Elsevier

The Lancet Neurology

Volume 10, Issue 8, August 2011, Pages 759-772
The Lancet Neurology

Review
Autoantibodies associated with diseases of the CNS: new developments and future challenges

https://doi.org/10.1016/S1474-4422(11)70096-5Get rights and content

Summary

Several CNS disorders associated with specific antibodies to ion channels, receptors, and other synaptic proteins have been recognised over the past 10 years, and can be often successfully treated with immunotherapies. Antibodies to components of voltage-gated potassium channel complexes (VGKCs), NMDA receptors (NMDARs), AMPA receptors (AMPARs), GABA type B receptors (GABABRs), and glycine receptors (GlyRs) can be identified in patients and are associated with various clinical presentations, such as limbic encephalitis and complex and diffuse encephalopathies. These diseases can be associated with tumours, but they are more often non-paraneoplastic, and antibody assays can help with diagnosis. The new specialty of immunotherapy-responsive CNS disorders is likely to expand further as more antibody targets are discovered. Recent findings raise many questions about the classification of these diseases, the relation between antibodies and specific clinical phenotypes, the relative pathological roles of serum and intrathecal antibodies, the mechanisms of autoantibody generation, and the development of optimum treatment strategies.

Introduction

The role of autoantibodies in several neuromuscular disorders has been recognised since the 1970s; antibodies to the acetylcholine receptor have a role in myasthenia gravis and antibodies to voltage-gated calcium channels in the Lambert-Eaton myasthenic syndrome. Both antibodies bind to the extracellular domain of essential membrane proteins. Patients with these diseases usually improve rapidly after plasma exchange, which removes circulating antibodies. The pathogenic roles of these antibodies were established by various in-vitro and in-vivo approaches.1 A major subsequent development in the field was the discovery of specific onconeural antibodies in patients with classic paraneoplastic neurological disorders associated with lung or gynaecological tumours, thymomas, or other tumours,2 but unfortunately patients with these disorders did not often respond to immunotherapies.

The excitement over the past 10 years has come from the discovery of diseases, in both adults and children, that are associated with antibodies to cell-surface proteins expressed in neurons, and the fact that these patients can improve with immunotherapies, although usually more slowly than do those with peripheral antibody-mediated disorders. Many patients present with amnesia, confusion, seizures, and psychiatric features, and some then develop a generalised encephalopathy with movement disorders, loss of consciousness, and hypothalamic disturbance. Some patients have ovarian teratomas, thymomas, or small-cell lung cancer, but most do not have detectable tumours. The disorders associated with these antibodies have previously been termed autoimmune channelopathies,1, 3 even though some of the antigens are not the channels themselves but proteins that are complexed with them on the plasma membrane of neurons, their axons, dendritic spines, or nerve terminals. These proteins are generally expressed throughout the nervous system; nevertheless, the diseases can be quite specific regarding the regions they affect (eg, limbic encephalitis), perhaps owing to the particular vulnerability of some neurons or the increased accessibility of the region to the antibodies.

Although rare, these disorders are beginning to be recognised and treated worldwide, and further specific antibodies will most likely be identified in the future. We describe the main clinical syndromes associated with neuronal antibodies that have been defined in the past few years. We start with limbic encephalitis, which is currently a well recognised syndrome associated with several different antibodies, and then describe other disorders that are less well known and affect wider brain systems. Finally, we briefly discuss the pathogenic roles of the antibodies and propose research priorities.

Section snippets

Autoimmune disorders affecting mainly the temporal lobe or the limbic cortex

Limbic encephalitis was originally described as a rare cliniconeuropathological entity, involving amnesia, seizures, and psychological disturbance, and associated with an underlying neoplasm.4 Since the 1980s, various onconeuronal antibodies have been discovered, which are biomarkers for these classic paraneoplastic syndromes.2 However, paraneoplastic limbic encephalitis is a rare complication of cancer and patients with a non-paraneoplastic form of limbic encephalitis associated with

Anti-NMDAR-encephalitis

NMDAR antibodies are detected in patients with a newly-described syndrome, termed anti-NMDAR encephalitis by the original authors.65, 66, 67 This syndrome is a severe encephalopathy that generally follows a characteristic temporal sequence of features.68 Some old case reports probably described the same disease.69 The outcome of these patients is often good, but recovery can be slow and 15–25% of patients relapse.66, 67, 68 A recent review70 discusses the clinical experience of 400 patients and

Challenges and questions for the future

All these findings in patients with disorders associated with autoantibodies raise crucial questions. How should the diseases be classified—on the basis of clinical presentation or the associated specific antibody? What are the causal mechanisms in patients without tumours? How do the antibodies access the brain parenchyma? Which cells are affected and by which mechanisms? What are the best treatment strategies?

Conclusions

Patients with disorders of the CNS associated with autoantibodies can now be diagnosed and treated. Importantly, anti-NMDAR antibodies have been identified in paediatric patients,67, 68 and VGKC-complex antibodies are beginning to be detected in children with limbic encephalitis or status epilepticus.37, 38, 123 The known antibodies might only be the tip of the iceberg—with others waiting to be identified in well recognised disorders or even in some not yet considered to have immune aetiology.

Search strategy and selection criteria

We searched the authors' own databases and Pubmed for reports in English published in the past 15 years, focusing on limbic encephalitis, stiff-person syndrome, PERM, Morvan's syndrome, potassium channels, autoimmune, VGKC, LGI1, CASPR2, GAD, GlyR, NMDAR, AMPA receptor, and GABABR receptor. We included the papers that we felt added to the descriptions of the diseases.

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