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Widening the spectrum of inflammatory disorders of the central nervous system

an update on autoimmune neurology

Graus, Francesca,b

Current Opinion in Neurology: June 2019 - Volume 32 - Issue 3 - p 449–451
doi: 10.1097/WCO.0000000000000682

aNeurology Program, August Pi Sunyer Biomedical Research Institute (IDIBAPS)

bHospital Clínic, Barcelona, Spain

Correspondence to Francesc Graus, MD, PhD, August Pi Sunyer Biomedical Research Institute (IDIBAPS), Casanova, 143; Floor 3a, Barcelona 08036, Spain. Tel: +34 932 271 738; fax: +34 932 271 726; e-mail:

The same year that I edited the manuscripts under the title of ‘widening spectrum of inflammatory disorders of the central nervous system (CNS’) in the July issue of Current Opinion in Neurology of 2017 [1], the Annual Meeting of the American Academy of Neurology, held the inaugural session of the ‘Autoimmune Neurology’ section. Autoimmune Neurology as a new subspecialty was born to put together an expanding list of CNS disorders, some of them were reviewed in that issue of Current Opinion in Neurology, with an inflammatory/autoimmune pathogenesis that are considered ‘outside the borders’ of multiple sclerosis (MS) and other demyelinating disorders [2]. There are several advantages of putting in the same basket a wide array of disorders that share common pathogenic mechanisms. It allows young neurologists to acquire experience in the diagnosis and treatment of these disorders in reference centers that offer fellowships in the topic. Patients benefit from an early diagnosis, which sometimes may be difficult, and prompt treatment becomes a key prognostic factor for improving [3]. Finally, if facilitates the research on basic and clinical issues that once tested in one disorder can be applied to others that share similar autoimmune mechanisms. For example, the recent design of a simple score that predicts 1-year functional status in patients with N-methyl-D-aspartate (anti-NMDA) receptor encephalitis could be of utility, or it might inspire similar scores, for other types of autoimmune, antibody-mediated encephalitis [4].

Most of us would agree that the characterization of CNS disorders associated with antibodies against synaptic receptors, and particularly the identification of the anti-NMDA receptor encephalitis represented the turning point that attracted the attention of many neurologists to a field, autoimmune neurology, that previously was considered restricted to paraneoplastic neurological disorders [5]. The identification of new antibodies and the characterization of the associated clinical disorders are still expanding and in this new edition of ‘Widening spectrum of inflammatory disorders of the CNS’ in Current Opinion in Neurology, several interesting topics are presented by leading experts in the field of autoimmune neurology. ‘Widening the spectrum’ sometimes leads to ‘crossing the borders’ an issue that make some people uncomfortable. In my opinion ‘crossing the borders’ between autoimmune neurology and demyelinating disorders is exciting and offers an excellent opportunity to test new hypothesis and to generate new ideas. Three articles of this section address topics that are good examples of this paradigm.

McKeon et al. (pp. 452–458) reviews our present knowledge of a new astrocytopathy associated with antibodies against glial fibrillary acidic protein (GFAP) that share some common clinical and radiological features with the neuromyelitis optica spectrum disorder with aquaporin 4 (AQP4) antibodies. Although GFAP antibodies were initially identified in patients with encephalitis, concurrent NMDA receptor antibodies, and ovarian teratoma, it was soon recognized that there were patients with isolated GFAP antibodies (present only in the CSF or both in serum and CSF) that presented a steroid-responsive disorder characterized by a combination of meningoencephalitis and myelitis. Brain MRI frequently shows linear radial gadolinium enhancement perpendicular to lateral ventricles. In patients with myelitis, spine MRI shows a longitudinally extensive T2 lesion [6]. GFAP antibodies probably are not responsible for the neurological syndrome because they target an intracellular antigen, and when they occur in association with AQP4 or NMDAR antibodies, the clinical syndromes are those typically associated with the later antibodies.

In the same line, Marignier et al. (pp. 459–466) update the clinical phenotypes associated with myelin oligodendrocyte glycoprotein (MOG) antibodies in adult patients. Although most patients with MOG antibodies have clinical symptoms compatible with the diagnosis of neuromyelitis optica spectrum disorder, 4% of patients present with an isolated brainstem syndrome that may mimic the MRI features of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids and 2% with encephalopathy or seizures that may be confused with viral or autoimmune encephalitis [7]. These findings reminds us that we have to keep in mind antibodies typically associated with demyelinating diseases in the differential diagnosis of patients with encephalitis or seizures of possible autoimmune origin.

Pseudotumoral demyelinating lesions are considered as a particular feature of MS. However, in up to 24% of patients, the pseudotumoral demyelinating lesion may be the first event of MS or to occur in patients that will not develop MS in the follow-up [8]. The diagnosis of patients with isolated pseudotumoral demyelinating lesions is difficult; Hardy (pp. 467–474) describes the MRI features of these lesions and provides a comprehensive list of disorders that may present with similar radiological features. Most important, he correctly emphasizes the need to test for AQP4 or MOG antibodies patients with pseudotumoral demyelinating lesions in patients without criteria for MS. Neurosarcoidosis must be considered in the differential diagnosis of autoimmune GFAP astrocytopathy, MOG-antibody-associated disease, or pseudotumoral demyelinating lesions. Drent et al. (pp. 475–483) review the criteria required for the diagnosis of neurosarcoidosis and updates the treatment strategies emphasizing of the need to tailor the treatment to the severity of the neurological manifestations.

Autoimmune cerebellar ataxias include a heterogeneous group of disorders characterized by isolated or predominant cerebellar dysfunction [9]. In many instances, the autoimmune target is the Purkinje cell with relative preservation of other neuronal cell types. Similar to limbic encephalitis, the first descriptions of autoimmune cerebellar ataxia were paraneoplastic but later, several types of cerebellar ataxias associated with neuronal antibodies or other immunological markers were characterized in absence of cancer. There are no comprehensive studies to ascertain the frequency of nonparneoplastic autoimmune cerebellar ataxias that probably are underdiagnosed. Joubert and Honnorat (pp. 484–492) review this topic. Unlike autoimmune encephalitis that associate with a wide array of antibodies against neuronal surface receptors, autoimmune cerebellar ataxias rarely associates with these antibodies with the exception of a few patients with anti-metabotropic glutamate receptor 1 or anti-contactin-associated protein-like 2 [10,11]. On the other hand, the role of autoimmune mechanisms in the pathogenesis of gluten ataxia remains controversial mainly because of the lack of definite immunological biomarkers and the poor predictive value of gliadin antibodies [12].

CNS syndromes associated with antibodies against neuronal surface antigens may occur in absence of CSF or neuroimaging evidence of brain inflammation and they can be misdiagnosed with neurodegenerative diseases [13]. The disease characterized by IgLON5 antibodies represent one step forward as it presents features suggestive of both autoimmune (association with a particular HLA allele; DRB1*10:01) and neurodegenerative disorders (neuronal deposits of hyperphosphorylated tau protein) [14]. Anti-IgLON5 disease was initially identified in patients with a novel sleep disorder with non-rapid eye movement parasomnias, sleep apnea, and stridor. However, patients present other neurological symptoms that may be more relevant than the sleep disorder [15]. Gaig and Compta (pp. 493–499) review the main presenting symptoms that include bulbar dysfunction, gait abnormalities, movement disorders like chorea or abnormal facial and mandibular movements, oculomotor abnormalities, cognitive impairment, and symptoms of nervous system hyperexcitability. Depending of the neurological symptoms at presentation, anti-IgLON5 disease may be confused with myasthenia, amyotrophic lateral sclerosis, progressive supranuclear palsy, or multiple system atrophy. The possibility of anti-IgLON5 disease must be suspected when patients do not fulfill definite diagnostic criteria of the disorders listed above and they associate with sleep problems.

Beyond the CNS disorders associated with antibodies against synaptic receptors, probably one of the hottest topics in autoimmune neurology is the neurological side-effects of novel cancer immunotherapies. One of these treatments consist in using genetically engineered T cells which express a chimeric antigen receptor (CAR) that recognizes molecules expressed in the membrane of tumor cells [16]. Another strategy uses monoclonal antibodies against immune checkpoint molecules [17], whereas CAR T-cell therapy can result in severe neurological side-effects related to a direct neurotoxic effect of cytokines, which reach the brain by passive diffusion or are produced by intrathecal CAR T-cells, the enhanced activation of the immune system by immune checkpoint inhibitors has been associated with an increased incidence of immune-related adverse effects, some affecting any part of the peripheral or central nervous system [18,19]. Hottinger et al. (pp. 500–510) review the neurological complications that may occur in the setting of CAR T-cell therapy and the treatment with immune checkpoint inhibitors and provide guidelines for its diagnosis and treatment. Immune checkpoint inhibitors have become a standard treatment for many tumors and in the future, CAR T-cell therapy will likely be used in a larger number of patients. This perspective highlights the need to increase the surveillance for the associated neurological complications. Patients on cancer immunotherapy that develop neurological symptoms should be evaluated by neurologists with expertise in autoimmune neurology as the best guarantee that they will have an accurate diagnosis and the most appropriate treatment. This is a perfect example that justifies the subspecialty of autoimmune neurology and the development of high-quality fellowship programs to cope with the demands of the coming years.

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Financial support and sponsorship

F.G. receives royalties from licensing fees to Euroimmun for the use of IgLON5 as a diagnostic test and honoraria from MedLink Neurology as senior associated editor.

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Conflicts of interest

There are no conflicts of interest.

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