EFFECT OF INTRACRANIAL BLEEDS ON THE HEALTH AND QUALITY OF

LIFE OF BOYS WITH HEMOPHILIA

SHOSHANA REVEL-VILK, MD, MEREDITH R. GOLOMB, MD, CAMILLE ACHONU, BSc, ANN MARIE STAIN, RN, DEREK ARMSTRONG, MD,
MARCIA A. BARNES, PHD, PETER ANDERSON, PHD, WILLIAM J. LOGAN, MD, LILLIAN SUNG, MD, MICHAEL MCNEELY, MD,
VICTOR BLANCHETTE, MD, AND BRIAN M. FELDMAN, MD, MSc

Objectives To compare the health, physical function, and quality of life (QoL) of boys with hemophilia with and without
a history of intracranial hemorrhage (ICH).
Study design Of 172 patients with hemophilia A or B, 18 (10%) had at least one episode of ICH. For outcome assessments,
16 of 18 (89%) boys with ICH and 32 controls, matched (1:2) for age and severity of hemophilia, were available. The outcome
measures were neurologic function, physical function, and QoL.
Results The median age of the boys at the first ICH was 5.9 months (range, 1 day to 2.7 years). Boys with ICH had a higher
incidence of inhibitors and lower mean household income. Neurologic examination was abnormal in seven of 16 (44%) boys
with ICH and nine of 32 (28%) controls (P = .3). The mean physical function in boys with ICH was lower (82% ± 25%)
compared with controls (93.5% ± 12%, P = .045). The QoL was decreased in boys with ICH compared with controls (6.8 ± 3.2
vs 8.5 ± 1.4, P = .02), whereas health-related QoL was not significantly different between groups.
Conclusion The poorer long-term outcomes of boys with hemophilia appropriately
treated for ICH, especially in the domain of QoL, suggest that new strategies to prevent
From the Pediatric Hematology/On-
ICH and to manage ICH effectively in this population are needed. (J Pediatr cology Unit, Hadassah Hebrew Uni-
2004;144:490-5) versity Hospital, Jerusalem, Israel; the
Division of Pediatric Neurology, Riley
Hospital for Children, Indiana Univer-
sity School of Medicine, Indianapolis,
ntracranial hemorrhage (ICH) is a relatively rare but very serious complication of Indiana; the Departments of Health

I hemophilia. The prevalence of ICH in persons with hemophilia varies between 4%1,2
and 12%3,4 in different populations, with an incidence between 545 and 2004 per 10,000
persons with hemophilia per year. The majority of ICHs in persons with hemophilia occur
Policy Management and Evaluation
and Population Health Science, Nurs-
ing, Diagnostic Imaging, and Psychol-
ogy, the Brain Behavior Program, and
the Divisions of Neurology, Hematol-
in the pediatric age group,3 in which trauma and birth-related injury are the most important ogy/Oncology, and Rheumatology,
risk factors.1 In a survey of 744 boys with hemophilia, 11 of 30 (37%) of ICHs occurred in the Hospital for Sick Children, Uni-
versity of Toronto, Ontario, Canada.
the first week, 18 of 30 (60%) occurred in the first year (including the first week), and six of Supported by the Aventis Behring
30 (20%) occurred in the second and third years of life.1 Understanding long-term outcomes Canada competition for hemophilia/
of boys with hemophilia who survive ICH is valuable for developing appropriate long-term von Willebrand disease bleeding dis-
orders. Dr Revel-Vilk is a recipient of
support and recommendation about the implementation of factor prophylaxis at a very the Baxter Bioscience Pediatric He-
young age with the goal of reducing the frequency of ICH. Unfavorable long-term outcome mostasis Fellowship at the Hospital for
Sick Children, Toronto, Canada
would support such a management strategy in very young boys with severe hemophilia.6 (2001–2002). Dr Feldman holds a Can-
Before the era of appropriate factor replacement therapy, ICH in persons with ada Research Chair in Childhood
Arthritis.
hemophilia led to high rates of morbidity and mortality.1,3,7 The objective of this study was
Submitted for publication Feb 5, 2003;
to compare the health, physical function, and quality of life (QoL) of boys with hemophilia last revision received Oct 29, 2003; ac-
with a history of ICH with those of boys with hemophilia without a history of ICH. All cepted Dec 8, 2003.
boys with ICH were treated with factor replacement therapy. Our cohort consisted of boys Reprint requests: Victor Blanchette,
Director, Comprehensive Care He-
with hemophilia treated for ICH in a single comprehensive care pediatric hemophilia mophilia Clinic, Division of Haematol-
center between 1984 and 2000. ogy/Oncology, Hospital for Sick
Children, 555 University Ave, Toron-
to, Ontario M5G 1X8, Canada.
E-mail: victor.blanchette@sickkids.ca.
0022–3476/$ - see front matter
ASK Activities Scale for Kids ICH Intracranial hemorrhage Copyright ª 2004 Elsevier Inc. All rights
CHAQ Childhood Health Assessment Questionnaire ITT Immune tolerance therapy reserved.
HRQoL Health-related quality of life QoL Quality of life
10.1016/j.jpeds.2003.12.016

490
 METHODS
Study Design
We studied an inception cohort from the Hospital for
Sick Children Pediatric Comprehensive Care Hemophilia
Center. This study was approved by the Hospital for Sick
Children Research Ethics Board, and informed consent was
obtained from all study subjects’ parents and all study subjects
able to consent. Subjects were recalled for on-site testing at the
Hospital for Sick Children, and all examiners were blinded
with respect to participants’ ICH history.
Study Population
Eligible subjects were identified by a review of hemo-
philia clinic and hospital records for all boys (n = 172) with
a diagnosis of hemophilia A or B registered as of June 1, 2000.
Eligible subjects were required to have at least one episode of
ICH during the period 1984 to 2000. When boys with
hemophilia reach 18 years of age, their hemophilia care is
transferred to an adult center. Therefore, older boys (born
before 1984) were not available for study. All eligible subjects
(n = 18) were invited to participate.
A neuroradiologist (D. A.) reviewed the original films
of the ICH to confirm the location and extent of the ICH. It
was not possible to verify the reports on five of the 24 ICHs
because films were unavailable. In these five cases, the location
of the bleed was derived from the original report. Data col-
lected included the subject’s clinical and neuroradiographic
presentation at the time of ICH, birth history, family and
socioeconomic history, general health status, and hemophilia
status.
Once the ICH patients were identified, two controls
(who had not had an ICH) were chosen from the hemophilia
registry for each study subject. Matching was performed by
using a hierarchical algorithm. The first priority for matching
controls was age. Second, controls were matched for disease
severity (severe, moderate, and mild defined by circulating
factor levels of < 1%, 1%–5%, and >5%, respectively). Finally,
they were matched for type of hemophilia (hemophilia A or
B). If there were more than two boys who met eligibility
criteria for being a control, two were chosen at random.
Data Collection
CLINICAL DATA. A standardized clinical questionnaire was
developed as part of the study and completed for all boys by
their accompanying parents. The following information was
obtained: development of inhibitors, current use of medica-
tion, past or current use of factor prophylaxis, history of joint
or liver abnormalities, and history of persistent neurologic
deficits, seizures, or headaches.
SOCIOECONOMIC STATUS. Socioeconomic status of the study
subject’s families was classified based on the midpoint of the
range chosen by the accompanying parent as best reflecting the
family’s annual income in dollars.8 A family’s annual income
<$65,000.00 CDN was considered indicative of low to
Effect of Intracranial Bleeds on the Health and Quality of Life of Boys with Hemophilia
moderate socioeconomic class, and a family’s annual income
$$65,000.00 CDN indicated high socioeconomic class.
NEUROLOGIC EXAMINATION. Neurologic examination was
based on a modification of the Pediatric Stroke Outcome
Measure,9 containing items in the area of mental status, cra-
nial nerve, motor function (fine and gross motor function,
tone, power, reflex, and involuntary movements), sensory
function, coordination, and gait. The Pediatric Stroke Out-
come Measure was originally developed and used in children
with arterial ischemic stroke and sinovenous thrombosis.
Three physicians performed the neurologic examinations. At
the completion of the examination, a sensorimotor score
ranging from 0 (normal) to 2 (severe deficit) was assigned. The
neurologic examination was scored without counting the
effects of hemophilic arthropathy.
PHYSICAL FUNCTION. The Activities Scale for Kids (ASK),
a validated self-report measure, was used for measurement of
physical function in boys >5 years.10 The ASK summary score
was calculated by averaging the answers to all completed
questions (scored from 0 to 4, with 4 indicating best function).
The average was divided by 4 and the result reported as
a percentage score (range, 0–100, with 100 indicating full
physical function). For boys #5 years, the accompanying
parent completed the Childhood Health Assessment
Questionnaire (CHAQ).11 The CHAQ summary score was
calculated as the average score of the maximum score of each
of eight subdomains (from 0 to 3, with 0 indicating the best
function). The average was subtracted from 3 (to reverse the
direction of the scores) and then divided by 3. The result was
reported as a percentage score (range, 0–100, with 100
indicating full physical function). Both instruments have been
found to be reliable and valid in children with musculoskeletal
disorders.10,11
QUALITY OF LIFE. The Quality of My Life questionnaire was
used to measure globally QoL and health-related quality of life
(HRQoL).12 The Quality of My Life questionnaire uses
double-anchored horizontal visual analogue scales with scores
ranging from 0 to 10, with 10 representing maximal QoL and
HRQoL. The Quality of My Life questionnaire has been
found to be a valid measure in children with musculoskeletal
disorders.12
Statistical Analysis
A paired analysis was performed comparing children
with a history of ICH and their matched controls. The
baseline demographics of children with a history of ICH were
compared with those of their matched controls by using
conditional logistic regression. Then, physical function, QoL,
and HRQoL of cases were compared with those of controls by
using a linear regression model that accounted for the matched
nature of the data. A similar model was used to examine other
predictors for QoL and for HRQoL, such as history of ICH,
regular use of prophylaxis, history of inhibitors, socioeconomic
status, and scored physical ability. All P values from regression
491
Table I. ICH in boys with hemophilia
Patient Factor Levels n Age Location

1 VIII <1% 1 1d Right subependymal and intraventricular, mild

hydrocephalus
2 VIII <1% 1 8 mo Left frontoparietal SD, slight shift of midline
3 VIII <1% 1 31 mo Right frontoparietal and facial SD, midline shift
4 VIII <1% 1 33 mo Right frontoparietal ED
5 VIII <1% 1 12 mo Right posterior fossa ED, deformation of 4th
ventricle
6 VIII <1% 1 6d Left frontoparietal SD (supra and infratentorial),
transtentorial herniation, massive left
hemisphere infarctions, tempo-parietal-
occipital sulci and Sylvian fissure subarachnoid
7 VIII <1% 1 2 mo Large left temporal IC and burst and SD space
8 VIII <1% 1 3d Right hemisphere SD, large occipital hematoma
plus compression, edema, and herniation
9 VIII <1% 1 At birth Unknown
10 VIII <1% 2 4 mo Left SD with midline shift
57 mo Right frontal SD, tentorial SD
11 VIII <1% 2 13 mo Left temporal IC, left SD and left lateral
intraventricular
21 mo Left frontoparietal SD and tentorial
12 VIII <1% 2 5 mo Left parietal IC at the level of the lateral ventricle
plus SD midline shift of 1 cm
18 mo Posterior ED extending from C4 to T2
13 VIII <1% 4 8 mo Left subtemporal and tentorial SD
27 mo Small right frontoparietal SD
42 mo Right temporoparietal ED
50 mo Small chronic left SD
14 VIII <1% 1 6d Left temporoparietal IC, midline shift, lateral
intraventricular, subarachnoid, infarction of left
temporal lobe
15 VIII <12% 1 27 mo Small SD associated with skull fracture of right
parietal region subarachnoid blood in the right
Sylvian fissure and over cerebral convexities
16 IX <1% 1 6 mo Right posterior fossa SD, hydrocephalus, mild
hydrocephalus, some mass effect
17* VIII <1% 2 10 mo Right ED, right parietal small IC
30 mo Right temporal and falcile SD, some mass effect, no
significant midline shift
18* VIII <1% 1 8 mo Right parietal ED with herniation into brain
SD, Subdural; ED, extradural; IC, intracerebral.
*Patients 17 and 18 were not included in the outcome study.

analyses were univariate. Analysis was performed by using
SAS for Windows (version 8.2; SAS Institute, Cary, NC). A P
value < .05 was considered significant.
RESULTS
Study Population
Of 172 patients with either hemophilia A or B, ranging
in severity from mild to severe, 18 (10%) had at least one
episode of ICH (Table I). Sixteen boys with hemophilia and
a history of at least one ICH (total, 22 ICH episodes), and 32
matched (1:2) controls participated in this outcome study.
Two boys with hemophilia and a history of ICH did not
consent to participate in the study (Table I, subjects 17 and
18). The reasons for refusal were parental refusal in one boy
and transition to another hospital in the second boy. By chart
review, neither of these two boys had a major neurologic
deficit. The median age at the time of study evaluation was 9.2
years (range, 3-18.1). The median age of the boys at the first
ICH was 5.9 months (range, 1 day to 2.7 years), and median
follow-up from the first ICH was 8.2 years (range, 3-16.8). A
preceding event for ICH was found in 12 cases: traumatic

492 Revel-Vilk et al The Journal of Pediatrics
April 2004

birth in four and other trauma in eight. Spontaneous ICH
occurred in nine episodes, all in patients with severe
hemophilia. In one case, the event precipitating the ICH
was not clear. The most frequent presenting symptoms for the
ICH were irritability, lethargy, and vomiting. Seizure activity,
abnormal neurologic examination, or both were present in two
thirds of the episodes of ICH at the time of initial
presentation. Headache was the main complaint in one child.
All subjects with ICH were treated with factor replacement
therapy at the time of the event and were admitted to the
hospital (median stay, 22 days; range, 5 days to 3 months).
Seven boys with ICH developed inhibitors: five with high titer
(>5 Bethesda unit) and two with low titer. The inhibitors
developed after the first event during a median interval of 78
days (range, 15 days to 8.4 years). The median age of boys at
the time of inhibitor development was 1 year (range, 21 days to
8.3 years). All recurrences (six ICH events in four boys)
occurred in the presence of inhibitors. Twenty-eight boys were
receiving prophylactic factor replacement therapy at the time
of the evaluation; indications for prophylaxis initiation were
enrollment into the Canadian primary prophylaxis study
(n = 5), immune tolerance therapy (ITT; factor VIII 100 U/kg
daily) for eradication of inhibitors (n = 4), and secondary
prophylaxis for target joints (n = 15) or for ICH (n = 4). The
prophylaxis regimens were started after the first ICH at a mean
interval of 2.8 years (range, 1 day to 11.5 years); no child was
treated with factor prophylaxis at the time of the original ICH.
Recurrence of ICH occurred during high-dose factor infusion
(ITT) in five of six cases. In one boy, the program of ITT
started after the second ICH. The clinical characteristics of
boys with a history of ICH and controls are presented in
Table II.
NEUROLOGIC EXAMINATION. Abnormal neurologic examina-
tion was found in seven of 16 (44%; 95% CI, 31.6-56.4) boys
with a history of ICH. Six boys had mild and one a severe
sensorimotor deficit. This proportion was not significantly
different from the proportion of abnormal neurologic ex-
amination in controls (9/32; 28%; 95% CI, 20.1-35.9). The
child with a severe deficit had one extensive ICH (Table I,
subject 6). He had right hemiparesis and was incapable of
performing minimal activities of daily living such as eating or
dressing independently. All four boys with more then one
episode of ICH had mild sensorimotor deficits. Mild gait
abnormalities were found in two boys who had a history of
ICH.
PHYSICAL FUNCTION. The mean score of physical function
ability of boys with hemophilia was 90% ± 18% (median,
97%). Twelve boys #5 years were assessed by CHAQ, and 36
boys >5 years were assessed by ASK. The score of physical
function in boys with a history of ICH (82% ± 25%) was lower
than in boys without a history of ICH (93.5% ± 12%, P < .05).
Reduced physical function (defined this as < 97%, which
corresponds to mild disability)10 was associated with a history
of ICH, but not with abnormal neurologic examination. Very
low physical function (<50%) was found in two boys: one with
Effect of Intracranial Bleeds on the Health and Quality of Life of Boys with Hemophilia
Table II. Clinical characteristics of boys with a history
of ICH and controls
ICH Controls P*
Age (y) mean ± SD 9.7 ± 4.5 9.9 ± 4.4 .01
Annual household 56,333 ± 23,685 70,962 ± 29,190 .01
income, CDN,
mean ± SD
Inhibitors 7/16, 44% 4/32, 13% .03
Current use of 14/16, 88% 14/32, 44% .02
prophylaxis
Joint abnormalitiesy 12/15, 80% 21/32, 66% .3
Liver abnormalitiesy 2/15, 13% 5/32, 16% .5
*P value from conditional logistic regression.
yMissing information in one subject with history of ICH.
a history of ICH and severe neurologic deficit (Table I, subject
6) and one without a history of ICH.
QUALITY OF LIFE. Overall QoL values in all boys with
hemophilia ranged from 0 to 10, with a median score of 8.65.
HRQoL was rated similarly, with a median value of 8.6
(range, 0.3-10). The HRQoL explained almost half of the
variability in QoL (adjusted R2 = 0.47). The predictors of
QoL and HRQoL are presented in Table III.
DISCUSSION
We found that boys with hemophilia and ICH have
a worse clinical outcome, especially in the domain of QoL,
than other boys with hemophilia. The long-term outcomes in
an unselected population of boys with hemophilia and ICH
were assessed through the use of multiple standardized tests,
and the effect of having hemophilia was controlled by using
boys with hemophilia as matched controls. Boys with ICH
differed from the control group in three demographic vari-
ables: higher percentage of inhibitors, increased use of factor
prophylaxis, and reduced annual household income. It is not
known whether the development of inhibitors in boys with
ICH was a response to an increased need for replacement
therapy (the inhibitors developed after the first ICH) or
whether boys who are genetically prone to inhibitor de-
velopment are also prone to more significant bleeding, such as
ICH. The development of inhibitors increased the chances of
recurrent ICH both in our and in others’ studies.5,7 The higher
proportion of factor prophylaxis in boys with a history of ICH
is consistent with the current practice in many hemophilia
treatment centers to start factor prophylaxis once an ICH has
occurred. The reasons for reduced annual household income in
families of boys with ICH are also not clear. The history of
ICH may decrease the annual household income by reducing
the ability of the parents to work. Alternatively, poor
socioeconomic status may be associated with delayed diagnosis
of hemophilia or higher incidence of trauma and thus higher
chances of early ICH. Another possibility is that in our
matching, we coincidentally selected for families of better
493
Table III. Predictors of QoL and HRQoL
QoL N Mean* Py HRQoL N Mean* Py

History of ICH
No 32 8.5 ± 1.4 .02 History of ICH No 32 8.0 ± 2.1 .4
Yes 16 6.8 ± 3.2 Yes 16 7.2 ± 3.2
Annual household incomez
Low 16 7.8 ± 2.7 .7 Annual household income Low 16 7.9 ± 2.7 .7
High 25 8.0 ± 2.3 High 25 8.0 ± 2.3
History of inhibitor
No 37 8.1 ± 2.1 .6 History of inhibitor No 37 7.6 ± 2.7 .1
Yes 11 7.5 ± 3.0 Yes 11 8.0 ± 2.8
Use of prophylaxis§
No 21 7.9 ± 2.5 1.0 Use of prophylaxis No 21 7.6 ± 2.9 .6
Yes 26 7.9 ± 2.2 Yes 26 7.7 ± 2.2
Physical function||
Low 24 7.2 ± 2.8 .01 Physical function Low 24 6.8 ± 2.8 .003
High 24 8.6 ± 1.4 High 24 8.6 ± 1.8
*Mean ± SD.
yP-value for regression coefficient from a linear regression model of univariate analysis.
zLow < $65,000 CDN: high $$65,000 CDN. Missing information in seven subjects.
§Missing information in one subject.
||Low < 97%; high $97%.

socioeconomic status, and this caused the difference in the
annual household income between study subjects and controls.
In this study, although abnormal neurologic ex-
aminations were found in both study subjects and controls,
the differences were not statistically significant. The neurologic
examination focused on sensory and motor outcomes, and only
one boy with ICH was found to have a severe sensorimotor
deficit. Of interest, the Hemophilia Growth and Development
Study found that coordination and gait abnormalities were not
associated with a history of ICH.13 One possible explanation
for similar neurologic status is that subclinical silent bleeding
episodes or other abnormalities were present in the control
group and accounted for the abnormal neurologic findings.
Silent bleeds have been detected in previous magnetic
resonance imaging studies.4,14 Cranial imaging studies were
not performed on our control group, so we cannot confirm or
reject this hypothesis. Another possible explanation is that our
neurologic examination tool was overly sensitive. A larger study
that includes magnetic resonance imaging studies on both boys
with ICH and controls would be needed to resolve this issue.
Reduced physical function was detected in boys with
ICH in this study by using two different standardized mea-
surements of functional status: one for boys < 5 years and one
for boys >5 years. The ASK capability questionnaire measures
what a child (age $5 years) is capable of doing; it was found to
be valid and reliable in children experiencing limitations in
physical activity because of musculoskeletal disorders.10 The
median ASK capability score of 97% is compatible with mild
disability in children with musculoskeletal limitations—that
is, mild difficulty in doing daily chores such as tooth brushing,
dressing, washing, and so forth.10 The CHAQ questionnaire
evaluates the effects of the child’s illness (in children as young
as 1 year) on ability to function in daily life and has been shown
to be a valid and reliable measurement of functional status in
children with arthritis.11 The median score of 0.13 (95.7%) in
study subjects is compatible with mild disability in children
with inflammatory arthritis.15 In our study of 48 boys with
hemophilia, a history of ICH was associated with mild or
worse functional disability (<97%), but not with abnormal
neurologic examination. This finding emphasizes the impor-
tance of physical function questionnaires for assessing the
long-term outcome of children with a history of ICH.
Our study demonstrated a decrease in QoL but not
HRQoL in boys with ICH as rated by the patients (or
parents). Reduced physical function score predicted both low
QoL and HRQoL. Different aspects of life influence the
overall QoL, whereas HRQoL is usually determined by the
observable consequences of illness or poor health.12 A history
of ICH could lead to developmental, behavioral, and social
problems that are captured in the QoL measure but not in the
HRQoL measure. On the other hand, decreased physical
function could be more accurately captured in the HRQoL
compared with the overall QoL measure. Differences in the
predictors of QoL and HRQoL were also found in children
with various musculoskeletal diseases.12 Different measure-
ment tools have been used in the hemophiliac population to
assess QoL and HRQoL. The EuroQol questionnaire showed
that the main predictors of HRQoL and QoL are age and
disease severity.16,17 In our study, subjects were matched for
age and severity of hemophilia; therefore, we would not expect
these variables to explain the difference between those with
and without ICH. Other studies in the hemophiliac
population supported our finding that the main predictor of
HRQoL is decreased physical function.18,19 The association of

494 Revel-Vilk et al The Journal of Pediatrics
April 2004

physical function with the QoL and HRQoL further stresses
the importance of routine assessments of physical function.
The use of prophylaxis therapy in patients with hemophilia
was also shown to have a positive effect on the HRQoL.20-22
The lack of association between prophylaxis therapy and
HRQoL in this study may be related to the fact that in all
cases, prophylaxis therapy started after the ICH event. Pre-
vious studies assessed the QoL and HRQoL in the adult
hemophilia population; similar studies in the pediatric popu-
lation are informative and valuable. Further studies are needed
to assess the association between the effects of factor prophy-
laxis in reducing morbidity (such as ICH) and in improving
QoL, HRQoL, or both in the hemophiliac population.
In our study, boys with hemophilia and at least one ICH
had decreased physical function and QoL when compared
with boys matched for age and severity of hemophilia. We
believe that these outcomes are important for the well being of
the child with hemophilia and should be considered when
discussing the benefit of prophylaxis in children at high risk for
ICH. Further data on long-term outcomes need to be
collected to calculate the long-term cost-effectiveness.23
Because the current timing of the prophylaxis regimen (1–2
years of age) may be too late to prevent ICH in some cases,
effort should be directed to developing new strategies to
prevent ICH and to manage ICH optimally in this population.
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