In early February of 2021, a previously healthy 57-year-old man was admitted to the local hospital with complaints of progressive dizziness, binocular diplopia, and unsteady gait for 9 days after neck chiropractic. He also stated mild hemiplegia of the left leg and hemidysesthesia of the left hand. The patient reported a history of cigarette smoking for more than 30 years and denied the history of oral and genital ulceration, uveitis, skin lesions, and arthritis. The score of neurological function assessed by the National Institutes of Health Stroke Scale (NIHSS) was 3, including ataxia in the left upper and lower extremities and mild sensory loss in the left hand. Meanwhile, a modified Rankin scale (mRS) score of 2.0 was obtained based on the disability of daily living due to an unsteady gait. The brain magnetic resonance imaging (MRI) performed 9 days after onset showed multifocal lesions scattered in bilateral basal ganglia and midbrain, and some of them showed hyperintensities on diffusion-weighted imaging (DWI). The magnetic resonance angiography (MRA) of the brain was normal, and the carotid artery ultrasound was unremarkable. The patient was initially diagnosed as multiple cerebral infarctions and aspirin, clopidogrel, and statins were prescribed, but his clinical status continued to worsen. Then the patient was referred to our department from a local hospital for a further comprehensive assessment of his condition in early March.
On admission, the patient was well nourished with a body mass index (BMI) of 31.12 kg/m2. His neurologic examination showed the cognitive function was intact. The patient had fluent speech and was oriented. The visual acuity and visual field were intact, and pupil size was normal and well reactive to light. Moderate limitation of adduction in both eyes was observed, and there was no spontaneous or gaze-evoked nystagmus. The numbness of distal fingers in the left hand and a mild decrease of muscle strength in the left lower limb (BMRC grade 4) were noted. Deep tendon reflexes were exaggerated in the left limbs, and bilateral Babinski's sign and the left Chaddock's sign were positive. Notable dysdiadochokinesia was seen in the left limbs, together with left dysmetria in the finger-nose test and left instability in the heel-knee-tibia test. His gait was unsteady and Romberg's test was positive. The aforementioned findings contributed to an increase of the mRS score to 3.
Repeat brain MRI scan revealed multifocal T1 hypointensities and T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensities scattered in the brainstem (midbrain and the tegmentum of pons), basal ganglia (head of caudate nucleus and putamen), right hippocampus, and paraventricular and subcortical white matters of bilateral frontal lobes ( Figure 1 ). Some of these lesions showed hyperintensities on both DWI and apparent diffusion coefficient (ADC) maps and heterogeneous patchy or ring-like enhancement on gadolinium (Gd)-enhanced MRI ( Supplemental Figure 1 ). Computerized tomography (CT) of the chest-abdomen-pelvis with and without contrast eliminated the presence of malignancies. The results of laboratory tests including complete blood count, urine and stool analyses, liver and kidney function, lipid profile, and blood glucose concentration were unremarkable. Serological tests for infections and autoimmune parameters were all normal. Cerebrospinal fluid (CSF) analysis revealed normal white blood cell count (0 x 106/L), protein level (285.0 mg/L; normal range: 80-430 mg/L), and immunoglobulin G level (28.9 mg/L; normal range: 0-34 mg/L). No malignant lymphocytes were found in CSF. Metagenomic next-generation sequencing (mNGS) did not detect any pathogenic microorganisms in CSF. Three oligoclonal IgG bands (OCBs) were detected exclusively in CSF. Anti-CASPR2 antibodies with a titer of 1:10 were detected by cell-based assays (CBA) using HEK293 cells transfected with CASPR2 isoform 1 and confirmed by tissue-based assay (TBA) using rat brain tissue sections exclusively in serum but not in CSF. Further analysis via immunofluorescence with secondary antibodies against specific for IgG subclasses documented a subclass of IgG1 but not IgG2, IgG3, or IgG4. Other antibodies against NMDAR, LGI1, AMPAR1, AMPAR2, GABAAR-alpha1, GABAAR-beta3, GABABR, Kelch-like protein 11, ganglionic AChR, mGluR1, mGluR5, D2R, Neurexin-3alpha, DPPX, IgLON5, GlyR-alpha1, AQP4, MOG, GFAP, Hu, Yo, Ri, CV2, Ma1, Ma2, SOX1, Zic4, GAD65, Tr/DNER, Titin, PKC-gamma, Recoverin, and Amphiphysin were detected negative in both CSF and serum by CBA at the reference center (MYBiotech Co., Ltd., Xi'an, China). Based on the presence of specific anti-CASPR2 antibodies, a diagnosis of anti-CASPR2 antibody-associated autoimmune encephalitis was eventually established.
Statins and antiplatelet drugs were discontinued immediately, and the patient was then treated with intravenous immunoglobulin therapy (IVIg; 0.4 g/kg body weight for 5 consecutive days) plus high-dose intravenous methylprednisolone pulse therapy (1,000 mg/day for 3 days, 500 mg/day for 2 days) followed by oral prednisone at an initial dose of 40 mg daily with a slow tapering schedule of 5 mg every month. There was a significant improvement in diplopia and ataxia obtained 1 week after the initiation of immunotherapy. Then he continued to adhere to the intervention and was well tolerated. At 2-month follow-up visit after discharge, the patient reported that he had achieved complete remission of diplopia, ataxia, and numbness in the left hand, and only mild weakness in his left lower limb was left. Follow-up brain MRI revealed that the lesions had shrunk or disappeared. At the last follow-up in August, the status of the patient remained stable with the mRS score of 0. He reported that no adverse and unanticipated events occurred and was satisfied with the treatment that he received and the prognosis. The timeline of patient 1 with relevant data of the episodes and interventions is presented in  Figure 2 .