A 63-year-old man was admitted to our hospital with altered cognition for the previous 4 months. He was disoriented in time and space and unable to recall any words after 3 min; in addition, he had a progressive headache with nausea and vomiting for 1 week. He had no history of underlying diseases. The day after admission, he entered a state of stupor [Glasgow Coma Scale (GCS): E2V2M2] with respiratory failure.
Laboratory tests, including malignancy workup [i.e., Ri, Yo, Hu, Ma2/Ta (PNMA2), LGI1, CV2/CRMP5, amphiphysin, NMDAR, GABAR, recoverin, CASPR2, and AMPAR2] and vasculitis workup (i.e., ESR, CRP, RF, ANA, C3, C4, CH 50, ANCA, RPR/VDRL, protein electrophoresis) yielded negative results. Brain MRI (T2-FLAIR) revealed abnormal hyperintensity with expansion in the hippocampi, temporal cortex, medial thalami, right insular cortex, left pulvinar, and left parietal lobe, without restricted diffusion (not shown) or contrast enhancement (Figures 1A,B). Brain MRI (T2-FLAIR) demonstrates the disappearance of hyperintense and expansion lesions after treatment for autoimmune encephalitis, especially in the medial thalami, right insular cortex, and left pulvinar. Brain MRI (T2-FLAIR) also shows T2-FLAIR hyperintensity with atrophy in the left medial temporal lobe (white arrow), right medial temporal lobe (white arrowhead), and left parietal lobe (Figures 1C-F).
A lumbar puncture showed no evidence of infection (white blood cells: 0 cells/muL) or malignant cells. Blood culture, urine culture, and CSF were negative for HSV-1, HSV-2, HHV-3, HHV-6, HHV-7, HHV-8, Epstein-Barr virus, cytomegalovirus, Enterovirus, HBV, HIV, HTLV, Treponema pallidum, human polyomavirus 2, Mycobacterium tuberculosis, Borrelia burgdorferi, Anaplasma phagocytophilum, tick-borne encephalitis virus, and polyomavirus BK. The CSF was also negative for antibodies, including Ri, Yo, Hu, Ma2/Ta (PNMA2), LGI1, CASPR2, recoverin, Sox1, Titin, Zic4, DNER/Tr, amphiphysin, CV2/CRMP5, GAD65, NMDAR, GABAR, IgLON5, AMPAR2, DPPX, glycine receptor, and mGluR5. Finally, additional auto-antibody detecting tests were performed to check for an AE with the patient's serum. A tissue-based assay was initially performed to screen for AE. Then, cell-based immunoassay and immunoblotting were performed to detect synaptic and intracellular auto-antibodies. In cases of an unknown auto-antibody being identified in the tissue-based assay, further tests were performed by staining cultured neuronal cells with the patients' serum. In addition, immunoprecipitation and mass spectrometry were performed to identify novel specific antigens. Despite this extensive testing of AE, no auto-antibodies were identified.
We suspected antibody-negative AE and started first-line treatment with high-dose intravenous methylprednisolone (1,000 mg) for 5 days, followed by oral prednisolone (Figure 1G). However, the patient's status deteriorated; he presented with episodes of right facial grimacing and right upper limb contraction, consistent with faciobrachial dystonic seizures. Continuous electroencephalogram demonstrated rhythmic sharp-and-waves arising from the left temporo-occipital lobe. These alterations were controlled with levetiracetam, valproic acid, and lacosamide.
The patient further deteriorated to a comatose state (GCS: E1VtM1) with generalized tonic-clonic seizures, requiring intravenous immunoglobulin (IVIg, 1 mg/kg for 5 days) on hospital day 16. His arousal level plateaued (GCS: E1VtM1) after receiving IVIg for 2 weeks. We then administered a second-line treatment, rituximab (IV, 375 mg/m2, once weekly x 4 doses); before rituximab administration, we checked the patient's B-cell counts (CD19+/CD20+) on hospital day 28. CD19+/CD20+ counts of total lymphocytes in the peripheral blood were 15.3 and 15.1%, respectively (Figure 1G). After receiving rituximab for 3 weeks, the patient's mental status started improving (GCS: E4VtM5), and follow-up brain MRI findings were markedly improved (Figures 1C-F). The patient was discharged to a rehabilitation center (GCS: E4VtM6). At the last follow-up 5 months later, CD19+/CD20+ B-cells both remained at 0% (GCS: E4V5M6).