Paraneoplastic neurological syndromes are immune-mediated disorders of the nervous system which occur in the setting of malignancy but are not related to direct malignant infiltration, metastatic deposits, metabolic or nutritional disorders, or adverse effects of therapy. The pathogenesis of paraneoplastic neurological syndromes is not fully understood. Cancer cells may express antigens which mimic neuronal epitopes, leading to the formation of self-reactive T cells and B cells. While there are several well-recognised syndromes associated with specific paraneoplastic antibodies and specific malignancies, it is not clear for all of these disorders whether the antibody is pathogenic (i.e. directly implicated in neuronal damage).
There are several recognised ‘classical’ paraneoplastic syndromes which should raise clinical suspicion for an underlying malignancy. However, many people presenting with these syndromes will not have underlying malignancy, and many people with an underlying malignancy may present with ‘non-classical’ neurology. Similarly, ‘paraneoplastic’ antibodies can be detected in well people without malignancy or neuronalogical disease. As neither clinical findings nor serology are 100% sensitive and specific, the diagnosis of a paraneoplastic neurological syndrome relies on a constellation of supportive clinical findings, with or without demonstration of an antibody, exclusion of other causes, and pursuit of the underlying malignancy.
Here are non-exhaustive lists of well-characterised paraneoplastic antibodies and classical paraneoplastic syndromes. Adapted from this great review.
Antibody associations with specific paraneoplastic syndromes:
Antibody | Features | Malignancies |
Anti-Hu | Encephalomyelitis
Limbic encephalitis Sensory neuronopathy Sensorimotor neuropathy |
Lung cancer (85% Small Cell)
Neuroblastoma Prostate cancer |
Anti-Yo | Paraneoplastic cerebellar degeneration | Ovarian cancer
Breast cancer |
Anti-CRMP2 | Encephalomyelitis
Limbic encephalitis Polyneuropathy Optic neuritis Paraneoplastic cerebellar degeneration |
Small cell lung cancer
Thymoma |
Anti-Ma | Limbic encephalitis | Testicular cancer |
Anti-Ri | Opsoclonus-myoclonus syndrome
Paraneoplastic cerebellar degeneration Jaw dystonia Laryngospasm |
Breast cancer
Small cell lung cancer |
Anti-recoverin | Retinopathy | Small cell lung cancer |
Classic paraneoplastic syndromes and their cognate antibodies:
Syndrome | Associated antibodies |
CNS | |
Subacute cerebellar degeneration | Hu, Yo, CRMP5, Ri, Tr, Amphiphysin, VGCC |
Encephalomyelitis | Hu, CRMP5, Amphiphysin |
Limbic encephalitis | Hu, Ma, CRMP5, Ri, Amphiphysin, NMDAR, Lgi1, CASPR2, GABAb, AMPAR, mGluR5, GlyR, GAD |
Opsoclonus-myoclonus | Ri, Hu, Ma, NMDAR |
Retinopathy | Hu, CRMP5, Recoverin |
Stiff person syndrome | Amphiphysin, GlyR, GAD |
Anti-amphiphysin | Stiff person syndrome |
PNS | |
Subacute sensory neuronopathy | Hu, CRMP5, Amphiphysin |
Chronic intestinal pseudoobstruction | Hu, CRMP5, Amphiphysin |
LEMS | VGCC, SOX1 |
Dermatomyositis | Mi2, Jo1, SRP |