A 47-year-old man was admitted to our hospital for progressive cognitive decline and apathy for 10 months. History taking revealed no infection, vaccination, or significant weight loss within 6 weeks and no other medical history. His family had no history of auto-immune and hereditary diseases. Further general and neurological examination of the body revealed no abnormalities except for cognitive decline and active tendon reflexes in limbs. The long-term and short-term memory, the ability of calculation, as well as temporal and spatial perception were found to be impaired.
In further elaboration, 10 months ago (September 3, 2019), the patient was admitted to the first hospital for memory loss in 4 days. The symptoms of the patient started with the inability to remember what happened just now, unresponsive, and apathy. But the ability of daily living was not significantly impaired. Intracranial infection and acute cerebrovascular disease were suspected, but initial brain MRI (Figure 1A) and lumbar puncture were normal. The autoantibodies and paraneoplastic antibodies in serum and CSF were not performed in the hospital. The scores of the Geriatric Depression Scale were 12, accordingly, the patient was treated with flupenthixol/melitracen and escitalopram.
About 2 months later (October 28, 2019), he was admitted to the second hospital because of his worsened short-term memory, temporal, and spatial perception. The examination of Mini-Mental State Examination (MMSE) scores was 22/30. Normal findings of routine blood tests included neutrophil/hemoglobin/platelet counts, liver and renal function tests. Other investigations included thyroid function, erythrocyte sedimentation rate, antinuclear antibody, anti-neutrophil cytoplasmic antibody, anti-beta2 glycoprotein antibody, anti-cardiolipin antibody, extractable nuclear antigen, complement levels, serum protein electrophoresis, porphyria screen, tumor biomarkers, organic acid, poison screening were within normal limits. Hepatitis B virus serology, HIV serology, treponema pallidum serology, tuberculosis, and CD4 T cell count were negative. CSF analysis was normal, including cells, protein, glucose, oligoclonal bands, herpes simplex virus 1 and 2, varicella-zoster virus, enterovirus, meningococcus, parasites, treponema pallidum. The metagenomic next-generation sequencing (mNGS) was also conducted in the CSF sample but no pathogen (detection ranging from viruses to bacteria, fungi, and parasites) was identified. A repeat MRI brain was normal. Video electroencephalogram (EEG) showed low-amplitude fast waves. Even though the MRI brain and CSF of the patient were normal, autoimmune or paraneoplastic encephalitis was suspected based on the clinical presentation. Further ultrasonography examination of the abdominal organs, thyroid gland, and CT scan of the thorax showed no evidence of malignancy. Screening tests were also negative for autoimmune encephalitis antibody (NMDA-R, CASPR2, AMPA1-R, AMPA2-R, and LGI1), paraneoplastic antibody (Hu, Yo, Ri, PNMA2, CRMP5, and amphiphysin), and myelin-related antibodies (MBP-Ab, MOG-Ab, AQP4-Ab). No special treatment was given due to an unclear diagnosis. While in hospital, he developed rapidly progressive memory deficits, abnormal behavior like teasing children and making funny faces, and personality changes with apathy. He was easy to get lost, in addition to confusion and fatigue. Based on the results of the preliminary physical examination and progression of the disease, autoimmune/viral encephalitis was suspected. Accordingly, the patient was treated with intravenous injection of methylprednisolone 1 g daily, halved every 3 days, and tapered over 12 days and at the same time with antiviral drug acyclovir. Oral prednisolone (70 mg/day) was initiated on day 13, and then gradually tapered to a maintaining dose (10 mg/day). The condition of the patient gradually improved, and he could come back to normal life and work.
In July 2020, the patient was admitted to our hospital for a relapse characterized by memory loss and agitation. Repeat brain MRI showed high signal changes on T2 and fluid-attenuated inversion recovery sequences predominantly affecting the bilateral medial temporal lobe combined with some parts of the temporal cortex (Figure 1B). CSF neural-specific antibodies detection via cell-based assay (further details around the laboratory were provided in Supplementary Materials) found antibodies against AMPA1R (titer, 1:1) and AMPA2R (titer, 1:10); serum also showed the presence of anti-AMPA2R (1:32), but anti-AMPA1R was undetected. EEG showed diffuse slow waves. CT scan of thorax/abdomen/pelvis was negative for neoplasia. The diagnosis of autoimmune encephalitis prompted immediate treatment with a second course of methylprednisolone for 12 days (methylprednisolone 1 g daily, halved every 3 days, and tapered over 12 days). A repeat brain MRI showed the increased signal in temporal lobes had improved and there was atrophy of the medial temporal lobe (Figure 1C). The memory of the patient improved, and he could take care of himself with the assistance of family members when discharged.
After 4 months (November 3, 2020), the patient was admitted to our hospital again for a relapse characterized by confusion, dramatic memory deficit, personality changes with irritability, and episodes of aggressive behavior. Antibodies against AMPAR1 and AMPAR2 were detected both in the serum and CSF of the patient. The titer of AMPAR1 is 1:10 in CSF (Figure 1E) and serum (Figure 1G), and the titer of AMPAR2 is 1:100 in CSF (Figure 1F), 1:1000 in serum (Figure 1H). Owing to the recurrence, the patient was treated with intravenous injection of immunoglobulin (IVIG) combined with a repeat course of methylprednisolone and oral immunosuppressive drug (mycophenolate mofetil). He responded well to the treatment with the improvement of abnormal and aggressive behavior. Repeat MRI brain 3 weeks after admission showed significant atrophy of bilateral medial temporal lobe and temporal cortex (Figure 1D). Mycophenolate mofetil (3 g/day) was maintained when discharged. During the follow-up of a half year, he has had no further relapses and returned to work (MMSE 27 and mRS 1).
The timeline of the case was summarized in Figure 2.