Neurocognitive Dysfunction in

Survivors of Childhood Brain Tumors

Nicole J. Ullrich, MD, PhD,*, and Leanne Embry, PhD

Newer treatments have resulted in increasing numbers of survivors of childhood cancer, for
whom neurological and neurocognitive toxicity directly impacts overall functioning and
quality of life. There are multiple disease- and host-related factors that influence the
development of cancer-related neurocognitive dysfunction, which can progress over time
and lead to significant functional impairments. This article provides an overview of the
types of neurocognitive deficits seen in survivors of childhood brain tumors, the tools used
to assess neurocognitive function, and the factors that impact its severity. This provides a
framework for consideration of potential areas for primary prevention by reducing treat-
ment-related toxicity as well as interventions, using behavioral and pharmacologic
treatments.
Semin Pediatr Neurol 19:35-42 2012 Elsevier Inc. All rights reserved.

C entral nervous system (CNS) tumors are the most com-

mon solid tumors in children, second only to leukemia
in overall incidence. Importantly, in the modern treatment
era, 60% of children diagnosed with a brain tumor are
expected to become long-term survivors; however, survival is
not without serious long-term effects, and many individuals
experience significant chronic medical complications.1 Neu-
rotoxic effects, often referred to as late effects, are thought
to fully manifest between 2 and 5 years after completion of
treatment and are often associated with pronounced and
chronic impairment. Late effects may occur in a variety of
domains, including physical, medical, social, emotional, be-
havioral, and neurocognitive functioning. Importantly, it is
estimated that 40%-100% of pediatric brain tumor survivors
experience deficits in cognitive function related to the tumor
and/or its treatment.1-3 Development of neurocognitive dys-
function is impacted by multiple host and treatment factors,
and deficits often increase over time. Importantly, many sur-
vivors and their families are unaware of the risks. This chap-
ter will focus on neurocognitive dysfunction in childhood
cancer survivors, particularly survivors of CNS tumors.
*Department of Neurology, Childrens Hospital Boston, Boston, MA.
Pediatric Brain Tumor Program, Dana-Farber Cancer Institute, Boston, MA.
University of Texas Health Science Center, San Antonio, TX.
Address reprint requests to: Nicole J. Ullrich, MD, PhD, Department of
Neurology, Childrens Hospital Boston, 300 Longwood Avenue, Boston,
MA 02115. E-mail: nicole.ullrich@childrens.harvard.edu
Which Major Cognitive
Domains Are Affected?
Cancer-related neuropsychological dysfunction describes a
complex of neurocognitive late effects that occur over time as
a result of childhood cancer and its treatment. There are
multiple neurocognitive, social, and psychological issues that
emerge, as children are expected to master increasingly com-
plex tasks. The pathogenesis is not well understood.
Neurocognitive late effects can be defined as problems
with thinking, learning, and remembering and may include
permanent disruptions in brain development.4,5 Survivors of
pediatric brain tumors are especially vulnerable to these late
effects, given the aggressive CNS-directed therapies required
for adequate treatment of these tumors. Research has consis-
tently demonstrated that brain tumor survivors have higher
rates of neurocognitive dysfunction than survivors of non-
CNS malignancies.
Cognitive impairment in brain tumor survivors may occur
in many different areas of functioning. These deficits can be
attributed to direct insult to the brain caused by tumor type,
size, and location, surgical resection, impact of cranial radi-
ation therapy (CRT), long-term effects of systemic chemo-
therapy, and treatment-related complications.2,5 Late effects
can increase in severity over time and in direct relation to
greater treatment intensity. The most commonly affected do-
mains and modifiers include effects on overall cognitive abil-
ity, memory, attention, and executive functions, as well as
deficits in motor skills, psychosocial functioning, adaptive
behaviors, and social skills, but there is no specific pattern of

1071-9091/12/$-see front matter 2012 Elsevier Inc. All rights reserved. 35

doi:10.1016/j.spen.2012.02.014
36 N.J. Ullrich and L. Embry

neurocognitive dysfunction that is pathognomonic for pedi- Table 1 Risk Factors for Neurocognitive Dysfunction
atric brain tumor survivors. A recent meta-analysis compris- Tumor-Related Factors Host Factors
ing 39 empiric studies estimated the magnitude of general
Presence/absence of Age at diagnosis
and specific neurocognitive late effects for survivors of pedi- hydrocephalus Age at treatment
atric brain tumors.5 By extracting information across 10 neu- Tumor location Gender
rocognitive domains, the authors discovered that these chil- Tumor size Genetic polymorphisms
dren exhibited significant and pervasive impairments in Weakness/sensory deficits Presence/absence of
multiple domains, and that survivors scores on measures of Cranial nerve deficits neurogenetic syndrome
global cognitive ability, both verbal and nonverbal, fell nearly Duration of symptoms Pretreatment/baseline level
one standard deviation below normative means. Survivors Presence/absence of of functioning
were also found to perform poorly on measures of attention, seizures Socioeconomic status
memory, executive function, processing speed, psychomotor Need for anticonvulsants Other medical
Steroid use complications/illnesses
skills, visual-spatial skills, and language. Examination of ef-
Sleep disorders
fect sizes across studies revealed more severe deficits in at-
Fatigue
tention, verbal memory, and language compared with the Hypertension
other domains assessed. Sensorineural hearing
Attention and memory are critical skills by which new loss
knowledge is acquired.6 Impairment in these areas has sig- Visual impairment
nificant implications for intellectual growth and develop- Endocrine dysfunction
ment and academic performance over time, as expectations Environmental/
and developmental demands increase with age. In fact, recent Treatment factors Psychosocial factors
research has suggested that many learning problems are
Surgery School absences
likely the result of difficulties in attending to and retaining
Neurologic injury Adequacy of educational
new information rather than the decay of previously learned Motor/sensory deficits supports
material.5 The resulting level of impairment can range from Ataxia Access to
mild learning problems to severely limited capabilities and Perioperative infarction neuropsychological
overall poor quality of life.2,7-12 Hemorrhage assessments
Brain tumor survivors treated with CRT have consistently Posterior fossa syndrome Hospital-based school
shown evidence of greater neurocognitive dysfunction than Chemotherapy consultation
those treated without CRT. The risk of impairment increases Neuropathy Educational/vocational
with higher doses of CRT, and there is a continuing pattern of Hearing deficit supports
decline over time.6,13 In a heterogeneous sample of 133 long- Headaches Technical support
Fatigue Books on tape
term survivors of pediatric brain tumors, 5% of individuals
Encephalopathy Assistive devices
had such severe cognitive impairment that they were unable Leukoencephalopathy Computers
to complete intelligence quotient (IQ) testing.9 For those Intrathecal chemotherapy Loss of socialization/peer
completing the assessment, the authors found several impor- Steroid use experiences
tant predictors of adverse outcomes. CRT was the single most Chemobrain Emotional distress (patient/
important risk factor for subsequent adverse neurocogni- Radiation therapy sibling/family)
tive functioning, accounting for an average loss of 18 full- Radiation dose Changes to physical
scale IQ points (normative mean IQ score 100; standard Radiation field appearance
deviation 15). However, other risk factors included shunt Use of radiosensitizer Psychological adjustment
insertion because of hydrocephalus (effect estimate of 11 full- Radiation tissue injury Self-image/psychological
White matter injury distress
scale IQ points) and cerebral hemisphere tumor location (ef-
Radiation necrosis Depression/anxiety
fect estimate of 10-15 full-scale IQ points). These authors
Stroke or vasculopathy
found no association between long-term cognitive function- Vision changes
ing and tumor grade, disease relapse, or chemotherapy. (cataracts)

Factors That Influence

Neurocognitive Outcome
There are multiple disease and host factors that influence the
development of cancer-related neurocognitive dysfunction.
These can be divided into tumor- and treatment-related fac-
tors, host- related factors, and environmental/psychosocial
(Table 1). One way to conceptualize the impact of a brain
tumor is to envision that tumor diagnosis, treatment, and
follow-up occur along the spectrum of neurodevelopment.
Overall neurologic and neurocognitive function is directly
impacted at each time point.
Tumor- and Treatment-related Factors
The location and size of the initial tumor can impact many
factors, such as symptoms at presentation, resectability, and
presence/absence of neurologic deficits. These deficits can be
focal, with specific relationship to the tumor location and
brain regions affected, or diffuse/poorly localizable, likely
Neurocognitive dysfunction in childhood cancer survivors
related to raised intracranial pressure and hydrocephalus.
The impact of hydrocephalus, both in terms of degree and
duration before correction, is poorly accounted.14
As many as 25% of children with a primary brain tumor
experience seizures at tumor presentation.15-17 Seizure onset
can occur at the time of diagnosis, can be the first sign to
herald relapse of tumor, or may occur/recur many years after
completion of therapy. There are several proposed causes of
seizures, which include the tumor itself, surrounding areas of
dysplasia, altered levels of neurotransmitters, peritumor
blood products/edema, and/or scar formation.17,18 The use of
necessary anticonvulsants can further contribute to cognitive
dysfunction in patients who are already at risk.19
Treatment for a primary brain tumor may involve a com-
bination of surgery, chemotherapy, radiation therapy, and
stem cell transplant; specific tumor-directed therapy is tai-
lored to the underlying tumor type and location in children.
Surgical resection remains the mainstay of therapy for most
primary brain tumors, both to provide histologic diagnosis
and to reduce tumor burden, and is often the most important
factor in overall prognosis. Deficits and long-term effects of
surgery are multifactorial and depend on tumor location.
Direct sequelae from surgical removal can impact neurocog-
nitive function in a variety of ways, including development of
focal weakness, sensory deficits, new cranial nerve deficits, or
truncal/appendicular ataxia. Surgery may also produce local
damage related to development of hemorrhage or vascular
injury. Recent studies suggest that even patients treated with
surgery alone are at risk for long-term effects, including
ataxia, hemiparesis, and persistent neurosensory and neuro-
cognitive deficits.2,20 One prime example of surgical toxicity
is cerebellar mutism, or posterior fossa syndrome, which oc-
curs postoperatively in 15%-25% of patients with tumors in
the posterior fossa, most commonly after medulloblastoma
resection.21 There is thought to be a delay of 12-48 hours
after surgery, followed by a loss of verbal expression, pseu-
dobulbar dysfunction, irritability, and ataxia. In addition,
poor attention and eye contact, vomiting, incontinence, and
emotional lability are common. Speech recovery ranges from
days to many months. These emotional, motor, and neuro-
cognitive effects may last months to years, and are often con-
founded by other aspects of cancer treatment.22
Chemotherapy, both systemic and intrathecal, can have an
important impact on neurologic function; the neurologic ef-
fects of chemotherapy are seen with increasing frequency as a
result of more aggressive therapy and prolonged survival.
Side effects may result from direct neurotoxicity or indirect
effects from metabolic encephalopathies, seizures, infections,
transient ischemic attacks, ataxia, and myelopathy, as well as
movement disorders. Because standard therapy often relies
on combinations of chemotherapy, it is often difficult to iso-
late the offending agent. Drug-induced encephalopathy can
be seen with chemotherapy, immunosuppressive agents, or
supportive treatments, such as steroids, and the effects are
often dose dependent and drug specific. Many patients now
receive intrathecal therapy or high-dose chemotherapy with
autologous stem cell rescue. There are a variety of experimen-
tal approaches that are being evaluated to enhance the effi-
37
cacy of conventional chemotherapy. Newer techniques are
also being designed to improve access to the CNS across the
blood brain barrier and to provide more molecularly di-
rected approaches. Neurologic effects of these new molecu-
larly targeted agents are only beginning to be recognized in
adults, but the impact on the developing nervous system is
far from clear. As neurocognitive assessments are incorpo-
rated into upcoming clinical trials as important outcome
measures, the effects from these specific treatments will be
better documented and appreciated.
Radiation therapy remains an important component of
cancer treatment in children. Individuals may experience dif-
ferent effects depending on age, disease status, concomitant
therapies, length of survival, and radiation features, such as
dose, size of the field, and fractionation schema. Radiation
injury can affect each level of the nervous system and can
occur at the time of therapy or months or even years after
completion of treatment. The most common neurologic com-
plications related to radiation are neurocognitive dysfunction
and neuroendocrine damage. Several studies have shown a
progressive deterioration in IQ among children who receive
whole-brain radiotherapy. For example, a craniospinal axis
dose of 3600 centigray (cGy) resulted in a 20- to 30-point
decline in IQ score when administered to children between
the ages of 3 and 7 years.23 Cognitive deficits are typically
progressive in nature, and younger children are more likely
to suffer the severest damage; however, no patient, regardless
of age, is free of the risk of damage.6,10,24 These long-term
effects on cognitive function and growth and development
emphasize the importance of examining the efficacy of re-
duced overall dose of therapy for diseases with high cure
rates.
Host-related Factors
Overall, neurologic and neurocognitive function is also di-
rectly impacted by characteristics of the child or host. Neu-
rodevelopment occurs over a prolonged period, during
which the central nervous system is susceptible to a variety of
insults. Critical features such as gender and age at diagnosis
and treatment, therefore, often dictate susceptibility to treat-
ment-related morbidities. Younger age at time of tumor di-
agnosis and treatment is likely the most important host factor
that impacts the development and severity of neurocognitive
dysfunction. However, sex of the child is also a significant
variable in some treatment protocols, where girls are known
to be at higher risk than boys for neurocognitive impair-
ment.13
Comorbid conditions, such as inherited genetic syn-
dromes, may also impact the timing and development of
neurocognitive dysfunction. For example, children with neu-
rofibromatosis type 1 may have baseline neurological and
neurodevelopmental issues, which can be difficult to distin-
guish from tumor- and treatment-related side effects and can
increase susceptibility to neurocognitive impairment result-
ing from treatment.25
A childs premorbid level of cognitive, developmental, or
neurological functioning may also be a significant predictor
38 N.J. Ullrich and L. Embry

of subsequent neurocognitive dysfunction. Children with a How/When Do We

history of neurodevelopmental disorders, such as Down syn-
drome, mental retardation, low birth weight, or learning dis-
abilities, may have an even greater risk of functional impair-
ment after cancer treatment.
Environmental Factors
Lastly, there are environmental factors in the life of a child
that affect neurocognitive functioning. These include socio-
economic status (SES), loss of schooling and socialization,
and alterations in family psychosocial functioning. Lower
SES is associated with greater cognitive decline in acute leu-
kemia and can impact the neurocognitive outcome in brain
tumor survivors.12,26 Children from families of higher SES
tend to score better on measures of IQ, achievement, and
adaptive functioning.27 Academic performance may also be
impacted by other sociodemographic factors, such as ethnic-
ity and parental education.13 It is likely that many children
from higher SES families benefit from greater parental sup-
port, more cognitively stimulating home environments, and
increased ability of parents to advocate for the unique needs
of their children. Furthermore, more affluent schools may
have greater resources to provide specialized services for chil-
dren experiencing treatment-related neurocognitive dys-
function.
A number of family characteristics are associated with the
behavioral and psychological adjustment of children with
chronic illnesses, including childhood cancer. For example,
stress and family conflict have been consistently linked to
child maladaptive behaviors. One study found that children
from 2-parent households and children who had experi-
enced fewer negative life events tended to be more emotion-
ally well adjusted and performed better on measures of intel-
lectual functioning.27 Although they are not directly related
to disease or treatment severity, all of these factors may have
differential impact on long-term neurocognitive outcomes of
childhood cancer survivors.13
Evaluate for Cognitive Impact?
Longitudinal evaluation of neurocognitive functioning for
childhood cancer survivors is not yet considered standard of
care,5 although many pediatric oncology programs empha-
size neurocognitive assessment for high-risk patients, includ-
ing those diagnosed with brain tumors. These assessments
are essential in facilitating access to needed special education
services and in tracking each childs developmental trajectory
over time. Estimates of the need for special education services
vary by diagnosis. In one study, 25% of a heterogeneous
sample of childhood cancer survivors qualified for special
education in school compared with only 8% of a sibling
control group.28 Other research has estimated that 40%-50%
of acute lymphoblastic leukemia survivors and up to 70%-
80% of brain tumor survivors will require special education
services at some point during their school years.13
A comprehensive neurocognitive assessment should target
global intellectual functioning and academic achievement as
well as the specific high-risk domains described previously.
The assessment battery should be modified as needed to ac-
commodate for other late effects of therapy, such as chronic
fatigue or hearing loss. The Childrens Oncology Group con-
sensus recommendations suggest that, at a minimum, all
high-risk survivors be evaluated when they transition into a
survivorship or long-term follow-up program. This should
be performed regardless of patient/parent report of concern,
both to detect subtle impacts on overall functioning and to
serve as a baseline for future assessments, as it is known that
cognitive late effects can progress over time.6 Reevaluation
should factor in academic performance, any acute changes or
emergence of new difficulties, and the individual childs spe-
cific risk factors. Table 2 includes relevant domains of neu-
rocognitive functioning that may be part of these assessments
along with commonly used measurement tools. These tools
include both traditional instruments that are administered to

Table 2 Neurocognitive Assessment in Children

Neurocognitive Domain Commonly Used Assessment Tools
Global cognitive functioning (IQ) WISC-IV; WPPSI-III; WJ-III; SB-5; KABC-II; BSID-III Mental Scale
Attention CPT-II; NEPSY-II; Trail Making Test Part A; Conners Rating Scales, Third Edition
Memory CMS; WRAML-2; CVLT-C; Rey-O
Processing speed WISC-IV Coding/Symbol Search; WJ-III Achievement Fluency; D-KEFS Fluency
Executive functioning BRIEF; D-KEFS; WCST; NEPSY-II; Trail Making Test Part B; Tower of London Test
Psychomotor skills VMI; Finger Tapping test; Grooved Pegboard; Rey-O; BSID-III Motor Scale
Academic achievement WIAT-III; WRAT-IV; WJ-III
BSID-III, Bayley Scales of Infant Development, Third Edition; BRIEF, Behavior Rating Inventory of Executive Function; CMS, Childrens Memory
Scale; CPT-II, Continuous Performance Test, Second Edition; CVLT-C, California Verbal Learning Test for Children; D-KEFS, DelisKaplan
Executive Function System; KABC-II, Kaufman Assessment Battery for Children, Second Edition; NEPSY-II, Developmental Neuropsycho-
logical Assessment, Second Edition; IQ, intelligence quotient; Rey-O, ReyOsterrieth Complex Figure Test; SB-5, Stanford Binet Intelligence
Scale, Fifth Edition; VMI, BeeryBuktenica Developmental Test of Visual Motor Integration Test; WCST, Wisconsin Card Sorting Test;
WIAT-III, Wechsler Individual Achievement Test, Edition; WISC-IV, Wechsler intelligence scale for children, Fourth Edition; WJ-III,
WoodcockJohnson Tests of Achievement and Cognitive Abilities, Third Edition; WJ-III, WoodcockJohnson Tests of Cognitive Abilities,
Third Edition; WPPSI-III, Wechsler Preschool and Primary Scale of Intelligence, Third Edition; WRAML-2, Wide Range Assessment of
Memory and Learning, Second Edition; WRAT-IV, Wide Range Achievement Test, Fourth Edition.
Neurocognitive dysfunction in childhood cancer survivors
the child by a trained professional and patient-reported out-
come measures, often captured via parent-report question-
naires.
In recent years, modern technologies have brought about
opportunities for computerized assessments of neurocogni-
tive functioning. According to one study, 40% of high
schools that employ athletic trainers now use some form of
computerized assessment for evaluation and management of
sports-related concussions.29 These computerized paradigms
are now being used more often with clinical populations,
such as adult cancer patients30 and children diagnosed with
attention-deficit/hyperactivity disorder.31 Potential advan-
tages include availability, convenience, and accuracy of ad-
ministration and scoring.29 In addition, test batteries can be
customized to evaluate the specific neuropsychological func-
tions of interest (eg, processing speed, working memory)
(http://www.cogstate.com). Trials are underway to evaluate
the use of computerized assessment programs with survivors
of pediatric cancer.
What Are the
Functional Implications?
Neurocognitive dysfunction can have significant implica-
tions for functional outcomes and overall quality of life for
survivors.1,2 Employability, interpersonal relationships, in-
dependent living, emotional functioning, and health status
are some of the domains that may be impacted by neurocog-
nitive late effects in survivors of pediatric brain tumors. This
ultimately can translate into increased risk for poor quality of
life for survivors and their families.32,33 For example, one
study demonstrated that only 30% of young adults who were
10-year survivors of medulloblastoma were able to drive, live
independently from their families, or find employment.34
There were also significantly lower rates of education, em-
ployment, and dating when compared with the general pop-
ulation. Several studies have suggested that the complex
needs of pediatric brain tumor survivors may be underesti-
mated and largely unmet. Many children spend excessive
time on preparation of homework, but demonstrate difficul-
ties in processing, storage, and integration of new informa-
tion.6,35 It is clear that intellectual functioning, attention,
memory, executive functioning, and a variety of other cogni-
tive abilities are negatively impacted by CNS disease and
treatment. However, questions remain about how these neu-
rocognitive deficits interact with other medical and psycho-
social factors to affect long-term functional outcomes for sur-
vivors.
Strategies for Intervention
Research into strategies to evaluate, prevent, and treat the
neurocognitive late effects of cancer therapy has mirrored the
progress of medical therapy. Interventions and therapeutic
strategies are targeted at each point along the road map of
diagnosis, treatment, and survivorship.
39
Prevention
Reduction in treatment-related toxicity has occurred with
advances in neurosurgical techniques, use of neuroprotective
agents, and improved radiation techniques. The overall goal
of treatment is to improve outcome in tumor subtypes that
have traditionally been resistant to therapies, and to reduce
the toxicity of treatment in tumor subtypes that are respon-
sive to therapies.
Modern literature suggests that maximum extent of tumor
resection with preservation of neurological function is asso-
ciated with improved overall outcome. The use of image-
guided surgery such as the intraoperative magnetic reso-
nance imaging suite has resulted in improved extent of
resection and reduction of residual tumor volume.36 There
will, however, always be tumors in eloquent regions of the
brain and infiltrative tumors that are less amenable to this
type of approach. The use of endoscopic biopsy is an impor-
tant minimally invasive method of diagnosis for the initial
management of lesions in children with intraventricular and
periventricular tumors and can be performed safely in con-
junction with procedures to divert cerebrospinal fluid for
obstructive hydrocephalus.37 Diagnostic efficacy and safety
are high priorities and can preempt the need for open surgical
biopsy in difficult locations. Intraoperative infusions are now
used in adults and children to deliver targeting agents di-
rectly to the operative bed.38
Over the past decade, there have been advances in chemo-
therapeutic strategies for treatment of primary brain tumors.
Specific protocols have included optimization of administra-
tion of chemotherapy, metronomic treatment,39 concomitant
use of chemotherapy and radiation therapy to the CNS, and
administration directly into the intrathecal/intraventricular
compartment. Moreover, there are refinements in the clinical
and molecular stratification of tumors that have facilitated a
movement toward risk-adapted treatment planning. This is
particularly true in medulloblastoma, where there are now 4
subclasses of tumor that are defined by molecular signature
that directly relates to clinical and pathologic outcome indi-
cators.40,41 Ultimately, this type of approach will lead to the
identification of the next generation promising molecularly
targeted therapies.42
Because of concerns over neurocognitive sequelae from
radiation, there is renewed interest in reduction of total radi-
ation dose, both for solid tumors and for primary brain tu-
mors. The use of fractionated and conformal techniques ef-
fectively reduces toxicity to the surrounding tissue.43 With
proton beam radiotherapy, there is less radiation to sur-
rounding tissues, which theoretically has the potential to de-
crease the area at risk for injury and, therefore, has long-term
implications for sparing of neurocognitive functioning.44,45
Treatment of Comorbidities
Survivors are at risk for significant comorbidities that have
been shown to impact neurocognitive functioning. This may
include neurosensory deficits such as visual impairment and
sensorineural hearing loss, as well as seizures, endocrine dys-
function, headaches, and peripheral neuropathy.15 It is cru-
40
cial to identify and treat any underlying health conditions
that may impact overall functioning, such as underlying en-
docrinopathies. In addition, screening for, identification of,
and correction of hearing deficits and visual impairments are
important. A significant proportion of adult survivors of
childhood cancer report disrupted sleep, increased daytime
sleepiness, and fatigue.46 Survivors with a history of radiation
therapy are more likely to be fatigued. Excessive daytime
sleepiness is seen in up to 60% of children with cancer and
80% of children with tumors involving the hypothalamus,
thalamus, and brainstem.47 These patients are also at risk for
sleep-disordered breathing. Lastly, early identification and
treatment of psychological comorbidities, such as anxiety,
depression, and post-traumatic stress syndrome, in the child
and in the family is important for overall quality of life as well
as cognitive functioning. The overall impact of these comor-
bidities is often hard to decipher, but given the frequency of
reported symptoms in survivor populations is important to
address.
Cognitive Rehabilitation
Given the prevalence of neurocognitive dysfunction in survi-
vors of pediatric brain tumors, efforts to determine effective
forms of cognitive remediation are imperative. One such
study focused on acquisition of cognitive strategies to im-
prove neuropsychological performance by completing a 4-5
month remediation program, including cognitive-behavioral
interventions.48 The authors reported improved attentional
skills and achievement scores over the course of the study;
effect sizes were small but comparable with other interven-
tion studies with similar population and methodology. A
similar 15-week training program for improving problem
solving, general cognitive skills, memory, and attention
showed some positive gains from pre-intervention to post-
intervention in each of the domains assessed.49 However, as
with the first study, participation rates were fairly low and the
mode of intervention may be impractical for families with few
resources or those who do not live near a large medical center
that could administer the intense treatment program.
These findings highlighted a need for effective short-term
interventions that could be widely administered without pro-
hibitive costs, travel requirements, or time commitments.
One such intervention is home-based, computerized cogni-
tive training programs. These programs have proven effective
in improving attention and working memory in children di-
agnosed with attention-deficit/hyperactivity disorder50 and
in a small sample of pediatric cancer survivors.51 This is no-
table, as some investigators believe that deficits in attention
and working memory are to blame for treatment-related de-
clines in intellectual functioning and academic performance.
In fact, studies of childhood cancer survivors have shown
that up to 45% of the variance in IQ scores and 70% of
functional impairments at school could be attributed to these
underlying processes.52,53 These results suggest that home-
based, computerized cognitive training may be useful in im-
proving survivors neurocognitive functioning, although
more research in this area is clearly indicated.
N.J. Ullrich and L. Embry
Pharmacologic Interventions
Although deficits in attention are common in survivors of
primary brain tumors and manifest with behavioral issues
that resemble attention deficit disorder in the general popu-
lation, it is likely that the mechanism is different. At the same
time, traditional stimulants have been shown to improve
neurocognitive functioning among survivors. Specifically,
both short-acting and long-acting doses of methylphenidate
lead to improvements in measures of attention, social skills,
and behavioral problems in survivors of childhood brain tu-
mors and acute lymphoblastic leukemia, and these benefits
were maintained across settings during the course of one
year.54
The acetylcholinesterase inhibitor donepezil has demon-
strated some promising initial results in a study of 34 adults
with primary brain tumors, with improvements in attention,
concentration, memory, and mood.55 These data formed the
basis of a feasibility study in childhood brain tumor survi-
vors, where it was well tolerated and demonstrated improve-
ments in executive function and memory.56
Alternative psychostimulants, such as the dopaminergic
agent modafinil, have demonstrated improved attention and
memory in adult breast cancer survivors57 as well as im-
proved cognition, mood, and symptoms of fatigue in adults
with brain tumors.58,59 A randomized, placebo-controlled
trial is currently underway through the pediatric cooperative
group to assess efficacy of modafinil in survivors of childhood
brain tumors. Thus, newer stimulant medications may also
hold some possibility to improve at least some aspects of
common cancer-related neurocognitive deficits.
Conclusions
With newer treatments and longer overall survival leading to
growing numbers of survivors, there is an increasing impact
of neurological and neurocognitive toxicity related to treat-
ment for primary brain tumors in children. As there are in-
creasing numbers of survivors of childhood brain tumors,
there is a population of patients in major need of support that
includes primary prevention as well as intervention and fol-
low-up over the lifespan with multidisciplinary care that in-
corporates evaluation of cognitive function. The quality of
survivorship depends on the ability of the individual to
meet developmental challenges as they move into adoles-
cence and adulthood.
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