Dawn of the “Immune Era” in Neurology: Are We Up to the Task?

The field of neurology is undergoing a rousing diagnostic and therapeutic revolution, anchored in a veritable explosion in the field of autoimmune neurology. This has, as a Domino's effect, ramified into paradigm shifts in the field of movement disorders, epilepsy, dementia, and demyelinating disorders, to name a few. A plethora of antibodies have been identified, and exciting phenotype–antibody correlations continue to be reported in the literature. The foremost group of disorders among this is the autoimmune encephalitis syndromes. Defined by Graus et al. in 2016 as disorders with a subacute evolution, the presence of typical magnetic resonance imaging changes in the mesial temporal lobes, and the presence of inflammation in the cerebrospinal fluid (CSF), the autoimmune encephalitis syndrome has widely broadened to include limbic encephalitis, autoimmune movement disorders, paraneoplastic cerebellar degeneration, peripheral nerve hyperexcitability syndromes, meningoencephalitis, sleep disorders, and many more.1 Some disorders, such as anti-IgLON5-related disease, remained perched on the tightrope of autoimmunity and neurodegeneration (tauopathy), providing valuable insights into pathophysiological underpinnings of both.2 Another important group is the paraneoplastic antibody-related disorders, the recognition of which must lead to a comprehensive search for an occult neoplasm. There is increasing evidence that prompt and aggressive treatment may lead to better outcomes in the long term.3 Testing for autoimmune or onconeural antibody panels is the cornerstone of diagnosis. Autoimmune encephalitis may be diagnosed in the absence of antibody positivity in the appropriate clinical context. However, antibody testing itself carries several caveats, which must be understood by all clinicians managing these patients. At present, antibody testing is available in the form of "panels" which contain a collection of antigen testing. Autoimmune or paraneoplastic panels must always be tested in an appropriate clinical context and interpreted in that clinical context only. Indiscriminate testing may lead to the conundrum of "antibodies of unknown significance (AUS)," which have been compared to the "variants of uncertain significance" in genetic disorders.4 AUS may appear in patients who have other neurological illnesses, which may closely resemble autoimmune encephalitis, such as Creutzfeldt–Jakob disease, schizophrenia, and multiple sclerosis. Such AUS must always be correlated with the patient's clinical phenotype, testing strategies (appropriate/inappropriate), and in some cases, titers (for example, in anti-glutamic acid decarboxylase (GAD) encephalitis). This can be considered to be the "3T" approach (type, test, and titer). The 3T paradigm is useful to apply when accosted with AUS. Appropriate testing invokes certain principles. For example, onconeural antibodies must be confirmed on at least two tests (brain immunohistochemistry or immunofluorescence, followed by immunoblot). Serum testing is recommended for anti-neuromyelitis optica (NMO) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies, and CSF testing will detect 14% of anti-NDMAR cases which would be missed on serum testing alone. Antibody panels are available in India in certain academic institutes and private laboratories, but the costs remain prohibitively high. Moreover, both serum and CSF testing are recommended, especially when testing onconeural/paraneoplastic antibodies and in the case of some cell-surface antibodies, such as anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. Obviously, this would double the cost. Some antibodies, such as the Kelch-like protein 11 antibodies, are not available in the country or are available at extremely high costs, which would be in addition to the autoimmune "panel." Furthermore, evaluation may also entail positron emission tomography scan, tumor markers, and biopsy. Treatment also comes with a hefty price and may entail intravenous steroids, intravenous immunoglobulins, and/or plasma exchange. None of these are available without significant cost at most centers in our country. Autoimmune neurological disorders, hence, become an expensive proposition for the patient.5 As this field continues to advance, neurologists must gear up for several challenges. We have to be abreast of the newer immune phenotypes as they continue to be reported but also have working knowledge of the principles of autoimmune testing. Perhaps, most importantly in our setting, we must also learn to balance economic challenges with appropriate therapy. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.