Autoimmune and paraneoplastic disorders of the nervous system

The aim of this PhD thesis is to investigate different clinical, radiological and biomarker aspects of the heterogeneous group of autoimmune and paraneoplastic disorders of the nervous system. After a brief overview of these conditions, including paraneoplastic neurological syndromes and complications of cancer immunotherapy, and autoimmune encephalitides, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), we will focus on specific topics that were investigated in this PhD project. In the first part, we will be focusing on the characterization of rare presentations of immune-related adverse events of cancer immunotherapy, including cerebellar involvement and movement disorders. Article 1 and Article 2 provide a characterization of these rare conditions through an extensive systematic review of the literature. We observed that some specific features such as subacute onset, inflammatory cerebrospinal fluid and negative imaging were supportive of the diagnosis, which largely relies on clinical evaluation. Regarding paraneoplastic neurological syndromes, Article 3 and Article 4 are focused on the definition of paraneoplastic neurological syndromes in two “low-risk antibodies”, aquaporin-4 (AQP4) and MOG. Our results suggested that MOGAD is not associated with neoplasms, thus cancer screening is not necessary in this condition, whereas, in AQP4+NMOSD, cancer can occur beyond the typical associations (longitudinally extensive myelitis and adenocarcinoma) suggested in the diagnostic criteria for paraneoplastic neurological syndromes, prompting a more extensive cancer screening. In the second part, in Article 5 and Article 6, we investigated the spectrum of differential diagnoses of autoimmune encephalitides and NMOSD, and the factors that were associated with misdiagnosis. In the third part, we will be discussing the characterization of clinical features of AQP4+NMOSD and MOGAD and the role of biomarkers in seronegative NMOSD. In Article 7, we will provide a characterization of clinical and radiological features of cerebellar involvement during AQP4+NMOSD attacks. In Article 8, we will discuss a study aiming to characterize peripheral nervous system involvement in patients with MOGAD. In this study we investigated samples obtained from patients that underwent sural nerve biopsy to identify those harboring MOG antibodies. We observed that a minority of cases were MOG positive either with combined peripheral and central demyelination or with isolated peripheral nerve involvement only. In Article 9, we aimed to investigate the role of a profile of serum biomarkers in discriminating seronegative versus AQP4+NMOSD. We observed that markers of axonal damage were similar in the two groups, but seronegative NMOSD had lower concentration of markers of astrocytopathy and neuronal death. The signature we identified can be useful for the differential diagnosis and for our understanding of the disease. In conclusion, this PhD project investigated different aspects of autoimmune and paraneoplastic disorders of the nervous system, including the characterization of rare clinical presentations and the investigation of potential biomarkers.