Extraocular Muscle Involvement Research Articles

Neuro-Ophthalmic Complications in Patients Treated With CTLA-4 and PD-1/PD-L1 Checkpoint Blockade.

In recent years, CTLA-4 and PD-1/PD-L1 checkpoint inhibitors have proven to be effective and have become increasingly popular treatment options for metastatic melanoma and other cancers. These agents work by enhancing autologous antitumor immune responses. Immune-related ophthalmologic complications have been reported in association with checkpoint inhibitor use but remain incompletely characterized. This study seeks to investigate and further characterize the neuro-ophthalmic and ocular complications of immune checkpoint blockade treatment. A survey was distributed through the secure electronic data collection tool REDCap to neuro-ophthalmology specialists in the North American Neuro-Ophthalmology Society listserv. The study received human subjects approval through the University of California at Los Angeles Institutional Review Board. The survey identified patients sent for neuro-ophthalmic consultation while receiving one or more of a PD-1 inhibitor (pembrolizumab, nivolumab, or cemiplimab); PD-L1 inhibitor (atezolizumab, avelumab, or durvalumab); or the CTLA-4 inhibitor ipilimumab. Thirty-one patients from 14 institutions were identified. Patient demographics, neuro-ophthalmic diagnosis, diagnostic testing, severity, treatment, clinical response, checkpoint inhibitor drug used, and cancer diagnosis was obtained. The checkpoint inhibitors used in these patients included pembrolizumab (12/31), nivolumab (6/31), combined ipilimumab with nivolumab (7/31, one of whom also received pembrolizumab during their course of treatment), durvalumab (3/31), ipilimumab (2/31), and cemiplimab (1/31). Malignant melanoma (16/31) or nonsmall cell lung carcinoma (6/31) were the most common malignancies. The median time between first drug administration and the time of ophthalmological symptom onset was 14.5 weeks. Eleven patients had involvement of the optic nerve, 7 patients had inflammatory orbital or extraocular muscle involvement, 6 patients had ocular involvement from neuromuscular junction dysfunction, 4 patients had cranial nerve palsy, and 4 patients had non neuro-ophthalmic complications. Use of systemic corticosteroids with or without stopping the checkpoint inhibitor resulted in improvement of most patients with optic neuropathy, and variable improvement for the other ophthalmic conditions. This study describes the variable neuro-ophthalmic adverse events associated with use of immune checkpoint inhibitors and contributes a more thorough understanding of their clinical presentations and treatment outcomes. We expect this will increase awareness of these drug complications and guide specialists in the care of these patients.

The feasibility of quantitative MRI of extra-ocular muscles in myasthenia gravis and Graves' orbitopathy.

Although quantitative MRI can be instrumental in the diagnosis and assessment of disease progression in orbital diseases involving the extra‐ocular muscles (EOM), acquisition can be challenging as EOM are small and prone to eye‐motion artefacts. We explored the feasibility of assessing fat fractions (FF), muscle volumes and water T2 (T2water) of EOM in healthy controls (HC), myasthenia gravis (MG) and Graves' orbitopathy (GO) patients. FF, EOM volumes and T2water values were determined in 12 HC (aged 22‐65 years), 11 MG (aged 28‐71 years) and six GO (aged 28‐64 years) patients at 7 T using Dixon and multi‐echo spin‐echo sequences. The EOM were semi‐automatically 3D‐segmented by two independent observers. MANOVA and t‐tests were used to assess differences in FF, T2water and volume of EOM between groups (P < .05). Bland–Altman limits of agreement (LoA) were used to assess the reproducibility of segmentations and Dixon scans. The scans were well tolerated by all subjects. The bias in FF between the repeated Dixon scans was −0.7% (LoA: ±2.1%) for the different observers; the bias in FF was −0.3% (LoA: ±2.8%) and 0.03 cm3 (LoA: ± 0.36 cm3) for volume. Mean FF of EOM in MG (14.1% ± 1.6%) was higher than in HC (10.4% ± 2.5%). Mean muscle volume was higher in both GO (1.2 ± 0.4 cm3) and MG (0.8 ± 0.2 cm3) compared with HC (0.6 ± 0.2 cm3). The average T2water for all EOM was 24.6 ± 4.0 ms for HC, 24.0 ± 4.7 ms for MG patients and 27.4 ± 4.2 ms for the GO patient. Quantitative MRI at 7 T is feasible for measuring FF and muscle volumes of EOM in HC, MG and GO patients. The measured T2water was on average comparable with skeletal muscle, although with higher variation between subjects. The increased FF in the EOM in MG patients suggests that EOM involvement in MG is accompanied by fat replacement. The unexpected EOM volume increase in MG may provide novel insights into underlying pathophysiological processes.

The Clinical and Radiologic Features Affecting the Ocular Symptoms in Patients With Paranasal Sinus Mucoceles Involving the Orbit.

Paranasal sinus (PNS) mucoceles may involve orbit and have ophthalmic manifestations. The objective of this study was to investigate the clinical and radiological features affecting the ophthalmic manifestations in patients with PNS mucoceles involving the orbit. Fifty-two patients underwent endoscopic sinus surgery for PNS mucoceles with orbital involvement were investigated. Ophthalmic manifestations included exophthalmos, ocular pain, diplopia, visual disturbance. The correlation between ocular symptoms and the mucocele volume, origin site of mucocele, and the involvement of extraocular muscles or optic nerve were evaluated. Ophthalmic manifestations were significantly higher in the anterior ethmoid and frontal sinus involvement. Exophthalmos was significantly increased in the involvement of anterior ethmoid sinus, frontal sinus, and superior group ocular muscles, but decreased in the mucocele of maxillary sinus. Ocular pain was significantly lower in the involvement of anterior ethmoid sinus, frontal sinus, and superior group ocular muscle. Diplopia showed no significant differences among clinical and radiological parameters. Visual disturbance was significantly higher in the involvement of posterior ethmoid sinus and sphenoid sinus. The volume of mucocele, relation to optic nerve, adjacent bony change, and duration of ocular symptom had no significant effect on ocular symptoms in patients with PNS mucoceles involving the orbit. The volume of mucocele did not affect the ophthalmic manifestations in patients with PNS mucoceles involving the orbit. Exophthalmos, ocular pain, and visual disturbance were significantly correlated with the involved sinus of PNS mucoceles.

Carcinoid Tumors of the Orbit and Ocular Adnexa.

Well-differentiated neuroendocrine or carcinoid tumors are found most commonly in the gastrointestinal tract. When metastatic to the orbit, they tend to have a propensity for the extraocular muscles. The purpose of this study was to better understand the diversity in presentation of orbital carcinoid disease and to determine predictors for survival. In this observational cross-sectional cohort study, data from 8 tertiary orbital practices were compiled. Demographic, clinical, pathologic, American Joint Committee on Cancer stage and grade, imaging, and management data were extracted for all the patients. Descriptive statistics were calculated. Subgroups were compared utilizing analysis of variance analyses and Kaplan-Meier curves. Time to progression and disease-specific and overall mortality were calculated. Comparisons were performed for the following a priori pairs: unknown versus known primary tumor, single versus multiple extraocular muscle involvement, unilateral versus bilateral orbital disease, extraocular muscle versus other orbital involvement, and excisional versus incisional surgery. A total of 28 patients with carcinoid tumors of the orbit were identified. Of these, 57.1% of patients were female, the mean age at diagnosis of the primary tumor was 58.8 years and the mean age at diagnosis of orbital disease was 62.6 years. At primary presentation, all patients were American Joint Committee on Cancer stage III or IV and 21.4% demonstrated carcinoid syndrome. Muscle involvement was noted in 78.6% of patients, and of these, 72% were noted to have single muscle disease. Eight patients had no primary tumor identified; 3 of these 8 demonstrated disseminated disease at the time of diagnosis. The overall 5-year survival rate was 81.8% from diagnosis of primary tumor and 50% from diagnosis of orbital disease. Subgroup analysis revealed that patients with unilateral orbital disease when compared with bilateral orbital disease had a longer progression-free survival and time to death from all causes (p = 0.025). Patients with disease localized to the orbit at presentation had longer time to death than those with disseminated disease. Treatment with surgery, radiation, or octreotide did not appear to affect survival. Patients managed with systemic chemotherapy had a shorter time of survival than the rest of the group. All other subgroup comparisons were not found to be statistically significant. Neuroendocrine tumors of the orbit represent a wide spectrum of disease, with some cases being part of disseminated disease, while others being localized presentations. This heterogeneity may be responsible for the slightly higher overall survival in these patients than others with metastatic carcinoid tumors in other locations.

Molecular basis of impaired extraocular muscle function in a mouse model of congenital myopathy due to compound heterozygous Ryr1 mutations.

Mutations in the RYR1 gene are the most common cause of human congenital myopathies, and patients with recessive mutations are severely affected and often display ptosis and/or ophthalmoplegia. In order to gain insight into the mechanism leading to extraocular muscle (EOM) involvement, we investigated the biochemical, structural and physiological properties of eye muscles from mouse models we created knocked-in for Ryr1 mutations. Ex vivo force production in EOMs from compound heterozygous RyR1p.Q1970fsX16+p.A4329D mutant mice was significantly reduced compared with that observed in wild-type, single heterozygous mutant carriers or homozygous RyR1p.A4329D mice. The decrease in muscle force was also accompanied by approximately a 40% reduction in RyR1 protein content, a decrease in electrically evoked calcium transients, disorganization of the muscle ultrastructure and a decrease in the number of calcium release units. Unexpectedly, the superfast and ocular-muscle-specific myosin heavy chain-EO isoform was almost undetectable in RyR1p.Q1970fsX16+p.A4329D mutant mice. The results of this study show for the first time that the EOM phenotype caused by the RyR1p.Q1970fsX16+p.A4329D compound heterozygous Ryr1 mutations is complex and due to a combination of modifications including a direct effect on the macromolecular complex involved in calcium release and indirect effects on the expression of myosin heavy chain isoforms.

Clinicogenetical Variants of Progressive External Ophthalmoplegia - An Especial Review of Non-ophthalmic Manifestations.

Progressive external ophthalmoplegia (PEO) is a slowly progressive myopathy characterized by extraocular muscles involvement, leading to frozen eyes without diplopia. The pattern of inheritance may be mitochondrial, autosomal dominant or, rarely, autosomal recessive. Sporadic forms were also reported. Muscular involvement other than extraocular muscles may occur with varying degrees of weakness, but this mostly happens many years after the disease begins. There are also scattered data about systemic signs besides ophthalmoplegia. This article aims to review non-ophthalmic findings of PEO from a clinicogenetical point of view.

P.230Phenotype and pathological variability in RYR1-related myopathy with compound heterozygous variants in Japan

Mutations in RYR1 are often associated with central core disease, and are also the most common cause of other congenital myopathies (CMs) such as multi-minicore disease, CFTD (congenital fiber type disproportion) and centronuclear myopathy (CNM). There is an increasing interest in the clinical variability and pathologic overlap among these CMs due to RYR1 mutations. In addition, it has been reported that the compound heterozygous RYR1 mutations can cause more severe phenotype compared to the autosomal dominant cases. Here we report clinical and pathological features of the 3 patients with compound heterozygous variants in RYR1 who were seen and received muscle biopsy at NCNP. Case 1: a 2.5-year-old girl with generalized hypotonia, swallowing and respiratory problems since her birth. She had a markedly myopathic face with extraocular muscle involvement, and required tracheostomy and gastrostomy. She was diagnosed with CNM by muscle pathology. Case 2: a 10-month-old girl with hypotonia, reduced antigravity movements, and swallowing and respiratory problems since neonatal period. Nasogastric feeding and non-invasive ventilation were needed. She was diagnosed with CFTD by muscle pathology. Case 3: a 1-year-old girl with delayed motor milestones and generalized mild hypotonia, sparing facial and extraocular muscles. She was diagnosed with CNM by muscle pathology. The RYR1 variants found in these patients included nonsense mutation, splicing mutation and deletion, all of which were predicted to be pathogenic. Presence of a case with mild phenotype such as Case 3 indicates the broad clinical variability of congenital myopathy due to biallelic RYR1 mutations.

Real-time ultrasound elastographic evaluation of extraocular muscle involvement in Graves’ ophthalmopathy

ABSTRACTPurpose: To evaluate the affected extraocular muscles (EOMs) of patients with Graves’ ophthalmopathy (GO) using real-time ultrasound elastography (UE) and to compare these results with those of healthy subjects.Methods: This prospective, comparative case series included 70 eyes of 35 patients with moderate-to-severe GO with type 2 orbitopathy (myogenic variant) according to their computed tomography (CT) scans. Forty-six eyes of 23 healthy subjects were evaluated as the control group. The strain ratio of orbital fat to medial rectus was calculated as the ratio of the medial rectus to orbital fat tissue, and the strain ratio of orbital fat to lateral rectus was calculated as the ratio of lateral rectus to orbital fat tissue.Results: The strain ratio of orbital fat to medial rectus was 3.03 ± 1.25 (range: 1.05–5.07) in the GO group, and 0.54 ± 0.20 (range: 0.14–1.08) in the control group (p = .0001). The strain ratio of orbital fat to lateral rectus was 0.97 ± 0.29 (range: 0.56–1.55) in the GO group, and 0.63 ± 0.23 (range: 0.18–1.09) in the control group (p = .0001).Conclusion: By using real-time UE, we found the medial and the lateral recti of GO patients to be stiffer compared to those of healthy subjects.

Vertical vergence in nonhuman primates depends on horizontal gaze position

ABSTRACTThe goal of this study was to compare vertical fusion capability at different orbital eye positions in normal nonhuman primates and attempt to use this information to isolate the extraocular muscles (EOMs) that mediate vertical vergence. Scleral search coils were used to record movements of both eyes as two normal nonhuman primates (M1, M2) performed a vertical vergence task at different horizontal eye positions. In a control experiment, M1 was also tested at different angles of horizontal vergence. To elicit vertical vergence, a 50° x 50° stimulus comprising a central fixation cross and random dots elsewhere was presented separately to each eye under dichoptic viewing conditions. Vertical disparity was introduced by slowly displacing the stimulus for one eye vertically. Vertical fusion amplitude (maximum disparity that the monkey was able to fuse) and vertical vergence (maximum difference in vertical position of the two eyes) were measured. Vertical fusion capability differed at different orbital eye positions. Monkey M1 had significantly smaller vertical fusion capabilities when the right eye (RE) was abducted than left eye (LE) while M2 had significantly smaller vertical fusion capabilities when the RE was adducted and LE abducted. M1 also showed greater vertical fusion capability for near gaze. M1 data suggested that the vertical recti mediated vertical vergence in the RE and the oblique muscles in the LE while M2 data suggested that the oblique muscles mediated vertical vergence in the RE and the vertical recti in the LE. The variable results within the same animal and across animals suggest that EOM involvement during vertical fusional vergence is idiosyncratic and likely a weighted combination of multiple cyclovertical muscles.

Thyroid eye disease presenting with superior rectus/levator complex enlargement

ABSTRACTPurpose: To describe the demographic and clinical characteristics of patients with thyroid eye disease (TED) who present with predominate superior rectus/levator complex involvement.Methods: A multi-institutional retrospective review was performed to identify patients with TED who presented with superior isolated or predominate rectus/levator involvement. Baseline and subsequent visits were reviewed to characterize the clinical course.Results: Nineteen patients were identified. All patients had imaging demonstrating an enlarged levator/superior rectus complex. At presentation, the mean clinical activity score (CAS) was 2.1 (range: 0–5). Nineteen (100%) patients had proptosis on the affected side. Lid abnormalities, including upper/lower eyelid retraction and ptosis were higher on affected side compared to the unaffected side. Eleven (58%) patients had vertical misalignment. Mean thyroid stimulating immunoglobulin (TSI) was 3.7 (range: 1–7.1). Mean follow-up time was 18 months (range: 0–60 months). At last follow-up, the mean CAS was 1.3 (range 0–5). Ten (53%) patients had proptosis. Eleven (58%) patients had vertical misalignment. Repeat imaging in eight patients showed interval enlargement of other extraocular muscles.Conclusions: The presentation of TED with superior rectus/levator complex enlargement may be under-appreciated. Orbital imaging, as well as laboratory evaluation, may help support a diagnosis of TED. In the setting of abnormal TSI and/or thyrotropin receptor antibody, presence of upper eyelid retraction, and an otherwise unremarkable laboratory and systemic evaluation, a presumptive diagnosis of TED may be made, and the patient can be followed closely, as he/she is likely to develop involvement of other extraocular muscles, consistent with a more typical presentation of TED.

Profiling of patient-specific myocytes identifies altered gene expression in the ophthalmoplegic subphenotype of myasthenia gravis

BackgroundWhile extraocular muscles are affected early in myasthenia gravis (MG), but respond to treatment, we observe a high incidence of treatment-resistant ophthalmoplegia (OP-MG) among MG subjects with African genetic ancestry. Previously, using whole exome sequencing, we reported potentially functional variants which associated with OP-MG. The aim of this study was to profile the expression of genes harbouring the OP-MG associated variants using patient-derived subphenotype-specific ‘myocyte’ cultures.MethodsFrom well-characterised MG patients we developed the ‘myocyte’ culture models by transdifferentiating dermal fibroblasts using an adenovirus expressing MyoD. These myocyte cultures were treated with homologous acetylcholine receptor antibody-positive myasthenic sera to induce muscle transcripts in response to an MG stimulus. Gene expression in myocytes derived from OP-MG (n = 10) and control MG subjects (MG without ophthalmoplegia; n = 6) was quantified using a custom qPCR array profiling 93 potentially relevant genes which included the putative OP-MG susceptibility genes and other previously reported genes of interest in MG and experimental autoimmune myasthenia gravis (EAMG).ResultsOP-MG myocytes compared to control MG myocytes showed altered expression of four OP-MG susceptibility genes (PPP6R2, CANX, FAM136A and FAM69A) as well as several MG and EAMG genes (p < 0.05). A correlation matrix of gene pair expression levels revealed that 15% of gene pairs were strongly correlated in OP-MG samples (r > 0.78, p < 0.01), but not in control MG samples. OP-MG susceptibility genes and MG-associated genes accounted for the top three significantly correlated gene pairs (r ≥ 0.98, p < 1 × 10− 6) reflecting crosstalk between OP-MG and myasthenia pathways, which was not evident in control MG cells. The genes with altered expression dynamics between the two subphenotypes included those with a known role in gangliosphingolipid biosynthesis, mitochondrial metabolism and the IGF1-signalling pathway.ConclusionUsing a surrogate cell culture model our findings suggest that muscle gene expression and co-expression differ between OP-MG and control MG individuals. These findings implicate pathways not previously considered in extraocular muscle involvement in myasthenia gravis and will inform future studies.

Severe unilateral orbitopathy in a patient with Hashimoto\u2019s thyroiditis - a case report

BackgroundThyroid-associated orbitopathy (TAO) constitutes an immune-mediated inflammation of the orbital tissues of unclear etiopathogenesis. TAO is most prevalent in hyperthyroid patients with Graves’ disease (GD); however, severe cases of orbitopathy associated with Hashimoto’s thyroiditis (HT) have rarely been described.Case presentationHerewith we report an unusual case of a middle-aged clinically and biochemically euthyroid woman with a stable HT, who developed a severe unilateral left-sided TAO. Thyrotropin receptor antibodies (TRAb) concentration was negative. Intraocular pressure in the left eye was mildly elevated (24 mmHg), while vision acuity was not compromised. Abnormal positioning of the eyeball suggested the extraocular muscles involvement. Unilaterally, von Graefe’s, Stellwag’s, Kocher’s and Moebius' signs were positive. Conjunctival erythema, redness and edema of the eyelid and an enlarged, swollen lacrimal caruncle were visible. She received 4/7 points in the Clinical Activity Scale (CAS) and class IV in the NO SPECS severity scale for the left eye (I-0, II-a, III-0, IV-b, V-0, VI-0). Magnetic resonance imaging (MRI) revealed thickening of the left medial rectus muscle with an increase in T2 signal intensity and prolonged T2 relaxation indicating an active form of TAO. The patient received therapy with glucocorticosteroids intravenously, followed by intramuscular injections with a cumulative dose of 3.24 g of methylprednisolone during a 9-week period with good tolerance. The applied therapy, combined with adequate L-thyroxine substitution, as well as vitamin D and selenium supplementation, resulted in a complete remission of ophthalmic symptoms.ConclusionsUnilateral exophthalmos in TRAb-negative patients with HT is not a typical manifestation of the disease, and requires a wider differential diagnosis with MRI of the orbits. Scheme of three iv. pulses of methylprednisolone intravenously and the continuation of treatment with im. injections seems to be an effective and safe method of treatment in this group of patients. What is more, adequate vitamin D supplementation and the maintenance of biochemical euthyroidism may help to achieve an ultimate therapeutic effect. Patients with TAO in the course of HT need a careful and continued interdisciplinary approach both ophthalmological and endocrinological. Further studies are needed to elucidate the etiopathogenesis of TAO in TRAb-negative patients.

Effect of Intravenous Methylprednisolone on the Signs &amp;amp; Symptoms of Graves’ Ophthalmopathy

Background: Graves’ ophthalmopathy (GO) is the most frequent extrathyroidal manifestation of Graves’ disease (GD). The effect of intravenous methylprednisolone on the signs and symptoms of GO has not been evaluated in the Bangladeshi population. Objective: To observe the effect of intravenous methylprednisolone in active Graves’ ophthalmopathy. Materials/Methods: This prospective study conducted in a tertiary hospital of Bangladesh from May 2009 to November 2010 included 30 patients having moderate to severe ophthalmopathy. In addition to the clinical activity score (CAS), eye involvement was assessed by using the “NOSPECS” scoring system. Results: The mean (±SD) age of the patients was 38.1 ± 10.6 years and male-female ratio was 1.2:1. NOSPECS eye findings before treatment and during the final (3rd) visit of the patients were observed. It was found that lid retraction or lid lag was improved in 21 (70%) of the patients during the final visit. All of the patients had soft tissue swelling initially and all of them improved at the final visit. Bilateral proptosis was present in 19 patients before treatment and improved in 12 (62%) patients during the final visit. Right eye proptosis was present in 9 patients before treatment and improved in 5 (60%) patients during final visit. Extraocular muscle involvement (Diplopia) was present in 15 patients before treatment but improved in 13 (86.0%) patients during the final visit. A significant number of subjects showed significant improvement in all of the NOSPECS eye findings (except unilateral right eye proptosis) during the final visit; all had inactive GO (CAS < 2) at the end of the 3rd visit. Conclusion: Intravenous methylprednisolone appears to be an effective treatment option for active Graves’ ophthalmopathy.

The epidemiological characteristics of patients with thyroid eye disease in a referral center in northern Iran

PurposeThis study was conducted to determine the demographics, clinical features, severity, and activity of thyroid eye disease (TED) in patients of a referral center in the north of Iran. MethodsPatients with TED who were referred to Amir-Almomenin Hospital, Rasht, Iran from March 2012 to March 2014 were enrolled in this cross-sectional study. The measurements of proptosis, lid width, lagophthalmos, extraocular muscle function, and visual acuity were recorded. The activity of ophthalmopathy was scored according to the clinical activity score (CAS). ResultsTED was diagnosed in 103 patients with a mean age of 42.1 ± 13.91 years. Of those patients, 52.4% were women, and 80% had hyperthyroidism. The mean duration of TED was 36.5 ± 53.12 months. Extraocular muscle involvement (98%) and eyelid retraction (88.3%) were the most common manifestations. Per the CAS results, 86 (83.5%) patients were at stage 0, and there was a significant difference in CAS scores between male and female patients, P = 0.02. ConclusionsThe characteristics of TED in patients of the studied referral center during a two-year period, including common signs and symptoms, disease duration, treatment, an activity of disease were determined. Notably, many patients in this study had orbital squeal of TED meaning that they had inactive TED. Proper management of this serious complication requires close cooperation between endocrinologists and ophthalmologists to ensure timely referrals for appropriate care.

Imaging Investigation of Thyroid Eye Disease

Thyroid eye disease (TED), is a term referring to the extrathyroidal manifestation of Grave's disease, a disorder which is currently the most common cause of hyperthyroidism and is characterised by underlying autoimmunity.The pathogenic course of the disease can be broadly classified into two stages, an early inflammatory and a late fibrotic stage. These stages are reflected in clinical severity and activity classifications, such as Clinical Activity Score and Class 0: No signs or symptoms, 1: Only signs, no symptoms (e. g. lid retraction), 2: Soft tissue involvement, 3: Proptosis, 4: Extraocular muscle involvement, 5: Corneal involvement, 6: Sight loss (NOSPECS). Classifications based on the latter, have important implications in treatment decisions since patients in the early active stage of the disease are more likely to respond to anti-inflammatory and immunosuppressive therapies, whereas patients in the late fibrotic stage require different therapeutic approaches, including rehabilitative surgery. We reviewed cases of TED investigated with CT and Magnetic Resonance Imaging (MRI) in our department. We assessed the findings of imaging studies and their role in the clinical investigation of patients with TED as well as in the differential diagnosis from other disorders. Imaging has a significant role in the investigation of TED, however a consensus on the use of different imaging modalities in the course of disease has yet to be reached. Nevertheless, imaging and specifically CT and MRI can have a vital role in the initial diagnosis of clinically atypical presentation of TED, in surgical planning, as well as in the differential diagnosis from other orbital disorders. In this review, we attempt to present current trends in imaging investigation of TED. Rather than focusing on the findings of each imaging modality separately, we present the two main imaging modalities focusing on CT and MRI, in the context of pathogenic stages of the disease.

Prevalence of Ocular Hypertension and Glaucoma as Well as Associated Factors in Graves' Orbitopathy.

The purpose of this study was to determine the prevalence of ocular hypertension (OHT) and open-angle glaucoma (OAG) in patients with Graves' orbitopathy (GO) and to investigate the associations between clinical features of the disease and the prevalence of OHT and OAG. A cross-sectional analytic study was conducted among a total of 1128 patients with GO. A complete ophthalmic examination was performed, including intraocular pressure, optic disc photography, visual field testing using a Humphrey visual field analyzer, and retinal nerve fiber layer thickness measured by optical coherence tomography. The results were analyzed by univariate and multivariate logistic regression. A 6.8% prevalence of OHT (77/1128) and a 1.6% prevalence of OAG (18/1128) were observed. When considering only patients older than 40 years, the prevalence of OHT and OAG was 9.5% and 3.4%, respectively. Twenty-nine of the 1128 patients (2.6%) developed compressive optic neuropathy. Of the factors evaluated, male sex [odds ratio (OR), 1.83; 95% confidence interval (CI), 1.08-3.10], duration of GO (6 to 24 mo; OR, 2.08; 95% CI, 1.17-3.71; 24 to 60 mo; OR, 3.45; 95% CI, 1.66-7.18), clinical activity score ≥3 (OR, 1.76; 95% CI, 1.03-3.01), extraocular muscle involvement (OR, 4.65; 95% CI, 2.54-8.50), and lid retraction (OR, 2.17; 95% CI, 1.19-3.96) were associated with the prevalence of OHT in GO. The prevalence of OAG was associated with male sex (OR, 4.29; 95% CI, 1.60-11.51) and duration of GO (≥60 mo; OR, 4.28; 95% CI, 1.11-16.47). The prevalence of OHT in patients with GO was higher and the prevalence of OAG was similar to that in the general population.

PD-1 Inhibitor-associated Myopathies: Emerging Immune-mediated Myopathies.

Programmed death-1 (PD-1) inhibitors are increasingly used in cancer immunotherapy. Various immune-related adverse events are reported, including infrequent individual case reports of myositis or rhabdomyolysis. The frequency and diagnostic spectrum of immune-related adverse events affecting skeletal muscle in PD-1 inhibitor-treated patients are unknown. We searched the Mayo Clinic Pharmacy database (2014-2016) to identify patients who developed myopathies during or after PD-1 inhibitor therapy. Among 654 cancer patients received PD-1 inhibitors (pembrolizumab=389; nivolumab=264; both=1), we identified 5 patients (pembrolizumab=5) with biopsy-proven myopathies (2 necrotizing myopathy, 1 early dermatomyositis, and 2 nonspecific myopathy). Four patients developed concomitant autoimmune disorders. Weakness occurred after a median of 2 treatments (range, 1-4). All patients had proximal or axial weakness. Four patients had either bulbar or extraocular weakness, but only 1 patient had acetylcholine receptor antibodies. Creatine kinase levels were elevated in 3 patients (necrotizing myopathy=2; nonspecific myopathy=1). Brain magnetic resonance imaging revealed abnormal T2 signal and enhancement of extraocular muscles in 1 patient with ophthalmoparesis. Pembrolizumab was discontinued in all patients. All patients received immunosuppressive therapy, with fatal outcome in 2 necrotizing myopathy patients and favorable outcome in others. We conclude that myopathy is a rare, but unique complication of PD-1 inhibitors with frequent involvement of extraocular or bulbar muscles, mimicking myasthenia gravis. Muscle biopsy is an important test for PD-1 inhibitor-treated patients who develop oculobulbar weakness and hyperCKemia, to distinguish patients with necrotizing myopathy from myasthenia gravis. Necrotizing myopathy patients may require more aggressive immunotherapy due to their grave prognosis.

Retrospective natural history of thymidine kinase 2 deficiency

BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease...

Orbital radiotherapy plus three-wall orbital decompression in a patient with rare ocular manifestations of thyroid eye disease: case report

BackgroundThyroid eye disease (TED) is a debilitating autoimmune orbital disease that is often a result of Graves’ disease. Dysthyroid optic neuropathy (DON) is a rare but sight-threatening manifestation of TED with therapeutic challenges that can potentially lead to visual loss.Case presentationA 74-year-old man experienced active TED with extremely severe redness and swelling of the conjunctiva, loss of visual acuity and exacerbation of disfiguring proptosis. Computed tomography revealed the involvement of extraocular muscles resulting in optic nerve compression. He was in poor general condition and was intolerant to steroids. To achieve the optimal operating conditions for orbital decompression surgery, the patient was initially treated with orbital radiotherapy. The patient responded well, with improvements in clinical activity score and visual acuity.ConclusionThis case demonstrates a rare and severe case of DON with therapeutic challenges. To date, no cases has been reported of a patient with such severe and unusual ocular manifestations. Early awareness of the occurrence of optic nerve compression and prompt treatment are important to prevent irreversible outcomes. Orbital radiotherapy should be considered as a useful surgery-delaying alternative for DON, especially in patients who have contraindications to steroids.

Congenital myopathies: disorders of excitation-contraction coupling and muscle contraction.

The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories. However, these entities seem to belong to a much wider phenotypic spectrum. To date, congenital myopathies have been attributed to mutations in over 20 genes, which encode proteins implicated in skeletal muscle Ca2+ homeostasis, excitation-contraction coupling, thin-thick filament assembly and interactions, and other mechanisms. RYR1 mutations are the most frequent genetic cause, and CCD and MmD are the most common subgroups. Next-generation sequencing has vastly improved mutation detection and has enabled the identification of novel genetic backgrounds. At present, management of congenital myopathies is largely supportive, although new therapeutic approaches are reaching the clinical trial stage.