A Treatment Approach in Congenital Fibrosis of Extraocular Muscles.

Background: Congenital fibrosis of extraocular muscles ( CFEOM) is a group of genetically defined eye-moving disorders. The syndrome is clinically characterized by congenital non-progressive ophthalmoplegia caused by dysinervation of the cranial nerves with or without ptosis. As a main sign of a CFEOM, extraocular muscles get shrunken and fibrotic, which makes surgery more technically demanding and the result more unpredictable, which makes the treatment challenging and highly customized. Our paper presents variations of the clinical picture and treatment cases of CFEOM1. Objective: To outline the importance of the clinical examination with the exact measurement of deviations for the patients with ocular fibrosis and passive duction test under general anesthesia, establishing them as the main criteria for treatment. Methods: We treated seven patients (14 eyes) with CFEOM1. The decision of the treatment was based on the measurement of the eye position in the primary position (PP), the severity of compensatory head position (CHP), restriction of motility, and passive motility test performed before surgery in general anesthesia. In 3 cases, patients were treated conservatively with the treatment of refractive error and amblyopia. However, in 4 patients, CHP and position of the eyes in PP were not acceptable, motility was severely impaired, and patients underwent surgery. The first surgery was performed on eye muscles: recession of inferior rectus muscle (IRM), anteposition, and resection of superior rectus muscle (SRM). As a second step procedure, ptosis surgery was performed. When the muscle was too tight, and it wasn't possible to have a satisfying result with conventional surgery, we used a tissue expander to improve the position and motility of the affected eyes. Results: In all operated cases, CHP has significantly improved and the position of the eyes in PP. Conclusion: Exact eye and head position measurements and a passive motility test during general anesthesia should guide the surgery. In the case when conventional surgery is not possible, implantation of a bovine pericard is a safe and effective method.

Acupuncture combined tuina for oculomotor paralysis: A protocol for systematic review and meta-analysis.

BACKGROUND: Oculomotor paralysis (OP) is a neurologic syndrome with multiple causes of oculomotor nerve and its dominant tissue and muscle dysfunction. Acupuncture combined with tuina is a wide-ranging used rehabilitation therapy, although there is short of supporting evidence for its efficacy and safety in patients with OP. The purpose of this systematic review was to estimate and synthesize evidence of the efficacy and safety of acupuncture combined with tuina in the treatment of OP. METHODS: Electronic databases, including PubMed, Web of Science, Cochrane Library, EMBASE, Technology Journal and China Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang,adopt an appropriate search strategy. RevMan V.5.3.5 software will be used for data synthesis, bias risk, and subgroup analyses. RESULTS: This study provides high-quality evidence to assess the effectiveness and safety of acupuncture combined with tuina for OP. CONCLUSION: This systematic review explores whether acupuncture combined with tuina is an effective and safe intervention for OP. ETHICS AND DISSEMINATION: Private information from individuals will not publish. This systematic review does not involve endangering participant rights. Ethical approval was not obtained. The results may be published in a peer-reviewed journal or disseminated at relevant conferences. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42021266447.

Hematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalopathy: A single-center experience underscoring the multiple factors involved in the prognosis.

BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive autosomal recessive disorder characterized by cachexia, gastrointestinal (GI) dysmotility, ptosis, peripheral neuropathy, and brain magnetic resonance imaging (MRI) white matter changes. Bi-allelic TYMP mutations lead to deficient thymidine phosphorylase (TP) activity, toxic accumulation of plasma nucleosides (thymidine and deoxyuridine), nucleotide pool imbalances, and mitochondrial DNA (mtDNA) instability. Death is mainly due to GI complications: intestinal perforation, peritonitis, and/or liver failure. Based on our previous observations in three patients with MNGIE that platelet infusions resulted in a transient 40% reduction of plasma nucleoside levels, in 2005 we performed the first hematopoietic stem cell transplantation (HSCT) worldwide as a life-long source of TP in a patient with MNGIE. PROCEDURE: HSCT was performed in a total of six patients with MNGIE. The multiple factors involved in the prognosis of this cohort were analyzed and compared to the literature experience. RESULTS: Cell source was bone marrow in five patients and peripheral stem cells in one, all from fully human leukocyte antigen (HLA)-matched related donors, including four who were TYMP mutation carriers. Four of six (66%) survived compared to the 37% survival rate in the literature. Reduced intensity conditioning regimen contributed to secondary graft failure in two patients. Fifteen years post HSCT, the first transplanted patient is seemingly cured. Severe GI symptoms before transplantation were mostly irreversible and were poor prognostic factors. CONCLUSIONS: Allogenic HSCT could constitute a curative therapeutic option for carefully selected, young, presymptomatic, or mildly affected patients. Timing, donor selection, and optimal conditioning protocol are major determinants of outcome. HSCT is inadvisable in patients with advanced MNGIE disease.

Efficacy of adeno-associated virus gene therapy in a MNGIE murine model enhanced by chronic exposure to nucleosides.

BACKGROUND: Preclinical studies have shown that gene therapy is a feasible approach to treat mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the genetic murine model of the disease (Tymp/Upp1 double knockout, dKO) has a limited functional phenotype beyond the metabolic imbalances, and so the studies showing efficacy of gene therapy have relied almost exclusively on demonstrating correction of the biochemical phenotype. Chronic oral administration of thymidine (dThd) and deoxyuridine (dUrd) to dKO mice deteriorates the phenotype of the animals, providing a better model to test therapy approaches. METHODS: dKO mice were treated with both dThd and dUrd in drinking water from weaning until the end of the study. At 8 - 11 weeks of age, mice were treated with several doses of adeno-associated virus (AAV) serotype 8 vector carrying the human TYMP coding sequence under the control of different liver-specific promoters (TBG, AAT, or HLP). The biochemical profile and functional phenotype were studied over the life of the animals. FINDINGS: Nucleoside exposure resulted in 30-fold higher plasma nucleoside levels in dKO mice compared with non-exposed wild type mice. AAV-treatment provided elevated TP activity in liver and lowered systemic nucleoside levels in exposed dKO mice. Exposed dKO mice had enlarged brain ventricles (assessed by magnetic resonance imaging) and motor impairment (rotarod test); both were prevented by AAV treatment. Among all promoters tested, AAT showed the best efficacy. INTERPRETATION: Our results show that AAV-mediated gene therapy restores the biochemical homeostasis in the murine model of MNGIE and, for the first time, demonstrate that this treatment improves the functional phenotype. FUNDING: This work was funded in part by the Spanish Instituto de Salud Carlos III, and the Generalitat de Catalunya. The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

A Very Rapidly Growing, Spontaneous, Internal Carotid Artery Dissecting Aneurysm Triggering Simultaneous Complete Ophthalmoplegia and a Cerebral Infarct.

BACKGROUND: Simultaneous ipsilateral complete ophthalmoplegia and multiple cerebral infarctions are very rare, especially secondary to a very rapidly growing, spontaneous dissecting aneurysm in the cavernous segment of the internal carotid artery (ICA). CASE DESCRIPTION: We describe a 26-year-old woman who presented with sudden-onset, right-sided, spontaneous ophthalmoplegia with left hemiparesis. Magnetic resonance imaging revealed a middle cerebral artery territory infarction. Digital subtraction angiography (DSA) revealed multiple arterial dissections involving both the vertebral artery and right ICA, with a dissecting aneurysm in the cavernous segment of the ICA. On day 3, the partial ophthalmoplegia worsened to complete ophthalmoplegia (third, fourth, and sixth cranial nerve palsies), despite conservative treatment. Follow-up DSA showed increased aneurysm size. The dissecting aneurysm was successfully managed by stent-assisted coil embolization. After endovascular treatment, the ophthalmoplegia, ptosis, and headache gradually resolved. CONCLUSION: This is the first reported case of simultaneous cerebral infarction and complete ophthalmoplegia attributed to a rapidly growing dissecting aneurysm of the cavernous ICA; such aneurysms readily cause thromboembolism. Physicians who treat patients with dissecting aneurysms should carefully monitor aneurysm growth.

The oculomotor neurovascular conflict: Literature review and proposal of management.

BACKGROUND: The Oculomotor nerve (OCN) lies in a close relationship with large arteries inside the basal cisterns. Therefore, it may be compressed by vascular malformations or aneurysms. Nevertheless, the compression is not always related to pathologic conditions. Indeed, some cases of neurovascular conflicts of the OCN have been described in the literature. METHODS: A case of neurovascular conflict of the OCN resolved after steroid treatment is reported. Additionally, a systematic literature review of those cases was performed. RESULTS: OCN palsy due to a neurovascular conflict has been described as acute or chronic persistent palsy, or with an intermittent presentation. Symptoms result from compression, although asymptomatic compression is not uncommon. Surgical treatment, pharmacological treatment, and observation have been reported as options in the literature. Microvascular decompression was employed effectively in some cases of OCN neurovascular conflict. Nevertheless, other cases were treated successfully with steroids (persistent presentation) and carbamazepine (intermittent presentation). A management algorithm based on the results of the literature review is proposed. CONCLUSIONS: Treatment options for OCN neurovascular conflicts and their results are heterogeneous. Based on the literature review, the pharmacological treatment seems to be the most appropriate first-line approach, reserving surgery for refractory cases. Collecting clinical information about new cases will allow defining treatment standards for this rare condition.

Ophthalmoplegia with skin necrosis after a hyaluronic acid filler injection.

Hyaluronic acid filler injection is commonly used for aesthetic purposes. However, many clinicians neglect the possibility of developing vascular occlusion and its devastating sequelae. Besides visual loss after iatrogenic ophthalmic artery occlusion, ophthalmoplegia without blindness is rare but may occur. Here, we report a 23-year-old woman with ptosis, lateral deviation of the right eye, and skin necrosis after hyaluronic acid filler injection. After hyaluronidase injection and steroid pulse therapy, ptosis and eye movement were completely restored. Skin necrosis was treated with a human epithelial growth factor ointment, followed by Nd:YAG laser. Complete healing with minimal scar was achieved.

Core myopathies - a short review.

Congenital myopathies represent a clinically and genetically heterogeneous group of early-onset neuromuscular diseases with characteristic, but not always specific, histopathological features, often presenting with stable and/or slowly progressive truncal and proximal weakness. It is often not possible to have a diagnosis on clinical ground alone. Additional extraocular, respiratory, distal involvement, scoliosis, and distal laxity may provide clues. The "core myopathies" collectively represent the most common form of congenital myopathies, and the name pathologically corresponds to histochemical appearance of focally reduced oxidative enzyme activity and myofibrillar changes on ultrastructural studies. Because of the clinical, pathological, and molecular overlaps, central core disease and multiminicore disease will be discussed together.

Thromboembolic risk with IVIg: Incidence and risk factors in patients with inflammatory neuropathy.

Our objective was to evaluate whether IV immunoglobulin (IVIg) increases the risk of thromboembolic events in neurology outpatients with inflammatory neuropathies, as there is conflicting evidence supporting this hypothesis, mainly from non-neurologic cohorts. We investigated this question over 30 months in our cohort of patients with inflammatory neuropathies receiving regular IVIg and found a greater incidence of arterial and venous thromboembolic events than population-based rates determined by hospital admissions data. Vascular risk factors were more common in the event group but there were no IVIg administration factors that contributed to the risk. This study suggests that IVIg may have a small but contributory role in determining thromboembolic risk in the inflammatory neuropathy cohort and more evidence is required before it is clear whether the current primary prevention guidelines are appropriate in this group of patients.

Update: the Miller Fisher variants of Guillain-Barré syndrome.

PURPOSE OF REVIEW: This article will update and review the Miller Fisher variants (MFV) of Guillain-Barré syndrome (GBS) including the clinical presentation, diagnostic testing, and treatment. RECENT FINDINGS: Although the diagnosis of GBS and MFV can be made on clinical grounds, cerebrospinal fluid (CSF) analysis, nerve conduction studies, imaging (e.g. ultrasound and MRI), and serologic testing can help to confirm the diagnosis. Some patients may need immunotherapy with either intravenous immunoglobulin (IVIg) or plasma exchange, and recent studies suggest that complement inhibition combined with IVIg could be of benefit, but further studies are needed to prove efficacy. SUMMARY: GBS is characterized by an acute, ascending polyneuropathy, ataxia, areflexia, and CSF albuminocytologic dissociation. The MFV of GBS is associated with ophthalmoplegia. Clinicians should have high index of suspicion for MFV of GBS in patients with acute ophthalmoplegia in order to establish the diagnosis, perform appropriate evaluation, and start treatment. SDC VIDEO LINK:.

A review of the histopathological findings in myasthenia gravis: Clues to the pathogenesis of treatment-resistance in extraocular muscles.

In myasthenia gravis autoantibodies target components of the neuromuscular junction causing variable degrees of weakness. In most cases, autoantibodies trigger complement-mediated endplate damage and extraocular muscles may be most susceptible. A proportion of MG cases develop treatment-resistant ophthalmoplegia. We reviewed publications spanning 65 years reporting the histopathological findings in the muscles and extraocular muscles of myasthenic patients to determine whether pathological changes in extraocular muscles differ from non-ocular muscles. As extraocular muscles represent a unique muscle allotype we also compared their histopathology in myasthenia to those in strabismus. We found that in myasthenia gravis, the non-ocular muscles frequently demonstrate neurogenic changes regardless of myasthenic serotype. Mitochondrial stress/damage was also frequent in myasthenic muscles and possibly more evident in muscle-specific kinase antibody-positive MG. Although myasthenia-associated paralysed extraocular muscles demonstrated prominent fibro-fatty replacement and mitochondrial alterations, these features appeared commonly in paralysed extraocular muscles of any cause. We postulate that extraocular muscles may be more susceptible than limb muscles to poor contractility as a consequence of myasthenia, resulting in a cascade of atrophy signaling pathways and altered mitochondrial homeostasis which contribute to the tipping point in developing treatment-resistant myasthenic ophthalmoplegia. Early strategies to improve force generation in extraocular muscles are critical.

The Non-surgical Management of Ophthalmoplegia.

Ophthalmoplegia can result from damage or dysfunction of the supranuclear eye movement pathways, the brainstem internuclear pathways, or the ocular motor nerves. Diplopia and impaired eye movements are commonly associated symptoms. The goal of non-surgical treatment is usually management of symptoms, and the primary tool used is prism. Results of recent studies in the neurorehabilitation literature have suggested that eye muscle exercise may do more than compensate for symptoms of ophthalmoplegia. They may accelerate recovery for those conditions in which recuperation is possible, and restore ocular mobility in chronic and degenerative conditions. A large, randomized, blind study is needed to investigate the efficacy of eye exercises in ophthalmoplegia.

Acupuncture for ophthalmoplegia: Protocol for a systematic review.

BACKGROUND: Ophthalmoplegia is a disease that affects many people every year and is caused by reasons, such as cavernous sinus lesion, intracranial aneurysm, diabetes, and trauma. Acupuncture has been widely used to treat ophthalmological diseases especially ophthalmoplegia in China. Many clinical trials indicate that acupuncture may promote the recovery of extraocular muscles in ophthalmoplegia patients. We aim to conduct a meta-analysis to evaluate the efficacy and safety of acupuncture for ophthalmoplegia. METHODS: We will retrieve the literature from the following electronic databases, by March 31, 2018, such as PubMed, EMBASE, the Cochrane Library, Web of Science database, Chinese BioMedical Literature Database, China National Knowledge Infrastructure, China Science and Technology Journal database, and Wanfang Database. We will also collect clinical trial registries, dissertations, grey literature, reference lists of studies, systematic reviews, and conference abstracts. Two people will review these articles, extract the data information, and assess the quality of studies separately. Data will be synthesized by either fixed-effects or random-effects model regarding to a heterogeneity test. The eyeball movement distance, size of fissure palpebrae, and the reduced degree of strabismus will be assessed as the primary outcomes. The secondary outcomes will be the size of the pupil, main symptom scores, ocular localization analysis, and functional impairment extent and safety. We will use the specific software called RevMan (version 5.3) to perform the meta-analysis. RESULTS: This study will provide a high-quality synthesis based on current evidence of acupuncture for ophthalmoplegia, especially its impacts on eyeball movement distance, size of fissure palpebrae, the reduced degree of strabismus, size of the pupil, main symptom scores, ocular localization analysis, and functional impairment extent and safety. EXPECTED CONCLUSION: Our systematic review will provide evidence to determine whether acupuncture is an effective and safe intervention for ophthalmoplegia patients. ETHICS AND DISSEMINATION: It is not necessary for this systematic review to acquire an ethical approval. This review will be disseminated in a peer-reviewed journal or conference presentation. PROSPERO REGISTRATION NUMBER: PROSPERO CRD42018091536.

Myasthenic ophthalmoparesis: Time To resolution after initiating immune therapies.

INTRODUCTION: Although immunotherapies such as prednisone are effective in treating myasthenic muscle weakness, their effect on resolution of myasthenic-induced persistent ophthalmoparesis is unknown. METHODS: We observed patients with myasthenia gravis during their first year of immunotherapy, documenting ophthalmoplegia scores and drug doses. RESULTS: Seventy-six of 87 cases had persistent ophthalmoparesis. With immunotherapy, the median time to resolution of ophthalmoparesis was 7 months, and 37% of cases resolved within 3 months. Patients starting therapy within 12 months of symptom onset were twice as likely to have resolution in the first year (P = 0.028). Resolution of ophthalmoparesis within 3 months, compared with later resolution, was associated with higher initial prednisone doses (mean 0.5 vs. 0.3 mg/kg/day; P = 0.014). However, 25% of the higher dose group also received intravenous immunoglobulin/plasma exchange; after their exclusion, the finding was not significant. DISCUSSION: One-third of cases with myasthenic ophthalmoparesis resolved within 3 months of immunotherapy, particularly in response to more aggressive immunotherapy. Muscle Nerve 58: 542-549, 2018.

A unique subphenotype of myasthenia gravis.

While extraocular muscles (EOMs) are affected early in generalized myasthenia gravis (MG), and their treatment responsiveness is similar to nonocular muscles, we have identified an ophthalmoplegic (OP) subphenotype that remains resistant to treatment. This subphenotype of ophthalmoplegic MG (OP-MG) most commonly affects acetylcholine receptor antibody-positive cases with juvenile-onset MG and African genetic ancestry. However, a few OP-MG cases have been found with MuSK antibodies and triple-seronegative MG. In a proportion of OP-MG cases, the EOM treatment resistance manifests from treatment initiation, while in others the EOMs may initially respond until a critical trigger, such as treatment interruption or crisis. The management of OP-MG is an unmet need. Managing the visual disability may require a surgical or nonsurgical solution. The ideal case selection for surgery and the timing of surgery should be carefully considered. The pathogenesis of OP-MG remains unknown. A genetic study, using extended whole-exome sequencing and an "extreme" phenotype sample of OP-MG versus control MG cases differing only by their EOM responsivity to therapy, discovered several potentially functional OP-MG risk variants. These variants implicate myogenesis and gangliosphingolipid biosynthesis pathways at the EOM endplates in OP-MG.

[Staged complex treatment of paralytic lagophthalmos (case report)]. / Kompleksnoe poetapnoe lechenie paraliticheskogo lagoftal'ma (klinicheskii sluchai).

Paralytic lagophthalmos, resulting from facial nerve palsy, is a difficult medical and social issue that requires cooperation of different specialists. Complications that arise in paralytic lagophthalmos may cause significant vision loss and even eye loss. Various techniques of paralytic lagophthalmos correction are used to protect the cornea and restore eyelid anatomy and functions. These comprise palliative (conservative), surgical, and alternative treatments (such as botulinum toxin type A therapy). Surgical treatment of paralytic lagophthalmos patients often has to be staged and complex. This article presents a clinical case of a female patient with paralytic lagophthalmos complicated by corneal perforation. Her staged complex treatment included lower eyelid surgery, chemodenervation of the upper eyelid levator and optical reconstructive surgery. The following positive results were achieved: the protective function of the eyelids was restored, residual visual functions - preserved, the risk of eye loss - eliminated, and the asymmetry between the two halves of the face - corrected.

Late recurrence of a completely occluded large intracranial aneurysm treated with a Tubridge flow diverter.

We report a rare case of recurrence of a large intracavernous aneurysm after angiography proved complete occlusion. The aneurysm was treated by a combination of a Tubridge flow diverter and coils, and balloon angioplasty, after flow diverter devices deployment for parent vessel stenosis. Six month angiographic follow-up demonstrated complete occlusion. Unfortunately, obvious aneurysm recurrence was confirmed on 2 year angiographic follow-up. The probable mechanism of recurrence was analyzed.