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Figure.
Box plot showing multivariate adjusted median diffusion-weighted magnetic resonance imaging (DWI) infarct volumes (solid bar), interquartile range (bar width), and minimum and maximum values (whiskers) across the range of serum calcium level quartiles. *Diffusion-weighted magnetic resonance imaging volume of quartile 1 greater than that of quartiles 2, 3, and 4 (P ≤ .05).

Box plot showing multivariate adjusted median diffusion-weighted magnetic resonance imaging (DWI) infarct volumes (solid bar), interquartile range (bar width), and minimum and maximum values (whiskers) across the range of serum calcium level quartiles. *Diffusion-weighted magnetic resonance imaging volume of quartile 1 greater than that of quartiles 2, 3, and 4 (P ≤ .05).

Table 1. 
Baseline Demographic and Clinical Characteristics of Serum Calcium Level Quartilesa
Baseline Demographic and Clinical Characteristics of Serum Calcium Level Quartilesa
Table 2. 
Relationship Between Serum Calcium Level Quartile at Admission and Pretreatment Diffusion-Weighted Magnetic Resonance Imaging (DWI) Infarct Volume Based on Univariate and Multivariate Quartile Regression Analysis
Relationship Between Serum Calcium Level Quartile at Admission and Pretreatment Diffusion-Weighted Magnetic Resonance Imaging (DWI) Infarct Volume Based on Univariate and Multivariate Quartile Regression Analysis
1.
Choi  DW Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 1995;18 (2) 58- 60
PubMed
2.
MacDonald  JFXiong  ZGJackson  MF Paradox of Ca2+ signaling, cell death and stroke. Trends Neurosci 2006;29 (2) 75- 81
PubMed
3.
D’Erasmo  EPisani  DRomagnoli  SRagno  AAcca  M Acute serum calcium changes in transient ischemic attack and cerebral infarction. J Med 1998;29 (5-6) 331- 337
PubMed
4.
Ovbiagele  BLiebeskind  DSStarkman  S  et al.  Are elevated admission calcium levels associated with better outcomes after ischemic stroke? Neurology 2006;67 (1) 170- 173
PubMed
5.
Saver  JLJohnston  KCHomer  D  et al. RANTTAS Investigators, Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. Stroke 1999;30 (2) 293- 298
PubMed
6.
Ovbiagele  BSaver  JLFredieu  A  et al.  PROTECT: a coordinated stroke treatment program to prevent recurrent thromboembolic events. Neurology 2004;63 (7) 1217- 1222
PubMed
7.
Liebeskind  DSKidwell  CSUCLA Thrombolysis Investigators, Advanced MR imaging of acute stroke: the University of California at Los Angeles endovascular therapy experience. Neuroimaging Clin N Am 2005;15 (2) 455- 466
PubMed
8.
Koenker  RHallock  KF Quantile regression. J Econ Perspect 2001;15 (4) 143- 156
9.
Frankel  MRMorgenstern  LBKwiatkowski  T  et al.  Predicting prognosis after stroke: a placebo group analysis from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial. Neurology 2000;55 (7) 952- 959
PubMed
10.
Shook  SJGupta  RVora  NATievsky  ALKatzan  IKrieger  DW Statin use is independently associated with smaller infarct volume in nonlacunar MCA territory stroke. J Neuroimaging 2006;16 (4) 341- 346
PubMed
11.
Adams  HP  JrBendixen  BHKappelle  LJ  et al.  Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24 (1) 35- 41
PubMed
12.
Kidwell  CSAlger  JRSaver  JL Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 2003;34 (11) 2729- 2735
PubMed
13.
Kristián  TGidö  GKuroda  SSchütz  ASiesjö  BK Calcium metabolism of focal and penumbral tissues in rats subjected to transient middle cerebral artery occlusion. Exp Brain Res 1998;120 (4) 503- 509
PubMed
14.
Peuler  JDSchelper  RL Partial protection from salt-induced stroke and mortality by high oral calcium in hypertensive rats. Stroke 1992;23 (4) 532- 538
PubMed
15.
Iso  HStampfer  MJManson  JE  et al.  Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999;30 (9) 1772- 1779
PubMed
16.
Umesawa  MIso  HDate  C  et al Dietary intake of calcium in relation to mortality from cardiovascular disease: the JACC Study [published online ahead of print December 8, 2005]. Stroke20063712026 doi:10.1161/01.STR.0000195155.21143.38
PubMed
17.
Schaefer  PWHunter  GJHe  J  et al.  Predicting cerebral ischemic infarct volume with diffusion and perfusion MR imaging. AJNR Am J Neuroradiol 2002;23 (10) 1785- 1794
PubMed
Original Contribution
September 2007

Association of Higher Serum Calcium Levels With Smaller Infarct Volumes in Acute Ischemic Stroke

Author Affiliations

Author Affiliations: Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario (Dr Buck); Stroke Center (Drs Buck, Liebeskind, Saver, Young Bang, Starkman, Ali, Kim, Villablanca, Salamon, and Ovbiagele and Mss Yun and Razinia) and Departments of Neurology (Drs Buck, Liebeskind, Saver, Young Bang, Starkman, Ali, Kim, and Ovbiagele and Mss Yun and Razinia), Radiology (Drs Villablanca and Salamon), and Emergency Medicine (Dr Starkman), University of California, Los Angeles; and Department of Neurology, Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (Dr Bang).

Arch Neurol. 2007;64(9):1287-1291. doi:10.1001/archneur.64.9.1287
Abstract

Background  Elevated serum calcium levels at admission in patients with stroke have been associated with less severe clinical deficits and with better outcomes; however, the relationship between serum calcium levels and volumetric measurement of cerebral infarct size on neuroimaging has not been studied, to our knowledge.

Objective  To assess the relationship between serum calcium levels at admission and initial diffusion-weighted magnetic resonance imaging (DWI) infarct volumes among patients with acute ischemic stroke.

Design  Secondary analysis of prospectively collected hospital quality improvement data.

Setting  Tertiary university hospital.

Patients  One hundred seventy-three consecutive patients with acute ischemic stroke initially seen within 24 hours of the last known well time.

Main Outcome Measures  Total serum calcium levels were measured on admission and were collapsed into quartiles. The DWI lesions were outlined using a semiautomated threshold technique. The relationship between serum calcium level quartiles and DWI infarct volumes was examined using multivariate quartile regression analysis.

Results  One hundred seventy-three patients (mean age, 70.3 years [age range, 24-100 years]; median National Institutes of Health Stroke Scale score, 4 [range, 0-38]) met the study criteria. The median DWI infarct volumes for the serum calcium level quartiles (lowest to highest quartile) were 9.42, 2.11, 1.03, and 3.68 mL. The median DWI infarct volume in the lowest serum calcium level quartile was larger than that in the other 3 quartiles (P < .005). After multivariate analysis, the median adjusted DWI infarct volumes for the serum calcium level quartiles (lowest to highest) were 8.9, 5.8, 4.5, and 3.8 mL. The median adjusted DWI infarct volume in the lowest serum calcium level quartile was statistically significantly larger than that in the other 3 quartiles (P < .05).

Conclusions  Higher serum calcium levels at admission are associated with smaller cerebral infarct volumes among patients with acute ischemic stroke. These results suggest that serum calcium level may serve as a clinical prognosticator following stroke and may be a potential therapeutic target for improving stroke outcome.

In ischemic stroke, excessive intracellular serum calcium accumulation triggers a cascade of cytotoxic events that lead to the activation of enzymes involved in cell death.1 In preclinical models, low extracellular serum calcium levels paradoxically enhance this overloading of intracellular serum calcium and potentiate cell death.2 Whether serum calcium levels affect serum calcium level–dependent excitotoxic pathways in the setting of human acute cerebral ischemia remains unclear, but mounting data indicate that higher serum calcium levels at admission are associated with better clinical outcomes after ischemic stroke.3,4

To our knowledge, no prior study has examined the relationship between serum calcium levels and actual volumetric measurements of cerebral infarct size on brain imaging. Infarct size is a key determinant of clinical outcome from stroke.5 In this study, we hypothesized that elevated serum calcium levels at admission would be independently associated with smaller diffusion-weighted magnetic resonance (MR) imaging (DWI) lesions, indicating advanced tissue bioenergetic compromise.

METHODS
PATIENTS

This is a secondary analysis of data that were collected prospectively during 18 months beginning January 1, 2004, on consecutive ischemic stroke admissions to a university hospital stroke program as part of an ongoing hospital quality improvement project.6 The inclusion criteria for enrollment into the study were age 18 years or older, diagnosis of acute ischemic stroke, serum total calcium level collected on admission, and multimodal MR imaging performed within 24 hours of the last known well time. Patients with contraindications to MR imaging were excluded, as were those who were initially seen or underwent imaging more than 24 hours from the last known well time. The study was approved by the hospital institutional review board.

MR IMAGING AND IMAGE ANALYSIS

Patients underwent imaging before receiving any reperfusion therapy using a 1.5-T scanner (Siemens Vision; Siemens Medical Systems, Erlangen, Germany) based on a protocol detailed previously7 that included DWI, perfusion-weighted imaging, gradient-recalled echo examination, and fluid-attenuated inversion recovery imaging. The DWI was performed using 2 levels of diffusion sensitization (b value, 0 and 1000 s/mm2) with the following variables: 5-mm section thickness, no gap, and 17 to 20 sections. The DWI infarct volumes were measured using available software (Medical Image Processing, Analysis and Visualization, version 3.0; National Institutes of Health, Bethesda, Maryland). Image raters (B.H.B. and O.Y.B.) outlined regions of acute diffusion abnormality on the image at 1000 s/mm2, consulting apparent diffusion coefficient and fluid-attenuated inversion recovery imaging sequences to distinguish acute from nonacute diffusion change. Acute diffusion lesions were defined on a section-by-section basis using a semiautomatic threshold approach by one of us (B.H.B.) blinded to all clinical information. Infarct volumes were calculated by multiplying section thickness by the total lesion area. To assess interrater reliability, infarct volumes were measured by a second rater (O.Y.B.) on a randomly selected subset of 19 patients.

STATISTICAL ANALYSIS

Serum calcium levels were collapsed into quartiles. Baseline demographics and clinical characteristics were compared across quartiles using χ2 test for percentages and Kruskal-Wallis rank sum test for medians. Interrater reliability for DWI measurements was assessed by calculation of the intraclass correlation coefficient, with greater than 0.80 set as the threshold for good agreement. The relationship between median DWI infarct volume and serum calcium level quartiles was evaluated using a semiparametric approach with univariate and multivariate quartile regression analysis.8 For the multivariate models, the median DWI infarct volumes were corrected for potential confounding variables. Categorical variables (stroke subtype, previous stroke, history of diabetes mellitus, and history of atrial fibrillation or statin use) and continuous variables (age, temperature, blood glucose level, time to MR imaging, and systolic blood pressure) were used as covariates based on prior literature.9,10

RESULTS

One hundred seventy-three of 322 patients met the study criteria. Reasons for exclusion were initial examination outside of 24 hours (85 patients) and unavailability of serum calcium level or MR imaging results (64 patients). Among 173 study patients, the mean age was 70.3 years (age range, 24-100 years), and 101 (58.4%) were women. The racial/ethnic distribution was 66.0% white, 12.0% black, 13.0% Asian, 8.4% Hispanic, and 0.6% other. The median National Institutes of Health Stroke Scale score at initial examination was 4 (range, 0-38), and the median time between the last known well time and the MR imaging was 7.1 hours (range, 0.7-24 hours). Stroke subtypes using the modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system11 were 41.0% cardioembolic, 25.4% small-vessel occlusion, 17.3% large-vessel atherothromboembolic, 10.5% stroke of undetermined cause, and 5.8% other cause. On discharge, the median National Institutes of Health Stroke Scale score was 3 (range, 0-30), and 94 patients (54.3%) had a discharge modified Rankin score of at least 2.

Calcium levels were obtained at a mean of 9.7 hours (range, 0.5-23.8 hours) after the last known well time. The mean ± SD serum calcium level was 8.95 ± 0.50 mg/dL (to convert to millimoles per liter, multiply by 0.25) (range, 7.60-10.40 mg/dL). Table 1 gives the demographic characteristics and frequency of clinical variables by quartile of serum calcium level. Patients in the lowest serum calcium level quartile had a higher median National Institutes of Health Stroke Scale score at admission compared with patients in the highest quartiles (P = .045). There were no statistically significant differences between serum calcium level quartiles in time to MR imaging or in the interval between MR imaging and serum calcium collection. There were no other differences in baseline clinical characteristics between serum calcium level quartiles.

There was good interrater reliability in the measurement of DWI infarct volumes (interclass correlation coefficient, 0.99). Across all patients, the median DWI infarct volume was 2.9 mL (interquartile range, 19.75-0.52 mL [full range, 0-279.0 mL]). The median DWI infarct volumes for the serum calcium level quartiles (lowest to highest) were 9.42, 2.11, 1.03, and 3.68 mL. The distribution of DWI infarct volumes was positively skewed, reflecting a larger proportion of patients with smaller infarct volumes (skewness, 3.4; kurtosis, 13.2). Nonparametric Spearman rank correlation revealed a statistically significant negative correlation between serum calcium level and DWI infarct volume (r = −0.199; P = .009).

The results of the univariate and multivariate analyses of the relationship between serum calcium level at admission and pretreatment DWI infarct volume are given in Table 2. Univariate analysis indicated that the overall quartile regression model for the relationship between median DWI infarct volume and serum calcium level quartile was statistically significant, with a negative slope (P ≤ .001). The median DWI infarct volume in the lowest serum calcium level quartile was statistically significantly larger than those in the upper 3 quartiles (P < .05). The multivariate analysis indicated again a statistically significant overall trend toward increased DWI infarct volumes across calcium quartiles (P ≤ .001). The median adjusted DWI infarct volumes, interquartile range, and full range for each of the serum calcium level quartiles are shown in the Figure and (lowest to highest) were 8.9, 5.8, 4.5, and 3.8 mL. Again, the median adjusted DWI infarct volume in the lowest serum calcium level quartile was larger than that in the upper 3 quartiles (P < .05).

COMMENT

In patients with acute ischemic stroke evaluated within 24 hours of symptom onset, our results show that total serum calcium levels at admission are inversely associated with the volume of DWI abnormality. Patients with serum calcium levels in the lowest quartiles had DWI infarct volumes almost twice as large as those in the upper 3 quartiles, and this difference persisted after adjusting for potential confounding factors.

These findings are consistent with previous studies that examined serum calcium levels in patients with acute ischemic stroke. Prior studies found that lower serum calcium levels were associated with worse clinical outcomes. Specifically, patients with stroke having lower serum calcium levels had more severe strokes as indexed by National Institutes of Health Stroke Scale score at admission and worse functional outcomes at discharge (modified Rankin score, ≥ 2)4 and were more likely to die during hospitalization.3 Although the better outcomes seen among patients with higher serum calcium levels in these prior studies were postulated to be caused by smaller infarct volumes, this hypothesis could not be directly evaluated because neither study included neuroimaging.

We used initial DWI lesions as a measure of infarct volume. Early in ischemic stroke, DWI demarcates brain tissue in which there has been a failure of cellular energy-dependent processes due to reduced cerebral perfusion. Initial DWI lesions correlate strongly with final infarct volumes.12

Several potential mechanisms may explain why serum calcium levels are related to the extent of bioenergetically compromised tissue in patients with acute ischemic stroke. These mechanisms can be divided into 2 broad and nonmutually exclusive categories. First, raised serum calcium levels directly or indirectly attenuate the volume of ischemic tissue; second, serum calcium levels may alternately drop in response in the presence of tissue ischemia.

Elevated serum calcium levels may reduce tissue ischemic injury by affecting excitotoxic pathways and ischemic preconditioning. Intracellular serum calcium level plays a central role in the mechanism of excitotoxicity in ischemic stroke. With tissue ischemia, there is excessive release of endogenous glutamate, which in turn leads to an uncontrolled accumulation of intracellular serum calcium level through N-methyl-D-aspartate receptors and voltage-dependent calcium channels.2 Brain ischemia is associated with at least a temporary depletion of cerebral tissue extracellular calcium,13 although it is unclear whether the magnitude and time course of this decrease is sufficient to account for the lower total serum calcium levels observed in patients with larger infarcts. Most important, decreased extracellular serum calcium levels are an important factor in the positive feedback mechanism that potentiates the inward serum calcium level currents following ischemic injury.2 During ischemia, decreased extracellular serum calcium levels lead to disinhibition of calcium-sensing nonselective channel currents and to further membrane depolarization and additional influx of calcium.

If low extracellular and serum calcium levels might potentiate ischemic injury, then it would be predicted that raising serum calcium levels might have neuroprotective effects. There is limited evidence to support this hypothesis. In a rodent model of ischemic stroke, stroke-prone animals fed a diet high in calcium had decreased stroke lesion volumes.14 There are also epidemiological studies15,16 that have linked increased dietary calcium intake to decreased mortality from ischemic and hemorrhagic stroke; however, neither of these studies measured serum calcium levels. Because dietary calcium intake is only 1 of the factors affecting calcium homeostasis, the extent to which these epidemiological observations reflect variations in serum calcium levels remains unclear.

This study is limited by its cross-sectional design and retrospective analysis. Other limitations are that we measured total serum calcium levels rather than ionized serum calcium levels, the physiologically active component. Also, only a single serum calcium level measurement was collected, so it is impossible to determine whether serum calcium levels at admission remained stable over time. Of particular interest in trying to better determine the potential cause and effect relationship would be to see if serum calcium levels change over time in relationship to DWI lesion growth. Initial DWI infarct volume was analyzed, not final T2-weighted infarct volume, as late T2-weighted studies were not obtained routinely in these patients. However, early DWI infarct volumes correlate well with final T2-weighted infarct volumes.17

In conclusion, elevated serum calcium levels in acute ischemic stroke are an early predictor of smaller volumes of ischemic tissue and better clinical outcomes. This effect was seen across a range of stroke subtypes and persisted after adjustment for other factors that could potentially affect infarct volume. Further investigations will be required to elucidate the mechanism of this effect and to assess the role of serum calcium level as a prognostic variable and of calcium modulation as part of a potential neuroprotective strategy.

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Article Information

Correspondence: Brian H. Buck, MD, FRCPC, Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Ave, Room A421, Toronto, ON M4N 3M5, Canada (brianhbuck@gmail.com).

Accepted for Publication: March 12, 2007.

Author Contributions:Study concept and design: Buck, Liebeskind, Saver, Ali, and Ovbiagele. Acquisition of data: Buck, Liebeskind, Young Bang, Starkman, Kim, Yun, Razinia, and Ovbiagele. Analysis and interpretation of data: Buck, Liebeskind, Young Bang, Villablanca, Salamon, and Ovbiagele. Drafting of the manuscript: Buck, Liebeskind, Saver, Young Bang, and Ovbiagele. Critical revision of the manuscript for important intellectual content: Buck, Liebeskind, Saver, Starkman, Ali, Kim, Villablanca, Salamon, Yun, Razinia, and Ovbiagele. Statistical analysis: Buck. Obtained funding: Buck, Saver, and Ovbiagele. Administrative, technical, and material support: Liebeskind, Saver, Starkman, Ali, Villablanca, Salamon, Yun, Razinia, and Ovbiagele. Study supervision: Liebeskind, Saver, Kim, and Ovbiagele.

Financial Disclosure: None reported.

Funding/Support: This study was supported in part by a Heart and Stroke Foundation of Canada fellowship award (Dr Buck) and by grant P50 NS044378 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health (Drs Saver and Ali).

References
1.
Choi  DW Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 1995;18 (2) 58- 60
PubMed
2.
MacDonald  JFXiong  ZGJackson  MF Paradox of Ca2+ signaling, cell death and stroke. Trends Neurosci 2006;29 (2) 75- 81
PubMed
3.
D’Erasmo  EPisani  DRomagnoli  SRagno  AAcca  M Acute serum calcium changes in transient ischemic attack and cerebral infarction. J Med 1998;29 (5-6) 331- 337
PubMed
4.
Ovbiagele  BLiebeskind  DSStarkman  S  et al.  Are elevated admission calcium levels associated with better outcomes after ischemic stroke? Neurology 2006;67 (1) 170- 173
PubMed
5.
Saver  JLJohnston  KCHomer  D  et al. RANTTAS Investigators, Infarct volume as a surrogate or auxiliary outcome measure in ischemic stroke clinical trials. Stroke 1999;30 (2) 293- 298
PubMed
6.
Ovbiagele  BSaver  JLFredieu  A  et al.  PROTECT: a coordinated stroke treatment program to prevent recurrent thromboembolic events. Neurology 2004;63 (7) 1217- 1222
PubMed
7.
Liebeskind  DSKidwell  CSUCLA Thrombolysis Investigators, Advanced MR imaging of acute stroke: the University of California at Los Angeles endovascular therapy experience. Neuroimaging Clin N Am 2005;15 (2) 455- 466
PubMed
8.
Koenker  RHallock  KF Quantile regression. J Econ Perspect 2001;15 (4) 143- 156
9.
Frankel  MRMorgenstern  LBKwiatkowski  T  et al.  Predicting prognosis after stroke: a placebo group analysis from the National Institute of Neurological Disorders and Stroke rt-PA Stroke Trial. Neurology 2000;55 (7) 952- 959
PubMed
10.
Shook  SJGupta  RVora  NATievsky  ALKatzan  IKrieger  DW Statin use is independently associated with smaller infarct volume in nonlacunar MCA territory stroke. J Neuroimaging 2006;16 (4) 341- 346
PubMed
11.
Adams  HP  JrBendixen  BHKappelle  LJ  et al.  Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24 (1) 35- 41
PubMed
12.
Kidwell  CSAlger  JRSaver  JL Beyond mismatch: evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke 2003;34 (11) 2729- 2735
PubMed
13.
Kristián  TGidö  GKuroda  SSchütz  ASiesjö  BK Calcium metabolism of focal and penumbral tissues in rats subjected to transient middle cerebral artery occlusion. Exp Brain Res 1998;120 (4) 503- 509
PubMed
14.
Peuler  JDSchelper  RL Partial protection from salt-induced stroke and mortality by high oral calcium in hypertensive rats. Stroke 1992;23 (4) 532- 538
PubMed
15.
Iso  HStampfer  MJManson  JE  et al.  Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke 1999;30 (9) 1772- 1779
PubMed
16.
Umesawa  MIso  HDate  C  et al Dietary intake of calcium in relation to mortality from cardiovascular disease: the JACC Study [published online ahead of print December 8, 2005]. Stroke20063712026 doi:10.1161/01.STR.0000195155.21143.38
PubMed
17.
Schaefer  PWHunter  GJHe  J  et al.  Predicting cerebral ischemic infarct volume with diffusion and perfusion MR imaging. AJNR Am J Neuroradiol 2002;23 (10) 1785- 1794
PubMed
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