Diagnosing NMOSD

These neurologic dysfunctions usually manifest as attacks, or relapses, evolving over a period of days, and slowly improve over weeks to months during remission.1,2 However, further relapses will inevitably lead to a stepwise increase in disability, and even single attacks can lead to permanent functional disabilty.1

Although the risk of relapses in NMOSD is very high, there have also been some (reportedly up to 10%) monophasic cases described.1–3 The definition for monophasic NMOSD remains elusive, but mainly includes cases that are seronegative for aquaporin-4 immunoglobulin G (AQP4‑IgG) antibodies, as well as a fraction of cases seropositive for myelin oligodendrocyte glycoprotein (MOG)-IgG.2,3 As the interval between attacks can be as long as several years, patients seropositive for AQP4‑IgG should be considered at risk for relapse attacks indefinitely.3

To identify NMOSD attacks, healthcare professionals rely on a combination of new clinical symptoms and neurologic signs.1 Furthermore, other possible causes have to be ruled out, such as multiple sclerosis (MS), convulsions and infection, that could mimic NMOSD.1
Nearly half (44.3%) of patients with NMOSD had a prior diagnosis of MS.*4

Diagnosis of NMOSD took more than three times longer if the initial presentation was optic neuritis vs myelitis.†5

Although many of the symptoms of NMOSD are indistinguishable from MS,6 patients with MS do not have antibodies against AQP4, whereas most patients with NMOSD are seropositive for AQP4‑IgG.1 Thus, according to international consensus criteria, NMOSD is almost ensured when a characteristic first attack is accompanied with a positive AQP4‑IgG status.1,3

As many as half of NMOSD patients seropositive for AQP4‑IgG also have other detectable serum autoantibodies, such as thyroperoxidase, and one third have other autoimmune diseases such as thyroiditis, systemic lupus erythematosus or Sjögren’s syndrome.1

For patients with these rheumatologic diseases, it is recommended to test for AQP4‑IgG before making a diagnosis of their central nervous system (CNS) complications, as a coexistence of NMOSD is possible, warranting treatment for NMOSD.1

While testing for AQP4‑IgG is the most important diagnostic tool for NMOSD, in equivocal or seronegative cases, magnetic resonance imaging (MRI), and sometimes also a test of the cerebrospinal fluid (CSF), can help differentiate NMOSD from MS or infectious myelitis.1,3,7

While MS is a much more common CNS inflammatory demyelinating disease than NMOSD in white adults, NMOSD accounts for more than 1/3 of cases in Asian populations.1,7 NMOSD mainly affects the optic nerve and spinal cord, with fewer occurrences of lesions in the brain stem.7 In contrast, MS commonly involves multiple brain regions (paraventricular region, cerebral cortex and subcortex, infratentorial region), along with the spinal cord and optic nerve.10 Because the different types of lesions can cause similar types of symptoms across NMOSD and MS, MRI is required to distinguish between the characteristic lesions for each disease (see table below), particularly in patients with a negative or unknown AQP4-IgG status.1,7 Other differences between NMOSD and MS can be seen in CSF white blood cell (WBC) counts and oligoclonal bands (see table below).2
*The percentage of AQP4-IgG seropositive individuals with NMO/NMOSD varies between sources but is usually estimated to be between 73–90%.2,11
The diagnostic workup for NMOSD should include a detailed medical history alongside physical and neurological examination.7 According to the international consensus for the diagnosis of NMOSD, the diagnostic criteria differs between NMOSD with and without AQP4‑IgG, but key criteria for the diagnosis of NMOSD include:3
  • The manifestation of at least one of the six core clinical syndromes of NMOSD
  • Serological evaluation of AQP4‑IgG
  • Exclusion on alternative diagnoses
  • Neuroimaging with MRI (NMOSD without AQP4‑IgG and NMOSD with unknown AQP4‑IgG status)

The presence of AQP4‑IgG autoantibodies is a hallmark of NMOSD.3,9 It is found in almost 80% of patients and is 99% specific for making the diagnosis, when accompanied by one or more core clinical characteristics of the disorder.1,3,4 Thus, testing for AQP4‑IgG is essential in the diagnostic workup of suspected NMOSD and aids in differential diagnosis with other autoimmune diseases.3,9

The standard and recommended reference test for serum AQP4‑IgG is a live cell-based flow cytometric assay (CBA).1,3 Other detection methods, such as enzyme-linked immunosorbent assays (ELISA), may yield false positive low-titre results.1,3

In patients with negative or unknown AQP4‑IgG status, the classification of NMOSD will require meeting stringent clinical and MRI criteria following the international consensus, as well as an investigation into other potential causes of the CNS symptoms.1,3 To avoid equivocal or false-negative test results for AQP4‑IgG, repeat testing is recommended.9

MRI of the entire CNS is a crucial tool in the differential diagnosis of NMOSD.3,7 The disorder is often characterised by distinct patterns visible in the brain, optic nerve and spinal cord. In fact, the detection of an LETM lesion in the spinal cord is a highly specific neuroimaging feature associated with acute myelitis in NMOSD, whereas area postrema syndrome includes associated medullary MRI lesions.3,9

Recently also bright spotty lesions (BSL) on spinal MRI images has emerged as a highly specific diagnostic imaging marker for NMOSD.7

* In a large retrospective, observational study (N = 1363).4

† A total of 55 months with optic neuritis vs 16 months with myelitis in a multicentre retrospective study involving Caucasian patients (N = 175).5
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APL, antiphospholipid syndrome; AQP4‑IgG, aquaporin-4 immunoglobulin G; BSA, bright spotty lesion; CBA, cell-based flow cytometric assay; CNS, central nervous system; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; GFAP, glial fibrillary acidic protein; IL-6; interleukin-6; LETM, longitudinally extensive transverse myelitis; MG, myasthenia gravis; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder​; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; WBC, white blood cell.
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 Lennon VA, et al. A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–2112.
 Jarius S, et al. 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. J Neurol. 2023;270(7):3341–3368). Srikajon J, et al. Differences in clinical features between optic neuritis in neuromyelitis optica spectrum disorders and in multiple sclerosis. Mult Scler J. 2018;4(3):2055217318791196.
 Trebst C, et al. Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol. 2014;261(1):1–16.  Ji Q, et al. Clinical characteristics and outcomes of multiple sclerosis and neuromyelitis optica spectrum disorder with brainstem lesions as heralding prodrome​. Front Neurol. 2022;13:836337. Hamid SHM, et al. What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients. J Neurol. 2017;264(10):2088–2094.