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Original Investigation |

Fingolimod for the Treatment of Intracerebral Hemorrhage:  A 2-Arm Proof-of-Concept Study

Ying Fu, MD1; Junwei Hao, MD, PhD1; Ningnannan Zhang, MD, PhD2; Li Ren, MD1; Na Sun, MD1; Yu-Jing Li, MD1; Yaping Yan, PhD1; DeRen Huang, MD, PhD3; Chunshui Yu, MD, PhD2; Fu-Dong Shi, MD, PhD1,4,5
[+] Author Affiliations
1Department of Neurology, Key Laboratory of Neurorepair and Regeneration, Tianjin and Ministry of Education, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China
2Department of Radiology, Tianjin Medical University General Hospital, Tianjin, China
3Neurology and Neuroscience Associates, Unity Health Network, Akron, Ohio
4Department of Immunology, Tianjin Medical University, Tianjin, China
5Department of Neurology, Barrow Neurological Institute, St Joseph’s Hospital and Medical Center, Phoenix, Arizona
JAMA Neurol. 2014;71(9):1092-1101. doi:10.1001/jamaneurol.2014.1065.
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Importance  Pronounced inflammatory reactions occurring shortly after intracerebral hemorrhage (ICH) contribute to the formation and progression of perihematomal edema (PHE) and secondary brain injury. We hypothesized that modulation of brain inflammation reduces edema, thus improving clinical outcomes in patients with ICH.

Objective  To investigate whether oral administration of fingolimod, a Food and Drug Administration–approved sphingosine 1–phosphate receptor modulator for multiple sclerosis, is safe and effective in alleviating PHE and neurologic deficits in patients with ICH.

Design, Setting, and Participants  In this 2-arm, evaluator-blinded study, we included 23 patients with primary supratentorial ICH with hematomal volume of 5 to 30 mL. Clinical and neuroimaging feature–matched patients were treated with standard care with or without oral fingolimod. The study was conducted in Tianjin Medical University General Hospital, Tianjin, China.

Interventions  All patients received standard management alone (control participants) or combined with fingolimod (FTY720, Gilenya), 0.5 mg, orally for 3 consecutive days. Treatment was initiated within 1 hour after the baseline computed tomographic scan and no later than 72 hours after the onset of symptoms.

Main Outcomes and Measures  Neurologic status and hematomal and PHE volumes (Ev) and relative PHE, defined as Ev divided by hematomal volume, were monitored by clinical assessment and magnetic resonance imaging, respectively, for 3 months.

Results  Patients treated with fingolimod exhibited a reduction of neurologic impairment compared with control individuals, regained a Glasgow Coma Scale score of 15 by day 7 (100% vs 50%, P = .01), and had a National Institutes of Health Stroke Scale score reduction of 7.5 vs 0.5 (P < .001). Neurologic functions improved in these patients in the first week coincident with a reduction of circulating lymphocyte counts. At 3 months, a greater proportion of patients receiving fingolimod achieved full recovery of neurologic functions (modified Barthel Index score range, 95-100; 63% vs 0%; P = .001; modified Rankin Scale score range, 0-1; 63% vs 0%; P = .001), and fewer reported ICH-related lung infections. Perihematomal edema volume and rPHE were significantly smaller in fingolimod-treated patients than in control individuals (Ev at day 7, 47 mL vs 108 mL, P = .04; Ev at day 14, 55 mL vs 124 mL, P = .07; rPHE at day 7, 2.5 vs 6.4, P < .001; rPHE at day 14, 2.6 vs 7.7, P = .003, respectively). We recorded no differences between groups in the occurrence of adverse events.

Conclusions and Relevance  In patients with small- to moderate-sized deep primary supratentorial ICH, administration of oral fingolimod within 72 hours of disease onset was safe, reduced PHE, attenuated neurologic deficits, and promoted recovery. The efficacy of fingolimod in preventing secondary brain injury in patients with ICH warrants further investigation in late-phase trials.

Trial Registration  clinicaltrials.gov Identifier:NCT02002390

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Figure 1.
Effects of Fingolimod in Patients With Intracerebral Hemorrhage

Twenty-three patients with supertentorial intracerebral hemorrhage were assigned into 2 arms with matched clinical characteristics and hematomal location and volume, as defined by computed tomography. Patients were assigned to receive standard management or standard management plus fingolimod (FTY720, Gilenya) at doses of 0.5 mg orally once daily for 3 consecutive days. Circulating lymphocyte subset counts were monitored by flow cytometry. Clinical assessments (Glasgow Coma Scale [GCS], National Institutes of Health Stroke Scale [NIHSS], modified Rankin Scale [mRS], and modified Barthel Index [mBI]) were conducted in blind fashion at the indicated points. All patients had noncontrast head computed tomography at admission and subsequent magnetic resonance imaging, also in blinded fashion. Hematomal volume, perihematomal edema volume, and relative perihematomal edema, defined as perihematomal edema volume/hematomal volume, were measured on gradient-recalled echo and fluid-attenuated inversion recovery at the indicated points and calculated.

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Figure 2.
Lymphocyte Subset Alteration in 12 Control Participants and 11 Patients With Intracerebral Hemorrhage Treated With Fingolimod

Blood was drawn from patients at the baseline (mean [SE], 19.5 [6.1] hours) and 72 hours after the first dose (mean [SE], 88.3 [6.1] hours). Mononuclear cells were extracted and stained with antibodies to cells. Percentages of CD4+ T cells, CD8+ T cells, and CD19+ B cells were determined by flow cytometry, and absolute numbers were calculated and expressed as ×106 per milliliter of blood for each patient with intracerebral hemorrhage. The range of counts for CD4+, CD8+, and CD19+ cells in control individuals on day 4 (mean [SE], 96 [3.4] hours) are depicted as gray background. CD4+ T cells, CD8+ T cells, and CD19+ B cell counts of every patient (depicted with individual lines) decreased significantly relative to baseline and were significantly lower than the numbers of the control group on day 4.

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Figure 3.
Evolution of Hemorrhage Volume and Perihematomal Edema in Control Participants and Fingolimod-Treated Patients With Intracerebral Hemorrhage

Significant decreases in relative perihematomal edema and perihematomal edema volume were noted in the fingolimod-treated group compared with the control group at 7 and 14 days after administration. Hemorrhage volume gradually decreased during the next 14 days in both groups and showed no significant difference on test days. Error bars represent SEs.aP < .05.bP < .001.cP < .01.

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Figure 4.
Representative Computed Tomographic and Magnetic Resonance Images of Control Participants and Fingolimod-Treated Patients With Intracerebral Hemorrhage

The upper panels depict tissues from a control patient with a spontaneous right putaminal hemorrhage. In the lower panels are views from a fingolimod-treated patient with a left putaminal hemorrhage. With similar location and hematomal volume at the baseline, the latter patient who received fingolimod had significant resolution of edema without a midline shift, whereas in control patients, perihematomal edema persisted between days 7 and 14, accompanied by a midline shift. Margins of perihematomal edema for both patients appear as lines. FLAIR indicates fluid-attenuated inversion recovery.

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