Stroke is a major cause of mortality and long-term neurological disability worldwide and continues to impose a substantial clinical, social, and economic burden, particularly in low- and middle-income countries. Acute ischemic stroke results from sudden interruption of cerebral blood flow due to arterial thrombosis or embolism, leading to deprivation of oxygen and glucose, failure of cellular energy metabolism, and irreversible neuronal injury if reperfusion is not achieved promptly [1,2]. The clinical presentation varies according to the location and extent of cerebral ischemia and may include hemiparesis, sensory impairment, speech disturbance, visual deficits, altered consciousness, and impaired coordination. Initial neurological severity is commonly quantified using the National Institutes of Health Stroke Scale (NIHSS), a standardized instrument assessing consciousness, gaze, visual fields, facial movement, motor power, sensation, language, dysarthria, and neglect. A higher NIHSS score indicates greater neurological impairment and is associated with larger infarct volume, functional dependence, and mortality [2].

Calcium plays a complex role in the pathophysiology of cerebral ischemia. Under normal physiological conditions, the marked concentration gradient between extracellular and intracellular calcium is essential for neuronal excitability, neurotransmitter release, enzymatic activity, and intracellular signalling. During ischemia, depletion of adenosine triphosphate causes failure of ion pumps and neuronal membrane depolarization. Excessive glutamate release activates N-methyl-D-aspartate and other excitatory receptors, producing uncontrolled intracellular calcium influx. Calcium overload subsequently activates proteases, phospholipases, endonucleases, nitric oxide synthase, mitochondrial dysfunction, oxidative stress, and inflammatory pathways, ultimately contributing to neuronal death [3]. Serum calcium may therefore reflect metabolic alterations accompanying acute cerebral ischemia, although extracellular serum calcium and intracellular neuronal calcium have different biological implications.

Previous clinical studies have reported inconsistent relationships between circulating calcium and ischemic stroke. Several studies observed that lower admission serum or ionized calcium levels were associated with higher NIHSS scores, larger infarct volumes, and less favourable clinical outcomes [4,5]. However, other investigations reported nonlinear associations or poorer outcomes at relatively elevated calcium levels, suggesting that the relationship may be influenced by albumin concentration, renal function, endocrine disorders, stroke subtype, infarct volume, timing of blood collection, and whether total, corrected, or ionized calcium was measured. Serum calcium is inexpensive, widely available, and routinely measured during hospital admission. Establishing its relationship with stroke severity could therefore provide a readily accessible adjunctive marker for early risk stratification.

AIM

To assess the clinical profile and relationship of serum calcium levels with stroke severity among patients with acute ischemic stroke.

OBJECTIVES

1. To describe the demographic, clinical, and risk-factor profile of patients presenting with acute ischemic stroke.
2. To measure admission serum calcium levels and classify patients into low-calcium and normal-calcium groups.
3. To compare NIHSS-defined stroke severity between the calcium groups and determine the correlation between serum calcium level and NIHSS score.

Source of Data The study population consisted of adult patients with a new-onset acute ischemic stroke who attended the outpatient department or emergency services or were admitted to the Department of General Medicine of hospitals attached to Bangalore Medical College and Research Institute (BMCRI), Bengaluru. Patients meeting the eligibility criteria and presenting within 48 hours of symptom onset were enrolled. Information was obtained through patient or attendant interviews, clinical examination, hospital case records, neuroimaging reports, and laboratory findings. Study Design A hospital-based cross-sectional observational study was conducted. Study Location The study was conducted in the Department of General Medicine at hospitals attached to Bangalore Medical College and Research Institute, Bengaluru, Karnataka. Study Duration The study was conducted over 19 months, from February 2021 to August 2022. Sample Size A total of 70 patients with acute ischemic stroke were included. On the basis of admission serum calcium values and the institutional laboratory reference range, the participants were classified as: • Low serum calcium: 46 patients (65.7%) • Normal serum calcium: 24 patients (34.3%) The original sample-size estimation was based on an anticipated correlation coefficient of approximately -0.42 between serum calcium and stroke severity, with a 95% confidence level and 95% statistical power. Using Fisher’s z transformation for a correlation coefficient, the minimum calculated sample size was 68: After allowing for a practical round-off, 70 patients were enrolled. Inclusion Criteria 1. Patients aged 18 years or older. 2. Patients with a new-onset acute neurological deficit clinically suggestive of ischemic stroke. 3. Patients presenting within 48 hours of the onset of stroke symptoms. 4. Patients in whom acute ischemic stroke was confirmed by computed tomography or magnetic resonance imaging of the brain. 5. Patients or legally acceptable representatives who provided written informed consent. 6. Patients for whom admission serum calcium and NIHSS assessments were available. Exclusion Criteria 1. Patients or representatives who did not provide informed consent. 2. Patients younger than 18 years. 3. Patients with intracerebral haemorrhage, subarachnoid haemorrhage, subdural haemorrhage, or another non-ischaemic lesion detected on neuroimaging. 4. Patients with chronic kidney disease or acute kidney injury likely to alter calcium homeostasis. 5. Patients with chronic liver disease or severe hypoalbuminaemia likely to affect total serum calcium interpretation. 6. Patients with known parathyroid disease, active malignancy, metabolic bone disease, or another established disorder of calcium metabolism. 7. Patients receiving calcium supplements, vitamin D therapy, bisphosphonates, calcitonin, or other medications that substantially affected serum calcium. 8. Patients with a previous stroke with significant residual neurological deficits that interfered with accurate NIHSS assessment. 9. Patients with conditions mimicking stroke, including hypoglycaemia, postictal paralysis, brain tumour, encephalitis, or significant electrolyte-related encephalopathy. 10. Patients whose blood sample was inadequate, haemolysed, or unavailable within the defined assessment period. Data Collection A predesigned and pretested case-record form was used. Demographic information included age, sex, residence, occupation, height, weight, and body mass index. Clinical information included time of symptom onset, time of admission, presenting neurological symptoms, affected side, level of consciousness, and relevant past history. Information regarding hypertension, diabetes mellitus, ischemic heart disease, previous transient ischemic attack, dyslipidaemia, hypothyroidism, chronic respiratory disease, smoking, alcohol consumption, and current medications was recorded. General physical examination included pulse rate, blood pressure, respiratory rate, temperature, pallor, icterus, cyanosis, clubbing, lymphadenopathy, jugular venous pressure, and pedal oedema. Detailed cardiovascular, respiratory, abdominal, and neurological examinations were performed. Laboratory and imaging findings were obtained from the patients’ hospital records. Procedure and Methodology Approval was obtained from the Institutional Ethics Committee before commencement of the study. Written informed consent was obtained from each participant or legally acceptable representative. Consecutive patients who fulfilled the eligibility criteria were enrolled until the required sample size was achieved. The diagnosis of acute ischemic stroke was based on a sudden focal or global neurological deficit of vascular origin and was confirmed using non-contrast computed tomography or magnetic resonance imaging of the brain. Neuroimaging was also used to exclude intracranial haemorrhage and other structural lesions. Each patient underwent a standardized neurological examination at admission. Stroke severity was assessed within 48 hours of symptom onset using the NIHSS, with a total score ranging from 0 to 42. For categorical analysis, stroke severity was classified as minor (NIHSS 1-4), moderate (NIHSS 5-15), moderate-to-severe (NIHSS 16-20), and severe (NIHSS 21-42). The investigator recorded the individual NIHSS components and calculated the total score. Serum calcium was measured from the admission blood sample obtained within 48 hours of stroke onset. According to the institutional laboratory reference interval, patients were classified into low-calcium and normal-calcium groups. Serum calcium values were then compared with the continuous NIHSS scores and NIHSS severity categories. The relationship of calcium status with demographic characteristics, vascular risk factors, and comorbidities was also examined. Sample Processing Approximately 3-5 mL of venous blood was collected under aseptic precautions into a plain serum-separator or clot-activator tube before initiation of calcium replacement therapy. The sample was allowed to clot and was centrifuged according to the hospital laboratory’s standard operating procedure. The separated serum was analysed promptly for total serum calcium using the laboratory’s validated automated biochemical analyser and standard colorimetric method. Results were expressed in mg/dL. Samples that were haemolysed, contaminated, insufficient, or improperly labelled were rejected and recollected whenever feasible. Internal quality-control procedures were followed by the laboratory. Other relevant investigations, including blood glucose, complete blood count, renal and liver function tests, electrolytes, and serum albumin, were recorded when available. Statistical Methods Data were entered into Microsoft Excel and analysed using IBM SPSS Statistics version 20. Continuous variables were summarized as mean and standard deviation when normally distributed and as median and interquartile range when skewed. Categorical variables were presented as frequencies and percentages. Normality was assessed using graphical methods and the Shapiro-Wilk test. The mean NIHSS score was compared between the low- and normal-calcium groups using the independent-samples t test; the Mann-Whitney U test was used if normality assumptions were not satisfied. Mean serum calcium levels across NIHSS severity categories were compared using one-way analysis of variance or the Kruskal-Wallis test, as appropriate. Associations between categorical variables were assessed using the chi-square test or Fisher’s exact test when expected cell frequencies were small. The relationship between the numerical serum calcium level and NIHSS score was assessed using Pearson’s correlation coefficient for normally distributed variables or Spearman’s rank correlation coefficient otherwise. Correlation coefficients were reported with direction, magnitude, 95% confidence intervals, and corresponding p values. All tests were two-tailed, and p<0.05 was considered statistically significant.

Table 1. Overall clinical profile and relationship of serum calcium with stroke severity among patients with acute ischemic stroke (N=70)

†Reference mean age=60 years.

‡Reference proportion=50%.

• Reference calcium level=8.5 mg/dL, representing the commonly used lower limit of normal total serum calcium.

¶Reference NIHSS score=15, the upper limit of the moderate-stroke category.

║Low-calcium versus normal-calcium groups.

*Statistically significant at p<0.05.

Table 1 presents the overall clinical profile and relationship between serum calcium and stroke severity among 70 patients with acute ischemic stroke. The mean age was 59.0±12.0 years (95% CI: 56.14-61.86), which did not differ significantly from the reference age of 60 years (p=0.488). Males constituted 62.9% of the participants, significantly exceeding the reference proportion of 50% (z=2.15, p=0.031). Low serum calcium was found in 46 (65.7%) patients, whereas 24 (34.3%) had normal calcium levels; this unequal distribution was statistically significant (z=2.63, p=0.009). Mean admission serum calcium was 7.9±1.2 mg/dL, significantly below the reference value of 8.5 mg/dL (t=-4.18, p<0.001). The overall mean NIHSS score was 22.0±10.0, indicating substantial neurological impairment and significantly exceeding the reference score of 15 (t=5.86, p<0.001). Severe stroke was present in 55.7% of patients, while 31.4% had moderate stroke. Patients with low calcium had a markedly higher mean NIHSS score than those with normal calcium (27.0±7.0 versus 11.0±4.0), with a mean difference of 16.0 points (95% CI: 13.37-18.63; t=12.16, p<0.001). Serum calcium showed a strong, statistically significant inverse correlation with NIHSS score (r=-0.674; 95% CI: -0.785 to -0.522; p<0.001).

Table 2. Demographic, clinical, and risk-factor profile of patients with acute ischemic stroke according to calcium category (N=70)

*Statistically significant at p<0.05.

Table 2 describes the demographic and risk-factor profile according to serum calcium category. The mean age was comparable between patients with low and normal calcium levels (58.0±12.0 versus 61.0±13.0 years; t=-0.94, p=0.352). Sex distribution was also similar: males represented 63.0% of the low-calcium group and 62.5% of the normal-calcium group (χ²=0.002, p=0.964). Diabetes mellitus was more frequent among patients with low calcium than among those with normal calcium (43.5% versus 20.8%); however, the association did not reach statistical significance (χ²=3.52, p=0.061). Hypertension was significantly more prevalent in the low-calcium group (58.7%) than in the normal-calcium group (29.2%; χ²=5.51, p=0.019). Similarly, ischemic heart disease was significantly more common among patients with low calcium (34.8% versus 12.5%; χ²=3.96, p=0.047). Although COPD and hypothyroidism were each more frequent in the low-calcium group (13.0% versus 4.2%), neither association was statistically significant (p=0.240 for each). Current smoking was reported by 57.1% of all patients and alcohol consumption by 55.7%; their distributions did not differ significantly between the calcium groups (p=0.513 and p=0.487, respectively).

Table 3. Admission serum calcium profile and classification of patients (N=70)

†Compared with a reference value of 8.5 mg/dL.

‡Compared with an expected equal proportion of 50%.

• Confidence interval calculated from the 95% CI for the observed low-calcium proportion and expressed.

*Statistically significant at p<0.05.

Table 3 summarizes the admission serum calcium profile. Mean admission serum calcium was 7.9±1.2 mg/dL (95% CI: 7.61-8.19), which was significantly below the reference lower limit of 8.5 mg/dL (t=-4.18, p<0.001). Low serum calcium was identified in 46 (65.7%) patients (95% CI: 54.0%-75.8%), while 24 (34.3%) had normal calcium levels (95% CI: 24.2%-46.0%). Compared with an expected equal distribution of 50%, the proportion of patients with low calcium was significantly higher (z=2.63, p=0.009). The absolute difference between the low- and normal-calcium proportions was 31.4 percentage points (95% CI: 8.0-51.6), which was also statistically significant (p=0.009).

Table 4. Comparison of NIHSS-defined stroke severity between calcium groups and correlation of calcium with NIHSS score (N=70)

†Pearson chi-square test.

‡One-way ANOVA recalculated from the reported category-specific sample sizes, means, and SDs.
*Statistically significant at p<0.05.

Table 4 demonstrates a marked relationship between serum calcium category and NIHSS-defined stroke severity. Among the 46 patients with low calcium, 39 (84.8%) had severe stroke and four (8.7%) had moderate-to-severe stroke; only two (4.3%) had minor stroke and one (2.2%) had moderate stroke. In contrast, none of the 24 patients with normal calcium had moderate-to-severe or severe stroke: 21 (87.5%) had moderate stroke and three (12.5%) had minor stroke. The overall association between calcium category and NIHSS severity category was highly significant (χ²=60.44, p<0.001). The mean NIHSS score was also substantially higher in the low-calcium group than in the normal-calcium group (27.0±7.0 versus 11.0±4.0), producing a mean difference of 16.0 points (95% CI: 13.37-18.63; t=12.16, p<0.001). Mean serum calcium showed a decreasing pattern from 8.5±2.5 mg/dL in minor stroke to 7.6±1.3 mg/dL in severe stroke; nevertheless, comparison of the four category-specific means using one-way ANOVA was not statistically significant (F=1.09, p=0.359), possibly because of the small and unequal numbers in some categories and considerable variability in the minor-stroke group. More importantly, the continuous analysis demonstrated a strong inverse correlation between serum calcium and NIHSS score (r=-0.674; 95% CI: -0.785 to -0.522; t=-7.52, p<0.001).

Table 1: Overall clinical profile and relationship of serum calcium with stroke severity The present study included 70 patients with acute ischemic stroke, with a mean age of 59.0±12.0 years. The concentration of patients around the sixth decade was consistent with the established age-related increase in stroke incidence. Katan et al. (2018)[1] described age as one of the strongest non-modifiable determinants of stroke, although the burden of stroke among younger and middle-aged adults has also increased in several low- and middle-income countries. Banerjee et al. (2016)[2] observed that Indian stroke populations frequently presented at a younger age than those reported in many high-income countries, possibly because of earlier development and inadequate control of hypertension, diabetes, smoking, and other vascular risk factors. Males comprised 62.9% of the present cohort, representing a statistically significant male predominance. This finding was comparable to Borah et al. (2016)[3], whose Northeast Indian study also recorded a predominantly male acute ischemic stroke population. Ishfaq et al. (2017)[4] and Badshah et al. (2018)[5] similarly reported male predominance in South Asian cohorts. The higher proportion of men in hospital-based studies may be related to greater exposure to smoking and alcohol, sex-related differences in vascular risk, and differences in healthcare access and hospital utilisation. Low serum calcium was found in 65.7% of patients, and the mean admission level was 7.9±1.2 mg/dL, significantly below the reference value of 8.5 mg/dL. This finding suggested that reduced total serum calcium was common during the acute phase of ischemic stroke. Gupta et al. (2015)[6] found that patients in lower albumin-corrected calcium quartiles had more severe neurological deficits and poorer functional outcomes than those in higher quartiles. Borah et al. (2016)[3] also demonstrated significant inverse correlations of total, corrected, and ionized calcium with cerebral infarct size. The overall mean NIHSS score was 22.0±10.0, and 55.7% of patients had severe stroke. The study therefore represented a relatively severe hospital-based stroke population. Badshah et al. (2018)[5] reported a comparable mean NIHSS score of 23.01±10.38 and a mean calcium concentration of 7.26±1.41 mg/dL. Their findings closely resembled the present results and suggested that cohorts with lower calcium concentrations may contain a greater proportion of patients with severe neurological deficits. The mean NIHSS score was significantly higher in the low-calcium group than in the normal-calcium group (27.0±7.0 versus 11.0±4.0), with a clinically substantial difference of 16 points. Serum calcium also demonstrated a strong inverse correlation with NIHSS score (r=−0.674, p<0.001). Ishfaq et al. (2017)[4] similarly reported that lower serum calcium was associated with greater acute ischemic stroke severity. Badshah et al. (2018)[5] found an even stronger inverse correlation between serum calcium and NIHSS score (r=−0.899). Gupta et al. (2015)[6] reported that higher calcium quartiles were associated with milder NIHSS categories and better functional outcomes at discharge and three months. Nevertheless, not all evidence supports a simple protective relationship between higher calcium and stroke outcome. Chung et al. (2015)[7] found that elevated albumin-corrected serum calcium was associated with poorer short-term functional outcome and increased long-term mortality. These apparently conflicting results may arise because total, ionized, and albumin-corrected calcium represent different biological measurements. In addition, studies have assessed different outcomes, including admission severity, infarct volume, functional disability, and mortality. Consequently, low calcium may be associated with greater initial neurological severity, while high corrected calcium may have a separate association with later mortality. Table 2: Demographic, clinical, and risk-factor profile according to calcium category The mean ages of the low- and normal-calcium groups were comparable, and their sex distributions were almost identical. These findings suggested that age and sex were unlikely to explain the large difference in NIHSS scores between the calcium groups. However, formal multivariable adjustment would still be required because other clinical characteristics could confound the observed association. Hypertension was present in 48.6% of the overall cohort and was significantly more frequent in the low-calcium group than in the normal-calcium group (58.7% versus 29.2%). O’Donnell et al. (2016)[8], in the international INTERSTROKE study, identified hypertension as the most important modifiable risk factor for stroke. They found that ten modifiable factors collectively accounted for approximately 90% of the population-attributable risk of stroke. Boehme et al. (2017)[9] also identified hypertension as the leading treatable determinant of both ischemic and haemorrhagic stroke. Thus, the high prevalence of hypertension in the present cohort was consistent with international evidence. Ischemic heart disease was significantly more common in patients with low calcium than in those with normal calcium (34.8% versus 12.5%). This clustering of low calcium, hypertension, and cardiac disease may reflect a greater overall burden of systemic atherosclerosis and vascular dysfunction. Benjamin et al. (2017)[10] emphasized the overlapping risk profiles of ischemic heart disease and ischemic stroke, including hypertension, diabetes, dyslipidaemia, smoking, obesity, and advancing age. However, the present cross-sectional data could not determine whether low calcium contributed to vascular disease or represented a metabolic marker of greater illness burden. Diabetes mellitus was present in 35.7% of patients and occurred more frequently in the low-calcium group than in the normal-calcium group (43.5% versus 20.8%). Although this difference narrowly missed statistical significance (p=0.061), its direction was clinically relevant. O’Donnell et al. (2016)[8] and Boehme et al. (2017)[9] established diabetes as a major risk factor for ischemic stroke through its effects on atherosclerosis, endothelial dysfunction, inflammation, and small-vessel disease. The absence of statistical significance in the current study may have been due to limited power arising from the sample of only 70 patients. Current smoking was reported by 57.1% of patients, while 55.7% consumed alcohol. Neither exposure differed significantly between the calcium groups. Smoking and harmful alcohol use are established stroke risk factors, but they may not be direct determinants of serum calcium category after stroke onset. INTERSTROKE demonstrated that smoking and excessive alcohol consumption contributed to stroke risk across different geographical regions, although their relative effects varied across populations and stroke subtypes [8]. COPD and hypothyroidism were each present in 10.0% of the patients and were numerically more frequent in the low-calcium group, but the differences were not significant. The very small numbers—only seven patients with each condition—produced limited statistical power. These findings should therefore be interpreted as inconclusive rather than as evidence of no association. Overall, Table 2 indicated that low calcium coexisted with a greater burden of hypertension, ischemic heart disease, and possibly diabetes. Because these risk factors may themselves influence stroke severity, an adjusted regression model would be needed to determine whether calcium remained independently related to NIHSS score. Table 3: Admission serum calcium profile The mean admission serum calcium level of 7.9±1.2 mg/dL was significantly below 8.5 mg/dL, and the proportion with low calcium exceeded the normal-calcium proportion by 31.4 percentage points. Gupta et al. (2015)[6] reported greater stroke severity among patients in lower calcium quartiles. Borah et al. (2016)[3] similarly observed that total, ionized, and albumin-corrected calcium were inversely correlated with infarct size. Prabhakar et al. (2020)[11] reported mean total, corrected, and ionized calcium levels of 9.13±0.89, 9.56±0.82, and 4.79±0.47 mg/dL, respectively, and found significant inverse relationships between these calcium measures, infarct size, and NIHSS severity. Although their mean calcium was higher than that of the present study, the direction of association was comparable. Potential mechanisms for reduced serum calcium during acute ischemic stroke include movement of extracellular calcium into ischemic neurons, altered protein binding, acute inflammation, haemodilution, nutritional deficiency, renal dysfunction, and changes in parathyroid hormone or vitamin D metabolism. During cerebral ischemia, energy failure causes membrane depolarisation and excessive glutamate release, leading to intracellular calcium accumulation. This activates proteases, phospholipases, endonucleases, oxidative stress, mitochondrial injury, and ultimately neuronal death. Powers et al. (2020)[12] described this excitotoxic and metabolic cascade as a central component of irreversible ischemic brain injury. Serum calcium must nevertheless be interpreted carefully. Total serum calcium is strongly influenced by albumin concentration, whereas ionized calcium represents the biologically active fraction. A low total calcium measurement may therefore reflect hypoalbuminaemia rather than true ionized hypocalcaemia. Prabhakar et al. (2020)[11] addressed this issue by examining total, corrected, and ionized calcium, while the present study primarily classified patients using total serum calcium. This difference may partly account for variation between studies. Dibaba et al. (2019)[13], in the REGARDS study, examined calcium intake and serum calcium in relation to incident ischemic stroke. Their findings indicated that the relationship between calcium exposure and stroke risk was complex and could differ according to whether dietary intake or circulating calcium was evaluated. Larsson et al. (2019)[14], using Mendelian randomisation, also found that observational associations between serum calcium and stroke should not automatically be interpreted as causal. Therefore, the current results support serum calcium as an associated severity marker but do not demonstrate that calcium supplementation would improve neurological outcomes. Table 4: NIHSS severity across calcium groups and calcium–NIHSS correlation The distribution of NIHSS severity categories demonstrated a marked difference between the calcium groups. Among patients with low calcium, 84.8% had severe stroke and 8.7% had moderate-to-severe stroke. In comparison, 87.5% of patients with normal calcium had moderate stroke, and none had moderate-to-severe or severe stroke. This association was highly significant (χ²=60.44, p<0.001). Borah et al. (2016)[3] reported that lower serum calcium was associated with larger cerebral infarcts, providing a radiological explanation for the greater clinical severity observed in the present study. Gupta et al. (2015)[6] found that patients in the lower calcium quartiles had higher NIHSS scores and worse modified Rankin Scale outcomes. Ishfaq et al. (2017)[4] likewise concluded that low calcium could be associated with more severe clinical findings at stroke onset. Badshah et al. (2018)[5] demonstrated a strong inverse calcium–NIHSS relationship, while Prabhakar et al. (2020)[11] reported significant negative correlations between calcium measurements, NIHSS severity, and infarct size. These studies strongly support the direction of the present findings. The mean calcium level showed a decreasing pattern across clinical severity categories, from 8.5±2.5 mg/dL in minor stroke to 7.6±1.3 mg/dL in severe stroke. However, the one-way ANOVA comparing the four category-specific means was not significant (p=0.359). This apparent inconsistency with the highly significant calcium-group comparison and continuous correlation was probably related to the small and unequal severity groups. Only five patients had minor stroke and four had moderate-to-severe stroke, while the standard deviation in the minor-stroke group was large. Categorisation therefore reduced statistical power and precision. The continuous analysis was more informative and demonstrated a strong inverse correlation between calcium and NIHSS score. Campbell et al. (2019)[15] emphasized that baseline neurological severity and infarct volume were major determinants of acute stroke outcome. Phipps et al. (2020)[16] similarly highlighted the NIHSS as an important standardized measure for early assessment, treatment decisions, prognosis, and clinical monitoring. The current correlation suggested that serum calcium might complement, but could not replace, clinical NIHSS assessment and neuroimaging.

The study demonstrated that low admission serum calcium was common among patients with acute ischemic stroke, affecting 65.7% of the study population. Patients with low serum calcium had substantially greater neurological impairment than those with normal calcium, as shown by the significantly higher mean NIHSS score (27.0±7.0 versus 11.0±4.0; p<0.001). Serum calcium showed a strong inverse correlation with NIHSS score (r=-0.674, p<0.001), indicating that lower calcium levels were associated with greater stroke severity. Hypertension and ischemic heart disease were also significantly more frequent in the low-calcium group. These findings suggest that admission serum calcium, an inexpensive and routinely available biochemical parameter, may be useful as an adjunctive marker for early assessment of stroke severity. Nevertheless, it should be interpreted along with clinical examination, NIHSS assessment, neuroimaging, serum albumin, renal function, and other prognostic indicators rather than used as an independent prognostic marker.

LIMITATIONS OF STUDY

1. The study was conducted at a single tertiary-care centre with a relatively small sample of 70 patients, limiting the precision and generalisability of the findings.
2. The cross-sectional design demonstrated association but could not establish whether low calcium preceded severe stroke or occurred as a consequence of the acute neurological insult.
3. Serum calcium was measured only at admission; serial changes during hospitalisation were not evaluated.
4. Total serum calcium was used without consistently measuring ionized calcium or albumin-corrected calcium. Consequently, hypoalbuminaemia may have resulted in apparent hypocalcaemia in some patients.
5. Important determinants of calcium homeostasis, including vitamin D, parathyroid hormone, magnesium, phosphate, nutritional status, and medication use, were not comprehensively assessed.
6. Infarct volume, vascular territory, stroke aetiological subtype, large-vessel occlusion, collateral status, and reperfusion treatment were not incorporated into the primary analysis.
7. The severity categories were markedly unequal, with few patients in the minor and moderate-to-severe groups, thereby reducing the reliability of category-wise comparisons.
8. Potential confounding variables were assessed using unadjusted comparisons, and multivariable regression was not performed to determine whether serum calcium was independently associated with NIHSS severity.
9. Long-term outcomes such as mortality, neurological improvement, functional disability, recurrent stroke, and modified Rankin Scale scores were not evaluated.
10. The hospital-based sampling method may have introduced referral or selection bias because patients with more severe stroke were more likely to be admitted to a tertiary-care centre.

1. Katan M, Luft A. Global burden of stroke. Semin Neurol. 2018;38(2):208–211. doi:10.1055/s-0038-1649503.
2. Banerjee TK, Das SK. Fifty years of stroke research in India. Ann Indian Acad Neurol. 2016;19(1):1–8. doi:10.4103/0972-2327.168631.
3. Borah M, Dhar S, Gogoi DM, Ruram AA. Association of serum calcium levels with infarct size in acute ischemic stroke: observations from Northeast India. J Neurosci Rural Pract. 2016;7(1):41–45. doi:10.4103/0976-3147.165396.
4. Ishfaq M, Ullah F, Akbar S, Rahim F, Afridi AK. Correlation of serum calcium with severity of acute ischemic stroke. J Pak Med Assoc. 2017;67(1):20–23.
5. Badshah L, Khan A, Malik S. Acute ischemic stroke: correlation between serum calcium levels and severity of infarct in patients. Professional Med J. 2018;25(2):297–301. doi:10.29309/TPMJ/18.4182.
6. Gupta A, Dubey U, Kumar A, Singh S. Correlation of serum calcium levels with severity and functional outcome in acute ischemic stroke patients. Int J Res Med Sci. 2015;3(12):3698–3702. doi:10.18203/2320-6012.ijrms20151425.
7. Chung JW, Ryu WS, Kim BJ, Yoon BW. Elevated calcium after acute ischemic stroke: association with a poor short-term outcome and long-term mortality. J Stroke. 2015;17(1):54–59. doi:10.5853/jos.2015.17.1.54.
8. O’Donnell MJ, Chin SL, Rangarajan S, Xavier D, Liu L, Zhang H, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016;388(10046):761–775. doi:10.1016/S0140-6736(16)30506-2.
9. Boehme AK, Esenwa C, Elkind MSV. Stroke risk factors, genetics, and prevention. Circ Res. 2017;120(3):472–495. doi:10.1161/CIRCRESAHA.116.308398.
10. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–e603. doi:10.1161/CIR.0000000000000485.
11. Prabhakar K, Pujitha SN, Phaneesh Bharadwaj BS. Correlation of serum calcium levels with infarct size and severity of stroke using NIHSS score in patients with acute ischemic stroke. Int J Res Med Sci. 2020;8(1):55–59. doi:10.18203/2320-6012.ijrms20195613.
12. Powers WJ. Acute ischemic stroke. N Engl J Med. 2020;383(3):252–260. doi:10.1056/NEJMcp1917030.
13. Dibaba DT, Xun P, Fly AD, Yokota K, He K. Calcium intake and serum calcium level in relation to the risk of ischemic stroke: findings from the REGARDS study. J Stroke. 2019;21(3):312–323. doi:10.5853/jos.2019.00542.
14. Larsson SC, Traylor M, Burgess S, Boncoraglio GB, Jern C, Michaëlsson K, et al. Serum magnesium and calcium levels in relation to ischemic stroke: Mendelian randomization study. Neurology. 2019;92(9):e944–e950. doi:10.1212/WNL.0000000000007001.
15. Campbell BCV, De Silva DA, Macleod MR, Coutts SB, Schwamm LH, Davis SM, et al. Ischaemic stroke. Nat Rev Dis Primers. 2019;5(1):70. doi:10.1038/s41572-019-0118-8.
16. Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020;368:l6983. doi:10.1136/bmj.l6983.