area with 2 mutations, whereas the only missense mutation linked to a "DOA plus" phenotype had the smallest ONH measurements. CONCLUSIONS: The DOA patients carrying OPA1 gene mutations present, as a group, a significantly smaller ONH compared with the range of size observed in a control population; this feature may be mutation specific. This observation suggests that OPA1 is involved in shaping the anatomic conformation of the ONH in patients with DOA. The relevance of OPA1 in regulating apoptosis and modeling the eye development has been recently shown by others. Thus, mutations in the OPA1 gene may determine the previously unrecognized feature of a smaller optic disc size and this in turn may have relevance for DOA pathogenesis. Furthermore, OPA1 gene polymorphic variants may contribute to the normal variability of ONH size in the general population.