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9 notes available
1 Last Minute Review 2 Multiple Sclerosis 3 Disease-Modifying Therapies 4 NMOSD & MOGAD 5 Systemic Diseases 6 Autoimmune Encephalitis 7 Paraneoplastic Syndromes 8 CNS Vasculitis 9 Other Neuroimmunology Topics
Clinical › Immunology

Paraneoplastic Syndromes

Paraneoplastic Neurological Syndromes

What You'll Learn

  • Two antibody classes: Cell-surface antibodies are directly pathogenic and immunotherapy-responsive; intracellular (onconeural) antibodies are biomarkers of T-cell–mediated neuronal destruction — poor immunotherapy response, treat the tumor
  • 2021 PNS-Care score: Numeric score combining phenotype + antibody + cancer + follow-up; Definite PNS ≥8, Probable 6–7, Possible 4–5; antibodies classified as high-, intermediate-, or low-risk — guides cancer screening intensity
  • Anti-Yo = paraneoplastic cerebellar degeneration: Most common cause of PCD; ovarian/breast cancer; irreversible Purkinje cell loss; poor prognosis despite treatment
  • Anti-Hu = sensory neuropathy/encephalomyelitis: SCLC; dorsal root ganglionopathy with painful asymmetric sensory ataxia; poor prognosis
  • Tumor removal is primary therapy: Especially for intracellular antibody syndromes where immunotherapy alone is insufficient
  • Negative cancer screen does NOT exclude malignancy: For high-risk phenotype + high/intermediate-risk antibodies with negative initial screen, repeat tumor screening every 4–6 months for 2 years (PNS-Care 2021); tumors may be occult or microscopic. Older EFNS-style longer-interval recommendations are historical guidance
  • Early treatment is critical: Cell-surface antibody syndromes are reversible if caught early; intracellular antibody syndromes cause irreversible damage before diagnosis
HighYield Pearls
  • Cell-surface vs intracellular: Surface antibodies (NMDAR, LGI1, CASPR2, AMPA, GABA-B, DPPX) are directly pathogenic, immunotherapy-responsive, often reversible; intracellular/onconeural (Hu, Yo, Ri, Ma2, CV2/CRMP5, amphiphysin) are T-cell–mediated biomarkers — treat the tumor, immunotherapy alone insufficient
  • Anti-Yo (PCA-1) → PCD → ovarian/breast: Subacute pancerebellar syndrome in older woman — image GYN tract (pelvic US, mammogram, CA-125); irreversible Purkinje cell loss; worst recovery of all paraneoplastic syndromes
  • Anti-Hu (ANNA-1) → SCLC: Causes sensory neuronopathy (DRG attack — asymmetric loss of ALL modalities + pseudoathetosis + sensory ataxia + areflexia), limbic encephalitis, encephalomyelitis, autonomic neuropathy — chest CT/PET for SCLC even in non-smokers
  • Anti-Ma2 → testicular germ cell in young man: Brainstem encephalitis + diencephalic/hypothalamic involvement → REM sleep behavior disorder, narcolepsy, endocrine dysfunction — testicular US (and orchiectomy if negative imaging but high suspicion)
  • Anti-NMDAR → ovarian teratoma in young woman: Psychiatric prodrome → orofacial dyskinesia + autonomic instability + seizures + extreme delta brush on EEG; may follow HSV encephalitis; pelvic US/MRI mandatory; excellent recovery with tumor removal + immunotherapy
  • Anti-LGI1 limbic encephalitis: Older men, faciobrachial dystonic seizures (FBDS — pathognomonic), hyponatremia (SIADH), memory loss; rarely paraneoplastic; best prognosis among limbic encephalitides if treated early
  • OMS age splits the workup: Children → neuroblastoma (urine HVA/VMA + abdominal MRI/MIBG); adults → breast/SCLC with anti-Ri (ANNA-2)
  • LEMS → anti-VGCC (P/Q-type) + SCLC: Proximal weakness with post-exercise facilitation, areflexia that returns after exercise, autonomic features (dry mouth); incremental response >100% on high-frequency RNS; treat with amifampridine + tumor + immunosuppression
  • Stiff person syndrome: High-titer anti-GAD65 (>100,000) — non-paraneoplastic, autoimmune, T1DM association; anti-amphiphysin — paraneoplastic SPS variant linked to breast cancer (always screen)
  • Negative cancer screen does NOT exclude tumor: Repeat FDG-PET/CT every 4–6 months for 2 years in high-risk phenotype + high/intermediate-risk antibody patients (PNS-Care 2021) — occult tumor surfaces in ~50% of initially negative high-risk antibody cases
  • Immune checkpoint inhibitor neuro-irAEs: Pembrolizumab/nivolumab/ipilimumab/atezolizumab → encephalitis, myasthenia + myositis + myocarditis triad (HIGH MORTALITY — check troponin/CK), GBS-like, hypophysitis; stop ICI + high-dose steroids + IVIG/PLEX
  • Treatment hierarchy: Find & treat tumor FIRST → first-line steroids/IVIG/PLEX → second-line rituximab/cyclophosphamide; surface-antibody syndromes are disease-modifiable, intracellular syndromes need tumor treatment to have any chance
🔍 Quick ReferenceClinical · Antibody · Tumor association / treatment
Clinical syndrome
  • Orofacial dyskinesia + psychiatric prodrome + extreme delta brush EEG + autonomic storm in young woman → anti-NMDAR encephalitis (ovarian teratoma)
  • Faciobrachial dystonic seizures (FBDS) + hyponatremia + amnesia in older man → anti-LGI1 limbic encephalitis
  • Subacute pancerebellar syndrome in older woman → anti-Yo PCD (ovarian/breast)
  • Asymmetric sensory loss of ALL modalities + pseudoathetosis + sensory ataxia + areflexia → anti-Hu sensory neuronopathy (SCLC)
  • Brainstem encephalitis + diencephalic syndrome + narcolepsy/REM-behavior + endocrine in young man → anti-Ma2 (testicular germ cell)
  • Opsoclonus-myoclonus “dancing eyes, dancing feet” in child → neuroblastoma; in adult woman → anti-Ri (breast/SCLC)
  • Morvan syndrome (insomnia + neuromyotonia + dysautonomia + encephalopathy) → anti-CASPR2 + thymoma
  • Chorea + optic neuritis + peripheral neuropathy + uveitis → anti-CV2/CRMP5 (SCLC/thymoma)
  • PERM (progressive encephalomyelitis with rigidity & myoclonus) + diarrhea + hyperekplexia → anti-DPPX or anti-GlyR
  • Axial/proximal stiffness + painful spasms + lumbar lordosis + agoraphobia → stiff person syndrome (anti-GAD65 high-titer or anti-amphiphysin)
  • Parasomnia + bulbar dysfunction + sleep-disordered breathing + tau pathology → anti-IgLON5
  • Proximal weakness with post-exercise facilitation + autonomic features (dry mouth) + areflexia returning after exercise → LEMS (anti-VGCC P/Q-type)
Antibody (intracellular vs surface)
  • Anti-Hu (ANNA-1) → intracellular — nuclear neuronal antigen; T-cell mediated; SCLC; encephalomyelitis spectrum
  • Anti-Yo (PCA-1) → intracellular — Purkinje cell cytoplasm; cdr2 antigen; ovarian/breast; PCD
  • Anti-Ri (ANNA-2) → intracellular — nuclear; breast/SCLC; OMS + brainstem encephalitis in adults
  • Anti-Ma2 → intracellular — nucleolar; testicular germ cell; limbic + diencephalic + brainstem
  • Anti-CV2/CRMP5 → intracellular — oligodendrocyte/neuronal cytoplasm; SCLC/thymoma; multifocal
  • Anti-amphiphysin → intracellular — presynaptic vesicle protein; breast cancer; SPS variant
  • Anti-Tr (DNER) → DNER is a transmembrane/surface protein on Purkinje cells; strongly associated with Hodgkin lymphoma and paraneoplastic cerebellar degeneration. Despite the surface target, clinical behavior is that of a high-risk PCD — do NOT apply the simple "surface antibody = reversible" rule here. Outcome is often tied to Hodgkin treatment response
  • Anti-NMDAR (GluN1) → surface — receptor internalization; ovarian teratoma; reversible
  • Anti-LGI1 → surface — VGKC complex; rarely paraneoplastic; FBDS + hyponatremia
  • Anti-CASPR2 → surface — VGKC complex; thymoma; Morvan + neuromyotonia + limbic
  • Anti-GABA-B → surface — metabotropic receptor; SCLC ~50%; intractable seizures + limbic
  • Anti-AMPA-R (GluR1/2) → surface — ionotropic receptor; thymoma/lung/breast; limbic
  • Anti-DPPX → surface — Kv4.2 regulator; CNS hyperexcitability + diarrhea + PERM
  • Anti-GAD65 (high-titer >100,000) → intracellular (but immunotherapy-responsive); SPS + cerebellar + TLE + T1DM
  • Anti-IgLON5 → surface (with tauopathy); parasomnia + bulbar + sleep apnea
Tumor association / treatment
  • SCLC → anti-Hu, anti-CV2/CRMP5, anti-Ri, anti-GABA-B, anti-VGCC (LEMS), anti-amphiphysin — chest CT + FDG-PET
  • Ovarian teratoma (mature/immature) → anti-NMDAR — pelvic US/MRI; tumor removal curative
  • Ovarian/breast adenocarcinoma → anti-Yo (PCD) — mammogram + pelvic US + CA-125
  • Breast cancer → anti-Ri (OMS/brainstem), anti-amphiphysin (SPS) — mammogram
  • Testicular germ cell (seminoma) → anti-Ma2 — testicular US; orchiectomy if high suspicion despite negative imaging
  • Thymoma → anti-CASPR2 (Morvan), anti-AMPA, anti-CV2, MG — chest CT
  • Hodgkin lymphoma → anti-Tr (DNER) cerebellar degeneration
  • Neuroblastoma (children) → OMS — urine HVA/VMA + abdominal MRI + MIBG scan
  • Immune checkpoint inhibitors (pembrolizumab/nivolumab/ipilimumab/atezolizumab) → encephalitis, MG + myositis + myocarditis triad, GBS-like, hypophysitis — stop ICI + high-dose steroids + IVIG/PLEX
  • First-line treatment → tumor removal + steroids + IVIG + PLEX
  • Second-line treatment → rituximab + cyclophosphamide (esp. for refractory anti-NMDAR)
  • Mayo paraneoplastic panel → PAVAL/RAVE (serum + CSF) — ANNA-1/2/3, PCA-1/2, Ma1/2, CV2, amphiphysin, NMDAR, LGI1, CASPR2, GABA-B, AMPA, DPPX, IgLON5, GFAP
  • Repeat tumor screen → FDG-PET/CT every 4–6 months for 2 years if initially negative (PNS-Care 2021; high-risk phenotype + high/intermediate-risk antibody; occult tumor surfaces in ~50%)
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