INTRODUCTION

 

Silent cerebral infarctions (SCIs) are defined as ischemic brain lesions that result from vascular occlusion and lack acute overt stroke-like symptoms. It is found incidentally by magnetic resonance imaging (MRI) or computed tomography (CT) of the brain in healthy subjects or during autopsy.¹ The prevalence of SCIs in healthy elderly has ranged from 5.84% to 28% in different studies using brain MRI as a diagnostic tool.²

It is known that diabetes mellitus (DM) is a potent risk factor for ischemic cerebrovascular strokes.³ The overall relative risk of stroke is 1.5 to 3 times greater in patients with DM.⁴ The presence of DM and accompanying hyperinsulinemia may accelerate the formation of multiple SCIs⁴. Diabetes mellitus cause tissue damage by micro and macro vascular complications and the last is more prevalent in type 2 DM due to state of hyperinsulinemia that precedes revealed hyperglycemia.⁵ This study is trying to clarify the relationship between type 2 DM and SCIs.

MATERIALS AND METHODS

 

Sixty elderly (30 patients and 30 controls) were recruited from the internal medicine outpatient clinic at the Suez Canal University Hospital.

The diabetic group: thirty elderly patients over 60 years old, known   to be suffering type 2 DM.

Non diabetic group: thirty elderly persons over 60 years old, non diabetic, matching age and sex to the diabetic group.

Participants had to be 60 years or older, able to give informed consent, and able to respond to questions without the aid of a surrogate respondent. People with past history of old strokes, with any cardiac illness including atrial fibrillation, or any type of arrhythmias, suffering dementia and those with MRI contraindications were excluded. Each participant gave informed consent. The medical ethics committee of the faculty of medicine, Suez Canal University approved the study.

Clinical information as age, gender, smoking habits, history of diabetes mellitus and duration of diabetes mellitus were collected by a personal interview. Studied subjects were subdivided in two groups according to smoking: current smokers (those who habitually smoke cigarettes and ex- smokers < 5 years) and non smokers (those who do not smoke and ex- smokers > 5 years).⁶ The diagnosis of type 2 diabetes mellitus is based on the presence of one or more of the following:⁷

·          History of a fasting plasma glucose level above 126 mg/dl in a previously performed laboratory investigation.

·          History of chronic hyperglycemia as indicated by an elevated level of HBA1C > 6% in a previously performed laboratory investigation.

·          History of use of any glucose lowering agent as oral antidiabetic agent or insulin therapy.

 

Physical examination included measurement of blood pressure and body mass index. the diagnosis of hypertension is based on the presence of history of persistently elevated blood pressure (systolic ≥140 mm Hg, and/or diastolic ≥ 90 mmHg) in three separate measurements at least one week apart or if the patient reported the use of a blood pressure lowering medication.⁸ Uncontrolled blood pressure is considered when average clinical systolic BP (SBP) ≥ 140 mm Hg and/or average clinical diastolic BP (DBP) ≥ 90 mmHg (average for each patient on > 2 occasions).⁹ Obesity was defined as having a body mass index of >25 kg/m².¹⁰

Laboratory data evaluated in the study included fasting blood glucose, post-prandial blood glucose, hemoglobin Hb A1c, total and differential lipogram.

All subjects included in the study underwent MRI of the brain with a superconducting magnet with a main strength of 1.5 T (Philips achieva R 2.5.3). The MRI images of the subjects were randomly stored and interpreted by radiology consultant blinded to subject names and clinical diagnosis. An SCI is defined as a low-signal-intensity area detected on T1-weighted images that is also visible as a hyper intense lesion on T2-weighted images.⁸ The subjects were divided into 2 groups: those with SCI lesions (the SCI group) and those without any lesions (the non-SCI group).

 

Data Management and Statistical Analysis

Gathered data were processed using SPSS (statistical package for social sciences) version 15. Quantitative data were expressed as means±SD (e.g. age, duration of diabetes mellitus, and age of onset of diabetes mellitus). While, qualitative data were expressed as numbers and percentages (e.g. history of hypertension, blood pressure control, obesity). Unpaired t test was used to test significance of difference between 2 means; while Chi square was used to test significance of difference between qualitative data. Multiple logistic regression was used to assess risk factors for silent cerebral stroke among studied patients. A probability value (P-value) < 0.05 was considered statistically significant; while a probability value (P-value) < 0.01 was considered statistically highly significant.

RESULTS

 

Silent cerebral infarctions were found in 19 diabetic patients out of 30 diabetic patients (63.3%) and in 9 non diabetic subjects out of 30 (30%) (Table 1). In the diabetic group only one diabetic patient (5.3%) had a single SCI and 18 diabetic patients (94.7%) had multiple SCIs; while in the non diabetic group 5 subjects (55.5%) had a single SCI and 4 subjects (44.5%) had multiple SCIs. The difference between the two groups was statistically significant (P<0.05).

The clinical characteristics and the laboratory results of the studied non diabetic group and the diabetic group are shown in tables (2) and (3).

Analysis of the clinical characteristics of the studied subjects showed that SCIs were found more frequently in males (88.9%) than in females (11.1%). Smoking and obesity were significantly more frequent in the SCI group than in the non SCI group (55.6% versus 14.3%, P<0.05). high levels of serum total cholesterol was found in 22.2% of the non diabetic subjects who had SCIs; and was not found in the non diabetic subjects who had no SCIs and the difference between the two groups was statistically significant (P<0.05). There were no significant differences among the SCI group and the non-SCI group regarding history of ischemic heart disease and left ventricular hypertrophy detected on ECG (P>0.05).

Analysis of clinical characteristics of the studied subjects showed that hypertension was found in 78.9% of the diabetic subjects who had SCIs; and in 36.4% of the diabetic subjects who had no SCIs and the difference between the two groups was statistically significant (P<0.05). Poor blood pressure control was found in 86.7% of the diabetic patients suffering chronic hypertension in the SCI group. While diabetic patients suffering chronic hypertension with good blood pressure control all had no SCIs. Obesity was found in 52.6% of the diabetic patients who had SCIs, while in diabetic patients with no SCIs obesity was not found. The difference between the two groups was statistically significant (P<0.05). Young age of onset of diabetes mellitus and long duration of the disease (> 10 years) were associated with increase in risk for the development of SCIs in diabetic subjects.

Fasting plasma glucose and glycated hemoglobin levels were significantly higher in the SCI group than in the non SCI group (P<0.05). Dyslipidemia was found more frequent in the SCI group of the diabetic patients than in the non SCI group. The difference between the two groups was statistically significant (P<0.05). History of ischemic heart disease and left ventricular hypertrophy detected on ECG showed no statistical significant difference between the SCI group and the non SCI group.

Multivariate analysis of the independent risk factors for the development of SCIs showed that obesity, poor blood pressure control in hypertensive patients, dyslipidemia, young age of onset of diabetes mellitus, long duration of the disease and poor glycemic control were significantly associated with SCIs.

Multivariate analysis of risk factors for development of silent cerebral infarctions among diabetic patients are shown in Table (4). An example of a small silent lacunar periventricular infarction is shown in figure (1).

 

Table 1. Incidence of silent cerebral infarctions among non diabetic and diabetic groups.

 

Silent Cerebral Infarction (SCI)	Non diabetic group (n = 30)	Diabetic group (n = 30)	P-value
SCI	9 (30%)	19 (63.3%)	0.01*

Chi square test was used

* Significant at p<0.01

 

Table 2. The clinical characteristics and the laboratory results of the studied non diabetic subjects.

 

		Non diabetic		P-value
		No SCI (n=21)	SCI (n=9)
Age ( Mean ± SD)		65.1± 4.8	66± 4.6	0.6
gender	Male	8 (38.1%)	8 (88.9%)	0.01**
	Female	13 (61.9%)	1 (11.1%)
Smoking		3 (14.3%)	5 (55.6%)	0.03*
BMI  ( > 25 Kg/m2 )		3 (14.3%)	5 (55.6%)	0.02*
History of hypertension		6 (28.6%)	4 (44.4%)	0.4
Uncontrolled blood pressure		0 (0%)	2 (50%)	0.1
Associated ischemic heart disease		3 (14.3%)	1 (11.1%)	0.8
Left ventricular hypertrophy on ECG		6 (28.6%)	4 (44.4%)	0.3
Total cholesterol  ( > 200 )		0 (0%)	2 (22.2%)	0.02*
HDL  ( ≤ 40 )		1 (4.8%)	3 (33.3%)	0.06
LDL  ( > 130 )		1 (4.8%)	1 (11.1%)	0.5
Triglycerides  ( > 150 )		1 (4.8%)	2 (22.2%)	0.2

 SCI silent cerebral infarction

*Significant at p<0.05 ** Significant at p<0.01

Table 3. The clinical characteristics and the laboratory results of the studied diabetic patients.

 

		Diabetic		P-value
		No SCI (n=11)	SCI  (n=19)
Age ( Mean±SD)		64±3.8	64±4.6	0.9
gender	Male	6 (54.5%)	10 (52.6%)	0.9
	Female	5 (45.5%)	9 (47.4%)
Smoking		0 (0%)	6 (31.6%)	0.06
BMI  ( > 25 Kg/m2 )		0 (0%)	10 (52.6%)	0.01**
History of hypertension		4 (36.4%)	15 (78.9%)	0.04*
Uncontrolled blood pressure		0 (0%)	13 (86.7%)	0.003**
Associated ischemic heart disease		0 (0%)	5 (26.3%)	0.1
Left ventricular hypertrophy on ECG		2 (18.2%)	7 (36.8%)	0.4
Age of onset (Mean ± SD)		56.1±3.1	52.6±4.4	0.02*
Duration of disease (Mean ± SD)		7.8±5.3	11.8±4.9	0.04*
Treatment	OHD	5 (45.5%)	11 (57.9%)	0.7
	Insulin	6 (54.5%)	8 (42.1%)
Fasting blood sugar  ( > 126 mg/dl )		2 (28.2%)	12 (63.2%)	0.02*
Postprandial blood sugar  ( > 200 mg/dl )		2 (28.2%)	12 (63.2%)	0.02*
Glycated hemoglobin  ( > 6% )		2 (28.2%)	14 (73.7%)	0.01**
Total cholesterol  ( > 200 )		0 (0%)	9 (47.4%)	0.01**
HDL  ( ≤ 40 )		1 (9.1%)	11 (57.9%)	0.01**
LDL  ( > 130 )		1 (9.1%)	9 (47.4%)	0.04*
Triglycerides  ( > 150 )		1 (9.1%)	10 (52.6%)	0.02*

HDL high density lipoprotein, LDL low density lipoprotein, OHD oral hypoglycemic drugs, SCI silent cerebral infarction, SD standard deviation

*Significant at p<0.05 ** Significant at p<0.01

Table 4. Multivariate analysis of risk factors for development of silent cerebral infarctions among diabetic patients.

 

	Odds ratio	β co-efficient	95% CI	P-value
Smoking	1.01	1.25	0.3 – 9.2	0.2
BMI  ( > 25 Kg/m2 )	1.9	2.31	1.34 – 3.5	0.03*
Age of onset	1.7	-1.89	1.12 – 2.68	0.04*
Duration of disease	1.5	1.37	0.68 – 1.93	0.02*
History of hypertension	1.16	1.29	0.09 – 11.3	0.06
Uncontrolled blood pressure	3.1	-8.2	2.4 – 6.3	0.001**
Fasting blood sugar ( > 126 mg/dl )	2.9	4.59	3.1 – 5.36	0.001**
Postprandial blood sugar ( > 200 mg/dl )	2.81	4.38	2.8 – 6.1	0.003**
Glycated hemoglobin  ( > 6% )	2.85	4.4	2.2 – 4.9	0.002**
Total cholesterol  ( > 200 mg/dl )	3.9	8.1	5.6 – 9.3	0.006**
HDL  ( ≤ 40 mg/dl )	3.21	-6.8	6.1 – 8.2	0.001**
LDL  ( > 130 mg/dl )	3.25	7.3	5.1 – 11.3	0.005**
Triglycerides  ( > 150 mg/dl )	3.3	7.6	4.5 – 8.6	0.004**

BMI body mass index, CI confidence interval, HDL high density lipoprotein, LDL low density lipoprotein

*Significant at p<0.05 ** Significant at p<0.01

 

 

 

Figure 1.  Small silent lacunar periventricular infarction.

 

 

DISCUSSION

 

Silent cerebral infarctions (SCIs) assessed by brain MRI are clinically important pathological conditions relating to the incidence of future stroke event.¹¹ and cerebrovascular dementia.¹² It is known that diabetes mellitus is an independent risk factor for atherogenesis and subsequently vascular ischemic events including cardiac, cerebral and peripheral territories.¹³ In our study we examined the association of diabetes mellitus with silent cerebral infarctions in neurologically asymptomatic elderly patients with type II diabetes mellitus to explore the determinants of these lesions.

The MRI examination demonstrated that prevalence of silent cerebral infarctions in diabetic subjects was 63.3%; which was two times higher than in non diabetic subjects. This goes along with some studies^4,14,15 where the incidence of SCIs in diabetic subjects was 2 to 5 times higher compared with normal subjects.

In non diabetic subjects the correlation between presence of SCI and age of the studied subjects was not statistically significant. This does not go along with the results of previous studies that reported that age is a powerful risk factor for the development of SCIs in the healthy elderly subjects.^2,16 This difference could be attributed to the narrow age range of our study population (60 – 75 years).

Our study revealed higher incidence of silent cerebral infarctions among males over the females matching age and other risk factors in the non diabetic subjects (P<0.05). This goes along with the results of Davis et al.¹⁷, who stated that male gender is a risk factor for the development of SCI. Such a gender difference may be due to differences in reporting and interpreting symptoms of stroke or TIA by both patients and physicians.

The results of our study showed that cigarette smoking, obesity (BMI > 25), and high levels of serum cholesterol represented risk factors for the development of SCI in non diabetic subjects (p<0.05). This is consistent with the results of Vermeer et al.¹³ and Schmidt et al.¹⁸. This could be explained by the vasoconstrictor and the atherogenic effects of cigarette smoking and dyslipidemia.

The presence of SCIs was found more frequently in hypertensive subjects and in subjects with poor blood pressure control however the difference was not statistically significant. This could be explained by the fact that most of subjects in our study populations had good control of blood pressure. This goes along with many studies^16,2 where history of hypertension represent a powerful risk factor for the development of silent cerebral infarctions. This can be explained by the fact that hypertensive small-vessel disease plays a crucial role in the pathogenesis of silent brain infarcts in hypertensive elderly patients.

In the current study, we could not find a significant association between other cardiovascular risk factors namely associated history of ischemic heart disease and presence of left ventricular hypertrophy diagnosed by electrocardiography and the occurrence silent cerebral infarctions in the non diabetic subjects.

In the diabetic patients, SCIs affected males as well as females. This is consistent with the results of Musen et al.¹⁹, who reported that SCIs affects males as well as females in the elderly diabetic subjects. This is explained by the atherogenic effect of diabetes that affects diabetic patients irrespective to their gender.

In diabetic subjects the correlation between cigarette smoking and development of SCIs was not statistically significant. This goes along with the results of Arauz et al.¹⁴. This could be explained by the fact that the cigarette smoking plays the role of an additive risk factor in diabetic patients as the atherogenic effect of hyperglycemia overrides the vasoconstrictor effect of cigarette smoking.

The SCIs were found more frequently in the obese diabetic elderly subjects (BMI > 25) (p<0.05). This goes along with the results of Longstreth et al.²⁰ and Schmidt et al.¹⁸, who reported that obesity is a risk factor for the development of SCIs in the diabetic patients.

In diabetic subjects presence of history of hypertension and poor blood pressure control in hypertensive patients represented risk factors for the occurrence of silent cerebral infarctions. This is consistent with the results of the study of Eguchi et al.²¹, who reported that the coexistence of diabetes mellitus and chronic hypertension predisposes the patients to the highest risk for development of multiple SCIs. It is well known that hypertensive small vessel disease is responsible for the occurrence of lacunar infarctions that may be clinically silent via lipohyalinosis in the deep perforating small blood vessels.

The SCIs were more frequent in diabetic patients with poor glycemic control detected through high levels of fasting and postprandial blood sugar and glycated hemoglobin than in those who enjoy good glycemic control. These results go along with the results of former studies.^21,14 In those studies chronic hyperglycemia [detected through elevated levels of HBA1c (> 6%)] was associated with increased risk for silent cerebral infarctions. This could be explained by the fact that uncontrolled hyperglycemia accelerate atherogenesis, leading to both macrovascular and microvascular complications.

SCIs were also more frequent in subjects with early age of onset of diabetes mellitus and those who have long duration of the disease. This finding is consistent with that of Enzinger et al.²². This could be explained by the fact that micro and macroangiopathic changes occurs in the cerebral blood vessels of the diabetic subjects and the last is more prevalent and inevitable in type II DM where insulin resistance precedes the frank hyperglycemia.⁵

In the diabetic group SCIs were also more frequent in subjects with dyslipidemia (serum total cholesterol > 200 mg/dl, HDL ≤ 40 mg/dl, LDL > 130 mg/dl and triglycerides > 150 mg/dl). This goes along with the results of Longstreth et al.²⁰ and Schmidt et al.¹⁹, who reported that dyslipidemia is a risk factor for the development of SCIs in the diabetic patients

In conclusion, diabetic patients are liable for the development of SCIs. Hypertension, poor blood pressure control, obesity, dyslipidemia, early onset and long duration of diabetes mellitus represent important risk factors for the development of silent cerebral infarctions in the elderly diabetic subjects. Elevated levels of fasting, postprandial blood sugar, and glycated hemoglobin represent the most important determinants for the occurrence of silent cerebral infarctions in diabetic patients.

 

[Disclosure: Authors report no conflict of interest]

 

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