Remodeling of the neuromuscular junction in myasthenia gravis increases serum neurofilament heavy chain levels.

INTRODUCTION/AIMS: In myasthenia gravis, prolonged muscle denervation causes muscle atrophy. We re-visited this observation using a biomarker hypothesis. We tested if serum neurofilament heavy chain levels, a biomarker for axonal degeneration, were elevated in myasthenia gravis. METHODS: We enrolled 70 patients with isolated ocular myasthenia gravis and 74 controls recruited from patients in the emergency department. Demographic data were collected alongside serum samples. Serum samples were analyzed by enzyme-linked immunosorbent assay (ELISA) for the neurofilament heavy chain (NfH-SMI35). The statistical analyses included group comparisons, receiver operator characteristic (ROC) curves, area under the curve (AUC), sensitivity, specificity, and positive and negative predictive values. RESULTS: Serum neurofilament heavy chain levels were significantly (p < 0.0001) higher in individuals with myasthenia gravis (0.19 ng/mL) than in healthy control subjects (0.07 ng/mL). A ROC AUC optimized cutoff level of 0.06 ng/mL gave a diagnostic sensitivity of 82%, specificity of 76%, positive predictive value of 0.77 and a negative predictive value of 0.81. DISCUSSION: The increase of serum neurofilament heavy chain levels in myasthenia gravis is consistent with observations of muscle denervation. We suggest that there is ongoing remodeling of the neuromuscular junction in myasthenia gravis. Longitudinal quantification of neurofilament isoform levels will be needed to investigate the prognostic value and potentially guide treatment decisions.

Clinical characteristics of ocular myasthenia gravis and outcomes of secondary generalisation: a systematic review protocol.

OBJECTIVE: We aim to systematically assess the clinical characteristics of ocular myasthenia gravis (OMG) and report on the proportion of patients who develop secondary generalised myasthenia gravis (SGMG). INTRODUCTION: OMG is an autoimmune neuromuscular junction disorder resulting in ptosis and diplopia. A proportion of patients with OMG develop weakness in their limbs, respiratory or bulbar muscles, that is, convert to SGMG. The proportion of patients converting to SGMG reported in the literature have been varied. We therefore aim to systematically assess the clinical characteristics of OMG and outcomes of SGMG reported in the literature to date. INCLUSION CRITERIA: Studies describing a population of adults with OMG, that is, MG with ocular symptoms and signs only, seen consecutively through a clinical service, reporting on patient characteristics and the outcome of SGMG. Studies on paediatric and congenital myasthenia gravis will be excluded. METHODS: We will conduct an electronic database search for randomised controlled trials, prospective non-randomised studies, observational studies and retrospective studies in MEDLINE, Embase, Cochrane Central Register of Controlled Trials and Web of Science. Exploratory database search was conducted on 1 December 2021. Eligibility criteria will include quantitative and qualitative articles written in any language and containing data on OMG. Additional studies will be identified by reviewing bibliographies of retrieved articles. Two independent reviewers will screen titles and abstracts and extract data from full texts, reporting outcomes according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data extraction of key characteristics will be completed using customised forms. Methodological quality will be assessed using the Joanna Briggs Institute critical appraisal forms. ETHICS AND DISSEMINATION: Ethical approval is not required for this review, as it will only include published data. Findings will be published in a peer-reviewed journal and disseminated across ophthalmic networks. PROSPERO REGISTRATION NUMBER: CRD42021285257.

Exploratory Study of the Association between the Severity of Idiopathic Intracranial Hypertension and Electroretinogram Photopic Negative Response Amplitude Obtained Using a Handheld Device.

The photopic negative response (PhNR) is a negative component of the photopic flash electroretinogram that follows the b-wave and is thought to arise from the retinal ganglion cells. Reduction in its amplitude in idiopathic intracranial hypertension (IIH) has been previously documented using formal electroretinography. This study explored the use of a handheld device (RETeval, LKC technologies, Gaithersburg, MD, USA) in 72 IIH patients of varying stages and severity (and seven controls) and investigated associations between PhNR parameters and disease severity. PhNR amplitudes at 72 ms (P72) and p-ratio (ratio to b-wave peak value) differed significantly across groups, with a trend towards smaller amplitudes in those with severe IIH, defined as papilloedema with Modified Frisén Scale (MFS) ≥ 3, retinal nerve fibre layer (RNFL) ≥ 150 µm or atrophic papilloedema (p = 0.0048 and p = 0.018 for P72 and p-ratio, respectively). PhNR parameters did not correlate with MFS, RNFL thickness, standard automated perimetry mean deviation or macular ganglion cell layer volume. This study suggests that PhNR measurement using a handheld device is feasible and could potentially augment the assessment of disease severity in IIH. The clinical utility of PhNR monitoring in IIH patients requires further investigation.

Optical coherence tomography (OCT) in neuro-ophthalmology.

Optical coherence tomography (OCT) is a non-invasive medical imaging technology that is playing an increasing role in the routine assessment and management of patients with neuro-ophthalmic conditions. Its ability to characterise the optic nerve head, peripapillary retinal nerve fibre layer and cellular layers of the macula including the ganglion cell layer enables qualitative and quantitative assessment of optic nerve disease. In this review, we discuss technical features of OCT and OCT-based imaging techniques in the neuro-ophthalmic context, potential pitfalls to be aware of, and specific applications in more common neuro-ophthalmic conditions including demyelinating, inflammatory, ischaemic and compressive optic neuropathies, optic disc drusen and raised intracranial pressure. We also review emerging applications of OCT angiography within neuro-ophthalmology.

miR-30e-5p as predictor of generalization in ocular myasthenia gravis.

Objective: To determine a predictive factor for the risk of conversion from ocular myasthenia gravis (OMG) to generalized MG (GMG) in a prospective study. Methods: RNA was isolated from serum samples and detection of microRNA (miRNA) expression analyzed with qPCR. In the discovery set, 179 human miRNAs were assayed for profiling of five OMG patients and four age- and gender-matched healthy controls. Based on the specific accumulation pattern of 19 miRNAs from the discovery set, in addition to miRNAs previously found elevated in generalized MG (GMG; miR-150-5p and miR-30e-5p), 21 miRNAs were subsequently analyzed in a validation cohort of 83 OMG patients (82 immunosuppression treatment naive; 49 male) within 3 months of diagnosis and at a follow-up visit (median duration 28 months from first visit). Results: Thirteen patients generalized 14.8 ± 12.0 months after the diagnosis and the majority (85%) belonged to the late onset MG group. Two miRNAs were significantly higher in secondary GMG (SGMG) patients compared to OMG patients with late onset MG: miR-30e-5p (9.1 ± 0.5 vs. 6.3 ± 0.9; P < 0.0001) and miR-150-5p (7.4 ± 1.1 vs. 6.4 ± 1.1; P = 0.01). The sensitivity for miR-30e-5p in differentiating OMG and SGMG was 96% in all OMG patients and 100% in late onset OMG patients. Interpretation: This is the first study to describe a potential predictive factor associated with the risk of generalization for patients with OMG. Raised levels (>8) of miR-30e-5p at initial presentation in patients with ocular MG symptoms, give a predictive cut-off for subsequent generalization of 96-100%.

Ocular Myasthenia Gravis: Toward a Risk of Generalization Score and Sample Size Calculation for a Randomized Controlled Trial of Disease Modification.

BACKGROUND: There is currently no prognostic test to determine the risk of developing generalized myasthenia gravis (GMG) risk in patients who first present with ocular disease. Most studies that report risk factors are flawed by the inclusion of patients on immunosuppression, which is likely to reduce the risk. OBJECTIVE: To create a prognostic score to predict the risk of GMG. METHODS: Multicenter retrospective cohort of patients with ocular myasthenia gravis for minimum 3 months, untreated with immunosuppression for minimum 2 years or until GMG onset. RESULTS: One hundred one (57 female) patients were included, with median follow-up of 8.4 years (2-42) from disease onset. Thirty-one developed GMG at median of 1.31 years (3.5 months-20.2 years); 19 occurred within 2 years. Univariable logistic regression analysis produced 3 significant predictors (P < 0.10), adjusted odds ratios in a multivariable logistic model (χ P = 0.01) with multiple imputations for missing data: seropositivity, 5.64 (95% CI, 1.45-21.97); presence of 1 or more comorbidities including autoimmune disorders, 6.49 (95% CI, 0.78-53.90); thymic hyperplasia, 5.41 (95% CI, 0.39-75.43). Prognostic score was derived from the coefficients of the logistic model: sum of the points (1 point for the presence of each of the above predictive factors), classified "low risk" if ≤1 and "high risk" if ≥2. Predicted probabilities were 0.07 (SD, 0.03) for low risk and 0.39 (SD, 0.09) for high risk. Negative predictive value was 91% (95% CI, 79-98), positive predictive value was 38% (95% CI, 23-54), sensitivity was 79% (95% CI, 54-94), specificity was 63% (95% CI, 50-74), area under receiver operating characteristic curve was 0.74 (95% CI, 0.64-0.85). CONCLUSIONS: In this preliminary study, we have shown by proof of principle that it is possible to stratify risk of GMG: an approach that may allow us to better counsel patients at diagnosis, complement decision-making, and move us toward addressing the question of modifying GMG risk in high-risk patients. Furthermore, the effect of comorbidities is novel and demands further elucidation.

Acquired Esotropia in Cerebellar Disease: A Case Series Illustrating Misdiagnosis as Isolated Lateral Rectus Paresis and Progression Over Time.

We highlight an under-recognised cause of acquired esotropia with this prospective observational case series of adults with diplopia secondary to cerebellar dysfunction. We also show deterioration of cerebellar esotropia over time, which has not been previously described. Seven adults (four women) developed diplopia at a median age of 63 years (range: 31-75 years), as the initial manifestation of the underlying cerebellar disorder. Causes of cerebellar dysfunction were familial cerebellar ataxia of unknown mutation (two patients), idiopathic cerebellar ataxia (four patients), and spinocerebellar ataxia 3 (one patient). At onset, three patients had unilateral and four had bilateral lateral rectus under-action. These were initially diagnosed as lateral rectus paresis, but the diagnosis was revised, as our examination showed no slowing of abducting saccades assessed clinically and full abduction with gaze-evoked nystagmus. Esotropia was concomitant and worse for distance, although at onset one patient's esotropia was equal for near and distance. There was a trend of worsening esotropia over time, following a median interval follow-up of 4 years (range: 1-18). All patients were first observed to have cerebellar eye signs after a median interval of 5 years (range: 1-30) from presentation, i.e., impaired pursuit (7/7 patients), gaze-evoked nystagmus (7/7), hypometric saccades (3/7), downbeat nystagmus (2/7), and skew deviation (4/7). Only two patients have not developed non-ocular cerebellar eye signs, after 5 and 8 years from diplopia onset, respectively; the other five patients had gait ataxia, which could be mild. The patients were successfully treated with prisms (7/7), botulinum toxin injections (1/7), and strabismus surgery (1/7).

Ocular myasthenia gravis: controversies and updates.

The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms. An unresolved question is whether there are clinical features at onset to guide clinicians to predict an individual patient's conversion risk from ocular MG (OMG) to generalized disease, or "secondary generalized MG" (SGMG), that is, a prognostic model. In light of the emerging theory that early corticosteroids may have a risk-modifying effect, the factors associated with secondary SGMG previously reported should be revisited. Studies showing potential risk-modifying effects of corticosteroids are useful, though flawed, owing to the heterogeneous retrospective studies and methods of reporting. Updates on other potential immunosuppressive agents are also discussed. Thymectomy in OMG has been recently reported in a few studies to be useful. MG associated with antibodies to muscle-specific kinase, usually associated with severe generalized MG, can cause a pure OMG syndrome. Recent serological developments in seronegative patients have also revealed antibodies to clustered anti-acetylcholine receptor and lipoprotein receptor-related protein-4.