Episodes Of Myelitis Research Articles

CD19-Directed CAR T-Cells in a Patient With Refractory MOGAD: Clinical and Immunologic Follow-Up for 1 Year.

In MOG antibody-associated disease (MOGAD), relapse prevention and the treatment approach to refractory symptoms are unknown. We report a patient with refractory MOGAD treated with CD19-directed CAR T-cells. CD19-directed CAR T-cells (ARI-0001) were produced in-house by lentiviral transduction of autologous fresh leukapheresis and infused after a conventional lymphodepleting regimen. A 18-year-old man developed 2 episodes of myelitis associated with serum MOG-IgG, which were followed by 6 episodes of left optic neuritis (ON) and sustained the presence of MOG-IgG over 6 years despite multiple immunotherapies. After the sixth episode of ON, accompanied by severe residual visual deficits, CAR T-cell treatment was provided without complications. Follow-up of cell counts showed complete depletion of CD19+ B cells at day +7; reconstituted B cells at day +141 showing a naïve B-cell phenotype, and low or absent memory B cells and plasmablasts for 1 year. MOG-IgG titers have remained undetectable since CAR T-cell infusion. The patient had an early episode of left ON at day +29, when MOG-IgG was already negative, and since then he has remained free of relapses without immunotherapy for 1 year. This clinical case shows that CD19-directed CAR T-cell therapy is well-tolerated and is a potential treatment for patients with refractory MOGAD. This provides Class IV evidence. It is a single observational study without controls.

Soluble biomarkers for Neuromyelitis Optica Spectrum Disorders: a mini review.

The Neuromyelitis Optica Spectrum Disorders (NMOSD) constitute a spectrum of rare autoimmune diseases of the central nervous system characterized by episodes of transverse myelitis, optic neuritis, and other demyelinating attacks. Previously thought to be a subtype of multiple sclerosis, NMOSD is now known to be a distinct disease with unique pathophysiology, clinical course, and treatment options. Although there have been significant recent advances in the diagnosis and treatment of NMOSD, the field still lacks clinically validated biomarkers that can be used to stratify disease severity, monitor disease activity, and inform treatment decisions. Here we review many emerging NMOSD biomarkers including markers of cellular damage, neutrophil-to-lymphocyte ratio, complement, and cytokines, with a focus on how each biomarker can potentially be used for initial diagnosis, relapse surveillance, disability prediction, and treatment monitoring.

The time course of complement blockage by ravulizumab in neuromyelitis optica spectrum disorder

AbstractThe classical 50% hemolytic complement test is commonly used to monitor complement function. However, its use in monitoring the effect of ravulizumab on complement assays is unknown. A 47‐year‐old man with anti‐aquaporin 4 antibody‐positive neuromyelitis optica spectrum disorder who was treated with oral prednisolone and azathioprine experienced several episodes of optic neuritis or myelitis. After his latest relapse, ravulizumab was administered to prevent relapse. Serum classical 50% hemolytic complement activity decreased below detectable levels (<10 U/mL) within 1 h of ravulizumab injection. Eighteen weeks later, the patient showed no adverse events or relapse, suggesting that serum classical 50% hemolytic complement activity can monitor ravulizumab effect. In Japan, where 3.5% of the population shows a reduced response to anti‐C5 therapy, serum classical 50% hemolytic complement activity proves useful in confirming ravulizumab efficacy.

P163 Grey matter myelitis is a severe phenotype of myelitis in systemic lupus erythematosus: experience from a tertiary care hospital in south India over a decade

Abstract Background/Aims Myelitis is a severe yet rare manifestation of systemic lupus erythematosus (SLE). Literature on lupus myelitis is limited to case reports and series. Birnbaum et al. reported the largest series (n = 22) with two distinct phenotypes based on clinical and imaging findings with mechanistic and therapeutic implications. Further validation of these two subtypes is not reported to date. The objective of the study was to identify distinct phenotypes in lupus myelitis and compare activity and outcomes with the formulation of a prediction model for survival. Methods This is a retrospective study. Data of 35 lupus myelitis patients with follow-up were extracted from the lupus registry (n = 1550) in the last 15 years (2007-2022). Grey matter myelitis (GMM) (i.e., flaccidity, hyporeflexia) and white matter myelitis (WMM) (i.e., spasticity, hyperreflexia) were two subtypes. Disease activity was assessed by SLEDAI-2K and outcome by death/recurrence/disability - modified Rankin score (MRS). MRS at discharge and SLEDAI at admission were used as predictors for survival outcomes among subtypes. Results Median age at presentation was 24.5 years (12.5-36.5); female-male ratio 32:3. 24 patients presented with GMM and 11 with WMM. GMM had more CNS events (p-0.02), high SLEDAI (p-0.021) and extra CNS involvement (p > 0.05). Anticardiolipin antibodies were increased in WMM (p-0.03). Weibull survival probability plot showed that 25%, 50% & 75% of GMM patients had probability of death within 13, 85, and 376 months from the myelitis episode respectively. The same for WMM was 96, 256, 556 months respectively, implying that GMM has a worse survival outcome. Using linear regression, MRS at discharge and SLEDAI can predict survival status in GMM (R = 0.64, p = 0.04) but not in WMM (R = 0.42, p = 0.46). Conclusion Lupus myelitis has two distinct subtypes. GMM is associated with more active disease, poor survival, and significant disability, and its survival status can be predicted by MRS and SLEDAI scores. Disclosure R. Baisya: None. K. Yerram: None. G. Murthy: None. P.K. Devarasetti: None. L. Rajasekhar: None.

Clinical and Radiologic Features Among Children With Myelin Oligodendrocyte Glycoprotein Antibody-Associated Myelitis

BackgroundMyelin oligodendrocyte glycoprotein (MOG) antibody–associated disease (MOGAD) often manifests as optic neuritis, transverse myelitis(TM), and acute disseminated encephalomyelitis. Patients with a TM phenotype are at high risk for neurological sequelae, so recognizing the characteristics of MOG-IgG myelitis is essential for early, accurate diagnosis and treatment. MethodsThis was a single-center retrospective study. Pediatric MOG antibody–associated disease patients who had clinical myelitis were recruited for this study. Data on clinical and radiologic features and outcomes were retrospectively collected. ResultsThirty-four patients (age range: 6 months to 13 years; median age, 7 years; female, 16) were enrolled in this study. As one patient had two clinical episodes of myelitis, 35 episodes were included. Isolated transverse myelitis was the initial manifestation in 28 (82%) patients. The most frequent clinical features of MOG-IgG myelitis were weakness and neurogenic bladder, and 80% were better than wheelchair-dependent at the nadir. There was a high presentation of weakness (91%), bowel/bladder dysfunction (63%), and sensory dysfunction (46%), and 80% were better than wheelchair-dependent at the nadir. In addition, seven patients (20%) had radicular pain, and six had flaccid areflexia. Magnetic resonance imaging features were often longitudinally extensive (63%) and prominently involved gray matter (H-sign) (63%), accompanied by leptomeningeal enhancement (4/14.29%) and spinal root enhancement (6/14.43%). At the final follow-up (median, 28 months; range, 8-109 months), 10 patients (29%) had developed one or more relapses, spinal cord lesions resolved entirely in 11 of 22 children (50%), and none had appreciable spinal cord atrophy. At the final follow-up, most patients had favorable outcomes, with median (interquartile range) Expanded Disability Status Scale scores of 0 (range, 0-2), four patients (12%) had sphincter dysfunction, and one patient had gait problems. ConclusionsPediatric MOG-IgG myelitis clinically presents with weakness and bowel and bladder dysfunctions. Prominent involvement of the gray matter, leptomeningeal enhancement, and spinal root enhancement are common in pediatric MOG-IgG myelitis.

Paroxysmal painful tonic spasms in neuromyelitis optica spectrum disorder

Recently, an association between painful tonic spasms (PTS) and Neuromyelitis Optica Spectrum Disorder (NMOSD) was established. To describe the clinical characteristics of PTS in NMOSD based on a video recording and to provide a literature review on the topic. We report a case of a 38years-old woman with a diagnosis of NMOSD and positive aquaporin-4 IgG antibody status who developed PTS five weeks after an episode of longitudinal extensive transverse myelitis (LETM). Repetitive, brief, and painful episodes of muscle contraction were observed on the patient's left hand, spreading to the left arm, and then extending to the four limbs. While pregabalin and topiramate had no influence on these episodes, the patient responded to carbamazepine (CBZ), without symptom recurrence after one year. PTS in association with LETM can be considered typical for NMOSD. Although the exact mechanism is unknown, ephaptic transmission after spinal cord damage and excitatory soluble factors released during acute inflammation responses are sought to be involved. Symptomatic treatment with CBZ achieved remission of spams in our case.

Painful tonic spasms in a patient with neuromyelitis optica spectrum disorder: A case report

Painful tonic spasms initially described in association with multiple sclerosis are actually more common in patients with neuromyelitis optica spectrum disorder. Characterized by fierce pain and tonic posture of limbs, painful tonic spasms are common in patients during the recovery phase after the first episode of myelitis. A 68-year-old man presented with painful tonic spasm after 2 months of diagnosis of neuromyelitis optica spectrum disorder. Eventual use of eslicarbazepine resulted in significant control of spasms. Early recognition of painful tonic spasms and appropriate therapeutic medications can significantly decrease the impact it can have on the quality of life among neuromyelitis optica spectrum disorder patients.

A RARE CASE NEUROMYELITIS OPTICA SPECTRUM DISORDER

Neuromyelitis Optica spectrum disorder or Devic's disease is an autoimmune disease characterized by by acute inammation of the optic nerve and spinal cord. A relapsing disease course is common, especially in untreated patients. In more than 80% cases it is caused by immunoglobulin G autoantibodies to aquaporin 4 the most abundant water channel protein in the central nervous system. Episodes of optic neuritis and myelitis can be simultaneous or successive.

Resolution of Recurrent VZV Myelitis With the Use of Intravenous (IV) Immunoglobulin (IG)

Objective To present a case of a patient with recurrent VZV myelitis successfully treated with Intravenous Immunoglobulin (IVIG). Background VZV myelitis is a rare complication of VZV reactivation that tends to be monophasic. There is no solid evidence for a particular treatment regimen for VZV myelitis. No prior reports or studies have looked at using intravenous immunoglobulin for this condition, particularly for refractory cases. Design/Methods 75 year old female with history of hypertension presented with paresthesia on lateral side of right lower extremity, followed by vesicular rash T2 dermatomal distribution. Over a period of 2 weeks patient started experiencing bilateral lower extremity weakness R>L. CNS imaging revealed C3-C6 enhancing lesion and T2 hyperintense lesion. VZV confirmed by skin biopsy. Lumbar puncture (LP) was remarkable only for mildly elevated protein (67 mg/dL), although this LP was 4 weeks after initial symptoms. Patient was treated initially with 5 days of 1 g IV Solumedrol and valacyclovir 1 g TID with improvement of weakness and rash. However, over the next two years, the patient continued to get occasional vesicles with a flare of her myelitis shortly after valacyclovir down-titration trial. She was started on monthly IVIG (1 g/kg IVIG over 2 days) given her refractory and recurrent myelitis. Since starting monthly IVIG, the patient has not had any more zoster outbreaks or further episodes of myelitis. She has gradually improved her balance and gait as well. Results N/A. Conclusions We present an unusual case of recurrent VZV myelitis successfully treated with monthly IVIG. The successful treatment of this patient with IVIG should prompt consideration for its use in similar cases of recurrent VZV myelitis and may provide insight for future studies on how to treat VZV-related diseases. Rapid initiation of this treatment when the condition is recognized early could significantly improve outcomes and patients' quality of life.

Myelitis features and outcomes in CNS demyelinating disorders: Comparison between multiple sclerosis, MOGAD, and AQP4-IgG-positive NMOSD.

Inflammatory myelopathies can manifest with a combination of motor, sensory and autonomic dysfunction of variable severity. Depending on the underlying etiology, the episodes of myelitis can recur, often leading to irreversible spinal cord damage and major long-term disability. Three main demyelinating disorders of the central nervous system, namely multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), can induce spinal cord inflammation through different pathogenic mechanisms, resulting in a more or less profound disruption of spinal cord integrity. This ultimately translates into distinctive clinical-MRI features, as well as distinct patterns of disability accrual, with a step-wise worsening of neurological function in MOGAD and AQP4+NMOSD, and progressive disability accrual in MS. Early recognition of the specific etiologies of demyelinating myelitis and initiation of the appropriate treatment is crucial to improve outcome. In this review article we summarize and compare the clinical and imaging features of spinal cord involvement in these three demyelinating disorders, both during the acute phase and over time, and outline the current knowledge on the expected patterns of disability accrual and outcomes. We also discuss the potential implications of these observations for patient management and counseling.

Seroprevalence of anti-myelin oligodendrocyte glycoprotein antibodies in adults with myelitis.

Although myelitis is the second most common presentation in adults with myelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD), studies on MOG‐IgG seroprevalence in patients with myelitis episodes are sparse. Herein, we investigated MOG‐IgG seroprevalence in Korean adults who exhibited myelitis since 2017. Among 151 adults with acute myelitis, 11 (7.3%) tested positive for MOG‐IgG by the initial screening and 10 (6.6%) patients were finally diagnosed with MOGAD during the study period. This study is the first to provide data on MOG‐IgG seroprevalence in adults with myelitis and supports the clinical utility and importance of MOG‐IgG testing in myelitis episodes.

Pure Relapsing Short Myelitis: Part of the Multiple Sclerosis Spectrum or New Entity?

Background and ObjectivesPure relapsing short myelitis with clinical and paraclinical features suggesting multiple sclerosis (MS) has been described recently. Here, we evaluated the existence of this potential new form of MS by retrospectively searching for similar cases in the databases of the French tertiary MS centers.MethodsPatients were included based on the present criteria: at least 2 short (<3 vertebral segments) myelitis episodes; minimum follow-up of 3 years; no MS-like brain lesion during all the follow-up; tested negative for both anti–myelin oligodendrocyte glycoprotein and anti–aquaporin 4 antibodies in serum; presence of oligoclonal bands in CSF; and comprehensive workup to exclude alternative diagnoses.ResultsEighteen patients fulfilled all criteria. The sex ratio (females/males) was 5/1; the median (range) age at first relapse was 35.5 (25–54) years, the disease duration was 80.5 (50–308) months, and the annualized relapse rate was 0.36 (0.1–0.5). The median (range) number of relapses per patient was 2 (2–5), and the median (range) Expanded Disability Status Scale score at last follow-up was 1 (0–7.5). In CSF, the median (range) protein level was 0.34 g/L (0.18–0.77), and the median (range) number of mononuclear cells was 3 (0–28). Spinal cord MRI demonstrated a median (range) number of 2 (1–5) lesions per examination and 3 [1–7] on the last examination. Fifty-five percent of lesions involved the cervical levels. Secondary progressive evolution occurred in 3 of 18 (17%) patients.DiscussionPure spinal MS could be a rare entity in the MS disease spectrum. However, the existence of a distinct entity in the inflammatory CNS disorders cannot be excluded.

A Child with Intractable Vomiting: Brainstem Mass or Neuromyelitis Optica Spectrum Disorder

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an immune-mediated disorder which is characterized by relapsing episodes of optic neuritis and myelitis. Brain stem related symptoms such as Intractable vomiting are not usually considered as the initial presentation and misdiagnosis has been frequently observed. Almost 4% of NMOSD cases are pediatric. Early differentiation of NMOSD from other childhood disorders including acute disseminated encephalmyelitis (ADEM), multiple sclerosis (MS), infections and mass lesions is critical.

Serum levels of interleukin-6 and Vitamin D at the onset of multiple sclerosis and neuromyelitis optica: A pilot study.

Interleukin-6 (IL-6) is an important mediator in the acute phase of inflammatory diseases such as neuromyelitis optica (NMO) and multiple sclerosis (MS). The level of IL-6 is higher in cerebrospinal fluid and serum of NMO patients compare to MS. Vitamin D has a regulatory effect on IL-6, so it may have a negative correlation with IL-6 in the acute phase of these diseases. This study was performed to evaluate the serum levels of IL-6 and Vitamin D in NMO and MS patients at the onset of disease to find differences that may help in early diagnosis. This case-control study was done on patients with the first episode of optic neuritis, transverse myelitis, and area postrema syndrome who were referred to Kashani MS Center in Isfahan, Iran, between January 2018 and January 2020. The serum levels of Vitamin D and IL-6 were assessed using enzyme-linked immunosorbent assay in blood sample taken at the time of first presentation in patients who had a definitive diagnosis of NMO and MS during subsequent workup. During a 2-year follow-up, definitive diagnosis of NMO was given in 25 cases, and they were compared with 25 cases that were randomly selected from patients with definite MS. Nineteen patients in the NMO group and 21 patients in the MS group were female. The mean age of patients in the NMO and MS groups was 29.64 ± 1.47 and 30.20 ± 1.42, respectively (P = 0.46). The mean of serum level of Vitamin D was 24.88 ± 15.2 in NMO patients and 21.56 ± 18.7 in MS patients without significant difference (P = 0.48). The mean of IL-6 was 30.1 ± 22.62 in the NMO group and 23.35 ± 18.8 in the MS group without significant difference (P = 0.28). The serum levels of Vitamin D were insufficient in both groups. No correlation between Vitamin D and IL-6 levels was found in our study (P > 0.05). Our results showed that serum IL-6 levels were higher at the onset of NMO disease compared with MS. The serum levels of Vitamin D were low in both groups and there was no association between serum levels of Vitamin D and IL-6 in either group. Future studies with large sample size are needed to confirm these findings.

Hope for patients with neuromyelitis optica spectrum disorders - from mechanisms to trials.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare inflammatory CNS disease that primarily manifests as relapsing episodes of severe optic neuritis and myelitis. Diagnosis of NMOSD is supported by the detection of IgG autoantibodies that target the aquaporin 4 (AQP4) water channel, which, in the CNS, is an astrocyte-specific protein. AQP4 antibody binding leads to AQP4 internalization, complement-dependent and antibody-dependent cellular cytotoxicity, and water channel dysfunction. Cumulative attack-related injury causes disability in NMOSD, so the prevention of attacks is expected to prevent disability accrual. Until recently, no regulator-approved therapies were available for NMOSD. Traditional immunosuppressant therapies, including mycophenolate mofetil, azathioprine and rituximab, were widely used but their benefits have not been assessed in controlled studies. In 2019 and 2020, five phase II and III randomized placebo-controlled trials of four mechanism-based therapies for NMOSD were published and demonstrated that all four effectively prolonged the time to first relapse. All four drugs were monoclonal antibodies: the complement C5 antibody eculizumab, the IL-6 receptor antibody satralizumab, the B cell-depleting antibody inebilizumab, which targets CD19, and rituximab, which targets CD20. We review the pathophysiology of NMOSD, the rationale for the development of these mechanism-based drugs, the methodology and outcomes of the five trials, and the implications of these findings for the treatment of NMOSD.

Neuromyelitis optica mimicking intramedullary mass in a child with isolated brainstem syndrome

NMOSD is an immune-mediated disorder which is characterized by relapsing episodes of optic neuritis and myelitis. Brain stem related symptoms such as Intractable vomiting are not usually considered as the initial presentation and misdiagnosis has been frequently observed. Almost 4% of NMOSD cases are pediatric. Early differentiation of NMOSD from other childhood disorders including ADEM, MS, infections and mass lesions is critical.

The efficacy of therapeutic apheresis in patients with refractory neuromyelitis optica spectrum disorders: a single-center retrospective study.

Neuromyelitis optica spectrum disorders (NMOSD) are associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in high attack-related disability. Therapeutic apheresis has been recommended as a second-line treatment for steroid-refractory NMOSD. To assess the efficacy and safety of two apheresis techniques, lymphoplasmapheresis (LPE) and therapeutic plasma exchange (TPE), in refractory NMOSD and to provide a new treatment option for patients with refractory NMOSD. This retrospective study examined NMOSD patients who had undergone either LPE or TPE treatment between January 2015 and January 2018. The patients were monitored for improvements in disabilities, incidences of adverse reactions, and safety of the procedure over a one-year follow-up period. The primary outcome measures included changes in the visual outcome scale (VOS) score, the expanded disability status scale (EDSS), and the annualized relapse rate (ARR). Neurological function and objective response rates were significantly improved in 76.5% of patients treated with LPE and 83.3% of patients treated with TPE. There were no significant differences in the two treatment groups (P=0.392). Similarly, there were no differences in the reduction in the relative relapse rate between the two groups (P=0.494). Adverse reactions, mostly of mild or moderate intensity, were recorded in 9.3% of procedures in 38% of patients. The most commonly observed adverse events (AEs) were similar between the two treatment cohorts. Patients treated with LPE showed improved neurological function comparable to that reported with TPE treatment. No superiority was shown for either of the apheresis techniques.

Effectiveness of treatments in Neuromyelitis optica to modify the course of disease in adult patients. Systematic review of literature.

Neuromyelitis Optica spectrum disorder (NMOSD) is an inflammatory disease, which manifests mostly as recurrent episodes of optic neuritis or myelitis that cause important disability. Early diagnosis and prompt initiation of immunosuppressive therapy are crucial in reducing relapses, disability, and mortality. Even though, there are few prospective randomized controlled trials, several drugs have proved to be both effective and safe. Azathioprine and Rituximab represent the standard of care and are used as first-line treatment agents worldwide. However, recent studies have unveiled new therapies, such as monoclonal antibodies. To make treatment recommendations and management guidelines, it is imperative to define an appropriate standard of care. A systematic literature review was performed in MEDLINE, EMBASE, and LILACS databases using the following terms: "(NMO OR Devic OR Neuromyelitis Optica) AND (Azathioprine OR Prednisone OR Rituximab OR Tocilizumab OR Bortezomib OR Inebilizumab OR Eculizumab OR Satralizumab)" including both, randomized clinical trials and observational studies published between January 2006 and January 2021. The inclusion criteria comprised patients aged 18 or older, NMOSD diagnosis following the Wingerchuck criteria, two or more therapies been compared, and the evaluation of both efficacy and safety outcomes. All studies comparing treatment only with placebo were excluded. Quality was assessed according with the design of the study, and results were synthesized through comparative tables for each outcome evaluated, differentiating the results of randomized and non-randomized studies. Thirteen studies with 1447 patients were included. Twelve studies evaluated the expanded disability status scale (EDSS) before and after treatment; in five of seven evaluating rituximab, it outperformed its comparators in improving the disability degree. Eleven studies assessed the annual relapse rate (ARR). Again, in six of seven evaluating rituximab, it was superior to other therapies. Time to relapse (TTR) was reported in five studies. The three studies that included Rituximab revealed a longer time to relapse in this arm of treatment. Finding were consistent in randomized and non-randomized studies. The new molecules Satralizumab, Eculizumab and Tocilizumab were evaluated in one study each, proving to be highly effective and safe. The safety profile analysis showed a higher number of adverse events for Azathioprine. This systematic review demonstrates a superiority tendency of Rituximab upon the other treatments strengthening the available evidence about NMOSD management. Superiority in EDSS outcomes, annual relapse rate, time to first relapse and relapses during treatment time was evidenced in the Rituximab group compared to other medications, with lower rates of adverse events. New molecules Tocilizumab, Eculizumab and Satralizumab also showed superiority in the evaluated results, especially in the relapses during treatment time outcome, although with subtle differences in EDSS and ARR outcomes. Our results suggest that monoclonal antibodies are highly effective and safe for the treatment of NMOSD; Rituximab showed better performance on multiple outcomes and has more evidence available. New molecules: Eculizumab, Tocilizumab, Satralizumab are good options for treatment. Drugs like Azathioprine and Mycophenolate are effective, but with a worse risk-benefit ratio, therefore, they are useful alternatives in places that do not have access to monoclonal antibodies.

A clinico-neurophysiological study of urogenital dysfunction in MOG-antibody transverse myelitis

To assess the clinical, urodynamic, and neurophysiologic features of patients with persisting bladder, bowel, and sexual dysfunction after transverse myelitis in myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease. Patients with a history of MOG-Ab disease-related transverse myelitis seen prospectively in a tertiary center uro-neurology service between 2017 and 2019 were included. They received cross-sectional clinical assessment; completed standardized questionnaires on bladder, bowel, and sexual symptoms; and underwent urodynamic and pelvic neurophysiologic investigations. Twelve patients (9 male) were included with a total of 17 episodes of transverse myelitis. Mean age at first attack was 26 (SD 9) years, and median follow-up duration was 50 (interquartile range 32-87) months. Acute urinary retention requiring bladder catheterization occurred in 14 episodes and was the first symptom in 10 episodes. Patients with lesions affecting the conus medullaris required catheterization for significantly longer durations than those without a conus lesion (median difference 15.5 days, p = 0.007). At follow-up, all patients had recovered full ambulatory function, but persisting bladder and bowel dysfunction moderately or severely affected quality of life in 55% and 36%, respectively, and 82% had sexual dysfunction. Pelvic neurophysiology demonstrated abnormal residual conus function in 6 patients. Urodynamic findings predominantly showed detrusor overactivity and/or detrusor-sphincter dyssynergia, indicative of a supraconal pattern of lower urinary tract dysfunction. Persisting urogenital and bowel dysfunction is common despite motor recovery. Although a proportion of patients had neurophysiologic evidence of residual conus abnormalities at follow-up, predominant urodyamic findings suggest that ongoing lower urinary tract dysfunction results from supraconal injury.

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders

BackgroundNeuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG.MethodsPurified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA.ResultsOral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and vascular endothelial growth factor (VEGF) in the spinal cord.ConclusionsOur findings support that glutamate excitotoxicity and neuroinflammation play important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.