Anti-AMPAR encephalitis

One such recently described encephalitis is due to antibodies directed at AMPAR (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors). AMPAR are a type of glutamate receptor responsible for the transmission of the bulk of the fast, excitatory synaptic signals in the brain and are important for memory, and learning. The prolonged activation of AMPAR is highly neurotoxic and plays a key role in generation and spreading of seizure activity. AMPAR encephalitis is rare and relatively less common than NMDAR encephalitis and more likely to have an underlying tumor associated with the disease.

Slightly more women than men have been found to have Anti-AMPAR encephalitis, the average age is 53 years old. There is high variability in age-at-symptomatic onset, with Anti-AMPAR encephalitis being diagnosed in patients from 20 to 90 years old.

AMPAR antibodies typically cause limbic encephalitis, with patients presenting with confusion, disorientation, memory loss, and often seizures.

Beyond clinical signs and symptoms, diagnostic tests recommended in the evaluation of patients with suspected autoimmune encephalitis (i.e., MRI, LP, EEG) were variably informative. Routine CSF studies were abnormal in approximately two-thirds of patients (commonly with an elevated CSF white blood cell count (pleocytosis), elevated protein, and positive oligoclonal bands). EEG was less sensitive with abnormalities detected in 44% (most commonly non-specific slowing). Brain MRI was frequently abnormal (86% of cases), commonly with typical findings of limbic encephalopathy including medial temporal lobe hyperintensities. Diagnosis is confirmed by detection of anti-AMPAR antibodies in CSF and/or serum in the proper clinical context.

A disease-associated malignancy was reported in 62% of patients, most commonly lung carcinoma, thymoma, breast or an ovarian tumor. Research shows that if a patient has psychiatric symptoms, often a tumor could be found as well, leading to less favorable outcomes.

In a recent literature review it was found that immunomodulatory therapies were provided to all patients; although, the agent of choice and duration of treatment varied widely within and between institutions. 82% received steroids of variable formulations and doses; 64% received intravenous immunoglobulin; 29% underwent plasma exchange. Second-line therapies were provided to fewer patients, including rituximab, cyclophosphamide, azathioprine, and mycophenolate mofetil. Patients with tumors identified also usually received oncologic treatments like removal of the tumor, chemotherapy, and radiation therapy depending on tumor specifics.

Complete neurologic improvement can occur, but most patients have partial recovery. In a study done by Dr. Dalmau, it was found that relapses occurred in 16% of patients, these were found to be in patients that had not received aggressive therapy. Also, the same study found that the combination of AMPAR antibodies, tumor and additional onconeuronal antibodies (GAD65, or SOX1 antibodies) had a negative effect on outcomes.

• Osvaldo Laurido-Soto et al., Patient Characteristics and Outcome Associations in AMPA Receptor Encephalitis, J Neurol. 2019.
• Höftberger et al., Encephalitis and AMPA receptor antibodies, Neurology, 2015
• Joubert et al., Clinical Spectrum of Encephalitis Associated with Antibodies Against the α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid Receptor: Case Series and Review of the Literature, JAMA Neurology 2015.
• Lai et al., AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location, Ann Neurology, 2009
• Scotton et al., Glutamate Receptor Antibodies in Autoimmune Central Nervous System Disease: Basic Mechanisms, Clinical Features, and Antibody Detection. Methods Mol Biol 2019.

Jeffrey Gelfand, MD, MAS, Department of Neurology, University of California San Francisco