Association Between Serum Vitamin D Levels and Physical Outcomes of Patients Who Underwent Rehabilitation Following Ischemic Stroke

Abstract

Background

Ischemic stroke is the most common cause of disability in adults. Deficiency of vitamin D in patients with cardiovascular diseases is increasing. Only a few studies have assessed the relationship between serum vitamin D levels and functional capacity and degree of disability. This study aimed to evaluate the association between serum vitamin D levels and physical outcomes of 94 patients who underwent physical rehabilitation following ischemic stroke.

Material/Methods

A group of 94 patients was enrolled; however, 80 patients (61.8±6.9 years) were included. They underwent a 6-week rehabilitation using proprioceptive neuromuscular facilitation (PNF, 60 min daily), mirror therapy (MT, 30 min daily), and occupational therapy (OT, 45 min daily). The Barthel Index (BI) and modified Rankin scale (mRS) were used for functional assessments. Laboratory blood tests for serum vitamin D and insulin-like growth factor 1 (IGF-1) levels were conducted.

Results

There was a significant increase in BI scores (median difference=2.0 points [pts]; P<0.001) and IGF levels (median difference=124.6 ng/ml; P<0.001) after rehabilitation. There was a significant decrease in mRS scores (median difference=7.0 pts; P<0.001), but there was no significant difference in vitamin D levels (P=0.40). The effect of age (B=−0.01, P=0.04) and serum vitamin D level (B=−0.02, P=0.01) on the BI score was demonstrated. The effect of body mass index (BMI) results (B=−0.07, P=0.02) on the mRS score was observed.

Conclusions

Lower serum vitamin D levels and more advanced age may be associated with worse functional outcomes in first-ever ischemic stroke patients.

Background

Ischemic stroke causes irreversible brain damage and affects people of all ages on all continents. It is the second leading cause of death [1], and it is the leading cause of disability in people aged over 45 years [2]. Despite significant improvements in primary prevention, stroke continues to affect more than 1.1 million Europeans [3] and Chinese [4] each year, which indicates the severity of the problem.

Established risk factors for ischemic stroke do not explain the occurrence of the disease in one-third of patients [5], warranting further exploration of potential risk factors. Serum vitamin D levels are positively associated with improved cardiovascular health, particularly with a reduced risk of stroke [6]. Recently, there has been an increased prevalence of vitamin D deficiency in patients with cardiovascular diseases, including post-stroke patients [7].

Vitamin D deficiency is described as a co-morbid condition in many diseases such as acute ischemic stroke, neurodevelopmental disorders and intellectual disability, and cardiovascular risk, and it is associated with increased mortality [8,9]. The discovery of the vitamin D receptor (VDR) made it possible to learn more about its effects on extraskeletal organs [10]. The identification of calcitriol (the active form of vitamin D) receptors in various tissues of the human body confirmed the pleiotropic, multidirectional effects of vitamin D [11].

Zhou et al [12], in their systematic review and meta-analysis, confirmed the hypothesis that low vitamin D levels are associated with an increased risk of ischemic stroke, which indicates they are a possible risk factor for stroke. In contrast, higher vitamin D concentrations significantly protect against stroke.

Vitamin D is a well-known neurosteroid hormone that plays an important role in modulating cognitive processes and regulating neurotrophic signaling [13] for neuroprotection, neuromodulation, vascular risk factors for stroke [14–16], and inflammation [17,18]. VitaminD, both from food and that synthesized in the skin, undergoes transformations that result in the formation of 2 metabolites. Hydroxylation to 25-hydroxyvitamin D (25(OH)D), a substrate for the synthesis of the biologically active 1,25 dihydroxyvitamin D (1,25(OH)₂D), occurs in liver cells, which takes place in the proximal cells of the kidneys. Both metabolites enter the bloodstream. Although 1,25(OH)₂ is a biologically active form of vitamin D, its serum levels do not correlate with the state of the body’s actual supply. A marker of vitamin D content is the measurement of 25(OH)D. The half-life of the circulating metabolite in the blood is approximately 21 days and is the best indicator of the total vitamin D content in the body. In contrast, the 1,25(OH)₂ present in serum has a short half-life of approximately 4 hours and determination of its content is not used for assessing vitamin D deficiency.

Many studies in the literature have assessed the relationship between vitamin D in terms of stroke risk [6,19]. Few studies have assessed the relationship between serum vitamin D levels and the functional capacity of patients and the associated degree of disability. Therefore, there was an attempt to assess the relationship between vitamin D levels in patients admitted to rehabilitation and functional outcomes. Therefore, this study aimed to evaluate the association between serum vitamin D levels and physical outcomes of 94 patients who underwent physical rehabilitation following ischemic stroke.

Material and Methods

Ethical Considerations

The study was approved by the Ethics Committee of Wrocław Medical University (permission no. KB-813/2020). The study was conducted in accordance with the Good Clinical Practice Guidelines and the Declaration of Helsinki. Each person was briefed and instructed on the conduct of the experiment before signing the consent to participate. All study participants were informed of the possibility of discontinuing their participation in the project in the case of health problems or for other reasons.

Trial Registration

The study was conducted as part of the project “Effectiveness of various therapeutic forms and their influence on nervous, muscular and vascular plasticity in patients after ischemic stroke” in collaboration with Dr. Sílvia Rocha-Rodrigues (Research Centre in Physical Activity and Health, Faculty of Sport, University of Porto, Portugal). The project was registered in the International Standard Randomized Controlled Trial Number Registry Platform (registry no. ISRCTN16891871).

Participants

A group of 94 post-ischemic stroke patients undergoing rehabilitation at the Neurological Rehabilitation Unit of the Wrocław Regional Specialist Hospital were enrolled in the study. Patients were qualified to participate in the research by a team consisting of a physician-specialist in medical rehabilitation, a neurologist, a neurologopedist, a clinical psychologist, and a physiotherapist. Inclusion criteria for the study included first-ever ischemic stroke, time of onset 2 weeks before admission for early neurological rehabilitation, stroke confirmed by magnetic resonance imaging (MRI) or computed tomography (CT), age >18 years, no contraindications to participate in the experiment (consent of attending physician), no neurological comorbidities, and written informed consent of the patient to participate in the study. Exclusion criteria included patients with an infection in the past 2 weeks, patients who took vitamin D and its derivatives or calcium in the past 3 months, patients with liver and kidney disorders, patients with thyroid disorders, patients with aphasia, and patients who did not provide consent. A group of 80 patients met the criterion of participating in 2 follow-up examinations was finally qualified for the study. There were 25 women (31.3%) and 55 men (68.7%) in that group. Patients were provided with proprioceptive neuromuscular facilitation (PNF) and mirror therapy (MT) for 42 days. At 6-week intervals, patients had blood drawn for routine tests and selected biochemical parameters were determined in the remaining blood. All tests and surveys were carried out by the same physician.

Measurements

On the day of admission, all patients underwent standard neurological examination, basic anthropometric measurements, and stroke severity assessment using the National Institutes of Health Stroke Scale (NIHSS). In terms of primary outcomes, functional tests were performed using Barthel Index (BI) and modified Rankin scale (mRS).

Barthel Index

The BI is a commonly used scale to assess the level of functional independence in patients undergoing physiotherapy after stroke. The BI measures deficits in self-care, mobility, and sphincter control. Scores ranging from 0 to 20 points are interpreted as follows: ≤4 points – very severe disability; 5–9 points – severe disability; 10–14 points – moderate severity of disability; 15–19 points – mild disability; 20 points – full independence.

Modified Rankin scale

The mRS is a commonly used tool to assess functional outcome after a stroke. It assigns a score ranging from 0 (no symptoms) to 6 (death), with higher scores indicating more severe disability. The scale is often used to assess a patient’s ability to carry out activities of daily living, such as eating, dressing, and mobility. The mRS has been shown to have good inter-rater reliability and validity, and is widely used in both clinical practice and stroke research.

Laboratory Blood Tests

Patients had their blood routinely drawn from the ulnar vein for basic laboratory tests such as complete blood count (CBC) and urinalysis. The following concentrations were determined: vitamin D and IGF-1 levels. The serum levels of those substances were determined on admission to the unit and after 6 weeks of rehabilitation training. Each patient had blood drawn from an ulnar vein, always at the same time, at 6: 30 a.m., on an empty stomach. Laboratory tests were performed at the Scientific Laboratory of the Research and Development Center at the Regional Specialized Hospital in Wrocław. Performing biochemical tests at the same time, using reagents from a single production batch, and ensuring the same measurement conditions was intended to minimize the occurrence of external, random errors that could alter the results of biochemical analyses. The tests were performed in the laboratory on an Alinity ci analyzer using reagents from Abbott (Chicago, Illinois, USA). This is a widely used, standardized immunochemical assay using a chemiluminescent microparticle immunoassay (CMIA) used to quantify 25(OH)D in human serum and plasma on an Alinity ci analyzer. The Alinity ci 25-OH Vitamin D test has been standardized against the National Institute of Standards & Technology Standard Reference Material 2972 (NIST SRM 2972). The test is used as an aid in assessing adequacy of vitamin D levels. It is a one-step immunochemical test with delayed conjugate addition, dedicated to the quantitative determination of 25-hydroxyvitamin D in human serum and plasma using microparticles and a chemiluminescent marker (CMIA). Paramagnetic microparticles coated with anti-vitamin D antibodies and assay diluent are added to the test sample, and the whole mixture was incubated. The 25-hydroxyvitamin D present in the sample was removed from the vitamin D-binding protein and then binds to the anti-vitamin D antibodies, coating the microparticles. A conjugate containing acridine-labeled vitamin D was added to form the reaction mixture. The reaction mixture was incubated. After a wash cycle, the Pre-Trigger Solution and the Trigger Solution that triggers the Trigger Solution reaction were added. The intensity of the signal produced by the chemiluminescence reaction was measured in relative light units (RLU), based on the relationship between the amount of 25-hydroxyvitamin D in the sample and the RLU values measured by the optical system. A normal serum vitamin D level was defined as a 25(OH)D concentration >30 ng/ml. Vitamin D deficiency was defined as a concentration of 25(OH)D <30 ng/ml.

Rehabilitation Procedures

Once stabilized during the early neurological rehabilitation period, post-ischemic stroke patients may develop a wide variety of disorders, the clinical picture of which will depend on the nature and extent of damaged brain tissues. Movement disorders are one of the most common clinical manifestations. Rehabilitation treatment (rehabilitation training) focuses on regaining motor function to a degree that enables patients to achieve and meet their self-care needs. Patients selected for the project were rehabilitated with neurophysiological methods (PNF and MT) for 5 days a week. Rehabilitation using the PNF method was oriented towards improvement of a specific lost function, not just a structure. The overriding aim of the therapy was to help the patient achieve the highest possible functional level. Each unit of treatment for mobility issues lasted 60 minutes. Moreover, each patient additionally had MT applied daily for 30 minutes. The rehabilitation training was 6 weeks long. Also, each patient had daily one-to-one sessions with a clinical psychologist for 30 minutes and an additional 45 minutes of occupational therapy (OT). For patient safety reasons, blood pressure and heart rate were measured before each kinesitherapy unit. Since patients with diabetes were also included in the study group, electroencephalography (ECG) changes indicative of myocardial hypoxia, which may also occur during exercise, were an absolute precondition for discontinuing the rehabilitation training. The rehabilitation training has always been individually tailored to each patient and their current abilities and needs, taking into account the patient’s capabilities.

Sample Size

The sample size analysis was based on the main objective of the study, which was to assess changes in vitamin D levels before and after 6 weeks of rehabilitation. Before the start of the study, it was assumed that there would be an increase in vitamin D levels. The minimum sample size needed to detect a difference of 20% assuming alpha=5%, power=80% and confidence level=95% is 79 patients. The sample size analysis was performed using the G*Power software. Statistical power analyses were performed using G*Power 3.1

Statistical Analysis

Statistical analysis was performed using Statistica 13 software (TIBCO, Inc., Palo Alto, USA). Arithmetic means and standard deviations or medians, upper and lower quartiles and the range of variability (minimum and maximum value) were calculated for measurable variables. Prevalence (%) was calculated for qualitative variables. All studied quantitative variables were verified using the Shapiro-Wilk test to determine distribution type. Comparisons between pre- and post-rehabilitation scores were made using non-parametric Wilcoxon test. The level of α=0.05 was used for all comparisons. Moreover, the analysis of the impact of selected variables on activities of daily living (BI) and disability/dependence in the daily activities (mRS) was performed using a linear regression (univariate model). The unstandardized and standardized regression coefficients, standard error and level of statistical significance were determined. The next step was to develop a multivariate model (stepwise progressive method), taking into account variables whose P value in the univariate model was ≤0.30. A p value less than.05 was considered statistically significant.

Results

Patients’ Characteristics

The study ultimately included 80 patients meeting the participation criterion; the mean age of participants was 61.8±6.9. In this group, 68.7% were men (55 individuals). Table 1 shows the characteristics of the group including age, height, weight, body mass index (BMI), number of days since stroke diagnosis, NIHSS score, sex, smoking, and history of chronic diseases.

Table 1.

Characteristics of the study group.

Variable	Study group (n=80)
	χ̄	SD	Min	Max
Age [years]	61.8	6.9	36.3	71.9
Height [cm]	168.5	8.5	150.0	186.0
Body weight [kg]	74.1	14.9	46.0	108.0
BMI [kg/m2]	26.0	4.3	16.3	35.4
Time since stroke onset [days]	21.9	3.8	14.0	30.0
NIHSS [points]	16.3	1.3	14.0	19.0
Sex	F – n=25; 31.3%
	M – n=55; 68.7%
Hypertension	No – n=26; 32.5%
	Yes – n=54; 67.5%
Diabetes mellitus	No – n=55; 68.8%
	Yes – n=25; 31.3%
Smoking	No – n=45; 56.3%
	Yes – n=35; 43.7%

n – number of participants; χ̄ – mean; SD – standard deviation; Min – minimum value; Max – maximum value; F – Female; M – Male; BMI – body mass index, NIHSS – National Institutes of Health Stroke Scale.

Outcomes’ Changes after Rehabilitation

Figures 1–4 show a comparison of BI, mRS, vitamin D, and insulin-like growth factor 1 (IGF-1) results before and after rehabilitation. After therapy, there was a statistically significant increase in BI scores (median difference is 2.0 points; P<0.001) and IGF levels (median difference is 124.6 ng/ml; P<0.001). There was also a statistically significant reduction in mRS scores (median difference is 7.0 points; P<0.001). There were no significant differences in vitamin D levels (P=0.40).

Figure 1.

A comparison of BI results before and after rehabilitation. BI – Barthel Index.

Figure 2.

A comparison of mRS results before and after rehabilitation. mRS – modified Rankin scale.

Figure 3.

A comparison of IGF results before and after rehabilitation. IGF – insulin-growth factor.

Figure 4.

A comparison of vitamin D results before and after rehabilitation.

Variables Affecting Outcomes

Table 2 shows the assessment of the impact of selected variables on activities of daily living (BI) and disability/dependence in the daily activities (mRS) of post-stroke patients (linear regression analysis in the univariate model). The effect of age (B=−0.01, P=0.04) and serum vitamin D levels (B=−0.02, P=0.01) on BI score was demonstrated. The effect of BMI results (B=−0.07, P=0.02) on mRS score was observed.

Table 2.

The assessment of the impact of selected variables on activities of daily living (BI) and disability/dependence in the daily activities (mRS) of post-stroke patients.

		BI					mRS
		B	SE	t	p-value	β	B	SE	t	p-value	β
Age [years]		−0.01	0.01	−2.04	0.04	−0.23	0.00	0.02	0.07	0.94	0.01
BMI [kg/m2]		0.00	0.01	−0.45	0.65	−0.05	−0.07	0.03	−2.33	0.02	−0.25
Time since stroke onset [days]		−0.01	0.01	−1.20	0.24	−0.13	−0.01	0.03	−0.18	0.86	−0.02
NIHSS [points]		−0.04	0.03	−1.43	0.16	−0.16	0.01	0.10	0.06	0.95	0.01
Sex [ref. M]	F	−0.02	0.04	−0.39	0.70	−0.04	0.11	0.14	0.76	0.45	0.09
Hypertension [ref. No]	Yes*	0.01	0.04	0.29	0.77	0.03	0.04	0.14	0.32	0.75	0.04
Diabetes mellitus [ref. No]	Yes	−0.02	0.04	−0.39	0.70	−0.04	−0.01	0.14	−0.08	0.94	−0.01
Smoking [ref. No]	Yes	0.02	0.04	0.53	0.60	0.06	−0.03	0.13	−0.22	0.83	−0.02
IGF [ng/ml]		0.00	0.00	−0.65	0.52	−0.07	0.00	0.00	−0.11	0.91	−0.01
Vitamin D [ng/ml]		0.02	0.01	2.51	0.01	0.27	−0.02	0.02	−0.74	0.46	−0.08

BMI – body mass index, NIHSS – National Institutes of Health Stroke Scale; M – Male; F – Female; BI – Barthel Index; mRS – modified Rankin Scale; IGF – insulin-like growth factor; B – unstandardized regression coefficient B; SE – standard error; t: B/standard error; β – standardized regression coefficient β.

Discussion

Vitamin D deficiency is now a widely well-known public health problem that affects almost 1 in 2 people worldwide. Recent evidence from many population-based studies indicates that vitamin D deficiency is a predictor of future strokes. This “pandemic” of vitamin D deficiency is worrying because low serum vitamin D levels are linked to cardiovascular, musculoskeletal, infectious, autoimmune, and malignant diseases. Wu and He [20] found that 80% of patients who were admitted to the neurological rehabilitation unit immediately after an acute stroke incident had low serum vitamin D levels. Also, Manson et al [21] reported that 75% of patients hospitalized for ischemic stroke had vitamin D levels <20 ng/ml. We believe that the lower percentage of counts in our study may be dictated by the small group size (80 subjects).

In our study, serum vitamin D levels were assessed in patients with first-ever ischemic stroke on admission to a rehabilitation unit. Vitamin D deficiency was defined as plasma 25(OH)D levels <30 ng/ml. In the study group, it was found that 67.5% of patients (54 patients) had vitamin D3 deficiency. Functional outcomes were assessed using the BI and mRS. The BI is a standard scale that is used for measuring performance in daily activities (DAs). It measures 10 basic aspects of self-care and dependence in DAs. The normal score is 20 and lower scores indicate increasing disability. The BI score >12 corresponds to assisted independence in DAs and BI <8 corresponds to severe dependence in DAs.

mRS scores of 0–2 are defined as no symptoms up to minimal disability and are equivalent to a good outcome, while scores of 3–6 indicate moderate to severe disability or death and are equivalent to a poor outcome [22].

Markišić et al [23], while conducting a non-interventional prospective clinical study of 50 patients with first-ever ischemic stroke, assessed the relationship between early functional outcomes of acute ischemic stroke and serum vitamin D levels in patients undergoing rehabilitation. The study group of 50 patients was slightly older (mean age 71.9±11.3 years and ranged from 45 to 90 years) compared to that in this project. It should be noted that in the elderly (aged over 60 years), vitamin D levels gradually decrease due to the reduced ability of the skin to synthesize vitamin D in old age.

In the present study the mean age of participants was 61.8±6.9 and ranged from 36 to 72 years. The sex distribution was also slightly different. In the group studied by Markišić et al [23], women predominated, with 28 women (56%) and 22 men (44%). In the present study, men predominated, with 55 men (68.7%) and 25 women (31.3%). For functional assessment, we used BI and mRS. Markišić et al [23] conducted the functional assessment at 3 time points: on admission and 3 and 6 months after stroke. On admission, the NIHSS was negatively correlated with vitamin D levels, which may indicate a relationship between neurological deficits and lower vitamin D levels, while the researchers did not detect a correlation between vitamin D levels and BI and mRS scores at both time points after adjusting for age and initial stroke severity.

The above results can be applied to the present results, as our clinical observations have shown that rehabilitation treatment for this group of patients is very important, resulting in significant functional improvement. After therapy, there was a statistically significant increase in BI scores (median difference of 2.0 points; P<0.001) and a statistically significant decreases in mRS scores (median difference of 7.0 points; P<0.001). Similar ro the study by Markišić et al [23], no significant differences in vitamin D levels were found in this study (P=0.40).

The linear regression analysis in a univariate model assessed the impact of selected variables on activities of daily living (BI) and disability (mRS). It was revealed that the older the person (B=−0.01, P=0.04), the worse the ability to perform activities of daily living (ADLs). In contrast, higher levels of vitamin D improved ADLs. It was also found that the higher the BMI (B=0.07, P=0.02) the lower the independence in DAs.

Similarly, Alfieri et al [8], who studied 168 patients with acute ischemic stroke, observed that lower 25(OH)D levels were negatively correlated with disability score as measured by mRS after 3 months of follow-up regardless of age, sex, and neurological deficits. Daubail et al [24] found that their patients with vitamin D deficiency with values of 25(OH)D <25.7 nmol/l had a worse functional prognosis compared to post-stroke patients with serum vitamin D levels of 25(OH)D >25.7 nmol/l.

Also, Zhang et al [25] investigated the relationship between vitamin D levels and clinical severity, as well as outcome at 3 months in post-stroke patients. Vitamin D concentration levels were measured at the beginning of the study. Patients’ clinical status after ischemic stroke was assessed at admission using the NIHSS scale. Functional outcome was assessed 3 months after the onset of the disease using the modified Rankin scale (mRS) (like our study, the authors used the same scales). The study group included 377 patients. They performed multivariate analyses using logistic regression models. They showed that vitamin D deficiency was not associated with NIHSS risk at admission in all patients. In contrast, patients without hypertension had significantly higher vitamin D levels. Patients with lower vitamin D levels had higher NIHSS scores at admission and at 3 months mRS compared to those with vitamin D levels ≥50 nmol/l. The odds ratio (95% confidence interval) was 5.51 (1.83–16.60) and 4.63 (1.53–14.05) in the multivariate-adjusted model (P for linear trend <0.05). The authors concluded that low serum vitamin D level was an independent predictor of functional outcomes in non-hypertensive ischemic stroke patients.

In contrast, Wei and Kuang [26] concluded that vitamin D levels below 20 ng/ml contribute to a 3.2-fold increased risk of poor functional outcome in post-ischemic stroke patients without diabetes assessed at 1-year follow-up after a stroke incident.

Li et al [27], similar to our study, analyzed the relationship between vitamin D levels in patients after cerebral stroke and functional outcomes of patients undergoing rehabilitation. Sixty-nine men and 31 women aged 32–82 years (mean age 54.75 ± 10.61) participated in the study. After 30 days of rehabilitation, they the effectiveness of rehabilitation was significantly positively correlated with serum vitamin D levels (r=0.562, P<0.003) and significantly negatively correlated with BMI (r=−0.347, P<0.05). Regarding the effectiveness of rehabilitation after the multivariate logistic regression analysis, Li et al [27] found that disease duration and NIHSS score were independent risk factors for the effectiveness of rehabilitation treatment (P<0.05), and vitamin D levels were a protective factor (P<0.05).

Park et al [28] also assessed whether baseline serum vitamin D levels affect functional outcome in patients with acute ischemic stroke. They used mRS and the relationship between baseline vitamin D levels and good functional outcome (mRS 0–2) after 3 months was analyzed using multiple logistic regression models. The study included 818 patients. The mean age was 66.2 (±12.9) years and 40.5% of the participants were women. The mean vitamin D level was 47.2±31.7 nmol/l, and the majority of patients had vitamin D deficiency status (<50 nmol/l; 68.8%), while the optimal vitamin D level (≥75 nmol/l) was present in only 13.6% of patients, and 436 (53.3%) patients showed a good functional outcome after 3 months. Serum vitamin D levels in patients with good results were significantly higher than in those with poor results (50.2±32.7 vs 43.9±30.0 nmol/l, P=0.007). The researchers found that serum vitamin D levels were an independent predictor of functional outcome in patients with acute ischemic stroke. They highlighted the need for further research to determine whether vitamin D supplementation can improve functional outcomes in patients with ischemic stroke.

Turetsky et al [29] investigated whether vitamin D was an independent predictor of cerebral infarct volume and poor outcome after 90 days (assessed by mRS >2) using multivariate linear and logistic regression analyses, finding that the risk of poor functional outcome (mRS >2) doubled with each 10-ng/ml reduction in serum 25(OH)D levels. They concluded that low serum vitamin D levels were independently associated with higher ischemic infarct volume, resulting in poorer functional outcomes for patients with vitamin D deficiency. Vitamin D deficiency in patients may increase susceptibility to brain ischemia and a tendency towards larger infarcts. As in this project, age was significantly correlated with serum vitamin D levels (r=0.398, P<0.01).

Siniscalchi et al [30] in their review highlighted the roles of vitamin D in post-stroke patients. They emphasized that low vitamin D levels are primarily associated with stroke of ischemic rather than hemorrhagic etiology. Vitamin D, as a neurosteroid with a neuroprotective role due to the presence of vitamin D receptors in neuronal and glial cells, has been proposed as a prognostic biomarker for functional outcomes in stroke patients. They pointed out that vitamin D deficiency causes changes in the vascular wall, and found no conclusive evidence that vitamin D supplementation in patients will translate into better functional outcomes.

In contrast, Daumas et al [31] evaluated the relationship between vitamin D levels in patients after ischemic stroke treated with thrombolytic therapy and functional outcome 3 months after the ischemic incident. The study group consisted of 325 patients mean age of 68.6±15.8 years, slightly outnumbered by women at 50.7%. Vitamin D levels were measured within 24 hours of hospital admission. On admission and at discharge, patients’ clinical stroke severity was assessed using the NIHSS scale. The mean vitamin D level in the study group was 43.4±24.2 nmol/l, and the median was 37.9 nmol/l (24.2–58.6). Patients with low vitamin D levels had a higher mean NIHSS score at discharge than the functional score assessed by mRS. It was concluded that lower vitamin D concentrations are associated with poorer functional outcomes, emphasizing the need for further research to understand and explain unexplored beneficial phenomena such as promoting neuronal plasticity or preventing early reocclusion.

Vitamin D deficiency causes muscle weakness and muscle pain, especially in post-stroke patients with neurological disorders [32]. Holick [33] emphasizes that normal vitamin D levels affect muscle strength and balance, which contributes to the effectiveness of rehabilitation. Patients with vitamin D deficiency are reported to have reduced muscle strength and balance disorders. This was also confirmed in experimental studies carried out on rats; skeletal muscle atrophy and a decrease in muscle strength were observed in the absence of vitamin D while there was an increase in muscle diameter and strength gain after adequate vitamin D supplementation [34].

In a systematic review, Antoniak and Greig [35] found that the combination of rehabilitation exercises with vitamin D supplementation affects muscle strength by contributing to improved functional outcomes in patients. On the other hand, a randomized clinical trial by Momosaki et al [36] found that daily supplementation with 2000 IU of vitamin D3 in post-acute stroke patients applied for 8 weeks did no significantly improve BI scores in relation to the ability to perform DAs.

As Murphy and Corbett [37] stated, current concepts of biological recovery after stroke suggest a narrow window of opportunity to stimulate plasticity and repair of brain function, so early vitamin D supplementation may make an important contribution to the recovery in these patients, which requires further research.

As stroke is the leading cause of disability and the elderly have often severe vitamin D deficiencies, studies evaluating the effectiveness of vitamin D supplementation should be extended. The results presented above include much interesting and relevant information, which has cognitive and practical relevance for rehabilitation planning in post-ischemic stroke patients in the period of recovery and compensation, but further research is needed for the implementation of this knowledge in clinical practice.

Study Limitations

Firstly, a limitation of this study was that the trial was not randomized and it took place at a single center. In the future, it would be advisable to conduct a multicenter study for validation in other cohorts. We cannot directly relate our results to the above studies due to the fact that our study group included only patients after ischemic stroke but not treated with thrombolytic therapy. Future studies, which we plan to expand to a larger patient population, should take this aspect into account. Furthermore, there was no way to exclude errors related to variables that were not measurable in this observational study, such as sun exposure, diet, physical activity, or parathormone levels. No in-depth analysis of nutritional status was carried out and no information on nutritional conditions was collected. Future research should consider whether vitamin D supplementation in patients undergoing rehabilitation improves functional outcomes in ischemic stroke patients. The BI and mRS tools used are recommended for functional assessment and have high inter-rater reliability. Nevertheless, there is no mandatory definition of a good score, and it is the researcher who sets the standards that determine the score. Neither scale takes into account the patient’s mental state, and anxiety or post-stroke depression can affect a patient’s functioning and quality of life. Future studies should also use other objective measurement methods that take into account all aspects of life, both physical and mental.

Conclusions

In conclusion, lower serum vitamin D levels and older age may be associated with worse functional outcome in first-ever ischemic stroke patients. It is urgent to evaluate in a prospective, randomized trial with a placebo group whether vitamin D supplementation in appropriate doses can improve prognosis and functional outcomes in first-ever ischemic stroke patients undergoing rehabilitation treatment.