AMPAR1 / AMPAR2¶

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor 1 / 2¶

Description¶

Anti-AMPAR antibodies are associated with a CNS syndrome dominated by cognitive impairment and psychiatric symptoms with secondary features of motor dysfunction, seizures, speech disorders, and dysautonomia.

It is highly associated with thymoma, SCLC, breast cancer, and ovarian cancer. It is best tested for with matched CSF and serum using CBA and confirmed with immunohistochemistry.

Mechanism of action¶

The ionotropic glutamate AMPA receptor is made up of GluR1, 2, 3, and 4 subunits and mediates fast excitatory neurotransmission in the brain. The target epitope of anti-AMPAR antibodies are on one or both of the GluR1 and GluR2 subunits with GluR2 being most frequently targeted. The regions with the most expression of these subunits are the hippocampus and other limbic areas (specifically the synaptic CA3-CA1 areas of the hippocampus, subiculum, cerebellum, caudate-putamen, and cerebral cortex).

Anti-AMPAR antibodies decrease the number of AMPARs expressed at the cell surface and results in accumulation of internalised AMPARs. This results in a decrease of inhibitory synaptic transmission and increase in intrinsic excitability.

Associated clinical features¶

• Cognitive impairment 81.8% manifesting as short term memory loss in 80.3% followed by disorientation, disorders of execution.
• Psychiatric disorders in 80.3%, mostly abnormal behaviour, agitation, mood disorders, psychosis, and hallucinations.
• Altered level of consciousness in 77.3% with confusion predominantly.
• Dyskinesia in 37.9% gait ataxia, hypermyotonia, tremor, involuntary movements.
• Seizure in 28.8%, status epilepticus in 7.6%.
• Speech disorder in 15.2% predominantly aphasia.
• Insomnia in 10.6%.
• Autonomic dysfunction 9.2%.
• Dysarthria in 4.5%.
• Hyponatraemia in 10%.
• MRI abnormal in 75% (T2/FLAIR signal in the temporal and medial temporal lobe predominantly).
• FDG18-PET abnormal in 6 of 8 patients (4 increased metabolism, 2 decreased metabolism).
• EEG epileptiform in 28%, generalised or focal slowing in 35%, normal in 37%.
• CSF 59% elevated WCC, 42% elevated protein (up to 425 mg/dL).
• Oligoclonal bands in 8%.

Associated neoplasia¶

More than 50% associated with malignancy, most commonly thymoma, SCLC, breast cancer, and ovarian cancer.

Laboratory method¶

Immunohistochemistry shows reactivity with the neuropil of the hippocampus, subiculum, caudate triatum, and molecular layer of the cerebellum.

Notes of performance characteristics¶

CSF has higher specificity and specificity than serum alone.

Positive matched CSF and serum samples are likely to have higher titres although this is of unclear clinical usefulness.

Grade¶

Next steps¶

After treatment half of patients will have residual cognitive impairment or psychiatric disorders.