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Clinical and pathological features of acute optic neuritis in Chinese patients Key Words:optic neuritis; demyelinating diseases, multiple sclerosis; neuromyelitis optica; Background:The factors that affect the onset and outcome of optic neuritis (ON) are not very clear. Methods:Medical records of patients with diagnosis of ON at Huashan Hospital, Fudan University between Mar, 2008 and Jun 2011 were reviewed. Clinical features, ophthalmologic and neurologic assessments, neuroimaging studies, laboratory examinations, visual recovery and final outcome of the patients were evaluated by the authors. Results:Records of 50 patients (32 females and 18 males), ages 15-56 years, were reviewed, in which 22% patients had a previous onset of ON. Maximal visual deficit was severe in 72.50%(<20/200). Abnormal rate of hormone levels and rheumatoid indicators were 54.2% and 25%. ANA test returned positive rate was 40%, oligoclonal banding (OCB) was identified in 31.3% and Serum NMO-IgG studies were abnormal in 25% of the patients. Neuroimaging abnormalities associated with ON were documented in 6 patients. Three of the 50 patients have been diagnosed with MS, and 2 with NMO. Visual acuity was 20/20 or better in 26.1% and 20/100 or worse in 39.1% affected eyes at the last visit. Poor visual acuity at onset is the main factor that would affect the final outcome of vision(P<0.05). Conclusions: Vision defects of this group of patients were severe. Female had a higher incidence of optic neuritis than male. Hormone Levels, rheumatoid indicators and immune parameters may be related to the onset of ON. The severe reduction of visual acuity at onset may be related to the poor outcome of vision in ON patients. Introduction Optic neuritis(ON) is one of the most common ophthalmological diseases, which mostly occurs in young adults and middle-aged. It is characterized by rapid onset of vision loss associated with or without an orbital or ocular pain during eye movement, color vision impairments, and visual field defects. To date, the pathogenesis of optic neuritis is still poorly understood, and factors that affect the prognosis of the disease are still not clearly identified. Genetics, viral infections, immune disorders may all be the predisposing factors of ON. Inflammatory demyelinating diseases including multiple sclerosis (MS) and neuromyelitis optica (NMO) are believed to be the most common cause of acute ON. Fifty ON patients were enrolled in this study. Their medical history, ophthalmological and neurological examinations, laboratory examinations, and imaging results were reviewed. Data was analyzed to get a comprehensive understanding of the clinical profile of ON, to identify the factors to help diagnose and clarify the pathophysiology of ON, and to investigate whether these factors were related to the prognosis of the patients. Materials and Methods 1 Paitient: A retrospective study was conducted in the Department of Ophthalmology, Huashan hospital, Fudan University, China. The study period was between March 1, 2008 and June 30, 2011. Medical records of 50 patients with diagnosis of ON were reviewed. Patients met the inclusion criteria for ON if they presented with an acute or subacute loss of vision without evidence of a metabolic, toxic, vascular, or compressive etiology as well as the presence of one or more of the following: relative afferent pupillary defect (RAPD) in the affected eye in unilateral cases, visual field deficit or scotoma, impaired color vision, optic disc edema, and abnormal visual evoked potentials (VEPs). Data: Demographic data. Information includes gender, age at onset, involvement of the eyes and medical histories. Clinical features. The following symptoms were recorded for each patient: visual loss, pain with ocular movements, and presence of other neurologic symptoms. Recent (within 30 days prior to ON onset) illness (rhinorrhea, cough, or fever), headache, or immunization was noted. Time from ON symptom onset to assessment by a neurologist or ophthalmologist and details of the initial ophthalmologic and neurologic assessments including visual acuity in each eye, pupillary reaction, the presence of an RAPD, characteristics of the optic disc and retina, visual field assessments, color vision, VEP results and the results of a complete neurologic exam were recorded. Laboratory investigations. Blood tests including routine blood test, erythrocyte sedimentation rate, hormone levels (estradiol, progesterone, dehydroepiandrosterone, testosterone, prolactin), C-reactive protein, rheumatoid factor, anti-streptolysin O, antinuclear antibody, extractable nuclear antigen, anti-double strand DNA antibody, anti-neutrophil granules antibody, and blood NMO-IgG which were considered to be related to the incidence of ON were obtained from the data. CSF cell counts, glucose and protein levels, presence or absence of CSF oligoclonal bands were recorded if patient had received a lumbar puncture. Neuroimaging studies. MRI scans performed on patient were reviewed. Abnormal signal or enhancement of the optic nerves and presence of white matter lesions was noted Treatment. All patients were received treatment with corticosteroids: Intravenous methylprednisolone 1000mg in one doses daily for 3 days, followed by conventional oral prednisone. Outcomes. The following outcome indexes were recorded: maximal visual acuity recovery, duration of clinical follow-up, further episodes of ON or other demyelinating events, and subsequent diagnosis of MS or NMO. To evaluate the outcome, visual acuity for each measure was defined using ONTT criteria published previously[1]. Statistical methods. Binary and multinomial logistic regressions were used to filter the possible factors related to the outcome of vision. Visual acuities were analyzed using Linear-by-Linear Association Chi-Square Tests. Results: General features Table 1 lists gender, age distribution, history of the similar onset and the eye involvement of this group of patients. Clinical features Clinical features including visual acuity, pupillary reaction, fundoscopy examination, visual field, VEPs and MRI results are showed in Table 2. All the patients were diagnosed with acute optic neuritis within two weeks from occurrence of visual symptoms. A few of them had exact history of infection of upper respiratory tract and no patient had any obvious systemic neurologic symptoms when first diagnosed as acute ON. Laboratory findings Hormone levels, Immunoserological findings and specific NMO/MS laboratory indicators at presentation are 2 summarized in Table 3. Oligoclonal banding (OCB) was positive in CSF of 5 patients. CSF OCB was negative in all patients with possible NMO diagnosis, but 2 of these patients had increased CSF cell counting. Blood-brain barrier damage was found in 7 patients. Serum NMO-IgG was tested in 24 patients, among which 6 were positive (3) or probable positive (3) for the test. Outcomes Towards the end of this study, 3 of the 50 patients (6%) were diagnosed to have MS, and 2 (4%) NMO. In the affected eyes, the probability of having better acuity at last visit was lower when the baseline acuity was more severely affected (P<0.001). This was particularly true when the baseline acuity was counting fingers or worse (Table 4&5). Logistic Regression showed that among gender, age at onset, worst visual acuity at onset, hormone level, anti “O”, ANA, OCB,NMO indicators, only severe reduction of visual acuity at onset had a significant correlation with the final outcome of vision(P<0.05). Discussion: In this study, the distribution of the age and gender of patients were similar to those reported on a group of ONTT patients previously[2]. Most patients were young and middle-aged, children and elderly people over age of 60 were rare. Female patients had a higher incidence of optic neuritis than male ones, but mostly in unilateral ON than in bilateral ON. Study[3] showed that, the western population were more likely to have unilateral ON, while patients with bilateral ON in our study accounted for a higher percentage, suggesting that Asian and Western populations had a different pattern of involvement of eyes in ON patients. Vision defect of this group of patients were severer compared to previous reports on patients from western countries[1], visual acuity worse than CF accounted for nearly half (46.6%) of the VA among these patients. Study shows that the severe reduction of visual acuity at onset is the main factor that may affect the final outcome of vision in ON patients particularly when the acuity worse than counting fingers. This may prompt that the more serious optic nerve was involved at ON onset, the worse final visual acuity would be. Most patients had various degrees of pupillary defects, and the percentage of papilledema was similar to previous reports [4, 5]. Decreased P100 wave amplitude more common than prolonged P100 wave latency in VEP performance may be due to the poor visual acuity. Acute optic neuritis associated with demyelinating diseases are the most common causes of inflammation of the optic nerve in western countries. The classification of the idiopathic inflammatory demyelinating diseases of the central nervous system remains confusing[6]. Neuromyelitis optica has recently been recognized as distinct from prototypic multiple sclerosis, but the differences are not fully understood, especially at first presentation with isolated optic neuritis[7]. The discovery of the neuromyelitis optica (NMO) antibody(Anti-aquaporin-4 antibody) first described in 2004[8] helped us to classify some cases of optic neuritis as different subtype of relapsing-remitting demyelinating disease, and might be helpful in predict the outcome of ON patients. The Optic Neuritis Treatment Trial (ONTT) demonstrated that patients with characteristic inflammatory lesions within the brain on MRI had a greater chance of developing clinically definite MS (CDMS). In our study, 3/4 patients with white matter lesions around lateral peri-prone semi-oval centers finally met the diagnostic criteria of MS, and both patients with multiple grey and white matter lesions in brain and spinal cord were diagnosed to have NMO. Although MRI abnormal rate was not very high in our study, which may due to the low incidence of demyelinating diseases, it still suggests that a routine MRI scan is needed in ON patients. Higher prevalence of ON among females suggests that hormones may play a role in the disease. Prolactin level was elevated in 27.1% (13/48) patients including two female patients during lactation. Testosterone levels were declined in more than half of the males(10/18). Combined the gender distribution of patients, this may suggest 3 that increasing of prolactin or declining of testosterone may be the predisposing factors of ON, Which met the similar conclusion to other researches regarding the hormones in optic neuritis[9, 10]. Although hormones may be related to the onset of ON, results from the present study suggest that they are not likely to affect the final vision outcome statistically. Studies suggest that vasculitis may be associated with NMO [7, 11]. Immune globulin, IgM deposition, complement cascade activation and eosinophilic infiltration can be found around the vessels in some early stage of demyelination disease. Our study shows that ON patients are more likely to be abnormal with anti-streptolysin O and ANA tests. However, these metrics may not affect the prognosis of ON. CSF abnormalities were common in severe ON patients, blood-brain barrier damage and elevated protein level prompt the presence of inflammation, and OCB was found in 5 patients including 3 MS patients. Patients who were suggested to be NMO were all negative in OCB, consistent with previous report that OCB may have a high sensitivity in MS patients, while a low rate in NMO patients[12]. CSF parameter in NMO patients would change with the pathogenesis of the disease, mainly be an increased counting of cerebrospinal fluid cells[13, 14]. Three cases of increased CSF cell counting were identified, two of them combined with positive blood NMO-IgG test and one defined to be NMO. As positive OCB test was significant related to the probability of developing to MS [15-17], lumbar puncture and CSF test should be considered for patients who have serious symptoms, atypical or have unusual MRI signs in order to help predicting their prognosis. As NMO might essentially be an anti-AQP4 antibody associated disorder[18] and loss of AQP4 may play an important role in the pathogenesis of NMO[19], NMO-IgG test was performed in many NMO patients. However, NMO-IgG detection has a high specificity (> 90%) and lower sensitivity (58-73%) in NMO patients[8, 20-22]. Our study showed a positive rate at 25%(including positive and probable positive) in ON patients which was similar to the report from Lennon et al[23], that 20% of patients with recurrent ON were seropositive for NMO antibodies. Whether serum NMO-IgG could be a predictor to the prognosis of NMO still need further research to confirm, study[23]suggest that NMO-IgG positive patients may had a poorer visual outcome and development of NMO in recurrent ON. Although the significant relationship between NMO antibody and the final visual acuity was not found in our study, the patients still has a trend to have either a bad vision or a recurrent event. Further studies with comparison, larger sample size, multi-center are still needed to get a more comprehensive impression of optic neuritis. 4 References: 1. Visual function more than 10 years after optic neuritis: Experience of the Optic Neuritis Treatment Trial. American Journal of Ophthalmology 2004;137(1):77-83. 2. The clinical profile of optic neuritis. Experience of the Optic Neuritis Treatment Trial.Optic Neuritis Study Group. Arch Ophthalmol 1991;109(12):1673-8. 3. de la Cruz J, Kupersmith MJ. Clinical profile of simultaneous bilateral optic neuritis in adults. British Journal of Ophthalmology 2006;90(5):551-4. 4. Hutchinson WM. Acute Optic Neuritis and Prognosis for Multiple-Sclerosis. J Neurol Neurosurg Psychiatry 1976;39(3):283-9. 5. Nikoskelainen E. Symptoms, Signs and Early Course of Optic Neuritis. Acta Ophthalmologica 1975;53(2):254-72. 6. Weinshenker BG, Miller D. MS: One disease or many? . Frontiers in multiple sclerosis 1999:37–46. 7. Weinshenker BG. Neuromyelitis optica: what it is and what it might be. Lancet 2003;361(9361):889-90. 8. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364(9451):2106-12. 9. Foster SC, Daniels C, Bourdette DN, Bebo BF. Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroimmunol 2003;140(1-2):78-87. 10. Darlington C. Multiple sclerosis and gender. Curr Opin Investig Drugs 2002;3(6):911-4. 11. Gold R, Linington C. Devic's disease: bridging the gap between laboratory and clinic. Brain 2002;125:1425-7. 12. Bergamaschi R, Tonietti S, Franciotta D, Candeloro E, Tavazzi E, Piccolo G, Romani A. Oligoclonal bands in Devic's neuromyelitis optica and multiple sclerosis: differences in repeated cerebrospinal fluid examinations. Mult Scler 2004;10(1):2-4. 13. Milano E, Di Sapio A, Malucchi S, Capobianco M, Bottero R, Sala A, Gilli F, Bertolotto A. Neuromyelitis optica: importance of cerebrospinal fluid examination during relapse. Neurol Sci 2003;24(3):130-3. 14. Zaffaroni M. Cerebrospinal fluid findings in Devic's neuromyelitis optica. Neurol Sci 2004;25:S368-S70. 15. Soderstrom M, Ya-Ping J, Hillert J, Link H. Optic neuritis - Prognosis for multiple sclerosis from MRI, CSF, and HLA findings. Neurology 1998;50(3):708-14. 16. Cole SR, Beck RW, Moke PS, Kaufman DI, Tourtellotte WW. The predictive value of CSF oligoclonal banding for MS 5 years after optic neuritis. Neurology 1998;51(3):885-7. 17. Tumani H, Tourtellotte WW, Peter JB, Felgenhauer K. Acute optic neuritis: combined immunological markers and magnetic resonance imaging predict subsequent development of multiple sclerosis. J Neurol Sci 1998;155(1):44-9. 18. Takahashi T, Fujihara K, Nakashima I, et al. Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 2007;130:1235-43. 19. Misu T, Fujihara K, Kakita A, et al. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 2007;130:1224-34. 20. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66(10):1485-9. 21. Takahashi T, Fujihara K, Nakashima I, et al. Establisbment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica. Tohoku J Exp Med 2006;210(4):307-13. 22. Jarius S, Franciotta D, Bergamaschi R, Wright H, Littleton E, Palace J, Hohlfeld R, Vincent A. NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007;68(13):1076-7. 23. Matiello M, Lennon VA, Jacob A, Pittock SJ, Lucchinetti CF, Wingerchuk DM, Weinshenker BG. NMO-IgG 5 predicts the outcome of recurrent optic neuritis. Neurology 2008;70(23):2197-200. 6 Table1:General features of ON patients No. Per% No. of patients 50 100% Total affected eyes 69 100% Female 32 64.0% Male 18 36.0% F/M Ratio 1.78 Gender Age at ON onset(year) Mean 35.3 Range 15 to 56 History of ON Yes 11 22.0% No 39 78.0% 31 62.0% Eye involvement Unilateral Female 24 Male 7 F/M Ratio 3.43 Bilateral 19 Female 8 Male 11 F/M Ratio 0.73 38.0% 7 Table2:Clinical features of ON patients No. Per% Visual acuity at onset (worst documented) >20/40 2 2.9% <20/40 to >20/200 17 24.6% <20/200 to >CF 18 26.1% 32 46.4% 30 60% RAPD present 18 36.0% No react to light 12 24.0% 50 100% 20 40.0% 4 8.0% Disc pallor 5 10.0% Normal 25 50.0% 58 100% Nerve fiber bundle abnormalities 20 34.5% Central abnormalities 23 39.7% Severe abnormalities 15 25.9% 42 100% 15 35.7% decreased P100 wave amplitude 25 59.5% prolonged P100 wave latency 16 38.1% 6 20.7% white matter lesions around lateral peri-prone semi-oval centers 4 13.8% multiple grey and white matter lesions in brain and spinal cord 2 6.9% CF to NLP Pupillary reaction Fundoscopy Disc edema Disc edema with bleeding Visual fields (n=58) VEPs(n=42) No significant P waveform MRI(n=29) 8 Table3:Laboratory investigations of ON patients No. Per% No. of patients 50 100 % Hormone levels (n=48) 26 54.2% prolactin 13 27.1% testosterone 10 20.8% estradiol 7 14.6% dehydroepiandrosterone 0 0% progesterone 0 0% 12 25% C-reactive protein 2 4.2% rheumatoid factor 0 0% anti-streptolysin O 10 20.8% Immune parameters(n=48) 20 41.7% antinuclear antibody 20 41.7% Extractable nucler antigen 1 2.1% 1 2.1% 0 0% Normal 18 75.0% probable positive 3 12.5% positive 3 12.5% Normal 5 31.3% Elevated protein level 4 25.0% Oligoclonal Banding (OCB) 5 31.3% Increased CSF cell counting 3 18.8% Blood-brain barrier damage 7 43.8% Rheumatoidindicators(n=48) anti-double antibody strand anti-neutrophil antibody DNA granules NMO-IgG(n=24) CSF(n=16) 9 Table4:Outcomes of ON patients No. Per% 50 100% MS 3 6.0% NMO 2 4.0% <20/400 5 7.2% >=20/400 to <20/200 5 7.2% >=20/200 to <20/100 17 24.6% >=20/100 to <20/40 5 7.2% >=20/40 to <20/25 11 15.9% >=20/25 to <20/20 8 11.6% >=20/20 18 26.1% Clinical outcome. visual acuity at las visit (n=69) 10 Table5:Visual Acuity in the Affected Eye According to Visual Acuity at Onset Visual Acuity at Onset Visual Acuity at <20/20 to >20/40 <20/40 to >20/200 <20/200 to >CF CF to NLP Total last visit (n =2) (n =17) (n =18) (n=32) (n=69) Total 100% 100% 100% 100% 100% >=20/400 100% 100% 94% 88% 93% >=20/200 100% 100% 83% 78% 86% >=20/100 100% 94% 56% 44% 61% >=20/40 100% 88% 56% 31% 54% >=20/25 100% 59% 28% 28% 38% >=20/20 50% 47% 11% 22% 26%