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Updated: Nov 5, 2025
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Published on: June 2, 2022
Autoimmune Global Amnesia as Manifestation of AMPAR Encephalitis and Neuropathologic Findings
Gerda Ricken1, Tobias Zrzavy1, Stefan Macher1
1From the Division of Neuropathology and Neurochemistry (G.R., A.F., R.H.), Department of Neurology, Medical University of Vienna, Austria; Department of Neurology (T.Z., S.M., P.A., P.R., T. Berger), Medical University of Vienna, Austria; Department of Neurology (J.T., J.W.), Klinikum Klagenfurt, Austria; Institute of Clinical Chemistry (K.K.F., K.-P.W., F.L.), University Hospital Schleswig-Holstein, Kiel/Lübeck, Germany; Institute of Pathology (A.K.), Klinikum Klagenfurt, Austria; Clinical Department of Laboratory Medicine (A.F., G.M.), Proteomics Core Facility, Medical University Vienna, Austria; Center of Physiology and Pharmacology (H.K.), Department of Neurophysiology and Neuropharmacology, Medical University of Vienna, Austria; and Department of Neurology (T. Bartsch, F.L.), University Hospital Schleswig-Holstein, Kiel, Germany.
Objective:
To report an unusual clinical phenotype of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis and describe associated neuropathologic findings.
Methods:
We retrospectively investigated 3 AMPAR encephalitis patients with autoimmune global hippocampal amnesia using comprehensive cognitive and neuropsychologic assessment, antibody testing by in-house tissue-based and cell-based assays, and neuropathologic analysis of brain autopsy tissue including histology and immunohistochemistry.
Results:
Three patients presented with acute-to-subacute global amnesia without affection of cognitive performance, attention, concentration, or verbal function. None of the patients had epileptic seizures, change of behavior, personality changes, or psychiatric symptoms. The MRI was normal in 1 patient and showed increased fluid-attenuated inversion recovery/T2 signal in the hippocampus in the other 2 patients. Two patients showed complete remission after immunotherapy. The one patient who did not improve had an underlying adenocarcinoma of the lung and died 3.5 months after disease onset because of tumor progression. Neuropathologic analysis of the brain autopsy revealed unilateral hippocampal sclerosis accompanied by mild inflammatory infiltrates, predominantly composed of T lymphocytes, and decrease of AMPAR immunoreactivity.
Conclusion:
AMPAR antibodies usually associate with limbic encephalitis but may also present with immune responsive, acute-to-subacute, isolated hippocampal dysfunction without overt inflammatory CSF or MRI changes.
Insights
This study details a rare form of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) encephalitis presenting as isolated amnesia. Neuropathology revealed hippocampal changes and reduced AMPAR immunoreactivity, highlighting a distinct clinical and pathological profile.
Area of Science:
- Neuroimmunology
- Neuropathology
- Autoimmune Encephalitis
Background:
- Autoimmune encephalitis associated with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antibodies typically affects the limbic system.
- Unusual presentations of AMPAR encephalitis can occur, challenging diagnosis and treatment.
Purpose of the Study:
- To describe a unique clinical presentation of AMPAR encephalitis characterized by global hippocampal amnesia.
- To detail the neuropathologic findings in these specific cases.
Main Methods:
- Retrospective analysis of three patients with autoimmune global hippocampal amnesia.
- Utilized comprehensive cognitive and neuropsychological assessments.
- Conducted antibody testing and detailed neuropathologic analysis of brain autopsy tissue, including histology and immunohistochemistry.
Main Results:
- Patients presented with acute-to-subacute global amnesia, without cognitive, attention, or behavioral deficits. Epileptic seizures and psychiatric symptoms were absent.
- Magnetic Resonance Imaging (MRI) findings varied, with one normal scan and two showing hippocampal signals.
- Two patients achieved complete remission with immunotherapy; one with underlying lung adenocarcinoma did not improve and died due to tumor progression. Autopsy revealed unilateral hippocampal sclerosis, mild T-lymphocyte infiltrates, and decreased AMPAR immunoreactivity.
Conclusions:
- AMPAR antibodies can manifest as isolated hippocampal dysfunction, even without typical limbic encephalitis features.
- This presentation may occur without clear cerebrospinal fluid (CSF) inflammation or MRI abnormalities.
- Early recognition and immunotherapy are crucial for immune-responsive cases.
