Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes

Abstract

Distinguishing aquaporin-4 IgG(AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD) from opticospinal predominant multiple sclerosis (MS) is a clinical challenge with important treatment implications. The objective of the study was to examine whether expert clinicians diagnose and treat NMO/MS overlapping patients in a similar way. 12 AQP4-IgG-negative patients were selected to cover the range of clinical scenarios encountered in an NMO clinic. 27 NMO and MS experts reviewed their clinical vignettes, including relevant imaging and laboratory tests. Diagnoses were categorized into four groups (NMO, MS, indeterminate, other) and management into three groups (MS drugs, immunosuppression, no treatment). The mean proportion of agreement for the diagnosis was low (po = 0.51) and ranged from 0.25 to 0.73 for individual patients. The majority opinion was divided between NMOSD versus: MS (nine cases), monophasic longitudinally extensive transverse myelitis (LETM) (1), acute disseminated encephalomyelitis (ADEM) (1) and recurrent isolated optic neuritis (RION) (1). Typical NMO features (e.g., LETM) influenced the diagnosis more than features more consistent with MS (e.g., short TM). Agreement on the treatment of patients was higher (po = 0.64) than that on the diagnosis with immunosuppression being the most common choice not only in patients with the diagnosis of NMO (98 %) but also in those indeterminate between NMO and MS (74 %). The diagnosis in AQP4-IgG-negative NMO/MS overlap syndromes is challenging and diverse. The classification of such patients currently requires new diagnostic categories, which incorporate lesser degrees of diagnostic confidence. Long-term follow-up may identify early features or biomarkers, which can more accurately distinguish the underlying disorder.

Brain lesion distribution criteria distinguish MS from AQP4-antibody NMOSD and MOG-antibody disease

“…The disagreement on the diagnosis of these patients is high even among NMO and MS experts 12. The diagnostic criteria cannot be easily validated in the ab-negative patients, who are heterogenous and often have overlapping features of NMOSD and MS,12 and some turn out to have a monophasic illness 13 14. Moreover, many studies have now found that MOG-abs define a subgroup within this AQP4-ab negative population and it was reassuring that the imaging criteria performed well in this group distinguishing the majority from MS 10 15–17…”

“…The disagreement on the diagnosis of these patients is high even among NMO and MS experts 12. The diagnostic criteria cannot be easily validated in the ab-negative patients, who are heterogenous and often have overlapping features of NMOSD and MS,12 and some turn out to have a monophasic illness 13 14.…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…Several classical immunosuppressants and some repurposed biologicals have been recommended for NMOSD and will be discussed below. Ambiguous cases of autoimmune neuroinflammation not fulfilling criteria for MS or NMOSD are often treated with broad-acting immunosuppressive drugs such as AZA or methotrexate (MTX) [70].…”

Epidemiology of neuromyelitis optica spectrum disorder in Denmark (1998–2008, 2007–2014)

“…Multiple factors may influence the assay results, such as sex, age, ethnicity, disease activity, immunotherapy, and variations in assay techniques (Melamed et al, ). In practical terms, AQP4‐IgG–negative NMOSD patients may be difficult to diagnose despite clinical and imaging evidence (Juryńczyk et al, ). Several techniques are currently available to test for serum AQP4‐IgG and can be categorized according to whether they are tissue, cell, or protein‐based (Waters et al, ).…”

“…AQP4‐IgG levels have been shown to be higher during relapse as opposed to during remission, and the retesting of initially seronegative patients during an acute attack or during a treatment‐free interval may show positivity (Jarius et al, , ). Even so, the absence of AQP4‐IgG leaves the clinician with the possibility of an alternative diagnosis, such as an optic‐spinal form of MS or another IDD of the CNS (Juryńczyk et al, ; Weinshenker & Wingerchuk, ).…”