Cognitive functioning and pain interference mediate pain predictive effects on health-related quality of life in pediatric patients with Neurofibromatosis Type 1
Introduction
Neurofibromatosis Type 1 (NF1) is a single-gene neurocutaneous disorder caused by a mutation in the gene encoding neurofibromin, and is the most common autosomal dominant disorder of the nervous system [[1], [2], [3]]. As a complex neurogenic chronic condition with wide variability in clinical manifestations [1,[4], [5], [6]], NF1 can impact the central and peripheral nervous systems, with a predisposition toward the development of benign and malignant nervous system tumors [7,8]. Plexiform neurofibromas (peripheral nerve sheath tumors) are estimated to occur in approximately 25–50% of pediatric patients, with both asymptomatic and symptomatic plexiform neurofibromas manifested [9,10]. Further, NF1 has been demonstrated to have a significantly adverse impact on generic (general or nondisease-specific) health-related quality of life (HRQOL) in pediatric patients [11].
Chronic and recurrent pain has been found to be a highly prevalent symptom in pediatric and adult patients with NF1, including peripheral neuropathic pain and headaches [[12], [13], [14], [15]]. Prior research has shown that pain has a negative effect on overall generic HRQOL in pediatric chronic pain populations [[16], [17], [18]]. Additionally, the concept of “pain impact” or “pain interference” has emerged as a construct that measures pain-specific impact or interference with daily functioning [16,19]. The items in pain impact/interference scales include specific reference to the interference or impact caused by pain on daily activities [19]. Although these measures are typically multi-item scales, a study of pain interference in NF1 used a single item from an existing scale which was predictive of lower functioning [20].
Cognitive functioning problems have also been identified as prevalent neurogenic manifestations in pediatric patients with NF1 [21]. These neurocognitive deficits include difficulties in executive functioning, memory problems, attention deficits, learning disabilities, and overall intellectual performance typically evidenced in the low average range, with moderate to severe impairment in one or more areas of cognitive functioning affected [3,22,23]. Estimated rates of cognitive dysfunction vary widely, ranging from 20% to as high as 80% of patients with NF1 [21,24].
Past research with other patient populations has demonstrated that chronic and recurrent pain has a deleterious effect on cognitive functioning [25,26]. Thus, while it would be expected that cognitive functioning problems in pediatric patients with NF1 would be exhibited as a consequence of their chronic health condition, it may be hypothesized that similar to other patient populations, pain would also have an additional deleterious direct effect on cognitive functioning in these patients.
Previously, we investigated the direct effects of pain as a predictor variable of overall generic HRQOL in children, adolescents, and young adults with NF1 [27]. A distinctive feature of the study was the inclusion of NF1-specific multi-item measurement scales developed specifically for NF1 through extensive cognitive interviews with children, adolescents, and young adults with NF1 and their parents [28], rather than utilizing generic measures of these constructs. These NF1-specific multi-item measurement scales were subsequently nationally tested during the PedsQL Neurofibromatosis Type 1 Module field test study, demonstrating excellent reliability and validity [29].
Nonetheless, unique to the current study, we are not aware of prior research which has investigated the hypothesized mechanism that may explain in part the predictive effects of pain on overall generic HRQOL in pediatric patients with NF1 utilizing an a priori conceptual model that includes NF1-specific perceived cognitive functioning and pain interference in daily living as hypothesized sequential mediating variables. By understanding the mechanism in which pain affects overall generic HRQOL, treatment strategies may be developed to ameliorate in part the negative impact of NF1-specific pain on overall HRQOL by targeting the hypothesized intervening variables that may be potentially modifiable.
To address this significant empirical gap in the pediatric NF1 research literature, we utilized the database from the PedsQL Neurofibromatosis Type 1 Module field test study to test the hypothesized mediators of pain predictive effects on overall total generic HRQOL in pediatric patients with NF1. We investigate a serial multiple mediator conceptual model in which the serial (sequential) mediating effects of perceived cognitive functioning and pain interference in daily living are hypothesized as intervening variables in the relationship between pain and overall generic HRQOL. We conducted a serial multiple mediator analysis to test the following hypothesized conceptual model: pain → cognitive functioning → pain interference → overall generic HRQOL in which the predictive effects of pain on generic HRQOL are mediated sequentially by cognitive functioning and pain interference.
Section snippets
Participants and settings
Pediatric patients with physician-diagnosed NF1 using the National Institutes of Health diagnostic criteria were recruited across the United States. Participants were recruited through the Children's Tumor Foundation (CTF) Neurofibromatosis (NF) registry, NF clinics at Indiana, Michigan, California, and Washington, D.C., and NF organizations including the Texas NF foundation, NF mid-west and NF network forums. A total of 343 families (323 pediatric patients ages 5–25 and 335 parents)
Bivariate intercorrelations between pain, cognitive functioning, and pain impact/interference scales with Generic Core Scales Total Scale Score
Table 1 contains the means, standard deviations, range, and bivariate correlations of the Pain, Cognitive Functioning, and Pain Impact (Interference) Scales with the Generic Core Total Scale Score for patient self-report and parent proxy-report. The Pain, Cognitive Functioning, and Pain Impact (Interference) Scales were significantly correlated with the Generic Core Scales Total Scale Score (all Ps < 0.001), demonstrating large effect sizes.
Correlational analyses and independent samples t-tests
Discussion
The findings demonstrate that cognitive functioning and pain-specific interference in daily living serially mediate the association between pain and overall generic HRQOL in pediatric and young adult patients with NF1. The mediators as a group (cognitive functioning and pain interference) contributed an additional 25% of the variance in patient self-reported generic HRQOL and an additional 21% of the variance in parent proxy-reported generic HRQOL for their children beyond the direct effects of
Limitations
Limitations include the absence of information in the database regarding the characteristics of any families who declined participation, there was no information on whether the parent who completed the parent proxy-report PedsQL scales on their child's HRQOL also had NF1, and the sample was predominantly White non-Hispanic which may limit the generalizability of the findings to other race/ethnicity groups. Although participants completed the PedsQL using either paper or Internet electronic
Conclusions
In conclusion, these findings from a large national survey research investigation with limited information on specific patient characteristics suggests that a serial multiple mediator intervening mechanism explains in part how perceived pain may predict overall generic HRQOL in pediatric patients with NF1. This serial multiple mediator conceptual model and its findings may facilitate the development of future targeted interventions to improve the health and well-being of these pediatric and
Funding
The field test study was funded by the Neurofibromatosis Therapeutic Acceleration Program (NTAP) at Johns Hopkins University School of Medicine, Baltimore, MD. The funding source was not involved in the data analysis or manuscript preparation.
Declaration of competing interest
Dr. Varni holds the copyright and the trademark for the PedsQL and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality of Life Inventory. The other authors report no competing interests related to this study.
Dr. Varni was involved in the conception and design of the study, in the writing of the first draft of the manuscript, the analysis of the data and the
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