Woman reports pain with eye movement, sudden vision loss
The patient previously presented with similar symptoms in her other eye, leading to a diagnosis of multiple sclerosis.
A 34-year-old woman with a history of multiple sclerosis and prior optic neuritis in the right eye presented to the neuro-ophthalmology clinic with 3 days of pain with eye movement and mildly decreased vision in the left eye. She reported fatigue and numbness in her hands with exposure to heat, but review of systems was otherwise negative.
The patient had been diagnosed with MS 1 year previously after presenting with similar symptoms in the right eye. Her exam at that time was notable for a right-sided afferent pupillary defect, decreased visual acuity to 20/25, decreased color vision and temporal optic nerve hyperemia. MRI of the brain revealed right retrobulbar optic nerve enhancement, consistent with optic neuritis, and scattered small white matter changes in the supratentorial region near the corpus callosum, suggestive of demyelinating disease. MRI of the spinal cord was normal. She was diagnosed with optic neuritis secondary to MS, and no treatment was initiated.
However, on follow-up exam 2 days later, the patient’s visual acuity had declined precipitously to light perception in the right eye. Given the severity of the vision loss, the patient was admitted to the hospital for a course of IV steroids, followed by 2 weeks of 60 mg of oral prednisone and slow prednisone taper. Over the next 2 months, the patient’s eye pain subsided and visual acuity slowly recovered to 20/30, and she remained asymptomatic until time of presentation.
Visual acuity was 20/25 in the right eye and 20/40 in the left eye. Ishihara color plates were 5/10 and 3/10, respectively. Pupils were reactive bilaterally, but with a new afferent defect in the left eye. External examination and IOPs were within normal limits. On slit lamp biomicroscopy, the anterior segment was unremarkable. The right optic nerve had stable temporal pallor, and the left optic nerve had new mild pallor (Figure 1). The remainder of the fundus exam was unremarkable. MRI of the brain and orbits with and without gadolinium showed new mild edema and contrast enhancement of the left retrobulbar optic nerve and stable white matter lesions within the brain (Figure 2). Two days after presentation, the patient’s visual acuity declined precipitously in the right eye to the level of light perception. OCT of the optic nerves showed severe retinal nerve fiber layer (RNFL) thinning in both eyes (Figure 3), as well as thinning on ganglion cell layer (GCL) analysis (Figure 4).
What is your diagnosis?
Pain with eye movement, decreased vision
Pain with eye movement, decreased color vision and afferent pupillary defect in the setting of optic nerve enhancement on MRI are consistent with optic neuritis (ON). The differential for ON is broad and includes demyelinating (MS, neuromyelitis optica), inflammatory (granulomatosis with polyangiitis, sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus) and infectious (Lyme, tuberculosis, Bartonella, herpetic) causes.
The severity and rapidity of the vision loss, which is atypical for MS, is consistent with the diagnosis of neuromyelitis optica (NMO). The patient was admitted to the hospital, and a laboratory work-up including AQP4 antibody (for NMO), ACE, RPR, Lyme antibodies, ANA, ANCA and lumbar puncture with CSF analysis was performed. Even though the patient was AQP4 negative in the serum and CSF, she was treated with a 5-day course of intravenous methylprednisolone on the clinical suspicion of NMO. The patient had improvement of symptoms while hospitalized, and she was discharged home on 60 mg of oral prednisone that was slowly tapered.
NMO, also known as Devic’s disease, is a rare inflammatory central nervous system disorder (incidence of 0.05 to 0.40 per 100,000) that primarily targets the optic nerves and spinal cord, causing severe debilitation. In his 1894 seminal report, “de Neuromyélite Optique Aiguë,” Eugene Devic first described 16 patients with a monophasic illness involving simultaneous bilateral optic neuritis and transverse myelitis without any brain involvement. While he noted similarities between NMO and MS, Devic initially postulated that NMO represented a separate entity. However, prevailing wisdom became that NMO and MS shared the same pathologic mechanism and that NMO was merely a subtype of MS, unique only in the acuity, severity and topography of its presentation. As more cases were reported over the next century, clinicians expanded upon Devic’s initial conception of the disease, recognizing that ON in NMO may be unilateral rather than bilateral, attacks may recur, and ON and transverse myelitis may be sequential rather than simultaneous.
In 2004, however, the discovery of a disease specific antibody against water channel aquaporin-4 (AQP4 IgG) solidified NMO’s status as a mechanistically distinct entity. While both MS and NMO are demyelinating diseases, the exact mechanism of demyelination in MS remains elusive, while NMO is now known to proceed via AQP4-mediated autoimmune targeting of astrocytes. The target antigen, AQP4, is a cell membrane protein expressed on the astrocytic end-feet forming the blood-brain barrier. Subsequent activation of the classic complement and the antibody dependent cell-mediated pathways lead to astrocyte injury and resultant demyelination. With current diagnostic assays, AQP4 IgG in the serum is found to be positive in 70% to 90% of patients with NMO, with a specificity of 97% to 99%.
It is now understood that NMO follows a relapsing course in 90% of patients, while only 10% experience the monophasic course. Relapses tend to occur quickly, in the range of 5 months to 12 months, although they have been documented after as much as a decade. Simultaneous ON and transverse myelitis occur in only 10% of cases. Classically, involvement of the brain is far less typical in NMO than in MS; however, when it does occur, NMO shows a propensity to the dorsal brainstem and hypothalamus, specifically, the circumventricular organs, leading to intractable nausea and vomiting (area postrema syndrome), and the diencephalon, leading to sleep disorders such as narcolepsy, endocrinopathies and syndrome of inappropriate antidiuretic hormone secretion.
Early recognition of features atypical for MS-related ON and more suggestive of NMO is critical in ensuring patient outcomes. As opposed to the progressive disease course in MS in which neurological deterioration progresses unrelated to acute attacks, disability in patients with NMO accumulates during each successive attack and can be attenuated with early intervention. These features include ON with severe vision loss, poor or delayed visual recovery, simultaneous or rapidly sequential bilateral ON, chiasmal lesions, and severe RNFL and GCL loss on OCT.
As yet, NMO is not a curable condition; rather, treatment focuses on attaining rapid remission to minimize debility from an acute attack and preventing relapse once remission is achieved. Treatment of acute NMO attacks consists of prompt administration of 5 days of 1 g/day of methylprednisolone. If there is no improvement or symptoms worsen, five to seven cycles of therapeutic plasma exchange (PLEX) have been shown to be effective in both seropositive and seronegative patients. Small recent studies suggest that in NMO patients who fail steroids plus PLEX, IVIG may be helpful in acute exacerbations. As for long-term maintenance therapy, expert opinion, retrospective analyses and prospective studies focus on several agents: azathioprine, rituximab and cyclophosphamide as first-line agents and methotrexate, mycophenolate mofetil and mitoxantrone as second-line treatments. Anti-IL-6 receptor, anti-complement or anti-AQP4-Ab biologicals are emerging as possible future therapies.
Two weeks after discharge, the patient had a sudden decline in vision in the left eye to hand motions, accompanied by unremitting eye pain. She was readmitted to the hospital and underwent multiple sessions of plasmapheresis. No improvement in vision or symptoms was noted. Subsequently, the patient received multiple doses of IVIG with mild diminution in eye pain and improvement of vision to count fingers. After discharge, the patient slowly regained vision and pain symptoms subsided, and she was found to have improved to 20/40 at follow-up 2 weeks after discharge.
Ultimately, the diagnosis of NMO remains unconfirmed without further core clinical characteristics or a positive AQP4 antibody. Based on the patient’s presentation of severe vision loss associated with optic neuritis, severe RNFL and GCL thinning, and MRI with minimal demyelinating lesions, there a is strong clinical suspicion for NMO despite her being seronegative. The decision was made to switch her from Copaxone (glatiramer acetate, Teva) to Rituxan (rituximab, Genentech) for greater neuroprotection, with close monitoring for any signs of recurrent events.
- Awad A, et al. Curr Neuropharmacol. 2011;doi:10.2174/157015911796557948.
- Devic E. Congrès français de médecine (Premiere Session; Lyon, 1894; procès-verbaux, mémoires et discussions; publiés par M. le Dr L. Bard) Paris: Lyon: Asselin et Houzeau, Louis Savy; 1895. Myélite aiguë dorso-lombaire avec névrite optique. - Autopsie; 434-439.
- Elsone L, et al. Mult Scler. 2014;doi:10.1177/1352458513495938.
- Gault F. De la neuromyélite optique aiguë. Thèse: Faculté de Médecine et de Pharmacie. 1894.
- Jarius S, et al. J Neuroinflammation. 2013;doi:10.1186/1742-2094-10-8.
- Kessler RA, et al. Curr Treat Options Neurol. 2016;doi:10.1007/s11940-015-0387-9.
- Kimbrough DJ, et al. Mult Scler Relat Disord. 2012;doi:10.1016/j.msard.2012.06.002.
- Kleiter I, et al. Neurotherapeutics. 2016;doi:10.1007/s13311-015-0400-8.
- Lennon VA, et al. Lancet. 2004;doi.org/10.1016/S0140-6736(04)17551-X.
- Optic Neuritis Study Group. Arch Ophthalmol. 1991;doi:10.1001/archopht.1991.01080120057025.
- Palace J, et al. Arch Neurol. 2010;doi:10.1001/archneurol.2010.188.
- Pittock SJ, et al. Ann NY Acad Sci. 2015;doi:10.1111/nyas.12794.
- Trebst C, et al. J Neurol. 2014;doi:10.1007/s00415-013-7169-7.
- Vodopivec I, et al. Curr Opin Ophthalmol. 2015;doi:10.1097/ICU.0000000000000202.
- Voss E, et al. Ther Adv Neurol Disord. 2011;doi:10.1177/1756285611398702.
- Wingerchuk DM, et al. Neurology. 2015;doi:10.1212/WNL.0000000000001729.
- For more information:
- Astrid Werner, MD, and Geetha Athappilly, MD, can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston, MA 02111; website: www.neec.com.
- Edited by Kristen E. Dunbar, MD, and Kendra Klein, MD. They can be reached at New England Eye Center, Tufts University School of Medicine, 750 Washington St., Box 450, Boston MA 02111; website: www.neec.com.