By Claire Henchcliffe, MD, PhD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is a consultant for ACADIA Pharmaceuticals and US WorldMeds.
Autoantibody-associated neurological disorders can mimic neurodegenerative and other movement disorders, but are likely under-diagnosed, resulting in missed treatment opportunities. This review is a “must read” for all neurologists.
Balint B, Vincent A, Meinck HM, et al. Movement disorders with neuronal antibodies: Syndromic approach, genetic parallels, and pathophysiology. Brain 2018;141:13-36.
Balint et al tackled an expanding and rapidly developing field, linking neuroimmunology and presence of specific autoantibodies to movement disorders. The concept is highly familiar, and has been well described in movement disorders such as Sydenham chorea, stiff person syndrome, and paraneoplastic cerebellar degeneration. The authors make the case that anti-neuronal antibody-associated syndromes likely are under-recognized and both under- and mis-diagnosed.
When should the clinical features of movement disorders lead the clinician to suspect an autoimmune etiology? Balint et al proposed a syndromic approach that takes into account the primary movement disorder type, such as dystonia, myoclonus, etc., together with age at onset, “red flags,” and associated features such as encephalopathy and seizures. This then would prompt identification of a panel of candidate autoantibodies for testing. In the first part of their review, Balint et al extensively described and summarized anti-neuronal, anti-glial, and anti-ganglioside antibodies occurring in association with movement disorders that are classified by phenomenology: chorea/dyskinesia, dystonia, myoclonus, parkinsonism, ataxia, sleep movement disorders, tremor, neuromyotonia/myokymia, paroxysmal dyskinesia, and stiff person disorders. The authors provided extensive examples to support their approach. As an example of effects of age at onset, anti-NMDAR antibody-associated encephalitis is more likely to manifest as a movement disorder in children, and anti-D2R antibodies associated with chorea and other symptoms are seen only in children. Uncharacteristic findings on imaging also may prompt further work-up; for example, in a patient with chorea, the presence of cognitive decline and MRI FLAIR hyperintensities would suggest testing for anti-CV2/CRMPS antibodies. Atypical localization of symptoms also may be a red flag (for example, hemidystonia or craniocervical dystonia in children with NMDAR antibodies). Sometimes, however, there may be little to provide the alert, and the authors provided the example of encephalopathy associated with anti-LGI1- and CASPR2- antibody mimicking Creutzfeldt-Jakob disease, which even may have a “cortical ribbon” visualized on MRI.
A second table that listed relative frequency of antibody findings in clinical practice adds context. For example, of multiple autoantibodies associated in the literature with cerebellar ataxia, certain ones are extremely rare to date (such as anti-AP3B2/Nb: single case; ARHGAP26/Ca: six cases), whereas others (anti-Yo or anti-Zic4) are more common. Finally, the authors reviewed the fascinating area of sleep behavior disorders, highlighted in this review as part of IgLON5-antibody-linked neurodegeneration. This tauopathy, associated with presence of IgLON5 antibodies, may begin with sleep disorder but progress to a constellation of symptoms, ultimately suggestive of progressive supranuclear palsy or multiple system atrophy.
Movement disorders arise from multiple etiologies, and a great deal of focus in our sub-specialty has been placed on neurodegenerative and genetic etiologies. Now, however, the clinician is faced with an expanding list of associated autoantibodies including a subset associated with paraneoplastic disease. Balint et al highlighted heterogeneous and overlapping clinical manifestations that may mimic neurodegenerative, genetic, infectious, and other movement disorders. Using phenomenology as a starting point will be extremely useful in the immediate future to the clinician faced with unusual movement disorders or movement disorders associated with “red flags,” such as rapid progressive, an odd combination of symptoms, or presence of autoimmune disorders in the family. On a practical level, it will help “flag” patients for more extensive testing and more frequent follow-up, and if testing reveals the presence of the suspected antibodies, this may open the path to data-driven and targeted treatment. However, this is a young field, and access to specific tests may be limited, there is variability in testing between facilities, and, importantly, the resulting treatments may depend on expert opinion rather than clinical trials. Nonetheless, this paper will serve as a platform upon which to build and as an outstanding reference for clinical practice and teaching in the immediate future. Moreover, it conceptually adds to the drive for precision medicine approaches in neurology and in movement disorders as a whole.