Frequency of Asymptomatic Optic Nerve Enhancement in a Large Retrospective Cohort of Patients With Aquaporin-4+ NMOSD

Abstract

Background and Objectives:Asymptomatic or persistent optic nerve enhancement in aquaporin (AQP)-4-immunoglobulin G (IgG) positive neuromyelitis optica spectrum disorder (NMOSD) is thought to be rare. Improved understanding may have important implications for assessment of treatment efficacy in clinical trials and in clinical practice. Our objective was to characterize NMOSD inter-attack optic nerve enhancement.Methods:This was a retrospective cohort study performed between 2000-2019 (median follow-up 5.5 [range 1-35] years) of AQP4-IgG positive optic neuritis (ON) patients evaluated at Mayo Clinic. MRI orbits were reviewed by a neuro-radiologist, neuro-ophthalmologist and neuroimmunologist blinded to clinical history. Inter-attack optic nerve enhancement (>30 days after attack) was measured. The correlation between inter-attack enhancement and Snellen visual acuity converted to Logarithm of the Minimum Angle of Resolution (LogMAR) at attack and at follow-up were assessed.Results:198 MRI scans in 100 AQP4-IgG+ NMOSD patients were identified, with 107 inter-attack MRIs from 78 unique patients reviewed. Seven scans were done prior to any ON median 61 days before attack [range 21-271 days]) and 100 after ON (median 400 days after attack [33-4623 days]).Optic nerve enhancement was present on 18/107 (16.8%) inter-attack scans (median 192.5 days from attack [33-2943]) of patients with preceding ON. On 15 scans, enhancement occurred at the site of prior attacks; the lesion location was unchanged, but the lesion length was shorter. Two scans (1.8%) demonstrated new asymptomatic lesions (prior scan demonstrated no enhancement). In a third patient with subjective blurry vision, MRI showed enhancement preceding detectable eye abnormalities on examination noted 15 days later. There was no difference in visual acuity at preceding attack nadir (LogMAR VA 1.7 versus 2.1; p=0.79) or long-term visual acuity (LogMAR VA 0.4 versus 0.2, p=0.56) between those with and without inter-attack optic nerve enhancement.Discussion:Asymptomatic optic nerve enhancement occurred in 17% of NMOSD patients at the site of prior ON attacks and may represent intermittent blood-brain-barrier breakdown or subclinical ON. New asymptomatic enhancement was only seen in 2% of patients. Therapeutic clinical trials for NMOSD require blinded relapse adjudication when assessing treatment efficacy and it is important to recognize that asymptomatic optic nerve enhancement can occur in ON patients.

Update on the diagnosis and treatment of neuromyelits optica spectrum disorders (NMOSD) – revised recommendations of the Neuromyelitis Optica Study Group (NEMOS). Part I: Diagnosis and differential diagnosis

“…Demonstration of optic nerve Gd enhancement may also facilitate the discrimination between true relapses and pseudorelapses (defined as worsening or re-occurrence of pre-existing neurological symptoms caused by systemic metabolic changes rather than immune-mediated mechanisms) by providing supportive information [199]. Of note, recent studies found Gd-enhancing lesions of the optic nerve in 20-50% of inter-attack MRI scans, i.e., in asymptomatic patients [159,193]. In one study, these lesions were mainly located to sites of previous ON attacks, whereas new asymptomatic lesions as detected by Gd-enhanced imaging at sites not previously affected were very rare [193].…”

Literature Commentary

“…These silently enhancing lesions can be problematic in clinical trials as well: are they consistent with drug failure? To address these questions, Shah et al (1) reviewed 198 MRI scans in 100 patients with AQP4-IgG+ NMOSD seen at the Mayo Clinic.…”

Author Response: Frequency of Asymptomatic Optic Nerve Enhancement in a Large Retrospective Cohort of Patients With Aquaporin-4+ NMOSD

“…We thank Dr. Cao and colleagues for raising several interesting points regarding our article. 1 We agree that recurrent optic neuritis (ON) cannot be definitively ruled out. However, patients' examinations at the time of scans did not reveal clinical evidence of ON.…”