A 9-year-old boy with no significant medical history presented to the emergency department with 2 days of painless blurry vision. What's the diagnosis?
A 9-year-old boy with no significant medical history presented to the emergency department with 2 days of painless blurry vision. His vision changes began at school and worsened over the next day to the point where he could see only outlines and shapes of objects. Associated symptoms included dizziness and a mild frontal headache. He denied any recent trauma or illness.
Evaluation and testing
His vital signs were within normal limits and he appeared well. However, he struggled to distinguish shapes or count fingers on visual field testing, leading to a consultation with an ophthalmologist, who noted bilateral optic disc swelling on fundoscopy.
Initial work-up revealed a mildly elevated erythrocyte sedimentation rate of 29 mm/h (reference range [ref], < 15) and C-reactive protein of 10.9 mg/L (ref, < 10); his complete blood cell count and basic metabolic results were unremarkable.
To assess structural causes of increased intracranial pressure, the ophthalmologist recommended an MRI of the brain. Brain MRI revealed abnormal thickening and enhancement of the optic nerves with bilateral papilledema; magnetic resonance venography was normal. Follow-up orbital MRI confirmed the presence of bilateral optic neuritis (Figure).
Lumbar puncture revealed normal opening pressure and mild pleocytosis with 13 nucleated cells per cubic millimeter (ref, < 7); remaining cerebrospinal fluid (CSF) studies were unremarkable, including the absence of oligoclonal bands. Infectious studies (HIV, syphilis, varicella, interferon γ-release assay, herpes simplex virus 1/2 plasma polymerase chain reaction, Lyme reflex) and rheumatologic studies (antinuclear antibodies, antineutrophil cytoplasmic antibodies) were negative. MRI spine showed no abnormalities.
Differential diagnosis: Optic neuritis
Optic neuritis (ON) occurs with inflammation of the optic nerves, typically leading to visual acuity loss, abnormal color vision, and visual field deficits over hours to days. A relative afferent pupillary defect occurs in unilateral ON, assuming the other eye is healthy. Children are much more likely than adults to present with bilateral ON, particularly those under 10 years of age. Furthermore, unilateral ON can progress to bilateral disease regardless of underlying etiology. Other symptoms are more variable, including pain with eye movement and headache.1-3 In the acute stage, fundoscopy may reveal papillitis with hyperemia and optic disc swelling. However, ON may occur with or without optic disc edema depending on the segment of optic nerve involved.3
ON may present as a clinically isolated syndrome or result from an array of neurologic, autoimmune (eg, Sjögren syndrome, systemic lupus erythematosus), rheumatological (eg, sarcoidosis, granulomatosis with polyangiitis), paraneoplastic (eg, small cell carcinoma), or infectious (eg, HIV, syphilis, Lyme disease, tuberculosis, herpes simplex virus, varicella zoster virus) etiologies.4 Among neurological causes, ON appears to be the most common clinical presentation of a variety of acquired demyelinating disorders in children (Table1-8) such as multiple sclerosis (MS), acute disseminated encephalomyelitis (ADEM), neuromyelitis optica (NMO), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing inflammatory optic neuropathy (CRION), and myelin oligodendrocyte glycoprotein antibody disease (MOG-AD).1-4 It is imperative to determine the underlying cause of ON because management strategies vary depending on the underlying etiology.
MS is a common autoimmune demyelinating disease that most often presents in young adults, who typically have a chronic relapsing-remitting course. A variety of clinical scenarios fulfill the diagnostic criteria for MS, including the presence of central nervous system (CNS) lesions that are disseminated in time and space.9,10 Diagnostic accuracy of MS in children improves in the presence of both recurrent ON and oligoclonal bands in the CSF.5
ADEM is a postinfectious demyelinating disease of the CNS presenting with encephalopathy and multifocal neurological symptoms, often including ON. It most often affects children under 10 years of age. MRI typically reveals polyfocal white matter lesions of the same age (ie, not disseminated in time) that spare the periventricular area.1,3
NMO is an autoimmune disease defined by the presence of aquaporin-4 (AQP4) antibodies that can present with ON, myelitis, and/or area postrema syndrome (eg, severe nausea, vomiting, hiccups). NMOSD presents similarly, but AQP4 antibodies are absent.2,3 Patients with ON in the setting of NMO or NMOSD tend to be less responsive to corticosteroids.4
CRION is a diagnosis of exclusion that consists of relapsing ON and loss of visual function. Episodes of ON respond to corticosteroid therapy but relapse on their withdrawal. Patients with CRION have progressive loss of vision between attacks, and long-term visual outcomes are poor.2-4
For this patient, send-out testing for serum MOG antibody was positive and AQP4 was negative, suggesting MOG-AD as the underlying cause of his bilateral optic neuritis.
MOG is an immunogenic protein expressed exclusively on myelin and oligodendrocytes in the CNS. MOG antibodies contribute to demyelination and are present in 30% to 50% of children at initial presentation of acquired demyelinating syndromes.6 Characteristic features of ON in MOG-AD include bilateral disease and longitudinally extensive lesions along the optic nerve with perineural enhancement. Both findings are atypical in isolated ON, MS, or NMOSD.3,6,7,8 Other hallmarks of MOG-AD include rapid visual impairment, the presence of optic disc edema, and good recovery with corticosteroid therapy.2,4,12,13
An international panel of experts has proposed diagnostic criteria for MOG-AD in adults and adolescents, noting that indications for MOG antibody testing in children should be less rigorous than in adults because of the higher frequency of seropositivity in children.14
Clinical phenotypes associated with MOG-AD include ON and transverse myelitis. However, MOG antibodies can also occur in ADEM and NMOSD.11,12 Of note, the presence of MOG antibodies is rare in patients with MS.6,12 Because of the clinical diversity of MOG-AD and overlapping features shared by differential diagnoses, patients presenting with a demyelinating event such as ON should have neuroimaging studies of the brain, optic nerves (in presence of visual symptoms), and entire spine.6 CSF pleocytosis occurs in more than 50% of patients with MOG-AD. Oligoclonal bands in the CSF are uncommon in these patients.7,8
Treatment and management
There are no evidence-based guidelines for acute treatment of children with MOG-AD. As such, treatment typically focuses on immunosuppression and antibody removal through high-dose intravenous (IV) corticosteroids, intravenous immunoglobulin, and plasma exchange (PLEX).6,8,12
The majority of children with bilateral ON from MOG-AD recover visual acuity after initial treatment. However, permanent injury and functional decline may occur over time.2 Thus, multidisciplinary care with pediatric ophthalmology, neurology, and, if possible, neuro-ophthalmology is key for recovery. The duration of corticosteroid treatment often depends on the severity of symptoms, and many clinicians favor an extended wean over weeks to months.
Controversy exists over whether to initiate long-term immunosuppression following the first demyelination episode in children with MOG-AD. Although most patients have monophasic disease, the risk of relapse remains difficult to predict. However, persistent seropositivity for MOG antibodies appears more common in children with recurrent disease.15 Bilateral ON from MOG-AD appears to have a higher likelihood of relapse than unilateral ON, with relapsing disease occurring in up to 50% of patients.8
The patient received pulse-dose IV corticosteroids and underwent PLEX 5 times over 10 days. Visual acuity progressed from perceiving only hand motions at admission to 20/100 and 20/200 in the right and left eyes, respectively, upon discharge. Fundoscopy revealed residual optic disc edema and temporal pallor.
The patient continued taking oral prednisone with plans to taper slowly over several months. His visual acuity gradually improved to 20/40 in the right eye and 20/30 in the left eye, but initial optic disc swelling caused permanent atrophy and thinning of his optic nerves. Development of multiple Cushingoid features led to a more aggressive taper of prednisone and initiation of maintenance immunosuppression with mycophenolate mofetil. Lifelong suppression may not be needed in the absence of future relapses.15