Table 1

Demographic, tumour, clinical, treatment response and prognosis in onconeuronal antibody-associated syndromes

Antibody (alternative names)Demographics and tumour frequencyMain associated tumour typesPredominant associated syndromesIT 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 benefitMedian 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% tumourBreast (~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 benefitOverall 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 tumourMainly 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 dependentVarious including lung/pleural (~30%), testicular, Gl tract, non-HL, breast cancer, renal cancer and melanomaLimbic and/or brainstem encephalitis ~45%–65%
Cerebellar/brainstem syndrome (up to ~75%)
Peripheral neuropathy ~10%
Little or no effect of IT on outcomesReported 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<4514% 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 myeloneuropathyReported with chemotherapy and steroids in stiff-person syndrome, and with IT especially cyclophosphamide in neuropathyIn 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 immunitiesPCD most common in both isolated Zic4 and Zic4+other onconeuronal antibodiesLimited to case reports, 50% of which improved with chemotherapy+IT, including rituximabNot 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-ERhombencephalitis, 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 tumourHL, cutaneous T lymphomaCerebellar syndrome (~90%)+cognitive/psychiatric featuresWith IT, ~50% stabilisation and ~40% improvement2/25 published patients, mainly IT-treated, died
mGluR5
49
Median age ~30, including paediatric cases, M=F, ~60% with tumourHL, SCLCNeuropsychiatric and cognitive deficits, poor sleep, seizures; Ophelia syndromeComplete recovery in more than 50%, mostly treated with cancer±IT; relapse responded to sameNo deaths in a contemporary cohort
Tr/DNER51 72 Median age ~60, ~80% MHL (~90%), occasionally also non-HLPredominantly a cerebellar syndrome, frequently pure in HLOften 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 tumourSCLC and thymomaVaried including neuropathy (largely an asymmetric painful polyradiculopathy), cerebellar ataxia, chorea, uvea/retinal involvement, LEMS, myeloneuropathyNeuropathy 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.SCLCPatients 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% MMainly cutaneous melanomaNight blindness, photopsias, visual field deficit and reduced visual acuityCase series only, benefit in some of varied IT regimes+cytoreductionAverage survival 5.9 years after melanoma onset
Recoverin/CAR:75 76 91 Mean age early 60s, ~40% to 60% womenSCLC, prostate and endometrial cancers, but also found in retinitis pigmentosaPainless visual loss and uveitisCancer therapy alone does not abate visual loss, benefit of various IT in some case reportsNot 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.