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Brief Rapid Communication

Hyperhomocysteinemia
A Risk Factor for Ischemic Stroke in Children
Ingrid M. van Beynum, MD; Jan A.M. Smeitink, MD, PhD; Martin den Heijer, MD, PhD;
Maria T.W.B. te Poele Pothoff; Henk J. Blom, PhD
BackgroundModerate hyperhomocysteinemia is a risk factor for arterial vascular disease and venous thrombosis in
adults. We performed a case-control study to assess a possible relation between moderate hyperhomocysteinemia and
ischemic stroke in Dutch children (age range, 0 to 18 years).
Methods and ResultsWe measured plasma total homocysteine levels (tHcy) in 45 patients with ischemic stroke and in
234 controls. Hyperhomocysteinemia was defined as a tHcy above the 95th percentile regression line for the respective
age of the controls. Hyperhomocysteinemia was present in 8 (18%) of the 45 patients with ischemic stroke. The odds
ratio was 4.4 (95% CI, 1.7 to 11.6).
ConclusionsWe conclude that moderate hyperhomocysteinemia is a risk factor for ischemic stroke in children.
(Circulation. 1999;99:2070-2072.)
Key Words: hyperhomocysteinemia n cerebral infarction n stroke n pediatrics

erebrovascular disease in childhood is relatively rare.


The incidence for ischemic and hemorrhagic strokes
together is 2.7 cases per 100 000 population per year.1
Despite extensive evaluation, an etiologic factor or associated
conditions remain undetermined in from 20% to 50% of all
stroke patients.2,3 Patients with classic homocystinuria, a rare
inborn error due to cystathionine b-synthase deficiency,
suffer from premature cardiovascular disease and venous
thrombosis at a very young age.4 Over the last 2 decades, it
has become evident that moderate hyperhomocysteinemia is
an independent risk factor for arteriosclerosis, including
stroke,5,6 as well as for venous thrombosis.7 These studies
have all been performed in adults. Whether moderate hyperhomocysteinemia is a risk factor for arterial vascular disease
or venous thrombosis in children is unknown.
We performed a case-control study to assess a possible
association between moderate hyperhomocysteinemia and
ischemic stroke in Dutch children.

Methods
In children with cerebrovascular disease, we analyzed blood samples for
total homocysteine (tHcy) from January 1989 through December 1997.
These samples were collected primarily for tHcy measurement. We
included 45 patients with objectively confirmed episodes of ischemic
stroke (30 boys and 15 girls). The diagnosis of stroke was radiologically
confirmed by CT scan or MRI. If required, MR angiography or single
photon emission computerized tomography (SPECT) was also performed. Hemiparesis was the most common presenting symptom (29
[64%] of 45 children). The medial cerebral artery (26 patients) and basal
ganglia (14 patients) were predominantly affected. The exclusion

criteria were overt liver and renal dysfunction, hormonal therapy,


neoplastic disease, and closure defects such as cleft lip and spina bifida.
Overall, we excluded 2 patients with neoplastic disease and 1 with overt
renal dysfunction. Classic risk factors for vascular disease, such as
smoking, diabetes, and hypertension, were not present in the patients.
Cholesterol was not routinely examined.
The control group, recruited in 1997, consisted of 234 subjects (115
boys and 119 girls). Children of secondary school age served as healthy
volunteers, whereas for ethical reasons, the younger children were
recruited in a hospital setting. Information about medical history was
obtained from medical records or by questionnaire. The same exclusion
criteria were applied for the control group as for the patients.
Blood was drawn by venipuncture, and in the very young, blood
obtained from capillaries was used. tHcy levels were determined in
EDTA plasma by an automated high-performance liquid chromatography method with reverse-phase separation and fluorescent detection.8
Because of a sharp increase in tHcy with age, we calculated a 95th
percentile regression line of tHcy against age. Hyperhomocysteinemia was defined as a concentration that exceeded this 95th percentile
regression line for the respective age. ORs and 95% CIs were
calculated to estimate the relative risk of hyperhomocysteinemia.
ORs were calculated with a logistic regression model. Analyses were
performed with the statistical package SPSS.
The protocol was approved by the local ethics committee.

Results
tHcy values plotted by age of individual patients and controls are
shown in the Figure. tHcy increased sharply with age for both
sexes in patients and the control group. There was no apparent
difference between girls and boys except that in adolescence,
tHcy tended toward higher levels in boys than in girls.
Patients with stroke had a median age at the time of blood
sampling of 1.8 years (range, 0 to 15.7 years), and controls

Received October 9, 1998; revision received February 26, 1999; accepted March 4, 1999.
From University Hospital Nijmegen, The Netherlands, Department of Pediatrics (I.M.v.B., J.A.M.S., M.T.W.B.t.P.P., H.J.B.) and Department of
Internal Medicine (M.d.H.).
Correspondence to Dr Henk J. Blom, Department of Pediatrics, University Hospital Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
E-mail h.blom@ckslkn.azn.nl
1999 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

2070
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van Beynum et al

April 27, 1999

2071

TABLE 1. ORs for Different Age-Corrected Cutoff Points of


Homocysteine Concentrations
Age-Corrected
Homocysteine
Concentration

Cases
(n545)

Controls
(n5234)

Adjusted OR
(95% CI)

10th percentile

41

211

1.1 (0.43.4)

20th percentile

36

188

1.0 (0.41.8)

25th percentile

35

176

1.2 (0.52.5)

30th percentile

34

164

1.3 (0.62.8)

40th percentile

32

140

1.6 (0.83.3)

50th percentile

28

117

1.6 (0.83.0)

60th percentile

24

94

1.7 (0.93.2)

70th percentile

22

70

2.2 (1.24.3)

75th percentile

20

58

2.4 (1.34.7)

80th percentile

18

46

2.7 (1.45.4)

90th percentile

12

23

3.3 (1.57.3)

95th percentile

11

4.4 (1.711.6)

97.5 percentile

5.7 (1.620.7)

present study, 15 children used anticonvulsant drugs for


therapeutic or prophylactic reasons. The OR remained 3.1
(95% CI, 0.9 to 10.5) after exclusion of these 15 subjects.
tHcy concentrations plotted against age for control subjects (A)
and patients with ischemic stroke (B). Linear regression line at
50th percentile, tHcy57.0510.21353age; at 95th percentile,
tHcy511.42910.21353age.

were 8.6 years of age (range, 0 to 19.3 years). Therefore, all


data had to be corrected for age. The highest incidence of
cerebrovascular disease in childhood is predominantly in the
very young, but cerebrovascular disease can occur at any age,
as previously published.2 The median time between onset of
symptoms and homocysteine determination was 0.1 year
(range, 0 to 11.9 years). The median tHcy level was
8.5 mmol/L (range, 5.0 to 77 mmol/L) for the patients and
9.1 mmol/L (range, 4.3 to 20.0 mmol/L) for the controls.
Among the patients with ischemic stroke, 8 (18%) of 45
versus 11 (5%) of 234 in the control group had a tHcy level
above the age-corrected cutoff points of homocysteine concentration. The OR for ischemic stroke was 4.4 (95% CI, 1.7 to
11.6). ORs for different age-corrected cutoff points of tHcy are
shown in Table 1 and demonstrate gradually increasing ORs at
higher cutoff points in the highest quartile. A continuous
dose-response relation seemed to be present above a threshold
tHcy value of '70th percentile of controls. To evaluate a
potential change in risk with increasing age of the child, we
calculated ORs for 3 different age groups, balanced for number
of cases (Table 2). A trend toward an increase in the risk of
ischemic stroke associated with hyperhomocysteinemia in increasingly older age groups is demonstrated.
Creatinine concentration is known to be positively correlated with tHcy.9 Creatinine concentrations were determined
in 178 controls and 29 patients. The calculated OR after
adjustment for creatinine concentration remained virtually
unchanged at 5.6 (95% CI, 0.9 to 34.2). The use of anticonvulsant drugs may influence homocysteine levels.9 In the

Discussion
Studies about tHcy in children are not commonly reported.
tHcy measurements performed in 41 macrobiotic infants
showed evidently higher tHcy in these children, predominantly due to cobalamin deficiency.10 In 12 children with
leukemia, tHcy levels varied during different stages of
chemotherapy treatment.11 A Norwegian study12 among 8- to
12-year-old children found that a modest elevation in tHcy
was related to premature cardiovascular death in their male
relatives and may account in part for the contribution of
family history to risk of cardiovascular disease. Recently,
Vilaseca et al13 screened for hyperhomocysteinemia in selected pediatric patients, including children who had suffered
a stroke. They found higher tHcy levels compared with
age-matched reference values, which supports our findings.
However, no subsequent analysis on this raw data was
performed, and both children with ischemic infarct and
hemorrhage were included, whereas only an association
between occlusive vascular disease and hyperhomocysteinemia has been found.
In the present study, moderate hyperhomocysteinemia was
related to a 4-fold increased risk for ischemic cerebrovascular
disease in childhood. This OR is comparable to the relative
TABLE 2. ORs for Ischemic Stroke With
Hyperhomocysteinemia (95th Percentile of Age-Corrected
Homocysteine Distribution) for Each Age Group
Above Cutoff Point

Below Cutoff Point

Cases

Controls

Cases

Controls

OR (95% CI)

0.0 1.2

12

46

1.9 (0.48.8)

1.24.8

12

32

4.0 (0.627.0)

4.819.3

13

145

7.4 (1.148.6)

All ages

11

37

223

4.4 (1.711.6)

Age, y

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Hyperhomocysteinemia and Ischemic Stroke in Children

risk found for ischemic vascular disease in adults.5 Although


the pathogenesis of vascular disease due to hyperhomocysteinemia is unknown, this same risk for ischemic stroke in
early childhood and in adults presumes a dysequilibrium of
the coagulation-fibrinolysis status that results in an enhanced
coagulation state rather than a prolonged, cumulative effect in
arterial vessel wall, as is seen in hypercholesterolemia.
Among the patients, a 16-month-old boy had a very high
tHcy level (77 mmol/L). It was suspected that he was
homozygous for cystathionine b-synthase deficiency, and this
diagnosis was confirmed by very low enzyme activity in
cultured fibroblasts and molecular genetic analysis that
showed homozygosity for the T833C mutation. After exclusion of this case, the adjusted OR remained virtually unchanged (3.8; 95% CI, 1.4 to 10.5). A vascular accident at this
age in cystathionine b-synthase deficiency is rare, but cases
have been described.5 Normalization of tHcy levels in vitamin B6responsive cystathionine b-synthase deficient patients with pyridoxine is effective in preventing complications such as arterial and venous thrombosis.5 Although blood
and urine amino acid measurements are recommended in the
pediatric textbooks, in our opinion they are still not performed routinely. On the basis of our findings, screening of
plasma tHcy levels in children with vascular disease or
venous thrombosis should be done at least to exclude rare
inborn errors causing severe hyperhomocysteinemia.
Our study contributes to elucidation of idiopathic cases of
ischemic cerebrovascular disease, indicating that moderate
hyperhomocysteinemia is a common risk factor for ischemic
stroke in children.

Acknowledgments
This study was supported in part by research grant D97.021 from the
Dutch Heart Foundation. We would like to acknowledge Dr E.
Rammeloo for her clinical contribution.

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Hyperhomocysteinemia: A Risk Factor for Ischemic Stroke in Children


Ingrid M. van Beynum, Jan A. M. Smeitink, Martin den Heijer, Maria T. W. B. te Poele Pothoff
and Henk J. Blom
Circulation. 1999;99:2070-2072
doi: 10.1161/01.CIR.99.16.2070
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 1999 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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