Accuracy of Repetitive Ocular Vestibular-Evoked Myogenic Potentials to Diagnose Myasthenia Gravis in Patients With Ptosis or Diplopia.

BACKGROUND AND OBJECTIVES: We developed repetitive ocular vestibular-evoked myogenic potentials (roVEMP) as an electrophysiologic test that allows us to elicit the characteristic decrement of extraocular muscles in patients with ocular myasthenia gravis (OMG). Case-control studies demonstrated that roVEMP reliably differentiates patients with OMG from healthy controls. We now aimed to evaluate the diagnostic accuracy of roVEMP for OMG diagnosis in patients with ptosis and/or diplopia. METHODS: In this blinded prospective diagnostic accuracy trial, we compared roVEMP in 89 consecutive patients presenting with ptosis and/or diplopia suspicious of OMG with a multimodal diagnostic approach, including clinical examination, antibodies, edrophonium testing, repetitive nerve stimulation of accessory and facial nerves, and single-fiber EMG (SFEMG). We calculated the roVEMP decrement as the ratio between the mean of the first 2 responses compared with the mean of the sixth-ninth responses in the train and used cutoff of >9% (unilateral decrement) in a 30 Hz stimulation paradigm. RESULTS: Following a complete diagnostic work-up, 39 patients (44%) were diagnosed with ocular MG, while 50 patients (56%) had various other neuro-ophthalmologic conditions, but not MG (non-MG). roVEMP yielded 88.2% sensitivity, 30.2% specificity, 50% positive predictive value (PPV), and 76.5% negative predictive value (NPV). For comparison, SFEMG resulted in 75% sensitivity, 56% specificity, 55.1% PPV, and 75.7% NPV. All other diagnostic tests (except for the ice pack test) also yielded significantly higher positive results in patients with MG compared with non-MG. DISCUSSION: The study revealed a high sensitivity of 88.2% for roVEMP in OMG, but specificity and PPV were too low to allow for the OMG diagnosis as a single test. Thus, differentiating ocular MG from other neuro-ophthalmologic conditions remains challenging, and the highest diagnostic accuracy is still obtained by a multimodal approach. In this study, roVEMP can complement the diagnostic armamentarium for the diagnosis of MG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with diplopia and ptosis, roVEMP alone does not accurately distinguish MG from non-MG disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03049956.

Outcomes of Strabismus Surgery Following Teprotumumab Therapy.

PURPOSE: To investigate the results of patients undergoing surgical treatment for strabismic diplopia in thyroid eye disease (TED) following teprotumumab. DESIGN: Multicenter, retrospective, case series. METHODS: We report 28 patients who underwent extraocular muscle surgery for strabismic diplopia after treatment with teprotumumab at 7 different academic centers. Elapsed time from last teprotumumab dose to the date of surgery, previous orbital decompression, primary preoperative horizontal and vertical deviation, surgical procedure, and 2-month postoperative results were collected from the patient records. RESULTS: Sixteen (57%) patients were diplopia-free after 1 surgery. Three (11%) chose prism spectacles to correct residual diplopia, 2 (7%) used compensatory head posture to resolve diplopia, and 1 (4%) had intermittent diplopia and was functionally improved (choosing no prisms or further surgery). These were considered treatment successes. Three (11%) patients required reoperation, and all were diplopia-free after their second procedure. CONCLUSIONS: Most patients requiring surgery for strabismic diplopia following teprotumumab achieve good outcomes with success rates comparable to series published before the availability of teprotumumab.

Interocular suppression in primary visual cortex in strabismus: impact of staggering the presentation of stimuli to the eyes.

Diplopia (double vision) in strabismus is prevented by suppression of the image emanating from one eye. In a recent study conducted in two macaques raised with exotropia (an outward ocular deviation) but having normal acuity in each eye, simultaneous display of stimuli to each eye did not induce suppression in V1 neurons. Puzzled by this negative result, we have modified our protocol to display stimuli in a staggered sequence, rather than simultaneously. Additional recordings were made in the same two macaques, following two paradigms. In trial type 1, the receptive field in one eye was stimulated with a sine-wave grating while the other eye was occluded. After 5 s, the occluder was removed and the neuron was stimulated for another 5 s. The effect of uncovering the eye, which potentially exposed the animal to diplopia, was quantified by the peripheral retinal interaction index (PRII). In trial type 2, the receptive field in the fixating eye was stimulated with a grating during binocular viewing. After 5 s, a second grating appeared in the receptive field of the nonfixating eye. The impact of the second grating, which had the potential to generate visual confusion, was quantified by the receptive field interaction index (RFII). For 82 units, the mean PRII was 0.48 ± 0.05 (0.50 = no suppression) and the mean RFII was 0.46 ± 0.08 (0.50 = no suppression). These values suggest mild suppression, but the modest decline in spike rate registered during the second epoch of visual stimulation might have been due to neuronal adaptation, rather than interocular suppression. In a few instances neurons showed unequivocal suppression, but overall, these recordings did not support the contention that staggered stimulus presentation is more effective than simultaneous stimulus presentation at evoking interocular suppression in V1 neurons.NEW & NOTEWORTHY In strabismus, double vision is prevented by interocular suppression. It has been reported that inhibition of neuronal firing in the primary visual cortex occurs only when stimuli are presented sequentially, rather than simultaneously. However, these recordings in alert macaques raised with exotropia showed, with rare exceptions, little evidence to support the concept that staggered stimulus presentation is more effective at inducing interocular suppression of V1 neurons.

Clinical Outcome and Technical Nuances After Resection of Orbital Cavernous Venous Malformations-A Single-Center Experience.

BACKGROUND: Cavernous venous malformations (CVMs) represent the most common benign intraorbital lesions. Enlarging or symptomatic CVMs (progressive proptosis or visual disturbances) are treated by surgical resection. For this, a variety of different surgical approaches have been described. The aim of this study was to present a contemporary series of orbital CVMs treated via open microsurgical approaches. METHODS: In this study, patients who underwent resection of orbital CVMs between 2002 and 2019 were included. Presenting symptoms were noted and neuro-ophthalmologic examinations performed pre- and postoperatively. For surgical resection, the location of the orbital CVM and its relation to the orbital anatomy led to decision-making for appropriate approaches. A comparison between anatomical location and surgical outcome was performed. RESULTS: Overall, 35 patients with orbital CVMs were included. Most common presenting symptoms were progressive proptosis (43%) and visual disturbances (34%). Most common location was the lateral quadrant (37%) followed by the superior quadrant (20%). A subfrontal craniotomy was performed in 40% of cases followed by a supraorbital craniotomy including the orbital rim in 34% of cases. For surgical excision, a cryo-probe was used in 30 patients, and complete resection was feasible in all cases. Location of a CVM within the superior quadrant was associated with improved postoperative recovery of visual acuity. No differences for clinical outcomes were observed depending on the surgical approach. CONCLUSIONS: Resection of orbital CVMs is indicated in patients with visual disturbances or progressive proptosis. In these, microsurgical approaches can be used with minimal morbidity for complete removal of these well-circumscribed lesions.

Double Vision and Gait Ataxia in an Immunocompetent 9-Year-Old Girl With Intracranial Phaeohyphomycosis.

ABSTRACT: A 9-year-old girl presented with morning headaches associated with vomiting, gait ataxia, and facial and ocular motor nerve palsies. Her initial imaging was concerning for demyelinating disease. After extensive infectious and rheumatologic workup returned negative, she was treated twice with intravenous immunoglobulin and intravenous steroids with near-complete resolution each time. She returned, however, with worsening neurologic deficits and imaging revealing focal ischemic infarction in the brainstem as well as new-onset hydrocephalus. A multispecialty workup was initiated without conclusive diagnosis. A novel, noninvasive test for plasma cell-free DNA established a diagnosis of Cladophialophora bantiana that was confirmed and validated by a brain biopsy taken during a clinical decompensation. Treatment was initiated with systemic voriconazole and intraventricular amphotericin B.

Fascicular Sixth Nerve Palsy as a Presenting Sign of Metastatic Ovarian Carcinoma.

ABSTRACT: The most common etiology of an isolated abducens nerve palsy in an older adult with vasculopathic risk factors is presumed microvascular ischemia. Because the diagnosis of microvascular ischemia in this setting would not alter patient management, there is debate as to whether further workup is warranted under these circumstances. In this report, we describe a fascicular sixth nerve palsy as the initial presenting sign of metastatic ovarian carcinoma, and we highlight the importance of considering additional workup in select cases of isolated abducens nerve palsies.

Ocular motility changes and diplopia in sutured versus unsutured implantation of the Baerveldt glaucoma device.

PURPOSE: To investigate the effect of two surgical techniques in primary Baerveldt glaucoma implant (BGI) surgery, that is the sutured technique and the unsutured (free) plate technique, on the ocular motility and prevalence of diplopia. We hypothesize that the free plate technique results in a lower diplopia prevalence. METHODS: We performed a prospective study of patients who underwent BGI surgery with the free plate technique and compared them with patients from a previous study who had undergone BGI surgery with the sutured technique. Their ductions, ocular alignment and fusion range and the prevalence of diplopia were measured before surgery and at 3 months, 6 months and 1 year postoperatively. RESULTS: We analysed 57 free plate and 51 sutured plate patients. One year postoperatively, we found no statistically significant difference in the prevalence of diplopia between the two techniques. All duction changes between baseline and 1-year follow-up were restrictions and occurred statistically significantly more frequently in the free plate than in the sutured plate group (p = 0.03; 60% versus 34%). About the ocular alignment, in the horizontal direction, a change in exodirection was more common in both groups, while in the vertical direction, a hyperdeviation of the operated eye was more common. The vertical ocular alignment change was smaller in the free plate group than in the sutured plate group (p = 0.04 at near and p = 0.02 at distance). CONCLUSIONS: One year postoperatively, the prevalence of diplopia was not significantly different between patients with the sutured plate and patients with the free plate technique. Both surgical techniques induce diplopia and changes in ocular motility and/or in ocular alignment.

Efficacy and safety of tripterygium glycosides for active moderate to severe Graves' ophthalmopathy: a randomised, observer-masked, single-centre trial.

BACKGROUND: Tripterygium glycosides (TG) has been used to treat a spectrum of inflammatory and autoimmune diseases. Our preliminary studies have shown that TG is effective in the treatment of active Graves' ophthalmopathy (GO). OBJECTIVE: We aimed to compare the efficacy and tolerability of TG with intravenous methylprednisolone (iv.MP) in patients with active moderate-to-severe GO. METHODS: This study was an observer-masked, single-centre, block-randomised trial. Patients with active moderate-to-severe GO were randomly assigned to receive iv.MP (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) or with TG (20 mg tablet three times per day for 24 weeks). The primary endpoints were the overall response rate and the patients' quality of life at 12 and 24 weeks. RESULTS: In this study, 161 patients were enrolled and randomised from 2015 to 2019. A total of 79 were randomly assigned to receive iv.MP and 82 to receive TG. A greater overall response rate was found in the TG group compared with the iv.MP group at week 24 (90.2% vs 68.4%, P = 0.000). Similarly, the patients' quality of life of the TG group showed a significantly higher response than the iv.MP group at week 24 (89.02% vs 72.15%, P = 0.001). The TG therapy showed a better CAS response than the iv.MP (91.5% vs 70.9% improved, P < 0.05), and up to 91.2% of patients were inactive. Also, the TG group showed a significantly higher improved rate of diplopia, proptosis, visual acuity, soft tissue involved and the decrease of eye muscle motility than the iv.MP group at week 24. Significantly more patients in the iv.MP group than the TG group experienced adverse events. CONCLUSION: Compared with iv.MP treatment, TG therapy is more effective and safer for patients with active moderate to severe GO.

The relationship between reflex eye realignment and the percept of single vision in young children.

Effective binocular vision is dependent on both motor and perceptual function. Young children undergo development of both components while interacting with their dynamic three-dimensional environment. When this development fails, eye misalignment and double vision may result. We compared the range of image disparities over which young children display reflex motor realignment of their eyes with the range over which they report a single versus double percept. In response to step changes in the disparity of a 2.2° wide stimulus, 5-year-olds generated an adult-like reflex vergence velocity tuning function peaking at 2° of disparity, with a mean latency of 210 ms. On average, they reported double vision for stimulus disparities of 3° and larger, compared to 1° in adult reports. Three-year-olds also generated reflex vergence tuning functions peaking at approximately 2° of disparity, but their percepts could not be assessed. These data suggest that, by age 5, reflex eye realignment responses and percepts driven by these brief stimuli are tightly coordinated in space and time to permit robust binocular function around the point of fixation. Importantly, the plastic neural processes maintaining this tight coordination during growth control the stability of visual information driving learning during childhood.

Cerebral protothecosis mimicking high-grade glioma.

Prototheca wickerhamii is a common, indolent alga that seldom causes central nervous system infections in humans. We report the first UK case of cerebral protothecosis in an immunocompetent 56-year-old woman who presented with a 5-month history of intermittent fatigue followed by a 2-week history of symptoms, including right arm and leg weakness, a loss of fine motor coordination, worsening gait, right facial tingling, diplopia and a metallic oral taste. MRI scans revealed a multifocal abnormality suggestive of high-grade glioma. Given the clinical presentation, absence of immunodeficiency and characteristic MRI features, a diagnosis of high-grade glioma was deemed most likely by the multidisciplinary team. Surgical biopsy provided material for histopathological and microbiological diagnosis. She underwent a 2-year course of antimicrobials with surveillance MRI scans. The patient made a good functional recovery but still retains mild neurological sequelae.

Quantification of Global Ocular Motility Impairment in Graves' Orbitopathy by Measuring Eye Muscle Ductions.

Background: The overall changes of ocular motility in Graves' orbitopathy (GO) are not easily quantifiable with the methods currently available, especially in clinical studies. The aim of the present study was to calculate parameters that quantify the changes of ocular motility in GO in relation to the Gorman score for diplopia. Methods: We studied 100 GO patients (Group 1) and 100 controls (Group 2). We also included 30 patients treated with intravenous methylprednisolone (iv-MP), assessed at baseline and after 12 and 24 weeks (Group 3), and 66 patients submitted to squint surgery, assessed at baseline and after 12 weeks (Group 4). Ocular ductions were measured in four gaze directions by a perimeter arc and were used to calculate a total motility score (TMS) as the sum of ductions in each direction; a biocular TMS (b-TMS) as the sum of the TMS of two eyes; and an asymmetry ratio (AR) as the sum of the differences of the corresponding ductions between the two fellow eyes divided by the mean difference found in controls. Quality of life was accessed by a specific questionnaire (Graves' orbitopathy quality of life [GO-QoL] questionnaire). Results: TMS and b-TMS were lower, while AR was higher, in Group 1 compared with controls (p < 0.001). In Group 1, TMS and b-TMS were inversely correlated with the Gorman score (p < 0.001) and AR was higher in patients with constant diplopia compared with the others (p < 0.001). In Group 3, TMS and b-TMS increased after treatment in responders to iv-MP (p < 0.001). In Group 4, TMS and b-TMS improved in all patients after surgery (p < 0.01), while AR and GO-QoL score improved only in those without residual constant diplopia (p < 0.001). Conclusion: We describe a quantitative method to assess eye motility dysfunction in any stage of GO to be used as an outcome measure in clinical studies.

Temporal Arteritis Revealing Antineutrophil Cytoplasmic Antibody-Associated Vasculitides: A Case-Control Study.

OBJECTIVE: Temporal arteritis (TA) is a typical manifestation of giant cell arteritis (GCA). Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are rarely revealed by TA manifestations, leading to a risk of misdiagnosis of GCA and inappropriate treatments. This study was undertaken to describe the clinical, biologic, and histologic presentations and outcomes in cases of TA revealing AAV (TA-AAV) compared to controls with classic GCA. METHODS: In this retrospective case-control study, the characteristics of patients with TA-AAV were compared to those of control subjects with classic GCA. Log-rank test, with hazard ratios (HRs) and 95% confidence intervals (95% CIs), was used to assess the risk of treatment failure. RESULTS: Fifty patients with TA-AAV (median age 70 years) were included. Thirty-three patients (66%) presented with atypical symptoms of GCA (ear, nose, and throat involvement in 32% of patients, and renal, pulmonary, and neurologic involvement in 26%, 20%, and 16% of patients, respectively). Blood samples were screened for ANCAs at the time of disease onset in 33 patients, and results were positive in 88%, leading to a diagnosis of early TA-AAV in 20 patients. The diagnosis of AAV was delayed a median interval of 15 months in 30 patients. Compared to controls with GCA, patients with TA-AAV were younger (median age 70 years versus 74 years), were more frequently men (48% versus 30%), and had high frequencies of atypical manifestations and higher C-reactive protein levels (median 10.8 mg/dl versus 7.0 mg/dl). In patients with TA-AAV, temporal artery biopsy (TAB) showed fibrinoid necrosis and small branch vasculitis in 23% of patients each, whereas neither of these characteristics was evident in controls with GCA. Treatment failure-free survival was comparable between early TA-AAV cases and GCA controls, whereas those with delayed TA-AAV had a significantly higher risk of treatment failure compared to controls (HR 3.85, 95% CI 1.97-7.51; P < 0.0001). CONCLUSION: TA-AAV should be considered diagnostically in cases of atypical manifestations of GCA, refractoriness to glucocorticoid treatment, or early relapse. Analysis of TAB specimens for the detection of small branch vasculitis and/or fibrinoid necrosis could be useful. Detection of ANCAs should be performed in cases of suspected GCA with atypical clinical features and/or evidence of temporal artery abnormalities on TAB.

Functional Anatomy of Muscle Mechanisms: Compensating Vertical Heterophoria.

PURPOSE: Magnetic resonance imaging (MRI) of extraocular muscle function was used to evaluate the role of newly recognized mechanisms underlying compensation of large heterophoria by vertical fusional vergence (VFV). DESIGN: Prospective case series. METHODS: At one academic center, 8 adults with large hyperphoria and supernormal VFV underwent MRI during monocular and binocular fixation of a centered, near target. Contractility of the rectus and superior oblique (SO) extraocular muscles in hypertropic and hypotropic eyes was determined from changes in posterior partial volume (PPV). RESULTS: Five of 8 patients could sustain binocular fusion in the scanner. In those patients, VFV corrected approximately 5-degree misalignment, approximately 5-fold greater than normal VFV. Vertical strabismus was compensated mainly by significant contractility of the lateral more than the medial compartment of the inferior rectus (IR) in both eyes (P < .005). The superior rectus (SR) and inferior oblique muscles had no significant contractile contribution, although the hypotropic SO relaxed significantly. The IR lateral compartment and SR medial compartment significantly co-relaxed when binocular fusion was attained from monocular target fixation (P < .01). CONCLUSIONS: Although VFV protects patients from small muscle imbalances over the lifespan, even enhanced VFV may be inadequate to avert diplopia. Compensation of hyperphoria by VFV is accomplished mainly by IR muscle relaxation in the hypotropic eye, principally in its selectively innervated lateral compartment, whereas the SO contributes little. Fusion involves compartmentally selective co-relaxation in hypotropic eye vertical rectus muscles. Taken together, these overall findings suggest a physiologic basis to prefer therapeutic surgical weakening of the medial IR in the hypotropic eye.

Autoantibodies in Japanese patients with ocular myasthenia gravis.

INTRODUCTION: The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features. METHODS: Seventy-three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, ß, δ, ε) and fetal (2α, ß, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK), and lipoprotein receptor-related protein-4 (LRP4). RESULTS: Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative. DISCUSSION: Abs against fetal-specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies.

The Clinical and Imaging Profile of Skew Deviation: A Study of 157 Cases.

BACKGROUND: Skew deviation, a vertical misalignment of the eyes caused by a lesion in the vestibulo-ocular pathway, is a common manifestation of brainstem dysfunction, yet comprehensive information about its clinical profile is lacking. The aim of this study was to document presenting symptoms, causes, ocular alignment features, accompanying neurologic signs, pertinent brain imaging abnormalities, and measures used to relieve diplopia. METHODS: We searched the electronic medical records text from 2000 to 2018 for "skew" or "skew deviation" at a tertiary care academic center, including only patients diagnosed under supervision of faculty neuro-ophthalmologists. After excluding patients with features suggesting an imitator of skew deviation, we collected data useful in answering the selected clinical issues. RESULTS: In a cohort of 157 patients, vertical misalignment ranged between 1 and 30 prism diopters (PD) (median 5 PD) and was comitant in 100 (64%) patients. Diplopia was reported by 87% and blurred vision by 11% of patients. Blurred vision was more common when vertical misalignment was less than 3 PD. At least one accompanying neurologic sign was present in 133 (85%) patients, most often nystagmus, followed by gaze paresis, ataxia, saccadic pursuit, and internuclear ophthalmoplegia. Stroke affecting the thalamus, brainstem, or cerebellum accounted for 82 (52%) of cases. Stroke was usually ischemic, mostly unprovoked, but also occurring after intracranial or extracranial surgical procedures. Brainstem tumor and operative injury caused most of the remaining cases. A subgroup of 17 (11%) patients had skew deviation as the only new clinical sign and had no pertinent brain imaging abnormalities. Resolution of skew deviation, documented in 58 (42%) of 137 patients who had at least one follow-up visit, usually occurred within 3 months, but sometimes not until after 12 months. Of 110 patients who still had diplopia on follow-up examinations, the diplopia was successfully relieved with prism spectacles in 68 (62%). The cause of the skew deviation, amount of vertical misalignment, and degree of incomitance did not predict the success in relieving diplopia. Accompanying neurologic signs, including ataxia, endured in 44% of patients and were often more debilitating than the diplopia of skew deviation. CONCLUSIONS: The amplitude of misalignment in skew deviation varies widely but is generally 5 PD or less. When misalignment is 3 PD or less, patients report blurred vision rather than diplopia. Skew deviation is usually accompanied by other neurologic signs reflecting brainstem dysfunction. Yet there is a small subgroup in which vertical misalignment is an isolated sign, and there are no supporting brain imaging abnormalities. The main cause of skew deviation is ischemic stroke, which affects not only the brainstem but also the thalamus. Diplopia from skew deviation frequently persists, in which case prism spectacles may be successful in palliating it. Accompanying neurologic signs, especially ataxia, may outlast skew deviation and be more debilitating.