Ningnannan Zhang

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

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.

Impact of an immune modulator fingolimod on acute ischemic stroke

Significance In patients with acute ischemic stroke (AIS), the abrupt and massive influx of lymphocytes from the periphery to the ischemic region orchestrates focal inflammatory responses, catalyzes tissue death, and worsens clinical outcomes. In this early phase clinical study, we reduced lymphocyte migration to the brain during the first 72 h of AIS via oral administration of three doses of fingolimod. This administration led to a significant reduction of secondary lesion enlargement, microvascular permeability, and better clinical outcomes during the acute phase and 3-mo follow-up visit. This study will provoke new investigations on the efficacy of modulation of brain inflammation in AIS. 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.

Structural MRI substrates of cognitive impairment in neuromyelitis optica

Objective: To identify the clinical and structural MRI markers for predicting cognitive impairment (CI) in patients with neuromyelitis optica (NMO). Methods: Fifty-four patients with NMO and 27 healthy controls underwent extensive neuropsychological testing and multimodal 3.0T MRI. The patient group was classified as CI or cognitively preserved (CP), using a criterion of ≤1.5 SD on at least 2 cognitive domains. MRI measurements included white matter (WM) lesion volume, gray matter (GM), WM, and deep GM (DGM) volume, cortical thickness, and the severity and extent of WM tract diffusion metric alterations based on fractional anisotropy and mean, axial, and radial diffusivity. Groups were compared using a multivariate general linear model, and clinical and MRI measurements were related to average cognition z scores by partial correlations and a stepwise linear regression model. Results: Twenty-six patients with NMO (48.2%) were classified as CI and showed WM tract diffusion abnormalities, particularly increased radial diffusivity, and GM especially DGM atrophy compared with healthy controls. Patients classified as CP also showed alterations of WM tract diffusion but without significant GM atrophy. Compared with the CP group, patients with CI demonstrated a lower level of education and decreased hippocampal volume. In the whole patient group, average cognition z scores were best predicted by the level of education and hippocampal volume (R2 = 0.46, p < 0.001). Conclusion: In patients with NMO, WM tract integrity disruption was identified in both CP and CI groups. GM atrophy, particularly in the DGM, was only found in the CI group. Hippocampal volume is the main MRI predictor of cognition in NMO.

Cognitive impairment in Chinese neuromyelitis optica.

Background: Cognitive dysfunction is frequently seen in neuromyelitis optica (NMO). However, the features and influencing factors of cognitive impairment of Chinese NMO patients are unclear. Objective: To investigate the patterns of cognitive impairment in Chinese NMO patients, and correlate the neuropsychiatric scores with clinical and MRI parameters. Methods: Thirty-six Chinese NMO patients, and 30 sex and age-matched healthy controls were recruited with extensive neuropsychological assessments, using the modified Minimal Assessment of Cognitive Function in MS (MACFIMS). The demographic and clinical characteristics as well as MRI parameters were compared between cognitively impaired (CI) and cognitively preserved (CP) patients. Results: NMO patients were significantly impaired in the Paced Auditory Serial Addition Task (P<0.05), the Symbol Digit Modalities Test (P<0.001), the California Verbal Learning Test-Second Edition (P<0.05), the Brief Visuospatial Memory Test-Revised (P<0.05) and semantic fluency (P<0.001). Only lower education level was associated with cognitive dysfunction in NMO (odds ratio: 0.57, P<0.05). There were no significant differences of MRI parameters regarding white matter (WM) lesions, grey matter and WM brain volume between CI and CP patients. Conclusions: Chinese NMO patients particularly demonstrated cognitive impairment in information processing speed, executive function and memory. Lower education level was the main factor contributing to cognitive impairment in NMO.

Olfactory dysfunction in patients with multiple sclerosis.

Association of changes in olfactory-related structures with olfactory function in patients with multiple sclerosis (MS) is not well understood. We used a T&T olfactometer test kit to evaluate olfactory function in 26 patients with MS and 26 age- and sex-matched healthy controls (HC). Then, Brain MRI were performed and olfactory-related structures were analyzed in these subjects. Olfactory detection and recognition threshold were significantly higher in the MS group, interestingly olfactory recognition threshold positively correlated with expanded disability status scale scores in these patients. Olfactory bulb (OB) volume reduced in patients with olfactory dysfunction (ODF). At the same time, reductions in gray matter (GM) volume were observed in the parahippocampal gyrus (PCG), amygdala, piriform cortex, and inferior frontal gyrus in patients with MS compared to HC. Atrophy of the PCG was more obvious in patients with ODF than patients without ODF and the PCG volume correlated with the olfactory recognition threshold, while no difference was found in fractional anisotropy values of tract-based spatial statistics analysis in the two groups. Olfactory function in patients with MS tends to become gradually more impaired with disability aggravation. Decreases in the volume of the OB and olfactory-related GM might provide valuable information about disease status in patients with MS with olfactory impairment.

Subregional structural and connectivity damage in the visual cortex in neuromyelitis optica

Patients with neuromyelitis optica (NMO) have shown structural and functional impairments in the visual cortex. We aimed to characterize subregional grey matter volume (GMV) and resting-state functional connectivity (rsFC) changes in the visual cortex in NMO. Thirty-seven NMO patients and forty-two controls underwent structural and functional MRI scans. The GMV and rsFC of each visual subregion were compared between the groups. Compared with controls, NMO patients had GMV reductions in the bilateral V1, V2, V3d, VP, and LO and in the left V3A. In canonical visual pathways, the relatively low-level subregions showed more significant GMV reductions than did the high-level ones. Regardless of GMV correction, NMO patients showed reduced rsFC in the bilateral LO and V4v and in the left V2. The GMVs of the bilateral V1 and LO and of the left V2 and V3d were negatively correlated with clinical disability in NMO patients; these correlation coefficients were associated with hierarchical positions in the visual pathways. These findings suggest that in NMO, the low-level visual subregions have more severe structural damage; structural damage is not the only factor affecting rsFC alterations of visual subregions; GMV reduction in the low-level visual subregions has the highest predictive value for clinical disability.

Comparison of olfactory function between neuromyelitis optica and multiple sclerosis

ABSTRACT Objectives: Olfactory dysfunction (ODF) has been reported in patients with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, the comparison of olfactory function and olfactory-related gray matter (GM) between patients with NMO and MS needed to be further elucidated. Materials and methods: Thirty-seven patients with NMO and 37 with MS were enrolled. Olfactory function was evaluated with a Japanese T&T olfactometer test kit, and the neuroanatomical features of olfactory-related GM were assessed using voxel-based morphometry. Results: Olfactory deficits were found in 51.4% of patients with NMO and 40.5% of patients with MS. Patients with NMO with ODF had significantly smaller olfactory bulbs than patients with MS with ODF (p = 0.031). Olfactory-related GM atrophy was found in patients with NMO in several regions of the right orbitofrontal cortex and right superior frontal gyrus; in patients with MS, reduced GM volume was found in the right parahippocampal gyrus and piriform cortex (p < 0.05, cluster size > 200 voxels). Conclusions: Olfactory deficits are common in both NMO and MS. However, the neuroanatomical features related to olfactory deficits differ greatly between the two diseases.

Impact of Autologous Mesenchymal Stem Cell Infusion on Neuromyelitis Optica Spectrum Disorder: A Pilot, 2-Year Observational Study

We evaluate safety and efficacy of autologous bone marrow‐derived mesenchymal stem cells (MSCs) as a potential treatment for neuromyelitis optica spectrum disorder (NMOSD).

Altered neurovascular coupling in neuromyelitis optica

Neurovascular coupling reflects the close relationship between neuronal activity and cerebral blood flow (CBF), providing a new mechanistic insight into health and disease. Neuromyelitis optica (NMO) is an autoimmune inflammatory demyelinating disease of the central nervous system and shows cognitive decline‐related brain gray matter abnormalities besides the damage of optic nerve and spinal cord. We aimed to investigate neurovascular coupling alteration and its clinical significance in NMO by using regional homogeneity (ReHo) to measure neuronal activity and CBF to measure vascular response. ReHo was calculated from functional MRI and CBF was computed from arterial spin labeling (ASL) in 56 patients with NMO and 63 healthy controls. Global neurovascular coupling was assessed by across‐voxel CBF‐ReHo correlations and regional neurovascular coupling was evaluated by CBF/ReHo ratio. Correlations between CBF/ReHo ratio and clinical variables were explored in patients with NMO. Global CBF‐ReHo coupling was decreased in patients with NMO relative to healthy controls (p = .009). Patients with NMO showed decreased CBF/ReHo ratio (10.9%–17.3% reduction) in the parietal and occipital regions and increased CBF/ReHo ratio (8.0%–13.3% increase) in the insular, sensorimotor, temporal and prefrontal regions. Some of these abnormalities cannot be identified by a single CBF or ReHo analysis. Both abnormally decreased and increased CBF/ReHo ratios were correlated with more severe clinical impairments and cognitive decline in patients with NMO. These findings suggested that patients with NMO show abnormal neurovascular coupling, which is associated with disease severity and cognitive impairments.

Cerebral Blood Flow Changes in Multiple Sclerosis and Neuromyelitis Optica and Their Correlations With Clinical Disability

Distinguishing relapsing-remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO) is clinically important because they differ in prognosis and treatment. This study aimed to identify perfusion abnormalities in RRMS and NMO and their correlations with gray matter volume (GMV) atrophy and clinical parameters. Structural and arterial spin labeling MRI scans were performed in 39 RRMS patients, 62 NMO patients, and 73 healthy controls. The gray matter cerebral blood flow (CBF) values were voxel-wisely compared among the three groups with and without GMV correction. The regional CBF changes were correlated with the Expanded Disability Status Scale scores in the corresponding patient groups. Although multiple brain regions showed CBF differences among the three groups without GMV correction, only three of these regions remained significant after GMV correction. Specifically, both the RRMS and NMO groups showed reduced CBF in the occipital cortex and increased CBF in the right putamen compared to the control group. The RRMS group had increased CBF only in the medial prefrontal cortex compared to the other two groups. The occipital CBF was negatively correlated with clinical disability in the NMO group; however, the CBF in the right putamen was positively correlated with clinical disability in both patient groups. These findings suggest that there are perfusion alterations independent of GMV atrophy in RRMS and NMO patients. The regional CBF in the occipital cortex and putamen could be used as imaging features to objectively assess clinical disability in these patients.