Non-demyelinating disorders mimicking and misdiagnosed as NMOSD: a literature review

Abstract

Background: Differentiating neuromyelitis optica spectrum disorder (NMOSD) from its mimics is crucial to avoid misdiagnosis, especially in the absence of aquaporin-4-IgG. While multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD) represent major and well-defined differential diagnoses, non-demyelinating NMOSD mimics remain poorly characterized.

Methods: We conducted a systematic review on PubMed/MEDLINE to identify reports of patients with non-demyelinating disorders that mimicked or were misdiagnosed as NMOSD. Three novel cases seen at the authors' institutions were also included. The characteristics of NMOSD mimics were analyzed and red flags associated with misdiagnosis identified.

Results: A total of 68 patients were included; 35 (52%) were female. Median age at symptoms onset was 44 (range, 1-78) years. Fifty-six (82%) patients did not fulfil the 2015 NMOSD diagnostic criteria. The clinical syndromes misinterpreted for NMOSD were myelopathy (41%), myelopathy + optic neuropathy (41%), optic neuropathy (6%), or other (12%). Alternative etiologies included genetic/metabolic disorders, neoplasms, infections, vascular disorders, spondylosis, and other immune-mediated disorders. Common red flags associated with misdiagnosis were lack of cerebrospinal fluid (CSF) pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of magnetic resonance imaging gadolinium enhancement (31%). Aquaporin-4-IgG positivity was detected in five patients by enzyme-linked immunosorbent assay (n = 2), cell-based assay (n = 2: serum, 1; CSF, 1), and non-specified assay (n = 1).

Conclusions: The spectrum of NMOSD mimics is broad. Misdiagnosis frequently results from incorrect application of diagnostic criteria, in patients with multiple identifiable red flags. False aquaporin-4-IgG positivity, generally from nonspecific testing assays, may rarely contribute to misdiagnosis.

Keywords: differential diagnosis; false positivity; mimickers; misdiagnosis; neuromyelitis optica spectrum disorder.

Figure 1 -. Spinal cord infarction misdiagnosed as seronegative NMOSD

A 41-year-old African American woman with medical history of Sjögren syndrome was admitted to the emergency department for sudden onset of chest tightness. The following day she reported severe back pain and, over the course of 2–3 hours, developed acute paraplegia accompanied by numbness in lower extremities, severe weakness of upper extremities and urinary retention requiring catheterization. Spinal cord MRI obtained five hours later was unremarkable (A). CSF analysis showed 7 white blood cells and absence of oligoclonal bands; infectious and immunological evaluations were negative, except for positive anti-nuclear antibodies. Aquaporin-4-IgG and myelin oligodendrocyte glycoprotein-IgG were negative in both serum and CSF by live cell-based assay. Repeat MRI 6 days later revealed a longitudinal extensive T2-hyperintense lesion in the cervico-thoracic spinal cord (B) with associated enhancement on post-gadolinium T1-weighted sequences (C). A working diagnosis of seronegative NMOSD was made and she was treated with intravenous immune-globulins, slow taper prednisone and rituximab induction with only mild improvement of symptoms. The patient underwent a repeat MRI 2.5 months later, which showed persistence of the T2-hyperintense lesion restricted to the ventral spinal cord, with a “snake eyes” appearance on axial images (D). The patient was later referred to the Mayo Clinic (Rochester, Minnesota) where a final diagnosis of spinal cord infarction was made and rituximab was discontinued. Despite investigations no cause for the spinal cord infarct was found.

Figure 2 -. Optic nerve sheath meningioma misdiagnosed as seronegative NMOSD

A 52-years old Caucasian woman developed blurred vision in the right eye over one week. She denied headache, diplopia, or other neurologic symptoms. Brain MRI showed marked swelling of the right optic nerve with associated gadolinium enhancement (not shown). A diagnosis of optic neuritis was made and she was treated with intravenous methylprednisolone (1 g daily for 5 days), with resolution of the visual symptoms. In the following two years, she experienced several recurrences of symptoms in the same eye interpreted as recurrent optic neuritis and treated with intravenous methylprednisolone pulses and oral prednisone taper. Repeat MRIs over the two years showed persistent enhancement of the right optic nerve, substantially unmodified compared to the first exam. Despite some temporary improvement with corticosteroid therapy, she experienced progressive vision impairment. NMOSD was eventually suspected and the patient was referred to the Neurology Unit of the University-Hospital of Sassari. Orbital MRI showed a discrete tissue mass surrounding the right optic nerve that was hyperintense on both axial (A) and coronal (B) T2-images and enhanced diffusely after gadolinium administration on fat-suppression sequences (C). The margins of the mass and adjacent optic nerve are highlighted in red and blue, respectively (D-F). A final diagnosis of probable optic nerve sheath meningioma was made based on clinical and MRI findings.

Figure 3 -. Intramedullary spinal cord abscess misdiagnosed as seronegative NMOSD

A 54-year-old Caucasian man developed severe neck and shoulder pain, followed by progressive weakness of the left limbs and sensory loss in both hands over 3 days. His medical history was unremarkable, except for several minor dentistry procedures over the prior months. Spinal cord MRI showed a longitudinally extensive T2-hyperintense lesion from C3 to C7 with a central core of higher T2-hyperintensity (A) surrounded by an irregular ring of enhancement on post-gadolinium T1 sequences (B). CSF examination revealed 85 white blood cells and protein elevation (90 g/dl). Extensive infectious screening on both serum and CSF (including blood and CSF culture) was unremarkable. Testing for aquaporin-4-IgG and myelin oligodendrocyte glycoprotein-IgG was negative on serum and CSF by live cell-based assay. He was started on intravenous methylprednisolone (1 g daily for 5 days) with no improvement. A new MRI showed extension of the lesion to the cervicomedullary junction and the thoracic spinal cord to the T4 level (C). A longitudinal extension of the ring enhancement was also observed after gadolinium administration, which appeared bilobate on axial images at cervical level (D). A working diagnosis of seronegative NMOSD was made and plasma exchange was started. Given further clinical deterioration after two plasma exchange sessions (the patient became tetraplegic), a spinal cord biopsy was performed. Cultures from intralesional material came back positive for Haemophilus Influenzae, and antibiotic therapy was started with slow improvement. No fever or increased serum procalcitonin levels were observed before the spinal cord biopsy.

Figure 4 -. Suggested diagnostic work-up in patients with suspected NMOSD

The left half of the figure shows the recommended diagnostic work-up in patients with new-onset demyelinating CNS syndromes compatible with NMOSD (e.g., optic neuritis, myelitis). Multiple sclerosis is the most common demyelinating CNS disorder and should be the first to considered in case of suggestive features (e.g., short myelitis lesions on MRI, CSF-restricted oligoclonal bands). If the clinical-MRI phenotype is not consistent with MS, testing for aquaporin-4-IgG and myelin oligodendrocyte glycoprotein-IgG by cell-based assay is recommended. In case autoantibody testing gives a negative result and a diagnosis of seronegative NMOSD is considered, a careful evaluation for common red-flags is important to avoid misdiagnosis. The right half of the figure shows the most common red-flags encountered in patients with NMOSD misdiagnosis and associated alternative etiologies reported in the literature. Once common red-flags have been excluded, a reasonable diagnosis of seronegative NMOSD can be made. In these patients, however, the lack of response to immunotherapy is another red flag that should prompt reconsideration of alternative diagnoses.