Optic neuritis: Experience from a south Indian demyelinating disease registry
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.103186
Source of Support: None, Conflict of Interest: None
Background: Natural history of optic neuritis (OPN) has not been studied in India. Aim: To study consecutive patients with optic neuritis as the initial manifestation of the neurologic disease and with disease duration of 3 or more years registered in the Mangalore Demyelinating Disease Registry. Materials and Methods: The study included 59 patients with a primary diagnosis of optic neuritis (confirmed by either an ophthalmologist or a neurologist or both). All the patients were investigated and followed-up in the clinic. Results: During the follow-up of the 59 patients, 29 (49%) patients developed multiple sclerosis (MS); 3 (5%) patients neuromyelitis optica (NMO); and 13 (22%) patients chronic relapsing inflammatory optic neuritis (CRION), while the remaining 14 (24%) did not either progress or relapse, monophasic OPN. An initial abnormal magnetic resonance imaging predicted conversion to MS in all 7 patients who had imaging at onset. Patients with NMO were left with significant residual visual loss distinguishing NMO from MS. In this large series of patients with CRION, nearly 50% of patients had deterioration in vision while steroids were being tapered. Long-term immunosuppression was essential for maintaining good visual outcome in both NMO and CRION. Conclusions: Optic neuritis in India appears similar to that in the West with nearly 50% developing MS in the long term.
Keywords: Chronic recurrent idiopathic optic neuritis, demyelinating disorders, multiple sclerosis, neuromyelitis optica, optic neuritis
Inflammatory optic neuropathy is typically characterized clinically by acute-onset unilateral visual loss accompanied by pain and color desaturation. Although toxic and infective etiologies are likely the causes for optic neuropathy in the tropical settings, demyelinating optic neuritis (OPN) is not uncommon cause. When OPN recurs at intervals in time, the suspicion that it is part of an ongoing central nervous system (CNS) disorder becomes stronger. In western populations, north American and European origin, the most obvious CNS disorder with recurring OPN is multiple sclerosis (MS).  In the Indian setup, although MS is less prevalent, there is no reason to believe that the disease behaves differently from the West.  In the pre-magnetic resonance imaging (MRI) era, hospital-based studies in India have shown that OPN is the initial manifestation of MS in 22%-50% of patients.  Recent studies have shown a frequency of 23.6% from the northwest,  44% from the south of the country,  and 53.3%  from the east of the country. Optic neuritis may be the initial manifestation of neuromyelitisoptica (NMO). Recurrent OPN without CNS involvement has recently been categorized as chronic relapsing idiopathic optic neuritis (CRION).  There are no Indian studies evaluating the natural course of first attack of OPN. Similarly no studies have evaluated the predictive risk of initial MRI in these patients for conversion to MS. In India there are few guidelines for investigations or cost-effective strategies for management, especially when OPN recurs. 
All patients included in this study were from the Mangalore Demyelination Registry. This Registry was started in 2007 with a purpose to establish a database of CNS demyelinating disorders seen by neurologists in the coastal city of Mangalore in south India. Patients within a radius of 250 km were referred to Mangalore for specialist consultation and treatment. Patients registered in this Registry were categorized and were under long-term follow-up. From 2007 till date, 257 patients with CNS demyelinating disorders have been registered in the Mangalore Demyelination Registry. This study included 59 consecutive patients with OPN as the first presenting illness and with minimum disease duration of illness of 3 years. Of the 59 patients followed, 40 patients were followed-up from the day of onset of OPN and in 19 patients history revealed OPN as the initial presenting feature. Demographic and clinical data were recorded. Clinical details recorded included onset and progression, laterality, presence or absence of pain, and recovery pattern of vision. Investigations done included magnetic resonance imaging (MRI) at the presentation. Treatment modalities were also recorded. Only those patients whose symptoms were consistent with the diagnosis of OPN and those who had records that documented the same were included in the study. Time of evolution into MS, NMO or recurrent optic neuritis (ROPN) was noted. Visual acuity (VA) at last follow-up was documented using Snellen's chart. Patients who had NMO and recurrent optic neuritis (ROPN) were tested for neuromyelitis optica antibody (NMO-IgG). All patients had hemogram, peripheral smear, human immunodeficiency virus (HIV) test, VDRL, anti-nuclear antibody (ANA), anti-double stranded DNA antibody (DsDNA) and chest X-ray done. In patients with CRION and NMO during the course of illness, anti-Sjogren antibody, serum angiotensin-converting enzyme, and neuromyelitis immunoglobulin (NMO-IgG) were done additionally. Lumbar puncture was not performed routinely in patients with MS or NMO. Five patients with CRION agreed to undergo lumbar puncture. NMO-IgG testing was done at Mayo Clinic, USA (using a cell-based assay) for all 3 patients with NMO and 7 patients with ROPN. Six patients with ROPN were tested at Metropolis Laboratory, Mumbai (by indirect immunofluorescence technique).
Optic neuritis was defined by history of unilateral or bilateral visual loss of acute onset associated with at least 2 of the following criteria: color vision abnormality, pain on eye movement, afferent papillary defect, centrocecalscotoma, and abnormal visual-evoked response.  Other causes of acute visual loss, including toxic, metabolic, vascular, and infective causes were reasonably excluded. A diagnosis of OPN was confirmed by an ophthalmologist or neurologist at onset. Multiple sclerosis was diagnosed using the McDonald criteria  and NMO by the criteria proposed by Wingerchuck.  Chronic recurrent idiopathic OPN (CRION) was diagnosed in patients with recurrent OPN, steroid responsive/dependent and normal MRI brain and no evidence of systemic illness on long-term follow-up.  Severe visual loss was defined as visual loss of 20/200 or more in worst affected eye (recommendationsof WHO consultation on development of standards for characterization ofvision lossand visual functioning).
During the study period 59 patients were identified with optic neuritis as the initial presentation of neurologic disease. During the follow-up: 29 patients developed MS, 3 NMO, 13 CRION, and 14 did not progress further and remained as monophasic OPN.
Optic neuritis associated with multiple sclerosis
Since the start of Mangalore Demyelination Registry in 2007 there were 112 patients of MS. There were 29 (25.8%) patients (18 females and 11 females) with OPN as the first attack [Table 1]. The mean age at onset of first attack of MS-associated OPN was 31 ± 10.01 years. The mean duration of illness (MS) was 7.6 ± 5.5 years. The duration from onset of OPN to second clinical attack was 2.4 ± 1.6 years. In 9 (31%) patients the second attack was a recurrent attack of optic neuritis. In 11 (9.8%) patients clinical attacks were confined to the spinal cord and optic nerve during the course of illness. All patients with optic-spinal presentation had spinal cord lesions on MRI, which were <3 vertebral segments. All but one had unilateral OPN. In 19 patients it was painful. Only 7 patients underwent MRI during the first attack, although all had MRI done after the second attack. All 7 patients had one or more brain lesions consistent with demyelination. Twenty-two patients received oral steroids (20-40 mg/day) for 7-21 days and the remaining 5 received intravenous methyl prednisolone (1 g intravenously for 5 days). All patients who underwent MRI and received intravenous steroids had been seen at onset by neurologists. There was no significant difference in mean duration to second attack in those treated with oral (2.2 years) as compared with parenteral steroids (2.5 years). VA at last follow-up was 6/6 in 18 patients and moderately impaired in all but one patient [Table 1].
Optic neuritis associated with neuromyelitis optica
Of the 20 patients in the Mangalore Demyelination Registry who fulfilled the criteria  of NMO, 3 patients presented with optic neuritis as the initial manifestation. The mean age at onset was 30.4 ± 20.7 years and duration of follow-up was 4.7 ± 1.8 years. The mean duration to second attack was 4.6 ± 3.8 years. None of the NMO patients had MRI at the onset of first attack of optic neuritis.
A 44-year-old woman (Case 1) developed the first of several attacks of optic neuritis for which she had received oral steroids 9 years earlier. She recalled that her vision had only improved partially. Following a second attack of optic neuritis 3 years later she became blind in the right eye. Interspersed with attacks of myelitis she developed recurrent OPN in left eye, which left her with only light perception 8 years after the onset of NMO. Serum NMO-IgG was positive. She was not on long-term disease-modifying agents and remains quadriplegic and blind.
Chronic recurrent idiopathic optic neuritis
There were 13 patients, 7 females and 6 males, presenting with recurrent OPN. Age at onset was 30.5 ± 7.2 years, mean duration of follow-up was 5 ± 3.6 (3-13 years) years. During this period all patients had undergone contrast MRI of the brain more than once. Four patients had increased signal intensities of one or both optic nerves on T2-weighted and FLAIR sequences [Figure 1]. Tests for vasculitis and chronic infection were negative. Serum NMO-IgG was negative in 10 patients in whom it was tested and cerebrospinal fluid examination was unremarkable. Six patients [Table 2], each having 2 attacks responded to IV steroids given during the acute phase of illness and remained well without residual visual loss. Five patients developed steroid dependence. In these patients the initial improvement in vision was not sustained while tapering of steroids. They were restarted on 1 mg/kg/day prednisolone along with another nonsteroidal immunosuppressant, such as azathioprine (AZT) 2.5 mg/kg/day or mycophenolatemoftil 1.5- 2.5 gm/day in divided doses. Oral steroids were tapered off within the next 6 weeks to 3 months. Patients on AZT complained frequently of fatigue, aphthous ulcers, hair loss, and/or anorexia. Out of 7 patients treated with AZT, 3 stopped medications on their own due to the side effects. In one patient there was recurrence of OPN while on AZT and mycophenolatemoftil had to be substituted.
A 26-year-old woman (Case 2) developed painful visual loss in right eye 4 years ago. A diagnosis of OPN was made, contrast MRI of the brain was normal and she was given IV methylprednisolone (1 gm/day ×5) followed by a short course of oral prednisolone. She recovered vision completely at the end of first month of illness. Six months later she had another episode of OPN involving left eye. The steroid course was repeated, but while on tapering dose of oral steroids, her vision in left eye which had initially improved started deteriorating. Oral steroids were increased to 1 mg/kg and additionally AZT was added, a total dose of 2.5 mg/kg/day. A gradual taper of steroids was attempted after 2 months when her symptoms relapsed. Repeat contrast MRI of the brain showed nonenhancing increased signals in the optic nerves, but normal brain parenchyma [Figure 1]. AZT was replaced by mycophenolatemoftil 1.5 gm/day in divided doses and steroids were tapered off in the next 6 weeks. The patient has remained well since then.
Isolated optic neuritis
Fourteen patients (7 males and 7 females) had isolated optic neuritis, 10 were unilateral and 4 bilateral. The mean age at onset was 35.9 ± 9.8 years. Two patients with bilateral OPN of monophasic course had significant residual visual loss in worst affected eye (both of whom tested negative for NMO-IgG). Three patients had concomitant diabetes at the time of clinical diagnosis. Ten patients had received intravenous methyl prednisolone, whereas 4 had oral steroids (ranging from initial dose of 20-40 mg/day in tapering doses for 2-3 weeks). The mean follow-up period was 3.7 ± 0.7 years. Initial contrast MRI of the brain was normal in all patients.
This study of 59 patients registered in the Mangalore Demyelination Registry evaluated for the first time the natural course of OPN in India. Unilateral OPN was much more common than bilateral. In this series, 49% of patients evolved into MS during follow-up. Patients who developed MS after the first attack of OPN did so within 5 years of disease onset. In our study not all the patients of OPN were not followed-up from the onset. Observations from the optic neuritis treatment trial (ONTT) suggest that the cumulative risk of MS after the first attack of OPN was 50%, the risk being highest in the first 5 years.  The results of our small series were similar. An abnormal MRI at the onset of OPN predicted conversion to MS in all the patients in whom MRI showed white matter lesions. The ONTT results have shown the predictive value of the initial MRI.A normal MRI at onset was associated with <25% MS, presence of a single lesion doubled the 15-year risk to 50%, whereas 3 or more lesions caused a 3-fold increase in the risk to 78%.
The severity of residual visual loss after an attack of OPN is important in determining further investigations and management. The hall mark of NMO is significant residual disability, although occasionally benign forms are seen. More than 60% of patients report significant vision loss in at least one eye.  In 2 of our NMO patients visual loss was significant after the first attack unlike in MS patients. Another condition associated with severe visual loss is ROPN associated with neuromyelitis spectrum disorders.  In the series from western countries 20% of ROPN are NMO-IgG seropositve with VA in the worst affected eye less than 20/200.  Chronic relapsing inflammatory optic neuritis is an important differential diagnosis for ROPN and this condition is under-reported in India.  This form of OPN is idiopathic, steroid responsive, and often shows predilection for steroid dependence.  Long-term immunosuppression is essential for preventing recurrences and maintaining a good visual outcome. None of our patients were seropositive for NMO-IgG. Severe visual loss has been reported with CRION when long-term immunosuppression was not maintained  as was the case in 2 of our patients. It is also possible that some patients with CRION requiring chronic immunosuppression may have been cases of seronegative NMO. 
The standard of care in acute phase of OPN is undoubtedly intravenous methylprednisolone. , In situations where there is steroid dependence for preserving vision as is often the case for patients with CRION and NMO, oral steroids especially prednisolone has a role in chronic immunosuppression. , Although the role of nonsteroidal immunosuppressants have not been explored in the large controlled studies, drugs such as AZT and mycophenolate moftil have been safely used as alternatives to chronic steroid therapy in NMO. , We have used myocophenolate moftil with very good results in CRION, especially when patients relapsed on AZT, so much so currently if the patient can afford mycophenolate moftil, we use the drugs as our first choice for chronic immunosuppression for OPN related to both CRION and NMO.
Based on our own experience we recommend a cost-effective approach to investigate and treat OPN [Figure 2]. Although a contrast MRI of the brain is absolutely essential, we do not recommend NMO-IgG testing routinely. The conditions in which we recommend NMO-IgG testing are (1) if there is severe residual visual loss (VA < 20/200) at 6 weeks; (2) recurrent OPN; and (3) an attack of myelitis associated with long segment lesion on MRI (defined as demyelinating spinal cord lesion extending ≥3 vertebral segments  ). We recommend NMO-IgG testing during the acute phase of illness, prior to administering of steroids. Reducing hospital visits are very cost effective for Indian patients. In our setup, patients should attend hospital only once after discharge for a 6-week follow-up and repeat VA testing. Subsequently, patients are subjected to review by telephone or through the post. Trained clinical assistants (nonmedical personnel who are science graduates) do the follow-up every 6 months. In our experience such an approach builds a rapport with the patient who is encouraged to call if he/she has any new complaints even earlier to the scheduled follow-up date. The choice of immunosuppressant is determined by cost and compliance of the patient. We generally use oral steroids for periods between 6 weeks and 3 months and also AZT or mycophenolate moftil following which steroids are tapered and stopped. Immuno suppressants are continued for an indefinite period of time under monitored conditions.
Long-term follow-up of patients in our Registry have enabled us to observe the natural history of OPN. Our study shows that the course of OPN is similar in India as it is in the West with nearly 50% of patients developing MS within 5 years of onset. Unless neurologists work in close partnership with ophthalmologists in their practice this vital link between the benign disease of isolated OPN and chronic inflammatory CNS disorders, such as MS and NMO, will be missed. Valuable time is lost and often irreversible neurologic dysfunction will set in before diagnosis is made.
This study was funded by the Indian Council of Medical Research. We are indebted to the following Ophthalmologists-Ashutosh Bolar, Govind Raj Bhat, Maya Natarajan, Manjunath Kamath, Shashikala Rao, RN Sujeer, and UR Shenoy.
[Figure 1], [Figure 2]
[Table 1], [Table 2]