Paraneoplastic Neurologic Syndromes

Peter Maat, Erasmus University Medical Center, Erasmus MC‘s‐Gravendijkwal 230, Rotterdam, The Netherlands
Peter AE Sillevis Smitt, Erasmus University Medical Center, Erasmus MC‘s‐Gravendijkwal 230, Rotterdam, The Netherlands

Published online: September 2009

DOI: 10.1002/9780470015902.a0021410

Paraneoplastic neurologic syndromes (PNS) are remote effects of cancer. Immunological factors appear important in the pathogenesis of PNS since the detection of antineuronal autoantibodies. Detection of paraneoplastic antibodies is very helpful in diagnosing an unexplained neurological syndrome as paraneoplastic and in directing the search towards the underlying neoplasm. There are seven well-characterized paraneoplastic antibodies reactive with the onconeural Hu, Yo, Ri, Ma2, CV2, amphiphysin and recoverin antigens. Recently, anti-VGKC and anti-NMDA receptor antibodies were identified in patients with limbic encephalitis (LE). Thirty per cent of patients with anti-VGKC and LE have an underlying tumour, while most patients with anti-NMDAR and LE are young women with an ovarian teratoma. Both VGKC- and NMDAR-related LE respond well to immunotherapy. In contrast, the effect of immunotherapy in patients with PNS associated with antibodies against the intracellular onconeural antigens is disappointing. These patients benefit most from early detection and treatment of the underlying tumour.

Keywords: paraneoplastic syndromes; tumour autoimmunity; onconeural antibodies

Figure 1. The hypothesized pathogenesis of antibody-associated PNS. Onconeural antigen expressing tumour cells are phagocytozed by antigen-presenting cells (APC) that migrate to lymph nodes, where they present antigenic peptides to specific CD8+ and CD4+ T cells via HLA-class I and HLA-class II molecules, respectively. Tumour cells themselves present onconeural antigens to CD8+ T cells via HLA-class I molecules. The CD4+ T cells support CD8+ T-cell activation and proliferation by cytokines such as IFN- and IL-2. CD4+ T cells stimulate B cells through cytokines including interleukin (IL)-4 and IL-5. B cells recognize soluble onconeural antigens through their B-cell receptor. After activation, B cells differentiate into plasma cells, which secrete specific antibodies. Upon engagement of their TCR and accessory molecules, CD8+ T cells can destroy tumour cells by secreting granzymes, perforins and cytokines such as TNF-, or by upregulation of CD95 (Fas ligand) on tumour cells. The remnants of destroyed tumour cells can be taken up by APC, processed and presented to T cells. In addition, they can be specifically recognized by antibodies and eliminated via Fc receptor-expressing phagocytes. Cytotoxic specific CD8+ T cells not only slow the tumour growth, but they also cross the blood brain barrier and similarly attack neurons expressing the onconeural antigen, causing severe neurological damage in these patients.
Figure 2. Antineuronal antibodies in paraneoplastic cerebellar degeneration. Staining of rat cerebellum (a–e) or cortex (f) using patients’ sera as primary antibody and peroxidase labelled secondary anti-IgG antibodies show nuclear more than cytoplasmic staining of granular and molecular layer neurons and Purkinje cells using anti-Hu (a) antibody positive serum; characteristic cytoplasmic staining of Purkinje cells by anti-Yo positive serum (b); cytoplasmic staining of Purkinje cells with staining of fine dots in the molecular layer by anti-Tr positive serum (c); strong staining of the molecular layer by anti-mGluR1 positive serum (d); synaptic interstitial staining of the molecular and granular layer by CV2 positive serum (e) and sub-nuclear staining of cortical neurons using anti-Ma2 positive serum (f). ML, molecular layer; PC, Purkinje cell; GL, granular layer; N, (cortical) neuron.
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Neurobiology of Disease | Autoimmunity
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Article Title: Paraneoplastic Neurologic Syndromes
 
How to Cite close
Maat, Peter, and Sillevis Smitt, Peter AE(Sep 2009) Paraneoplastic Neurologic Syndromes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021410]