Demographic, tumour, clinical, treatment response and prognosis in onconeuronal antibody-associated syndromes
| Antibody (alternative names) | Demographics and tumour frequency | Main associated tumour types | Predominant associated syndromes | IT responsive? | Life expectancy |
| Hu (ANNA-1) 24 39 57 70 | Median age 60s, men ~75% Tumour frequency up to 98% with 4-year follow-up after onset of paraneoplastic syndrome | SCLC in ~75% Others include other lung, prostate, breast, bladder, GI tract, ovary, neuroendocrine, unknown origin | Sensory neuropathy (~50%), of which sensory neuronopathy ~30% Cerebellar ataxia/PCD (~20%) Limbic or cortical encephalitis (up to ~20%) Rhombencephalitis (up to ~20%) Sensorimotor neuropathy (~5%) Autonomic dysfunction (up to ~24%) Multifocal deficits (~20%) Myeloneuropathy – newly reported | Limited evidence of symptomatic benefit with early use in patients with sensory neuropathy, no evidence of survival benefit | Median survival ~11.8 months in a cohort with ~80% receiving oncological treatment and ~45% IT |
| Yo (PCA-1)6 50 54 67 70 | Almost always women with median age 60s, and at least ~90%–100% tumour | Breast (~20%) Gynaecological (ovary/fallopian tube ~60%) Rarely in men: upper GI adenocarcinoma or prostate | PCD (at onset or within disease course ~90%) Peripheral neuropathy (10%) Myeloneuropathy—newly reported | No evidence of sustained symptomatic or survival benefit | Overall median survival ~24 months. An analysis of 25 oncologically treated patients showed survival significantly longer in breast cancer (~100 months) than ovarian (~22 months) cancer. |
| Ri (ANNA-2)52 61 | Mainly (~80%) women, median age mid-60s, ~90% with a tumour | Mainly breast (up to 70%) and lung (up to 25%) | Cerebellar syndrome (~66%) Opsoclonus±myoclonus (~30%) Dystonia and parkinsonism, ~20% each; with jaw dystonia specifically up to 20% depending on cohort | Reports of improved jaw dystonia with early aggressive cancer/IT No evidence of survival benefit in a mixed cohort | Survival ~70% at 12 months, ~60% at 24 months, and ~50% at 36 months, with all patients receiving antitumour therapy and 58% IT |
| Ma1 (PNMA1 and 2)55 56 | M: ~40%–75%, median age ~60, tumour in 77%–100%, cohort dependent | Various including lung/pleural (~30%), testicular, Gl tract, non-HL, breast cancer, renal cancer and melanoma | Limbic and/or brainstem encephalitis ~45%–65% Cerebellar/brainstem syndrome (up to ~75%) Peripheral neuropathy ~10% | Little or no effect of IT on outcomes | Reported in small cohorts only, 36%–38% death due to tumour or neurological progression with oncological/IT in ~50% where ascertainable |
| Ma2/Ta (PNMA2 only) 25 42 55 56 | Consistently ~75% M, median age younger in M (mid-30s) than mixed or F (early 60s) cohorts, tumour ~90% | Most commonly testicular germ cell (up to ~70%) or lung tumours (non-SCLC) | Encephalitis—limbic, diencephalic, and/or brainstem (95%) but ‘classic’ limbic ~25% Distinctive aspects include excessive daytime sleepiness (~30%) and eye movement abnormalities in encephalitis patients (~90%) | Some tumour and syndrome response to orchidectomy±IT (steroids, intravenous immunoglobulins, plasma exchange) especially men<45 | 14% death reported in one cohort of 28 patients (treatment details not specified) |
| Amphiphysin 62 65 70 87 | M:F 40:60, higher F (~90%) in neuropathy, mean age ~65, malignancy in ~80% (in patients with only amphiphysin antibodies) | Lung cancer (mainly SCLC)~70%, breast cancer ~25% | Common associations include neuropathies (~60%) and stiff-person-spectrum disorders (~30%–40%), but also myelopathy, encephalitis/encephalopathy, cerebellar ataxia and myeloneuropathy | Reported with chemotherapy and steroids in stiff-person syndrome, and with IT especially cyclophosphamide in neuropathy | In mixed phenotypes, survival ~7–9 months,~50% of patients receiving oncological and/or IT; in mainly treated neuropathy cases~30% mortality at 5 years |
| Zic422 90 | Median mid-60s, nearly 90% M,~90% with tumour (in patients with only Zic4 antibodies and no other immunities) | SCLC in ~90% of patients with Zic4±other immunities | PCD most common in both isolated Zic4 and Zic4+other onconeuronal antibodies | Limited to case reports, 50% of which improved with chemotherapy+IT, including rituximab | Not systematically reported |
| KELCH11 (KLHL11) 37 43 44 | In clinical cohorts, all patients are M, with median age mid-40s, and cancer found in ~70% | ~65% testicular cancer (mainly seminoma) in clinical cohorts. In serological studies, also found with teratoma (ovarian or testicular) and NMDAR-Ab-E | Rhombencephalitis, with ataxia (~80%), diplopia (~60%), vertigo (~50%) and auditory symptoms (hearing loss and tinnitus ~40% each, tinnitus often an early manifestation), dysarthria (~30%), and seizures (~20%) | ~60% achieved neurological improvement or stability with IT, trend to better outcomes with testicular cancer | ~25% mortality at median of 55 months in a cohort in which almost all received oncological and IT |
| mGluR1 58 | Median age ~55, ~2:1 M:F, ~11% with tumour | HL, cutaneous T lymphoma | Cerebellar syndrome (~90%)+cognitive/psychiatric features | With IT, ~50% stabilisation and ~40% improvement | 2/25 published patients, mainly IT-treated, died |
| mGluR5 49 | Median age ~30, including paediatric cases, M=F, ~60% with tumour | HL, SCLC | Neuropsychiatric and cognitive deficits, poor sleep, seizures; Ophelia syndrome | Complete recovery in more than 50%, mostly treated with cancer±IT; relapse responded to same | No deaths in a contemporary cohort |
| Tr/DNER51 72 | Median age ~60, ~80% M | HL (~90%), occasionally also non-HL | Predominantly a cerebellar syndrome, frequently pure in HL | Often irreversible. Remission in ~15% of patients mainly under-40 treated for HL (no patients without tumour improved) | No systematic data; in one small observational cohort, 2/16 patients with a cerebellar syndrome and HL, of which 10 had Tr/DNER, died. |
| CV2/CRMP5 57 63 66 | Median age ~60, ~75% men, ~90% with tumour | SCLC and thymoma | Varied including neuropathy (largely an asymmetric painful polyradiculopathy), cerebellar ataxia, chorea, uvea/retinal involvement, LEMS, myeloneuropathy | Neuropathy may be responsive to high dose intravenous steroids. | Median survival 48 months if CRMP5/CV2 antibodies in isolation, death in ~40% |
| LEMS–VGCC: P/Q type59 68 93 LEMS–Sox1 (AGNA1) 69 94 | In paraneoplastic and non-paraneoplastic LEMS, median age is in the early 60s; ~70% of LEMS have underlying cancer; and ~2/3 paraneoplastic patients are M. | SCLC | Patients with VGCC antibodies may present with LEMS alone, or LEMS+PCD; VGCC antibodies may also denote ataxia without LEMS in ~40% lung cancer PCD Sox1 Indicates paraneoplastic LEMS (seen in ~60% paraneoplastic but not in idiopathic cases); background Sox positivity rate of ~20%–30% in SCLC±Hu antibodies | The myasthenic syndrome, but not the cerebellar syndrome, responds well to IT. | Median survival of 12 months in patients with PCD (mostly with tumour treatment, but some with only IT or none) With Sox1 positivity, SCLC and LEMS, median survival of ~15 months in mostly oncologically treated patients |
| Retinopathies: MAR74 | Mean age mid-50s, >80% M | Mainly cutaneous melanoma | Night blindness, photopsias, visual field deficit and reduced visual acuity | Case series only, benefit in some of varied IT regimes+cytoreduction | Average survival 5.9 years after melanoma onset |
| Recoverin/CAR:75 76 91 | Mean age early 60s, ~40% to 60% women | SCLC, prostate and endometrial cancers, but also found in retinitis pigmentosa | Painless visual loss and uveitis | Cancer therapy alone does not abate visual loss, benefit of various IT in some case reports | Not systematically reported |
AGNA1, antiglial nuclear antibody; ANNA, antineuronal nuclear antibody; CAR, cancer-associated retinopathy; CRMP5, collapsin response-mediator protein-5; DNER, delta and notch-like epidermal growth factor-related receptor; F, female; GI, gastrointestinal; HL, Hodgkin's lymphoma; IT, immunotherapy; KELCH11, Kelch-like protein 11; LEMS, Lambert-Eaton myasthenic syndrome; M, male; MAR, melanoma-associated retinopathy; mGluR1/5, metabotropic glutamate receptor 1/5; NMDAR-Ab-E, NMDAR-antibody encephalitis; PCA, Purkinje cell cytoplasmic antibody; PCD, paraneoplastic cerebellar degeneration; PNMA1/2, paraneoplastic antigen Ma1/2; SCLC, small cell lung cancer; VGCC, voltage-gated calcium channel.