A 25-year-old previously healthy man was admitted to a local hospital for progressive hypersomnolence preceded by 1 week of fever and 2 days of headache. General convulsions developed the next day after admission, therefore, he was transferred to our hospital. On examination, his body temperature was 38.6 C, blood pressure 143/94 mm Hg, and he was in a stuporous status with prominent nuchal rigidity and bilateral rales on chest auscultation. His chest X-ray showed patchy consolidation over the right lower lung zone (shown in Fig. 1). The initial brain MRI showed prominent leptomeningeal enhancement at bilateral brainstem, cerebellum, and right cerebral sulci (shown in Fig. 2a, b) and a non-enhanced oval shape lesion at the SCC with increased signals in diffusion-weighted imaging (DWI), low signals in apparent diffusion coefficient (ADC), and hyperintensity in T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) (shown in Fig. 3a-d). The cerebrospinal fluid (CSF) analysis revealed turbid appearance, significantly high pressure (420 mmH2O), lymphocyte-predominant pleocytosis (white blood cells 148/muL, lymphocytes 95/muL), reduced glucose (43 mg/dL), and elevated protein (519 mg/dL). The biochemistry assay was all normal, including sodium, which was 136 mmol/L. The CSF pathogen studies were negative in bacteria, syphilis, fungus, tuberculosis, and virus via multiple polymerase chain reaction (FilmArray Meningitis/Encephalitis). The viral serology surveys including varicella zoster virus, herpes simplex virus, cytomegalovirus, and Japanese encephalitis virus were also negative. Serology detection for M. pneumoniae using rapid immunochromatographic test (Biocard  M. penunoniae IgM kit, Labsystems Diagnostics, Finland) showed IgM positive at a titer of 1:320 (normal value <1:40) on the 2nd admission day, indicating an acute M. pneumoniae infection. Neither polymerase chain reaction analysis nor antibody detection of M. pneumoniae in the CSF was available in our hospital. He was treated with empirical antibiotics, antiviral agents, antiseizure medications, osmotic diuretics, and steroids. Resolution of the pneumonic patch was noted in the subsequent chest X-ray. The repeated CSF analysis 10 days later showed improvement, with a white cell count of 1/muL and a normal protein level at 13.2 mg/dL. However, his neurological condition deteriorated into a comatose state with full-dilated unreactive pupils, flaccid quadriplegia, and ventilator support. The follow-up MRI 3 weeks after admission revealed apparent regression of the leptomeningeal inflammation (shown in Fig. 2c, d), but emergence of symmetric confluent hyperintensities on T2-weighted fluid-attenuated inversion recovery images involving the whole corpus callosum, bilateral internal capsules, and adjacent subcortical areas were without enhancement (shown in Fig. 3e-g). The extensive and symmetric white matter changes on the MRI did not conform to the typical findings in ADEM. Moreover, a nerve conduction velocity study disclosed severe amplitude reduction of compound muscle action potentials and mild reduction in sensory action potentials, compatible with a critical-illness polyneuropathy. Under the presumption of extensive inflammation affecting the central nervous system, we tried immunotherapies with intravenous methylprednisolone pulse therapy and intravenous immunoglobulin successively. His pupil responses recovered rapidly 2 days after completing the immunotherapies, and the consciousness and brainstem reflexes improved gradually within 2 weeks. The ventilator-support was weaned off successfully. The follow-up MRI on the 44th and the 79th admission day displayed continuing regression of the cytotoxic change in the corpus callosum and the white matter (shown in Fig. 3h-m). Three months after admission, he was discharged to a rehabilitation institution with clear consciousness and paraplegia. Six months after discharge, he could speak, eat, and move his upper limbs without efforts but still continued his rehabilitation for the moderate paraparesis.