Understanding the diagnostic challenges of Miller Fisher syndrome in children: a case report from an ophthalmological perspective.

We report a case of a 6-year-old boy with autism spectrum disorder presenting with new-onset squint and 'ptosis' following a recent infection. Clinical examination revealed ataxia and areflexia alongside a dilated pupil poorly reactive to light. Subsequently, his eye movements deteriorated to near-complete ophthalmoplegia at 1-week review. Further investigations inclusive of a magnetic resonance imaging (MRI) brain scan, a computed tomography (CT) venogram and a lumbar puncture were conducted to consider and rule out differential diagnoses. Cerebrospinal fluid analysis revealed an albuminocytologic dissociation. The clinical triad of progressive ophthalmoplegia, areflexia and areflexia alongside albuminocytologic dissociation led to the diagnosis of Miller Fisher syndrome. The patient was commenced on intravenous immunoglobulin and his symptoms showed significant improvement. We use this interesting case to provide context for key learning points about diagnosing Miller Fisher syndrome in children.

Clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles.

OBJECTIVE: This study aimed to describe the clinical and genetic characteristics of Chinese patients with congenital fibrosis of the extraocular muscles (CFEOM), and to evaluate the phenotype-genotype correlations in these patients. METHODS: This was a retrospective study. Patients with CFEOM underwent detailed ophthalmic examinations and magnetic resonance imaging (MRI). Panel-based next-generation sequencing was performed to identify pathogenic variants of disease-causing genes. RESULTS: Sixty-two patients with CFEOM were recruited into this study. Thirty-nine patients were diagnosed with CFEOM1 and 23 with CFEOM3. Forty-nine of the 62 patients with CFEOM carried either KIF21A (41/49) or TUBB3 variants (8/49). Six known missense variants in the KIF21A and TUBB3 genes, and a novel variant (c.3906T > A, p.D1302E) in the KIF21A gene were detected. Most patients with CFEOM1 carrying the KIF21A mutation displayed isolated CFEOM, whereas patients with CFEOM3 carrying the TUBB3 mutation had a wide range of clinical manifestations, either CFEOM alone or syndromes. Nystagmus was also present in 12 patients with CFEOM. Furthermore, the MRI findings varied, ranging from attenuation of the extraocular muscles to dysgenesis of the cranial nerves and brain structure. CONCLUSIONS: The novel variants identified in this study will further expand the spectrum of pathogenic variants in CFEOM-related genes. However, no phenotype-genotype correlations were established because of the diversity of the clinical characteristics of these patients.

Ophthalmoparesis as an unusual manifestation of anti-3­hydroxy-3-methyl-glutaryl-coenzyme A reductase antibody-associated myopathies.

We describe two anti-3­hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) antibody-positive patients with treatment-responsive ophthalmoparesis. Patient 1 was a 53-year-old male with progressive proximal limb weakness, dysphagia, ptosis, and diplopia over 6 weeks and creatine kinase (CK) of 3,512 units/L. Patient 2 was a 55-year-old female with progressive proximal weakness, dysarthria, ptosis, diplopia, and dyspnea over 2 weeks with CK of 31,998 units/L. Both patients had normal thyroid studies and repetitive nerve stimulation, myopathic electromyography with fibrillation potentials, magnetic resonance imaging demonstrating abnormal enhancement of extraocular muscles, muscle biopsy showing necrotic myofibers, and positive anti-HMGCR antibodies. Patient 1 also had weakly positive anti-PM/Scl antibodies. Immunomodulatory therapies led to resolution of oculobulbar weakness and normalization of CK levels in both patients, while limb weakness resolved completely in patient 1 and partially in patient 2. These cases expand the phenotypic spectrum of anti-HMGCR antibody-associated myopathies to include subacute ophthalmoparesis with limb-girdle weakness and markedly elevated CK.

Silent threat of isolated sphenoid sinus tuberculosis resulting in blindness and ophthalmoplegia.

A diabetic woman in her fifties presented with a sudden onset of failing vision and diplopia involving the right eye for two days, along with fever and headache. Radiological investigations revealed right sphenoid sinusitis along with inflammation around the right orbital apex and optic nerve. Functional endoscopic sinus surgery, with orbital and optic nerve decompression improved the ocular movements, but not the visual acuity. Histopathology was suggestive of a granulomatous inflammatory lesion, and high-resolution computed tommography (HRCT) of the thorax revealed lung lesions suggestive of an old tubercular infection, and antitubercular treatment (ATT) was then initiated.At the end of two months of ATT, there was complete resolution of ophthalmoplegia, relative afferent pupillary defect, direct and consensual light reflex however, failure of improvement in her visual acuity, indicated damage to the optic nerve.Extrapulmonary tuberculosis involving an isolated sphenoid sinus is rare and elusive. Prompt radiological investigations, followed by orbital decompression and ATT, provide the best possible outcomes.

Clinical Reasoning: A 60-Year-Old Woman With Rapidly Progressive Muscle Weakness and Ophthalmoparesis.

The clinical assessment of patients with proximal muscle weakness represents a frequent yet intricate challenge. We present the case of a 60-year-old woman who experienced a progressive, symmetrical weakness in proximal limbs and bulbar muscles over 6 months. Notable clinical findings included bilateral ophthalmoparesis; widespread muscle atrophy; and pronounced weakness in craniobulbar, cervical, and proximal muscles, more severe than in distal ones. We elucidate a methodical diagnostic approach, focusing on constructing a comprehensive differential diagnosis and identifying potential causes of proximal muscle weakness. Special emphasis is placed on exploring the etiologies in cases presenting with both progressive muscle weakness and ophthalmoparesis. We further describe the role of muscle biopsy results and their integration with genetic testing outcomes.

Clinical reading-related oculomotor assessment in visual snow syndrome / Evaluación oculomotora clínica relacionada con la lectura en el síndrome de nieve visual

Purpose: Visual snow syndrome (VSS) is a complex neurological condition presenting with an array of sensory, motor, and perceptual dysfunctions and related visual and non-visual symptoms. Recent laboratory studies have found subtle, basic, saccadic-based abnormalities in this population. The objective of the present investigation was to determine if saccadic-related problems could be confirmed and extended using three common clinical reading-related eye movement tests having well-developed protocols and normative databases. Methods: This was a retrospective analysis of 32 patients (ages 16–56 years) diagnosed with VSS in the first author's optometric practice. There was a battery of three reading-related tests: the Visagraph Reading Eye Movement Test, the Developmental Eye Movement (DEM) Test, and the RightEye Dynamic Vision Assessment Test, all performed using their standard documented protocols and large normative databases. Results: A high frequency of oculomotor deficits was found with all three tests. The greatest percentage was revealed with the Visagraph (56%) and the least with the RightEye (23%). A total of 77% of patients failed at least one of the three tests. Conclusion: The present findings confirm and extend earlier investigations revealing a high frequency of saccadic-based oculomotor problems in the VSS population, now including reading-related tasks. This is consistent with the more general oculomotor/motor problems found in these individuals.(AU)

Congenital cranial dysinnervation disorder with homozygous KIF26A variant.

Congenital fibrosis of the extraocular muscles (CFEOM) type 1 is associated with heterozygous missense variants in KIF21A, which encodes a kinesin-like motor protein. Individuals with CFEOM1 have severe paralysis of upgaze and ptosis, resulting in a pronounced chin-up head posture. There can also be limitations of horizontal eye movements. Loss of function of KIF26A, an unconventional kinesin motor protein that lacks ATP-dependent motor activity, has been recently reported to cause a spectrum of congenital brain malformations associated with defects in migration, localization, and growth of excitatory neurons. It has also been associated with megacolon resembling Hirschsprung's disease. We report the case of a boy with homozygous loss of function of KIF26A with restricted eye movements, specifically restricted upgaze and downgaze with variable nystagmus and dissociated vertical eye movements. This case represents a congenital cranial dysinnervation disorder, most similar to CFEOM, and is the first report of a congenital cranial dysinnervation disorder caused by a kinesin other than KIF21A.

Identification of a Novel Frameshift Variant in MYF5 Leading to External Ophthalmoplegia with Rib and Vertebral Anomalies.

Myogenic transcription factors with a basic helix-loop-helix (bHLH) such as MYOD, myogenin, MRF4, and MYF5 contribute to muscle differentiation and regulation. The MYF5 gene located on chromosome 12 encodes for myogenic factor 5 (MYF5), which has a role in skeletal and extraocular muscle development and rib formation. Variants in MYF5 were found to cause external ophthalmoplegia with rib and vertebral anomalies (EORVA), a rare recessive condition. To date, three homozygous variants in MYF5 have been reported to cause EORVA in six members of four unrelated families. Here, we present a novel homozygous MYF5 frameshift variant, c.596dupA p. (Asn199Lysfs*49), causing premature protein termination and presenting with external ophthalmoplegia, ptosis, and scoliosis in three siblings from a consanguineous family of Pakistani origin. With four MYF5 variants now discovered, genetic testing and paediatric assessment for extra-ocular features should be considered in all cases of congenital ophthalmoplegia.

Factors affecting resolution of oculomotor nerve palsy following endovascular embolization of posterior communicating artery aneurysms / Factores que influyen en el tratamiento de la parálisis oculomotora con embolización endovascular de aneurismas comunicantes posteriores

Purpose: To investigate the effect of endovascular embolization of posterior communicating artery (Pcom) aneurysms on concomitant oculomotor nerve palsy (OMNP) and factors affecting the effect of treatment. Materials and methods: Patients with the Pcom aneurysms concomitant with OMNP were retrospectively enrolled for endovascular treatment of the aneurysms. All patients had the endovascular management. The clinical effect, degree of OMNP, size of the aneurysm, type of treatment, subarachnoid hemorrhage (SAH), and time from onset to treatment were analyzed on the resolution of OMNP. Results: Ninety-six patients with 99 Pcom aneurysms were enrolled and treated endovascularly, with the success rate of 100%. Immediately after endovascular treatment, 75 aneurysms (75.75%) got complete occlusion, and 24 (24.24%) nearly complete occlusion. Followed up for 3–18 (mean 8.52 ± 0.56) months, complete resolution of the OMNP was achieved in 63 patients (65.63%), partial resolution in 21 (21.88%), and non-recovery in the other 12 (12.50%). The degree of OMNP at onset, SAH, and time from onset to treatment were significantly (P < 0.05) correlated with the resolution of OMNP. Univariate analysis revealed that younger age of the patient, degree of OMNP at onset, presence of subarachnoid hemorrhage, and time from disease onset to treatment were significantly (P < 0.05) associated with the recovery of OMNP. Multivariate analysis revealed that the younger age, degree of OMNP at onset, and time from disease onset to treatment were significantly (P < 0.05) associated with the recovery of OMNP. Conclusion: Endovascular embolization of Pcom aneurysms concomitant with OMNP can effectively improve the OMNP symptoms, especially for patients with moderate and a shorter history of OMNP. Younger age, degree of oculomotor nerve palsy at onset, and time from onset to treatment may significantly affect recovery of oculomotor nerve palsy.(AU)

Objetivo: Investigar la eficacia de la embolización intravascular del aneurisma de comunicación posterior (Pcom) en pacientes con parálisis oculomotora (OMNP) y los factores que influyen en la eficacia. Materiales y métodos: Se analizaron retrospectivamente los datos clínicos de la terapia intravascular en pacientes con aneurismas Pcom con OMNP. Todos los pacientes recibieron tratamiento intravascular. Se analizaron los efectos de la eficacia clínica, el grado de OMNP, el tamaño del aneurisma, el método de tratamiento, la hemorragia subaracnoidea y el tiempo desde el inicio hasta el tratamiento en la regresión de OMNP.Resultados: Un total de 96 pacientes con 99 aneurismas Pcom fueron tratados con éxito. Inmediatamente después del tratamiento intravascular, 75 casos (75,75%) de aneurismas fueron completamente ocluidos y 24 casos (24,24%) casi completamente ocluidos. Durante el seguimiento de 3 a 18 meses (promedio: 8,52 ± 0,56 meses), se logró la resolución completa en 63 casos (65,63%), la resolución parcial en 21 (21,88%) y la no recuperación en los otros 12 (12,50%). El grado de OMNP al inicio, la hemorragia subaracnoidea y el tiempo de inicio a tratamiento se correlacionaron significativamente con la resolución de la OMNP (p < 0,05). El análisis univariado mostró que la menor edad del paciente, el grado de OMNP, la presencia de hemorragia subaracnoidea y el tiempo transcurrido desde el inicio de la enfermedad hasta el tratamiento se correlacionaron significativamente con la recuperación de OMNP (p < 0,05). Conclusión: La embolización intravascular del aneurisma Pcom combinada con OMNP puede mejorar eficazmente los síntomas de OMNP, especialmente en pacientes con OMNP a corto y mediano plazo. La edad temprana, el grado de parálisis del nervio oculomotor al inicio y el tiempo desde el inicio hasta el tratamiento tuvieron un efecto significativo en la recuperación de la parálisis del nervio oculomotor.(AU)

COQ7 defect causes prenatal onset of mitochondrial CoQ10 deficiency with cardiomyopathy and gastrointestinal obstruction.

COQ7 pathogenetic variants cause primary CoQ10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613_617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis.

Expanding Clinical Spectrum of Anti-GQ1b Antibody Syndrome: A Review.

Importance: The discovery of the anti-GQ1b antibody has expanded the nosology of classic Miller Fisher syndrome to include Bickerstaff brainstem encephalitis, Guillain-Barré syndrome with ophthalmoplegia, and acute ophthalmoplegia without ataxia, which have been brought under the umbrella term anti-GQ1b antibody syndrome. It seems timely to define the phenotypes of anti-GQ1b antibody syndrome for the proper diagnosis of this syndrome with diverse clinical presentations. This review summarizes these syndromes and introduces recently identified subtypes. Observations: Although ophthalmoplegia is a hallmark of anti-GQ1b antibody syndrome, recent studies have identified this antibody in patients with acute vestibular syndrome, optic neuropathy with disc swelling, and acute sensory ataxic neuropathy of atypical presentation. Ophthalmoplegia associated with anti-GQ1b antibody positivity is complete in more than half of the patients but may be monocular or comitant. The prognosis is mostly favorable; however, approximately 14% of patients experience relapse. Conclusions and Relevance: Anti-GQ1b antibody syndrome may present diverse neurological manifestations, including ophthalmoplegia, ataxia, areflexia, central or peripheral vestibulopathy, and optic neuropathy. Understanding the wide clinical spectrum may aid in the differentiation and management of immune-mediated neuropathies with multiple presentations.

Lysosomal dysfunction and overload of nucleosides in thymidine phosphorylase deficiency of MNGIE.

Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.

Leiomioma orbitario gigante en un paciente pediátrico: reto diagnóstico y terapéutico / Giant orbital leiomyoma in a pediatric patient: Diagnostic and therapeutic challenge

Este manuscrito presenta un caso de un leiomioma orbitario de larga evolución en un joven de 14años. El tumor era inusualmente grande y causaba una proptosis severa y una afectación importante de la musculatura ocular. El paciente presentaba amaurosis, una oftalmoplejía completa, dolor ocular espontáneo e incapacidad para cerrar los párpados. Debido al tamaño del tumor y a su progresión, se realizó una exenteración orbitaria derecha para eliminar todo el contenido orbitario, incluyendo el tumor y el globo ocular. El procedimiento quirúrgico tenía como objetivo prevenir la recurrencia del tumor y mejorar la calidad de vida del paciente. El análisis histopatológico confirmó el diagnóstico de leiomioma orbitario. Este caso presenta un interés particular por el grado de evolución que ha alcanzado. La extirpación completa del tumor y un seguimiento a largo plazo son necesarios para prevenir la recurrencia y garantizar resultados óptimos para el paciente. Además, este caso refleja las grandes diferencias en el acceso a la sanidad en las diferentes regiones del mundo. (AU)

This manuscript describes an exceptional case of a long-standing orbital leiomyoma in a 14-year-old male. The tumor was unusually large, causing severe proptosis and significant involvement of the ocular muscles. The patient presented with amaurosis, complete ophthalmoplegia, spontaneous eye pain, and the inability to close the eyelids, leading to psychological distress. Due to the tumor's size and progression, a right orbital exenteration was performed to remove all orbital contents, including the tumor and the eyeball. The surgical procedure aimed to prevent tumor recurrence and improve the patient's quality of life. The histopathological analysis confirmed the diagnosis of orbital leiomyoma. This case presents a particular interest due to the degree of evolution it has reached. Complete tumor excision and long-term follow-up are necessary to prevent recurrence and ensure optimal patient outcomes. This report underscores global healthcare disparities and the complexity of managing rare orbital neoplasms in diverse country settings. (AU)

Surgery for longer duration supranuclear ophthalmoplegia secondary to brain stem cavernoma: A case report and literature review.

BACKGROUND: Previous reports revealed that patients with acquired paralytic strabismus caused by central nervous system diseases are primarily affected by the etiology and treatment of the condition. Strabismus correction for these acquired paralytic strabismus should be performed as soon as the primary disease has been stabilized for 6 months in order to archive a favorable surgical outcome. CASE: We followed an infrequent case of longer-lasting supranuclear ophthalmoplegia secondary to brain stem cavernoma. OBSERVATION: A 25-year-old Chinese Han female developed aberrant head posture and ipsilateral conjugate gaze palsies 8 years after the first brainstem hemorrhage caused by pontine cavernoma. The patient was diagnosed with supranuclear ophthalmic palsy and brain stem cavernoma after surgery. A resection-recession procedure along with a rectus muscle transposition was performed. The patient's abnormal head position disappeared, with a normal primary position. CONCLUSION: Resection-recession procedures combined with rectus muscle transposition works very well for longer duration large-angle strabismus caused by brain stem cavernoma.

Oculomasticatory rhythmic movements, insomnia and stroke-like episodes in a patient with POLG mutation.

The POLG mutation, a leading cause of mitochondrial diseases, exhibits a wide-ranging age of onset and a complex clinical presentation. We encountered an atypical clinical profile in an elderly man with a POLG mutation, characterised by a stroke-like episode, chronic insomnia and transient oculomasticatory rhythmic movement. History revealed chronic constipation since his 50s and progressive bilateral ophthalmoplegia since his early 60s. Subsequently, he had experienced acute encephalopathy and later developed chronic insomnia. The present neurological examination showed bilateral complete ophthalmoplegia, ptosis, and rhythmic ocular and jaw movements. Imaging indicated findings suggestive of a stroke-like episode and eventual genetic analysis revealed a homozygous missense mutation in the POLG gene. This case expands the clinical spectrum of POLG mutations in individuals over 60 years, showcasing the rare combination of a stroke-like episode, chronic insomnia and oculomasticatory rhythmic movement.

Juvenile ocular myasthenia gravis: a report of two cases.

We report 2 cases of pediatric ocular myasthenia gravis. The first case was a 7-year-old girl who presented with bilateral ophthalmoplegia and ptosis that correlated with the onset of upper respiratory symptoms. Neuroimaging and acetylcholine receptor antibody testing were unremarkable. The ice pack test was positive. Symptoms greatly improved with pyridostigmine, with full resolution of ophthalmoplegia achieved by 8-month follow-up. The second case was a 4-year-old girl who presented emergently with ptosis and bilateral ophthalmoplegia. Acetylcholine receptor antibodies testing was positive. The patient was started on pyridostigmine and intravenous immunoglobulin and is scheduled to follow-up with pediatric ophthalmology in the outpatient setting.