Movement Disorders With Neuronal Antibodies

Syndromic Approach, Genetic Parallels and Pathophysiology

Bettina Balint; Angela Vincent; Hans-Michael Meinck; Sarosh R. Irani; Kailash P. Bhatia

Disclosures

Brain. 2018;141(1):13-36. 

In This Article

Abstract and Introduction

Abstract

Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological 'red flags', and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

Introduction

Neuroimmunology is a rapidly evolving field, fuelled by the discovery of new autoantibodies and syndromes (Lancaster and Dalmau, 2012; Irani et al., 2014). Movement disorders are a prominent and common feature in many autoantibody-mediated neurological diseases, with an expanding spectrum of autoantibodies, but there is a need to establish a phenomenological approach to guide categorization and diagnosis in clinical practice. Although these disorders were generally considered rare and precise prevalences are unknown, it has emerged that, for example, NMDAR antibodies are the most frequent single cause of encephalitis under the age of 30 years (Gable et al., 2012).

These disorders can be encountered by general neurologists or movement disorders specialists alike and it is imperative not to miss these potentially treatable disorders, which can also be an alert to an occult neoplasia. An early diagnosis is important for the prognosis, yet many patients are misdiagnosed, or diagnosed late (Irani et al., 2013; Titulaer et al., 2013). With adequate treatment (immunosuppression or immunomodulation, tumour treatment as appropriate), many patients show a good recovery, although lasting deficits may occur (McKeon et al., 2013; Titulaer et al., 2013; Balint et al., 2014a). Often, prolonged and aggressive immunotherapies are required, which carry a risk of serious adverse effects (e.g. toxicity, infections) and significant expenditure to health systems. Hence, rapid recognition and improved therapies are urgently required.

In this review, we outline the spectrum of movement disorders related to neuronal autoantibodies, highlight useful pointers to these conditions, and present a syndromic approach to guide antibody testing. We also discuss the underlying pathophysiological mechanisms, the emerging parallels to genetic movement disorders, the interface between neuroimmunology and neurodegeneration, and conclude on future therapeutic perspectives.

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