INTRODUCTION:

Stroke is one of cerebrovascular diseases that is defined as the emergence of deficits in quick neurological function caused by vascular lesions. Therefore, the definition of stroke is based on clinical circumstances, laboratory studies, and brain imaging, which are used as enforcers or advocates of diagnosis^1,2Stroke is a global health problem³. In the United States, stroke ranks fourth in the causes of death, following heart disease, cancer, and chronic lung disease. About 800,000 new stroke cases occur and 130,000 people die from strokes each year^4,5.

Based on the 2013 basic health research that was conducted in all 33 provinces including 497 districts/cities and 294,959 households in Indonesia, the stroke prevalence was 7.1 per mile, and the prevalence increased to 10.9 per mile in the 2018 research^5,7.

The prevalence was similar in males and females and majority in urban areas. According to age, the prevalence was higher (50.2 per mile) in people aged 75 years and over, followed by people aged 65-74 years (45.3 per mile), and 55-64 years (32.4 per mile)⁷. Based on the Instituefor Health Metrics and Evaluation (IHME) Global Burden of Disease (GBD) study, stroke and ischemic heart disease were the first and the second leading cause of death in Indonesia, both in 2007 and 2017; and included in the top ten causes of disability-adjusted life years (DALYs) in 2017. Whereas, high fasting plasma glucose,high blood pressure, dietary risks and tobacco were risk factors contributing to DALYs in 2017⁸.

There is a strong evidence that stroke has become a treatable disease⁹, and good recovery can be achieved if stroke patient is treated earlier within 60 minutes of treatment onset, the golden hour^10,11. One of several factors that contribute to the completion is the improvement of pre- and intra-hospital system^12,13. The accuracy of stroke treatment has an effect on cognitive function, including nerve production, regrowth of damaged neurons, and capillary formation^14,15. However, such a good health-care system might be difficult to beimplemented in low-resource settings, such as in many parts of Indonesia. This study was aimed to determine the correlation between onset of symptoms of cerebral ischemic until they visited Dr. Ramelan naval hospital, referred to as onset-to-door (OTD) and cognitive function in ischemic stroke patients at Dr.Ramelan naval hospital, Surabaya, Indonesia.

Participant and Methods:

This research was conducted in 31 ischemic stroke patients collected from medical records. The cognitive function was measured using Mini-Mental State Examination (MMSE)¹⁶. The purpose, potential risks and procedure of the study were explained beforehand to the patients who met the inclusion criteria. Confidentially and anonymity were assured in the consent form. This study was approved by the Human Research Ethics Committee of Dr Ramelan Naval Hospital. Data were analyzed using Somer’sd correlation and Mann-Whitney U test.

Study participants were patients with the first occurrence of ischemic strokewho came to emergency room and eventually treated in neurology ward at Dr.Ramelan naval hospital(Figure 1). The diagnosis was made by neurologist, with criteria as the following: sudden onset, focal involvement of the central nervous system, and vascular cause⁴.

Figure 1: Sampling process in patients with Ischemic Stroke

Onset-to-door (OTD) was the period from the first onset of symptoms of ischemic stroke to getting help in the emergency room Dr Ramelan naval hospital, which was divided into two groups: the golden period (onset-to-door ≤ 6 hours) and non-golden period (onset-to-door > 6 hours). The exclusion criteria were patients with cognitive deficits before experiencing ischemic stroke, having disabilities (blind, deaf, mute, and physically disabled) before experiencing the first stroke, cannot speak Indonesian language, and having severe impairment of consciousness and or communication.

Mini-Mental State Examination (MMSE):

The independent variable in this study was OTD, that was obtained through auto anamnesis or heteroanamnesis (from the family or the closest person to the patient who knew the patient's history). The dependent variable in this study was the cognitive function, that was obtained by using Mini-Mental State Examination (MMSE) carried out by researchers. MMSE was initially used to examine cognitive function among the elderly¹³. However, many neurologists use this test as an instrument for examining cognitive function in stroke patients who are hospitalized¹⁷. It is a 30-pointquestionnaire to ascertain cognitive status, including orientation (10 points), registration (three points), attention and calculation (five points),recall (three points), language and praxis (nine points). Responses are scored 0 for incorrect answer and 1 for correct answer. If the response is ambiguous, it is put in the margin and decision is made on its appropriateness. Someone with MMSE total score of 24-30 is interpreted as having no cognitive impairment; 18-23 is having mild cognitive impairment, and 0-17 as havingsevere cognitive impairment¹⁶.

RESULT:

Table 1: The Characteristic of patients with Ischemic Stroke

Gender	Male (%)	Female (%)
	17 (54.8)	14(45.2)
Age
< 40 years	3 (17.6)	2 (14.3)
40-60 years	9 (52.9)	8 (57.1)
> 60 years	5 (29.4)	4 (28.6)
Risk Factor
Hypertension	12 (70.6)	9 (64,3)
Diabetes Mellitus	7 (41,2)	7 (50.0)
Dyslipidemia	9 (52.9)	5 (35.7)
Heart disease	3 (17.6)	2 (14.3)
Pasca Stroke	4 (23.5)	3 (21.4)
Onset-to-Door
Golden Period (≤ 6 hours)	12 (70.6)	9(64.3)
Non golden Period (> 6 hours)	5 (29.4)	5(35.7)
MMSE Score
No Impairment	10(58.8)	4(28.6)
Mild	4(23.5)	3(21.4)
Severe	3 (17.7)	7 (50.0)

MMSE= Mini Mental State Examination

There were 17(54.8%) male patients and 14(45.2%) female patients. n patients, ischemic stroke occurs in males with onset-to-door in golden period, it is found in 12(70.6%) patients and in non-golden period 5(29.4%) patients, and occurs in women with onset-to-door in golden periodwas found in 9(64.3%) patients and in non-golden period 5(35.7%) patients.Fourteen (45.2%) patients did not show cognitive impairment, seven (22.6%) patients showed mild cognitive impairment, and 10(32.3%) patients showed severe cognitive impairment (Table 1).

Table 2: Statistical Crosstab Onset-to-door with Cognitive Function use MMSE

Onset-to-door	MMSE (Cognitive Impairment)			Total	P-Value
Onset-to-door	No Impairment	Mild	Severe	Total	P-Value
≤ 6 hours	13	4	4	21	0.004* (Coeff Correlation = 0.502)
≤ 6 hours	61.90%	19.00%	19.00%	100.00%
> 6 hours	1	3	6	10
> 6 hours	10.00%	30.00%	60.00%	100.00%
Total	14	7	10	31

MMSE = Mini Mental State Examination, P-value = Probability value, Coeff = Coefficient

The 21 ischemic stroke patients in golden period group, there were 13(61.9%) patients with no cognitive impairment, four (19%) patients with mild cognitive impairment, and four (19%) patients with severe cognitive impairment. From ten patients in non-golden period group, there was one (10.0%) patient with no cognitive impairment, three (30.0%) patients with mild cognitive impairment, and six (60.0%) patients with severe cognitive impairment. The Somer’sd correlation test with α = 0.05 showed d = 0.576 and p = 0.001, meaning there was a significant correlation between onset-to-door and cognitive function in ischemic stroke patients. The correlation strength of0.576 indicated a moderate correlation, which also reflected around 42.4% of cognitive function were affected by other variables outside the study (Table 2).

Table 3. Mann-Whitney Correlation between MMSE Point with Onset-to-Door

MMSE	Golden period (≤ 6 hours)	Non-golden period (> 6 hours)	P-Value
	Mean±Std. Deviation
	8.000 ±3.768 2.762 ±0.768 2.191 ±2.205 1.619±1.244 7.524 ±1.887	5.100 ±4.095 2.400 ±1.265 0.800 ±1.619 1.800 ±1.229 5.200 ±1.619
Orientation Registration Attention Remembering Language			0.02* 0.384 0.086 0.692 0.001*

MMSE= Mini Mental State Examination, P-value = Probability value

In table 3, the average scores of cognitive function components were assessed and compared between the golden period and non-golden period groups. For the orientation function, the average score in golden period group was 8.0 and in non-golden period was 5.1. The average registration function in golden period group was 2.8 and in non-golden period was 2.4. The average attention function in golden period group was 2.2 and in non-golden period was 0.8. The average function of recall in golden period group was 1.6 and in non-golden period groupwas 1.8. The average language function in golden period group was 7.5 while in non-golden period group was 5.2. The average function of orientation, registration, attention, and language was found to be higher in the golden period group, while the average recall function was higher in the non-golden period group.Table 3 also indicated there were significant differences regarding orientation (p = 0.020) and language (p = 0.001) functions between golden period and non-golden period groups.

DISCUSSION:

The data results were obtained from 31 respondents. Majority of stroke patients were males. This result was in accordance with a research by Rahman, which stated the 93 samples of ischemic stroke patients he studied, there were 52 (55.9%) male patients and 41 (44.1%) female patients¹⁸.In our study, most ischemic stroke patients had OTD in the golden period. According to research conducted in Sibuhuan Hospital, North Sumatra Province, Indonesia,majority of stroke patients(89.5%) came with OTDin the golden period¹⁷. However, a research conducted in multicenter hospital, Fukuoka City, Japanshowed only 36.1% of patients came with OTD in the golden period¹⁹. This variation might be influenced by several factors, such as the severity of the symptoms, history of stroke or TIA, living or not living alone, knowledge and perception of severity and urgency, time of onset (daytime or evening/ night), transport to hospital, and other factors²⁰.

The majority of patients (45.2%) had no impaired cognitive function, 22.6% of patients had mild cognitive impairment, and 32.3% of patients had severe cognitive impairment. Previous study in Riau Province, Indonesia, found more ischemic stroke patients (78.05%) were hospitalized with impaired cognitive function²⁰. A research conducted in Changsha City, China, found that majority of stroke ischemic patients (58.2%) were cognitively normal and 41.8% of patients had post-stroke cognitive impairment^20,21.Previous research has also explained that impaired cognitive function after stroke can vary depending on demographic data, medical history, clinical manifestations, behavior and lifestyle, dietary habits, social support, as well as public awareness and attitudes towards stroke^14,21.

The analysiswith Somer’sd test showed a significant correlation between OTD of ischemic stroke patients with cognitive function based on MMSE examination (d = 0.576, p = 0.001, α = 0.05),with a moderate strength correlation.A previous research in multicenter hospital, Fukuoka City, Japan, concluded that early hospital arrival within 6 hours after ischemic stroke onset is associated with favorable outcomes, for both neurological improvement (p = 0.001) and good functional outcome (p = 0.001) regardless of the potential indication for reperfusion treatment or the severity of the stroke¹⁹.

The risk of cognitive impairment after stroke is more likely when there are vascular comorbidities such as hypertension, atrial fibrillation, diabetes mellitus, myocardial infarction, and congestive heart failure. The condition and duration of hypertension are the most frequent causes and are important determinants of cognitive impairment after stroke^21,22.Stroke is associated with a two to nine-fold increased risk of cognitive impairment²³. Therefore, adequate primary prevention (any antihypertensive can be effective in reducing risk) and neuroprotective intervention after stroke has a major impact. Secondary prevention recommends the use of a combination of an ACE inhibitor and a diuretic agent. While the combination of aspirin and dipyridamole (relative risk, 0.8) and statins (relative risk 0.9) also showed a reduced risk of cognitive impairment. In patients given a combination of neurotrophic, antihypertensive, antithrombotic, and lipid-lowering drugs showed a protective effect against cognitive impairment (relative risk, 0.55)^24,25.

Moreover, previous study by Matsuo and de Haan indicated if the patient's OTD was more than six hours, the effectiveness of some therapy was lower(12) that led to increased risk of cognitive impairment following stroke²².With a shorter OTD, the time from stroke onset to treatment will also be shorter. First, the benefits of anticoagulants, antiplatelet agents, blood pressure control, and neuroprotective statins are increased. Second, early arrival increases collateral flow or microcirculation and early protection of neurons from ischemia. Third, earlier supportive care and treatment for acute complications will reduce morbidity and mortality after acute ischemic stroke¹⁹.

The cognitive functions examined based on the MMSE consist of several components, including the functions of orientation, registration, attention, recall, and language. In our research, the average score functions of orientation, registration, attention, and language in the golden period groupseemed to be higher than the non-golden period group. However, after the Mann-Whitney U test, the average score of cognitive functions between golden period and non-golden period group were significantly different in orientation function (p = 0.020) and language function (p = 0.001).

A maximum score of the orientation function (10 points) in the golden period group was obtained in 13 (61.9%) patients, while the maximum score in the non-golden period group only was obtained only in two (20%) patients. Meanwhile, the minimum score (0 point) of orientation function in the golden period group was found in three (14.28%) patients, but it was found in three (30%) patients in the non-golden period group. The mean rank of the orientation functionwas significantly higher in golden period than in the non-golden period groups.

A maximum score of the language function (nine points) in the golden period group was obtained ineight patients (38.1%), butthere was not any patients from the non-golden period group achieved a maximum score. The highest score of language function obtained in the non-golden period group was seven, which was achieved by three (30%) patients. The lowest score in the golden period group was two, and it was found in one (4.8%) patient. However, the minimum scoreof language function in the non-golden period group was three, and it was found intwo (20.0%) patients. The mean rank of language function in the golden period was significantly higherin the golden period group than in the non-golden period group.

Thisresearch, the mean rank of registration and attentionfunctionswere higher in the golden period group than in the non-golden period, but the mean rank of recall fundtion was higher in the non-golden period group than in the golden period group. However, these differences were not statistically significant. The focused on the correlation between OTDand cognitive function, that was measured using MMSE. There werelimitations in our study. First, we did not analysearterial lesions. Second, we did not analyse the contribution of life style in our study. In previous study, life style could influence episodic memory function (recall), such as certain drug consumption (anti histamine, antianxiety, analgesics), alcohol consumption, emotional stress, sleep deficiency, nutritional deficiency (vitamin B1 and B12), and marijuana consumption²⁴. Based on Matsuo’s research, OTD with six hours cut off affected clinical function independently from age, sex, stroke severity, and stroke subtype differences, but there was no life style noted. Therefore, life style could possiblyaffected the episodicmemory function. Third, psychiatric factor, such as motivation, might affect data retrieval about recall. Motivated patients might have higher chance to memory retrieval than those who were not motivated²⁶.

CONCLUSION:

Onset-to-door is associated with impaired cognitive function in ischemic stroke patients, especially in orientation and language function.

ACKNOWLEDGMENTS:

We would like to thank all participants.

CONFLICT OF INTEREST:

All authors declare that there is no conflict of interests regarding the publication of this article.

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Received on 08.11.2022 Modified on 22.06.2023

Research J. Pharm. and Tech. 2024; 17(3):1040-1044.

DOI: 10.52711/0974-360X.2024.00161