Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis¶
Chapter 99 | Part 4: Oncology and Hematology · Part 4 – Oncology: Solid Tumors · Chapter 99
Key Clinical Points¶
- Paraneoplastic neurologic disorders (PNDs) affect any part of the nervous system; 60% present with neurologic symptoms before cancer diagnosis.
- High-risk antibodies (>70% tumor probability): Anti-Hu, Anti-Yo, Anti-Ri, Anti-Tr, Anti-PCA2, Anti-Ma, and Anti-AMPA.
- Intracellular antigen syndromes (e.g., Anti-Hu) involve T-cell mediated cytotoxicity; surface antigen syndromes (e.g., Anti-NMDAR) are antibody-mediated and more responsive to immunotherapy.
- Anti-NMDAR encephalitis: Characterized by psychiatric symptoms, seizures, and autonomic instability; often associated with ovarian teratomas in young women/children.
- Anti-LGI1 encephalitis: Typically affects adults >50 years; characterized by faciobrachial dystonic seizures and hyponatremia (rarely associated with thymoma).
- Tumor control is critical for intracellular antigen syndromes; first-line immunotherapy (steroids, IVIg, plasma exchange) is used for surface antigen syndromes.
- MRI findings: Limbic encephalitis shows medial temporal lobe hyperintensity on FLAIR; Anti-NMDAR often has normal MRI or mild FLAIR changes.
- MOG antibody encephalitis: 85% respond to immunotherapy but have high relapse rates (approximately 30%).
- Differential diagnosis must exclude metastatic spread, leptomeningeal disease, and viral infections (HSV, HHV-6).
- Antineuronal antibodies in serum/CSF support PND diagnosis; negative results do not rule out PND in low-risk scenarios.
1. DEFINITION & OVERVIEW¶
Paraneoplastic neurologic disorders (PNDs) are cancer-related syndromes affecting any part of the nervous system. Most PNDs have an autoimmune pathogenesis triggered by underlying cancers.
Clinical Prevalence: • 60% of patients present with neurologic symptoms before cancer diagnosis. • Overall prevalence: 0.5–1% of all cancer patients. • Neuroblastoma/SCLC: 2–3% prevalence. • Thymoma: 30–50% prevalence.
1.1 Classification by Risk¶
PNDs are categorized based on the probability of an underlying tumor associated with specific antineuronal antibodies.
High-risk antibodies (>70% tumor probability): • Anti-Hu (ANNA1), Anti-Yo (PCA1), Anti-Ri (ANNA2), Anti-Tr (DNER), Anti-PCA2 (MAP1B), Anti-Ma, and Anti-AMPA.
Intermediate-risk (30–70%): • Anti-NMDAR, Anti-GABAR, Anti-mGluR5.
Low-risk (<30%): • Anti-LGI1, Anti-DPPX, Anti-IgLON5, Anti-MOG, Anti-AChR, Anti-mGluR1, Anti-aquaporin 4.
1.2 Pathogenesis Overview¶
• Intracellular antigen syndromes: Triggered by T-cell mediated cytotoxicity, microglial activation, and gliosis → significant neuronal loss. • Surface antigen syndromes: Driven by direct antibody effects on cell-surface proteins; typically show less neuronal loss and are more responsive to immunotherapy. • Immune Response Pathway: 1. Antigen release (Tumor/Viral) → 2. APC uptake racks 3. Lymph node activation of B cells & T cells → 4. Plasma cell differentiation → 5. Antibody production and entry into CNS.
2. EPIDEMIOLOGY¶
• General Prevalence: 0.5–1% of all cancer patients. • Specific Associations: ◦ Neuroblastoma/SCLC: 2–3% prevalence. ◦ Thymoma: 30–50% prevalence. ◦ Anti-NMDAR encephalitis: Predominates in young women and children (rarely associated with tumors in men or older adults). ◦ Anti-LGI1 encephalitis: Primarily affects patients >50 years (65% male). ◦ Anti-IgLON5 disease: Median age 60s, equal sex distribution.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Most PNDs result from immune responses to ectopic neuronal proteins in tumors (e.g., SCLC) or altered immunologic responses in thymomas/lymphomas.
Pathogenic Mechanisms: • Intracellular Antigens: T-cell cytotoxicity, microglial activation, and gliosis → neuronal loss. • Surface Antigens: Antibody-mediated receptor dysfunction; less cellular infiltration.
Antibody-Mediated Synaptic Dysfunction (Figure 4): 1. Functional Blocking: Antibodies physically block receptors from binding neurotransmitters (e.g., GABAR). 2. Cross-linking and Internalization: Antibodies cause internalization of receptors, reducing surface density (e.g., NMDAR). 3. Disruption of Protein-Protein Interaction: Antibodies interfere with complex interactions; e.g., LGI1 antibodies disrupt interaction with ADAM22/ADAM23 → decrease in Kv4.1 potassium channels and AMPAR.
IgG Subclasses: • IgG1: Frequently crosslink and internalize target antigens. • IgG4: Less effective at crosslinking; more likely to alter protein-protein interactions.
4. CLINICAL FEATURES¶
PNDs present with diverse clinical phenotypes based on the specific antigen targeted.
Syndromes by Antibody: • Anti-Hu (ANNA1): Encephalomyelitis, sensory neuronopathy, cerebellar syndrome. • Anti-Yo (PCA1): Rapidly progressive cerebellar syndrome. • Anti-Ri (ANNA2): Cerebellar degeneration, opsoclonus, brainstem encephalitis. • Anti-NMDAR: Psychiatric symptoms, seizures, autonomic instability. • Anti-LGI1: Faciobrachial dystonic seizures, hyponatremia. • Anti-IgLON5: Sleep disorders (NREM/REM), brainstem dysfunction, obstructive sleep apnea.
Specific Markers & Associations: • CRMP5: Chorea, uveitis, optic neuritis. • Ma proteins: Limbic/hypothalamic encephalitis, hypersomnia, cataplexy. • Kelch-like 11: Brainstem encephalitis, hearing loss, seminomas/germ cell tumors. • Amphiphysin: Stiff-person syndrome (SPS), myelitis. • MOG antibodies: Optic neuritis, myelitis, ADEM.
4.1 Clinical Syndromes by Location¶
• CNS/Dorsal Root Ganglia: Encephalomyelitis with autonomic dysfunction. • Peripheral Nerve/Muscle: ◦ LEMS → SCLC association. ◦ Myasthenia gravis → Thymoma association. ◦ Autonomic ganglionopathy → SCLC. ◦ Pure autonomic neuropathy → Cancer/melanoma.
5. DIFFERENTIAL DIAGNOSIS¶
Clinical presentation of PNDs must be differentiated from other conditions that mimic autoimmune encephalitis.
Must Exclude: 1. Direct metastatic spread of cancer. 2. Leptomeningeal disease. 3. Viral encephalitis (HSV, HHV-6). 4. Nonparaneoplastic autoimmune limbic encephalitis. 5. Immune checkpoint inhibitor-related neurologic events.
Specific Mimics: • MOG antibody encephalitis may mimic viral encephalitis or neuroleptic malignant syndrome.
6. INVESTIGATIONS & DIAGNOSIS¶
Diagnostic approach involves a combination of serology, imaging, and CSF analysis.
1. Antineuronal Antibody Testing: • Perform serum and CSF testing for antineuronal antibodies. • Note: Serum/CSF antibodies are limited to CNS PNDs; <20% of peripheral nerve cases show them.
2. Imaging (MRI): • Limbic encephalitis: Medial temporal lobe FLAIR hyperintensity. • Anti-NMDAR: Often shows normal MRI or mild FLAIR changes. • MOG antibody: Cortical necrosis with enhancement on T2-weighted images. • Anti-IgLON5: Often unrevealing MRI; CSF may show transient lymphocytosis.
3. CSF Analysis: • Mild pleocytosis (<200 lymphocytes). • Elevated protein. • Oligoclonal bands.
6.1 Risk Category Summary¶
• High-risk (>70%): Anti-Hu, Anti-Yo, Anti-Ri, Anti-Tr, Anti-PCA2, Anti-Ma, Anti-AMPA. • Intermediate-risk (30–70%): Anti-NMDAR, Anti-GABAR, Anti-mGluR5. • Low-risk (<30%): Anti-LGI1, Anti-DPPX, Anti-IgLON5, Anti-MOG, Anti-AChR, Anti-mGluR1, Anti-aquaporin 4.
6.2 Tumor Screening¶
• Standard Imaging: CT/PET for occult cancers. • Specific Targets: Ultrasound/MRI for germ cell tumors or teratomas. • Enhanced Detection: Combined CT/PET scans are used to detect tumors missed by other modalities.
7. MANAGEMENT & TREATMENT¶
Management is tailored based on the specific antibody and the presence of an underlying malignancy.
1. Tumor Control: • Identify and treat underlying tumor (surgery, chemotherapy). • Critical for patients with intracellular antigen syndromes (e.g., Anti-Hu).
2. First-line Immunotherapy (Surface Antigens): • Glucocorticoids. • IVIg. • Plasma exchange.
3. Second-line Immunotherapy: • Rituximab (increasingly used as first-line for surface antigen syndromes). • Cyclophosphamide.
4. Specific Protocols: • Anti-NMDAR: Combination of glucocorticoids, IVIg, and plasma exchange; use rituximab if non-responsive. • MOG antibody: 85% respond to immunotherapy; monitor for relapses (approx. 30%). • Anti-LGI1: Treat hyponatremia with vasopressin analogs.
7.1 Tumor Detection Strategy¶
• Germ cell tumors/teratomas: Use Ultrasound, MRI, or CT. • Undetected tumors: Utilize combined CT/PET scans to identify occult malignancies.
8. PROGNOSIS & COMPLICATIONS¶
• Neurologic Improvement: 85–90% of patients show improvement or full recovery. • Relapses: Total relapses occur in 12–24% of cases; 12% occur within the first 2 years. • Intrathecal Synthesis: Antibody synthesis in CSF is common in most patients.
9. SPECIAL CONSIDERATIONS¶
• Pediatric Patients: ◦ Anti-NMDAR encephalitis: High association with ovarian teratomas. ◦ Anti-IgLON5: May present with sleep disorders and brainstem dysfunction in children.
Immunotherapy Considerations: • Rituximab: Effective for surface antigen syndromes; monitor for infections/B-cell depletion. • IVIg/Plasma exchange: First-line for anti-NMDAR and MOG antibody encephalitis.
10. KEY PEARLS & CLINICAL TRAPS¶
• Anti-NMDAR: Normal MRI does not rule out the diagnosis; must test for antibodies. • Anti-LGI1: Hyponatremia is a hallmark; treat with vasopressin analogs. • MOG Antibodies: High response rate to immunotherapy but high risk of relapse. • Negative Results: Negative antineuronal antibodies do not rule out PND in low-risk scenarios. • Intracellular vs. Surface: Intracellular antigens (e.g., Hu) are T-cell mediated; surface antigens (e.g., NMDAR) are antibody-mediated and more responsive to immunotherapy.
Reference Tables¶
TABLE 99-2 High-Risk Antibodies (>70% Probability of an Underlying Cancer), Syndromes, and Associated Tumors ANTIBODY a…¶
Harrison's 22e, p.743
| 99 | Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis Josep Dalmau, Francesc Graus |
|---|---|
TABLE 99-2 High-Risk Antibodies (>70% Probability of an Underlying Cancer), Syndromes, and Associated Tumors
| ANTIBODYa | ASSOCIATED NEUROLOGIC SYNDROME(S) |
TUMORS |
|---|---|---|
| Anti-Hu (ANNA1) | Encephalomyelitis, sensory neuronopathy |
SCLC |
| Rapidly progressive cerebellar syndrome |
||
| Anti-Ri (ANNA2) | Cerebellar degeneration, opsoclonus, brainstem encephalitis |
Breast, gynecologic, SCLC |
| Encephalomyelitis, chorea, optic neuritis, uveitis, peripheral neuropathy |
||
| Anti-Tr (DNER) | Rapidly progressive cerebellar syndrome |
Hodgkin’s lymphoma |
| Limbic, hypothalamic, brainstem encephalitis |
||
| Anti-PCA2 (MAP1B) | Sensorimotor neuropathy, rapidly progressive cerebellar syndrome, and encephalomyelitis |
SCLC, non-SCLC, breast cancer |
| Brainstem encephalitis, ataxia, sensorineural hearing loss |
||
| Anti-amphiphysinb | Stiff-person syndrome, encephalomyelitis |
Breast, SCLC |
| LEMS, rapidly progressive cerebellar syndrome with and without LEMS |
TABLE 99-1 Paraneoplastic Syndromes of the Nervous System¶
Harrison's 22e, p.743
| CLASSIC SYNDROMES: HIGH RISK OF ASSOCIATED CANCERa |
NONCLASSIC SYNDROMES: MODERATE OR LOW RISK OF ASSOCIATED CANCER |
|---|---|
| Encephalomyelitis Limbic encephalitis Cerebellar degeneration (adults) Opsoclonus-myoclonus Sensory neuronopathy Gastrointestinal pseudo- obstruction (enteric neuropathy) Dermatomyositis (adults) Lambert-Eaton myasthenic syndrome Cancer- or melanoma-associated retinopathy |
Brainstem encephalitis Stiff-person syndrome Progressive encephalomyelitis with rigidity and myoclonus Necrotizing myelopathy Motor neuron disease Subacute axonal sensory-motor neuropathies Paraproteinemic neuropathies Pure autonomic neuropathy Acute necrotizing myopathy Polymyositis Optic neuropathy BDUMP Peripheral nerve hyperexcitability (neuromyotonia) Myasthenia gravis |
TABLE 99-3 Intermediate-Risk Antibodies (30–70% Probability of an Underlying Cancer), Syndromes, and Associated Tumors…¶
Harrison's 22e, p.743
| ANTIBODYa | NEUROLOGIC SYNDROME | TUMOR TYPE WHEN ASSOCIATED |
|---|---|---|
| Anti-NMDARb | Anti-NMDAR encephalitis | Teratoma in young women (children and men rarely have tumors) |
| Limbic encephalitis with relapses | ||
| Anti-GABARc B |
Limbic encephalitis with early and prominent seizures |
SCLC |
| Morvan syndrome | ||
| Anti-mGluR5b | Autoimmune encephalitis without distinctive features |
Hodgkin lymphoma |
| LEMS, cerebellar degeneration |
TABLE 99-4 Low-Risk Antibodies (<30% Probability of an Underlying Cancer), Syndromes, and Associated Tumors ANTIBODY a…¶
Harrison's 22e, p.744
| ANTIBODYa | NEUROLOGIC SYNDROME | TUMOR TYPE WHEN ASSOCIATED |
|---|---|---|
| Anti-LGI1b | Limbic encephalitis, hyponatremia, faciobrachial dystonic seizures |
Rarely thymoma |
| Encephalitis with prominent seizures and status epilepticus |
||
| Anti-DPPXb | Agitation, myoclonus, tremor, seizures, hyperekplexia, encephalomyelitis with rigidity |
No cancer, but frequent diarrhea or cachexia suggesting paraneoplasia |
| PERM, stiff-person syndrome | ||
| Anti-IgLON5b | NREM and REM sleep disorder, brainstem dysfunction, movement disorder, obstructive sleep apnea, stridor |
No tumor association |
| Stiff-person, cerebellar syndrome, encephalitis with seizures, limbic encephalitis |
||
| Anti-mGluR1b | Cerebellar syndrome | Hodgkin’s lymphoma in <10% of patients |
| Meningoencephalitis and myelitis | ||
| Anti-aquaporin 4b | Neuromyelitis optica spectrum disorders |
Lung and breast adenocarcinomas in a few patients |
| ADEM, optic neuritis, myelitis, cortical encephalitis |
||
| Anti-AChR (muscle)b |
Myasthenia gravis | Thymoma |
| Autonomic ganglionopathy |