Clinical Neurology · Neuro-Immunology
Intracellular / Onconeuronal Antibodies
Nuclear and cytoplasmic antibodies are the classic paraneoplastic (onconeural) antibodies. The antigen is intracellular, the immune response is cell-mediated, and these disorders are strongly associated with cancer and respond poorly to immunotherapy. The table lists antibody, antigen, cancer association, and clinical presentation.
| Antibody | Association | Description / Notes |
|---|---|---|
| ANNA-1 (Hu) | Antigen: Hu (ELAVL) Drosophila embryonic lethal abnormal visual like protein Cancer: Small cell lung cancer (80%); Neuroendocrine tumors |
Limbic encephalitis. Brainstem encephalitis. Peripheral neuropathy (mainly sensory & autonomic). |
| ANNA-2 (Ri) | Antigen: Ri (NOVA) Cancer: Small cell lung cancer; Breast adenocarcinoma (50%); Ovarian, uterine cancer |
Limbic encephalitis. Brainstem encephalitis. Paraneoplastic Opsoclonus-Myoclonus Ataxia syndrome (POMA). Cerebellar ataxia. Myelopathy. Peripheral neuropathy. |
| ANNA-3 | Antigen: Unknown Cancer: Small cell lung cancer; Digestive system carcinomas |
Limbic encephalitis. Brainstem encephalitis. Myelopathy. Peripheral neuropathy. |
| Ma1 – Ma2 | Antigen: PNMA-1; PNMA-2 Cancer: Ma2: Testicular cancer; Ma1: Testicular, breast & colon |
Hypothalamic disorders. Limbic encephalitis. Brainstem encephalitis. |
| PCA-1 (Yo) | Antigen: CDR2 Cancer: Mullerian/breast adenocarcinoma |
Paraneoplastic cerebellar degeneration. Brainstem encephalitis. Myelopathy. Peripheral neuropathy. |
| PCA-2 | Antigen: MAP1B Cancer: Small cell lung cancer |
Paraneoplastic cerebellar degeneration. Limbic encephalitis. Brainstem encephalitis. Peripheral neuropathy. LEMS. |
| CRMP-5 (CV2) | Antigen: Collapsin response-mediator protein Cancer: Small cell lung cancer; Thymoma |
Subacute dementia, Depression. Cerebellar ataxia, Chorea. Myelopathy. Radiculopathy, Neuropathy. LEMS. |
| Amphiphysin | Antigen: Amphiphysin (Protein present on cytoplasmic surface of synaptic vesicles) Cancer: Small cell lung cancer; Breast adenocarcinoma |
Subacute dementia. Aphasia. Limbic encephalitis. Stiff person syndrome. Myelopathy. Neuropathy. |
| GAD65 | Antigen: GAD65 (Glutamic acid decarboxylase) Cancer: Rarely Thymoma, Renal cell carcinoma, Breast or colon adenocarcinoma |
Cerebellar ataxia. Seizures. Limbic encephalitis. Brainstem encephalitis. Parkinsonism. Ophthalmoplegia. Myelopathy. Stiff person syndrome. Stiff Person Syndrome Plus (PERM; progressive encephalopathy, rigidity & myoclonus). |
| GFAP | Antigen: GFAP Cancer: Teratoma |
Meningoencephalitis. |
| Recoverin | Antigen: Recoverin Cancer: Small cell lung cancer; Neuroendocrine carcinomas |
Retinopathy. |
| AGNA (anti-glial nuclear) | Antigen: SOX-1 Cancer: Small cell lung cancer |
Limbic encephalitis. LEMS. Peripheral neuropathy. |
Abbreviations: ANNA: anti-neuronal nuclear antibody – AGNA: anti-glial nuclear antibodies – ELAVL: Drosophila Embryonic lethal abnormal visual like protein – LEMS: Lambert Eaton Myasthenic syndrome.
Steps to memorize clinical manifestations of classical Paraneoplastic antibodies
There are 12 cytoplasmic/nuclear antibodies, 11 are classic and only one (GAD65) is not classic. Classic means associated with cancer and poor response to immunotherapy.
Antibody-based memorization: Out of the 12, 2 are associated with single Paraneoplastic syndrome (GFAP – Recoverin), while 10 may present with multiple syndromes. The other 10, all can cause limbic encephalitis, myelopathy and neuropathy plus the following:
- ANNA2: Opsoclonus-myoclonus
- Ma: hypothalamic dysfunction
- PCA1: cerebellar ataxia
- PCA2: ataxia and LEMS
- CRMP: ataxia, LEMS and Subacute dementia
- Amphiphysin: Stiff person syndrome, aphasia & Subacute dementia
- GAD65: Stiff person syndrome, parkinsonism, seizures, ataxia, Ophthalmoplegia
- AGNA: LEMS
Syndrome-based memorization:
- Paraneoplastic Limbic encephalitis (LE): Almost all classic antibodies can cause it, big ones are ANNA1, ANNA2, Ma2, CRMP5.
- Paraneoplastic cerebellar degeneration (PCD): PCA1, PCA2, ANNA2, Ma, CRMP5, AGNA, DNER (surface Ab).
- Paraneoplastic Opsoclonus myoclonus syndrome (POMS/POMA): ANNA1 in children (with neuroblastoma), ANNA2 in adults (with breast cancer).
- Paraneoplastic Encephalomyelitis: ANNA1, CRMP5, Ma2, Amphiphysin.
- Paraneoplastic Subacute sensory neuropathy (SSN): ANNA1, CRMP5.
- Paraneoplastic Stiff person syndrome: Amphiphysin.
Ahmed Koriesh, MD