Sergio Ferrari

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.

Background and purpose Immune checkpoint inhibitors (ICIs) targeting programmed death receptor 1 (PD‐1), cytotoxic T‐lymphocyte‐associated‐4 (CTLA‐4) and programmed cell death ligand 1 can be associated with immune‐related adverse events (iRAEs). Amongst neurological iRAEs, cerebellar involvement seems to be rare and currently lacks a proper characterization. The aim of this study was to phenotype cerebellar iRAEs. Methods A systematic review was performed according to PRISMA guidelines including reported patients with cerebellar involvement related to ICIs and with available individual data. Results After screening 2765 records, 32 studies with 46 patients were included. Median age was 63 years (20–82), and most patients were male (63.0%). Isolated cerebellitis was observed in 32.6% of cases, whilst the remaining cases had “cerebellitis plus”, mostly associated with encephalitis/encephalopathy. Associated tumors included most frequently lung cancer, melanoma and Merkel cell carcinoma. PD‐1 inhibitor was the most administered treatment ( n = 29, 64.4%), whilst exposure to CTLA‐4 inhibitor was rare ( n = 2, 4.5%). Magnetic resonance imaging was abnormal in 43.2% of patients and inflammatory cerebrospinal fluid findings were frequently observed. Autoantibodies were detected in 61.9% of patients and included novel reactivities. Amongst treatment strategies, the most common were steroids ( n = 36) and ICI discontinuation ( n = 28, 90.3%). Relapses were reported in 10% of patients. Most patients showed improvement/remission ( n = 31) but, at last follow‐up, 12 had died. Isolated cerebellitis versus cerebellitis‐plus differed in terms of outcomes, whilst seropositive versus seronegative patients had distinct tumor associations. Discussion Cerebellar iRAEs are usually multifocal, have heterogeneous tumor associations, are most associated with PD‐1 inhibitor exposure and are related to autoantibodies, including novel reactivities.

Background and purpose Anti‐myelin oligodendrocyte glycoprotein antibodies (MOG‐Abs) distinguish a group of inflammatory disorders which can be preceded by specific or non‐specific infections. A few single cases have been reported in association with SARS‐CoV‐2 infection, but a specific study on the correlation between COVID‐19 and myelin oligodendrocyte glycoprotein (MOG)‐associated disorder (MOGAD) has not yet been performed. The aim of this study was to determine the impact of the pandemic on this condition. Methods We analysed SARS‐CoV‐2 serology in patients newly diagnosed with MOGAD (1 August 2020 to 31 May 2021). MOG‐Ab‐seronegative age‐ and time‐matched subjects were used as controls. SARS‐CoV‐2 immunoglobulin G (IgG) levels were analysed using an anti‐SARS‐CoV‐2 US Food and Drug Administration‐approved ELISA assay and confirmed with a trimeric anti‐SARS‐CoV‐2 S1/S2 IgG immunochemiluminescent test, concomitantly assaying the anti‐receptor binding domain (RBD) of spike protein IgG and anti‐RBD total Ig. We actually compared the number of cases referred in each of the last 3 years. Results Presence of SARS‐CoV‐2 IgG antibodies was more common (12/30, 40%) in MOGAD patients than in controls (6/30, 20%), although the difference was not significant ( p = 0.16; odds ratio 2.67, 95% confidence interval 0.85–9.17). The most common clinical presentations of MOGAD SARS‐CoV‐2‐seropositive patients included optic neuritis ( n = 6) and myelitis ( n = 3). The number of diagnosed cases increased over the last 3 years, in particular, when including cases referred to us before the COVID‐19 pandemic, in the initial phase of the first wave and in the late phase of the second wave ( n = 9, rate 10.6% in 2019; n = 13, rate 12.3% in 2020; n = 15, rate 14.7% in 2021). Conclusion Our findings provide preliminary data on SARS‐CoV‐2 as a potential trigger of MOGAD.