Introduction

Optic neuritis(ON) is related to multiple sclero  sis¹.Most  multiple  sclerosis-related  optic  neuritis (MS-ON) is idiopathic. ON should be differentially diagnosed  from  alternative  diseases. Meantime, ON is regarded as initial symptom of multiple sclerosis, neuromyelitis  optica(NMO),and  acute  disseminated   encephalomyelitis(ADEM),which   significantly differ in terms of treatment and prognosis².Wingerchuk's et al. found that AQP-4 could be used as specific antibodies in the diagnosis of NMO via AQP4 antibody.NMO spectrum disorder(NMOSD)has been further understood,and recurrent optic neuritis and binocular optic neuritis belong to the NMOSD³ .

ON results from ocular infection and the causes of ON infection include syphilis⁴, AIDS⁵ and Lyme disease⁶. ON is also related to systemic immune diseases such as Sjogren's syndrome⁷, systemic lupus erythematosus⁸, sarcoidosis⁹ and Behcet's disease.

Along with the development of ON,differential diagnosis between ON and other eye diseases have been far from satisfaction. ON could be classified into MS-ON, neuromyelitis optica-related neuritis (NMO-ON),infection-related ON and immune-related ON¹0. Treatment and prognosis of ON caused by different etiological factors significantly differ. Hence, early differential diagnosis plays a pivotal role in clinical practice. The purpose of this retrospective study is to determine the causes of MS-ON misdiagnosis. 

Materials and methods

Epidemiological data

Data were collected from 527 patients(123 males and 404 females)diagnosed MS-ON between June 2008 and June 2013 in the Department of Ophthalmology,PLA  General  Hospital.All  patients  were first  diagnosed  with  ON. Patients  presenting  with systemic symptoms were excluded from this study. 

AQP4 antibody served as an antibody distinguishing idiopathic demyelinating optic neuritis(IDON)from NMO-ON.In this  study,ON  patients  with  positive AQP4 antibody were allocatedinto the NMO-ON group.

Neuro-ophthalmic examination

Routine ophthalmic examinations included visual acuity,optometry,visual field,slit-lamp microscopy,  and indirect ophthalmoscopy(20 D). All ophthalmic examinations  and  records  were  conducted  by the same associate chief ophthalmologist.MRI scanning was  performed  using   GE  3.0T, T2WI  TR  20003000ms,TE  80-100ms:T1WI  TR  300-400  ms,and TE 10-15 ms.The paramagnetic contrast agent GdDTPA(0.1 mm/Kg)was used to enhance the scan ning.Optical  coherence  tomography(OCT)exami nation  was  conducted  using  the  Cirrus  HD-OCT (Carl Zeiss Meditec Inc.Dublin,CA).Macular scan  ning was performed at 512×128 resolution and peripapillary nerve fiber layer thickness was measured at 200×200 resolution.

Autoimmune antibody test

Fasting serum extraction was performed to test rheumatoid immune antibody without glucocorticoid administration.Serum anti-AQP-4 antibody was tested by cytological detection. All subjects underwent serum sampling measurement for at least two times. The titer of detection was at least 1:100.All patients enrolled  in  this  study  were  followed  up  for>one year  in  the  Neuro-ophthalmology  Department  of PLA General Hospital.

Results

Etiology misdiagnosis

The highest rate of misdiagnosis for IDON was 25.49%, mainly misdiagnosed as Sjogren's syndromerelated optic neuritis(1765%). The second most com mon misdiagnosis was vascular lesion(15.03%),with the most important type being non-arteritic anterior ischemic   optic   neuropathy(NAION)(13.73%).Tumor lesions(22/14.38%)were  confirmed  as malig nant by biopsy,including 6 craniopharyngioma, 5 pituitary  adenoma, 2  metastases(Figure 3), 3 optic nerve glioma(Figure 4), 4 optic nerve sheath menin gioma(Figure 5), 1 inflammatory pseudotumor(Figure 6) and l lymphoma. Genetic testing confirmed 17 cases of hereditary disease including 15 Leber's hereditary optic atrophy(Figure 7), 2 autosomal dom inant optic atrophy,15 radiation optic neuropathy, 14 optic  neuropathy-related  infection,3  poisoning and malnutrition optic neuropathy and 20 other eye diseases.

Imaging findings

Orbital MRI scanning was conducted in 168 MSON  patients,and   159(94.64%)showed  high  signal on T2WI. In total, 100(59.52%) cases were found high signaling by Gad enhancement scanning, 0 (0%) in the  intraocular segment,166(98.81%) in the orbit, l in the tubula segment(0.60%) and l (0.60%)in the intracranial segment. The size of the  lesion was <15 mm in 90 cases(53.57%),15-30 mm in 76(45.24%)and  >30  mm  in  2(1.19%), as  illustrated in Figure l and Table 2.

Discussion

The pathogenesis and clinical features of MS-ON have been investigated by this single-center retrospective study.Most optic neuritis is classified based on the sites of pathological changes. In 2014, neuroophthalmologists  in  China began to  classify  optic neuritis based on the etiology,which was of significance in the prognosis and treatment of MS-ON.At present,few detailed studies focusing upon MS-ON have been performed.

It has been proposed that specific AQP4 antibody can be used in the diagnosis of NMO³.The studies focusing on AQP4 and its clinical significance further widen the classification of NMO.Patients with positive AQP4 antibody can be diagnosed as either NMO or NMO-ON.ON is also associated with infection and systemic immune diseases,so currentre searchers have concluded that the etiology of optic neuritis might be due to syphilis",AIDS⁵,and Lyme disease¹².In recent years,IDON diseases,such as Sjogren's syndrome³, systemic lupus erythematosus¹⁴,sarcoidosis⁹ and  Behcet's  disease⁹ have  captivated widespread attention.

In this study,118 patients initially diagnosed with MS-ON were positive for AQP-4 antibody and 40 of them had a prognosis of NMO.Compared to MSON,NMO-ON tends to affect bilaterally and recur. Hence,abnormal  autoimmune  antibodies  and  connective tissue diseases are easily misdiagnosed. AQP4 antibody is a highly specific biomarker for the diagnosis ofNMO¹⁵.Positive AQP-4 antibody reaction aids in the diagnosis of NMO and plays an important role in judging ON as the initial symptom of the isolated syndrome disease¹⁵.

NMO-ON should be mainly distinguished from MS-ON.Our study found that the complications of immune diseases should be emphasized and distinguished from MS-ON.Recent studies demonstrated that  Sjogren's  syndrome is associated with central nervous system diseases,especially MS and NMO¹.  NMO correlates with autoimmune diseases, especially Sjogren's syndrome, but rarely occurs in MS patients(0-3.3%)^7,18. In the NMO-ON group,20 patients suffered from autoimmune diseases,which is consistent with previous studies.

Tumor lesions are still the main cause of misdiag nosis.The rate of misdiagnosis was  14.38%, domi nantly as craniopharyngiomas and pituitary tumors. Imaging test is utilized in the diagnosis of ON,especially in identifying atypical ON.Currently,it  is widely accepted that IDON and multiple sclerosis share similar mechanism and pathological changes,  manifested as optic nerve inflammation and demyelination.Irreversible damages to optic nerve could oc cur during the recovery and remission of axonal in jury due to axon damage¹9. These pathological manifestations are characterized as increasing abnormal signals and optic nerve thickening on T2-weighted MRI image.SPIR-FLAIR is able to explicitly and accurately  locate  and  measure  the  length  of  optic nerve. Gd-DTPA contrast enhancement scanning can reflect the onset of acute ON 20, 21,whereas it tends to weaken or disappear in convalescence after corticos teroid use².

In this study,optic nerve enlargement was observed during acute stage of ON.Due to widespread application  of imaging tools,the misdiagnosis rate has increased in recent years,mainly because acute optic nerve diseases showed strengthened signals and thickened optic nerves.We therefore proposed that these differences could help in the early and differ ential diagnosis of MS-ON.The main manifestations of NMO are ON and acute myelitis².In this study,  we found that NMO-ON affected a large lesion of optic neuropathy could affect bilateral eyes,mainly involved with the whole orbital nerve in the posterior segment and significantly elevated after contrast en hancement.Pula et al.demonstrated that optic nerve thickening by>40 mm hinted the lineage diagnosis of NMO²⁴.However,MS-ON patients  in this  study were unilaterally affected presenting with small lesions that generally did not involve with the optic nerve of entire orbit.Early and accurate imaging di agnosis of neuromyelitis optica influences the treat ment and prognosis of MS-ON.

Previous studies suggested that gradual thinning of optic atrophy was detected in patients with hereditary diseases,such as Leber's hereditary optic neuropathy (LHON).However, recent research  found that  LHON patients showed high T2WI signal of long segment in both eyes during acute or sub-acute phas es,and displayed mild to moderate enhancement after strengthening^25,26. LHON is generally characterized as long lesions,occasionally involving with the optic  chiasm.These  changes  in  acute  or  sub-acute LHON are considered to be caused by damages to the blood brain barrier²⁷.It is of great importance to understand typical MRI manifestations of IDON.In this  study,the misdiagnosis  of ON was more  fre quently observed in patients with tubular lesions,   probably resulting from narrow space among tubular segments,optic nerve hyperemia and edema caused by compression during early stage.The lesions aggravating for>6 months should be potentially considered as a tumor.with the presence of long lesions involving with the optic nerve of entire orbit should be considered as an indication of NMO or LHON.

Ischemic injuries to the optic nerve are more common  in the  elderly population  compared with  the young counterparts².Ischemic optic neuropathy and ON share similar clinical symptoms²,which are difficult to distinguish. Differential diagnosis requires detailed inquiry of medical history, physical and ocular  examination and MRI scanning of the optic nerve.Other eye diseases show similar features to ON.For instance, open angle glaucoma is accompa nied by optic nerve atrophy and some hereditary eye diseases(Leber,Stargardt disease,etc.)are mani fested as defects in the central visual field.Decreased visual acuity caused by psychological factors should be distinguished from ON30,probably associated with the improvement in neuro-ophthalmic examinations.

The present study has several limitations.This is a single center study with a relatively  small  sample size and short follow-up.A multi-center prospective study with a large sample size remains to be conducted.

In conclusion,MS-ON is likely to be misdiagnosed as NMO-ON,followed by optic nerve damage caused by autoimmune diseases,malignant tumors and ischemic optic neuropathy.Early differential diagnosis of MS-ON  from  alternative  diseases  contributes to the treatment and prognosis of MS-ON.