Table 1.
Main features of autoimmune diseases of the central nervous system.
| Target antigen | Auto-Ab pathogenic | Auto-Ab marker | Main auto-antibody effect/pathology | Main clinical features | Tumor association (%) | Tumor types (%) |
|---|---|---|---|---|---|---|
| Pathogenic autoantibodies against neuronal cell surface and synaptic proteins; Predominantly B cell (Antibody mediated); Generally responsive to immunotherapy | ||||||
| Glu N1 | NMDAR IgG1 |
Autoantibodies cause reduction of cell surface NMDAR secondary to cross linking, internalization. Disruption of NMDAR-EPHB2 interaction leads to dispersal and loss of NMDAR from synaptic sites and disrupted glutamatergic transmission; reduced LTP; increased cortical excitability. Brain shows little neuronal loss; no complement activation; mainly CD4+ T cells, B cells. Markers of cytotoxicity (granzyme–B, perforin) scant. | Median age 22, 80% women, Hallucinations, delusions, memory loss, mania, catatonia, seizures, confusion, coma Oro-facial and limb dyskinesias, choreo-athetosis, dystonic postures, autonomic dysfunction: tachycardia, hypertension, hyperthermia |
~60 | Ovarian teratoma | |
| LGI1 Secreted Synaptic protein |
LGI1 IgG4 |
Autoantibodies cause reversible reduction of synaptic AMPAR and Kv1.1 by disrupting interaction of LGI1 with pre and post synaptic proteins ADAM23 and ADAM22; increased epileptiform activity in hippocampal CA3 neurons secondary to Kv1.1 inactivation. Neuronal cell loss; immunoglobulin and complement deposition. |
Median age 60, M:F, 2:1 Limbic encephalitis; Facio-brachial or crural dystonic seizures, brief (<3 s), repetitive (median 50 per day) Hyponatremia |
5–10% | Thymoma | |
| GluA1 GluA2 |
AMPAR | Autoantibodies cause cross linking, internalization and decrease of synaptic AMPAR. Mild perivascular and interstitial lymphocytic infiltration in hippocampus. |
Limbic encephalitis Non-focal enecephalitis |
>50% | NSCLC ~35 Thymus ~30 Breast ~20 |
|
| β1 subunit GABABR | GABABR | Directly blocks function of GABABR without decreasing levels of cell surface receptor. | Limbic encephalitis Cerebellar Ataxia Opsoclonus-myoclonus |
>50% | SCLC | |
| GABAAR α1,β3 subunit |
GABAAR | Crosslinking, internalization and downregulation of synaptic GABAAR | Intractable seizures, status epilepticus Altered behavior, cognition Dyskinesias |
~30% | Thymoma | |
| GlyRα1 subunit |
GlyR | Autoantibodies cause cross linking, internalization of inhibitory glycine receptors (strychnine sensitive chloride channels) expressed mainly in brain stem, spinal cord and hippocampus. | Progressive encephalitis with rigidity and myoclonus (PERM); muscle stiffness, painful spasms, hyperkplexia, Brain stem encephalitis |
— | ||
| CASPR2 | CASPR2 IgG4, IgG1 |
CASPR2 is an adhesion protein which promotes juxtaparanodal clustering of Kv1 channels in CNS and PNS. Antibodies react with juxtaparanodal region of myelinated peripheral nerves and also hippocampal inhibitory neurons. | Limbic encephalitis, insomnia, Neuromyotonia, neuropathic pain, dysautonomia, Morvan syndrome (above) Episodic ataxia |
20% | Thymoma | |
| mGluR1 | mGluR1 | Autoantibodies react with cerebellar Purkinje neurons and reduces Purkinje cell activity. Brain shows significant loss of Purkinje neurons in cerebellum. | Cerebellar ataxia Loss of taste |
~10% | Hodgkin's lymphoma | |
| mGluR5 | mGluR5 | Autoantibodies target mGluR5 which regulates rapid synaptic transmission in the hippocampus. | Ophelia syndrome: Confusion, agitation, memory loss, psychosis, seizures | <10% | Lymphoma | |
| IgLON5 Cell adhesion molecule |
IGLON5 IgG4 |
Autoantibodies cause a decrease of cell surface IgLON5. Neuronal loss, gliosis without inflammation; Neuronal hyperphosphorylated tau predominantly in hypothalamus, brain stem tegmentum, upper spinal cord. |
Disturbed sleep, obstructive sleep apnoea, parasomnias, stridor, gait instability, chorea, supranuclear gaze palsy | |||
| DPPX Extracellular subunit of Kv4.2 channel |
DPPX IgG4;IgG1 |
Autoantibodies react with neuronal DPPX in hippocampus, cerebellum and myenteric plexus. | Prodromal diarrhea, weight loss, encephalitis, seizures, cerebellar ataxia, PERM | <10% | Lymphoma | |
| Non-pathogenic autoantibodies targeting intra-cellular antigens (classical paraneoplastic disorders); Predominantly cytotoxic CD8+ T cell mediated; Generally resistant to immunotherapy | ||||||
| Ma1, Ma2 | Ma, Ma2 | Ma1, Ma2 expressed in subcellular organelles including nucleoli of neurons. Neuronal loss, granzyme B +ve cytotoxic CD8+ cells. |
Limbic, brain stem/diencephalic encephalitis, opthalmoplegia, excessive daytime sleepiness | >90% | Testicular ~50% NSCLC ~15% GI, Breast, Ovary, Colon |
|
| HuD (Elav4) | Hu (ANNA1) | Neuronal loss, gliosis, CD4+ and CD8+ cytotoxic T cell infiltration. | Sensory neuronopathy, limbic encephalitis, PCD, encephalomyelitis, gastroparesis, pseudo-obstruction, cardiac dysrhythmias | >90% | SCLC ~75% NSCLC ~10% Prostate, Breast, GI |
|
| CDR2, CDR2L | Yo (PCA1) | Multifocal inflammation in cerebellum, brain stem, spinal cord. Neuronal loss, mainly CD8+ T cell infiltration | PCD: Cerebellar ataxia, dysarthria, nystagmus | >90% | Ovarian ~60% Breast ~25% Fallopian tube |
|
| DNER | Tr | DNER is expressed by cerebellar Purkinje cells | PCD | >90% | Hodgkin's lymphoma | |
| SOX1 | SOX1 | Eaton-Lambert Syndrome (see Table 3) PCD |
>95% | SCLC~ 90% | ||
| NOVA1 NOVA2 |
Ri (ANNA2) | Neuronal loss in brain stem, cerebellum, spinal cord. Predominantly CD8+ T cell inflammatory infiltrates | ~80% female; PCD: Cerebellar ataxia; Brain stem encephalitis, opsoclonus/myoclonus, laryngospasm, trismus | >85% | Breast ~50% Lung ~30% |
|
| Amphiphysin | Amphiphysin | Pre-synaptic protein important in clathrin mediated endocytosis which may cause decreased GABA/glycine uptake into vesicles and release | Encephalitis, stiff person syndrome, myelopathy, neuronopathy/neuropathy | >80% | SCLC ~60% Breast ~35% |
|
| CRMP5 | CRMP5 (CV2) | Nerve fiber and myelin loss in brain, optic nerve, spinal cord, sensory ganglia, peripheral nerves. Mainly CD8+ T cell infiltrates | Encephalomyelitis; sensory, sensorimotor and autonomic neuropathy, chorea, optic neuritis, GI motility disorders | >90% | SCLC ~80% NSCLC ~5% Thymoma ~8% |
|
| MAP1B | MAP1B (PCA2) | Encephalomyelitis, ataxia, sensorimotor neuropathy | >90% | SCLC ~45% NSCLC ~25% |
||
| Kelch-like protein 11 | Anti-Kelch11 | Kelch 11 is a member of E3 ubiquitin ligase complex located intra-cellularly. T cell predominant inflammation in brain lesions and non-necrotizing granulomas. | Rhombencephalitis presenting with ataxia, vertigo, diplopia, hearing loss, seizures | ~80% | Testicular germ cell tumors | |
| Neurexin-3α | Anti-neurexin3α | Antibody decreases density of surface neurexin- 3α and total number of synapses in neurons undergoing development | Encephalitis Confusion, seizures |
None | ||
| D2R | Anti-D2R | Receptor internalization and decrease in D2R surface density | Basal ganglia encephalitis Parkinsonism, dystonia, psychiatric symptoms |
None | ||
| GAD65 | Anti-GAD65 | Clinical pathology only associated with high titer of antibodies. Likely cytotoxic T cell mediated pathology |
Stiff person spectrum disorder; Cerebellar ataxia; epilepsy; limbic encephalitis |
4% | Breast, lung, thyroid, thymoma | |
AMPAR, αamino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA, anti-neuronal nuclear antibody; CASPR2, contactin associated protein2; CRMP5, collapsing response mediator protein; DNER, delta and notch like epidermal growth factor-related receptor; DPPX, dipeptidyl aminopeptidase-like protein 6; GABAAR, γ-aminobutyric acid type A receptor; GABABR, GABA type B receptor; GAD65, Glutamic acid decarboxylase 65; GluN1, glutamate receptor subunit of NMDA 1; GluA1/A2, glutamate receptor subunits of AMPAR; GlyR, Glycine receptor; IgLON5, Immunoglobulin like cell adhesion molecule 5; IgG4, immunoglobulin G4; Kv1.1, voltage gated potassium channel subunit; LGI1, leucine-rich glioma inactivated protein1; LTP, Long-term potentiation; MAPB1, microtubule associated protein 1B; mGluR, metabotropic glutamate receptor; NMDAR, N-methyl-D-aspartate receptor; NOVA, neuro-oncological ventral antigen; NSCLC, non-small cell lung cancer; PCD, paraneoplastic cerebellar degeneration; PERM, Progressive encephalomyelitis with rigidity and myoclonus; SCLC, small cell lung cancer. CSF complements serum and should also be tested in evaluation for auto-antibodies.
Rasmussen encephalitis which presents in children with focal seizures (epilepsia partialis continua) and encephalopathy is considered likely to be autoimmune in origin (44–51).