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Paraneoplastic Neurological Syndromes
Introduction
Paraneoplastic neurological syndromes (PNS) are immune-mediated disorders triggered by an occult or known malignancy. They can affect any part of the nervous system and often precede cancer diagnosis by months to years. The 2021 updated PNS-Care criteria provide a systematic framework for diagnosis, antibody classification, and cancer screening.
Pathophysiology
Tumor cells express neuronal antigens (onconeural antigens) that trigger an immune response cross-reacting with the nervous system. Intracellular antibodies (such as anti-Hu and anti-Yo) mediate T-cell directed neuronal destruction that is typically irreversible, carries a strong cancer association, and responds poorly to immunotherapy. Cell-surface antibodies (such as anti-NMDAR and anti-LGI1) are directly antibody-mediated, potentially reversible, have variable cancer association, and respond better to immunotherapy. Early detection and cancer treatment are the most important prognostic factors.
2021 PNS-Care Diagnostic Criteria
Definite PNS requires a high-risk antibody plus a compatible syndrome plus cancer within the expected window. Probable PNS requires a high- or intermediate-risk antibody plus a compatible syndrome without cancer yet identified, or a classical syndrome with cancer and no antibody identified. Possible PNS indicates clinical suspicion without confirmatory antibody or cancer. Antibodies are classified as high-risk (greater than 70% cancer association) or intermediate-risk (30-70%).
Classical Paraneoplastic Syndromes
Subacute Cerebellar Degeneration
This presents as a rapidly progressive pancerebellar syndrome over weeks to months with truncal and limb ataxia, dysarthria, nystagmus, and vertigo. Associated antibodies include anti-Yo (ovarian, breast cancer), anti-Tr/DNER (Hodgkin lymphoma), anti-Hu, and anti-CV2. MRI is initially normal but later shows cerebellar atrophy. Purkinje cell loss is irreversible, making early cancer treatment critical.
Sensory Neuronopathy (Denny-Brown Syndrome)
This causes subacute, asymmetric, painful sensory neuropathy affecting all modalities with prominent sensory ataxia and pseudoathetosis due to proprioceptive loss. The pathology is dorsal root ganglion inflammation and neuronal destruction. The associated antibody is anti-Hu (ANNA-1) with small cell lung cancer (SCLC). Nerve conduction studies show absent or low-amplitude sensory potentials with preserved motor responses.
Encephalomyelitis
This is a multifocal syndrome combining limbic encephalitis, brainstem encephalitis, myelitis, and autonomic neuropathy. Anti-Hu is the most common antibody, and SCLC is the most common associated malignancy. It is often combined with sensory neuronopathy.
Lambert-Eaton Myasthenic Syndrome (LEMS)
LEMS presents with proximal weakness, hyporeflexia, and autonomic dysfunction (dry mouth). It is caused by anti-VGCC (P/Q-type) antibodies. Approximately 60% of cases are associated with SCLC; the remainder are autoimmune. EMG shows low CMAP amplitudes that increment more than 100% with rapid repetitive nerve stimulation or post-exercise facilitation. 3,4-diaminopyridine (3,4-DAP) is the first-line symptomatic treatment.
Opsoclonus-Myoclonus Syndrome
This manifests as involuntary, chaotic, multidirectional saccadic eye movements (opsoclonus) with myoclonus and ataxia. In adults, it is associated with anti-Ri antibodies (breast, lung cancer). In children, neuroblastoma is present in 50% of cases. Children may have no detectable antibody, and tumor screening with urine catecholamines and chest/abdominal imaging is mandatory.
Antibodies and Cancer Associations
High-Risk Intracellular Antibodies
| Antibody | Cancer Association | Neurological Syndrome | Reversibility |
|---|---|---|---|
| Anti-Hu (ANNA-1) | SCLC | Encephalomyelitis, sensory neuronopathy | Poor |
| Anti-Yo (PCA-1) | Ovarian, breast | Cerebellar degeneration | Poor (irreversible) |
| Anti-Ri (ANNA-2) | Breast, SCLC | Opsoclonus-myoclonus | Partial |
| Anti-CV2/CRMP5 | SCLC, thymoma | Chorea, neuropathy, optic neuritis | Partial |
| Anti-amphiphysin | Breast, SCLC | Stiff person spectrum | Partial |
| Anti-VGCC (P/Q) | SCLC (60%) | LEMS | Good with 3,4-DAP + tumor Rx |
| Anti-TIF1-gamma | Various (adults) | Dermatomyositis | With cancer treatment |
Anti-Hu (ANNA-1) is associated with SCLC and causes encephalomyelitis and sensory neuronopathy. Anti-Yo (PCA-1) is associated with ovarian and breast cancer and causes cerebellar degeneration. Anti-Ri (ANNA-2) is associated with breast cancer and SCLC and causes opsoclonus-myoclonus and brainstem encephalitis. Anti-CV2/CRMP5 is associated with SCLC and thymoma and causes chorea, neuropathy, and optic neuritis. Anti-amphiphysin is associated with breast cancer and SCLC and causes stiff person spectrum disorder.
Cell-Surface Antibodies with Paraneoplastic Associations
Anti-NMDAR is associated with ovarian teratoma (in young women) and causes encephalitis. Anti-GABA-B is associated with SCLC and causes limbic encephalitis with seizures. Anti-AMPAR is associated with breast cancer, lung cancer, and thymoma, causing limbic encephalitis. Anti-CASPR2 is associated with thymoma and causes neuromyotonia and Morvan syndrome.
Diagnostic Workup
The evaluation should include a comprehensive antibody panel (serum and CSF) covering both intracellular and cell-surface antigens. Initial cancer screening begins with CT chest/abdomen/pelvis. Whole-body PET-CT is the most sensitive modality for occult malignancy and is recommended when CT is negative. Testicular ultrasound (young men) and pelvic MRI/ultrasound (women with anti-NMDAR antibodies) should be performed as appropriate. Cancer screening should be repeated every 3-6 months for 2 years if the initial screen is negative and clinical suspicion remains high.
Treatment
Cancer Treatment
Oncological therapy is the most effective intervention because tumor removal can halt immune-mediated neuronal destruction. Rapid tumor identification and treatment improves neurological outcomes.
Immunotherapy
Cell-surface antibody syndromes respond well to immunotherapy (corticosteroids, IVIG, PLEX, rituximab, cyclophosphamide). Intracellular antibody syndromes generally have a poor response to immunotherapy due to irreversible T-cell mediated neuronal loss. Nevertheless, a trial of immunotherapy is still recommended even for intracellular antibody syndromes, especially early in the course.
Symptomatic Management
3,4-DAP is used for LEMS weakness. Antiseizure medications manage seizures. Clonazepam is used for opsoclonus-myoclonus. Rehabilitation and supportive care complete the management approach.
Clinical Pearls
Paraneoplastic syndromes often precede cancer diagnosis, and a negative initial cancer screen does not exclude malignancy; imaging should be repeated every 3-6 months for 2 years. Intracellular antibody syndromes (anti-Hu, anti-Yo) cause irreversible damage, and early cancer treatment offers the best chance of stabilization. LEMS with anti-VGCC antibodies requires screening for SCLC, and post-exercise facilitation on EMG is a key diagnostic clue. Cell-surface antibody syndromes (anti-NMDAR, anti-LGI1) are more responsive to immunotherapy and have better neurological outcomes.
References
- Graus F, Vogrig A, Muniz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurology Neuroimmunol Neuroinflamm. 2021;8(4):e1014.
- Dalmau J, Graus F. Antibody-mediated encephalitis. N Engl J Med. 2018;378(9):840-851.
- Titulaer MJ, Lang B, Verschuuren JJ. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10(12):1098-1107.
- Pittock SJ, Lucchinetti CF. Inflammatory and demyelinating disorders. In: Bradley's Neurology in Clinical Practice. 7th ed. Elsevier; 2016.