J Neurooncol DOI 10.1007/s11060-015-1725-1
TOPIC REVIEW
Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature Ana-Maria Vranceanu • Vanessa L. Merker Elyse R. Park • Scott R. Plotkin
•
Received: 1 August 2014 / Accepted: 1 February 2015 Ó Springer Science+Business Media New York 2015
Abstract The aim of this research is to identify, within a systematic review, aspects of quality of life (QoL) that are adversely affected in children and adolescents with neurofibromatosis (NF), and to report predictors of quality of life in this population. Published reports of original research were included if they described QoL in children and/or adolescents with NF, and met methodological quality according to a list of predefined criteria. Seven studies conducted between 2006 and 2013 met inclusion criteria. All seven studies examined patients with NF1 and reported that these patients have lower general QoL compared to population norms. Parents’ proxy ratings of QoL were generally lower than children’s self-report ratings. By parent proxy, familial NF1 was a strong protective factor for QoL, while the opposite was found by child report. By parent proxy, male sex was significantly associated with lower scores on the parental time impact of QoL. Skinrelated QoL was only slightly altered in this population, and vision-specific QoL was impacted only in patients with bilateral blindness. The majority of findings regarding predictors of QoL in children with NF1 were weak, due to a lack of studies, heterogeneity of samples, and heterogeneity of measurements/predictors assessed. Future studies should examine more comprehensively the psychosocial factors affecting the NF population, especially in young
A.-M. Vranceanu (&) E. R. Park Department of Psychiatry, Massachusetts General Hospital/ Harvard Medical School, ne Bowdoin Square, Boston, MA 02114, USA e-mail: [email protected] V. L. Merker S. R. Plotkin Department of Neurology and Cancer Center, Massachusetts General Hospital/Harvard Medical School, ne Bowdoin Square, Boston, MA 02114, USA
patients with NF2 and schwannomatosis, who have been neglected in prior research. The use of consistent QoL measures is preferred to allow better comparison among studies and conditions. Interventions, including comprehensive mind–body treatments, are warranted to address impaired QoL in children and adolescents with NF1. Keywords Neurofibromatosis 1 Quality of life Children Adolescents
Introduction The neurofibromatoses, which include neurofibromatosis 1(NF1), neurofibromatosis 2 (NF2) and schwannomatosis, are a set of heterogeneous, neurogenetic disorders characterized by multiple nerve sheath tumors. NF1 is characterized by cafe´-au-lait macules, cutaneous neurofibromas, and gliomas; development of plexiform neurofibromas; a high incidence of orthopedic complications; and a relatively high incidence of learning disabilities [1]. NF2 is characterized by bilateral vestibular schwannomas, deafness, tinnitus, and problems with balance [2]. Schwannomatosis is characterized by non-vestibular schwannomas and chronic pain. NF1 is the most common of these disorders (1 in every 2,700 births); NF2 is less common (1 in 33,000 births) [3, 4]. Schwannomatosis is the least common disorder, and only recently have germline mutations in the SMARCB1 and LZTR1 genes been associated with the condition [5]. Advances in genetics have led to the early and/or presymptomatic diagnosis of NF1 and NF2, resulting in an increased prevalence in children and adolescents. The diagnostic criteria for schwannomatosis continue to evolve rapidly but until recently, a diagnosis of schwannomatosis
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in an individual \ 30 years of age was difficult to establish [6]. Even for healthy youth, childhood and adolescence are socially and emotionally challenging phases of life, in which individuals must focus on modulating emotions, negotiating relationships, developing a sense of self, and mastering academics. Periods of rapid growth in adolescence may exacerbate physical deformities [7] at an age when appearance, peer acceptance, and social integration are of paramount importance. Late adolescence is a time of learning about love and sexuality. For individuals with NF, fears about a change in appearance, about the concern that pregnancy may exacerbate physical symptoms, and about the risk of giving birth to an affected child may have complex repercussions on their psychosocial and sexual development. In addition, children and adolescents with NF1 must deal with institutional and sociocultural problems that have a great influence on their life choices. However, no review of QoL in children and adolescents with NF has been performed. A recent systematic review conducted by our team has shown that adult patients with NF1, NF2 and schwannomatosis have lower QoL compared to normal controls [8], and has identified predictors of QoL in this heterogeneous population. The specific aims of this review were: 1) to identify the specific aspects of QoL that are adversely affected in children and adolescents with NF, and 2) to identify predictors of QoL in this population.
Methods We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria [9] to identify, select, and determine eligibility of studies for inclusion in this systematic review. We used a similar methodology to the one employed in the systematic review of QOL in adults with NF [8]. Search strategy/identification Reports of original research studies investigating QoL in children and adolescents affected by NF1, NF2, or schwannomatosis were identified for review. Articles published in peer-reviewed journals as of April 29, 2014
were identified via searches of PubMed and PsychINFO, using the terms neurofibromatosis, schwannomatosis, NF1, and NF2 in conjunction with one or more of the following: quality of life, QoL, health related quality of life, and well being. 183 articles were identified; after removing duplicates, 178 articles remained for screening by abstract. Selection criteria/study eligibility Inclusion and exclusion criteria were defined by the authors a priori (Table 1). 167 studies did not meet inclusion criteria. Of these, 55 studies did not address individuals with a diagnosis of NF, and 112 did not address QoL according to the specific selection criteria (22 reported only biomedical characteristics, 6 cognitive/emotional measures only, 9 addressed adults, 4 were case studies/qualitative reports, 48 were review articles/chapters, 13 were not in English, and 10 were excluded for miscellaneous reasons). A total of 11 abstracts met inclusion criteria and the full-text articles were assessed to determine final eligibility. 3 of these studies were excluded because they did not use a standardized, reliable, and valid measure of QoL, and 1 was not a peer-reviewed publication. Thus, 7 studies were selected for inclusion in the review. Data extraction/quality assessment Two investigators extracted data from the selected studies. A standardized 10-item checklist of predetermined criteria (Table 2) was used to assess the methodological quality of each individual study. The checklist was developed from a previously established criteria list for systematic reviews [10, 11], and modified for the NF population. The modified version was used in a systematic review for adults with NF [8]. There was a 90 % agreement between the two reviewers; all disagreements were resolved upon discussion and review of the articles. Quality assessment for each individual study was done as follows. Each item that met a particular criterion was assigned one point. If an item did not meet the criterion or was described insufficiently, zero points were assigned. The highest possible score was 10 which corresponds to 100 %. Studies scoring 70 % or more of the maximum attainable score corresponding to a score C7 were
Table 1 Selection criteria Inclusion criteria
Exclusion criteria
Original research in peer-reviewed journal
Biomedical description only
Study population of patients with NF1, NF2, and/or schwannomatosis
Cognitive/emotional scales only
Includes children and/or adolescents (individuals \ 18 years old) Use of a standardized, validated QoL measure
Article not available in English Qualitative study, book chapters, reviews or case report
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J Neurooncol Table 2 Criteria for assessing methodological quality of studies included in this review A
Socio-demographic and medical data described (e.g., age, race, employment, education, NF type)
B
Process of data collection clearly described (e.g., interviews, questionnaires)
C
Type of NF described (e.g. NF1, NF2, or schwannomatosis)
D
Results are compared between 2 or more groups (e.g., healthy populations, between patient groups, etc.)
E
Participation and response rate reported and more than 75 %
F
Differences between responders/nonresponders are presented when they exist
G
Results are described also for physical, psychological and social domains when the QoL measure captures that
H
Standard statistics (mean, median, ranges, SD) are present for the main study variables
I
Patients and/or their parents signed an informed consent prior to study participation, and this was explicitly stated in the manuscript
J
Selection of participants is adequately described
Table 3 Level of evidence (adapted from [12]) Strong
Consistent findings (C70 %) in at least 2 high quality studies
Moderate
Consistent findings (C70 %) in one quality study and at least one moderate or low quality study
Weak
Findings in one high quality study or consistent findings (C70 %)in at least 3 or more low quality studies
Inconclusive
Inconsistent findings, or less than 3 low quality studies available
No evidence
No data present
considered ‘‘high quality. ‘‘Studies scoring between 50 and 70 % (corresponding to scores between 5 and 6) were considered of ‘‘moderate quality.’’ Studies scoring lower than 50 % were considered of ‘‘low quality’’ (score B4). Findings regarding predictors of QoL were summarized according to level of evidence [10], (Table 3) and considered consistent if C70 % of the studies that investigated a factor showed the same direction of the association. Consistent with previously determined criteria [12], and prior systematic review in adults with NF [8], level of evidence was considered ‘‘strong’’ when findings were consistent in at least 2 high quality studies; ‘‘moderate’’ if consistent in one high quality study and at least one moderate or low quality study; ‘‘weak’’ if finding was present in one high quality study or if consistent findings were present in at least 3 or more low quality studies; ‘‘inconclusive’’ if findings were inconsistent or less than 3 low quality studies were available; and ‘no evidence’’ when no data was present.
Results Study characteristics A total of 7 studies were included [13–19]. All were crosssectional studies published between 2006 and 2013. All 7 studies included patients with NF1. Taken together, the studies included measures for 265 children and adolescents
with NF (aged 1–18 years), 410 healthy controls, 206 parents, and 460 children/adolescents with other health conditions. Table 4 presents a summary of the studies’ characteristics and findings, as well as their quality scores. The mean quality score for the studies was 8, with a range from 7 to 9. Most studies compared patients with NF1 with population norms for healthy youth and/or youth with acute and chronic illnesses [13, 14, 16–18]. One study compared patients with NF1 with vision loss versus those without vision loss [15]. Finally, one study compared patients with NF1 with healthy patients and other patients with 5 chronic illnesses within the same study [19]. QoL measures The validated instruments used to measure QoL in these studies can be categorized as general and disease-specific measures. Each instrument was used by at least one study included in this review. General measures utilized youth and parent reports, parent report only for infants and toddlers, and adolescent reports only for adolescents. Below we describe the measures, as they were depicted and used in the studies included in this review. The Pediatric Quality of Life Inventory (PedsQL) is a general QoL measure completed by youth and parent proxy. It is is a modular, 23-item multidimensional measure assessing children’s (8-12) and adolescent’s (13–18) perceptions of their QoL during the past month. The PedsQL includes four generic core scales in Physical,
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Study quality score
8
9
9
8
Study
Garwood et al. 2006 [13]
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Oostenbrink et al. 2007 [14]
Avery & Hardy 2013 [15]
Wolkenstein et al. 2008 [16]
79 children with NF1 with variable manifestations and families; comparison with children with norms for youth with asthma and atopic dermatitis
36 children with sporadic or NF1-specific optic pathway gliomas; comparison between children with vision loss versus those without vision loss
34 children with NF1 (13 with complications, and in majority with mild visibility) and 34 families; comparisons with healthy population norms
27 adolescents with NF1 in the minimal to moderate range of severity and 25 families; comparison with youth with acute and chronic illnesses and normal youth norms
Participants
8–16 years M = 12.1
1.8–10.6 years M = 5.1
12–72 months M = 48
12–18 years
Age range (Mean)
Children’s Dermatology Life Quality Index (CDLQI), child selfreport
DISABKIDS, child selfreport and parent proxy
Children’s Visual Function Questionnaire (CVFQ), parent proxy
Infant/Toddler Quality of Life Questionnaire (ITQOL), parent proxy
Functional disability index (FDI), child/adolescent self-report and parent proxy
Pediatric Quality of Life Inventory (PedsQL), child/adolescent selfreport and parent proxy
QoL measure
Table 4 Overview of studies on quality of life among patients with NF1, NF2 and sSchwannomatosis
The CDLQi score was only slightly altered in patients with NF1. The impact of NF1 was significantly lower than that of psoriasis, generalized eczema or acne, but higher than that of naevi (considered as a subnormal sample). Children with plexiform neurofibromas were significantly more impaired on the dimensions of symptoms and feelings, and school or holidays. Dermatological signs such as cafe´ au lait spots and freckling did not significantly impact the CDLQI
Children with NF1 had lower QoL compared to patients with asthma both globally and on the DISABKIDS subscales of independence, social inclusion and social exclusion. Scores were lower on parental versus child reports on the social inclusion and social exclusion subscales. Familial NF1 was associated with higher quality of life when measured by parent proxy report. Learning disabilities were associated with lower QoL in all domains. Orthopedic manifestations were associated with lower QoL in all domains except Social Inclusion. The presence of two or more plexiform neurofibromas was associated with lower QoL in domains of Independence, Social Inclusion, and Emotion
Children with optic pathway glioma-induced vision loss scored significantly lower than children with the same tumors, but no vision loss. Loss of visual acuity was significantly predictive of lower scores on domains of Competence and Family Impact. Children with loss of vision in both eyes had lower scores on Competence and Personality compared to those who lost vision in one eye or did not lose vision. Visual field loss was associated with lower Competence only. Chemotherapy or NF1 were not predictive of CVFQ score
Preschool children with NF1 had significantly lower QoL as compared to population norms on 6 subscales: Physical Functioning, Growth and Development, General Behavior, General Health Perceptions, Parent Emotional Impact, and Parental Time Impact. Presence of NF1-related complications, perceived severity of disease, and disease visibility significantly predicted lower QoL. Bodily pain was a significant predictor of lower QoL scores only for children with documented NF1 complications. Family history of NF1 and parental education predicted improved QoL
Youth ratings of QoL were comparable to youth with other acute and chronic illnesses, and lower than healthy youth. Parents’ ratings of their child’s quality of life were lower than those previously published for chronically and acutely ill children. Emotional functioning (but not pain or cognitive functioning) significantly predicted both youth-reported and parent-reported HRQoL. Total days of pain during the past month predicted higher levels of disability on child self-report but not by parent report. Gender and age did not impact scores on the PedsQL or FDI
General conclusion
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Study quality score
8
7
7
Study
Krab et al. 2009 [17]
Graf et al. 2006 [18]
Spuijbroek et al. 2011 [19]
Table 4 continued
34 children with NF1; comparison with healthy population norms and groups of youth with: bronchiolitis, wheezing illness, functional abdominal complaints, and burns.
46 children with NF1 in majority with mild severity and 43 families; comparison with healthy population norms
comparison with healthy population norms
43 children with NF1 in mild and moderate severity in majority 58 parents
Participants
6 and younger
7-16 years M = 11.15
10-14 years M = 12.2
Age range (Mean)
Infant/Toddler Quality of Life Questionnaire (ITQOL), parent proxy
TNO-AZL Questionnaire for Children’s HealthRelated Quality of Life (TACQOL), child selfreport and parent proxy
Child Health Questionnaire (CHQ), child self-report and parent proxy
QoL measure
QoL in patients with NF1 was comparable to patients with wheezing illness, RSV infection, functional abdominal complaints, and burn injuries, and lower than normal controls. The lowest score was on general health perception for all but burn injuries. Parental time impact and parental emotional impact were significantly lower than the healthy children group. Age predicted bodily pain and family cohesion. Parents of girls reported better scores than parents of boys on the scales ‘general behavior’ and ‘getting along’
By child self report, illness severity and disease visibility were associated with impaired QoL in the domain of positive emotions; visibility was associated with lower QoL in the domain of negative emotions. Familial NF1 was significantly correlated with more physical complaints. Parental QoL report revealed a significant negative correlation between positive emotional functioning and familial NF1. High family cohesion positively affected most QoL domains. Demographics did not predict QoL
Children with NF1 scored lower than population norms on domains of motor, cognitive, social, and emotional functioning on both parent and child reports. Children also scored lower on autonomy only in parental reports
High SES predicted more bodily pain in children’s ratings. Familial NF was predictive of higher self esteem on parents’ ratings. Male sex significantly predicted parental time impact. Severity and general health perception but not NF1 visibility predicted lower QoL. Behavioral problems reported by teacher significantly predicted multiple domains of QoL, including general health, general behavior and parent time impact
Parents, but not children, reported significantly lower QoL compared to normal controls on General Health Perceptions, Physical Functioning, General Behavior, Mental Health, Self Esteem, Family Activities, Role Functioning, and Parent Emotional Impact on HRQOL. Children reported QoL not different than general population norms, except for significantly lower QoL on the bodily Pain subscale and higher QoL on general behavior
General conclusion
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Emotional, Social, and School domains. Both item-level and scale-level measurements have been found to be valid and reliable in both healthy and acutely/chronically ill pediatric populations [20]. For the study in question, the Functional Disability Index (FDI) was used as a complement to PedsQL, as an assessment of functional disability associated with NF1 symptoms. The TNO-AZL Child QoL (TACQOL) is a general QoL measure validated for children and adolescents ages 7–16, designed to parse individuals’ functioning and the way they feel about their functioning [21]. The TACQOL can be completed via self-report and parent proxy. The TACQOL assesses 8 components: physical complaints, basic motor functioning, autonomy, cognitive, social, positive emotional and negative emotional functioning. The Infant/Toddler Quality of Life Questionnaire (ITQOL) is a measure of health related QoL in children 2 months to 5 years old, completed by parent report. The ITQOL includes 47 items on 11 scales to measure aspects of physical functioning, growth and development, pain, temperament and mood, general behavior, getting along, general health perceptions, parental emotional impact, parental time impact, family cohesion, and change in health. The ITQOL has been demonstrated as reliable and valid in early childhood disease populations [22]. The DISABKIDS is a general health questionnaire that was constructed to assess health related QoL in children and adolescents ages 8-16 with chronic health conditions, as well as their families [23]. This holistic measure is completed by self-report and parent proxy. Each item is assigned to 6 dimensions: independence, physical limitations, social inclusion, social exclusion, emotion and treatment. The subscales can be measured separately, or combined to produce a total score. The Child Health Questionnaire (CHQ) is a comprehensive measure assessing the physical, psychological and social aspects of health related QoL in children and adolescents, both healthy populations and those with chronic/ acute health conditions [24]. It has a parent form to be completed by parents of 5-18 year olds, and a child form to be completed by children aged 10 or older. The CHQ contains 14 subscales, within physical and psychosocial domains. Domains include general health perception, physical functioning, role/social physical functioning, bodily pain, role/social emotional functioning, role/social behavioral functioning, parent time impact, parent emotional impact, self esteem, mental health, behavior, family activities, family cohesion, and change in health [24]. The Children’s Visual Function Questionnaire (CVFQ) is a 39 item (or 34 item, for children younger than 3) questionnaire that assesses vision specific QoL by parent proxy [25]. The measure has 4 domains: competence (impact of vision loss on ability to engage in physical
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activity and activity of daily living), personality (peer-interactions, demeanor, enjoyment of life), family impact (impact of self and family) and treatment (not applicable for the young child population). The Children’s Dermatology Quality of Life Index (CDLQI) is a pediatric self-reported disease-specificQoL questionnaire for children with skin diseases, designed to measure disease impact on life [26]. It consists of 10 written questions each with 4 possible replies. The CDLQI is measured under five domains: symptoms and feelings, school or holidays, personal relationships, sleep and treatment. A cartoon version exists for use with young children, and was used in the study included in this review. QoL specific results Overall, children and adolescents with NF1 reported lower global QoL compared to population norms. Parent-reported measures on the ITQOL revealed significantly lower HRQoL in preschool children with NF1 when compared to population norms on six subscales [14]. These subscales included: Physical Functioning, Growth and Development, General Behavior, General Health Perceptions, Parent Emotional Impact, and Parental Time Impact. Older children with NF1 (7–16 year old) scored lower than population norms on the TACQOL domains of motor, cognitive, social functioning, and emotional functioning on both parent and child reports [18]. However, in a study using the CHQ with patients aged 10–14 years, the Bodily Pain QoL subscale was the only domain in which children reported lower than normal QoL [17]. In this study, youth and parents reported fairly low levels of functional disability, although there was a considerable range with some reports of moderate impairment [17]. Regarding disease-specific QoL, young children (1–10 years old) with optic pathway glioma-induced vision loss scored significantly lower on parent reports of visionspecific quality of life than children with the same tumors but no vision loss. However, this deficit was true in both children with and without NF1, and children with NF1associated optic pathway gliomas did not have worse quality of life than children with sporadic tumors [15]. By child report on the CDLQI, skin-specific QoL was only slightly lowered in children with NF1 ages 8–16 [16]. Parents’ ratings of their child’s QoL were lower than child self-ratings on both the CHQ and TACQOL [17, 18]. Parent ratings on the TACQOL were also lower than previously published parent ratings for chronically and acutely ill youth [18]. Interestingly, while parents reported significantly lower QoL on multiple domains of the CHQ compared to normal controls, children (10–14 years old) generally reported their own QoL as not different from population norms [17].
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A number of studies compared QoL ratings from children and adolescents with NF1 to patients with other disorders. Child self-report ratings on the TACQOL were comparable to those of youth with acute and chronic illnesses [18]. In addition, ITQOL scores in children with NF1 were comparable to those for young children with wheezing illness, RSV infection, functional abdominal complaints, and burn injuries [19]. On the DISABKIDS measure, children with NF1 reported lower QoL on domains of independence, social inclusion and social exclusion than children with asthma, but significantly better QoL related to physical limitations [16]. Finally, the impact of childhood NF1 on skin-specific QoL was significantly lower than that of psoriasis, generalized eczema or acne, but higher than that of nevi considered as a subnormal sample [16]. Predictors of QoL The predictors of QoL assessed by each article are listed in Table 5. Strong evidence was found that having familial NF1 (as opposed to sporadic NF1) serves as a protective factor in parental reports of QoL for children of all ages. In contrast, the evidence of the role of familial NF1 in children’s reports was weak, with only one study showing an association, which was in the opposite direction of parental reports. This study found that familial NF1 is associated with more physical complaints in children aged 7–16 [18]. Strong evidence was also found for the lack of association between reports of bodily pain and QoL (in 1–6 year olds and 12–18 year olds [13, 14]), with the exception of patients with specific NF1 complications, where bodily pain was negatively associated with QoL in children 1–6 year old [14]. Strong evidence was also found that males had lower scores on parental time impact QoL by parent report for 1–6 year olds and 10–14 year olds [14, 17]. All other relationships between predictors and QoL were weak (see Table 5), due to presence of only one qualifying study assessing the specific predictor. In sum, levels of emotional functioning, cognitive functioning, learning disabilities, orthopedic problems, presence of plexiform neurofibromas, severity and general health perceptions by parent proxy, and behavioral problems by teacher report were significantly associated with lower QoL. Parental education and family cohesion were positively associated with QoL. Age was not significantly associated with QoL. By parent proxy, disease visibility was not associated with QoL, while, by child report, severity and visibility were significantly associated with lower QoL. Results were also weak for skin related QoL, where presence of 4–5 plexiform neurofibromas but not cafe´ au lait and freckling negatively predicted QoL [16]. Similarly,
loss of visual acuity, visual field, and bilateral loss of vision significantly predicted lower vision related QoL [15].
Discussion This systematic review summarizes the results of 7 studies on the quality of life of children and adolescents affected by NF1. All studies received high quality ratings. No studies on NF2 or schwanommatosis met inclusion criteria, likely due to the low prevalence of these conditions and the lack of recognition by health providers. When studies assessed general QoL, this was lower in youth with NF1 compared to the general population in at least some subdomains, regardless of the instrument used [13, 14, 17–19]. Parental reports of QoL were generally lower than the child self-reports [13, 16, 17]. This finding is consistent with results reported in other samples of children and adolescents with various chronic illnesses [27–29]. Contrary to expectations, when a skin specific QoL measure was used in one study [16], QoL was only slightly altered, and not as impaired as that of patients with skin conditions such as eczema and psoriasis. This is likely because cutaneous neurofibromas typically develop in adolescence but don’t become a major concern until mid 20 s and later. When a vision specific QoL measure was used in one study [15] in patients with optic pathway gliomas, QoL was lower for children with vision loss versus those without vision loss according to parental reports. Results concerning predictors of QoL in children and adolescents provide inconclusive results due to low number of studies and heterogeneity of predictors assessed. Results somewhat differed between parental versus children reports. For example, by parent report there was a strong protective effect of familial NF on children’s QoL, but by child reports there was an association between more physical complaints and familial NF in one study [18]. This reflects not only a general perception difference in parents versus children, but also parental misinterpretations of their children’s QoL, as well as the role of their own NF in their child’s adjustment. Contrary to expectations, strong evidence was found for the lack of association between bodily pain and QoL in 2 studies of very young children and adolescents [13, 14]. This finding, combined with the inconclusive evidence for an association between pain and QoL in patients with NF1 complications suggests that children and adolescents have generally low pain or that they are able to manage it appropriately, but that additional pain associated with complications impacts QoL. Strong evidence was found for male sex in predicting more parental time impact stress in studies of very young children and adolescents.
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J Neurooncol Table 5 Predictors of QOL in NF1 Possible predictor
Direction of association
Strong evidence
Weak evidence
Inconclusive
Age of youth
General QoL—parent proxy Emotional functioning (13)
Negative
Pain (13, 14)
No association
X X
12–18 12–18 12–72 months
Negative for children with NF complications
X
12–72 months
Cognitive functioning (13)
Negative
X
12–18
Gender (13) Male sex (17, 19)
No association Negative
X
12–18 10–14
Age (13)
No association
Familial NF1 (14, 16, 17, 18)
Positive
Parental education (14)
Positive
X
8–16
Learning disabilities (16)
Negative
X
8–16
Orthopedic problems (16)
Negative
X
8–16
Visibility (17)
No association
X
10–14
Plexiform neurofibromas (16)
Negative
X
8–16
Severity (18)
Negative
X
7–16
General Health Perception (18) Behavioral problems from teacher (18)
Negative Negative
X X
7–16 7–16
High family cohesion (16)
Positive
X
7–16
X
12–72 months 12–18 X
12–72 months; 8–16 years
General QoL—youth report Emotional functioning (11)
Negative
X
12–18
Pain (11)
No association
X
12–18
Cognitive functioning (11)
Negative
X
12–18
Gender (11)
No association
X
12–18
Age (11)
No association
X
12–18
Severity (16)
Negative
X
7–16
Visibility (16)
Negative
X
7–16
Familial NF1 (16)
Negative
X
7–16
Specific QoL measures Skin related QoL (14) Plexiform neurofibromas Cafe´ au lait, freckeling
Negative
X
8–16
No association
X
8–16
Negative
X
1.75–10.58
Loss of visual field
Negative
X
1.75–10.58
Loss of bilateral vision
Negative
X
1.75–10.58
Vision related QoL (13) Loss of visual acuity
Studies examining predictors of QoL in children/adolescents mirror those in adults, and were mostly focused on disease-related variables; this resulted in mixed evidence regarding the importance of factors such as clinical severity in influencing QoL. Only one study [13] assessed the role of emotional functioning in predicting QoL, thus being
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considered weak evidence. Given the strong association of psychosocial factors with QoL reported for other chronic illnesses [30, 31] it is important to increase the body of research exploring the impact of psychosocial factors on QOL in patients with NF, particularly in light of the lack of cure and limitations of medical treatments in this
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population. Only a few studies thus far assessed the role of psychosocial factors in children and adolescents with NF, and these did not explore associations with QOL [32, 33]. The development of adolescent specific mind body interventions addressing QoL could be particularly important; such interventions are generally inexpensive, and have the potential to positively influence the life trajectory of young patients with NF. A novel mind body intervention has recently been shown to have promising results in improving QoL and psychosocial factors in adults with NF [34] and it may be efficacious, with mild adaptation, for children and adolescents in need. Despite the strong methodology in all studies that met inclusionary criteria, results described in this review were partly weak or inconclusive due to heterogeneity of the NF population (age, severity, complications), small number of studies), and heterogeneity of measurements. The Response Endpoints in Neurofibromatosis and Schwannomatosis (REINS) International Collaboration is working on determining specific measures that can be used consistently in the NF research; this is an important endeavor that has the potential to allow for more conclusive reports in NF specific Qol research in the future [35]. In conclusion this review shows that children and adolescents with NF1 suffer from impaired general QoL, and that generally parents’ perception of their children’s QoL is lower than children’s reports. Because of the small number of studies, results should not be generalized to all children with NF. The field of QoL research in children and adolescents with NF will be advanced by uniting around a clear conceptualization of QoL using consistent scales, addressing the potential predictive role of psychosocial factors, using prospective studies, thoroughly describing the samples to facilitate comparisons among studies, and attending also to children/adolescents with NF2 and schwannomatosis. This research will yield more potent evidence for clinical applications and interventions to facilitate improvements in the healthcare and development of mind body interventions for both children/adolescents with NF and their parents.
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17. Conflict of interest of interest.
The authors declare that they have no conflict 18.
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TOPIC REVIEW
Quality of life among children and adolescents with neurofibromatosis 1: a systematic review of the literature Ana-Maria Vranceanu • Vanessa L. Merker Elyse R. Park • Scott R. Plotkin
•
Received: 1 August 2014 / Accepted: 1 February 2015 Ó Springer Science+Business Media New York 2015
Abstract The aim of this research is to identify, within a systematic review, aspects of quality of life (QoL) that are adversely affected in children and adolescents with neurofibromatosis (NF), and to report predictors of quality of life in this population. Published reports of original research were included if they described QoL in children and/or adolescents with NF, and met methodological quality according to a list of predefined criteria. Seven studies conducted between 2006 and 2013 met inclusion criteria. All seven studies examined patients with NF1 and reported that these patients have lower general QoL compared to population norms. Parents’ proxy ratings of QoL were generally lower than children’s self-report ratings. By parent proxy, familial NF1 was a strong protective factor for QoL, while the opposite was found by child report. By parent proxy, male sex was significantly associated with lower scores on the parental time impact of QoL. Skinrelated QoL was only slightly altered in this population, and vision-specific QoL was impacted only in patients with bilateral blindness. The majority of findings regarding predictors of QoL in children with NF1 were weak, due to a lack of studies, heterogeneity of samples, and heterogeneity of measurements/predictors assessed. Future studies should examine more comprehensively the psychosocial factors affecting the NF population, especially in young
A.-M. Vranceanu (&) E. R. Park Department of Psychiatry, Massachusetts General Hospital/ Harvard Medical School, ne Bowdoin Square, Boston, MA 02114, USA e-mail: [email protected] V. L. Merker S. R. Plotkin Department of Neurology and Cancer Center, Massachusetts General Hospital/Harvard Medical School, ne Bowdoin Square, Boston, MA 02114, USA
patients with NF2 and schwannomatosis, who have been neglected in prior research. The use of consistent QoL measures is preferred to allow better comparison among studies and conditions. Interventions, including comprehensive mind–body treatments, are warranted to address impaired QoL in children and adolescents with NF1. Keywords Neurofibromatosis 1 Quality of life Children Adolescents
Introduction The neurofibromatoses, which include neurofibromatosis 1(NF1), neurofibromatosis 2 (NF2) and schwannomatosis, are a set of heterogeneous, neurogenetic disorders characterized by multiple nerve sheath tumors. NF1 is characterized by cafe´-au-lait macules, cutaneous neurofibromas, and gliomas; development of plexiform neurofibromas; a high incidence of orthopedic complications; and a relatively high incidence of learning disabilities [1]. NF2 is characterized by bilateral vestibular schwannomas, deafness, tinnitus, and problems with balance [2]. Schwannomatosis is characterized by non-vestibular schwannomas and chronic pain. NF1 is the most common of these disorders (1 in every 2,700 births); NF2 is less common (1 in 33,000 births) [3, 4]. Schwannomatosis is the least common disorder, and only recently have germline mutations in the SMARCB1 and LZTR1 genes been associated with the condition [5]. Advances in genetics have led to the early and/or presymptomatic diagnosis of NF1 and NF2, resulting in an increased prevalence in children and adolescents. The diagnostic criteria for schwannomatosis continue to evolve rapidly but until recently, a diagnosis of schwannomatosis
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in an individual \ 30 years of age was difficult to establish [6]. Even for healthy youth, childhood and adolescence are socially and emotionally challenging phases of life, in which individuals must focus on modulating emotions, negotiating relationships, developing a sense of self, and mastering academics. Periods of rapid growth in adolescence may exacerbate physical deformities [7] at an age when appearance, peer acceptance, and social integration are of paramount importance. Late adolescence is a time of learning about love and sexuality. For individuals with NF, fears about a change in appearance, about the concern that pregnancy may exacerbate physical symptoms, and about the risk of giving birth to an affected child may have complex repercussions on their psychosocial and sexual development. In addition, children and adolescents with NF1 must deal with institutional and sociocultural problems that have a great influence on their life choices. However, no review of QoL in children and adolescents with NF has been performed. A recent systematic review conducted by our team has shown that adult patients with NF1, NF2 and schwannomatosis have lower QoL compared to normal controls [8], and has identified predictors of QoL in this heterogeneous population. The specific aims of this review were: 1) to identify the specific aspects of QoL that are adversely affected in children and adolescents with NF, and 2) to identify predictors of QoL in this population.
Methods We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria [9] to identify, select, and determine eligibility of studies for inclusion in this systematic review. We used a similar methodology to the one employed in the systematic review of QOL in adults with NF [8]. Search strategy/identification Reports of original research studies investigating QoL in children and adolescents affected by NF1, NF2, or schwannomatosis were identified for review. Articles published in peer-reviewed journals as of April 29, 2014
were identified via searches of PubMed and PsychINFO, using the terms neurofibromatosis, schwannomatosis, NF1, and NF2 in conjunction with one or more of the following: quality of life, QoL, health related quality of life, and well being. 183 articles were identified; after removing duplicates, 178 articles remained for screening by abstract. Selection criteria/study eligibility Inclusion and exclusion criteria were defined by the authors a priori (Table 1). 167 studies did not meet inclusion criteria. Of these, 55 studies did not address individuals with a diagnosis of NF, and 112 did not address QoL according to the specific selection criteria (22 reported only biomedical characteristics, 6 cognitive/emotional measures only, 9 addressed adults, 4 were case studies/qualitative reports, 48 were review articles/chapters, 13 were not in English, and 10 were excluded for miscellaneous reasons). A total of 11 abstracts met inclusion criteria and the full-text articles were assessed to determine final eligibility. 3 of these studies were excluded because they did not use a standardized, reliable, and valid measure of QoL, and 1 was not a peer-reviewed publication. Thus, 7 studies were selected for inclusion in the review. Data extraction/quality assessment Two investigators extracted data from the selected studies. A standardized 10-item checklist of predetermined criteria (Table 2) was used to assess the methodological quality of each individual study. The checklist was developed from a previously established criteria list for systematic reviews [10, 11], and modified for the NF population. The modified version was used in a systematic review for adults with NF [8]. There was a 90 % agreement between the two reviewers; all disagreements were resolved upon discussion and review of the articles. Quality assessment for each individual study was done as follows. Each item that met a particular criterion was assigned one point. If an item did not meet the criterion or was described insufficiently, zero points were assigned. The highest possible score was 10 which corresponds to 100 %. Studies scoring 70 % or more of the maximum attainable score corresponding to a score C7 were
Table 1 Selection criteria Inclusion criteria
Exclusion criteria
Original research in peer-reviewed journal
Biomedical description only
Study population of patients with NF1, NF2, and/or schwannomatosis
Cognitive/emotional scales only
Includes children and/or adolescents (individuals \ 18 years old) Use of a standardized, validated QoL measure
Article not available in English Qualitative study, book chapters, reviews or case report
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J Neurooncol Table 2 Criteria for assessing methodological quality of studies included in this review A
Socio-demographic and medical data described (e.g., age, race, employment, education, NF type)
B
Process of data collection clearly described (e.g., interviews, questionnaires)
C
Type of NF described (e.g. NF1, NF2, or schwannomatosis)
D
Results are compared between 2 or more groups (e.g., healthy populations, between patient groups, etc.)
E
Participation and response rate reported and more than 75 %
F
Differences between responders/nonresponders are presented when they exist
G
Results are described also for physical, psychological and social domains when the QoL measure captures that
H
Standard statistics (mean, median, ranges, SD) are present for the main study variables
I
Patients and/or their parents signed an informed consent prior to study participation, and this was explicitly stated in the manuscript
J
Selection of participants is adequately described
Table 3 Level of evidence (adapted from [12]) Strong
Consistent findings (C70 %) in at least 2 high quality studies
Moderate
Consistent findings (C70 %) in one quality study and at least one moderate or low quality study
Weak
Findings in one high quality study or consistent findings (C70 %)in at least 3 or more low quality studies
Inconclusive
Inconsistent findings, or less than 3 low quality studies available
No evidence
No data present
considered ‘‘high quality. ‘‘Studies scoring between 50 and 70 % (corresponding to scores between 5 and 6) were considered of ‘‘moderate quality.’’ Studies scoring lower than 50 % were considered of ‘‘low quality’’ (score B4). Findings regarding predictors of QoL were summarized according to level of evidence [10], (Table 3) and considered consistent if C70 % of the studies that investigated a factor showed the same direction of the association. Consistent with previously determined criteria [12], and prior systematic review in adults with NF [8], level of evidence was considered ‘‘strong’’ when findings were consistent in at least 2 high quality studies; ‘‘moderate’’ if consistent in one high quality study and at least one moderate or low quality study; ‘‘weak’’ if finding was present in one high quality study or if consistent findings were present in at least 3 or more low quality studies; ‘‘inconclusive’’ if findings were inconsistent or less than 3 low quality studies were available; and ‘no evidence’’ when no data was present.
Results Study characteristics A total of 7 studies were included [13–19]. All were crosssectional studies published between 2006 and 2013. All 7 studies included patients with NF1. Taken together, the studies included measures for 265 children and adolescents
with NF (aged 1–18 years), 410 healthy controls, 206 parents, and 460 children/adolescents with other health conditions. Table 4 presents a summary of the studies’ characteristics and findings, as well as their quality scores. The mean quality score for the studies was 8, with a range from 7 to 9. Most studies compared patients with NF1 with population norms for healthy youth and/or youth with acute and chronic illnesses [13, 14, 16–18]. One study compared patients with NF1 with vision loss versus those without vision loss [15]. Finally, one study compared patients with NF1 with healthy patients and other patients with 5 chronic illnesses within the same study [19]. QoL measures The validated instruments used to measure QoL in these studies can be categorized as general and disease-specific measures. Each instrument was used by at least one study included in this review. General measures utilized youth and parent reports, parent report only for infants and toddlers, and adolescent reports only for adolescents. Below we describe the measures, as they were depicted and used in the studies included in this review. The Pediatric Quality of Life Inventory (PedsQL) is a general QoL measure completed by youth and parent proxy. It is is a modular, 23-item multidimensional measure assessing children’s (8-12) and adolescent’s (13–18) perceptions of their QoL during the past month. The PedsQL includes four generic core scales in Physical,
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Study quality score
8
9
9
8
Study
Garwood et al. 2006 [13]
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Oostenbrink et al. 2007 [14]
Avery & Hardy 2013 [15]
Wolkenstein et al. 2008 [16]
79 children with NF1 with variable manifestations and families; comparison with children with norms for youth with asthma and atopic dermatitis
36 children with sporadic or NF1-specific optic pathway gliomas; comparison between children with vision loss versus those without vision loss
34 children with NF1 (13 with complications, and in majority with mild visibility) and 34 families; comparisons with healthy population norms
27 adolescents with NF1 in the minimal to moderate range of severity and 25 families; comparison with youth with acute and chronic illnesses and normal youth norms
Participants
8–16 years M = 12.1
1.8–10.6 years M = 5.1
12–72 months M = 48
12–18 years
Age range (Mean)
Children’s Dermatology Life Quality Index (CDLQI), child selfreport
DISABKIDS, child selfreport and parent proxy
Children’s Visual Function Questionnaire (CVFQ), parent proxy
Infant/Toddler Quality of Life Questionnaire (ITQOL), parent proxy
Functional disability index (FDI), child/adolescent self-report and parent proxy
Pediatric Quality of Life Inventory (PedsQL), child/adolescent selfreport and parent proxy
QoL measure
Table 4 Overview of studies on quality of life among patients with NF1, NF2 and sSchwannomatosis
The CDLQi score was only slightly altered in patients with NF1. The impact of NF1 was significantly lower than that of psoriasis, generalized eczema or acne, but higher than that of naevi (considered as a subnormal sample). Children with plexiform neurofibromas were significantly more impaired on the dimensions of symptoms and feelings, and school or holidays. Dermatological signs such as cafe´ au lait spots and freckling did not significantly impact the CDLQI
Children with NF1 had lower QoL compared to patients with asthma both globally and on the DISABKIDS subscales of independence, social inclusion and social exclusion. Scores were lower on parental versus child reports on the social inclusion and social exclusion subscales. Familial NF1 was associated with higher quality of life when measured by parent proxy report. Learning disabilities were associated with lower QoL in all domains. Orthopedic manifestations were associated with lower QoL in all domains except Social Inclusion. The presence of two or more plexiform neurofibromas was associated with lower QoL in domains of Independence, Social Inclusion, and Emotion
Children with optic pathway glioma-induced vision loss scored significantly lower than children with the same tumors, but no vision loss. Loss of visual acuity was significantly predictive of lower scores on domains of Competence and Family Impact. Children with loss of vision in both eyes had lower scores on Competence and Personality compared to those who lost vision in one eye or did not lose vision. Visual field loss was associated with lower Competence only. Chemotherapy or NF1 were not predictive of CVFQ score
Preschool children with NF1 had significantly lower QoL as compared to population norms on 6 subscales: Physical Functioning, Growth and Development, General Behavior, General Health Perceptions, Parent Emotional Impact, and Parental Time Impact. Presence of NF1-related complications, perceived severity of disease, and disease visibility significantly predicted lower QoL. Bodily pain was a significant predictor of lower QoL scores only for children with documented NF1 complications. Family history of NF1 and parental education predicted improved QoL
Youth ratings of QoL were comparable to youth with other acute and chronic illnesses, and lower than healthy youth. Parents’ ratings of their child’s quality of life were lower than those previously published for chronically and acutely ill children. Emotional functioning (but not pain or cognitive functioning) significantly predicted both youth-reported and parent-reported HRQoL. Total days of pain during the past month predicted higher levels of disability on child self-report but not by parent report. Gender and age did not impact scores on the PedsQL or FDI
General conclusion
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Study quality score
8
7
7
Study
Krab et al. 2009 [17]
Graf et al. 2006 [18]
Spuijbroek et al. 2011 [19]
Table 4 continued
34 children with NF1; comparison with healthy population norms and groups of youth with: bronchiolitis, wheezing illness, functional abdominal complaints, and burns.
46 children with NF1 in majority with mild severity and 43 families; comparison with healthy population norms
comparison with healthy population norms
43 children with NF1 in mild and moderate severity in majority 58 parents
Participants
6 and younger
7-16 years M = 11.15
10-14 years M = 12.2
Age range (Mean)
Infant/Toddler Quality of Life Questionnaire (ITQOL), parent proxy
TNO-AZL Questionnaire for Children’s HealthRelated Quality of Life (TACQOL), child selfreport and parent proxy
Child Health Questionnaire (CHQ), child self-report and parent proxy
QoL measure
QoL in patients with NF1 was comparable to patients with wheezing illness, RSV infection, functional abdominal complaints, and burn injuries, and lower than normal controls. The lowest score was on general health perception for all but burn injuries. Parental time impact and parental emotional impact were significantly lower than the healthy children group. Age predicted bodily pain and family cohesion. Parents of girls reported better scores than parents of boys on the scales ‘general behavior’ and ‘getting along’
By child self report, illness severity and disease visibility were associated with impaired QoL in the domain of positive emotions; visibility was associated with lower QoL in the domain of negative emotions. Familial NF1 was significantly correlated with more physical complaints. Parental QoL report revealed a significant negative correlation between positive emotional functioning and familial NF1. High family cohesion positively affected most QoL domains. Demographics did not predict QoL
Children with NF1 scored lower than population norms on domains of motor, cognitive, social, and emotional functioning on both parent and child reports. Children also scored lower on autonomy only in parental reports
High SES predicted more bodily pain in children’s ratings. Familial NF was predictive of higher self esteem on parents’ ratings. Male sex significantly predicted parental time impact. Severity and general health perception but not NF1 visibility predicted lower QoL. Behavioral problems reported by teacher significantly predicted multiple domains of QoL, including general health, general behavior and parent time impact
Parents, but not children, reported significantly lower QoL compared to normal controls on General Health Perceptions, Physical Functioning, General Behavior, Mental Health, Self Esteem, Family Activities, Role Functioning, and Parent Emotional Impact on HRQOL. Children reported QoL not different than general population norms, except for significantly lower QoL on the bodily Pain subscale and higher QoL on general behavior
General conclusion
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Emotional, Social, and School domains. Both item-level and scale-level measurements have been found to be valid and reliable in both healthy and acutely/chronically ill pediatric populations [20]. For the study in question, the Functional Disability Index (FDI) was used as a complement to PedsQL, as an assessment of functional disability associated with NF1 symptoms. The TNO-AZL Child QoL (TACQOL) is a general QoL measure validated for children and adolescents ages 7–16, designed to parse individuals’ functioning and the way they feel about their functioning [21]. The TACQOL can be completed via self-report and parent proxy. The TACQOL assesses 8 components: physical complaints, basic motor functioning, autonomy, cognitive, social, positive emotional and negative emotional functioning. The Infant/Toddler Quality of Life Questionnaire (ITQOL) is a measure of health related QoL in children 2 months to 5 years old, completed by parent report. The ITQOL includes 47 items on 11 scales to measure aspects of physical functioning, growth and development, pain, temperament and mood, general behavior, getting along, general health perceptions, parental emotional impact, parental time impact, family cohesion, and change in health. The ITQOL has been demonstrated as reliable and valid in early childhood disease populations [22]. The DISABKIDS is a general health questionnaire that was constructed to assess health related QoL in children and adolescents ages 8-16 with chronic health conditions, as well as their families [23]. This holistic measure is completed by self-report and parent proxy. Each item is assigned to 6 dimensions: independence, physical limitations, social inclusion, social exclusion, emotion and treatment. The subscales can be measured separately, or combined to produce a total score. The Child Health Questionnaire (CHQ) is a comprehensive measure assessing the physical, psychological and social aspects of health related QoL in children and adolescents, both healthy populations and those with chronic/ acute health conditions [24]. It has a parent form to be completed by parents of 5-18 year olds, and a child form to be completed by children aged 10 or older. The CHQ contains 14 subscales, within physical and psychosocial domains. Domains include general health perception, physical functioning, role/social physical functioning, bodily pain, role/social emotional functioning, role/social behavioral functioning, parent time impact, parent emotional impact, self esteem, mental health, behavior, family activities, family cohesion, and change in health [24]. The Children’s Visual Function Questionnaire (CVFQ) is a 39 item (or 34 item, for children younger than 3) questionnaire that assesses vision specific QoL by parent proxy [25]. The measure has 4 domains: competence (impact of vision loss on ability to engage in physical
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activity and activity of daily living), personality (peer-interactions, demeanor, enjoyment of life), family impact (impact of self and family) and treatment (not applicable for the young child population). The Children’s Dermatology Quality of Life Index (CDLQI) is a pediatric self-reported disease-specificQoL questionnaire for children with skin diseases, designed to measure disease impact on life [26]. It consists of 10 written questions each with 4 possible replies. The CDLQI is measured under five domains: symptoms and feelings, school or holidays, personal relationships, sleep and treatment. A cartoon version exists for use with young children, and was used in the study included in this review. QoL specific results Overall, children and adolescents with NF1 reported lower global QoL compared to population norms. Parent-reported measures on the ITQOL revealed significantly lower HRQoL in preschool children with NF1 when compared to population norms on six subscales [14]. These subscales included: Physical Functioning, Growth and Development, General Behavior, General Health Perceptions, Parent Emotional Impact, and Parental Time Impact. Older children with NF1 (7–16 year old) scored lower than population norms on the TACQOL domains of motor, cognitive, social functioning, and emotional functioning on both parent and child reports [18]. However, in a study using the CHQ with patients aged 10–14 years, the Bodily Pain QoL subscale was the only domain in which children reported lower than normal QoL [17]. In this study, youth and parents reported fairly low levels of functional disability, although there was a considerable range with some reports of moderate impairment [17]. Regarding disease-specific QoL, young children (1–10 years old) with optic pathway glioma-induced vision loss scored significantly lower on parent reports of visionspecific quality of life than children with the same tumors but no vision loss. However, this deficit was true in both children with and without NF1, and children with NF1associated optic pathway gliomas did not have worse quality of life than children with sporadic tumors [15]. By child report on the CDLQI, skin-specific QoL was only slightly lowered in children with NF1 ages 8–16 [16]. Parents’ ratings of their child’s QoL were lower than child self-ratings on both the CHQ and TACQOL [17, 18]. Parent ratings on the TACQOL were also lower than previously published parent ratings for chronically and acutely ill youth [18]. Interestingly, while parents reported significantly lower QoL on multiple domains of the CHQ compared to normal controls, children (10–14 years old) generally reported their own QoL as not different from population norms [17].
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A number of studies compared QoL ratings from children and adolescents with NF1 to patients with other disorders. Child self-report ratings on the TACQOL were comparable to those of youth with acute and chronic illnesses [18]. In addition, ITQOL scores in children with NF1 were comparable to those for young children with wheezing illness, RSV infection, functional abdominal complaints, and burn injuries [19]. On the DISABKIDS measure, children with NF1 reported lower QoL on domains of independence, social inclusion and social exclusion than children with asthma, but significantly better QoL related to physical limitations [16]. Finally, the impact of childhood NF1 on skin-specific QoL was significantly lower than that of psoriasis, generalized eczema or acne, but higher than that of nevi considered as a subnormal sample [16]. Predictors of QoL The predictors of QoL assessed by each article are listed in Table 5. Strong evidence was found that having familial NF1 (as opposed to sporadic NF1) serves as a protective factor in parental reports of QoL for children of all ages. In contrast, the evidence of the role of familial NF1 in children’s reports was weak, with only one study showing an association, which was in the opposite direction of parental reports. This study found that familial NF1 is associated with more physical complaints in children aged 7–16 [18]. Strong evidence was also found for the lack of association between reports of bodily pain and QoL (in 1–6 year olds and 12–18 year olds [13, 14]), with the exception of patients with specific NF1 complications, where bodily pain was negatively associated with QoL in children 1–6 year old [14]. Strong evidence was also found that males had lower scores on parental time impact QoL by parent report for 1–6 year olds and 10–14 year olds [14, 17]. All other relationships between predictors and QoL were weak (see Table 5), due to presence of only one qualifying study assessing the specific predictor. In sum, levels of emotional functioning, cognitive functioning, learning disabilities, orthopedic problems, presence of plexiform neurofibromas, severity and general health perceptions by parent proxy, and behavioral problems by teacher report were significantly associated with lower QoL. Parental education and family cohesion were positively associated with QoL. Age was not significantly associated with QoL. By parent proxy, disease visibility was not associated with QoL, while, by child report, severity and visibility were significantly associated with lower QoL. Results were also weak for skin related QoL, where presence of 4–5 plexiform neurofibromas but not cafe´ au lait and freckling negatively predicted QoL [16]. Similarly,
loss of visual acuity, visual field, and bilateral loss of vision significantly predicted lower vision related QoL [15].
Discussion This systematic review summarizes the results of 7 studies on the quality of life of children and adolescents affected by NF1. All studies received high quality ratings. No studies on NF2 or schwanommatosis met inclusion criteria, likely due to the low prevalence of these conditions and the lack of recognition by health providers. When studies assessed general QoL, this was lower in youth with NF1 compared to the general population in at least some subdomains, regardless of the instrument used [13, 14, 17–19]. Parental reports of QoL were generally lower than the child self-reports [13, 16, 17]. This finding is consistent with results reported in other samples of children and adolescents with various chronic illnesses [27–29]. Contrary to expectations, when a skin specific QoL measure was used in one study [16], QoL was only slightly altered, and not as impaired as that of patients with skin conditions such as eczema and psoriasis. This is likely because cutaneous neurofibromas typically develop in adolescence but don’t become a major concern until mid 20 s and later. When a vision specific QoL measure was used in one study [15] in patients with optic pathway gliomas, QoL was lower for children with vision loss versus those without vision loss according to parental reports. Results concerning predictors of QoL in children and adolescents provide inconclusive results due to low number of studies and heterogeneity of predictors assessed. Results somewhat differed between parental versus children reports. For example, by parent report there was a strong protective effect of familial NF on children’s QoL, but by child reports there was an association between more physical complaints and familial NF in one study [18]. This reflects not only a general perception difference in parents versus children, but also parental misinterpretations of their children’s QoL, as well as the role of their own NF in their child’s adjustment. Contrary to expectations, strong evidence was found for the lack of association between bodily pain and QoL in 2 studies of very young children and adolescents [13, 14]. This finding, combined with the inconclusive evidence for an association between pain and QoL in patients with NF1 complications suggests that children and adolescents have generally low pain or that they are able to manage it appropriately, but that additional pain associated with complications impacts QoL. Strong evidence was found for male sex in predicting more parental time impact stress in studies of very young children and adolescents.
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J Neurooncol Table 5 Predictors of QOL in NF1 Possible predictor
Direction of association
Strong evidence
Weak evidence
Inconclusive
Age of youth
General QoL—parent proxy Emotional functioning (13)
Negative
Pain (13, 14)
No association
X X
12–18 12–18 12–72 months
Negative for children with NF complications
X
12–72 months
Cognitive functioning (13)
Negative
X
12–18
Gender (13) Male sex (17, 19)
No association Negative
X
12–18 10–14
Age (13)
No association
Familial NF1 (14, 16, 17, 18)
Positive
Parental education (14)
Positive
X
8–16
Learning disabilities (16)
Negative
X
8–16
Orthopedic problems (16)
Negative
X
8–16
Visibility (17)
No association
X
10–14
Plexiform neurofibromas (16)
Negative
X
8–16
Severity (18)
Negative
X
7–16
General Health Perception (18) Behavioral problems from teacher (18)
Negative Negative
X X
7–16 7–16
High family cohesion (16)
Positive
X
7–16
X
12–72 months 12–18 X
12–72 months; 8–16 years
General QoL—youth report Emotional functioning (11)
Negative
X
12–18
Pain (11)
No association
X
12–18
Cognitive functioning (11)
Negative
X
12–18
Gender (11)
No association
X
12–18
Age (11)
No association
X
12–18
Severity (16)
Negative
X
7–16
Visibility (16)
Negative
X
7–16
Familial NF1 (16)
Negative
X
7–16
Specific QoL measures Skin related QoL (14) Plexiform neurofibromas Cafe´ au lait, freckeling
Negative
X
8–16
No association
X
8–16
Negative
X
1.75–10.58
Loss of visual field
Negative
X
1.75–10.58
Loss of bilateral vision
Negative
X
1.75–10.58
Vision related QoL (13) Loss of visual acuity
Studies examining predictors of QoL in children/adolescents mirror those in adults, and were mostly focused on disease-related variables; this resulted in mixed evidence regarding the importance of factors such as clinical severity in influencing QoL. Only one study [13] assessed the role of emotional functioning in predicting QoL, thus being
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considered weak evidence. Given the strong association of psychosocial factors with QoL reported for other chronic illnesses [30, 31] it is important to increase the body of research exploring the impact of psychosocial factors on QOL in patients with NF, particularly in light of the lack of cure and limitations of medical treatments in this
J Neurooncol
population. Only a few studies thus far assessed the role of psychosocial factors in children and adolescents with NF, and these did not explore associations with QOL [32, 33]. The development of adolescent specific mind body interventions addressing QoL could be particularly important; such interventions are generally inexpensive, and have the potential to positively influence the life trajectory of young patients with NF. A novel mind body intervention has recently been shown to have promising results in improving QoL and psychosocial factors in adults with NF [34] and it may be efficacious, with mild adaptation, for children and adolescents in need. Despite the strong methodology in all studies that met inclusionary criteria, results described in this review were partly weak or inconclusive due to heterogeneity of the NF population (age, severity, complications), small number of studies), and heterogeneity of measurements. The Response Endpoints in Neurofibromatosis and Schwannomatosis (REINS) International Collaboration is working on determining specific measures that can be used consistently in the NF research; this is an important endeavor that has the potential to allow for more conclusive reports in NF specific Qol research in the future [35]. In conclusion this review shows that children and adolescents with NF1 suffer from impaired general QoL, and that generally parents’ perception of their children’s QoL is lower than children’s reports. Because of the small number of studies, results should not be generalized to all children with NF. The field of QoL research in children and adolescents with NF will be advanced by uniting around a clear conceptualization of QoL using consistent scales, addressing the potential predictive role of psychosocial factors, using prospective studies, thoroughly describing the samples to facilitate comparisons among studies, and attending also to children/adolescents with NF2 and schwannomatosis. This research will yield more potent evidence for clinical applications and interventions to facilitate improvements in the healthcare and development of mind body interventions for both children/adolescents with NF and their parents.
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15. 16.
17. Conflict of interest of interest.
The authors declare that they have no conflict 18.
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