The spectrum of autoimmune neurological syndromes has expanded rapidly in recent years due to the discovery of novel neuronal autoantibodies. Many newly identified autoantibodies are directed against cell surface proteins, as opposed to the mainly intracellular antigens targeted by classical neuronal antibodies. Neural surface antibodies are often non-paraneoplastic and are considered to be directly pathogenic in autoimmune encephalopathies. Particularly in unexplained neurological cases, a comprehensive autoantibody screening can help to establish a diagnosis, enabling immediate commencement of life-saving therapy. Autoantibodies against intracellular neuronal proteins like Hu, Yo, Ri, CV2/CRMP5, GAD65/67, and amphiphysin are well-recognized biomarkers in several immune-mediated brain disorders. They are generally considered to be epiphenomena of a T-cell driven paraneoplastic autoimmune reaction.
In contrast, reports on autoantibodies that are often non-paraneoplastic were published in recent years. Most of them are directed against neural surface-associated receptor and channel proteins including aquaporin-4 (AQP4), N-methyl-D-aspartate receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid receptor type B (GABABR), leucine-rich glioma inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), dipeptidyl-peptidase-like protein-6 (DPPX), metabotropic glutamate receptor 5, and IgLON5. Most of the non-paraneoplastic autoantibodies are considered to be pathogenic that generally occur in association with inflammatory damage to the brain and can induce seizure, stroke, impairment of vision, psychosis-like symptoms, and/or movement disorders. Most patients with autoantibodies against neural surface antigens dramatically improve after immunomodulation by plasmapheresis or by treatment with immunosuppressive drugs.
Aquaporin 4, the most abundant water channel in the central nervous system (CNS), was identified in 2005 as the target antigen of autoantibodies in neuromyelitis optica (NMO). Prior to that, these antibodies had simply been referred to as NMO-IgG. NMO is a severe inflammatory CNS disorder, which predominately affects the spinal cord and optic nerves. Symptoms comprise acute visual disorders including blindness, impaired mobility, and loss of bladder and bowel control. The determination of AQP4 antibodies is particularly useful for early serological differentiation of NMO from MS, which is crucial for therapy decision.
Autoantibodies against glutamate receptors (type NMDA) are highly specific markers for anti-NMDA receptor encephalitis, an inflammatory encephalopathic autoimmune disease, which was first described in 2007. The determination of NMDAR autoantibodies in serum or CSF is particularly important for differential diagnosis in patients with encephalitis of unknown origin, i.e., with non-infectious etiology, and in young women with de novo epilepsy.
LGI1 and CASPR2 were recently identified as the main antigenic targets of autoantibodies, formerly referred to as “voltage-gated potassium channel (VGKC) antibodies.” LGI1 autoantibodies are found almost exclusively in patients with limbic encephalitis. Autoantibodies against CASPR2 are also found in patients with limbic encephalitis, but mostly occur in acquired neuromyotonia and Morvan’s syndrome
Autoantibodies against GABAB receptors were first identified in a group of patients with paraneoplastic or immune-mediated limbic encephalitis. Patients with these autoantibodies show epileptic seizures, confusion, and memory deficits. For the monospecific determination of autoantibodies directed against neural surface antigens, recombinant cell-based indirect immunofluorescence assays (RC-IFA) are available that present the relevant antigens in their authentic form. Differently transfected cell substrates can be combined in multiplex-RC-IFA and used in conjunction with cryosections of, for example, hippocampus, cerebellum or optic nerve in the form of biochip mosaics. This comprehensive approach greatly assists the differentiation of clinically similar encephalitis subtypes (autoimmune, infectious, paraneoplastic) and thus supports fast decision making.