A 56-year-old Japanese woman was admitted to our hospital because of rapidly progressive decline in her consciousness. The patient was in her usual state of health until 11 days before admission, when she developed headache. Eight days before admission, the patient had low-grade fever and her headache persisted despite treatment with analgesics. Five days before admission, memory loss and anomia developed; however, no psychobehavioral alterations were noted. Three days before this admission, the patient was admitted to another hospital for fever and memory loss. On examination, the patient was unable to state her date of birth or name. Brain magnetic resonance imaging (MRI) revealed bilateral hyperintensities on fluid-attenuated inversion recovery (FLAIR) in the medial temporal lobes. Cerebrospinal fluid (CSF) examination revealed 292 white blood cells (WBCs)/µL (mononuclear cell 83%) with normal protein and glucose levels. Herpes simplex encephalitis was suspected, and intravenous acyclovir was initiated. However, the patient’s mental state progressively deteriorated, resulting in an unresponsive state on day 3 of admission, ultimately leading to her transfer to our hospital for further evaluation and treatment. Her medical history was notable for chronic thyroiditis diagnosed 6 years earlier, for which she was not receiving treatment. Her family history was unremarkable. The patient did not smoke, drink alcohol, or use illicit drugs.
On examination, her temperature was 38.3°C, oxygen saturation was 98% on ambient air, and other vital signs were normal. The patient exhibited nuchal rigidity. The patient was mute and unresponsive to verbal stimuli, with eyes closed, no spontaneous or involuntary movements, and no withdrawal response to noxious stimuli; the Glasgow Coma Scale score was E1V1M1. Despite this, the patient exhibited resistance to passive eye-opening by closing the eyes tightly. Furthermore, the patient exhibited periodic contraction of the orbicularis oculi every 1 s. Muscle tone increased in the upper limbs with the elbows, wrists, and fingers held in a flexed posture, whereas tone was normal in the lower limbs with the knees extended. In the arm drop test, the patient exhibited avoidance of the face; when her hand was released above the face, it did not strike her face but instead slowly descended while maintaining the elbow extension posture. These findings were consistent with catatonic stupor and fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 5th edition criteria for catatonia (positive for catalepsy, stupor, mutism, negativism, and grimacing). The resistance to passive movement distinguished her condition from akinetic mutism. The Bush Francis Catatonia Rating Scale (BFCRS) severity score was 18/69.
Laboratory investigations revealed elevated serum D-dimer levels (39.8 µg/mL) and positive test results for thyroglobulin antibodies (197 IU/mL, reference < 19.3 IU/mL) and thyroid peroxidase antibodies (6.3 IU/mL, reference < 3.3 IU/mL), with normal thyroid hormone levels. Autoantibodies against classical paraneoplastic (intracellular) antigens and glutamic acid decarboxylase 65 were examined in serum using a commercial immunoblotting assay, and the results were negative. CSF examination on admission (day 1) revealed 40 WBCs/µL (mononuclear cell 90%) with normal protein and glucose levels. The IgG index was elevated (0.83); however, no CSF-restricted oligoclonal bands were observed. Bacterial culture and real-time PCR for herpes simplex virus or varicella zoster virus were negative. DNA detection for cytomegalovirus, human herpesvirus-6, enterovirus, and human parechovirus was performed via multiplex PCR (FilmArray®); however, the results were negative. Brain MRI obtained on day 3 revealed two slightly increased diffusion-weighted image/FLAIR signals in the right cerebellar hemisphere and left-sided predominant increased FLAIR signals in the medial temporal lobes with mild edema (Fig. 1A). Cerebral blood flow single-photon emission computed tomography (CT) using N-isopropyl-p-[123I]-iodoamphetamine as a flow tracer performed on day 8 revealed mild focal hypoperfusion in the right-sided predominant frontal lobes and right temporal lobe. Chest and abdominal contrast-enhanced CT revealed thrombi in the main trunk of the right pulmonary artery and deep veins in bilateral legs, without the findings of thymoma, ovarian teratoma, or malignancy. Additional laboratory tests confirmed negative results for anticardiolipin antibodies and lupus anticoagulant. Electroencephalogram (EEG) data recorded on day 2 revealed alternating patterns comprising either frontal predominant 1-Hz delta activity or frontocentral predominant 5-Hz theta activity without evolution or epileptiform discharges (Fig. 2A).
Brain MRI findings. Brain MRI obtained on day 3 (A) revealed two increased FLAIR signals in the right cerebellar hemisphere (arrows) and left-sided predominant increased FLAIR signals with mild edema in the medial temporal lobes (arrow heads). Brain MRI obtained on day 49 (B) showed that these lesions had almost completely resolved
EEG findings. EEG recorded on day 2 (A) revealed alternating patterns comprising either frontal predominant 1-Hz delta activity or frontocentral predominant 5-Hz theta activity without evolution or epileptiform discharges. EEG recorded on day 21 (B) exhibited intermittent 8–9-Hz alpha activity mixed with low-amplitude beta activity in the occipital regions, along with blink-related artifacts in the frontal regions. EEG recorded on day 29 (C) exhibited continuous but slightly arrhythmic 8–9-Hz alpha activity
Autoantibodies against neuronal surface (NS) antigens were first examined at Kitasato University using a commercial kit (Euroimmun AG, product No: FA 111 m-3) following the instructions of the company with an indirect immunofluorescent assay. The patient’s CSF (diluted 1:2) exhibited intense reactivity with NS antigens (Fig. 3A). The rat brain immunostaining pattern—characterized by homogenous reactivity on the dentate gyrus and cerebellar molecular layers, dot-like reactivity on the cerebellar granular layer, and some reactivity with cytoplasmic antigens in the dentate granule and Purkinje cells—strongly suggested the presence of AMPAR antibodies [5]. Autoantibodies against the GluN1 subunits of NMDAR were not detected in the CSF using a commercial fixed cell-based assay (CBA) (Fig. 3B); however, antibodies against the GluA2 subunits of AMPAR were detected in both the CSF (diluted 1:2) and serum (diluted 1:10), confirming the diagnosis of anti-AMPAR encephalitis (Fig. 3C). The presence of AMPAR antibodies was subsequently confirmed at the laboratory of Josep Dalmau (Dalmau Lab, IDIBAPS Hospital Clinic, Barcelona) using an established in-house CBA; however, no other NS antibodies, including GluN1, GABAA and GABAB receptors, mGluR1, mGluR5, LGI1, Caspr2, DPPX, Neurexin-3, or Iglon5 antibodies, were detected.
Tissue- and cell-based assays. Tissue-based assay demonstrating intense reactivity with neuronal surface antigens: homogenous reactivity on the DG-ML and CB-ML, dot-like reactivity on the CB-GL, and some reactivity with cytoplasmic antigens in the DGCs and PCs, an immunostaining pattern highly suggestive of AMPAR reactivity (A). Cell-based assays reveal that CSF is negative for GluN1 antibodies (B) but positive for the GluA2 subunits of AMPAR (C). All assays were performed using CSF (diluted 1:2) with a commercial kit (Euroimmun AG) AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CB-GL, cerebellar granular layer; CB-ML, cerebellar molecular layer; DGC, dentate granule cell; DG-ML, dentate gyrus molecular layer; NMDAR, N-methyl-D-aspartate receptor; PC, Purkinje cells
After admission, the patient was initially treated with corticosteroids alone due to concomitant pulmonary embolism: two cycles of intravenous high-dose methylprednisolone (1 g/day, 3 days) from day 1, followed by oral prednisolone (60 mg, daily) (Fig. 4). Additionally, the patient was treated with continuous heparin for venous thromboembolism, which was subsequently switched to edoxaban. D-dimer levels declined progressively, and intravenous immunoglobulin (0.4 g/kg/day, 5 days) was administered from day 16. Catatonic stupor ameliorated gradually over the following weeks, along with reductions in CSF, WBC count, and IgG index. One month after admission, the patient was able to speak, follow simple commands, and walk with assistance. EEG recorded on day 29 exhibited continuous but slightly arrhythmic 8–9-Hz alpha activity (Fig. 2B and C), and brain MRI obtained on day 49 revealed that all lesions had almost completely resolved (Fig. 1B). The patient was transferred to a rehabilitation hospital on day 59. At discharge, the BFCRS severity score had improved to 0/69, and the Mini-Mental State Examination (Japanese version) score to 30/30; however, the modified Rankin scale score was 2 due to residual short-term memory impairment.
Overview of the clinical course and treatment. Clinical symptoms worsened in a monophasic manner until the initiation of treatment, suggesting that the encephalitis developed primarily rather than secondarily following infection. Following the initiation of immunosuppressive therapy, the patient’s symptoms ameliorated and the IgG index decreased, indicating a decrease in intrathecal antibody production PSL, prednisolone; mPSL, methylprednisolone; IVIg, intravenous immunoglobulin