RESEARCH ARTICLE

Neuroanatomic Correlates of Poststroke Hyperglycemia Klemens Winder, MD,1 Frank Seifert, MD,1 Tessa Ohnemus,1 Eva-Maria Sauer, MD,1 Stephan Kloska, MD,2 Arnd D€ orfler, MD,2 Max J. Hilz, MD,1 Stefan Schwab, MD,1 and Martin K€ ohrmann, MD1 Objective: A study was undertaken to determine associations between ischemic stroke sites and poststroke hyperglycemia (PSH). Methods: Nondiabetic patients with first ever ischemic stroke confirmed by imaging were prospectively included. Blood glucose level (BGL), National Institute of Health Stroke Scale (NIHSS) score, and clinical parameters were assessed on admission. BGL was dichotomized for elevated versus normal levels using a cutoff value of >7.0 mmol/l. Clinical parameters were correlated with BGL and were compared between patient groups with elevated versus normal glucose values. A voxel-based lesion symptom mapping (VLSM) analysis adjusted for confounding variables was performed correlating sites of ischemic lesions with PSH. Results: Of 1,281 stroke patients screened, 229 (mean age 5 66.3 6 15.9 years) met the inclusion criteria. Patients with elevated BGL were older, had higher NIHSS scores, and had larger infarcts compared to those without elevated glucose levels. Spearman rank analysis showed correlations between BGL and age, infarct size, heart rate (HR), and NIHSS scores (p  0.05). The VLSM analysis adjusted for these confounding factors demonstrated associations between PSH and damaged voxels in right hemispheric insular and opercular areas. Interpretation: The data indicate that damage in the right insulo-opercular areas contributes to PSH. The association between sympathetically mediated increase of HR and BGL suggests disinhibition of sympathetic outflow as a possible mechanism for PSH. ANN NEUROL 2014;00:000–000

A

cute ischemic stroke is frequently associated with hyperglycemia even in the absence of diabetes mellitus.1–3 Poststroke hyperglycemia (PSH) is associated with poor clinical outcome,1–7 increased risk of secondary hemorrhagic transformation,2,6 increased infarct size,1,2,5,7 and reduced recanalization rates after intravenous thrombolysis.8 The mechanism leading to PSH is still under debate. Unmasking of occult diabetes mellitus, acute stress reactions, or imbalances of autonomic regulation due to strokerelated dysfunction of the central autonomic network have been proposed.1,9 Hyperglycemia may result from sympathetic overactivity because adrenergic substances increase gluconeogenesis and facilitate glycogen breakdown.1,10 Acute lesions of brain areas, especially in the right insular cortex, cause autonomic imbalance and increase sympathetic tone.11–14 We hypothesize that elevation of glucose levels in

patients with acute ischemic stroke is related to lesions of brain regions that contribute to central autonomic control. Therefore, we assessed blood glucose level (BGL) and clinical parameters on admission in a well-defined cohort of nondiabetic patients with first ever supratentorial ischemic stroke. Lesion site was correlated with BGL on admission using a voxel-based lesion symptom mapping (VLSM) analysis.

Patients and Methods All patients with acute stroke admitted to the Department of Neurology at University Hospital Erlangen are entered into a prospective database containing baseline demographic variables, information regarding medical history, and parameters on the present stroke. For the study consecutive patients with first ever ischemic stroke confirmed by imaging presenting in 2011 and

View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24322 Received Jul 11, 2014, and in revised form Oct 26, 2014. Accepted for publication Nov 24, 2014. Address correspondence to Dr Winder, Department of Neurology, University Hospital Erlangen, Schwabachanlage 6, 91054 Erlangen. E-mail: [email protected] From the Departments of 1Neurology and 2Departments of Neuroradiology, University Hospital Erlangen, Erlangen, Germany.

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2012 were screened. Patients with the following conditions were excluded: (1) imaging not available in suitable form or of poor quality, (2) pre-existing older ischemic lesions on imaging, and (3) malignant and infratentorial ischemic infarcts. In addition, to examine only patients with nondiabetic PSH, patients with HbA1c  6.2%,9 history of antidiabetic medication, and newly diagnosed diabetes mellitus according to standard guidelines (serum fasting glucose level > 7.0 mmol/l, random glucose levels > 11 mmol/l) were excluded. BGL was assessed on admission. Mean blood pressure (MBP) and heart rate (HR) were continuously assessed using a multimodal monitoring system (Infinity Series; Dr€ager, L€ubeck, Germany). Neurological scales were rated by certified personnel only. The National Institute of Health Stroke Scale (NIHSS) score was assessed on admission and at least 4 times per day during hospital stay to rate stroke symptoms and severity. The study was approved by the local institutional ethics committee.

Imaging Techniques All patients underwent cranial magnetic resonance imaging (MRI; 3T Magnetom Trio or 1.5T Magnetom Sonata; Siemens Healthcare, Erlangen, Germany) or computed tomography (CT; Sensation 64 or Somatom Definition AS1; Siemens Healthcare). Imaging modality was at the discretion of the treating physician. Patients who had a CT but no MRI were only included when a CT scan was available that was acquired >24 hours after stroke onset and clearly showed demarcation of the ischemic infarct. Noncontrast CT was used to assess the lesion in these patients. In patients who had MRI only, the ischemic lesion was delineated on diffusion-weighted imaging sequences on MRI performed 7.0 mmol/l)17 was performed using the Liebermeister test. For these analyses a false discovery rate (FDR) correction of 0.01 was applied. VLSM analysis was adjusted for confounding factors identified in the univariate analysis (age, NIHSS scores on admission, and ischemic lesion size). Only voxels that were damaged in at least 5% of the subjects were included in the analysis. Lesion volumes in milliliters were calculated using nonparametric mapping software. In addition, a logistic regression analysis18 was performed with voxel damage as the binary dependent variable and a FDR correction of 0.05. To determine damaged brain regions, affected voxels were overlaid on the Automated Anatomical Labeling atlas.19 The peak coordinates of the involved regions are presented in Montreal Neurological Institute (MNI) space.

Statistical Analysis For statistical analysis a commercially available statistic software package (SPSS 20.0; IBM, Armonk, NY) was used. Data were tested for normal distribution using the Shapiro–Wilk test and are presented as median and interquartile range (IQR). Age, distribution of gender, NIHSS scores, HR, MBP, and infarct size were compared between patients with elevated glucose levels (PSH) and those without PSH using Mann–Whitney U test or Fisher exact test as appropriate. In patients with MRI and CT available for analysis, lesion volumes derived independently from both modalities were compared using Mann-Whitney U test and correlated using Spearman rank correlation coefficient. BGL on admission was correlated with patient age, baseline NIHSS scores, infarct volumes, MBP, and HR using Spearman rank correlation coefficient. Statistical significance was set a priori at p  0.05.

Results Patient Characteristics From an initial cohort of 1,281 patients who were admitted to the stroke unit with the clinical diagnosis of ischemic stroke during the study period, 1,052 patients were excluded for the following reasons: (1) imaging could not be obtained in sufficient quality (73 patients), (2) imaging did not reveal ischemic lesion (267 patients), (3) presence of infratentorial stroke (217 patients), (4) malignant supratentorial stroke with midline shift (76 patients), (5) pre-existing ischemic lesions (151 patients), (6) BGL could not be obtained (41 patients), and (7) presence of diabetes mellitus (227 patients). Overall 229 subjects met the inclusion criteria and were eligible to be included in the VLSM analysis. Median patient age was 68 years (IQR 5 55–79 years) and 95 (41.5%) were women. Median BGL on admission was 6.2 mmol/l (IQR 5 5.5–7.0 mmol/l) and median NIHSS score on admission was 4 (IQR 5 1–7). Median MBP was 115.7 mmHg (IQR 5 104.7–130.0 mmHg) and median HR was 81/min (IQR 5 68–92/min). Median volume of ischemic lesions was 7.4 ml (IQR 5 1.2–31.1 ml). Volume 00, No. 00

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TABLE 1. Clinical Characteristics of the Patients Dichotomized into 2 Groups with Elevated (PSH) versus Normal Blood Glucose Values (no PSH)

Parameter

PSH, n 5 54

No PSH, n 5 175

p

Age, median yr (IQR)

75.5 (61.8–82.3)

65 (53–78)

0.004a

M/F

37/17

97/78

n.s.b

NIHSS, median (IQR)

5 (2–11.3)

3 (1–6)

0.037a

Admission MBP, median mmHg (IQR)

114.3 (103–124.1)

116 (105–130.8)

n.s.a

HR, median/min (IQR)

85 (70.8–95.3)

80 (68–90)

n.s.a

BGL, median mmol/l (IQR)

7.9 (7.4–8.6)

5.9 (5.4–6.4)

7.0 mmol/l

Lesion Sitea

Voxels

x

y

z

Precentral

5

40

212

37

Rolandic oper

2,182

63

25

11

Insula

173

47

26

7

Postcentral

823

55

27

21

Supramarginal

499

53

211

25

Heschl

230

62

23

7

Temporal sup

396

62

23

6

Temporal pole

12

61

4

0

Counts of damaged voxels and peak coordinates outlined in Montreal Neurological Institute space are shown. a Ischemic lesions in right hemispheric areas associated with elevated BGL > 7.0 mmol/l. BGL 5 blood glucose level; Rolandic oper 5 rolandic operculum; Temporal sup 5 superior temporal gyrus.

the right insular cortex of the rat in the conscious state promotes primarily sympathoinhibitory control over the more sympathoexcitatory regions in the central autonomic network including the anterior insular cortex.42 Thus, lesions in the right posterior insula may lead to loss of sympathoinhibitory control with consecutive sympathetic disinhibition as a possible mechanism for PSH.1,42 Previous work in humans has linked right hemispheric stroke with insular damage to decreased HR variability, sympathetic disinhibition, troponin increase, and myocardial damage, as well as overall poor prognosis.11–14,43–45 Notably, right posterior and superior insular and opercular damage, as found in our analysis, was linked to stroke-related myocardial injury in the voxelwise analysis by Ay et al.45 However, the high proportion of patients on antihypertensive medication at the time of admission may account for the absent correlation between blood pressure and PSH possibly due to drug-related mitigation of sympathetically mediated vasoconstriction. Because previous studies focused on the insular region only, associations of PSH with lesions in the operculum adjacent to the insula as well as in the hippocampus and temporal pole found in our analysis have not been observed in previous work.9,20,21 The latter represent areas that have been shown to be functionally closely linked to the insular cortex.46 The posterior insular cortex and opercular region are frequently supplied by the same branch of the middle 6

cerebral artery, thus it is conceivable that the opercular region may only be affected as a bystander area.47 Our VLSM analysis has limitations, most notably by the nature of the method. The results do not allow causal conclusions and rather represent correlations. Comprehensive autonomic parameters to further investigate the role of autonomic dysfunction on BGL elevation were not available within the study. To harmonize our sample and isolate the effect of acute lesion site on BGL regulation, we limited the analysis to supratentorial ischemic lesions and excluded patients with old ischemic lesions or underlying diabetes mellitus. These patient groups may be analyzed in future work. In conclusion, our VLSM data provide evidence that PSH is associated with right hemispheric ischemic damage in areas that contribute to autonomic modulation. Thus, PSH may accompany an underlying autonomic imbalance with a shift toward sympathetic overactivity.

Authorship K.W. and F.S. contributed equally.

Potential Conflicts of Interest M.J.H.: advisory board, speaking fees, Genzyme; grant, Bayer Pharma.

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Neuroanatomic correlates of poststroke hyperglycemia.

A study was undertaken to determine associations between ischemic stroke sites and poststroke hyperglycemia (PSH)...
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