Case 1
A two-year-old girl presented with a history of delayed motor skills and language development. She could lift her head and hold its position at 6 months, sit in a tripod fashion without support at 12 months, stand with support at 13 months, and walk with assistance at 18 months. There had been no improvement in language after she could say “mum” and “dad” at 18 months. Additionally, she had symptoms of hyperactivity and agitation. Family, prenatal, perinatal, and neonatal histories were normal. Pathologic reflexes were negative.
After admission, laboratory tests showed lymphocytosis (4.81 × 109 cells/L, normal: 1.6–3.2 × 109) and herpes simplex virus (HSV) infection (serologically reactive HSV-1/2 IgM 1.25; normal: < 1.00). Inflammation was also present, based on elevated tumor necrosis factor alpha (TNF-α; 16.10 pg/mL, normal: < 2.8), interleukin-2 (IL-2) receptor (794.0 U/mL, normal: 100–500), and CD4+ (1972.74 cells/µL, normal: 500–1200) and CD19 + cells (1336.82 cells/µL, normal: 103–581). Thyroid function and its associated antibody tests were normal. Results of gas chromatography-tandem mass spectrometry of blood, urine, and blood lactic acid were normal, but anti-dsDNA was found in the serum.
MRI showed bilateral T2 hyperintensity within the occipital lobes (Fig. 1-A). EEG results did not show any abnormalities. Lumbar puncture results were unremarkable, with an absence of oligoclonal bands and normal levels of IgG, IgA, and IgM. HSV and cytomegalovirus (CMV) were not seen in real-time PCR of the CSF. While serum immunofluorescence detected ANNA-2, it was not found in the CSF. Gesell developmental diagnosis scale on day 8 of hospitalization, showed delays in adaptability, gross motor skills, fine motor skills, language skills, and social ability. Auditory and visual evoked potentials showed prolongation of the P100 latency and increased hearing thresholds bilaterally.
The patient received acyclovir (30 mg/kg/day, 14 days) for HSV infection. On day 6, sporadic irregular tremors were observed in both hands, which worsened when holding things and being emotional. Immunosuppressive therapy for possible autoimmune encephalitis was administered as follows: intravenous immunoglobulin (1 g/kg/day for 2 days) and methylprednisolone (20 mg/kg/day for 5 days, followed by 10 mg/kg/day for 5 days, 5 mg/kg/day for 5 days, and 2 mg/kg/day for 5 days). During treatment, CMV DNA was detected in her urine. Hence, the acyclovir treatment was followed by 14 days of ganciclovir. After treatment, HSV IgM decreased to normal levels (0.70). However, the hyperintensity seen on the previous MRI showed no improvement after treatment (Fig. 1-B). While there was little improvement in her language and motor skills, the hyperactivity and agitation symptoms decreased dramatically and the tremors reduced in severity.
Case 2
A six-month-old male infant presented with major motor development retardation. He could lift his head but not hold the position. Family and birth history were normal. A neurological examination revealed symmetrical increased muscular tension in the lower extremities. Pathologic reflexes were negative on both sides. Sucking reflex, cuddling reflex, parachute reflex, and foraging reflex were negative. After being admitted to our hospital, we observed more than 10 episodes of lateral body dystonia with crying daily.
Upon admission, laboratory results showed lymphocytosis (10 × 109 cells/L) and CMV infection (serological CMV IgM 27.4 U/mL). CMV DNA was found in the urine but not in serum. Elevated TNF-α (14.6 pg/mL), IL-2 receptor (1359 U/mL), and CD4+ (4300.51/µL) and CD19 + cells (2262.08/µL) demonstrated inflammation. Like case 1, test results for thyroid function and its associated antibodies, blood, urine, and blood lactic acid were normal. Serum immunofluorescence was positive for ANNA-2. Tests for HSV and CMV antibodies, other autoimmune antibodies, oligoclonal bands, and immunoglobulins were negative in the CSF. Long-term EEG did not show any abnormalities. MRI and CT were unremarkable. Intelligence assessment was performed with Bayley scales, indicating motor and cognitive developmental delays. The patient failed the distortion product otoacoustic emission test for newborn hearing screening.
He had received ganciclovir (10 mg/kg/day, 14 days) for the CMV infection before admission to our hospital. We continued ganciclovir for another 14 days and administered immunosuppressive therapy for possible autoimmune encephalitis including intravenous immunoglobulin and methylprednisolone. Additionally, oxcarbazepine and benzhexol were administered to treat dystonia. During treatment, there was minor improvement in gross motor function, but the dystonia showed no alleviation. To exclude the possibility of a concurrent tumor, serological tumor markers were evaluated and PET-CT was performed (Fig. 3), which showed reduced fluorodeoxyglucose uptake bilaterally in the parietal lobes. We performed exome sequencing and copy number variation analysis, which detected no significant genetic alteration. Serological CMV IgM persisted throughout the treatment. After discharge, the patient was advised to go to a rehabilitation center for regular cognitive and physical therapy. His muscular tension was alleviated with therapy, but there was little improvement in gross motor skills and dystonia.