Clinical and laboratory diagnostic assessment of immune-mediated neurological disorders

Abstract

Paraneoplastic neurologic syndromes (PNSs) are rare neurological disorders associated with cancer, resulting from a remote effect of a malignant neoplasm. The disease is caused by immune reaction against intracellular antigens (Ma2, Yo, CV2, Hu, amphiphysin, Ri, Tr, GAD65, Zic4, titin, SOX1, recoverin) expressed in tumours, resulting in production of onconeural autoantibodies cross-reacting with neuronal structures and presenting with various neurological symptoms. Onconeural autoantibodies are not likely to be pathogenic, however, their detection in sera can indicate the presence of an underlying tumour, making it possible to conduct targeted cancer screening in affected patients. During the past few years, it has been recognized that there are central nervous system (CNS) disorders presenting in the form of limbic encephalitis (LE), in which the presence of autoantibodies against the neuronal cell surface receptors such as NMDAR, GABABR, and AMPAR or synaptic proteins, LGI1 and Caspr2, has been documented and shown to be responsible for the development of the symptoms. Autoimmune encephalitis (AE) may present with a wide spectrum of clinical symptoms, such as behavioural and psychiatric disorders, cognitive impairment, changes in the level of consciousness, seizures and movement disorders. The distinction between PNSs associated with autoantibodies against intracellular neuronal antigens and neuronal cell surface antibody-mediated AE is crucial. In onconeural antibody-associated PNSs, systemic tumour association is frequent, occurring in >90% of cases, whereas, neuronal cell surface antibody-mediated AE is variably associated with tumours. The better outcome and the effectivity of immunotherapy (steroids, plasmapheresis, immunosuppression, IVIG) in AE, might be explained by reversible neuronal dysfunction, which is caused by pathologic autoantibodies binding to extracellular epitopes of neuronal cell surface proteins, and altering their structure and function. In PNSs, T cell-mediated irreversible neuronal damage is frequently present, thus immunotherapies are generally not effective; however, proper treatment of the tumour can lead to stabilization of the patients. Early clinical diagnosis of these disease groups is important as they can have fatal outcome. Besides clinical features and auxiliary examinations, such as electroencephalography (EEG) and structural magnetic resonance imaging (MRI), accurate diagnosis of PNSs and AE requires detection of characteristic autoantibodies in the serum and/or cerebrospinal fluid (CSF).