Impact of an immune modulator fingolimod on acute ischemic stroke

Abstract

Peripheral lymphocytes entering brain ischemic regions orchestrate inflammatory responses, catalyze tissue death, and worsen clinical outcomes of acute ischemic stroke (AIS) in preclinical studies. However, it is not known whether modulating brain inflammation can impact the outcome of patients with AIS. In this open-label, evaluator-blinded, parallel-group clinical pilot trial, we recruited 22 patients matched for clinical and MRI characteristics, with anterior cerebral circulation occlusion and onset of stroke that had exceeded 4.5 h, who then received standard management alone (controls) or standard management plus fingolimod (FTY720, Gilenya, Novartis), 0.5 mg per day orally for 3 consecutive days. Compared with the 11 control patients, the 11 fingolimod recipients had lower circulating lymphocyte counts, milder neurological deficits, and better recovery of neurological functions. This difference was most profound in the first week when reduction of National Institutes of Health Stroke Scale was 4 vs. -1, respectively (P = 0.0001). Neurological rehabilitation was faster in the fingolimod-treated group. Enlargement of lesion size was more restrained between baseline and day 7 than in controls (9 vs. 27 mL, P = 0.0494). Furthermore, rT1%, an indicator of microvascular permeability, was lower in the fingolimod-treated group at 7 d (20.5 vs. 11.0; P = 0.005). No drug-related serious events occurred. We conclude that in patients with acute and anterior cerebral circulation occlusion stroke, oral fingolimod within 72 h of disease onset was safe, limited secondary tissue injury from baseline to 7 d, decreased microvascular permeability, attenuated neurological deficits, and promoted recovery.

Keywords: acute ischemic stroke; fingolimod; immune modulation.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Effects of fingolimod in patients with AIS: trial profile. Twenty-two patients with AIS, who exceeded therapeutic window for tPA upon enrollment, were assigned into one of two groups with matched clinical characteristics and subtypes of infarct. All were treated with conventional stroke management and half (n = 11) also received fingolimod (FTY720, Gilenya, Novartis) 0.5 mg orally once daily for 3 consecutive days at the indicated time points. Counts of circulating lymphocyte subsets were monitored by flow cytometry. Clinical assessments (NIHSS, mRS, and mBI) were conducted at the indicated time points. Alterations of infarct volume and microvascular permeability were measured by MRI at the indicated time points.

Fig. 2.

Dynamics of lymphocyte subset counts during fingolimod treatment. Blood was draw from patients at the baseline (20 ± 15 h) and at 1, 3, 7, and 90 d after first dose of fingolimod. Blood was drawn from control subjects at the same time points. Mononuclear cells were purified and stained with antibodies to cells. Percentages of CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD56+ NK cells were determined by flow cytometry; absolute numbers were calculated, and as × 106/mL of blood for patients. *P < 0.05, **P < 0.01, ***P < 0.001 versus baseline of fingolimod-treated patients and #P < 0.05, ##P < 0.01, ###P < 0.001 versus control at same time point. Mean ± SE is shown.

Fig. 3.

Clinical outcomes in control and fingolimod-treated groups. (A) Trends of NIHSS scores from control and fingolimod-treated patients at the indicated time points. (B) Sharp contrasts are clear in NIHSS changes for control and fingolimod-treated subjects in the first week. (C) The comparison of mBI between groups. (D) The comparison of mRS between groups.

Fig. 4.

Impact of fingolimod on lesion volumes and vascular permeability in patients and representative MRIs. (A) Representative MRI scans showed an acute right hemisphere infarct in control (Upper) and a fingolimod-treated patient (Lower). At day 7, striking differences were evident in that the infarct volume enlarged in the control patient, and signal intensity was relatively high in FLAIR. In contrast, the infarct volume progress was restrained in our fingolimod-treated patient. Contrast-enhancement T1 images demonstrated prominent contrast in control patient at day 7, largely consistent with infarct volume. Margins of lesion for both patients are marked with lines. (B) Lesion volumes were measured on DWI (base line) and FLAIR (7 d). (C) The ratio of infarct volume increase = infarct volume change from baseline to day 7/infarct volume at baseline. (D) Vascular permeability (Lower) compared in two groups. Microvascular permeability of the infarct lesion were evaluated on CET-WI (7 d), the degree of enhancement on CET-WI was expressed as rT1%, rT1% = (mean signal intensity of a region of the infarction-mean signal intensity of the contra lateral homologous normal brain area)/mean signal intensity of the contra lateral homologous normal brain area. Values are mean ± SE; comparisons were performed with independent t test.