Diagnostic yields and clinical features of ocular myasthenia gravis.

ABSTRACT: To investigate clinical features and diagnosis process of ocular myasthenia gravis (OMG) in ophthalmology department.A total of 36 patients with ptosis or diplopia who had follow-up for at least 3 months between March 2016 and December 2019 were included in this study. Clinical symptoms of patients and the test results were analyzed. According to the positivity of serologic test, these patients were divided into 2 groups (confirmed OMG and possible OMG with relief of symptoms after antimyasthenic treatment) for comparison.Ptosis was present in 12 (33.33%) patients, diplopia was present in 14 (38.89%) patients, and both ptosis and diplopia were present in 10 (27.78%) patients. Acetylcholine receptor auto-antibody (AchR Ab) was positive in 14 (38.89%) of 36 patients and ice test was positive in 15 (71.43%) of 21 patients with ptosis. Unequivocal response to pyridostigmine was observed in 31 (86.11%) patients. For seropositive cases, AchR Ab titer was significantly higher in the group with 2 clinical symptoms than that in the 1 clinical symptom (P = .011).This study presents the usefulness and diagnostic validity of antimyasthenic treatment for OMG, especially seronegative OMG, with detailed symptom analysis.

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.

Double seronegative myasthenia gravis with low density lipoprotein-4 (LRP4) antibodies presenting with isolated ocular symptoms.

The detection of low density lipoprotein-4 (LRP4) antibodies in double seronegative (dSN) myasthenia gravis (MG) patients has provided new insights in the diagnosis and treatment of MG. However, there are limited data regarding the clinical presentation and treatment response in dSN MG patients with LRP4-antibodies. We present a case series of three Caucasian dSN MG patients with positive LRP4-antibodies sharing a common ethnic background that presented with isolated ocular symptoms (MGFA I). The demographic and clinical characteristics, the diagnostic work-up as well as the treatment response during a follow-up period of 12-24 months are described in detail. All patients were treated successfully with acetylcholinesterase inhibitors (AcheI) and prednisone with two exhibiting full remission of their symptoms, while the remaining exhibited mild residual diplopia. Notably, we documented no signs of generalized disease progression, while no patient required immunosuppressive treatment. In conclusion, the distinct clinical phenotype of our patients highlights the clinical relevance of screening for LRP4-antibodies in patients presenting with isolated ocular MG independent of age and gender, since it may lead to the timely diagnosis of MG and prompt initiation of effective therapy with ACheI and corticosteroids.

Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function.

The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.

Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques.

A 70-year-old male was referred to the oculoplastic clinic with left-sided ptosis and floppy eyelids. During follow-up, bilateral upper lid xanthelasma developed with worsening ptosis and proptosis, which was worse on the left side. A left orbital biopsy showed xanthogranulomatous inflammation of the orbit. The patient was treated with a variety of immune modulator regimes but due to a variety of side-effects, treatment was discontinued. The left orbit was surgically debulked twice and histology revealed xanthogranulomatous inflammation, with the additional features of sclerosis, lymphoid aggregates and a prominent population of plasma cells. Around 80% of the plasma cells expressed immunoglobulin G4 (IgG4). This case report reveals an association between xanthogranulomatous inflammation of the orbit and a prominent population of IgG4-positive plasma cells. We propose that the overall disease is a novel variant of IgG4 sclerosing disease of the orbit and suggest that cases of histologically proven xanthogranulomatous inflammation should be stained for IgG4 if there is an accompanying plasma cell population.

Isolated ptosis as acute ophthalmoplegia without ataxia, positive for anti-GQ1b immunoglobulin G.

Anti-GQ1b IgG antibody syndrome comprises a wide range of diseases presenting with ophthalmoplegia and ataxia. Anti-GQ1b antibodies have been strongly associated in the literature with Miller Fisher Syndrome, with acute ophthalmoplegia associated with Guillain-Barré syndrome, and with isolated ophthalmoplegia. Acute ophthalmoplegia presents as various combinations of external and internal ophthalmoplegia. Reported here is a novel case of isolated ptosis as a manifestation of ophthalmoplegia. The present finding of bilateral ptosis and areflexia with anti-GQ1b IgG antibody positivity helps confirm the existence of the syndrome. Further research is needed on diagnosis and treatment.

Myasthenia gravis in a patient affected by glycogen storage disease type Ib: a further manifestation of an increased risk for autoimmune disorders?

Glycogen storage disease type Ib (GSD Ib, OMIM 232220) is an inborn disorder of glucose metabolism, caused by mutations in the G6PT gene, encoding a glucose 6-phosphate transporter (G6PT). GSD Ib is mainly associated with fasting hypoglycaemia and hepatomegaly. Most GSD Ib patients also show neutropenia and neutrophil dysfunction and therefore are at risk of developing severe infections and inflammatory bowel disease (IBD). An increased risk for autoimmune disorders, such as thyroid autoimmunity and Crohn-like disease, has also been demonstrated, but no systematic study on the prevalence of autoimmune disorders in GSD Ib patients has ever been performed. We describe a 25-year-old patient affected by GSD Ib who developed 'seronegative' myasthenia gravis (MG), presenting with bilateral eyelid ptosis, diplopia, dysarthria, severe dysphagia, dyspnoea and fatigue. The repetitive stimulation of peripheral nerves test showed signs of exhaustion of neuromuscular transmission, particularly evident in the cranial area. Even in the absence of identifiable anti-acetylcholine receptor antibodies, seronegative MG is considered an autoimmune disorder and may be related to the disturbed immune function observed in GSD Ib patients.

Anti-MuSK myasthenia gravis presenting with purely ocular findings.

BACKGROUND: Antibodies to a muscle-specific receptor tyrosine kinase (MuSK) have been found in approximately 40% of patients with generalized myasthenia gravis who are seronegative for the antiacetylcholine receptor antibody. Many of the patients with anti-MuSK antibodies have prominent oculobulbar symptoms or weakness of the neck and respiratory muscles, but patients with ocular myasthenia have not been described. OBJECTIVE: To report a case of ocular myasthenia due to anti-MuSK antibodies. PATIENT: A young woman with ocular myasthenia and antibodies to MuSK. RESULTS: Anti-MuSK antibody was detected by radioimmunoassay using highly purified MuSK recombinant antigen. CONCLUSION: Ocular myasthenia gravis is a presentation of the anti-MuSK antibody syndrome.

Long-term botulinum toxin efficacy, safety, and immunogenicity.

To determine the long-term efficacy of botulinum toxin (BTX) treatments, we analyzed longitudinal follow-up data on 45 patients (32 women; mean age, 68.8 years) currently followed in the Baylor College of Medicine Movement Disorders Clinic, who have received BTX treatments continuously for at least 12 years (mean 15.8 +/- 1.5 years). Their mean response rating after the last injection, based one a previously described scale 0-to-4 scale (0 = no effect; 4 = marked improvement) was 3.7 +/- 0.6 and the mean total duration of response was 15.4 +/- 3.4 weeks. Although the latency and total duration of the response to treatment have not changed over time, the peak duration of response (P < 0.005) and dose per visit (P < 0.0001) have increased since the initial visit. Furthermore, global rating (P < 0.02) and peak effect (P < 0.05) have improved. In total, 20 adverse events occurred in 16 of 45 (35.6%) patients after their initial visit and 11 adverse events in 10 of 45 (22.2%) patients at their most recent injection visit. Antibody (Ab) testing was carried out in 22 patients due to nonresponsiveness; blocking Abs were confirmed by the mouse protection assay in 4 of 22 (18%) patients. Of the Ab-negative patients, 16 resumed responsiveness after dose adjustments and 2 persisted as nonrespondents. Except for 1 patient, the 4 Ab-positive and the 2 clinical nonresponders are being treated with BTX-B. This longest reported follow-up of BTX injections confirms the long-term efficacy and safety of this treatment.

Immunological and electrophysiological investigations of severe ptosis after bone marrow transplantation.

Ocular problems are common in recipients of stem cell transplantation (SCT), but ptosis is rarely reported and investigated. Among 346 consecutive SCT recipients, severe bilateral ptosis was noticed or reported in six cases (five women and one man), all with acute graft-versus-host disease (aGVHD) and chronic graft-versus-host disease (cGVHD). On univariate analysis, both aGVHD (P=0.001) and cGVHD (P<0.001) were associated with post SCT ptosis, while a trend was shown for female sex (P=0.086). The median level of anti-acetylcholine receptor antibody was significantly higher in ptosis cases than controls with cGVHD (student's t-test, P=0.01). Antistriated muscle antibody was detected in three cases and was not significantly different from controls (Fisher's exact test, P=0.29). Tensilon tests were uniformly negative. However in five cases, single fibre electromyogram at frontalis muscle showed irregular recruitment effort, suggesting localized neuromuscular transmission defect reminiscent of ocular myasthenia gravis (MG). Two patients were observed, while three patients did not respond to mestinon or steroids treatment and one patient underwent aponeurosis advancement surgery. Transplant physicians and ophthalmologists should be aware of the problem of post SCT ptosis, which may be related to alloimmune causes of neuromuscular transmission block. Diagnosis can be difficult to confirm even with invasive SF-EMG testing. Most cases warrant conservative treatment due to chronicity, benign course and poor response to medication.

Myasthenia gravis with a paraneoplastic marker.

Ocular manifestations of myasthenia gravis are very common. Myasthenia gravis may be associated with lung carcinoma. Lambert-Eaton syndrome is also commonly associated with lung carcinoma and can have ocular manifestations. Overlap of these two entities has been described. The case of a patient with fatigable diplopia and ptosis 3 years after removal of a large-cell lung carcinoma is presented. Tests results for acetylcholine receptor binding and modulating antibodies were positive for myasthenia gravis. Test results for presynaptic voltage-gated calcium channel antibodies of the N-type were also positive. However, test results for the P/Q-type voltage-gated calcium channel antibodies, which are consistent with Lambert-Eaton syndrome, were negative. Autoantibodies can be used to serologically distinguish paraneoplastic myasthenia gravis from Lambert-Eaton syndrome.

[Experimental research and clinical application of homologous dura mater in ocular plastic surgery].

OBJECTIVE: To explore the clinical value of the dura mater implantation in ocular plastic surgeries. METHODS: Alcohol preserved homologous dura mater was implanted into the upper fornix under the conjunctiva of rabbit eye and light, electron microscopic histological and immunological examinations were made for the implant. 38 eyes consisting of 30 eyes of blepharoptosis, 4 eyes of blepharo-coloboma, 3 eyes of hollow socket and 1 eye of teleepicanthus were treated by homologous dura mater implantation. RESULTS: In the follow-up periods ranging from 1.5 to 2.5 years, 26 eyes in the treated eyes were cured, 9 eyes were markedly improved, 3 eyes failed. Histological findings showed that after 1 week of implantation there was cell infiltration around the implant, at 2 weeks new collagenous tissue developed at the margin of the implant and 2-3 months after transplantation, the grafts were replace by the patient's own connective tissue. The histological examination of 3 failure cases showed that the cause of the failure was due to the ischemia of homograft. The results of unidirectional mixed lymphocyte culture showed that the stimulation index before implantation in comparison with that at 96 and 120 hours after implantation had statistical significant differences, while in comparison with that at 144 hours after implantation had no such difference. Before the implantation, the stimulation index of the lymphocyte culture at 96 hours was significantly different from that at 144 hours statistically (P < 0.05). In the comparison of specific killing activity before and after implantation, there was statistical significant difference. CONCLUSION: The effects of transplantation of homologous dura mater employed in ocular plastic surgeries of blepharoptosis, blepharocoloboma, teleepicanthus and hollow socket are fairly good.

An evaluation of signs in ocular myasthenia gravis and correlation with acetylcholine receptor antibodies.

Fifteen patients with ocular myasthenia gravis were examined in detail for 21 different signs, and tested for acetylcholine receptor antibodies. The major signs of ocular myasthenia gravis included ptosis, disorders of ocular rotations, weakness of eyelid closure, "pseudosupranuclear" signs and the lid twitch sign. Acetylcholine receptor antibodies were found in eight of the 15 patients. One hundred and four normal, non-myasthenic patients were also examined for the lid twitch response, and the relationship between the lid twitch of ocular myasthenia gravis and that found in normal subjects is discussed.

The effect of plasmapheresis on post-thymectomy ocular dysfunction.

Five myasthenia patients with post-thymectomy residual ocular signs were treated with plasmapheresis. Despite a significant reduction in AChR antibody titer, there was no clinical improvement. Subsequently, there was a dramatic response to prednisone. The AChR antibody titer did not correlate with the clinical state of the individual patient. It is suggested that plasmapheresis may operate by removing a thymic factor and that prednisone acts by a different mechanism.