Paraneoplastic Antibodies

Paraneoplastic neurologic syndromes (PNS) are remote effects of cancer mediated by an immune response directed against onconeural antigens — proteins normally expressed only in neurons but ectopically expressed by certain tumors. The immune response targets the tumor but cross-reacts with neural tissue, producing characteristic neurologic syndromes that frequently precede the cancer diagnosis. Detection of “classical” paraneoplastic antibodies (Hu, Yo, Ri, Ma2, CV2/CRMP5, amphiphysin) virtually mandates an exhaustive tumor search. This page covers the major paraneoplastic antibodies, their associated syndromes and cancers, the 2021 PNS-Care diagnostic criteria, and the clinical approach to a patient with a suspected paraneoplastic syndrome.

🔹 Bottom Line: Paraneoplastic Antibodies

  • Intracellular (“classical”) antibodies — Hu, Yo, Ri, Ma2, CV2/CRMP5, amphiphysin, SOX1 — are cancer markers, not the pathogenic mechanism (T-cell-mediated injury). Almost always paraneoplastic; poor immunotherapy response.
  • Cell-surface antibodies (NMDAR, AMPAR, GABA-B, CASPR2, LGI1) are pathogenic; variable tumor association; better immunotherapy response — covered on the autoimmune-encephalitis page.
  • Anti-Hu + SCLC + sensory neuronopathy: classical triad. Anti-Yo + gynecologic cancer + cerebellar degeneration: women, poor outcome. Anti-Ma2 + testicular germ-cell tumor + limbic/hypothalamic encephalitis: young men, better treatment response.
  • Anti-VGCC + SCLC + LEMS: cell-surface antibody; treatable with amifampridine + tumor treatment.
  • Tumor workup is mandatory: CT chest/abdomen/pelvis + organ-specific imaging; whole-body FDG-PET if standard imaging negative. Surveillance every 3–6 months × 2 years if initial workup is negative.
  • Tumor treatment is the cornerstone of therapy; immunotherapy is secondary and often disappointing for intracellular-antibody syndromes.
  • Immune checkpoint inhibitors can unmask or trigger paraneoplastic syndromes — high-acuity; requires ICI cessation + aggressive immunosuppression.

Two Mechanistic Categories — Critical Distinction

Intracellular (Onconeural) Antibodies — Classical Paraneoplastic Markers

  • Targets: nuclear or cytoplasmic neural antigens.
  • Examples: Hu (ANNA-1), Yo (PCA-1), Ri (ANNA-2), Ma2/Ta, CV2/CRMP5, amphiphysin, SOX1.
  • The antibody is a marker, not the pathogenic mechanism — cytotoxic T-cell-mediated neuronal injury causes the damage.
  • Almost always paraneoplastic; the antibody is a strong cancer predictor.
  • Generally poor response to immunotherapy; outcomes depend on tumor treatment.
  • Tumor treatment is the cornerstone of therapy.

Cell-Surface (Synaptic) Antibodies — Mixed Paraneoplastic / Idiopathic

  • Targets: ion channels, receptors, adhesion molecules.
  • Examples: NMDA receptor, AMPA receptor, GABA-B receptor, CASPR2, LGI1, glycine receptor, mGluR5.
  • The antibody itself is pathogenic.
  • Variable tumor association (anti-NMDAR ~50% ovarian teratoma in young women; anti-GABA-B ~50% SCLC; anti-AMPA thymoma/SCLC; anti-LGI1 ~10% thymoma).
  • Better immunotherapy response.
  • Covered in detail on the Autoimmune Encephalitis Antibodies page.

Major Intracellular (Classical) Paraneoplastic Antibodies

Anti-Hu (ANNA-1)

Target & Cancer

  • HuD antigen (RNA-binding protein in neurons).
  • Small cell lung cancer (SCLC) in >85%.
  • Less commonly: neuroblastoma, prostate, other carcinomas.

Associated Syndromes

  • Paraneoplastic sensory neuronopathy (most characteristic): subacute, asymmetric, sensory ataxia, painful dysesthesias, areflexia, autonomic involvement.
  • Paraneoplastic limbic encephalitis.
  • Paraneoplastic cerebellar degeneration.
  • Brainstem encephalitis.
  • Autonomic neuropathy (severe gastroparesis).
  • Often multifocal “encephalomyelitis.”

🔹 Clinical Relevance: The Brain Can Diagnose Occult Cancer

A middle-aged smoker presenting with subacute sensory neuronopathy — painful, asymmetric sensory loss with profound ataxia and areflexia — with positive anti-Hu antibodies points to small cell lung cancer, often only visible on PET. Treating the SCLC at an early stage can stabilize the neurologic syndrome and dramatically improve survival. The neurologic syndrome is often the first and best window for cancer detection.

  • Send a paraneoplastic panel (serum + CSF) for any subacute, multifocal neurologic syndrome of unclear cause — especially in older adults or in the setting of known cancer.
  • If positive, pursue tumor workup aggressively (CT chest/abdomen/pelvis → whole-body FDG-PET if negative).
  • If clinical picture is compelling but antibodies are negative, still pursue tumor workup; some PNS are seronegative.
  • Surveillance every 3–6 months × 2 years if initial workup is unrevealing.

Anti-Yo (PCA-1)

Target & Cancer

  • Purkinje cell antigen (CDR2/CDR2L).
  • Gynecologic cancers: ovarian, breast, fallopian tube (~95%).
  • Almost exclusively women.

Associated Syndrome

  • Paraneoplastic cerebellar degeneration: subacute pancerebellar syndrome — gait and limb ataxia, dysarthria, nystagmus, vertigo.
  • Progresses over weeks-months to wheelchair-bound.
  • MRI early may be normal; later shows cerebellar atrophy.
  • Very poor response to immunotherapy.

Anti-Ri (ANNA-2)

Target & Cancer

  • Nova-1/Nova-2 antigens.
  • Breast cancer, SCLC, gynecologic cancers.

Associated Syndromes

  • Opsoclonus-myoclonus-ataxia (OMA) syndrome in adults.
  • Brainstem encephalitis with jaw dystonia, laryngospasm.

Anti-Ma2 (Ta)

Target & Cancer

  • Ma2 antigen.
  • Young men: testicular germ cell tumors.
  • Older patients: lung, breast, other carcinomas.

Associated Syndromes

  • Limbic encephalitis + hypothalamic involvement (excessive daytime sleepiness, narcolepsy-like features, hyperphagia, hyperthermia).
  • Brainstem encephalitis (vertical gaze palsy classical).
  • May respond to tumor treatment + immunotherapy (better than other intracellular antibodies).

Anti-CV2 / CRMP5

Target & Cancer

  • CRMP5 (collapsin response mediator protein 5).
  • SCLC, thymoma.

Associated Syndromes

  • Variable: chorea, optic neuritis, retinitis, sensory or sensorimotor neuropathy, cerebellar ataxia, limbic encephalitis.
  • Chorea is relatively distinctive for anti-CV2.
  • Often coexists with anti-Hu.

Anti-Amphiphysin

Target & Cancer

  • Amphiphysin (synaptic vesicle protein).
  • Breast cancer (women), SCLC.

Associated Syndromes

  • Paraneoplastic stiff-person syndrome (more often than anti-GAD-related SPS for paraneoplastic cases).
  • Encephalomyelitis with rigidity.
  • Sensory neuropathy.

Anti-SOX1 (AGNA)

  • SCLC.
  • Associated with Lambert-Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar degeneration.
  • Strong cancer marker.

Anti-Tr (DNER)

  • Delta/Notch-like epidermal growth factor (DNER).
  • Hodgkin lymphoma (young patients).
  • Paraneoplastic cerebellar degeneration.
  • Better prognosis than other PCD (response to tumor treatment).

Anti-VGCC (P/Q-type)

  • Voltage-gated calcium channel — pre-synaptic.
  • SCLC in ~60%.
  • Causes Lambert-Eaton myasthenic syndrome (LEMS).
  • Cell-surface antibody (pathogenic) — responds to symptomatic treatment (3,4-DAP, amifampridine), immunotherapy, and tumor treatment.

Quick Reference — Antibody → Most Likely Cancer

When a paraneoplastic antibody returns positive, the antibody itself directs the tumor search. The strongest cancer associations are below; for any positive intracellular (“classical”) antibody, a full tumor workup is mandatory regardless of which one was detected.

Antibody Most likely cancer Other associations
Anti-Hu (ANNA-1) Small cell lung cancer (~85%) Neuroblastoma (children), prostate, other carcinomas
Anti-Yo (PCA-1) Gynecologic — ovarian, breast, fallopian tube (~95%, women) —
Anti-Ri (ANNA-2) Breast cancer SCLC, gynecologic
Anti-Ma2 (Ta) Young men: testicular germ-cell tumor Older patients: lung, breast, other carcinomas
Anti-CV2 / CRMP5 SCLC, thymoma —
Anti-Amphiphysin Breast cancer (women) SCLC
Anti-SOX1 (AGNA) SCLC Strong cancer marker; often co-positive with anti-VGCC in LEMS
Anti-Tr / DNER Hodgkin lymphoma (younger patients) —
Anti-PCA-2 SCLC —
Anti-VGCC (P/Q-type, LEMS) SCLC (~60%) Cell-surface antibody — also drives the LEMS syndrome itself
Anti-NMDAR Ovarian teratoma in ~50% of young women Testicular germ-cell tumors (rare), SCLC, breast — image the ovaries in women
Anti-AMPAR Thymoma, SCLC, breast —
Anti-GABA-B-R SCLC (~50%) —
Anti-LGI1 Thymoma in ~10% Usually NOT paraneoplastic
Anti-CASPR2 Thymoma in ~20–30% —
Anti-mGluR5 Hodgkin lymphoma (Ophelia syndrome) —
Anti-DPPX Usually no tumor; rarely B-cell lymphoma —
Anti-IgLON5 Generally none —
Anti-GFAP ~25% paraneoplastic — ovarian teratoma; others Most cases not tumor-associated

Classical Paraneoplastic Syndromes (PNS-Care 2021)

The 2021 PNS-Care criteria identify “high-risk” syndromes (high probability of paraneoplastic etiology):

  • Encephalomyelitis.
  • Limbic encephalitis.
  • Cerebellar degeneration (subacute).
  • Opsoclonus-myoclonus syndrome.
  • Sensory neuronopathy.
  • Chronic gastrointestinal pseudo-obstruction.
  • Lambert-Eaton myasthenic syndrome.
  • Anti-NMDAR encephalitis in adults >45 or with teratoma.

“Intermediate-risk” syndromes (moderate probability):

  • Encephalitis with NMDAR antibodies in adults <45 without teratoma.
  • Morvan syndrome.
  • Stiff-person syndrome.
  • Necrotizing myopathy.
  • Other autoimmune encephalitides.

Quick Reference — Syndrome → Cancer + Usual Culprit Antibody

Working from the other direction: given a paraneoplastic clinical syndrome, the cancer and the antibody most likely to be responsible.

Syndrome Most likely cancer(s) Usual culprit antibody/-ies
Limbic encephalitis (subacute) SCLC; testicular germ-cell tumor (young men); thymoma; breast Ma2 (testis); Hu (SCLC); GABA-B (SCLC); AMPA (thymoma/SCLC/breast); LGI1 (rarely thymoma); CV2/CRMP5
Anti-NMDAR encephalitis Ovarian teratoma (young women); testicular germ-cell tumors (rare) NMDAR
Paraneoplastic cerebellar degeneration (PCD) Gynecologic (ovarian / breast); SCLC; Hodgkin lymphoma Yo (gynecologic); Hu (SCLC); Tr / DNER (Hodgkin); P/Q-VGCC (SCLC)
Sensory neuronopathy (subacute, painful, asymmetric) SCLC Hu (ANNA-1)
Encephalomyelitis (multifocal) SCLC Hu; CV2/CRMP5
Opsoclonus-myoclonus-ataxia (OMA) — adult Breast, SCLC, gynecologic Ri (ANNA-2)
Opsoclonus-myoclonus — pediatric Neuroblastoma Often seronegative; rarely Hu
Lambert-Eaton myasthenic syndrome (LEMS) SCLC (~60%) P/Q-type VGCC; SOX1 (cancer marker)
Stiff-person syndrome (paraneoplastic) Breast (women); SCLC Amphiphysin; rarely high-titer GAD65
Brainstem encephalitis Testicular germ-cell tumor; breast / SCLC Ma2; Ri; Hu
Chorea (paraneoplastic) SCLC; thymoma CV2 / CRMP5; rarely Hu
Myelopathy (paraneoplastic / autoimmune) SCLC; breast CRMP5; amphiphysin
Autonomic neuropathy / gastrointestinal pseudo-obstruction SCLC Hu (paraneoplastic); ganglionic AChR (α3) — usually idiopathic
Morvan syndrome / neuromyotonia Thymoma (~20–30%) CASPR2; LGI1
Ophelia syndrome (limbic encephalitis + Hodgkin) Hodgkin lymphoma (young) mGluR5

Diagnostic Criteria (PNS-Care 2021)

Categories

  • Definite PNS: high-risk syndrome + high-risk antibody (e.g., Hu, Yo, Ri, Ma2, CV2) + cancer found within 2 years OR high-risk syndrome + high-risk antibody + cancer-typical antibody for typical cancer.
  • Probable PNS: lower-confidence combinations.
  • Possible PNS: even lower confidence.

Scoring System (PNS-Care Score)

  • Points assigned for: clinical phenotype (high-risk vs intermediate-risk), antibody (high-risk vs intermediate-risk), cancer identification (present, treated, follow-up duration).
  • Total score determines category.

How to Test — Phenotype-Driven Panels (Mayo)

The legacy “paraneoplastic panel” approach has been replaced by phenotype-specific evaluations. The dominant US reference lab — Mayo Clinic Laboratories — retired the broad PAVAL (Paraneoplastic, Autoantibody Evaluation, Serum) panel in mid-2024 and now offers panels named for the clinical syndrome (encephalopathy, epilepsy, dementia, movement disorders, myelopathy, peripheral / autonomic), each available in parallel serum + CSF versions. The new strategy: pick the panel that matches the patient’s leading clinical phenotype.

🔹 Clinical Relevance: PAVAL Is Gone — Order by Phenotype

Don’t try to order PAVAL. Mayo retired it in mid-2024. The phenotype-specific panels collectively contain nearly all the antibodies PAVAL did plus the cell-surface targets PAVAL never covered (NMDAR, LGI1, CASPR2, AMPAR, GABA-B, DPPX, etc.), delivered in the right sample type for each.

  • Decide on the leading clinical phenotype — encephalopathy, epilepsy, dementia, movement disorder, myelopathy, peripheral/autonomic neuropathy.
  • Send the matching Mayo panel in both serum AND CSF unless one is clearly preferred (see below).
  • Use the APE2 (Antibody Prevalence in Epilepsy & Encephalopathy) scorecard to gauge pre-test probability — it helps decide whether antibody testing is likely to be informative at all.
  • Collect samples before starting steroids / IVIG / plasma exchange when possible — immunotherapy can transiently lower titers and cause false negatives.

Mayo Phenotype Panels (2024–2025 catalog)

Phenotype Serum CSF When to choose
Encephalopathy — limbic encephalitis, behavioral / amnestic / psychiatric presentations, FBDS, brainstem encephalitis ENS2 ENC2 Most autoimmune encephalitis presentations; contains the bulk of PAVAL’s antibodies plus cell-surface targets
Epilepsy — adult new-onset focal seizures, refractory epilepsy of unclear cause EPS2 EPC2 Adult new-onset focal epilepsy without structural cause, especially with autonomic features or rapid cognitive decline
Dementia — rapidly progressive or atypical dementia, “young dementia” DMS2 DMC2 Rapidly progressive dementia <65 years; atypical cognitive decline; AD mimics — order after CJD workup
Movement disorders — chorea, ataxia, parkinsonism, brainstem encephalitis, dyskinesias MDS2 MDC2 Subacute ataxia / chorea / parkinsonism with cancer risk or atypical features; includes Mayo-only antibodies (Septin 5/7, TRIM46)
Myelopathy MAS2 MAC2 Subacute or longitudinally extensive myelitis without alternative cause
Peripheral / autonomic AIAES (axonal neuropathy, autoimmune/paraneoplastic, serum) — Subacute sensory neuronopathy, dysautonomia, or sensorimotor axonal neuropathy in cancer-risk setting

CSF vs Serum — Which Is Better for Which Antibody

  • CSF more sensitive than serum: NMDA-R, GFAP-IgG, some glycine-receptor and DPPX cases. Don’t rule out anti-NMDAR encephalitis on a negative serum alone.
  • Serum more sensitive than CSF: LGI1, CASPR2, MOG-IgG, AQP4-IgG, and most intracellular onconeural antibodies (Hu, Yo, Ri, Ma2, CV2, amphiphysin).
  • Send both when the syndrome is compelling and the most-likely antibody can’t be pre-specified — pairing serum + CSF maximizes sensitivity for the broadest set of antibodies.
  • Cell-based assays (CBAs) are the modern methodology for cell-surface antibodies; older IIF results without CBA confirmation should be interpreted with caution.

Practical Notes

  • The phenotype panels already include the major intracellular onconeural antibodies (Hu, Yo, Ri, Ma2, CV2, amphiphysin, SOX1) plus the cell-surface antibodies relevant to that syndrome — you generally don’t need a separate paraneoplastic panel.
  • If the clinical picture spans multiple phenotypes (e.g., limbic encephalitis + movement disorder), order both phenotype panels rather than trying to find a single “do-everything” test.
  • Repeat a borderline / low-titer surface-antibody result on a fresh sample 8–12 weeks later — persistence supports significance.
  • Equivalent phenotype-based panels are available from other US labs (Quest / Athena, ARUP); the codes differ but the same paradigm applies.

Tumor Workup — Mandatory

First-Line

  • CT chest, abdomen, pelvis with contrast.
  • Mammography (women).
  • Pelvic ultrasound or MRI (women).
  • Testicular ultrasound (men).
  • Skin examination (for melanoma).

Second-Line (If First-Line Negative)

  • Whole-body FDG-PET/CT — high sensitivity for small or hidden tumors.
  • MRI of high-suspicion organs.
  • Endoscopy if GI clinical concern.

Surveillance When Initial Workup Negative

  • Repeat tumor screening every 3-6 months for at least 2 years (most cancers appear within this window).
  • Cancer may be tiny and undetectable initially (especially SCLC, ovarian).

Treatment

Tumor-Directed (Cornerstone)

  • Most important intervention.
  • Tumor removal/treatment often stabilizes or improves the neurologic syndrome (less so with anti-Yo, anti-Hu PCD).

Immunotherapy

  • First-line: high-dose steroids + IVIG or plasmapheresis.
  • Second-line: rituximab, cyclophosphamide.
  • Response is generally poor for intracellular-antibody syndromes (anti-Hu, Yo, Ri, Ma2, CV2, amphiphysin) — irreversible neuronal loss has often occurred by diagnosis.
  • Better response for anti-Ma2 and anti-Tr-associated PCD.
  • Cell-surface antibody syndromes (NMDAR, AMPA, GABA-B, LGI1, CASPR2, VGCC-LEMS) respond well.

Symptomatic Management

  • 3,4-DAP / amifampridine for LEMS.
  • Treatment of seizures, pain, autonomic symptoms.
  • Rehabilitation and supportive care.

Immune Checkpoint Inhibitor-Related Paraneoplastic Syndromes

  • Immune checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4) can unmask or trigger paraneoplastic syndromes.
  • Can produce limbic encephalitis, myasthenia gravis, myocarditis, autoimmune cerebellitis.
  • Severe and potentially fatal; requires immediate ICI cessation and aggressive immunosuppression.
  • Antibodies may be present (anti-Ma2, NMDAR, etc.) or absent.

Workup Algorithm Summary

  1. Recognize a clinical syndrome suggestive of paraneoplastic neurology (subacute, multifocal, no clear infectious/metabolic cause, often in older adults or in setting of known malignancy).
  2. MRI brain ± spinal cord.
  3. CSF analysis (often shows pleocytosis, elevated protein, OCBs).
  4. Comprehensive paraneoplastic antibody panel (serum and CSF).
  5. If antibody positive — pursue tumor workup aggressively, including PET if standard imaging negative.
  6. If clinical picture compelling but antibody negative — still pursue tumor workup; some PNS are seronegative.
  7. Treatment: tumor treatment + immunotherapy + symptomatic management.
  8. If initial tumor workup negative — surveillance every 3-6 months × 2 years.

Pitfalls and Pearls

  • Intracellular antibodies = markers, not pathogenic mechanism; almost always paraneoplastic; poor immunotherapy response.
  • Cell-surface antibodies = pathogenic; variable cancer association; better immunotherapy response.
  • Anti-Hu + SCLC + sensory neuronopathy: classical triad.
  • Anti-Yo + gynecologic cancer + cerebellar degeneration: classical triad; women; very poor outcome.
  • Anti-Ri + OMA in adults: opsoclonus-myoclonus suggests Ri (children: neuroblastoma-related).
  • Anti-Ma2 + testicular germ cell tumor + limbic/hypothalamic encephalitis: young men; better treatment response than other intracellular syndromes.
  • Anti-CV2/CRMP5 + chorea: relatively distinctive.
  • Anti-amphiphysin + breast cancer + stiff-person syndrome: paraneoplastic SPS.
  • Anti-SOX1 + SCLC + LEMS: cancer marker.
  • Anti-Tr/DNER + Hodgkin lymphoma + PCD: better prognosis.
  • Anti-VGCC + SCLC + LEMS: cell-surface antibody; treatable with 3,4-DAP/amifampridine + tumor treatment.
  • 2021 PNS-Care criteria: scoring-based diagnostic framework.
  • Cancer workup mandatory: CT chest/abdomen/pelvis + organ-specific imaging + PET if negative.
  • Surveillance × 2 years if initial workup negative.
  • Tumor treatment is the cornerstone; immunotherapy is secondary.
  • Immune checkpoint inhibitors can trigger paraneoplastic syndromes (myasthenia, limbic encephalitis, myocarditis).
  • Subacute, multifocal, otherwise unexplained neurologic syndrome in middle-aged or older adult: think paraneoplastic.

References

  1. Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e1014.
  2. Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-340.
  3. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56(5):715-719.
  4. Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol. 2011;18(1):19-e3.
  5. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135-1140.
  6. Vogrig A, Muñiz-Castrillo S, Joubert B, et al. Cranial nerve disorders associated with immune checkpoint inhibitors. Neurology. 2021;96(6):e866-e875.
  7. Mayo Clinic Laboratories. Autoimmune Neurology Testing — phenotype-specific evaluations (ENS2/ENC2, EPS2/EPC2, DMS2/DMC2, MDS2/MDC2, MAS2/MAC2, AIAES). news.mayocliniclabs.com/neurology/autoimmune-neurology/.
  8. Mayo Clinic Laboratories. PAVAL (Paraneoplastic Autoantibody Evaluation, Serum) — retired mid-2024 in favor of phenotype-driven panels.
  9. Dubey D, Singh J, Britton JW, et al. Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. 2017;58(7):1181-1189 (APE2 score).
  10. Dubey D, Pittock SJ, Kelly CR, et al. Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177.