Analysis Of The Clinical Characteris And Relapse Correlation Factors Of Neuromyelitis Optica Spectrum Disorders

BackgroundNeuromyelitis optica spectrum disorders (NMOSD) is an idiopathic, inflammatory, demyelinating diseases of the central nervous system (CNS), which characterized by involvement of optic nerve and spinal cord simultaneously or sequentially. NMOSD is relapsing and aggressive. In 2004, NMO-immunologlobulin G (NMO-IgG) was reported, which was combined with water channel aquaporin-4 (AQP4) which mainly expressed in CNS. The target antigen of NMO-IgG thus also called water channel aquaporin-4 antibody (AQP4-Ab). NMO-IgG was a highly specific serum autoantibody marker for diagnosis of NMOSD. With the constant updating of diagnostic criteria of NMOSD in 2015, the core clinical characteristics, laboratory data, magnetic resonance imaging (MRI) and the recurrence become more valued. Consequently, it is a very key problem how to analysis the clinical characteristics and relapse correlation factors of NMOSD.Objective1. To analysis the general clinical characteristics of NMOSD.2. To summarize serum and cerebrospinal fluid (CSF) laboratory statistics of NMOSD.3. To analysis the optic nerve, spinal cord, and brain MRI characteristics of NMOSD.4. To compare the clinical, laboratory and MRI characteristics of serum AQP4-Ab positive and negative.5. To compare the clinical, laboratory and MRI characteristics of CSF AQP4-Ab positive and negative.6. To compare the clinical characteristics of serum AQP4-Ab positive at different titer levels.7. To observe the relapse correlation factors of NMOSD in the 3 years.Methods1. The clinical data of 73 cases who visited the Department of Neurology at our hospital from July 29th 2009 to December 31th 2015, including clinical material, laboratory statistics and neuroimaging features (optic nerve, spinal cord and brain MRI). Serum and period cerebrospinal fluid (CSF)both in acute and remission period were collected. The CSF specimens were collected for the count of routine examination, biochemical detection, cytology, myelin basic protein (MBP), oligo clonal bands (OB).24 hours IgG synthesis rate, IgG index and Blood brain barrier index were calculated. The serum and CSF AQP4-Ab were detected. The serum examinations were detected for includes OB, MBP, and autoimmune antibodies, such as serum ANA, anti-SSA, anti-SSB and anti-Ro-52 antibody. The expanded disability status scale (EDSS) scores were recorded and then building database.2. NMOSD was defined as cases fulfilling all items of 2015 NMOSD criteria. None of cases was complicated other autoimmune diseases, such as Systems Lupus Erythematosus, Behcet’s Disease and Sjogren Syndrome, and cancer-free.3. Positive test for AQP4-Ab using best available detection method (cell-based assay strongly recommended). Statistical analysis was done by SPSS 19.0.Results1. Clinical characteristics:(1)General clinical data:①Patients included 12 males,61 females. Male to female ratio was 1 to 5 among the patients. The median onset age of NMOSD was 38 years old; ②Follow up:All patients were followed up (from September lth 2009 to April 20th 2016, the median follow-up time was 3 years);③EDSS:The mean of EDSS score was 6.2±1.9 of NMOSD in acute exacerbation. The median EDSS score of NMOSD was 3 in remission stage. (2) To all the patients, the longest disease course was 27 years and the shortest was 3 years, the median course of NMOSD was 7 years. The duration from the first relapse to the onset was 6 months. The duration from the second relapse to the first relapse was 5 months. The median recurrence rate was 4. The median recurrent times per years was 0.8. The average annual recurrence rate was 91.8%. Two years later, the recurrent rate of NMOSD had come to 93.2%.Three years later, the recurrent rate of NMOSD had come to 94.5%. Five years later, the recurrent rate of NMOSD had come to 100%; (3) The initial clinical symptoms was visual loss (n=22), numbness of the limbs (n=17), limb pain (n=13), neuropathic pruritus (n=11), limb paresthesia (n=10), hiccup (n=9), trunk or four limbs paresthesia (n=6), zonesthesia (n=4), Lhermitt’s sign (n=2), bradycardia (n=1), abdominal distension and constipation (n=1), diplopia (n=1); (4) The core clinical characteristics had ON (n=22), LETM (n=40), area postrema syndrome (n=5), acute brainstem syndrome e(n=4), ON combined LETM (n=2)at onset. In relapse stage, the core clinical symptoms include recurrent ON combined LETM (n=26), recurrent LETM (n=26), recurrent ON (n=6), area postrema syndrome (n=2), LETM combined area postrema syndrome (n=5), recurrent ON combined area postrema syndrome (n=2),symptomatic cerebral syndrome with NMOSD-typical brain lesions (n=2),ON combined LETM and area postrema syndrome (n=4).2. Laboratory examination:①Serum immunologic test:There was a remarkable difference (P=0.000)in AQP4-Ab titres between with the acute and remission period (median titer of 1:20 to 1:40).The positive rate of serum MBP was 15.8%(9/57). The positive rate of autoimmune antibodies positive was 72.6%(53/73);②CSF immunologic test:The positive rate of CSF protein was 43.1%(25/58). The positive rate of CSF white blood cells was 39.7%(23/58). The positive rate of 24h IgG synthesis rate was 22.8%(13/57). The positive rate of IgG index was 28.1%(16/57). The positive rate of blood brain barrier index was 24.6%(14/57). ③The CSF AQP4-Ab was positive rate 45.1%(23/51) in serum AQP4-Ab positive patients.3. Neuroimaging Features:(1)Optic nerve MR:①The detection rate of optic nerve MRI lesion was82.3%(51/62).Optic nerve MRI lesion were detectable in unilateral 41.2%(21/51)and bilateral 58.8%(30/51). The optical nerve MRI lesion were located at posterior 1/2 of optic nerve 88.2%(45/51), frontier 1/2 of optic nerve 9.8%(5/51)and involving optic chiasm 2.0%(1/51);②Optic nerve edema and thickening was 92.2%(47/51) cases in acute period;③The last follow-up showed optic atrophy in 39.2%(20/51), including unilateral atrophy 40.0%(8/20), bilateral atrophy 55.0%(11/20)and optic chiasm atrophy 5.0%(1/20);(2)Spnial cord MRI:① 82.2%(60/72)of NMOSD have>3 contiguous segments and 16.7%(12/72)in the onset<3 contiguous segments of LETM;②Lesions of LETM were sliver 77.8% (56/72), litter patch 6.9%(5/72), roundish5.6%(4/72), slender 2.8%(2/72), diffuse 4.2%(3/72), large patch 1.4%(1/72)and quasi-circular 1.4%(1/72);③Spinal cord lesions:Lesions were involved the cervical spinal cord 38.9% (28/72), cervical spinal cord combined with thoracic spinal cord 34.7%(25/72), thoracic spinal cord 34.7%(13/72), medulla oblongata combined with cervical and thoracic spinal cord 2.8%(2/72), cervical combined with thoracic and thoracic cord 2.8%(2/72), medulla oblongata combined with cervical spinal cord 1.4%(1/72), craniospinal cord 1.4%(1/72). Lesions living in the spinal cord central 73.6%(53/72), center leans to back 8.3%(6/72), leans to front 4.2%(3/72)and slants 13.9%(10/72); @The characteristic of enchanced lesions of LETM are patchy enchancement 41.7% (30/72), ring-like enchancement 4.2%(3/72), linear enchancement 4.2%(3/72), ring-like combined with apot enchancement 4.2%(3/72), sliver enchancement 5.6% (4/72), nodule-like combined with sliver enchancement 2.8%(2/72)and 37.5%(27/72) lack of enhancement. (3)The positive rate of NMOSD brain lesions was 53.4% (39/73).The patchy lesions were located at around ventricles (n=33), near the outer wall of periventricular (n=21), along the fourth ventricle (n=10), along the third ventricle (n=2), centrum semiovale (n=28), basal ganglia (n=22), brainstem (n=14), the frontal lobe (n=12).4. The Clinical, laboratory and imaging characteristics of serum AQP4-Ab with positive and negative:(1)There was a remarkable difference (P=0.001)in ESSS ans total recurrence between with serum AQP4-Ab with positive and negative;(2) The positive rate of autoimmune antibodies positive and CSF AQP4-Ab in serum AQP4-Ab positive was statistically significant difference with and serum AQP4-Ab negative group (P=0.028、P=0.001).5. The Clinical, laboratory and imaging characteristics of CSF AQP4-Ab with positive and negative:White blood cells, MBP and 24h IgG synthesis rate of CSF AQP4-Ab in positive patients were slightly higher than that of negative patients, the difference was statistically significant (P=0.008, P=0.043, P=0.012).6. The clinical features of AQP4-Ab positive cases at different titer levels:(1) There was a remarkable difference (Z=-4.400,P=0.000)in geometric mean of serum AQP4-Ab titres between with CSF AQP4-Ab positive (1:111.4)and CSF AQP4-Ab negative (1:29.0). (2) There was a remarkable difference (Z=-2.199,P=0.028)in geometric mean of serum AQP4-Ab titres between with permanent complete blindness (1:105.6)and without permanent complete blindness (1:64.0). (3)There was no statistical significance (Z=-0.626, P=0.366)in the of geometric mean serum AQP4-Ab titres compared with or without spine shrinked and became thin. (4)The of geometric mean serum AQP4-Ab titres was 1:57.8 in large cerebral lesions on MRI groups and the group without cerebral lesions (1:74.6)was no statistically significant difference with cerebral lesions group (Z=-0.903, P=0.366). (5)We also compared the serum AQP4-Ab titres (n=60, 1:64.3)with>3 VS spinal cord lesions and those<3 VS spinal cord lesions on MRI (n=12,1:63.9). Of the 29 patients with myelitis, there was no statistic difference among them (Z=-0.178, P=0.859).5. Single factor analysis showed that there was significant statistically significant difference between the serum AQP4-Ab and other autoimmune antibody positive and negative for the recurrence times in three years. Serum AQP4-Ab and other autoimmune antibodies positive is independent risk factors for affecting the incidence of NMOSD 3 years recurrence times proved by ordinal logistic regression analysis, which serum AQP4-Ab positive (OR=14.556>1)and autoimmune antibodies positive (OR=4.328>1)are positive correlated with NMOSD onset within 3 years recurrence times.Conclusion1. NMOSD were predominantly woman with an median age 38 (years old and has a 5:1 F:M ratio.2. The characteristic of serum AQP4-Ab positive patients which is abundant with higher recurrence suggests that serum AQP4-Ab plays a crucial role in relapse again.3. NMOSD had various clinical manifestations and initial symptoms was visual loss, numbness, pain and weakness of the limbs, hiccup, and pruritus. Some nonspecific clinical symptom that neuropathic pruritus, zonesthesia and intractable hiccup appear only for serum AQP4-Ab positive. The misdiagnosis rate was 54.8%. Erroneous diagnoses includes Multiple sclerosis, reflux esophagitis, peripheral neuropathy, cerebral infarction, syringomyelia, somatization disorders, sinus bradycardia, space occupying lesion, ADEM and other (allergic dermatitis, nervous vomiting). Most patients with nonspecific clinical symptom should be paid more attention by neurologist. Careful medical examination and serum AQP4-Ab should be checked as sooner as possible including CSF OB and CSF white blood cells. Examinations might be repeated when necessary in order to reduce misdiagnosis of NMOSD.4. Serum AQP4-Ab titres of NMOSD in acute stage was higher than in remission. It is confirmed that the AQP4-Ab were increased in the acute phase. The positive rate of autoimmune antibodies in serum AQP4-Ab positive was significant higher suggests that other autoimmune antibodies in serum may be involved in the humoral immunity of NMOSD. The EDSS and nervous system disability status of patients with serum AQP4-Ab positive was seriously than that in negative patients. Morever, the titres were significantly higher in the patients with permanent complete blindness.5. White blood cells, MBP and 24h IgG synthesis rate of CSF AQP4-Ab in positive patients were slightly higher than negative patients suggests that the activity of the demyelinating disease.6. AQP4 Ab was consistently positive in CSF when the serum AQP4-Ab titres > 1:160. AQP4-Ab weren’t detectable in CSF samples when matched serum titres were<1:20.7. The onset of serum AQP4-Ab and other autoimmune antibody positive is independent risk factors for affecting the incidence of NMOSD 3 years recurrence times.