Encephalitis is an infectious or inflammatory disorder of the brain parenchyma (1). There were 5-10 per 100,000 inhabitants suffering from encephalitis every year across all age groups (2, 3). Though classically attributed to infection, an autoimmune basis was reported with similar frequency for encephalitis (4). Autoimmune encephalitis (AE) is the umbrella term for autoimmune disorders in the central nervous system (CNS) characterized by the presence of autoantibodies against intracellular or membrane antigens (5). Over the past decade, the identification of an increasing number of antibodies have aided in the identification and characterization of AE (4). Anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis, a rare subtype of AE mediated by AMPAR antibodies, was first reported by Lai et al. in 2009 (6). More than half of the patients were characterized by limbic encephalitis (LE), including short-term memory loss, confusion, abnormal behavior and seizures. In recent years, anti-AMPAR encephalitis has been increasingly reported with atypical clinical manifestations.

We searched PubMed, Web of Science and Embase for all articles published in English between April 2009 and November 2020, using the search terms [(AMPA OR AMPAR OR anti-AMPA OR anti-AMPAR OR AMPAR-antibody OR AMPA receptor OR anti-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AND (encephalitis OR autoimmune encephalitis OR limbic encephalitis)]. We identified 66 cases from 6 case series and 20 individual case reports (6–31) ( Table 1 and Supplementary Figure 1 ). We summarized the clinical presentations, diagnostic tests and treatments of anti-AMPAR encephalitis, in order to raise the awareness among neurologists ( Supplementary Table 1 ).

Unlike anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, only a few patients reported prodromal viral infections (6/66). Forty patients (60.6%) had a history of tumor or detected tumors, with thymoma being the most common (16/40, most of them under 60 years old), followed by small cell lung cancer (SCLC) (8/40), breast cancer (6/40) and ovarian cancer (3/40). There were also cases reporting concomitant medullary thyroid carcinoma, bladder carcinoma, melanoma and Ewing’s sarcoma.

AMPARs are ionotropic receptors which belong to glutamate receptors. AMPARs are mainly heterotetramers and are composed of four subunits (GluA1-4) with several auxiliary subunits (32, 33). AMPARs, together with other ionotropic glutamate receptors, mediate the majority of excitatory synaptic transmission (32, 34). AMPARs, especially GluA1 and GluA2 subunits, are ubiquitously expressed throughout the central nervous system. In particular, there is a rich expression of GluA1/2 and GluA2/3 levels in the hippocampus and other limbic regions (35). The majority of synaptic AMPARs are GluA1/2 subunits and, to a less extent, GluA2/3 subunits in hippocampus (32, 33). GluA1/2 subunits are also widely expressed in the cerebellum, basal ganglia and cerebral cortex (35). The AMPAR antibodies target against the extracellular portion of cell surface proteins, i.e. the extracellular epitopes of the GluA1 or GluA2 subunits of the receptor (36). In vitro experimental studies indicated that AMPAR antibodies selectively decreased the surface synaptic AMPAR clusters and disrupted the balance between internalization and reinsertion of AMPARs, leading to the accumulation of internalized AMPARs (37). The AMPAR-mediated decrease in synaptic transmission led to a compensatory decrease of inhibitory synaptic transmission and an increase of intrinsic excitability (33, 37). Synaptic and neuronal changes induced by antibodies may contribute to the short-term memory loss and seizures in anti-AMPAR encephalitis patients.

Most patients (46/66) had an acute or subacute onset. The median age of onset was 57 years old with a wide range from 32-month-old to 92-year-old. The vast majority of patients developed the disease in adulthood (64/66) and patients aged 50 to 70 years old account for nearly 50% among adults. Anti-AMPAR encephalitis was more common in women, with a male to female ratio of about 1:2. The clinical manifestations of encephalitis were varied ( Table 2 ).

Cognitive dysfunction was the most common (54/66) clinical manifestation of anti-AMPAR encephalitis, including short-term memory loss (53/66), disorientation (13/66), executive dysfunction (9/66), etc. It could progress to dementia in severe cases. Psychiatric symptom was the second most common clinical manifestation (53/66), among which abnormal behaviors were most frequent (28/66). Less frequently, manifestations in order of decreasing frequency included agitation (15/66), mood disorders (14/66) and psychosis (11/66). There were 3 patients who developed mutism. An altered level of consciousness was not uncommon as well (51/66). Confusion could develop in most patients (45/66). Patients with dyskinesia (25/66) could manifest as gait disturbance or ataxia, parkinsonism and involuntary movement. Nineteen patients had seizures during the disease course, with only 5 patients having status epilepticus. There were various types of seizures, including myoclonic seizures, paroxysmal feeling of tightness, etc. Speech disorder occurred in 10 patients, mainly manifested as aphasia. In addition, some patients may have insomnia (7/66), autonomic dysfunction (6/66) and dysarthria (3/66).

The diagnosis of anti-AMPAR encephalitis was based on the criteria published in the Lancet by Graus et al. (2). In particular, anti-AMPAR encephalitis should be considered in patients with the following characteristics: 1) acute or subacute onset, mostly manifested as short-term memory loss, confusion, abnormal behavior, dyskinesia and seizure; 2) MRI may present with unilateral or bilateral limbic lobe T2/FLAIR hyperintensity; 3) reactive to immunotherapy. In addition, for patients suspected with anti-AMPA encephalitis, a thorough evaluation for tumors, such as thymoma and SCLC, should be conducted.

Diseases mimicking anti-AMPAR encephalitis abound, including infectious, neoplastic, and other immunological diseases ( Table 4 ) (2, 42–44). Caution is needed to identify anti-AMPAR-encephalitis from other types of encephalitis, like anti-NMDAR encephalitis and viral encephalitis ( Table 5 ) (43, 45, 46).

There was no standard management for anti-AMPAR encephalitis. Therapies were usually chosen with reference to other autoimmune encephalitis (47), such as anti-NMDAR encephalitis. About 60-80% of autoimmune encephalitis with antibodies against neuronal surface antigens responded well to immunotherapy (48, 49). Similar to other neuronal surface autoantibody-mediated encephalitis, immunotherapy was recommended as early as possible after diagnosis (2, 50, 51).

First-line treatments included high-dose corticosteroids (methylprednisolone 1000 mg intravenously for 3 to 5 days), intravenous immunoglobulin (0.4 g/kg/day for 5 days) and plasma exchange. High-dose corticosteroids subsequently were followed by a tapering schedule. However, the optimal duration of steroid treatment remains inconclusive. There were 17 patients starting second-line treatment after first-line drugs. Timely initiation of second-line treatment was critical for patients non-reactive to first-line treatment. The exact timing of initiation of second-line therapy was unknown and may depend on the patients’ acceptance to side effects of first-line treatments, drug availability and neurologist’s preference. Major second-line drugs included rituximab and cyclophosphamide. Due to the small number of cases, the impact of second-line prevention on prognosis remained unclear. It was reported that patients who received second-line treatments during the first episode had a lower relapse rate and death rate than those who did not receive second-line immunotherapies (13, 48). Eight patients received long-term treatment in the remission period to prevent recurrence. Long-term treatment included azathioprine and mycophenolate mofetil. However, whether long-term treatment was needed for relapse prevention were still unclear.

In addition, symptomatic treatments were needed for mental disorders and seizures associated with anti-AMPAR-encephalitis. The effect of symptomatic treatment alone may be limited, and combined immunotherapy is usually required.

There were no significant differences in prognosis between patients with and without tumors in anti-AMPAR-encephalitis (13). Nevertheless, early treatment of tumors was important for a good prognosis (52). In 40 patients with concomitant tumors, 27 cases were treated for the neoplasms, such as tumor resection, chemotherapy and radiotherapy. Tumor screening should be conducted regularly for at least 2 years for anti-AMPAR encephalitis patients, even after resolution of neurological deficit (49, 53).

Most anti-AMPAR encephalitis patients were responsive to immunotherapy. However, 18.5% patients (12/65, prognosis of 1 patient was not available) had a poor response. There were 30.8% patients (20/65) who returned to baseline. 50.8% patients (33/65) with anti-AMPAR encephalitis left some sequelae such as cognitive impairment and mental disorder ( Figure 3 ). Previous study reported that the relapse rate was about 23.8% (48), which was higher in those who did not receive aggressive therapy (chemotherapy or rituximab) (13). The relapses of encephalitis did not mean the recurrence of tumors (6). Death rate was 16.7% (11/66), which was mostly related to the progression of the primary tumor. In a few cases, the causes of death were status epilepticus, cardiorespiratory arrest, myocardial infarction and urinary sepsis (6, 11).

Anti-AMPAR encephalitis is an autoimmune disease of the central nervous system. Given the small number of reported cases, our understanding of anti-AMPAR encephalitis is still limited. Consensus was not reached regarding its diagnosis and standard management strategies. For patients with cognitive-psychiatric disorders with an acute or subacute onset, anti-AMPAR encephalitis should be considered. Serum and CSF AMPAR antibody should be tested as soon as possible for further confirmation. Timely immunotherapy should also be initiated upon diagnosis. An extensive screening for tumors, especially thymoma and lung cancer, is warranted in such patients.

T-YZ and M-TC drafted the initial manuscript, summarized available data and selected the references. YZ, Q-LL, and C-HS contributed to the manuscript. Y-XZ and SQ designed and revised the manuscript. All authors approved the final version of the manuscript.

This study was supported by the Science and Technology Program of Zhejiang Province (2018C37132).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.