Pietro Zara’s research while affiliated with University of Cagliari and other places

Introduction/Aims The global incidence and prevalence of myasthenia gravis (MG) range between 6–31/million and 10–37/100,000, respectively. Sardinia is a high‐risk region for different immune‐mediated disorders, but the epidemiology of MG remains unclear. We determined the epidemiology of MG with acetylcholine receptor (AChR)‐immunoglobulin G (IgG) and muscle‐specific tyrosine kinase (MuSK)‐IgG in the district of Sassari (North‐Western Sardinia; population, 325,288). Methods From the laboratory of the University Hospital of Sassari (reference for AChR/MuSK‐IgG testing in Sardinia since 1998) and the main neurology units in Sardinia, we retrospectively identified MG patients with (1) AChR‐IgG and/or MuSK‐IgG positivity by radioimmunoprecipitation assay; and (2) residency in the district of Sassari. Incidence (January 2010–December 2019) and prevalence (December 31, 2019) were calculated. Results A total of 202 patients were included (incident, 107; prevalent, 180). Antibody specificities were AChR ( n = 187 [93%]) and MuSK ( n = 15 [7%]). The crude MG incidence (95% confidence interval) was 32.6 (26.8–39.2)/million, while prevalence was 55.3 (47.7–63.9)/100,000. After age‐standardization to the world population, incidence decreased to 18.4 (14.3–22.5)/million, while prevalence decreased to 31.6 (26.1–37.0)/100,000. Among incident cases, age strata (years) at MG onset were: <18 (2%), 18–49 (14%), 50–64 (21%), and ≥65 (63%). Discussion Sardinia is a high‐risk region for MG, with a prevalence that exceeds the European threshold for rare disease. Identification of the environmental and genetic determinants of this risk may improve our understanding of disease pathophysiology.

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 analysed and red flags associated with misdiagnosis identified. Results: A total of sixty-eight patients were included; 35 (52%) were female. Median age at symptoms onset was 44 years (range, 1-78). 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 CSF pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of MRI 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.

The diagnosis of autoimmune encephalitis (AE) requires reasonable exclusion of other conditions. The aim of this study is to characterize mimickers and misdiagnoses of AE, thus we performed an independent PubMed search for mimickers of AEs or patients with alternative neurological disorders misdiagnosed as AE. Fifty-eight studies with 66 patients were included. Neoplastic (n = 17), infectious (n = 15), genetic (n = 13), neurodegenerative (n = 8), and other neurological (n = 8) or systemic autoimmune (n = 5) disorders were misdiagnosed as AE. The lack of fulfillment of diagnostic criteria for AE, atypical neuroimaging findings, non-inflammatory CSF findings, non-specific autoantibody specificities and partial response to immunotherapy were major confounding factors.

Objective To assess the potential association between TNF-inhibitors and MOGAD Background The association of tumor necrosis factor-a (TNF)-inhibitors with MS has previously been suggested, whereas little is known about MOG-IgG-associated disease (MOGAD) in the context of these drugs. We recently encountered two patients who developed MOGAD while receiving TNF-inhibitors, prompting a search for similar cases in the literature and clinical practice. Design/Methods The two cases were seen at Mayo Clinic, Rochester (bilateral optic neuritis) and the University-Hospital of Sassari (brainstem syndrome). Three additional cases of MOGAD presenting during treatment with TNF-inhibitors were identified through Pubmed. We searched the medical records of 336 MOGAD patients seen at the Mayo Clinic, to assess if they had been treated with TNF-inhibitors. Results A total of 5 patients were identified. The median age at MOGAD presentation was 40 years (range, 36-49); 4/5 were male (80%). The median time from TNF-inhibitor initiation to MOGAD presentation was 6.5 years (range, 2-18). Of 4 patients who discontinued the TNF-inhibitor due to MOGAD onset, two subsequently had a MOGAD relapse. While in another patient, neurological symptoms subsided with corticosteroids despite TNF-inhibitor being maintained. The frequency of MOGAD presenting during TNF-inhibitors treatment at Mayo Clinic was 0.3% (1/336 cases). Conclusions We found that MOGAD is unlikely to present during treatment with TNF-inhibitors. The outcomes in these patients seemed not to be influenced by TNF-inhibitor treatment duration or discontinuation. These findings suggest the benefit of TNF-inhibitor withdrawal is not obvious, and the choice of discontinuing vs maintaining treatment with TNF-inhibitors should be weighted based on symptoms severity and activity status of the underlying systemic disorder. When withdrawal is considered, immunosuppression with agents potentially effective for both MOGAD and the immune-mediated disease originally managed by the TNF-inhibitor, could serve as dual purpose treatment.

Inflammatory myelopathies can manifest with a combination of motor, sensory and autonomic dysfunction of variable severity. Depending on the underlying etiology, the episodes of myelitis can recur, often leading to irreversible spinal cord damage and major long-term disability. Three main demyelinating disorders of the central nervous system, namely multiple sclerosis (MS), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders (AQP4+NMOSD) and myelin oligodendrocyte glycoprotein-IgG associated disease (MOGAD), can induce spinal cord inflammation through different pathogenic mechanisms, resulting in a more or less profound disruption of spinal cord integrity. This ultimately translates into distinctive clinical-MRI features, as well as distinct patterns of disability accrual, with a step-wise worsening of neurological function in MOGAD and AQP4+NMOSD, and progressive disability accrual in MS. Early recognition of the specific etiologies of demyelinating myelitis and initiation of the appropriate treatment is crucial to improve outcome. In this review article we summarize and compare the clinical and imaging features of spinal cord involvement in these three demyelinating disorders, both during the acute phase and over time, and outline the current knowledge on the expected patterns of disability accrual and outcomes. We also discuss the potential implications of these observations for patient management and counseling.