A Study Of Diagnosis,Clinical Features And Electrophysiology Of Neuromyelitis Optica Spectrum Disorders

Background: Neuromyelitis optica spectrum disorders(NMOSD)is an idiopathic inflammatory disease of the central nervous system.In 2015,the International Panel for neuromyelitis optica(NMO)diagnosis established a new diagnostic criteria for NMOSD.There has been no validation study of 2015 NMOSD diagnostic criteria in Chinese patients and there has been no study evaluating the association between myelin oligodendrocyte glycoprotein immunoglobulin G(MOG-IgG )and NMOSD.There were few studies about clinical features and prognosis of NMOSD patients based on 2015 NMOSD criteria.The clinical manifestations of NMOSD and multiple sclerosis(MS)are similar,so it is difficult to differentiate them.Pruritus was described as a frequent and specific feature in aquaporin4-immunoglobulin G(AQP4-IgG )positive NMOSD,but there has been no comparison study about pruritus in AQP4-IgG positive/negative NMOSD and multiple sclerosis(MS)patients.Transverse myelitis is of great significance in the diagnosis of NMOSD,but there has been no systemic electrophysiological study evaluating involvement of lower motor neurons in NMOSD patients.Materials and methods:Study 1.The consecutive NMOSD patients who were first admitted in the Department of Neurology of our hospital from January 2016 to December 2019 were selected as the research objects.The 2006 NMO diagnostic criteria and 2015 NMOSD diagnostic criteria were applied when the AQP4-IgG status was known or assumed unknown,respectively,to validate the 2015 NMOSD diagnostic criteria.The association between MOG-IgG and 2015 NMOSD diagnostic criteria was also evaluated.Study 2.The consecutive AQP4-IgG positive NMOSD patients who were first admitted in the Department of Neurology of our hospital from January 2016 to December 2019 were selected as the research objects,and their clinical characteristics and prognostic factors were analyzed.Study 3.The NMOSD and MS patients who were admitted in the Department of Neurology of our hospital from January 2017 to December 2018 were selected as the research objects.Demographic data,clinical features,with or without pruritus,AQP4-IgG status and MRI findings were analyzed and compared between NMOSD and MS patients.Study 4.NMOSD patients with results of concentric needle electromyography(EMG)and nerve conduction studies(NCS)who were first admitted in the Department of Neurology of our hospital from January 2016 to December 2019 were selected as the research objects.The results of EMG,NCS and MRI of brain and spinal cord in the patients were analyzed,to evaluate involvement of lower motor neurons in NMOSD patients.Results:Study 1: Validation of the 2015 NMOSD diagnostic criteria in a cohort of Chinese patients.A total of 185 patients fulfilling the 2015 NMOSD criteria(154 AQP4-IgG positive,23 AQP4-IgG negative,8 AQP4-IgG status unknown)were included,whereas only 43.2%(80/185)fulfilled the 2006 NMO criteria.If all the patients with NMOSD were assumed with unknown AQP4-IgG status,69.7%(129/185)still fulfilled the 2015 NMOSD criteria,whereas only 39.5%(73/185)met the 2006 NMO diagnostic criteria(p < 0.001).Most NMOSD patients(n = 55,29.7%)disqualified because of not meeting the criterion of dissemination in space.The median time to diagnosis was 3 months(129 patients,range: 1–145 months)by the2015 NMOSD criteria and 10 months(73 patients,range: 1–185 months)by the 2006 NMO criteria(Log-rank test: p < 0.01).Positive MOG-IgG was found in 28.6%(4/14)of the AQP4-IgG negative and 2.8%(1/36)of the AQP4-IgG positive NMOSD patients(p < 0.01).NMOSD with MOG-IgG was more frequent in male(3/1 vs 2/33,p < 0.01)and with younger onset age(24.8 vs 41.4,p < 0.05),in comparison with NMOSD with AQP4-IgG .Study 2: The study of clinical features and prognosis of AQP4-IgG positive NMOSD patients.154 AQP4-IgG positive NMOSD patients were included,and 60(39.0%)of them were diagnosed as NMO.The mean onset age was 40.2 years and the female to male ratio was9.3:1.The median disease duration was 12 months(range: 1-264).The median of “interval from the first episode to relapse” and “attack times to develop NMO” was 5 months and 2times respectively.All the AQP4-IgG positive NMOSD patients were divided into four subgroups based on their manifestations at first attack episode:(i)NMOSD without optic neuritis or acute myelitis(NMOSD-ON-AM-,n = 27);(ii)NMOSD with optic neuritis(NMOSD-ON+,n = 42);(iii)NMOSD with acute myelitis(NMOSD-AM+,n = 76);and(iv)NMOSD with optic neuritis and acute myelitis(NMOSD-NMO+,n = 9).The age of onset was the lowest in NMOSD-ON-AM-phenotype group among all groups,and was significantly lower than NMOSD-AM+ group(35.4 years vs 43.2 years,p < 0.05).The interval from the first episode to relapse was significantly longer in the NMOSD-ON+ group(9.0 months)than that in NMOSD-ON-AM-(3.5 months)and NMOSD-AM+ group(5.0months)(p < 0.05,p < 0.01).Conversion rate of NMO and attack times required to NMO diagnosis in the NMOSD-ON+ group was the highest and lowest respectively among 3non-NMOSD-NMO+ groups(p <0.05,p < 0.05).Only 12 patients(7.8%)had pure brain abnormalities during disease course,of which 9 had only one attack episode.52.6% of NMOSD patients had persist visual or motor function disability at last follow-up,21.4% and37.0% of them had persist visual and motor function disability respectively.Multi-variate analysis showed that male,NMOSD-ON+ and NMOSD-NMO+ onset phenotype,attack times≥ 3 were independent risk factors for visual function disability,while onset age over 40 years old,NMOSD-AM+ phenotype were independent risk factors for motor function disability.Study 3: Pruritus in NMOSD and MS patients.Pruritus was reported in 21.0%(22/105)of NMOSD patients and 2.1%(2/96)of MS patients during disease course(p < 0.01).Pruritus was presented in 20.5%(18/88)of AQP4-IgG positive and 23.5%(4/17)of AQP4-IgG negative NMOSD patients during disease course(p = 0.775).At the first attack episode of disease,12.4 %(13/105)of NMOSD and 1.0 %(1/96)of MS patients reported pruritus(p < 0.01).At the first and second attack episodes of disease,pruritus was reported in20.0%(21/105)of NMOSD and 1.0%(1/96)of MS patients(p < 0.01).The distribution of pruritus in 81.8% of NMOSD patients with pruritus and 100.0% of MS patients with pruritus was correlated with dermatomal distribution of involved spinal cord or brainstem.63.6% of NMOSD patients with pruritus had neuropathic pain at distribution areas of pruritus.Study 4: The electrophysiological study of the NMOSD patients.The acute and/or chronic denervation was found in 22.0% of NMOSD patients by EMG.EMG and NCS showed that lower motor neurons were involved in 15.3% of NMOSD patients.There was no significant difference in the proportion of lower motor neuron involvement between AQP4-IgG positive and AQP4-IgG negative NMOSD patients(17.0% vs 10.0%,p = 0.940).The lower motor neuron involvement indicated by EMG and NCS which can be attributed to spinal cord or brainstem MRI lesions was found in 6.8% of NMOSD patients.The peripheral or cranial neuropathy indicated by abnormal NCS changes was found in 11.9% of NMOSD patients and the denervation indicated by EMG can be accounted for by NCS abnormality was found in 6.8% of NMOSD patients,while 3.4% of NMOSD patients had only NCS abnormality not denervation indicated by EMG.ConclusionStudy 1.Compared with the 2006 NMO criteria,the 2015 NMOSD criteria markedly improved the diagnostic rate and reduced the time taken to diagnosis in our cohort of Chinese patients,even when AQP4-IgG status was unknown.Missing the criterion of dissemination in space,that is,having isolated core clinical features is the chief factor precluding NMOSD diagnosis under unknown AQP4-IgG status.NMOSD with MOG-IgG is not uncommon in NMOSD without AQP4-IgG and has unique features regarding gender predominance and onset age.Study 2.Among AQP4-IgG positive NMOSD patients,the most common onset phenotype is NMOSD-AM+ onset phenotype.Among non-NMOSD-NMO+ onset phenotype groups,NMOSD-ON+ onset phenotype group has the longest relapse interval,the highest conversion rate to NMO and the least required attack times to NMO diagnosis.Male,NMO-ON+ and NMOSD-NMO+ onset phenotype,attack times ≥ 3 are independent risk factors for visual function disability.The age of onset over 40 years,NMOSD-AM+ onset phenotype are independent risk factors for motor function disability.Study 3.Pruritus is a common and relatively specific feature in either AQP4-IgG positive or negative NMOSD.More frequent involvement of grey matter of spinal cord results in a significantly higher pruritus reported rate in NMOSD than MS.Pruritus occurred more frequently in NMOSD than MS,which might help in distinguishing NMOSD from MS,especially at early stage.Neuropathic pruritus and neuropathic pain can be caused by the spinal cord or brainstem lesions of same location.Study 4.Not uncommon lower motor neuron involvement exists in NMOSD patients,so needle EMG and NCS studies should be performed in NMOSD patients with suspected lower motor neuron involvement.