Relapsing Optic Neuritis Research Articles

Рецидивирующий оптический неврит при оптиконейромиелите

This report presents a clinical case of complex differential diagnosis of optical neuritis in demyelinating disease (multiple sclerosis and neuromyelitis optica). We observed 5 relapses of optic neuritis within 4 years from the onset of the disease, in the absence of both clinical and neuroimaging signs of myelitis. The diagnosis of neuromyelitis optica became valid only after the neurologist identified motor symptoms and the corresponding criteria on the MRI picture. Recurrent optic neuritis, especially bilateral with incomplete recovery of visual functions (despite the absence of acute myelitis and postrema area syndrome and a negative blood test for AQP4-IgG) requires special caution of the doctor and can be considered as a potential case of Devic’s neuromyelitis optica. Key words: devic’s neuromyelitis optica, neuromyelitis optica, optic neuritis, multiple sclerosis, neuromyelitis optica spectrum disorders, AQPR4

Different clinical phenotypes of AQP4-IgG positive NMOSD in two first degree relatives

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) are autoimmune inflammatory disorders of the CNS in which patients have severe relapses of optic neuritis and myelitis. Aquaporin-4 antibody (AQP4-IgG) positive NMOSD has not been reported in members of the same family in Sub Saharan Africa. We report the uncommon scenario in which both a Ugandan HIV positive woman and her HIV negative daughter were diagnosed with AQP4-IgG positive NMOSD. We discuss pathogenic mechanisms that may underlie familial presentation of AQP4-IgG positive NMOSD.Case PresentationCase 1, a 54-year-old female teacher with a 20-year history of HIV infection and virally suppressed on Tenofovir, Lamivudine and Dolutegravir HAART regimen, presented with 8 months of progressive quadriparesis and urinary incontinence with a T6 sensory level. She had gadolinium enhancing longitudinally extensive transverse myelitis on MRI and was AQP4-IgG positive on serum studies. She received IV Methylprednisone 1 g daily for 3 days as a pulse and was continued on tapering doses of oral Prednisone with maintenance doses of Azathioprine. She showed slow improvements in limb motor function. Her daughter, case 2, is a 35-year-old HIV negative nutritionist, independently ambulant, with no known comorbidities or precedent autoimmune disease. She presented 1 year before her mother’s AQP4-IgG positive NMOSD diagnosis with 7 months history of bilateral visual loss of rapid onset, with gadolinium-enhancing optic nerves on Brain and orbit MRI, in keeping with bilateral optic neuritis. She was AQP4-IgG positive on serum studies. She stabilized on tapered doses of oral Prednisone and continues daily oral Azathioprine with moderate improvement in her vision and no further relapses as yet.ConclusionsWe add to existing literature and hypothesize that NMOSD appears to show a complex genetic background. To our knowledge, this is the first report in Sub-Saharan Africa, of familial AQP4-IgG positive NMOSD presenting with clinical heterogeneity between first degree relatives. A better understanding of the pathogenic mechanisms involved, including genome wide studies for particular risk loci for familial NMOSD, will be pivotal for future preventative and therapeutic strategies.

Перспективы диагностики оптического неврита при оптиконейромиелите Девика

The review presents data on the prospects for the diagnosis of optic neuritis in neuromyelitis optica (NMO). The differential diagnosis of NMO with multiple sclerosis and other autoimmune diseases is complicated by the similarity of the clinical manifestations of optic neuritis. The diagnostic approach, tactics of using and interpreting the results of modern laboratory, instrumental and hardware research methods are described. Additional diagnostic criteria are described for AQPR4-IgGseronegative patients with clinical symptoms of acute urinary tract infections. NMO is characterized by severe unilateral damage to the optic nerve with poor recovery of visual functions after conservative therapy, frequent recurrences of optic neuritis in one or both eyes, bilateral simultaneous damage to the optic nerves or chiasm. Timely diagnosis makes it possible to prescribe pathogenetic therapy for NMO and reduce the number of relapses of optic neuritis and prevent patients’ blindness. Key words: neuromyelitis optica, optic neuritis, OCT, multiple sclerosis, neuromyelitis optica spectrum disorders, AQPR4

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) as a novel presentation of CNS autoimmunity in a pediatric patient with Wiskott-Aldrich syndrome (WAS)

Objective Report a novel case of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) presenting as relapsing bilateral optic neuritis in a pediatric patient with Wiskott-Aldrich syndrome (WAS). Background WAS is a rare X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Known CNS autoimmune manifestations include cerebral vasculitis, but optic neuritis, CNS demyelination, and MOGAD have not been previously reported. Design/Methods Chart review Results A 5-year-old boy with a history of chronic immune thrombocytopenia, hypogammaglobulinemia, anemia, and focal epilepsy developed binocular vision loss. MRI of the brain demonstrated enlargement of bilateral optic nerves with marked enhancement of the nerve sheaths consistent with optic neuritis, as well as multiple small enhancing supratentorial lesions. He was treated with pulse methylprednisolone followed by oral steroid taper, and he returned to baseline with no reported residual visual deficits. Five months later, he experienced a relapse of bilateral vision loss, and repeat MRI re-demonstrated bilateral optic neuritis as well as resolution of prior brain lesions. He was treated with repeat course of steroids and experienced moderate improvement in his vision. Rituximab was then initiated to prevent further relapses of optic neuritis while treating his chronic suspected immune-mediated thrombocytopenia. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of MOGAD. At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression consistent with a diagnosis of WAS. Conclusions We describe a case of pediatric MOGAD presenting with multiphasic bilateral optic neuritis in a patient with WAS. This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform indications for therapeutic options such as bone marrow transplant.

Myelin Oligodendrocyte Glycoprotein Encephalomyelitis

Background: Myelin oligodendrocyte glycoprotein encephalomyelitis (MOG-EM) includes patients with (i) monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, or encephalitis; (ii) magnetic resonance imaging (MRI) or electrophysiological evidence of central nervous system (CNS) demyelination; and (iii) MOG-immunoglobulin G (IgG) seropositivity. Clinical Description: A 4-year-old girl presented with fever and excruciating headache for 10 days. Her vitals were stable and systemic examination was normal. Cerebrospinal fluid (CSF) analysis revealed 10 lymphocytes and normal biochemistry. After 5 days, she developed a fever and a seizure. Repeat CSF showed increased cells (60% lymphocytes), normal protein, and sugar. MRI brain was normal. She was managed symptomatically. CSF meningoencephalitis panel was negative. The child improved and was discharged. After 2 weeks, the headache recurred with associated blurring of vision. Bilateral papillitis, MRI brain abnormalities suggestive of acute disseminated encephalomyelitis (EM), and bilateral prolonged latency on visual evoked potential (VEP) were found. Anti-MOG antibodies were positive. The final diagnosis was MOG-EM. Management: The child was started on methylprednisolone therapy as per standard protocol. The vision improved and headache disappeared. She is on regular follow-up and is asymptomatic. Conclusion: MOG-IgG testing should be done in patients with (i) monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, or encephalitis; (ii) radiological or VEP findings compatible with CNS demyelination; and (iii) at least 1 of 25 delineated findings on MRI, fundoscopy, CSF, histopathology, clinical phenotype, or treatment response.

Automated grating contrast-sensitivity: The easy test for hidden visual loss in recovered optic neuritis patient.

PURPOSE:Residual visual loss is an important predictor of optic neuritis relapse and progression. This study aimed to investigate the hidden residual visual loss in patients with optic neuritis using automated contrast-sensitivity (CS) function testing.MATERIALS AND METHODS:This cross-sectional study investigated 29 recovered optic neuritis patients (age: 27.69 ± 13.32 years, range: 13–51). Twenty age-matched controls with normal visual acuity (VA, in LogMAR) were recruited, for comparison with patients' VA and CS function after stable recovery from optic neuritis (6 months of follow-up). CS tests used a novel software that displays a single set of Gabor patches (2 cycles per degree at 10° ×10° of visual angle) with contrasts grating from 100% to 0.1%.RESULTS:There were 13 adolescent patients (63.6%: retrobulbar neuritis [RN]; 36.4%: papillitis), 14 adult patients (50%: RN; 42.9%: papillitis), and only 2 older patients (all with neuroretinitis). There was improvement of VA in the patient group at first diagnosis and follow-up (VA initial vs. final: 1.438 ± 1.134 vs. 0.235 ± 0.272, P < 0.001). This VA improvement was similar to control group (P = 0.052). In CS, there were significant differences in patient versus control groups (69.069% ± 70.235% vs. 27.215% ± 25.27%, P = 0.025). Linear regression showed that initial VA and CS function could not predict final VA (P = 0.183 and P = 0.138, respectively).CONCLUSIONS:Patients with optic neuritis showed decreased CS compared to control group which indicated the residual visual loss. Automated CS testing is useful in detecting residual visual loss in patients who recovered from optic neuritis.

E.U. paediatric MOG consortium consensus: Part 1 - Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Over the past few years, increasing interest in the role of autoantibodies against myelin oligodendrocyte glycoprotein (MOG-abs) as a new candidate biomarker in demyelinating central nervous system diseases has arisen. MOG-abs have now consistently been identified in a variety of demyelinating syndromes, with a predominance in paediatric patients. The clinical spectrum of these MOG-ab-associated disorders (MOGAD) is still expanding and differs between paediatric and adult patients. This first part of the Paediatric European Collaborative Consensus emphasises the diversity in clinical phenotypes associated with MOG-abs in paediatric patients and discusses these associated clinical phenotypes in detail. Typical MOGAD presentations consist of demyelinating syndromes, including acute disseminated encephalomyelitis (ADEM) in younger, and optic neuritis (ON) and/or transverse myelitis (TM) in older children. A proportion of patients experience a relapsing disease course, presenting as ADEM followed by one or multiple episode(s) of ON (ADEM-ON), multiphasic disseminated encephalomyelitis (MDEM), relapsing ON (RON) or relapsing neuromyelitis optica spectrum disorders (NMOSD)-like syndromes. More recently, the disease spectrum has been expanded with clinical and radiological phenotypes including encephalitis-like, leukodystrophy-like, and other non-classifiable presentations. This review concludes with recommendations following expert consensus on serologic testing for MOG-abs in paediatric patients, the presence of which has consequences for long-term monitoring, relapse risk, treatments, and for counselling of patient and families. Furthermore, we propose a clinical classification of paediatric MOGAD with clinical definitions and key features. These are operational and need to be tested, however essential for future paediatric MOGAD studies.

Subcortical structural abnormalities in female neuromyelitis optica patients with neuropathic pain

Neuromyelitis optica (NMO) is a disease characterised by severe relapses of optic neuritis and longitudinally extensive transverse myelitis and it has a strong female predilection. Pain is one of the most typical symptom in NMO. However, few studies have been conducted to examine the neuropathic pain mechanism of NMO patients or gender-specific effects using magnetic resonance imaging technique. A total of 38 female patients with NMO, 28 with pain (NMOWP) and 10 without pain (NMOWoP), were classified using the Brief Pain Inventory (BPI); 22 healthy females were also recruited. We used the FSL Image Registration and Segmentation Toolbox (FIRST) for subcortical region volumes quantifications, and voxel-based morphometry analysis for cortical gray matter (GM) volume, to examine the brain morphology in NMOWP patients. In addition, correlation test between structural measurements of NMO patients and clinical indexes was also performed. The results showed: 1) no significant differences in cortical GM density between the NMOWP and NMOWoP groups; 2) significantly smaller hippocampus and pallidum volumes in the NMOWP group compared with the NMOWoP group; 3) significant negative correlation between the average BPI and volumes of the accumbens nucleus and thalamus in NMO patients. These results revealed that structural abnormality exists in NMO female patients who have pain, with significant implications for our understanding of the brain morphology in NMO patients with pain.

Clinical Characteristics of Patients With Neuromyelitis Optica Spectrum Disorders With Early Onset.

Neuromyelitis optica spectrum disorder is a severe and disabling disease that manifests with severe relapses of optic neuritis, longitudinally extensive myelitis, and/or brainstem syndromes. The disease is complex and, although onset typically occurs in middle age, children and adolescents may be affected. The present study adds to the literature through detailed clinical data from 36 Brazilian patients with neuromyelitis optica spectrum disorder starting before age 21. This was a retrospective assessment of medical records from 14 specialized units in Brazil. The results showed that the course of neuromyelitis optica spectrum disorder was worse in patients with disease onset before the age of 12 years. Gender and ethnic background did not influence disability accumulation. Over a median period of 8 years, 14% of the patients who presented the initial symptoms of neuromyelitis optica spectrum disorder before the age of 21 years died. In conclusion, the present study adds to the reports from other authors examining the severity of early-onset neuromyelitis optica spectrum disorder.

Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders.

Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.

Chronic relapsing inflammatory optic neuropathy: a literature review

Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory disease characterized by painful recurrent episodes of optic neuritis with clear response to steroids and relapses with treatment withdrawal. To performed a systematic review of the literature about CRION, since 2003 to present in medical database. We excluded pediatric or animal research articles. Search terms: CRION, chronic relapsing inflammatory optic neuropathy, recurrent optic neuritis, steroid dependent optic neuritis, and immunosuppression dependent optic neuritis. CRION is a relapsing optic neuritis of unknown aetiology. The strong response to corticosteroids to avoid recurrence suggests that it might be an immune-mediated disease. CRION typically presents as a subacute and recurrent optic neuropathy with severe visual loss. The principal differential diagnoses are the demyelinating (multiple sclerosis, neuromyelitis optica spectrum disorders and anti-MOG), systemic (mostly sarcoidosis) and infectious diseases. CRION has a dramatic and dependent corticoids response; to avoid adverse events, we use immunosuppressive treatment in long-term. CRION is a rare, recurrent and cortico-dependent disease of optic nerve. An early diagnosis and accuracy treatment will improve the prognosis.

Clinical, Radiologic, and Prognostic Features of Myelitis Associated With Myelin Oligodendrocyte Glycoprotein Autoantibody

Recognizing the characteristics of myelin oligodendrocyte glycoprotein autoantibody (MOG-IgG) myelitis is essential for early accurate diagnosis and treatment. To evaluate the clinical, radiologic, and prognostic features of MOG-IgG myelitis and compare with myelitis with aquaporin-4-IgG (AQP4-IgG) and multiple sclerosis (MS). We retrospectively identified 199 MOG-IgG-positive Mayo Clinic patients from January 1, 2000, through December 31, 2017, through our neuroimmunology laboratory. Fifty-four patients met inclusion criteria of (1) clinical myelitis; (2) MOG-IgG positivity; and (3) medical records available. We excluded 145 patients without documented myelitis. Myelitis of AQP4-IgG (n = 46) and MS (n = 26) were used for comparison. Outcome variables included modified Rankin score and need for gait aid. A neuroradiologist analyzed spine magnetic resonance imaging of patients with MOG-IgG and control patients blinded to diagnosis. Of 54 included patients with MOG-IgG myelitis, the median age was 25 years (range, 3-73 years) and 24 were women (44%). Isolated transverse myelitis was the initial manifestation in 29 patients (54%), and 10 (19%) were initially diagnosed as having viral/postviral acute flaccid myelitis. Cerebrospinal fluid-elevated oligoclonal bands occurred in 1 of 38 (3%). At final follow-up (median, 24 months; range, 2-120 months), 32 patients (59%) had developed 1 or more relapses of optic neuritis (n = 31); transverse myelitis (n = 7); or acute disseminated encephalomyelitis (n = 1). Clinical features favoring MOG-IgG myelitis vs AQP4-IgG or MS myelitis included prodromal symptoms and concurrent acute disseminated encephalomyelitis. Magnetic resonance imaging features favoring MOG-IgG over AQP4-IgG or MS myelitis were T2-signal abnormality confined to gray matter (sagittal line and axial H sign) and lack of enhancement. Longitudinally extensive T2 lesions were of similar frequency in MOG-IgG and AQP4-IgG myelitis (37 of 47 [79%] vs 28 of 34 [82%]; P = .52) but not found in MS. Multiple spinal cord lesions and conus involvement were more frequent with MOG-IgG than AQP4-IgG but not different from MS. Wheelchair dependence at myelitis nadir occurred in one-third of patients with MOG-IgG and AQP4-IgG but never with MS, although patients with MOG-IgG myelitis recovered better than those with AQP4-IgG. Myelitis is an early manifestation of MOG-IgG-related disease and may have a clinical phenotype of acute flaccid myelitis. We identified a variety of clinical and magnetic resonance imaging features that may help clinicians identify those at risk in whom MOG-IgG should be tested.

Rebound of relapses after discontinuation of rituximab in a patient with MOG-IgG1 positive highly relapsing optic neuritis: a case report

BackgroundMyelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG1)-associated disease is suggested as a separate disease entity distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Nonetheless, the optimal treatment regimen for preventing relapses in MOG-IgG1-associated disease remains unclear.Case presentationWe describe the case of a 45-year-old man with MOG-IgG1-positive highly relapsing optic neuritis who had experienced 5 attacks over 21 months and had monocular blindness despite prednisolone and azathioprine therapy. He began treatment with rituximab, which reduced the rate of relapse markedly. Following discontinuation of rituximab, however, the patient experienced two successive optic neuritis attacks 2 and 4 months after B-lymphocyte restoration.ConclusionsHighly relapsing MOG-IgG1-associated disease can be prevented with rituximab even when the MOG-IgG1 titers are relatively stationary. Discontinuation of rituximab and restoration of B-lymphocytes may be associated with the rebound of disease activity.

Clinical characteristics of 153 Brazilian patients with neuromyelitis optica spectrum disorder (NMOSD)

BackgroundThe 2015 criteria for diagnosing neuromyelitis optica spectrum disorder (NMOSD) have encouraged several groups across the world to report on their patients using these criteria. The disease typically manifests with severe relapses of optic neuritis, longitudinally extensive myelitis and/or brainstem syndromes, often leading to severe disability. Some patients are seropositive for antibodies against aquaporin-4 (AQP4), others are positive for anti-myelin oligodendrocyte glycoprotein (MOG), while a few are negative for both biomarkers. The disease is complex, and only now are specific therapeutic clinical trials being carried out. The present study adds to the literature through detailed clinical data from 153 medical records of Brazilian patients. MethodsRetrospective assessment of medical records from nine specialized units in Brazil. ResultsNMOSD was more prevalent in females (4.1:1), who had significantly fewer relapses than males (p = 0.007) but presented similar levels of disability over time. African ancestry was associated with higher levels of disability throughout the disease course (p < 0.001), although the number of relapses was similar to that observed in white patients. Concomitant autoimmune diseases were relatively rare in this population (6.5%). Positivity for anti-AQP4 antibodies was identified in 62% of the patients tested, while 3% presented anti-MOG antibodies. Anti-AQP4 antibodies were not associated to worse disease course. The last medical record showed that six patients had died and 13 were wheelchair-bound. Seventy percent of the patients did not respond to first-line therapy (azathioprine and/or corticosteroids), and five patients continued to relapse even after four different courses of treatment. ConclusionThe present study adds to the reports from other countries presenting original data on Brazilian patients diagnosed with NMOSD according to the 2015 criteria.

Chronic relapsing inflammatory optic neuropathy (CRION): a manifestation of myelin oligodendrocyte glycoprotein antibodies

BackgroundKey clinical features of chronic relapsing inflammatory optic neuropathy (CRION) include relapsing inflammatory optic neuritis (ON) and steroid dependency, both of which have been reported among patients with myelin oligodendrocyte glycoprotein antibodies (MOG-Abs). We investigated the relevance of the presence of serum MOG-IgG with the current diagnostic criteria for CRION among patients with idiopathic inflammatory optic neuritis (iON).MethodsRetrospective reviews of a database prospectively collated between 2011 and 2017 from the tertiary referral center for multiple sclerosis and neuromyelitis optica were performed. Sixty-four patients with iON, who did not meet the diagnostic criteria for multiple sclerosis, neuromyelitis optica (NMO) spectrum disorder with/without NMO-IgG, or acute disseminated encephalomyelitis and who had no symptomatic central nervous system (CNS) lesions other than on the optic nerve, were included from a cohort of 615 patients with inflammatory demyelinating diseases of the CNS. Fulfillment of the current diagnostic criteria for CRION, assay results for the serum IgG1 MOG-Ab, and characteristics of CRION patients with MOG-IgG were compared to those of non-CRION patients with MOG-IgG.ResultsTwelve iON patients fulfilled the current diagnostic criteria for CRION, 11 patients were positive for MOG-IgG, and one patient was borderline. Among the other 52 iON patients not meeting the criteria for CRION, 14 had relapsing disease courses and 38 had monophasic courses, of which MOG-IgG positivity were 0% and 29%, respectively. CRION patients with MOG-IgG had more relapsing disease courses (first steroid-dependent worsening/relapse in 2.3 months, range 0.4–7.0) and poorer optical coherence tomography outcomes at follow-up than non-CRION patients with MOG-IgG. However, patients in the two groups did not differ in terms of age of onset, sex, or steroid treatment duration after initial attack.ConclusionsCRION, according to the current diagnostic criteria, is a relapsing optic neuritis associated with MOG-IgG. Among iON patients with MOG-IgG, the absence of steroid-dependent attacks in the early stages of the disease may predict a long-term non-relapsing disease course and a more favorable outcome.

B-cell depletion is ineffective in a patient with granulomatous optic neuropathy.

A 49-year-old woman had sudden visual loss in her left eye associated with retrobulbar pain and decrease in visual evoked potential amplitude. With suspected optic neuritis, the patient was treated successfully with a 5-day therapy of methylprednisolone (MP) infusion of 1 g per day (figure 1A). Within several days after MP, partial visual loss reoccurred. MRI showed increased signal and contrast enhancement of the left optic nerve (figure 1, B and C); further diagnostic workup including cerebral and spinal MRI and CSF analysis with oligoclonal bands and soluble Il-2 receptor was normal. Serum antibody screening for aquaporin 4, myelin oligodendrocyte glycoprotein (MOG) and myelin-associated glycoprotein (MAG) was negative. Chest CT did not show signs of hilar adenopathy, interferon-gamma release assays for tuberculosis were negative, and ophthalmologic examination excluded optic retinitis. Optic neuritis relapsed 3 times within the next 4 months and was treated with IV MP and with the suspected diagnosis of atypical relapsing optic neuritis (RON) therapy with azathioprine and overlapping oral MP was initiated (figure 1A). After a stable period of 8 months, azathioprine had to be discontinued because of severe leucopenia. Thereafter, another series of relapses with complete visual loss of the left eye occurred that was refractory to a total dose of 15 g MP and additional cycles of plasma exchange after initial partial relief. Since another approach with azathioprine had to be terminated because of leukopenia, B-cell depletion with rituximab together with oral MP was applied. However, further relapses occurred together with continuous deterioration of visual loss in the left eye (figure 1A). In another MRI follow-up, 2.5 years after the initial episode, a granulomatous-like contrast-enhancing process of the left optical nerve was seen (figure 1, D and E). Because there was complete amaurosis in the left eye, we decided to perform a biopsy. Neuropathologic examination revealed a perineural located granulomatous lesion with characteristic multinucleated giant cells, histiocytes and massive lymphocytic infiltration, and small areas of focal noncaseating necrosis (figure 1, F–H). Anti-CD138 stains showed only single plasma cells and no CD20-expressing B cells could be detected, thus confirming effective B-cell depletion with rituximab (figure 1, I and J). Langerhans cell histiocytosis was excluded by CD1a-negative histiocytes without granulocytic infiltration (figure 1K). No infectious origin, especially no fungal or mycobacterial origin, could be detected. There was no evidence of systemic sarcoidosis because chest CT, bronchoalveolar lavage, and bronchial biopsies were negative. CSF analysis was repeated and still normal. Thus, based on the clinical presentation and the neuropathologic results, we diagnosed chronic relapsing granulomatous optic neuropathy, and we started immunotherapy with methotrexate to prevent progress of the granulomatous inflammation also to the right optic nerve.

Baseline Brain Activity Changes in Patients With Single and Relapsing Optic Neuritis.

Purpose: To investigate spontaneous brain activity amplitude alterations in single and relapsing optic neuritis (sON and rON, respectively) and their relationships with clinical variables.Methods: In total, 42 patients with sON, 35 patients with rON and 50 healthy volunteers were recruited. Resting-state functional Magnetic Resonance Imaging (rs-fMRI) scans were acquired for all participants and compared to investigate the changes in the amplitude of low-frequency fluctuations (ALFFs) among the three groups. The relationships between the ALFFs in regions with significant differences in the groups and clinical variables, including the logarithm of minimal angle of resolution (LogMAR), Expanded Disability Status Scale (EDSS) score and disease duration, were further explored.Results: Compared with healthy volunteers, the sON and rON patients showed significantly decreased ALFFs in several regions of the occipital and temporal lobes (i.e., inferior occipital gyrus and superior temporal gyrus; corrected p < 0.01 using AlphaSim). The sON patients showed significantly increased ALFFs in the left caudate and certain regions in the frontal lobes (i.e., medial frontal gyrus), whereas the rON patients showed increased ALFFs in the bilateral inferior temporal gyrus and left medial frontal gyrus (corrected p < 0.01 using AlphaSim). Significantly decreased ALFFs were observed in the right inferior parietal lobule (IPL), left posterior cingulate and precuneus in the rON patients compared with those in the sON patients (corrected p < 0.01 using AlphaSim). Significant correlations were observed between the disease duration and ALFF in the left middle temporal gyrus, left inferior occipital gyrus, right lingual gyrus and right IPL (p < 0.05).Conclusion: Functional impairment and adaptation occurred in both the sON and rON patients. Impairment mainly involved the occipital cortex, and functional adaptions predominantly occurred in the frontal lobe. Functional damage was more severe in the rON patients than in the sON patients and correlated with the disease duration.

Retinal nerve fibre layer thinning is associated with worse visual outcome after optic neuritis in children with a relapsing demyelinating syndrome.

Optic neuritis may be monophasic or occur as part of a relapsing demyelinating syndrome (RDS), such as multiple sclerosis, aquaporin-4 antibody (AQP4-Ab) neuromyelitis optical spectrum disorder (NMOSD), or myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-associated disease. The aims of this study were to test whether clinical, electrophysiological, and microstructural parameters differ in multiple-sclerosis-associated optic neuritis (MS-ON) and antibody-associated optic neuritis (Ab-ON); to identify the clinical and paraclinical characteristics of children suffering worse long-term visual outcome of RDS-optic neuritis; and to explore the relationship between RNFL thickness and clinical parameters in RDS-optic neuritis. Forty-two children with optic neuritis were retrospectively studied: 22 with multiple sclerosis (MS-ON) and 20 with antibody-associated demyelination (Ab-ON: MOG-Ab=16 and AQP4-Ab=4). Clinical and paraclinical features were analysed. Complete recovery of visual acuity was reported in 25 out of 42 children; eight out of 38 (21%) suffered moderate or severe visual impairment (logarithm of the minimum angle of resolution [logMAR]>0.5) in their worse eye, including four out of 38 who were blind (logMAR>1.3) in their worse eye (two with multiple sclerosis, two with AQP4-Ab NMOSD). None of the children with MOG-Ab were blind. Recurrence of optic neuritis was more common in the Ab-ON group than the MS-ON group (15 out of 20 vs seven out of 22, p=0.007). Retinal nerve fibre layer (RNFL) thickness at baseline inversely correlated with visual acuity at final follow-up (r=-0.41, p=0.008). There was no significant relationship between the number of episodes of optic neuritis and mean RNFL (r=-0.08, p=0.628), nor any significant relationship between the number of episodes of optic neuritis and visual impairment (r=0.03, p=0.794). In children with RDS, long-term visual impairment inversely correlated with RNFL thickness, but not with the number of relapses of optic neuritis. Optical coherence tomography may have a role in assessing children with optic neuritis to monitor disease activity and inform treatment decisions. Long-term visual impairment is reported in 40% of children with a relapsing demyelinating syndrome following optic neuritis. Relapse of optic neuritis, occurring more frequently in the non-multiple-sclerosis group. Retinal nerve fibre layer thinning is associated with worse visual outcome. Optical coherence tomography can be used alongside clinical parameters as an objective measure of neuroretinal loss.

Anti-Myelin Oligodendrocyte Glycoprotein Antibodies in Paediatric Patients with Optic Neuritis

Background Myelin oligodendrocyte glycoprotein (MOG) is located on the surface of oligodendrocytes and myelin in the central nervous system. MOG-IgG is associated with acute disseminated encephalomyelitis (ADEM), relapsing and bilateral optic neuritis (NNO), and transverse myelitis (TM) in both paediatric and adult patients. The combination of NNO and TM or other inflammatory brain lesions is a typical feature of neuromyelitis optica spectrum disorders (NMO-SD) which are associated with specific pathogenic autoantibodies against the water channel aquaporin-4 (AQP4-IgG). However, children with NMO-SD are often seronegative for AQP4-IgG but seropositive for MOG-IgG. Therefore, the course and therapy of MOG-IgG positive NNO in children were of special interest. Patients The course of disease of two male patients with acute NNO is presented (bilateral NNO, age of onset 8 years each, AQP4-IgG negative, MOG-IgG positive). Several relapses of NNO occurred in patient 1 with persisting MOG-IgG in spite of immunsuppressive therapy. He suffered from increasing optic atrophy, considerable visual loss and transient brainstem affection. Patient 2 showed a monophasic course of disease with a rapid decline in MOG-IgG titre and only minor asymmetric optic atrophy. Conclusions MOG-IgG in children is associated with recurrent NNO and cerebral lesions characteristic of ADEM or NMO-SD. High titres of MOG-IgG are observed during the acute phase of clinical symptoms. Relapses of NNO lead to increasing loss of retinal nerve fibre layer. Diagnostic investigation includes the determination of AQP4-IgG and MOG-IgG as well as magnetic resonance imaging (MRI) of brain and spinal cord. The therapeutic consequence of this is consistent immunsuppressive treatment, starting with intravenous steroids and followed by second-line therapy with steroid sparing immunosuppressants, including mycophenolate or azathioprine, followed in refractory cases by rituximab. The therapeutic effect should be controlled by laboratory tests of MOG-IgG titre.

Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.

To establish whether children with relapsing acquired demyelinating syndromes (RDS) and myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) show distinctive clinical and radiologic features and to generate a diagnostic algorithm for the main RDS for clinical use. A panel reviewed the clinical characteristics, MOG-Ab and aquaporin-4 (AQP4) Ab, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with RDS. A neuroradiologist blinded to the diagnosis scored the MRI scans. Clinical, radiologic, and serologic tests results were compared. The findings showed that 56.4% of children were diagnosed with multiple sclerosis (MS), 25.4% with neuromyelitis optica spectrum disorder (NMOSD), 12.7% with multiphasic disseminated encephalomyelitis (MDEM), and 5.5% with relapsing optic neuritis (RON). Blinded analysis defined baseline MRI as typical of MS in 93.5% of children with MS. Acute disseminated encephalomyelitis presentation was seen only in the non-MS group. Of NMOSD cases, 30.7% were AQP4-Ab positive. MOG-Ab were found in 83.3% of AQP4-Ab-negative NMOSD, 100% of MDEM, and 33.3% of RON. Children with MOG-Ab were younger, were less likely to present with area postrema syndrome, and had lower disability, longer time to relapse, and more cerebellar peduncle lesions than children with AQP4-Ab NMOSD. A diagnostic algorithm applicable to any episode of CNS demyelination leads to 4 main phenotypes: MS, AQP4-Ab NMOSD, MOG-Ab-associated disease, and antibody-negative RDS. Children with MS and AQP4-Ab NMOSD showed features typical of adult cases. Because MOG-Ab-positive children showed notable and distinctive clinical and MRI features, they were grouped into a unified phenotype (MOG-Ab-associated disease), included in a new diagnostic algorithm.