Clinical Prognosis Of Optic Neuritis And The Effect Of IGF-1 On Its Remyelination

Objectives:1) According to serum AQP-4 antibody status, to investigate the frequency of different type of ON, clinical features and analyze the risk factors of clinical prognosis in Chinese patients. 2) To detect the serum and CSF levels of insulin-like growth factor 1(IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3), andanalyze the correction of these factors and visual recovery, as to supply experimental evidence of prognosis and mechanism in remyelination.3) To establish the rat model of experimental autoimmune encephalomyelitis and to observe expression of the IGF1 in optic nerve, brain and spinal cord,as to supply the foundation for pathogenesis and therapies of ON.Methods:1) This study retrospectively analyzed medical records in a cohort of Chinese patients with 5-year follow up according to AQP4-Ab status from January 2009 to December 2010 in the ophthalmology department of the Chinese People's Army General Hospital (PLAGH). The frequency of AQP4-Ab, clinical features and risk factors for prognosis were analyzed.2) A part of hospitalized patients with acute ON attack were collected from January 2015 to September 2016 in the ophthalmology department of the Chinese PLA General Hospital.Serum and CSF samples of patients were analyzed for the concentration of IGF-1 and IGFBP-3 by enzyme linked immunesorbent assay (ELISA), to calculator the ratio of IGF-1 to IGFBP-3 to evaluate the availability of IGF-1.The correlation analysis was made for these factors and visual recovery.3) The rats were given spinal cord homogenate mixed with CFA in subcutaneous injection by tail and pertussis toxin in intraperitonealinjection to establish the EAE model and made motor function score. The dynamic expression of IGF-1 in optic nerve, brain and spinal cord was investigated in EAE Lewis rats.Results:1) A total of 128 ON patients were included. Serum AQP4-Ab was positive in 45 (35.2 %)patients, with greater frequency in the female, bilateral, and recurrent ON groups (48.2,42.5 and 53.6 %, respectively). Seropositive AQP4-Ab ON patients had worse visual recovery at first ON attack and 5-year follow-up compared to seronegative patients (p =0.033 and p < 0. 001). At 5-year follow-up, the ON recurrence rate was higher in the seropositive AQP4-Ab patients (37/ 45, 82.3 %) than in the seronegative patients (35/83,42.2 %, p < 0. 001). Among the seropositive patients, 40 % (18/45) patients developed neuromyelitisoptica (NMO). Only1.2 % (1/83) of the seronegative patients developed NMO and 4.8 % (4/83) developed to MS. Further, the multi-variate analysis in seropositive AQP4-Ab patients showed that two risk factors for transverse myelitis (TM) episode were ocular pain and recurrence within 1 year.2) In AQP-4 antibody seropositive ON patients, there were same levels of the concentration of IGF-1 and IGFBP-3, and the ratio of IGF-1:IGFBP3 in serum and CSF compared to control group. In AQP-4 antibody seronegative ON patients, lower IGF-1 levelsand ratio of IGF-1 :IGFBP-3 in the serum and CSF were found compared to control and AQP4-Abseropositive groups. A increased IGFBP-3 levels was found in CSF compared to other two groups. We could make conclude that the availability of IGF-1 decreased in serum and CSF of AQP4-Ab seronegative ON patients. The CSF IGF-1 level and IGF-1: IGFBP-3 had positive correlation with visual recovery in AQP4-Ab seronegative group. Patients with a higher CSF level of IGF-lorhigher IGF-1 :IGFBP-3 usually had a good visual recovery in seronegative group.3) We established an EAE model in Lewis ratsfollowing subcutaneous injection of spinal cord homogenate. Behavioral observations showed impaired motor function in the rats on the days of 11 post-immunization. We observed that the time of onset were from day 11 to 13 post immunization, the peak of onset were from day 13 to 15 post immunization and the recovery phase were from day 16 to 21. The decreased expression of MBP, myelin sheath damage, arising fracture and white blood cells in filtration in lesions were observed in optic nerve, brain and spinal cord by immunofluorescent staining. The expressionof IGF-1 an IGF-1Rinoptic nerve, brainandspinal tissue decreased.Conculsion:1) This study confirmed the higher frequency of AQP4-Ab and rate of converting to NMO in Chinese ON patients. Two risk factors of TM episode were ocular pain and recurrence within 1 year in AQP4-Ab seropositive ON patients. Serum AQP4-Ab can be a predictor of poor visual recovery and the prognosis of NMO.2) Patients with a higher CSF level of IGF-lor higher IGF-1 :IGFBP3 had a good visual recovery in AQP-4 anbody seronegative ON group. IGF-1 may act a protective role in promoting remyelination in optic nerve demyelinating diseases.3) EAE model was successful induced by injecting subcutaneously spinal cord homogenate to Lewis rats. The decreased expression of IGF-1 was further confirmed by histopathology.This model can be applied to investigate the role of IGF-1 in ON pathology and to test novel therapeutics for ON.