Diabetic and non diabetic subjects with
Nutrition, Metabolism & Cardiovascular Diseases (2008) 18, 152e157
www.elsevier.com/locate/nmcd
Diabetic and non-diabetic subjects with
ischemic stroke: Differences, subtype
distribution and outcome
Antonino Tuttolomondo a,*, Antonio Pinto a, Giuseppe Salemi b,
Domenico Di Raimondo a, Riccardo Di Sciacca a,
Paola Fernandez a, Paolo Ragonese b, Giovanni Savettieri b,
Giuseppe Licata a
a
Biomedical Department of Internal and Specialistic Medicine, University of Palermo,
P.zza delle Cliniche n.2, 90127 Palermo, Italy
b
Neurology Department, University of Palermo, Palermo, Italy
Received 28 July 2006; received in revised form 17 January 2007
KEYWORDS
Ischemic stroke;
Diabetes mellitus;
TOAST classification;
Scandinavian Stroke
Scale
Abstract Background and aim: Diabetes mellitus increases the risk of stroke, and
pathophysiological changes of diabetic cerebral vessels may differ in comparison
with non-diabetic ones; nonetheless, the clinical and prognostic profile of stroke
in diabetic patients is not yet fully understood. On this basis, the aim of our study
was to evaluate cerebrovascular risk factor prevalence in diabetic stroke patients
in comparison with non-diabetics, to analyze whether diabetics have a different
prevalence of stroke subtypes as classified by the TOAST classification, and determine whether diabetics and non-diabetics have a different prognosis.
Methods and results: We enrolled 102 diabetics and 204 non-diabetic subjects with
acute ischemic stroke, matched by sex and age ( 3 years). We used as outcome
indicators the Scandinavian Stroke Scale (SSS) score at admission and the modified
Rankin disability scale at discharge and at a 6-month follow-up. We classified ischemic stroke according to the TOAST classification.
Diabetes was associated with lacunar ischemic stroke subtype, with a record of
hypertension, and with a better SSS score at admission. The association of diabetes
* Corresponding author. Tel.: þ39 091 655 2128; fax: þ39 091 655 2285.
E-mail address: pinto@neomedia.it (A. Tuttolomondo).
0939-4753/$ - see front matter ª 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.numecd.2007.02.003
Diabetes and ischemic stroke: A comparison study
153
with lacunar stroke remained significant even after adjustment for hypertension or
for large artery atherosclerotic and cardioembolic stroke subtypes.
Conclusion: Our study shows some significant differences in acute ischemic stroke
among diabetics in comparison with non-diabetics (higher frequency of hypertension, higher prevalence of lacunar stroke subtype, lower neurological deficit at
admission in diabetics).
ª 2007 Elsevier B.V. All rights reserved.
Introduction
Methods
Diabetes mellitus (DM) is a well-established
independent risk factor for ischemic stroke (IS)
[1e3]. The Framingham Study [4] found a 2.5-fold
incidence of ischemic stroke in diabetic men and
a 3.6-fold one in diabetic women. In the largest
case control study with adjustment for multiple
known risk factors [5], the risk of stroke for diabetic individuals increased by 2.3. Two other large
studies [6,7] reported similar findings with odds
ratios (OR) of 2.12 and 2.47. However, it is difficult to determine the level of association between DM and IS, as DM is also associated with
a twofold higher incidence of hypertension and
cardiac disease and with an increased incidence
of asymptomatic carotid artery disease and hyperlipidemia [8], all strong independent risk factors
for IS.
Other studies [8e11] have established that the
association between DM and stroke is related to
the pathologic changes observed in brain vessels.
As diabetic angiopathy is presumed to differ
from atherosclerotic angiopathy, strokes experienced by diabetic vs. non-diabetic individuals
may also differ. However, data on stroke type,
topography, and outcome in diabetic persons conflict [10,11]. Moreover, most studies did not assess
the interaction between DM and hypertension and
the distinct clinical impact of cerebral diabetic
angiopathy.
We therefore addressed the hypothesis that
ischemic stroke of diabetic patients could differ
from stroke in non-diabetic ones and on this basis
the aim of this study was:
Case findings
1. to evaluate cerebrovascular risk factor prevalence in diabetic stroke patients in comparison
with non-diabetics;
2. to analyze if diabetics have a different prevalence of stroke subtypes as classified by the
TOAST group classification [12]; and
3. to determine if diabetics and non-diabetics
have different severity at onset of the stroke,
and functional outcome at discharge, and on
a 6-month follow-up.
Our cases were consecutive diabetic patients diagnosed with acute ischemic stroke admitted to
the Department of Internal Medicine of Policlinico
Universitario ‘‘P. Giaccone’’, Palermo, Italy, in the
period 1998e2004.
Patients were defined as type 2 diabetics if they
had known diabetes treated by diet, oral hypoglycemic drugs or insulin before stroke (see Risk
factors assessment). We excluded patients with
stress hyperglycemia and new-onset diabetes because we intended to analyze only chronic hyperglycemia effects on stroke subtype prevalence and
clinical outcome. Stroke was defined as a clinical
syndrome of rapidly developing symptoms or signs
of focal loss of cerebral function with symptoms
which had lasted more than 24 h and had no apparent cause other than vascular origin [13]. Brain CT
findings excluded primary intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage. Diabetic stroke patients were
matched with non-diabetic patients with acute
ischemic stroke admitted to the Department of Internal Medicine of the University of Palermo with
a diagnosis of acute ischemic stroke; two controls
were matched to each case by sex and age
(3 years).
The study was approved by the local ethics
committee; the patients, or, when not possible,
a family member, gave informed consent. All the
procedures followed were in accordance with
Italian guidelines.
Clinical protocol and TOAST classification
of ischemic stroke
A standard clinical and neurological history, blood
tests, neurological examination, neurological deficit score according to the Scandinavian Stroke
Scale (SSS) on admission, and disability degree at
discharge and after a 6-month follow-up on the
Rankin disability scale were obtained for both
154
cases and controls. The SSS was used to assess
neurological deficit of the acute phase of stroke,
through an evaluation of consciousness level, eye
movement, strength in arms, hand, and legs,
orientation, language, facial weakness, and gait,
giving rise to a score ranging from 58 (absence of
deficit) to 0 (severely impaired). According to the
modified Rankin disability score the functional
ability and functional outcome after stroke were
graded by a score ranging from 1 (no significant
disability, able to perform all usual activities of
everyday life) to 6 (death). SSS and Rankin score
were assessed by an experienced neurologist and
by four internists that received specific training.
Intrahospital mortality was ascertained. At followup the modified Rankin score was ascertained by
the same staff in a outpatient modality.
Both diabetic and non-diabetic patients with
ischemic stroke underwent the following diagnostic
instrumental evaluations at admission: electrocardiography, 24-h electrocardiography monitoring,
transthoracic echocardiography, carotid ultrasound, and brain computed tomography in baseline
conditions and after 48e72 h. The type of acute
ischemic stroke was classified according to the
TOAST classification in one of the following five
sub-groups: (1) large artery atherosclerosis (LAAS);
(2) cardio-embolic infarct (CEI); (3) Lacunar infarct (LAC); (4) stroke of other determined etiology (ODE); (5) stroke of undetermined etiology
(UDE) [12].
Risk factors assessment
Type 2 diabetes was determined on the basis of
clinical records and by using a clinically based
algorithm that considered age at onset, presenting
weight and symptoms, family history, onset of
insulin treatment, and history of ketoacidosis.
Hypertension was defined according to older World
Health Organization criteria (systolic 160 and/or
diastolic 95 mmHg or on antihypertensive treatment on admission) [14].
Statistical methods
Both univariate and multivariate analysis were
performed using conditional logistic regression
analysis by the SAS package to analyze the association between diabetes and TOAST subtypes of
ischemic stroke, and to evaluate the association
between diabetes and lacunar stroke after correction for other TOAST subtypes and hypertension.
To compare acute neurological deficit between
diabetic and non-diabetic subjects with ischemic
A. Tuttolomondo et al.
stroke, SSS was dichotomized according to the
median value of the pooled distribution in both
groups (diabetic and non-diabetic, median value 33).
The modified Rankin disability scale was dichotomized as 0 (raw score from 0 to 2) and 1 (raw score
from 3 to 6).
Results
We enrolled 102 type 2 diabetes subjects with
acute ischemic stroke and 204 non-diabetic patients with acute ischemic stroke. Diabetics and
non-diabetics were matched by age (3 years) and
sex. Among diabetic subjects, 44 (43%) were
women and 58 (57%) were men; the median age
at inclusion was 66 years (range 49e88 years).
Among non-diabetics 87 (43.1%) were women and
115 (56.9%) were men, and the median age was 67.
In diabetic patients mean glycated hemoglobin
(A1c) level was 7.3 mg/dl, mean diabetes duration was 9.6 years; mean systolic blood pressure
(SBP) was 147.5 mm/Hg; mean diastolic blood
pressure (DBP) was: 92.3 mm/Hg; 43 (42.1%) had
a previous diagnosis of retinopathy (background
or proliferative), 29 (28.4%) had a CAD (coronary
artery disease), 33 (32.3%) had a PAD (peripheral
artery disease) and 29 (28.4%) had a diabetic
nephropathy.
In non-diabetic patients mean systolic blood
pressure (SBP) was 146.4 mm/Hg; mean diastolic
blood pressure (DBP) was 94.5 mm/Hg; 51 (25%)
had a CAD (coronary artery disease), 62 (30.3%)
had a PAD (peripheral artery disease).
Age and sex distribution, by means of matching
procedure, was similar for patients and controls
and also similar was the distribution of each type
of previous pharmacological treatment (antihypertensive treatment, statins, antiplatelet treatment)
and in particular no difference was ascertained
between diabetics and non-diabetics with regard
to treatment with ACE inhibitors or angiotensin
receptor blocker (see Table 1).
We evaluated prevalence of risk factors for
stroke (hypertension, hypercholesterolemia, previous transient ischemic attack or stroke) and of
each TOAST subtype of ischemic stroke (LAAS, CEI,
LAC, ODE, UDE). We also analyzed the association
between diabetes and some outcome indicators
such as the SSS score and Rankin score at discharge
and at a 6-month follow-up.
Table 1 shows the frequency of each variable and
the results of univariate conditional logistic regression analyses. Diabetes clearly appears to be
associated with LAC ischemic stroke subtype
(OR 3.89, 95% confidence interval (CI) 2.23e6.80),
Diabetes and ischemic stroke: A comparison study
Table 1
155
General characteristics of diabetic and non-diabetic stroke patients and univariate analysis
Variables
Exposure frequency
Males, n (%)
Female, n (%)
Age (median)
LAAS, n (%)
CEI, n (%)
Lacunar, n (%)
ODE, n (%)
UDE, n (%)
SSS at admission
(>34 vs.
www.elsevier.com/locate/nmcd
Diabetic and non-diabetic subjects with
ischemic stroke: Differences, subtype
distribution and outcome
Antonino Tuttolomondo a,*, Antonio Pinto a, Giuseppe Salemi b,
Domenico Di Raimondo a, Riccardo Di Sciacca a,
Paola Fernandez a, Paolo Ragonese b, Giovanni Savettieri b,
Giuseppe Licata a
a
Biomedical Department of Internal and Specialistic Medicine, University of Palermo,
P.zza delle Cliniche n.2, 90127 Palermo, Italy
b
Neurology Department, University of Palermo, Palermo, Italy
Received 28 July 2006; received in revised form 17 January 2007
KEYWORDS
Ischemic stroke;
Diabetes mellitus;
TOAST classification;
Scandinavian Stroke
Scale
Abstract Background and aim: Diabetes mellitus increases the risk of stroke, and
pathophysiological changes of diabetic cerebral vessels may differ in comparison
with non-diabetic ones; nonetheless, the clinical and prognostic profile of stroke
in diabetic patients is not yet fully understood. On this basis, the aim of our study
was to evaluate cerebrovascular risk factor prevalence in diabetic stroke patients
in comparison with non-diabetics, to analyze whether diabetics have a different
prevalence of stroke subtypes as classified by the TOAST classification, and determine whether diabetics and non-diabetics have a different prognosis.
Methods and results: We enrolled 102 diabetics and 204 non-diabetic subjects with
acute ischemic stroke, matched by sex and age ( 3 years). We used as outcome
indicators the Scandinavian Stroke Scale (SSS) score at admission and the modified
Rankin disability scale at discharge and at a 6-month follow-up. We classified ischemic stroke according to the TOAST classification.
Diabetes was associated with lacunar ischemic stroke subtype, with a record of
hypertension, and with a better SSS score at admission. The association of diabetes
* Corresponding author. Tel.: þ39 091 655 2128; fax: þ39 091 655 2285.
E-mail address: pinto@neomedia.it (A. Tuttolomondo).
0939-4753/$ - see front matter ª 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.numecd.2007.02.003
Diabetes and ischemic stroke: A comparison study
153
with lacunar stroke remained significant even after adjustment for hypertension or
for large artery atherosclerotic and cardioembolic stroke subtypes.
Conclusion: Our study shows some significant differences in acute ischemic stroke
among diabetics in comparison with non-diabetics (higher frequency of hypertension, higher prevalence of lacunar stroke subtype, lower neurological deficit at
admission in diabetics).
ª 2007 Elsevier B.V. All rights reserved.
Introduction
Methods
Diabetes mellitus (DM) is a well-established
independent risk factor for ischemic stroke (IS)
[1e3]. The Framingham Study [4] found a 2.5-fold
incidence of ischemic stroke in diabetic men and
a 3.6-fold one in diabetic women. In the largest
case control study with adjustment for multiple
known risk factors [5], the risk of stroke for diabetic individuals increased by 2.3. Two other large
studies [6,7] reported similar findings with odds
ratios (OR) of 2.12 and 2.47. However, it is difficult to determine the level of association between DM and IS, as DM is also associated with
a twofold higher incidence of hypertension and
cardiac disease and with an increased incidence
of asymptomatic carotid artery disease and hyperlipidemia [8], all strong independent risk factors
for IS.
Other studies [8e11] have established that the
association between DM and stroke is related to
the pathologic changes observed in brain vessels.
As diabetic angiopathy is presumed to differ
from atherosclerotic angiopathy, strokes experienced by diabetic vs. non-diabetic individuals
may also differ. However, data on stroke type,
topography, and outcome in diabetic persons conflict [10,11]. Moreover, most studies did not assess
the interaction between DM and hypertension and
the distinct clinical impact of cerebral diabetic
angiopathy.
We therefore addressed the hypothesis that
ischemic stroke of diabetic patients could differ
from stroke in non-diabetic ones and on this basis
the aim of this study was:
Case findings
1. to evaluate cerebrovascular risk factor prevalence in diabetic stroke patients in comparison
with non-diabetics;
2. to analyze if diabetics have a different prevalence of stroke subtypes as classified by the
TOAST group classification [12]; and
3. to determine if diabetics and non-diabetics
have different severity at onset of the stroke,
and functional outcome at discharge, and on
a 6-month follow-up.
Our cases were consecutive diabetic patients diagnosed with acute ischemic stroke admitted to
the Department of Internal Medicine of Policlinico
Universitario ‘‘P. Giaccone’’, Palermo, Italy, in the
period 1998e2004.
Patients were defined as type 2 diabetics if they
had known diabetes treated by diet, oral hypoglycemic drugs or insulin before stroke (see Risk
factors assessment). We excluded patients with
stress hyperglycemia and new-onset diabetes because we intended to analyze only chronic hyperglycemia effects on stroke subtype prevalence and
clinical outcome. Stroke was defined as a clinical
syndrome of rapidly developing symptoms or signs
of focal loss of cerebral function with symptoms
which had lasted more than 24 h and had no apparent cause other than vascular origin [13]. Brain CT
findings excluded primary intracerebral hemorrhage, intraventricular hemorrhage, and subarachnoid hemorrhage. Diabetic stroke patients were
matched with non-diabetic patients with acute
ischemic stroke admitted to the Department of Internal Medicine of the University of Palermo with
a diagnosis of acute ischemic stroke; two controls
were matched to each case by sex and age
(3 years).
The study was approved by the local ethics
committee; the patients, or, when not possible,
a family member, gave informed consent. All the
procedures followed were in accordance with
Italian guidelines.
Clinical protocol and TOAST classification
of ischemic stroke
A standard clinical and neurological history, blood
tests, neurological examination, neurological deficit score according to the Scandinavian Stroke
Scale (SSS) on admission, and disability degree at
discharge and after a 6-month follow-up on the
Rankin disability scale were obtained for both
154
cases and controls. The SSS was used to assess
neurological deficit of the acute phase of stroke,
through an evaluation of consciousness level, eye
movement, strength in arms, hand, and legs,
orientation, language, facial weakness, and gait,
giving rise to a score ranging from 58 (absence of
deficit) to 0 (severely impaired). According to the
modified Rankin disability score the functional
ability and functional outcome after stroke were
graded by a score ranging from 1 (no significant
disability, able to perform all usual activities of
everyday life) to 6 (death). SSS and Rankin score
were assessed by an experienced neurologist and
by four internists that received specific training.
Intrahospital mortality was ascertained. At followup the modified Rankin score was ascertained by
the same staff in a outpatient modality.
Both diabetic and non-diabetic patients with
ischemic stroke underwent the following diagnostic
instrumental evaluations at admission: electrocardiography, 24-h electrocardiography monitoring,
transthoracic echocardiography, carotid ultrasound, and brain computed tomography in baseline
conditions and after 48e72 h. The type of acute
ischemic stroke was classified according to the
TOAST classification in one of the following five
sub-groups: (1) large artery atherosclerosis (LAAS);
(2) cardio-embolic infarct (CEI); (3) Lacunar infarct (LAC); (4) stroke of other determined etiology (ODE); (5) stroke of undetermined etiology
(UDE) [12].
Risk factors assessment
Type 2 diabetes was determined on the basis of
clinical records and by using a clinically based
algorithm that considered age at onset, presenting
weight and symptoms, family history, onset of
insulin treatment, and history of ketoacidosis.
Hypertension was defined according to older World
Health Organization criteria (systolic 160 and/or
diastolic 95 mmHg or on antihypertensive treatment on admission) [14].
Statistical methods
Both univariate and multivariate analysis were
performed using conditional logistic regression
analysis by the SAS package to analyze the association between diabetes and TOAST subtypes of
ischemic stroke, and to evaluate the association
between diabetes and lacunar stroke after correction for other TOAST subtypes and hypertension.
To compare acute neurological deficit between
diabetic and non-diabetic subjects with ischemic
A. Tuttolomondo et al.
stroke, SSS was dichotomized according to the
median value of the pooled distribution in both
groups (diabetic and non-diabetic, median value 33).
The modified Rankin disability scale was dichotomized as 0 (raw score from 0 to 2) and 1 (raw score
from 3 to 6).
Results
We enrolled 102 type 2 diabetes subjects with
acute ischemic stroke and 204 non-diabetic patients with acute ischemic stroke. Diabetics and
non-diabetics were matched by age (3 years) and
sex. Among diabetic subjects, 44 (43%) were
women and 58 (57%) were men; the median age
at inclusion was 66 years (range 49e88 years).
Among non-diabetics 87 (43.1%) were women and
115 (56.9%) were men, and the median age was 67.
In diabetic patients mean glycated hemoglobin
(A1c) level was 7.3 mg/dl, mean diabetes duration was 9.6 years; mean systolic blood pressure
(SBP) was 147.5 mm/Hg; mean diastolic blood
pressure (DBP) was: 92.3 mm/Hg; 43 (42.1%) had
a previous diagnosis of retinopathy (background
or proliferative), 29 (28.4%) had a CAD (coronary
artery disease), 33 (32.3%) had a PAD (peripheral
artery disease) and 29 (28.4%) had a diabetic
nephropathy.
In non-diabetic patients mean systolic blood
pressure (SBP) was 146.4 mm/Hg; mean diastolic
blood pressure (DBP) was 94.5 mm/Hg; 51 (25%)
had a CAD (coronary artery disease), 62 (30.3%)
had a PAD (peripheral artery disease).
Age and sex distribution, by means of matching
procedure, was similar for patients and controls
and also similar was the distribution of each type
of previous pharmacological treatment (antihypertensive treatment, statins, antiplatelet treatment)
and in particular no difference was ascertained
between diabetics and non-diabetics with regard
to treatment with ACE inhibitors or angiotensin
receptor blocker (see Table 1).
We evaluated prevalence of risk factors for
stroke (hypertension, hypercholesterolemia, previous transient ischemic attack or stroke) and of
each TOAST subtype of ischemic stroke (LAAS, CEI,
LAC, ODE, UDE). We also analyzed the association
between diabetes and some outcome indicators
such as the SSS score and Rankin score at discharge
and at a 6-month follow-up.
Table 1 shows the frequency of each variable and
the results of univariate conditional logistic regression analyses. Diabetes clearly appears to be
associated with LAC ischemic stroke subtype
(OR 3.89, 95% confidence interval (CI) 2.23e6.80),
Diabetes and ischemic stroke: A comparison study
Table 1
155
General characteristics of diabetic and non-diabetic stroke patients and univariate analysis
Variables
Exposure frequency
Males, n (%)
Female, n (%)
Age (median)
LAAS, n (%)
CEI, n (%)
Lacunar, n (%)
ODE, n (%)
UDE, n (%)
SSS at admission
(>34 vs.