Medical history before cell therapy
The child developed normally during the first 58 months until suffering from convulsions, weakness of the left arm and foot on August 10th, 2018. On EEG, slow delta waves with a frequency of 2-3 kz were observed in the right hemisphere of the brain. The patient was diagnosed with AE based on positive anti-NMDA receptor in cerebral spinal fluid on August 22nd, 2018. Treatment was initiated with Solumedrol 20mg/kg/day for five days followed by Prednisolone with 30 mg/day, decreasing by 10 mg every seven days and lasting for 16 days; IVIG 5 g/day for 7 days; Depakine 300 mg/day; and Risperidone 1mg/day. From September 1st, 2018 onwards, the patient became unresponsive so that oral feeding through nasogastric tube was required. Treatment was switched to Cellcept 500 mg per day and Topamax 2 mg/kg/day for 10 days as of September 11th, 2018, without success. Rituximab 240 mg was given resulting in reduced myoclonus, but general muscular spasticity increased. An examination on December 27th, 2018, indicated complete loss of awareness, intense muscle spasticity of the whole body, and intermittent seizures. The patient did not respond to Cellcept 250 mg/day, Tocilizumab 120 mg, Depakine 150 mg/day, and Keppra 500 mg/day. The patient received acupuncture therapy in another hospital for two months without improvement.
Evaluation before cell therapy
The patient was admitted to Vinmec International Hospital on March 26th, 2019 (7 months after the onset of the illness). Her body weight was 17 kg. Her awareness was completely lost with a CRS of 6 points (Table 1). Intermittent seizures were observed. The GMFCS scored at the level V, the GMFM-88 at 23 points, and poor hand function with a MACS at the level V. Increased muscle tone measured using Modified Ashworth Scale was two points for upper and lower limbs (Table 2). Feedings were maintained through the nasal gastric tube. Urinary incontinence and constipation were noted. Personal-social, fine motor, language, and gross motor ability according to the Denver II were impaired (Table 3). Brain MRI revealed diffuse cerebral atrophy in the supratentorial region, dilatation of the third ventricle and bilateral lateral ventricles (Fig. 1A).
Allogeneic UC-MSC infusion and improvements
In accordance with the patient’s severe condition, the parents were explained in detail the potential risks and benefits of the cell therapy and intrathecal infusion. Upon obtaining their written informed consent and approval from the Hospital’s Board of Directors, UC-MSC therapy was applied.
The first infusion was performed on April 4th, 2019, with 17 million UC-MSCs. The characteristics of the MSC product is presented in the Table S1. No severe adverse events occurred during and after the procedure and the patient was discharged 48 hours after the infusion. Medication was continued with Risperidone 1 mg/day and Keppra 500 mg/day. Daily physical therapy was done at home by the patient’s mother.
At re-examination on November 26th, 2019 (7 months 22 days after the first cell infusion), the patient’s body weight increased to 19.5 kg. Muscle spasticity and dysphasia were reduced so that the nasogastric tube feeding was discontinued and switched to normal oral feeding. The patient was able to react to external stimuli with a German CRS of 10 points (Table 1). Motor functions showed no significant change, both GMFCS and MACS remained at the level V, and GMFM-88 scored 24 points. Muscle spasticity measured 2 points in the upper extremities and 1 point in the lower extremities (Table 2). Better head and neck control was also observed. The patient was able to turn to the sides. Denver scores remained unchanged (Table 3). Constipation and urinary incontinence persisted.
The second infusion of UC-MSCs was safely carried out on December 6th, 2019, with 19 million UC-MSCs (Table S1). The patient was discharged after two days and then continued to receive Risperidone 1 mg/day, Keppra 500 mg per day, and daily physical therapy at home. The doses of medication were reduced gradually and discontinued one month after the second infusion without the manifestation of epilepsy.
Re-examination on June 9th, 2020 (14 months 5 days after the first MSC therapy) showed her improved awareness with a German CRS of 19 points (Table 1). Patient’s gross and fine motor skills resulted in better scores in all analysed tests: the GMFCS reduced to the level IV, GMFM-88 increased to 106 points, and MACS improved to the level II. Muscle spasticity was reduced from 2 points to 0 point for the upper limbs and remained 1 point for the lower limbs (Table 2). The patient was able to sit and use her hands to pick up foods and other objects. Denver II scores also showed improvement in all areas including personal-social, gross motor, fine motor-adaptive, and language (Table 3). However, urinary incontinence and constipation remained unimproved.
The third administration of 22 million UC-MSCs was performed without side effects on June 10th, 2020 (Table S2), followed by daily physical therapy at home after discharge.
Re-examination four months later (18 months after the first infusion) revealed that patient’s awareness further improved with a German CRS of 21 points (Table 1). Examination of motor function indicated GMFCS at the level I, GMFM-88 of 255 points. MACS was at the level I and muscle tone reverse to normal with the modified Ashworth scale at score 0 (Table 2). She could walk normally, eat independently, and practice writing. Significant improvements were also observed at Denver II tests (Table 3). Urinary incontinence and constipation were slightly improved. Brain MRI indicated cerebral atrophy reduced remarkably with mild dilatation in the left lateral ventricle (Fig. 1B).
Three months later (21 months after the first infusion), she could draw, write, and speak some words. Her urinary and fecal function were completely controlled. In the last examination (28 months after the first infusion, 14 months after the third infusion), she could count numbers and prepared for school.