Several autoimmune CNS inflammatory diseases, including autoimmune glial fibrillary acidic protein astrocytopathy (A-GFAP-A), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and aquaporin-4-immunoglobulin-G-positive neuromyelitis optica spectrum disorders (AQP4-IgG+NMOSD) often presented initially with similar symptoms mimicking intracranial infection, are not easy to be differentiated during early-onset lacking the detection of autoantibody.In our single-center cohorts, those patients mimicking intracranial infection as initial symptoms, including 9 with A-GFAP-A, 17 with MOGAD and 11 with AQP4-IgG+NMOSD, were retrospectively included. The autoantibodies were detected by cell-based assays. The clinical, immunological and radiological characteristics were summarized.In the cohort, tremor and positive Kernig's sign were predominated in A-GFAP-A (44.4% and 77.8%, respectively) over MOGAD (5.9%, p = 0.034; 29.4%, p = 0.038) and AQP4-IgG+NMOSD (0, p = 0.026; 18.2%, p = 0.022). Ten patients (A-GFAP-A, 4; MOGAD, 5; AQP4-IgG+NMOSD, 1) were initially misdiagnosed as tubercular or viral meningoencephalitis, however, resistant to empiric anti-tuberculosis or anti-viral treatment, and finally were in partial or complete remission with the immunotherapy when adjusted treatments. On cerebrospinal fluid (CSF) examination, white blood cell counts in CSF was higher in A-GFAP-A cohort (median, 90×106/L [IQR, 41-209]) compared to AQP4-IgG+ NMOSD (median, 6 × 106/L [IQR, 1-10], p = 0.018). Importantly, the higher increase in CSF protein (1319 mg/L [IQR, 1035-1519]), lactate dehydrogenase (LDH, 53.9 ± 37.2 U/L), lactic acid (3.50 ± 0.88 mmol/L), IgG (130.9 ± 60.4 mg/L), IgM (8.6 ± 6.1 mg/L) and IgA (23.0 ± 11.4 mg/L) levels in A-GFAP-A was found compared to MOGAD (CSF protein: 441 mg/L [IQR, 330-776], p = 0.004; LDH: 53.9  ±  37.2 U/L, p = 0.005; lactic acid: 2.15 ± 0.62 mmol/L, p = 0.001; IgG: 77.9 ± 71.3 mg/L, p = 0.018; IgM, 2.7 ± 2.9 mg/L, p = 0.015) and AQP4-IgG+ NMOSD (CSF protein: 386 mg/L [IQR, 369-453], p = 0.002; LDH: 23.7 ± 11.0 U/L, p = 0.048; lactic acid: 2.40  ±  0.66 mmol/L, p = 0.040; IgG, 53.2 ± 30.3 mg/L, p = 0.015; IgM, 2.1 ± 3.9 mg/L, p = 0.004; IgA, 5.2 ± 5.0 mg/L, p < 0.001). Of Note, smaller (< 2 cm), symmetrical lesions in ganglia and thalamus (5/8, 62.5%) were showed in over half of the A-GFAP-A patients (5/8, 62.5%), but never in MOGAD (0%, p = 0.001) and AQP4-IgG+NMOSD (0%, p = 0.026). In addition, diffuse meningeal enhancement was more common in A-GFAP-A (8, 88.9%) compared to MOGAD (5, 29.4%, p = 0.011) and AQP4-IgG+NMOSD (1/6, 16.7%, p = 0.011), respectively. Acute disseminated encephalomyelitis (ADEM) -like lesions occurred more frequently in MOGAD (6/16, 37.5%) but never in A-GFAP-A and AQP4-IgG+NMOSD (p = 0.02).Our study demonstrates that several distinct features including the symptom of tremor, higher CSF immunological profiles, bilateral symmetrical lesions in ganglia, and diffuse meningeal enhancement are frequent in A-GFAP-A, whereas ADEM-like lesions seem to occur mainly in MOGAD. These signs provide crucial clinical implications in differential diagnosis for those mimicking intracranial infection as initial symptoms. Clinicians should consider the possibility of these autoimmune CNS inflammatory diseases masquerading as intracranial infection.Copyright © 2022. Published by Elsevier B.V.