Download Monocyte count is an underlying marker of lacunar subtype of

European Journal of Neurology 2008, 15: 671–676
doi:10.1111/j.1468-1331.2008.02145.x
Monocyte count is an underlying marker of lacunar subtype of hypertensive
small vessel disease
M. Gomis Cortinaa, A. Rodrı́guez Campelloa, J. Jiménez Condea, A. Oisa, A. Voustianioukb,
M. J. Télleza, E. Cuadradoa and J. Roquera
a
Stroke Unit, Neurology Department, Hospital del Mar, Departament de Medicina de la Universitat Autónoma de Barcelona, Barcelona,
Spain; and bNeurology Department, Mount Sinai School of Medicine, New York, NY, USA
Keywords:
deep intracerebral hemorrhage, lacunar infarct,
monocyte count
Received 6 December 2007
Accepted 25 March 2008
Background: In the hypertensive small vessel disease (HSVD), it remains unclear why
some patients develop lacunar infarcts (LIs) whilst others develop deep intracerebral
hemorrhages (dICHs). Inflammation might be related to LI, and leukocyte and
monocyte counts are regarded as an inflammatory marker of ischemic stroke.
Objective: We investigated the relationship between leukocyte and monocyte counts
determined in the first 24 h after stroke onset in HSVD patients. Methods: We
prospectively studied 236 patients with first acute stroke because of HSVD (129 LI and
107 dICH). We analyzed demographic data, vascular risk factors, and white blood cell
count subtypes obtained in the first 24 h after stroke. Results: The multivariate
analysis showed that LI subtype of HSVD was correlated with hyperlipidemia
(P < 0.0001), a higher monocyte count (P = 0.002), and showed a trend with current
smoking (P = 0.051), whereas dICH subtype was correlated with low serum total
cholesterol (P = 0.003), low serum triglycerides (P < 0.0001), and high neutrophil
count (P = 0.050). Conclusions: In patients who developed HSVD-related stroke,
high monocyte count, current smoking, and hyperlipidemia are prothrombotic factors
related to LI, whereas low cholesterol and triglyceride values are related to dICH.
Monocyte count might be an inflammatory risk marker for the occlusion of small
vessels in hypertensive patients.
Introduction
The term hypertensive small vessel disease (HSVD)
includes two distinct entities that occur in the same
structures, lacunar infarcts (LI) and deep intracerebral
hemorrhages (dICH). Fisher [1] distinguished in
autopsies two different underlying vascular pathologies
for small vessel disease (SVD): lipohyalinosis and
microatheromatosis. Lipohyalinosis was present mainly
in patients with small, multiple and asymptomatic
lacunae, and this type of vessel lesion is most commonly
associated with dICH [2–5]. Microatheromatosis was
found mainly in patients with single, large, and symptomatic lacunae, being the second most common cause
of LI.
Hypertension is the major risk factor for LI and
dICH but it fails to account for much of the risk.
Inflammation was shown to play an important role in
lacunar infarctions [6]. Several markers of inflamma-
Correspondence: Meritxell Gomis Cortina, MD, Stroke Unit,
Neurology Department, Hospital del Mar-IMIM, Departament de
Medicina de la Universitat Autónoma de Barcelona, Passeig Marı́tim
25-29, 08003 Barcelona, Spain (tel.: +34 93 248 3234; fax: +34 93 248
3376; e-mail: [email protected]).
2008 The Author(s)
Journal compilation 2008 EFNS
tion, such as leukocyte and monocyte counts, have been
identified as predictors of ischemic stroke [7]. Studies
demonstrate that leukocyte count independently predicts ischemic risk [8–10], mainly in the atheroesclerotic
group. Studies also demonstrated that monocyte count
is a better marker for proinflammatory state in carotid
atherosclerosis than leukocyte count [11–13].
Our aim was to analyze differences between LI and
dICH patients in demographic data, vascular risk factors, and on leukocyte count determined in the first
24 h after the stroke onset. We sought to determine
whether increase in leukocyte or monocyte count might
be related to the development of clinical LI in patients
with acute HSVD stroke.
Methods
Study population
From January 2001 to February 2006, 2193 consecutive
patients with acute stroke were admitted to our hospital
and enrolled in the stroke register. We selected the
consecutive patients with the diagnosis of primary
intracerebral hemorrhages and with the diagnosis of LI.
A total of 284 patients had primary intracerebral
671
672
M. Gomis Cortina et al.
hemorrhages and 166 amongst them had dICH. From
this subgroup of dICH patients, we excluded patients
receiving anticoagulant treatment (n = 13), patients
without hypertension as a risk factor (n = 9), patients
with history of infection or fever the week before stroke
onset (n = 4), patients with large hemorrhages of unclear origin (n = 6), patients with previous ischemic or
hemorrhagic stroke (n = 15). Patients with incomplete
data (n = 12), because they had died during the first
24 h (n = 10) or because blood tests could not be obtained, were also excluded. A total of 443 patients had
LIs, from this LI subgroup we excluded patients without history of hypertension (n = 71), embolic heart
disease (n = 62), carotid atherosclerosis (n = 61),
current anticoagulant treatment (n = 46), patients with
history of infection or fever the week before stroke
onset (n = 5), previous ischemic or hemorrhagic stroke
(n = 54), and patients with incomplete data (n = 15).
Finally, the remaining 236 patients were analyzed: 129
fulfilled the TOAST criteria of LI [14], and 107 had the
diagnosis of dICH.
Classifications and variables
Lacunar infarct was defined according to the TOAST
criteria [14]. The definition for intracerebral hemorrhage (ICH) is adapted from the Classification of
Cerebrovascular Disease III (1989). ICH was defined
as non-traumatic abrupt onset of severe headache, altered level of consciousness, and/or focal neurological
deficit that is associated with a focal collection of
blood within the brain parenchyma as observed on a
head CT scan or at autopsy and is not because of
hemorrhagic conversion of a cerebral infarction. Only
the hemorrhages located at deep zone (involving predominately the basal ganglia, periventricular white
matter or internal capsule) were considered eligible for
the study.
A neurologist examined all patients during the first
24 h after the stroke onset. Standard blood tests, 12lead electrocardiogram (ECG), chest X-ray, ultrasound
studies, and head CT scan were obtained during the
12 h after stroke. Echocardiography, 24-h ECG
(Holter) monitoring, and cerebral angiography were
performed in selected patients.
All patients fulfilled a clinical protocol which included demographic data and the presence of the following vascular risk factors: arterial hypertension
(defined as evidence of at least two blood pressure
measurements >140/90 mmHg recorded on different
days before the stroke onset, a physicianÕs diagnosis, or
use of antihypertensive treatment), diabetes (fasting
serum glucose level ‡7.0 mmol/l, a physicianÕs diagnosis, or use of diabetic medication), hyperlipidemia
(serum cholesterol concentration >12.2 mmol/l or
serum triglyceride concentration >11.1 mmol/l, a
physicianÕs diagnosis, or use of medication), and current smoking status and alcohol overuse (>60 g/day).
Stroke severity was evaluated by the National Institute
Health Stroke Scale (NIHSS) [15] performed at
admission. We also recorded the following basic biological markers obtained at admission: plasma glucose
levels, white blood cell count (WCC) (leukocytes, neutrophils, lymphocytes, and monocytes), hemoglobin,
hematocrit, mean corpuscular volume (MCV), platelet
count, prothrombin, urea, and creatinin. Cholesterol
and triglyceride levels were measured in blood samples
taken from fasting patients 12–48 h after admission. All
patients were evaluated with a minimum of two ECG
procedures.
Statistical analysis
Demographic data, clinical characteristics, and vascular risk factors of LI and dICH patients were compared using t-tests, and chi-square tests, with the
exception of NIHSS scores, where the analysis was
performed using Mann–Whitney rank sum test, as the
data distribution failed the normality requirement. We
have also used t-tests to check correlations between
alcohol overuse and cholesterol and triglyceride values.
Variables with P < 0.15 were included in the multivariate analysis.
A logistic regression model was used to analyze differences between LI and dICH patients after controlling
for potentially confounding variables according to the
results of the initial analysis: age, neutrophil count,
monocyte count, NIHSS, prothrombin, cholesterol level, triglyceride level (independent continuous variables) and male gender, current smoking status,
hyperlipidemia (dichotomous variables). In order to
avoid a colinearity effect between cholesterol and triglyceride values, we chose the variable hyperlipidemia
for our model.
In order to explore the association between monocyte
count and stroke severity, we performed a SpearmanÕs
rho analysis. In all tests, results with probability values
<0.05 were considered statistically significant. Statistical analyses were performed with the SPSS 13.0 software package (SPSS Inc., Chicago, IL, USA).
Ethics
The data for the study were collected from our hospitalÕs prospective clinical protocols, which complied with
the local ethical guidelines, and have been performed in
accordance with the ethical standards laid down in the
1964 Declaration of Helsinki.
2008 The Author(s)
Journal compilation 2008 EFNS European Journal of Neurology 15, 671–676
The role of monocyte count in lacunar stroke
673
Table 1 Demographics, vascular risk factors, and clinical data of patients according to lacunar infarcts or deep intracerebral hemorrhage
(univariate analysis)
Agea (years)
Male gendera (%)
Diabetes mellitus (%)
Hyperlipidemiaa (%)
Current smokinga (%)
Alcohol overuse (%)
NIHSS score
In-hospital death (%)
Cholesterol (mmol/l)
Triglycerides (mmol/l)
Glucose (mmol/l)
Leucocytes (·109/l)
Neutrophilsa (·109/l)
Lymphocytes(·109/l)
Monocytesa (·109/l)
Hemoglobin (mmol/l)
Haematocrit (%)
Platelets (·109)
Prothrombina (%)
Urea (mmol/l)
Creatinin (mmol/l)
Total cases (n = 236)
LI (n = 129)
dICH (n = 107)
P-value (OR; 95% CI)
70.7
135
69
77
63
44
5.0
13.1
11.1
7.4
7.8
9.213
6.224
1.637
0.634
9.2
41.6
218.7
92.6
2.6
0.06
69.8
80
44
62
44
25
4.0
2.3
11.7
8.5
7.9
9.177
5.640
1.722
0.698
9.3
41.8
224.6
94.8
2.5
0.06
71.7
55
25
15
19
19
6.3
26.1
10.4
6
7.7
9.257
6.928
1.534
0.555
9.1
41.5
211.7
89.9
2.7
0.06
0.23
0.10 (0.64; 0.38–1.08)
0.071 (0.58; 0.33–1.04)
0.001 (0.17; 0.92–0.33)
0.005 (0.41; 0.22–0.77)
0.75 (0.89; 0.46–1.73)
0.001
0.001
0.001
0.001
0.73
0.012
0.001
0.14
0.003
0.25
0.28
0.75
0.006
0.10
0.98
(12.5)
(57.2)
(29.2)
(32.6)
(26.6)
(18.6)
(4.4)
(2.7)
(3.6)
(3.7)
(8.716)
(2.833)
(972)
(0.369)
(1.1)
(5)
(75.3)
(13.7)
(1.1)
(0.03)
(12.8)
(62.1)
(34.1)
(48)
(34.1)
(19.3)
(3.6)
(2.7)
(3.9)
(3.3)
(11.328)
(2.309)
(710)
(0.383)
(1.1)
(4.6)
(75.4)
(14.1)
(1.2)
(0.02)
(11.9)
(51.4)
(23.3)
(14)
(17.7)
(17.7)
(4.9)
(2.5)
(2.6)
(4.2)
(3.670)
(3.231)
(1.210)
(0.336)
(1.2)
(5.4)
(74.9)
(12.8)
(1.1)
(0.04)
Values are given as mean (SD). NIHSS, National Institute Health Stroke Scale; LI, lacunar infarcts; dICH, deep intracerebral hemorrhages; OR,
odds ratio.
a
Variables included in the logistic regression.
Results
Baseline characteristics of patients and the results of
univariate analyses are shown in Table 1. Patients with
LI had significantly higher leukocyte and monocyte
counts than patients with dICH. No differences were
found between LI and dICH with regard to age and
gender. Amongst the known vascular risk factors, current smoking and previous history of hyperlipidemia
were more common in patients with LI, whereas no
differences were found for diabetes and alcohol intake.
We checked for correlations between alcohol overuse
and cholesterol and triglyceride values, and there were
no differences between groups: cholesterol was 206.9
(57.1) for alcohol drinkers versus 199.6 (47.1) for nondrinkers (P = 0.38). Triglyceride mean was 134.7
(52.3) for alcohol drinkers versus 133.3 (68.8) for nondrinkers (P = 0.86). In order to explore other indication of alcohol overuse we compared the MCV values
showing that alcoholic patients had higher MCV values
[92.7 (5.1)] than non-drinkers [90.9 (5.5)], P = 0.038.
There were no differences between MCV for dICH,
[91.40 (5.52)] and LI [91.04 (5.38)], P = 0.61.
National Institute Health Stroke Scale and percentage of in-hospital deaths were higher in dICH than in
LI patients. Likewise, dICH patients had lower triglycerides and cholesterol values, higher neutrophil count,
and longer protrombine time.
The logistic regression model with hyperlipidemia
(which includes those patients with high cholesterol
and/or triglyceride values) showed that the following
variables independently distinguished LI from dICH:
current smoking, neutrophil count, monocyte count,
hyperlipidemia, and prothrombin time (Table 2). The
logistic regression model with cholesterol or triglycerides instead of hyperlipidemia showed that cholesterol
(P = 0.003) and triglyceride (P < 0.0001) values were
significantly lower in dICH than in LI.
We explored the association between monocyte count
and stroke severity. The SpearmanÕs correlation coefficient was: )0.077, P = 0.237, so we were unable to find
Table 2 Differences between lacunar and deep intracerebral hemorrhage
Vascular risk factor
P
OR
95% CI
Age
Male gender
Current smoking
Neutrophils
Monocytes
Hyperlipidemia
Prothrombin
NIHSS
0.714
0.705
0.051
0.050
0.002
0.0001
0.031
0.020
0.995
1.145
2.213
1.002
0.999
5.769
0.974
1.119
0.970–1.021
0.568–2.311
0.996–4.914
0.997–1.003
0.998–0.999
2.877–11.811
0.950–0.998
1.017–1.231
Logistic regression model including hyperlipidemia. OR, odds ratio;
NIHSS, National Institute Health Stroke Scale.
2008 The Author(s)
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674
M. Gomis Cortina et al.
any correlation between monocyte count and stroke
severity.
Discussion
The main finding in this study is that monocyte count
determined in the first 24 h after acute stroke is higher
in LI than in dICH patients. The monocyte count has a
predictive role independent from smoking. Previous
studies [16,17] reported that the monocyte count rise
appears between 3 and 7 days after the stroke onset, so
the monocyte count difference we found may be more
related to the pre-stroke inflammatory status rather
than as a consequence of stroke. Neutrophils have been
in evidence from day 1 after stroke, and appear to be
most numerous on days 2 and 3 following the clinical
onset [16,17]. It is probable that the relationship between the neutrophil count and dICH represents a
marker for injury. In addition, we found that atherothrombotic-related factors such as the current smoking
status and hyperlipidemia are related to LI, whilst low
blood levels of cholesterol and triglycerides are related
to dICH. Despite the fact that elevated monocyte count
could be a reflection of the severity of the stroke, we
were unable to find any correlation between the
variables.
Amongst the non-traditional risk factors, only blood
WCC is related to lacunar stroke [18]. Previous studies
demonstrated that leukocyte count predicts ischemic
risk for first cerebral infarction [8] as well as for
recurrent ischemic events [9]. Relative elevation in
baseline leukocyte count predicts first cerebral infarction, mainly not only in atherosclerotic subtype, but
also in cardioembolic and cryptogenic stroke subtypes.
The leukocyte count elevation is not clearly associated
with the lacunar stroke. These findings are consistent
with the hypothesis that leukocyte count, as a surrogate
for inflammation, is primarily associated with atherosclerosis. Grau et al. [9] demonstrated that leukocyte
count is a predictor of ischemic recurrent attacks, and
specifically showed the neutrophil count to be the most
important predictor of recurrent events, whilst that of
monocytes plays a smaller role. Neutrophils are not an
important factor in atherogenesis, so it is possible that
atherogenesis causes an inflammatory response and the
high leukocyte count serves only as a risk marker for
the atherosclerotic process [8]. So, the mechanisms
which link leukocyte counts to cardiovascular risks are
insufficiently understood. Cellular inflammation and
especially monocytes/macrophages ratio play an
important role in atherogenesis [19]. Monocyte count is
an independent inflammatory risk marker for subclinical carotid atherosclerosis [12] and for plaque
development in subjects without pre-existing carotid
atherosclerosis [13]. Also, the relationship between
preoperative monocyte count and acute neurocognitive
weakens after carotid endarterectomy for asymptomatic stenosis has been established [11]. So, on the basis
of LI hypothesis, we think that the role of monocyte
count in LI is related to the microatheromatosis
mechanism.
Current smoking status is a known etiologic risk
factor for ischemic stroke; we found it to be an independent risk factor that distinguished LI from dICH.
Although the strongest association between ischemic
stroke and current smoking status is with the atherothrombotic group, other studies [20] have also shown a
relationship between smoking and small vessel cerebrovascular disease, specifically in the silent small vessel
stroke.
Cholesterol and triglyceride effects as a risk factor are
different in ischemic and hemorrhagic strokes: whereas
high levels of cholesterol and triglycerides are related to
ischemic stroke [21], low cholesterol serum concentrations can increase the risk of hemorrhagic stroke [22–
26]. We found that hyperlipidemia was related to LI,
whereas blood levels of cholesterol and triglycerides
obtained in the acute phase of stroke distinguish LI
from dICH. A relationship was seen to exist [27] between lipid profile and the severity of hypertension with
the existence of microbleeds in the ICH. Some epidemiologic studies have concluded that low levels of
total cholesterol are a risk factor for ICH [22–26] and
that low levels of cholesterol and triglycerides are predictors of 30 days mortality in patients with supratentorial ICH [28]. As alcohol consumption lowers
cholesterol level and it could be a likely explanation for
the increased risk of bleeding, we have checked for
correlations between alcohol overuse and cholesterol
and triglyceride values, but we did not find differences
between groups. In order to explore other effects of
alcohol overuse we compared the MCV values in LI
and dICH, but we did not find differences.
Labovitz et al. [29], comparing LI and dICH cases
derived from a population-based incidence study,
demonstrated higher cholesterol levels in LI patients
compared with those with dICH, and proposed hypercholesterolemia as a risk factor for symptomatic LI and
microatheromatosis mechanism. Our data indicate that
high monocyte count, hyperlipidemia, and current
smoking are also related to LI and, probably, to the
mechanism of microatheromatosis.
The strength of this study is based on a consecutive
and well documented sample of patients including both
those that required hospitalization and those that did
not.
Our study has limitations, as the study sample was
derived from patients admitted to the hospital on
2008 The Author(s)
Journal compilation 2008 EFNS European Journal of Neurology 15, 671–676
The role of monocyte count in lacunar stroke
account of stroke, we have no information on the
normal counts of leukocyte and their subtypes in our
patients prior to the stroke, but we excluded the patients with history of infection or fever the week before
the stroke onset.
In conclusion, we found that high monocyte count,
current smoking status, and hyperlipidemia mark patients with hypertension as more vulnerable to an
ischemic subtype of HSVD, whilst low levels of cholesterol and triglycerides are related to dICH development. Monocyte count might be an inflammatory risk
marker for the occlusion of small vessels in hypertensive
patients.
Disclosure
11.
12.
13.
14.
15.
The author and all the co-authors report no conflicts of
interest.
16.
Acknowledgement
This study was funded in part by the Ministerio de
Sanidad y Consumo, Instituto de Salud Carlos III (Red
HERACLES RD06/0009), and by the FIS grant number PI 051737.
17.
18.
References
1. Fisher CM. Capsular infarcts: the underlying vascular
lesions. Archives of Neurology 1979; 36: 65–73.
2. Fisher CM. Pathological observations in hypertensive
cerebral hemorrhage. Journal of Neuropathology and
Experimental Neurology 1971; 30: 536–550.
3. Masuda J, Tanaka K, Omae T, Ueda K, Sadoshima S.
Cerebrovascular diseases and their underlying vascular
lesions in Hisayama, Japan – a pathological study of autopsy cases. Stroke 1983; 14: 934–940.
4. Rosenblum WI. Miliary aneurysms and ‘‘fibrinoid’’
degeneration of cerebral blood vessels. Human Pathology
1977; 8: 133–139.
5. Takebayashi S, Kaneko M. Electron microscopic studies
of ruptured arteries in hypertensive intracerebral hemorrhage. Stroke 1983; 14: 28–36.
6. Castellanos M, Castillo J, Garcı́a MM, et al. Inflammation-mediated damage in progressing lacunar infarctions.
Stroke 2002; 33: 982–987.
7. Hankey GJ. Potential new risk factors for ischemic
stroke. What is their potential? Stroke 2006; 37: 2181–
2188.
8. Elkind MSV, Sciacca RR, Boden-Albala B, Rundek T,
Paik MC, Sacco RL. Relative elevation in baseline leukocyte count predicts first cerebral infarction. Neurology
2005; 64: 2121–2125.
9. Grau AJ, Boddy AW, Dukovik DA, et al. for the CAPRIE Investigators. Leukocte count as an independent
predictor of recurrent ischemic events. Stroke 2004; 35:
1147–1152.
10. Ernst E, Hammerschmidt DE, Bagge U, Matrai A,
Dormandy JA. Leukocytes and the risk of ischemic
19.
20.
21.
22.
23.
24.
25.
26.
2008 The Author(s)
Journal compilation 2008 EFNS European Journal of Neurology 15, 671–676
675
diseases. Journal of the American Medical Association
1987; 257: 2318–2324.
Mocco J, Wilson DA, Ducruet AF, et al. Elevations in
preoperative monocyte count predispose to acute neurocognitive decline after carotid endarterectomy for asymtomatic carotid artery stenosis. Stroke 2006; 37: 240–242.
Chapman CM, Beilby JP, McQuillan BM, Thompson PL,
Hung J. Monocyte count, but not C-reactive protein or
interleukin-6, is an independent risk marker for subclinical carotid atherosclerosis. Stroke 2004; 35: 1619–1624.
Johnsen SH, Fosse E, Joakimsen O, et al. Monocyte
count is a predictor of novel plaque formation. A 7-year
follow-up study of 2610 persons without carotid plaque at
baseline. The Tromsø Study. Stroke 2005; 36: 715–719.
Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions
for use in a multicenter clinical trial. TOAST. Trial of Org
10172 in Acute Stroke Treatment. Stroke 1993; 24: 35–41.
Lyden P, Brott T, Tilley B, et al.; for the NINDS t-PA
Stroke Study Group. Improved reliability of the NIH
Stroke Scale using video training. Stroke 1994; 25: 2220–
2226.
Sornas R, Ostlund H, Muller R. Cerebrospinal fluid
cytology after stroke. Archives of Neurology 1972; 26:
489–501.
Price CJS, Warburton EA, Menon DK. Human cellular
inflammation in the pathology of acute cerebral ischemia.
Journal of Neurology, Neurosurgery and Psychiatry 2003;
74: 1476–1484.
Ohira T, Shahar E, Chambless LE, Rosamond WD,
Mosley TH Jr, Folsom AR. Risk factors for ischemic
stroke subtypes: the Atherosclerosis Risk in Communities
study. Stroke 2006; 37: 2493–2498.
Ross R. Atherosclerosis – an inflammatory disease. New
England Journal of Medicine 1999; 340: 115–126.
Eguchi K, Kario K, Hoshide S, et al. Smoking is associated with silent cerebrovascular disease in a high-risk
Japanese community-dwelling population. Hypertension
Research 2004; 27: 747–754.
Tanne D, Koren-Morag N, Graff E, Goldbourt U; for the
BIP study group. Blood lipids and first-ever ischemic
stroke/transient ischemic attack in the Bezafibrate
Infarction Prevention (BIP) Registry. High triglycerides
constitute and independent risk factor. Circulation 2001;
104: 2892–2897.
Yano K, Reed DM, MacLean CJ. Serum cholesterol and
hemorrhagic stroke in the Honolulu Heart Program.
Stroke 1989; 20: 1460–1465.
Giroud M, Creisson E, Fayolle H, et al. Risk factors for
primary cerebral hemorrhage: a population-based study –
the Stroke Registry of Dijon. Neuroepidemiology 1995; 14:
20–26.
Segal AZ, Chiu RI, Eggleston-Sexton PM, Beiser A,
Greenberg SM. Low cholesterol as a risk factor for primary intracerebral hemorrhage: a case–control study.
Neuroepidemiology 1999; 18: 185–193.
Iribarren C, Jacobs DR, Sadler M, Claxton AJ, Sidney S.
Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men?
The Kaiser Permanente Medical Care Program Stroke
1996; 27: 1993–1998.
Shimamoto T, Iso H, Lida M, Komachi Y. Epidemiology
of cerebrovascular disease: stroke epidemic in Japan.
Journal of Epidemiology 1996; 6: S43–S47.
676
M. Gomis Cortina et al.
27. Seung-Hoon L, Hee-Joon B, Byung-Woo Y, Ho K,
Dong-Eog K, Jae-Kyu R. Low concentration of serum
total cholesterol is associated with multifocal signal loss
lesions on gradient-echo magnetic resonance imaging.
Stroke 2002; 33: 2845–2849.
28. Roquer J, Rodriguez Campello A, Gomis M, Ois A,
Munteis E, Bohm P. Serum lipid levels and in-hospital
mortality in patients with intracerebral hemorrhage.
Neurology 2005; 65: 1198–1202.
29. Labovitz DL, Boden-Albala B, Hauser A, Sacco RL.
Lacunar infarct or deep intracerebral hemorrhage. Who
gets which? The Northern Manhattan Study. Neurology
2007; 68: 606–608.
2008 The Author(s)
Journal compilation 2008 EFNS European Journal of Neurology 15, 671–676