Clinical Neurology · Neuro-Immunology
Neuronal Surface Antibodies
Neuronal surface antibodies target cell-membrane and synaptic antigens. Because the antigen is accessible on the cell surface, the immune response is direct and antibody-mediated, and these disorders generally respond well to immunotherapy. Cancer association is highly variable. The table below groups antibodies as autoimmune channelopathies, receptoropathies, and cell-adhesion proteinopathies, with antigen, cancer association, clinical presentation, and the preferred sample.
| Antibody | Association | Description / Notes |
|---|---|---|
| Autoimmune Channelopathies | ||
| LGI1 (VGKC complex) |
Antigen: Leucine-rich, glioma inactivated protein 1. Part of VGKC complex that interacts with other epilepsy-related proteins. Cancer: Thymoma in 10% Sample: Serum |
Limbic encephalitis (focal seizures followed by memory loss, disorientation and behavioral abnormalities). Focal seizures may be dyscognitive, dysautonomic or facio-brachial dystonic seizures (FBDS). Facio-brachial dystonic seizures: very brief repetitive dystonic contraction of the arm and face, refractory to AED treatment. Insomnia and RBD (REM behavior disorder). Hyponatremia in 60%. Ab positive in: serum > CSF. CSF with lymphocytosis and OCB in 50% of patients. MRI with T2 hippocampal hyperintensity in 74% of patients. Response to immunomodulation: quick and marked response. Residual deficits: amnesia for the disease period in 86%. Relapses: third of patients develop relapses, can be as far as 8 years after initial episode. N.B: mutation in LGI1 protein results in autosomal dominant lateral temporal lobe epilepsy. |
| CASPR2 (VGKC complex) |
Antigen: Contactin associated protein type 2. Part of VGKC complex, present in the brain & juxtaparanodal regions of myelinated axons and responsible for local differentiation of the axons at node of Ranvier. Cancer: Thymoma (10:30%) Sample: Serum |
Neuromyotonia (Isaac Syndrome). Morvan syndrome: more in patients with thymoma. Presents with diffuse hyperexcitability involving autonomic (hyperhidrosis & dysautonomia), peripheral (neuromyotonia, hyperexcitability) and central nervous systems (limbic encephalitis). Limbic encephalitis (focal seizures followed by memory loss, disorientation and behavioral abnormalities) in few cases. N.B: CASPR2 mutation is seen in patients with autism. |
| DPPX (VGKC complex) |
Antigen: Dipeptidyl-peptidase–like protein 6. Part of VGKC complex, responsible for blocking of back-propagation of action potentials. Present in the brain and myenteric plexus. Cancer: Lymphoma Sample: CSF & Serum |
Triad of GI symptoms (diarrhea–weight loss), cognitive dysfunction, CNS hyperexcitability. Starts with diarrhea, weight loss (average 20Kg) followed by CNS hyperexcitability (myoclonus, seizures, hyperekplexia) and cognitive dysfunction (memory loss, hallucinations, agitation) over a few months period. |
| Contactin2 (VGKC complex) |
Antigen: Contactin2 protein. Part of VGKC complex that interacts with CASPR2 and form bridges between the axon surface and myelin. Cancer: None |
Although Contactin2 Ab were detected in a small number of patients with multiple sclerosis, it is not associated with disease activity and not associated with specific set of symptoms. |
| LGI1/CASPR2/DPPX negative VGKC | Antibodies against other parts of the VGKC complex. | Uncertain significance. |
| VGCC P/Q & N | Antigen: P/Q & N type VGCC Cancer: SCLC Sample: Serum |
Lambert Eaton Myasthenic Syndrome (proximal weakness, dry mouth, constipation). Patients with LEMS should be screened with CXR every 6 months for lung cancer. |
| Cerebellar ataxia | ||
| NMO-IgG | Antigen: Aquaporin-4 Cancer: None Sample: Serum |
NMO Spectrum Disorders (NMOSD). |
| Autoimmune Receptoropathies | ||
| NMDA | Antigen: GluN1 receptor Cancer: Fertile women: Ovarian teratoma in 50%. Elderly: cancer in 25%. Children: no cancer. Sample: CSF |
Sometimes symptoms are preceded by headache and flu like symptoms that can persist for weeks/months then patients developed psychiatric symptoms (agitation, paranoia, psychosis), later on confusion, memory impairment and seizures proceed. Ab positive in: CSF > Serum. MRI with variable T2 hyperintensities (percent). Response to immunomodulation: responsive but may take 1–2 years for full recovery – very sensitive to neuroleptics (may develop NMS). Residual deficits: 20% may attain residual deficits. Relapses: |
| AMPA | Antigen: GluR1,2 receptor Cancer: SCLC, breast, thymus cancer in 70% Sample: CSF |
Varies from a single symptom (Confusion, disorientation – memory impairment – seizures) to multi-symptoms (similar to limbic encephalitis) to fulminant encephalitis. |
| Metabotropic glutamate 1 | Antigen: mGluR1 Cancer: Hodgkin lymphoma |
Cerebellar ataxia (idiopathic or paraneoplastic). |
| Metabotropic glutamate 5 | Antigen: mGluR5 Cancer: Hodgkin lymphoma |
Ophelia Syndrome (Limbic encephalitis in patients with Hodgkin lymphoma). |
| GABA-B | Antigen: GABA-B receptor Cancer: SCLC in 50% |
Limbic encephalitis with marked refractory seizures. |
| GABA-A | Antigen: GABA-A receptor Cancer: None |
Limbic encephalitis with marked refractory seizures. |
| Dopamine-2 | Antigen: Dopamine-2 receptor Cancer: None |
Sydenham chorea. Basal ganglia encephalitis (parkinsonism, chorea, dystonia). |
| Muscle AChR | Antigen: Muscle AChR | |
| Ganglionic AChR | Antigen: Ganglionic AChR | |
| Glycine | Antigen: α1 subunit of GlyR (Present in brainstem & Spinal cord) Cancer: Cancer in 10% |
Stiff person syndrome. PERM: progressive encephalopathy, rigidity and myoclonus – more severe form of stiff person syndrome. Hyperekplexia. |
| Cell Adhesion Proteinopathies | ||
| IgLON-5 | Antigen: Cell adhesion protein IgLON (LAMP, OBCAM, Ntm) Cancer: None |
Parasomnias – REM and non-REM behavior disorder – Chorea – Dementia – Ataxia – Vertical gaze palsy. |
| Neurexin-3 α | Antigen: Cell adhesion protein Cancer: None |
Prodrome of headache, fever, GI upset followed by seizures and altered mental status. |
| DNER (previously known as Anti-Tr) |
Antigen: Delta/notch-like epidermal growth factor-related receptor Cancer: Hodgkin lymphoma in 90% |
Paraneoplastic cerebellar degeneration → nystagmus, dysarthria, limb ataxia and gait ataxia. History: Hodgkin disease patients with cerebellar degeneration were found to have their sera react against Purkinje cells in a specific pattern, named “Anti-Tr Ab pattern”. In 2015, the target of Anti-Tr was found to be DNER. Protein: transmembrane protein carrying extracellular EGF-like repeats, DNER is upregulated in various cancers and knocking this protein down decreased cell proliferation and invasion. |
Ahmed Koriesh, MD