Successful treatment with efgartigimod as an add-on therapy in acute attack of anti-AQP4 antibody-positive NMOSD: a case report.

BACKGROUND: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an autoimmune demyelinating disease characterized by recurrent myelitis and optic neuritis. It is associated with high rates of relapse and disability. The main treatment strategies for acute attacks include intravenous methylprednisolone pulse (IVMP) treatment and rescue treatment with plasma exchange (PLEX). Recently, the blockade of neonatal Fc receptor (FcRn)-IgG interaction has gained momentum as a therapeutic strategy. Efgartigimod, the first approved FcRn inhibitor for treating generalized myasthenia gravis, has shown impressive safety, efficacy, and tolerability, and is being regarded as "PLEX in a bottle". CASE DESCRIPTION: We report a 65-year-old female patient who was diagnosed with anti-AQP4 antibody positive NMOSD. Add-on treatment with efgartigimod to IVMP and intravenous immunoglobulin (IVIG) at the second acute relapse showed favorable results. CONCLUSION: This case suggests that efgartigimod is a potentially effective add-on therapy in acute attacks of AQP4-IgG-positive NMOSD.

Pathological observations of a long spinal cord lesion in a patient with multiple sclerosis.

We report an autopsy case of multiple sclerosis (MS) manifesting as a long spinal cord lesion. The patient was a Japanese woman. At the age of 59 years, she presented with a one-month history of progressive paraplegia, dysesthesia in the lower extremities, and urinary retention. Magnetic resonance imaging revealed a long, hyperintense lesion on T2-weighted images that extended from the inferior portion of the medulla oblongata to the cervical segments of the spinal cord and an isolated lesion at the T6 level. Cerebrospinal fluid (CSF) examination revealed the presence of oligoclonal bands and increased myelin basic protein levels (999 pg/mL). Serum antibody against aquaporin 4 (AQP4) was undetectable in this patient. She was diagnosed as having atypical MS and experienced symptom improvement following immunotherapy with corticosteroids and plasma exchange. She died of pneumonia and renal failure at the age of 62 years. Postmortem examination revealed a long demyelinating lesion that extended from the inferior portion of the medulla oblongata to the sacral segments of the spinal cord. The lesion was comprised of numerous demyelinating plaques with inflammatory cell infiltration. A long spinal cord lesion is usually indicative of neuromyelitis optica spectrum disorder (NMOSD), and there are limited reports of postmortem observations of long spinal cord lesions among patients with anti-AQP4 antibody-seronegative MS. Our findings suggest that the pathomechanisms of such long spinal cord lesion formation differ between anti-AQP4 antibody-seronegative MS and NMOSD.

Treatment response, risk of relapse and clinical characteristics of Taiwanese patients with neuromyelitis optica spectrum disorder.

BACKGROUND/PURPOSE: The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. RESULTS: A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1-420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan-Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10-7). CONCLUSION: Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Dementia and Parkinson-like syndrome with basal ganglia lesion in neuromyelitis optica spectrum disorders.

Brain lesions in neuromyelitis optica spectrum disorders (NMOSD) are generally located at sites of high anti-aquaporin 4 (AQP4) expression. Clinical features of NMOSD associated with basal ganglia damage in sites not enriched with AQP4 remain unknown. Here we describe the case of an 82-year-old woman who developed dementia and bradykinesia for 5 weeks. Brain magnetic resonance imaging revealed obvious basal ganglia abnormalities. Test for serum anti-AQP4 antibody was positive, and she was diagnosed with NMOSD. Our case showed that NMOSD associated with dementia and/or Parkinson-like syndrome with basal ganglia lesions could be another clinical presentation in NMOSD.

A case of anti-aquaporin-4 antibody-positive optic neuritis treated by selective immunoadsorption.

Anti-aquaporin-4 (AQP4) antibody-positive optic neuritis is a condition in which a patient testing positive for anti-AQP4 antibody presents with optic neuritis only. The disease is classified as a neuromyelitis optica spectrum disorder (NMOSD) and is a steroid-resistant refractory optic neuritis. Patients are treated by oral administration of steroids, steroid pulse therapy, and apheresis therapy. The patient in our case was a 48-year-old female who was diagnosed with anti-AQP4 antibody-positive optic neuritis by her ophthalmologist, and was referred to our hospital. Selective plasma exchange (SePE) was initially started, but she strongly preferred treatment as an outpatient due to family circumstances. Therefore, selective immunoadsorption (SeIA) was used from the second session to minimize loss of coagulation factors. The RRs were 16.5-33.3% for anti-AQP4 antibody, 7.48-18.57% for fibrinogen, and 0.8-4.57% for factor XIII. After the 7th SeIA session, the patient was followed up with a maintenance dose of 10 mg/day oral prednisolone as an outpatient at our Department of Ophthalmology. This is the first report to investigate the removal rate (RR) of anti-AQ4 antibody using SeIA. In our case, the anti-AQP4 antibody level before the last SeIA session was still not completely negative, but there was clinical improvement in vision. SeIA was highly effective in maintaining coagulation factor levels. Therefore, our results suggest that SeIA is a safe treatment that can be performed in an outpatient setting.

Differential patterns of interhemispheric functional connectivity between AQP4-optic neuritis and MOG-optic neuritis: a resting-state functional MRI study.

BACKGROUND: Several neuroimaging studies demonstrated that optic neuritis (ON) leads to functional and anatomical architecture changes in the brain. The alterations of interhemispheric functional connectivity (IFC) in patients with AQP4-ON and myelin oligodendrocyte glycoprotein (MOG)-ON are not well understood. PURPOSE: To investigate the differential patterns of VMHC in patients with AQP4-ON and MOG-ON. MATERIAL AND METHODS: Twenty-one patients with AQP4-ON, 11 patients with MOG-ON, and 34 healthy controls underwent resting-state MRI scans. One-way ANOVA was used to identify regions in which the zVMHC differed among the three groups. Post hoc two-sample t-tests were then conducted to compare zVMHC values between pairs of groups. Pearson correlation analysis was conducted to reveal relationships between mean zVMHC values and clinical variables in the AQP4-ON and MOG-ON groups. RESULTS: The results revealed significant differences in zVMHC values in the PreCG among the three groups. Compared to the control group: the AQP4-ON group showed significantly lower VMHC values in the superior temporal gyrus, inferior frontal gyrus, and PreCG; and the MOG-ON group showed significantly higher zVMHC values in the PostCG. Compared to the AQP4-ON group, the MOG-ON group showed significantly lower zVMHC values in the PreCG/PostCG (voxel-level P<0.01, GRF correction, cluster-level P<0.05). CONCLUSION: Patients with AQP4-ON and those with MOG-ON showed abnormal VMHC in the motor cortices, sensorimotor cortices, and frontal lobe, possibly indicating impaired sensorimotor function in patients with ON. Moreover, differential patterns of VMHC in patients with AQP4-ON, compared to patients with MOG-ON, might serve as a clinical indicator for classification of ON.

Clinical Characteristics of Anti-aquaporin 4 Antibody Positive Optic Neuritis in Japan.

To investigate the clinical characteristics and the effectiveness of maintenance therapy of anti-AQP4 antibody positive optic neuritis in Japanese patients, medical records from 69 patients (103 eyes) were retrospective reviewed. The status of relapse in patients who received maintenance therapy following acute therapy was compared with that before maintenance therapy in patients who started maintenance therapy ≥6 months after acute therapy. In Japan, anti-AQP4 antibody positive optic neuritis was characterized by older onset age and poor visual outcome. The yearly rate and total number of relapses were lower when maintenance therapy was followed immediately after acute therapy.

Spontaneous Improvement of Visual Acuity in a 13-Year-Old Boy with Neuromyelitis Optica Spectrum Disorder.

Ophthalmic and MRI evaluations of a 13-year-old boy who reported loss of visual acuity in his right eye demonstrated the presence of unilateral optic neuritis. After serological tests showed positivity for anti-aquaporin 4 antibody, he was diagnosed with neuromyelitis optica spectrum disorder. Encephalopathy and myelitis were not observed. Since his unilateral optic neuritis was considered to reflect mild disease activity, only follow-up observations were performed. Visual acuity and central scotoma improved 1 week after the first examination. In the absence of any specific treatments, good visual acuity has remained for 20 months, with no relapse of optic neuritis.

Refractory neuromyelitis optica spectrum disorder in systemic lupus erythematosus successfully treated with rituximab.

We present a case of a woman with systemic lupus erythematosus (SLE) who had refractory episodes of neuromyelitis optica spectrum disorder (NMOSD) and was successfully treated with rituximab. She was positive for anti-aquaporin-4 (AQP4) antibody and had typical cranial and longitudinally extended spinal lesions but no optic nerve involvement. There is no established treatment for NMOSD/SLE overlap cases. Our experience suggests that rituximab may be effective for patients with combined SLE and anti-AQP4 antibody-positive NMOSD.

Gender effect on neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G.

BACKGROUND: Neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G (NMOSD-AQP4) is an inflammatory disease characterised by a high female predominance. However, the effect of gender in patients with NMOSD-AQP4 has not been fully evaluated. OBJECTIVE: The aim of this study was to determine the effect of gender in clinical manifestations and prognosis of patients with NMOSD-AQP4. METHODS: The demographics, clinical and radiological characteristics, pattern reversal visual evoked potential (VEP) test results, and prognosis of 102 patients (18 males) with NMOSD-AQP4 were assessed. RESULTS: Male patients had a higher age at onset (48.7 vs 41 years, p = 0.037) and less optic neuritis as the onset attack (17% vs 44%, p = 0.026), higher tendency to manifest as isolated myelitis over the follow-up period (67% vs 28%, p = 0.005), fewer optic neuritis attacks per year (0.08 vs 0.27, p < 0.001), and shorter relative P100 latency on VEP testing (97.1% vs 108.3%, p = 0.001). Moreover, male gender was significantly associated with the absence of optic neuritis attacks over the follow-up period independent of their age of onset. CONCLUSION: In NMOSD-AQP4 patients, gender impacts on disease onset age and site of attack. This may be an important clue in identifying NMOSD-AQP4 patients with limited manifestations as well as in predicting their clinical courses.

Spinal cord involvement in Behçet's disease.

BACKGROUND: Spinal cord involvement in Behçet's disease is not well studied. OBJECTIVE: To evaluate the clinical, laboratory and magnetic resonance imaging characteristics of spinal cord involvement in Behçet's disease. METHODS: We retrospectively reviewed 10 spinal cord involvements in seven patients with Behçet's disease. RESULTS: The median age of onset for spinal cord involvement was 32 (23-45 years). Two patients showed a secondary progressive course. Cerebrospinal fluid findings revealed mild to moderate pleocytosis and/or elevated protein levels. In eight spinal cord involvements, the lesion was longer than three vertebrae. Serum anti-aquaporin-4 antibody was negative in all four patients tested. CONCLUSIONS: Longitudinally extensive transverse myelitis is a characteristic manifestation of spinal cord involvement in Behçet's disease.

Pregnancy-related relapse risk factors in women with anti-AQP4 antibody positivity and neuromyelitis optica spectrum disorder.

BACKGROUND: Few reports describe the influence pregnancy has on the annualized relapse rate (ARR) in neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: To examine pregnancy-related attacks (attacks during pregnancy or within 1 year postpartum) and identify the risk factors for an attack in Japanese NMOSD patients. METHODS: We retrospectively reviewed 139 Japanese women whom had aquaporin-4 (AQP4) antibody-positive NMOSD. Among the 114 patients with information, 47 women had 56 pregnancies. We compared the ARR before, during and after pregnancy. RESULTS: Of the 47 NMOSD patients with pregnancy, 22 women (46.8%) had a pregnancy-related attack of the disease (either an onset event or a relapse). The ARR was significantly higher in the first 3 months postpartum (1.80 ± 2.04), than before the pregnancy (0.57 ± 1.16; p = 0.0043) and did not significantly decrease during pregnancy. The ARR before hospitalization and treatment was analyzable in 55 patients without pregnancy and was 1.09 ± 1.17. Among the 11 patients with onset before pregnancy, nine patients had a pregnancy-related attack with a relapse in the previous year, and their immunosuppression was discontinued or made to be at low doses; while the two patients on higher-dose therapies were relapse-free. CONCLUSION: In the present study, pregnancy-related attack was common in NMOSD, and unlike in multiple sclerosis, the ARR was not reduced during pregnancy. Discontinued or insufficient immunosuppression appeared to increase the risk of pregnancy-related attack.

The role of anti-aquaporin 4 antibody in the conversion of acute brainstem syndrome to neuromyelitis optica.

BACKGROUND: Acute brainstem syndrome (ABS) may herald multiple sclerosis (MS), neuromyelitis optica (NMO), or occur as an isolated syndrome. The aquaporin 4 (AQP4)-specific serum autoantibody, NMO-IgG, is a biomarker for NMO. However, the role of anti-AQP4 antibody in the conversion of ABS to NMO is unclear. METHODS: Thirty-one patients with first-event ABS were divided into two groups according to the presence of anti-AQP4 antibodies, their clinical features and outcomes were retrospectively analyzed. RESULTS: Fourteen of 31 patients (45.16 %) were seropositive for NMO-IgG. The 71.43 % of anti-AQP4 (+) ABS patients converted to NMO, while only 11.76 % of anti-AQP4 (-) ABS patients progressed to NMO. Anti-AQP4 (+) ABS patients demonstrated a higher IgG index (0.68 ± 0.43 vs 0.42 ± 0.13, p < 0.01) and Kurtzke Expanded Disability Status Scale (4.64 ± 0.93 vs 2.56 ± 0.81, p < 0.01) than anti-AQP4 (-) ABS patients. Area postrema clinical brainstem symptoms occurred more frequently in anti-AQP4 (+) ABS patients than those in anti-AQP4 (-) ABS patients (71.43 % vs 17.65 %, p = 0.004). In examination of magnetic resonance imaging (MRI), the 78.57 % of anti-AQP4 (+) ABS patients had medulla-predominant involvements in the sagittal view and dorsal-predominant involvements in the axial view. CONCLUSIONS: ABS represents an inaugural or limited form of NMO in a high proportion of anti-AQP4 (+) patients.

Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report.

A 38-year-old woman with relapsing longitudinal extensive transverse myelitis and Sjogren's syndrome (SS) was admitted with lower extremity muscle weakness. Studies showed high serum titer of anti-aquaporin4 antibody and gadolinium-enhanced-MRI T1-weighted lesions within thoracic cord. Clinical findings suggested neuromyelitis optica-spectrum disorder (NMO-SD). High-dose corticosteroids, plasma exchange and cyclophosphamide were not effective. After starting tocilizumab, her neurological findings gradually improved. This report describes the first evidence to show tocilizumab could be effective for NMO-SD with SS.

Progressive cerebral atrophy in neuromyelitis optica.

We report two cases of neuromyelitis optica patients with progressive cerebral atrophy. The patients exhibited characteristic clinical features, including elderly onset, secondary progressive tetraparesis and cognitive impairment, abnormally elevated CSF protein and myelin basic protein levels, and extremely highly elevated serum anti-AQP-4 antibody titer. Because neuromyelitis optica pathology cannot switch from an inflammatory phase to the degenerative phase until the terminal phase, neuromyelitis optica rarely appears as a secondary progressive clinical course caused by axonal degeneration. However, severe intrathecal inflammation and massive destruction of neuroglia could cause a secondary progressive clinical course associated with cerebral atrophy in neuromyelitis optica patients.

Relapsing inappropriate antidiuretic hormone secretion in an anti-aquaporin-4 antibody positive paediatric patient.

Paediatric patients with the syndrome of an inappropriate antidiuretic hormone secretion (SIADH), as a manifestation of inflammatory demyelinating disorders of the central nervous system, have been rarely described until now, in only a few cases of neuromyelitis optica spectrum disorders (NMOSDs). We present a case of relapsing SIADH associated with NMOSD, in an anti-aquaporin-4 antibody positive 14-year-old girl, who is, to our best knowledge, the first reported paediatric patient with relapsing SIADH and NMOSD. Additionally, our case further supports the notion that paediatric encephalomyelitis associated with SIADH should suggest the diagnosis of NMOSD.

Sudden onset of sleep due to hypothalamic lesions in neuromyelitis optica spectrum disorder positive for anti-aquaporin-4 antibody.

We report a patient with neuromyelitis optica spectrum disorders who presented with sudden onset of sleep as the sole manifestation. Magnetic resonance imaging investigation revealed lesions in the hypothalamus bilaterally, which vanished completely after methylprednisolone pulse therapy.

A case of neuromyelitis optica harboring both anti-aquaporin-4 antibodies and a pathogenic mitochondrial DNA mutation for Leber's hereditary optic neuropathy.

We report the first case of definite neuromyelitis optica (NMO) with a pathogenic mitochondrial DNA (mtDNA) mutation for Leber's hereditary optic neuropathy (LHON) (G11778A point mutation). A 36-year-old Japanese woman had experienced recurrent neurological symptoms originating from involvements of the optic nerves and spinal cord. She finally lost her bilateral vision, and spastic paraparesis and sensory disturbances below the T6 level remained despite intensive immunotherapies. Brain and spinal magnetic resonance imaging (MRI) revealed T2-high-intensity lesions in the optic nerves and thoracic spinal cord, but no lesions in the brain. A blood examination revealed positivity for both anti-aquaproin-4 antibodies and an LHON mtDNA mutation.

Brain and spinal cord atrophy in NMOSD and MOGAD: Current evidence and future perspectives.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe form of inflammation of the central nervous system (CNS) including acute myelitis, optic neuritis and brain syndrome. Currently, the classification of NMOSD relies on serologic testing, distinguishing between seropositive or seronegative anti-aquaporin-4 antibody (AQP4) status. However, the situation has recently grown more intricate with the identification of patients exhibiting the NMOSD phenotype and myelin oligodendrocyte glycoprotein antibodies (MOGAD). NMOSD is primarily recognized as a relapsing disorder; MOGAD can manifest with either a monophasic or relapsing course. Significant symptomatic inflammatory CNS injuries with stability in clinical findings outside the acute phase are reported in both diseases. Nevertheless, recent studies have proposed the existence of a subclinical pathological process, revealing longitudinal changes in brain and spinal cord atrophy. Within this context, we summarise key studies investigating brain and spinal cord measurements in adult NMOSD and MOGAD. We also explore their relationship with clinical aspects, highlight differences from multiple sclerosis (MS), and address future challenges. This exploration is crucial for determining the presence of chronic damage processes, enabling the customization of therapeutic interventions irrespective of the acute phase of the disease.

Double Seronegative Neuromyelitis Optica Spectrum Disorder with Longitudinally Extensive Transverse Myelitis and Optic Neuritis: A Challenging Case Report.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare antibody-mediated neuroinflammatory disease of the central nervous system, typically manifesting in the optic nerves, spinal cord, and other regions of the central nervous system. We hereby report a case of a 16-year-old girl who presented with a six-month history of transverse myelitis with an acute episode of bilateral retrobulbar optic neuritis. MRI revealed patchy contrast enhancements over bilateral retrobulbar intraorbital optic nerves together with long-segment spinal cord hyperintensities (C2 to T2 level). Visual evoked potential testing during the acute presentation showed the absence of P100 bilaterally. However, both serum AQP4-IgG and MOG-IgG were reported to be negative. Despite remarkable improvement in bilateral optic nerve functions, she continued to have disabling bilateral lower limb spasticity, contractures, and loss of bilateral lower limb sensation after five cycles of plasma exchange. This case summarizes the challenges to diagnosing double seronegative NMOSD and its immediate therapeutic significance.