Treatment Choices in Optic Neuritis: Corticosteroids, Intravenous Immunoglobulin, Plasma Exchange, or Other?^[*]

Plasma Exchange and Immunoadsorption in Pediatric Inflammatory Optic Neuropathy Resistant to Corticosteroid Therapy: Four French Cases

The case series by Jacquet et al in this edition of Neuropediatrics describe four children with heterogeneous presentations of optic neuritis who were treated with plasma exchange (PE) or immune absorption.[1] The cases highlight the heterogeneous etiologies of optic neuritis, and also the varying treatments and the limited evidence base available to the treating clinician.

Optic neuritis can be a monophasic event or represent the first event of a chronic disorder such as multiple sclerosis (MS) or neuromyelitis optica (NMO). Magnetic resonance imaging (MRI) at baseline and during follow-up is an important investigation to discriminate the monophasic or chronic nature of the problem.[2] A recent large study of 357 children with optic neuritis found that after a median follow-up of 4.0 years, 145/357 (41%) of the children had MS, and found that the cerebrospinal fluid (CSF) oligoclonal bands and an abnormal MRI brain were the strongest predictors of MS.[2]

Serological autoantibody biomarkers have changed the approach to a child with optic neuritis, and the presence of autoantibodies can have significant therapeutic and prognostic implications. Aquaporin-4 (AQP4) antibodies (NMO IgG) are strongly associated with NMO, and positive AQP4 antibody is associated with a relapsing course in the majority.[3] The natural history of AQP4-associated NMO is potentially poor (visual and spinal cord related), and for this reason patients with AQP4 antibodies should be treated aggressively during acute episodes, and should be given chronic immune suppression to minimize the chance of relapse.[3] A further biomarker is myelin oligodendrocyte glycoprotein (MOG) autoantibody, which is found in a proportion of children with acute disseminated encephalomyelitis, optic neuritis, and transverse myelitis.[4] [5] Generally, children with MOG antibody (ab) have a monophasic course, although some patients have a relapsing course associated with steroid responsiveness (and in some patients steroid dependence). Patients with MOG ab do not tend to have asymptomatic brain lesions at follow-up (unlike MS), but instead can have resolution of brain-lesion activity at follow-up. Typically, patients with MOG ab-associated disease are negative for CSF oligoclonal bands, but can have an elevated erythrocyte sedimentation rate.[6] The radiological involvement of the optic nerve, optic chiasm, and brain vary according to etiology.[7]

Despite these recent advances, a significant proportion of children with optic neuritis are seronegative for AQP4 and MOG abs, and do not have MS using clinical or MRI criteria—it is likely that some of these patients have as yet unidentified autoantibodies or immune processes that are yet to be described.

The varied etiology of optic neuritis is exemplified in this cohort by Jacquet et al.[1] No patient was positive for AQP4 antibodies, and MOG ab was not performed (case 4 had a phenotype most reminiscent of MOG ab-associated disease). One of the cases had a disease course suggestive of MS (although unproven, case 1), and the other two cases did not have a clear etiology, although one of these patients had a preexisting disease (phenylketonuria), which could have contributed to the disease course. The four cases were treated with corticosteroids, but had a poor initial response, resulting in the clinicians' trialing PE or immune absorption—the cases, therefore, represent real-life examples of the challenges in the treatment of inflammatory demyelination of the central nervous system.

Corticosteroids are generally used in inflammatory optic neuritis, and are considered to shorten the duration of visual illness, but do not alter the prognosis or risk of relapse.[8] AQP4 ab-associated disease is a particularly destructive disease and can result in permanent blindness—therefore, if the patient is known to have, or suspected to have AQP4 ab disease, the patient should be treated promptly with corticosteroids while planning further treatments.[3] If the patient fails to respond adequately in the 1st week of corticosteroids, further adjunctive therapies can be considered such as intravenous immunoglobulin(IVIG), or as in this report, PE. IVIG and PE have different mechanisms of action, but both attempt to modify the immune milieu or remove autoantibodies and immune complexes via binding or removal mechanisms. The mechanisms of action of both therapies are likely multiple and complex.

If the patient is thought to have MS, then MRI monitoring is required—if there is a further event or radiological asymptomatic lesions then MS disease modifying therapies should be considered. By contrast, if the patient has AQP4 ab-associated disease, chronic immune suppression is warranted after the first event and rituximab, cyclophosphamide, or other immune suppressants can be rationalized.[3] [9] Some of the optic neuritis patients have an apparent steroid dependence and relapse during the later phases of steroid weaning or shortly after stopping steroids—this is seen in MOG ab-associated disease, AQP4 ab-associated disease and other chronic inflammatory optic neuropathies. In this scenario, nonsteroid immune therapies, such as IVIG, PE, or chronic immune suppression can be considered, although some patients remain highly steroid dependent and need low doses of steroids to remain relapse free.

The big question that remains is whether any of these agents, if used early and aggressively, can alter the natural history of disease—can PE or IVIG or early rituximab turn a potentially relapsing disease into a monophasic disease?

Finally, there needs to be consideration of side effects of therapy—the four cases of Jacquet et al emphasize that immune therapies are not without risk—two of the four patients treated with PE or immune absorption developed Staphylococcus aureus infection at the catheter site, one of whom developed sepsis and needed line removal. Although potent immune suppression can reduce the risk of permanent residual neurological deficit, immune suppression has inherent risk, particularly in sick children in the intensive care unit.[10] Therefore, all clinical decisions should include a “risk versus benefit” determination.

^* This article is an editorial on “Plasma Exchange and Immunoadsorption in Pediatric Inflammatory Optic Neuropathy Resistant to Corticosteroid Therapy: Four French Cases” by Jacquet et al (Neuropediatrics 2016;47(3):175–178).

• References

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• 2 Heussinger N, Kontopantelis E, Gburek-Augustat J , et al; for GRACE-MS (German-speaking Research Alliance for ChildrEn with Multiple Sclerosis). Oligoclonal bands predict multiple sclerosis in children with optic neuritis. Ann Neurol 2015; 77 (6) 1076-1082
• 3 Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007; 6 (9) 805-815
• 4 O'Connor KC, McLaughlin KA, De Jager PL , et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007; 13 (2) 211-217
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• 6 Dale RC, Tantsis EM, Merheb V , et al. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Neurol Neuroimmunol Neuroinflamm 2014; 1 (1) e12
• 7 Ramanathan S, Prelog K, Barnes EH , et al. Radiological differentiation of optic neuritis with myelin oligodendrocyte glycoprotein antibodies, aquaporin-4 antibodies, and multiple sclerosis. Mult Scler 2015;
• 8 Beck RW, Cleary PA, Anderson Jr MM , et al; The Optic Neuritis Study Group. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. N Engl J Med 1992; 326 (9) 581-588
• 9 Nosadini M, Alper G, Riney CJ , et al. Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2016; 3 (1) e188
• 10 Dale RC, Brilot F, Duffy LV , et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014; 83 (2) 142-150