Antibody-Mediated Autoimmune Diseases of the CNS: Challenges and Approaches to Diagnosis and Management

Abstract

Antibody-mediated disorders of the central nervous system (CNS) are increasingly recognized as neurologic disorders that can be severe and even life-threatening but with the potential for reversibility with appropriate treatment. The expanding spectrum of newly identified autoantibodies targeting glial or neuronal (neural) antigens and associated clinical syndromes (ranging from autoimmune encephalitis to CNS demyelination) has increased diagnostic precision, and allowed critical reinterpretation of non-specific neurological syndromes historically associated with systemic disorders (e.g., Hashimoto encephalopathy). The intracellular vs. cell-surface or synaptic location of the different neural autoantibody targets often helps to predict the clinical characteristics, potential cancer association, and treatment response of the associated syndromes. In particular, autoantibodies targeting intracellular antigens (traditionally termed onconeural autoantibodies) are often associated with cancers, rarely respond well to immunosuppression and have a poor outcome, although exceptions exist. Detection of neural autoantibodies with accurate laboratory assays in patients with compatible clinical-MRI phenotypes allows a definite diagnosis of antibody-mediated CNS disorders, with important therapeutic and prognostic implications. Antibody-mediated CNS disorders are rare, and reliable autoantibody identification is highly dependent on the technique used for detection and pre-test probability. As a consequence, indiscriminate neural autoantibody testing among patients with more common neurologic disorders (e.g., epilepsy, dementia) will necessarily increase the risk of false positivity, so that recognition of high-risk clinical-MRI phenotypes is crucial. A number of emerging clinical settings have recently been recognized to favor development of CNS autoimmunity. These include antibody-mediated CNS disorders following herpes simplex virus encephalitis or occurring in a post-transplant setting, and neurological autoimmunity triggered by TNFα inhibitors or immune checkpoint inhibitors for cancer treatment. Awareness of the range of clinical and radiological manifestations associated with different neural autoantibodies, and the specific settings where autoimmune CNS disorders may occur is crucial to allow rapid diagnosis and early initiation of treatment.

Update on Paraneoplastic Cerebellar Degeneration

“…Identification of autoantibodies in the setting of a rapidly progressive cerebellar syndrome is paramount to (1) establish the diagnosis of PCD, (2) allocate the specific treatment, and (3) predict the association of cancer and direct cancer search [ 22 ]. As described in Section 2 , antibodies can be classified according to the cellular localization of their target antigens.…”

“…In about 80% of the patients presenting with PCD, neuronal antibodies can be detected [ 21 ]. In principle, these antibodies are classified according to the cellular localization of their target antigens; namely, intracellular, cell-surface, or synaptic [ 22 ]. Antibodies targeting intracellular structures are usually not considered directly pathogenic.…”

“…Antibodies targeting intracellular structures are usually not considered directly pathogenic. Rather, they are regarded as biomarkers of a predominantly cell-mediated cytotoxic process, although the pathogenic role of some antibodies targeting intracellular structures is still a matter of debate [ 1 , 6 , 22 ]. In this regard, Yo- and Hu-antibodies have been studied extensively.…”

“…Antibodies targeting cell-surface proteins, on the other hand, are thought to have a direct pathogenic effect. In the context of PCD, VGCC- and mGluR1-antibodies are relevant autoantibodies targeting cell-surface proteins and synaptic proteins, respectively [ 1 , 22 ]. Calcium channels targeted by VGCC-antibodies rest on the membrane of Purkinje-cells and are responsible for calcium homeostasis [ 14 ].…”

“…Yo-antibodies are associated with ovarian or breast cancer which can be detected in about 80% of patients. DNER-antibodies associate with Hodgkin lymphoma (detected in 80% of patients) and mGluR1-antibodies associate with hematologic malignancies (detected in about 30% of patients) [ 22 ]. Cognitive deficits, however, can be detected in approximately 20% of patients with Yo-antibodies and an otherwise isolated cerebellar ataxia [ 15 ].…”