Balance Impairment in Survivors of Pediatric Brain Cancers: Risk Factors and Associated Physical Limitations

Abstract

Purpose

The study aims were to determine the prevalence of balance impairments in adult survivors of pediatric CNS tumors, and to identify predictors of and limitations associated with balance impairments.

Methods

Participants were adult survivors (N=329) of pediatric CNS tumors. Balance was considered impaired among those with composite scores <70 on the sensory organization test. Potential predictors of impaired balance were evaluated with generalized linear regression. Multivariable logistic regression was used to evaluate associations between balance impairment and function.

Results

Balance impairment was observed in 48% of survivors, and associated with infratentorial tumor location (OR = 4.0, 95% CI, 2.0–7.6), shunt placement (OR = 3.5, 95% CI, 1.8–6.7), increased body fat percentage (OR = 1.1, 95% CI, 1.0–1.1), hearing loss (OR = 11.1, 95% CI, 5.6–22.2), flexibility limitations (OR = 2.0, 95% CI, 1.0–3.9), peripheral neuropathy (OR = 2.4, 95% CI, 1.2–4.5), and cognitive deficits (OR = 2.2, 95% CI, 1.1–4.7). In adjusted models, impaired balance was associated with limitations in overall physical performance (OR=3.6, 95% CI, 2.0–6.3), mobility (OR=2.6, 95% CI, 1.5–4.4), diminished walking endurance (OR=2.9, 95% CI, 1.7–5.0), and non-independent living (OR=2.0, 95% CI, 1.0–4.3).

Conclusions

Nearly half of adult survivors of pediatric CNS tumors have impaired balance, which is associated with mobility and physical performance limitations. Interventions to address the complex needs of this population should be prioritized.

Implications for Cancer Survivors

Survivors with identified risk factors should be closely evaluated for presence of balance impairment. Interventions tailored to improve balance also can positively affect function and mobility in survivors.

Introduction

Balance, which is defined as the ability to maintain one’s center of mass within the base of support, is a prerequisite for normal upright mobility and physical activity [1]. Thus, impaired balance may interfere with physical activity and foster a sedentary lifestyle. Maintaining balance is dependent on a complex interaction between several resources, including sensory/perceptual systems responsible for the detection of body position and motion, motor systems responsible for the organization and execution of motor synergies, and higher-level central nervous system (CNS) processes responsible for the integration of sensory information and action plans [1]. Balance changes throughout the lifespan. During childhood balance control improves with development of sensory systems [2], with children reaching adult-like sensory integration for maintaining balance by 12 years old [3]. It remains constant through most of the adult life, until around age 60, when it starts to decline [4].

Persons diagnosed and treated for pediatric CNS tumors are at risk for balance impairments because both tumor and treatment can negatively affect the systems that contribute to maintaining balance. The primary cause of impaired balance in CNS tumor survivors is the tumor location. For example, survivors of medulloblastoma, which by definition occurs in the cerebellum, are likely to have poor balance, because the cerebellum is involved in regulating balance and posture. Survivors of optic nerve or chiasm tumors, or retinoblastoma survivors, are likely to have poor balance due to losing visual information which plays an important role in maintaining balance, while survivors of cerebellopontine angle tumors are likely to have poor balance due to impaired function of the vestibular system. Treatment exposures also can contribute to poor balance performance in survivors. For example, platinum agents such as cisplatin and carboplatin can damage vestibular and auditory systems [5] which are important centers in maintaining balance. Other chemotherapy agents such as vincristine have more general neurotoxic effects and can cause sensory and motor peripheral neuropathy, limiting the amount of available sensory information to brain to maintain balance and impacting function of distal muscles [6, 7]. Sadly, chemotherapy induced peripheral neuropathy, visual deficits and hearing loss, are frequent among CNS tumor survivors [8, 9]. Additionally, brain tumor survivors are likely to suffer from neurocognitive deficits, including problems with attention, working memory, and processing speed [10], which interfere with the ability to process sensory information and adequately respond to displacement of center of mass. All of these factors can contribute to balance impairment in CNS tumor survivors. Furthermore, the sensory systems which contribute to maintaining balance do not reach functional maturity until age nine years [2]. Tumor or treatment exposures may have a more substantial negative effect on development of balance in young patients. Previous studies reported the prevalence of balance impairment among persons treated for CNS tumors to be between 50% and 70% [11]. While some risk factors for balance impairment have been identified such as a posterior fossa tumor location, radiation therapy to occipital or parietal lobe, or a history of treatment with alkylating or platinum based agents, further research is needed to verify these findings since most of the conducted studies had small sample sizes, ranging from 5 to 88 survivors, or focused only on patients with a posterior fossa tumor location [11]. Additionally, the functional implications of balance impairments among adult survivors of childhood CNS tumors has not been determined [12]. Therefore, the aims of this study were to: 1) determine the prevalence of balance impairment in adults treated for pediatric CNS tumors; 2) identify demographic, treatment, and physical characteristics associated with risk of balance impairment; and 3) determine if the presence of balance impairment is associated with limitations in mobility, physical activity, and daily participation.

Materials and Methods

Participants

Participants were members of the St. Jude Lifetime cohort, a study designed to clinically examine health outcomes among aging survivors of childhood cancer [13, 14]. Survivors were included in the current study if they were treated for childhood CNS tumors from January 1, 1962 to December 31, 2006, and at the time of assessment were ≥18 years of age, and ≥10 years from primary cancer diagnosis. The study protocol was approved by St. Jude Children’s Research Hospital Institutional Review Board. All participants provided written informed consent.

Outcomes

Balance

Balance was evaluated using the Sensory Organization Test (SOT) on a computerized dynamic posturography device (Neurocom SMART Equitest, Natus Medical, Pleasanton CA) [15, 16]. Postural sway (i.e. the ability to maintain an upright posture within a 12° sway envelope) was examined under six conditions. During conditions 1–3 participants stand on a fixed surface with their eyes open, eyes closed, and their eyes open but sway referenced (i.e. the visual surround moves in reference to anterior-posterior sway), respectively. During conditions 4–6 the respective visual input is identical to conditions 1–3, however the standing surface moves in reference to anterior-posterior sway for all conditions. Two or three trials, each 20-seconds in duration, were collected for each condition. Scores from these six conditions were used to derive a composite SOT score. A composite score of less than 70 was used to categorize survivors as having impaired balance [17, 18]. The ability of participants to use various sensory inputs to control balance was also quantified using performance ratios calculated from combinations of test conditions; somatosensory ratio (condition 2/condition1), vision ratio (condition 4/condition1), and vestibular ratio (condition 5/condition 1). Ratios closer to 1 reflect an individual’s ability to effectively use the sensory input from the specific source to maintain balance. Normative data obtained from healthy individuals were used to determine the cut-off ratios of 0.94, 0.78, and 0.58 to classify an individual as having impaired ability to use somatosensory, visual, and vestibular information, respectively [19].

Independent variables

Cancer diagnosis and treatment data were abstracted from medical records by trained abstractors and included tumor type, primary tumor location, extent of surgery, intraventricular shunt placement, agent and cumulative doses of chemotherapy, and site and dosage of radiation therapy. Participants were categorized as having an infratentorial tumor if they had tumors located on the brainstem, spine, or cerebellum. All other tumor locations were categorized as supratentorial. Body composition was characterized using whole-body fat percentage, determined with Dual Energy X-ray Absorptiometry (Hologic, Inc, Bedford, Mass). Peripheral nervous system integrity was evaluated with the modified Total Neuropathy Score (mTNS) [20], a measure that includes both self-report of sensory and motor symptoms and quantitative neurological evaluations of pin sensibility, vibration threshold, muscle strength, and deep tendon reflexes. mTNS scores range from 0 to 24; with higher scores indicating greater impairment. In accordance with previous studies of pediatric cancer survivors [21, 22], those with a mTNS score ≥4 were classified as having peripheral neuropathy. Survivors with scores ≥3 on the sensory subscale, or ≥2 on the reflex subscale (i.e., absence of a response) were considered impaired on these measures.

Lower extremity muscle strength was evaluated using an isokinetic approach, with Biodex Medical Systems IV dynamometer (Shirley, NY, USA) [23]. This method of testing was chosen, because it simulates functional activities better than isometric testing and provide isolated evaluation of target muscle groups. Knee extensor strength was determined as the maximum value from five repetitions at 60 degrees per second (°/sec); ankle plantar flexor and dorsiflexor strength were determined as the maximum value from five repetitions at 90°/sec. For all isokinetic testing, participants were positioned in sitting with the hip flexed to 90° and the back supported. During testing of the knee extensor, ankle dorsiflexors and ankle plantar flexors participants were verbally encouraged to “kick”, “push”, and “pull” as fast and as hard as possible, respectively. Testing was performed only after participants were adequately familiarized with the device. Weakness was considered present when average of bilateral peak torque was greater than 1.3 standard deviations below height-, weight-, age-, and sex-specific values [18]. This cut-off was chosen because it represents the lowest 10th percentile of general population; those with a score below this cut-off has a meaningful deficit

Hamstring and lower back flexibility was measured using the sit and reach test with the Flex-tester (Novel Products, Rockton, IL) [24]. Participants were instructed to sit with their legs fully extended and the soles of their feet in contact with Flex-tester box. They were then asked to overlap their hands and reach forward without bending their knees. The distance between the participant’s finger tips and the bottom of the feet was recorded in centimeters. The longest reached distance over two trials was used as a measure of combined hamstring and lower back flexibility. Active ankle dorsi- and plantar-flexion range of motion were measured with goniometer on both sides while the participant was sitting with hips and knees in 90° of flexion [25], the mean value of the left and right side was reported. Flexibility was considered impaired when performance was greater than 1.3 standard deviations below height-, weight-, age-, and sex-specific values.

Ophthalmology and audiometry examinations were performed to evaluate visual and auditory system integrity. Chronic visual and auditory system impairments were classified using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE v4.03) modified for the SJLIFE cohort study [14]. Participants were characterized as having impaired vision if the visual acuity in one or both eyes was Grade 3–4. Audiometric assessment was performed for both ears and participants were classified as having hearing loss if the auditory impairment was Grade 2–4.

Cognitive functioning was assessed using the Wechsler Abbreviated Scale of Intelligence-Second Edition [26]. Two subtests, vocabulary and matrix reasoning, were used to obtain an estimated Full-Scale IQ score. Age- and sex-specific normative data were used to calculate t-scores with an expected population mean of 50 and standard deviation of 10. Those in the lowest 10th percentile of the normative distribution were considered impaired.

Dependent variables

Overall motor performance was evaluated with the Physical Performance Test. This test includes seven timed tasks used to assess fine and gross motor ability [27]. These tasks are similar to basic activities of daily living and include writing a sentence, simulated eating, lifting a folder and placing it on a shelf, picking a penny up off the floor, putting on and taking off a jacket, turning 360°, and a 50-foot walk test [27]. The items were scored based on the time required to complete the task. Participants with scores greater than 1.3 standard deviations below the mean of height-, weight-, age-, and sex-specific values were classified as having a physical performance limitation. Mobility was quantified with the 50-foot walk test for gait speed and the Timed Up and Go (TUG), a measure of the time needed for an individual to rise from a chair, walk a distance of 10 feet, return and sit down [28]. Walking endurance was determined with the 6-minute walk test [29, 30]. Participants with scores greater than 1.3 standard deviation below height-, weight-, age-, and sex-specific values were identified as individuals with limitations in mobility (TUG, gait speed) or endurance (6-minute walk test).

Sociodemographic information was obtained from questionnaires [13]. Participants were classified as having a non-independent living situation if they lived with their parents, siblings or other relatives (not including minor children), or with roommates (excluding college students), and reported requiring assistance with routine or personal care needs. Sedentary behavior was considered present if the participant reported engaging in no physical activity over the past month. Health-related quality of life was measured using the Medical Outcome Survey Short Form-36, which includes questions about general health, well-being and quality of life over the previous four weeks [31]. Results were reported as t-scores with a population mean of 50 and a standard deviation of 10. A score of ≤40 is indicative of a poor health related quality of life.

Statistical Analysis

Demographic, treatment, and performance outcomes were compared between groups with and without balance impairments using chi-square and t-tests. Multivariable generalized linear regression with a logit link and a binomial distribution was used to identify potential predictors of impaired balance, using elastic net to select independent variables [32]. These analyses were adjusted for age at assessment and sex due to the confounding effects age and sex might have on balance. Multivariable logistic regression was used to assess associations between balance and physical performance, mobility, walking endurance, sedentary behavior, non-independent living and quality of life, adjusted for age, sex, percentage body fat, and cognitive deficits. Analyses were conducted using SAS 9.4 statistical software (SAS institute, Cary, NC).

Results

Study inclusion criteria were met by 329 individuals (Figure 1), who form the basis for this analysis. Study participants and non-participants did not differ by sex or treatment exposures; however non-participants were more likely to report their race as non-white and were younger at diagnosis (Supplementary Table 1). Participants aged between 18 and 53 years at the time of study assessments. Among them, 30 individuals had no posturography data and were classified with impaired balance because they were physically unable to stand long enough to complete testing. Table 1 shows characteristics of the study participants, overall and stratified by balance status. Most participants were male (58%), white (83%), and non-Hispanic ethnicity (99.9%). Among participants; 23.7% were diagnosed before age 5 years, 35% between 5 and 9 years old, 31% between 10 and 14 years old, and 10.3% when are 15 years or older. Treatment exposures among participants included surgery (97.9%), radiation (65.1%), and chemotherapy (34.7%).

Figure 1.

Participants selection process

Table 1.

Characteristics of study participants

	Total (n=329)	Impaired Balance (n=158)	Intact Balance (n=171)	P Value
Demographics
Age (years)				0.15
18–29	221 (67.2)	98 (62.0)	123 (71.9)
30–39	100 (30.4)	55 (34.8)	45 (26.3)
40+	8 (2.4)	5 (3.2)	3 (1.8)
Mean (Sd)	27.5 (5.91)	28.2 (6.17)	26.8 (5.61)	0.03
Sex				0.11
Male	191 (58.1)	84 (53.2)	107 (62.6)
Female	138 (42.0)	74 (46.8)	64 (37.4)
Anthropometrics
Height Mean (Sd) (cm)
Male	171.5 (10.5)	167.5 (11.0)	174.7 (8.8)	<0.001
Female	159.9 (7.7)	158.3 (8.0)	161.7 (7.1)	0.01
Weight Mean (Sd) (kg)
Male	82.5 (20.0)	78.3 (19.9)	85.8 (19.7)	0.01
Female	72.8 (19.1)	71.8 (19.5)	74.0 (18.9)	0.50
BMI Mean (Sd)
Male	27.9 (5.6)	27.7 (5.6)	28.0 (5.6)	0.72
Female	28.3 (6.7)	28.4 (6.7)	28.3 (6.8)	0.88
Percent Body Fat Mean (Sd) (%)
Male	29.6 (7.5)	31.4 (7.0)	28.2 (7.6)	0.004
Female	39.7 (6.4)	40.7 (6.1)	38.6 (6.6)	0.06
Cancer and Treatment
Age at Diagnosis (y)				0.50
<5	78 (23.7)	42 (26.6)	36 (21.1)
5–9	115 (35.0)	57 (36.1)	58 (33.9)
10–14	102 (31.0)	44 (27.9)	58 (33.9)
15–22	34 (10.3)	15 (9.5)	19 (11.1)
Mean (Sd)	8.40 (4.68)	7.82 (4.66)	8.93 (4.64)	0.03
Time since Diagnosis (y)				<0.001
10–14	85 (25.8)	34 (21.5)	51 (29.8)
15–19	113 (34.4)	43 (27.2)	70 (40.9)
≥20	131 (39.8)	81 (51.3)	50 (29.2)
Mean (Sd)	18.6 (5.5)	19.9 (5.9)	17.4 (4.8)	<0.001
Tumor Type				<0.001
Astroglial	172 (52.3)	61 (38.6)	111 (64.9)
Craniopharyngioma	24 (7.3)	6 (3.8)	18 (10.5)
Germ Cell	10 (3.0)	5 (3.2)	5 (2.9)
Medulloblastoma/Ependymoma	115 (35.0)	84 (53.2)	31 (18.1)
Other	8 (2.4)	2 (1.3)	6 (3.5)
Primary Tumor Location				<0.001
Infratentorial	156 (47.4)	108 (68.4)	48 (28.1)
Supratentorial	173 (52.6)	50 (31.7)	123 (71.9)
Extent of surgery
None	7 (2.1)	2 (1.3)	5 (2.9)	0.51
Biopsy	69 (21.0)	27 (17.1)	42 (24.6)	0.13
Partial Resection	112 (34.0)	58 (36.7)	54 (31.6)	0.39
Near Total Resection	20 (6.1)	11 (6.7)	9 (5.3)	0.68
Gross Total Resection	155 (47.1)	79 (50.0)	76 (44.4)	0.37
Shunt Placement				<0.001
Yes	87 (26.4)	61 (38.6)	26 (15.2)
No	242 (73.6)	97 (61.4)	145 (84.8)
Chemotherapy				<0.001
Yes	114 (34.7)	79 (50.0)	35 (20.5)
No	215 (65.4)	79 (50.0)	136 (79.5)
Vincristine Median (range) (mg/m2)		11.9 (1.5–125.0)	20.0 (1.4–62.9)	0.05
Cisplatin Median (range) (mg/m2)		294.4 (64.0–1380.8)	303.4 (84.3–605.9)	0.50
Carboplatin Median (range) (mg/m2)		2947.8 (172.7–11058.9)	2880.0 (827.7–10876.3)	0.81
Cranial and/or Spinal Radiation				<0.001
Yes	214 (65.1)	123 (77.9)	92 (53.8)
No	115 (35.1)	35 (22.2)	80 (46.8)
Site Specific Radiation Doses Median (range) (Gy)
Posterior Fossa		54.0 (2.0–106.0)	2.0 (0.2–72.0)	<0.001
Temporal Lobe		54.0 (2.0–106.0)	54.0 (0.2–101.0)	0.02
Frontal Cortex		32.5 (2.0–126.0)	2.0 (0.2–70.0)	0.13
Occipital/Parietal Lobe		32.5 (2.0–85.0)	2.0 (0.2–70.0)	<0.001

Cells contain number (%), unless otherwise determined.

Impaired balance: Participants are classified as having balance impairment if they have a composite score <70% on sensory organization test. For survivors without this evaluation, clinical notes indicated a balance impairment.

Impaired balance was present in 158 survivors (48%, 95% CI, 42.6–53.4%). Male survivors with impaired balance were shorter and weighed less, but had a higher percentage of body fat mass than male survivors without balance impairment. Female survivors with impaired balance were shorter than female survivors without balance impairment. Survivors with impaired balance, had a longer interval between diagnosis and assessment of balance, were more likely to have an infratentorial tumor, a history of intraventricular shunt placement, and treated with cranial and/or spinal radiation. Chemotherapy exposure was more common in survivors with impaired balance; however, the total cumulative dose for neurotoxic agents such as vincristine, cisplatin, or carboplatin was not statistically different between groups. Radiation doses to posterior fossa, temporal, parietal/occipital lobes were higher among survivors with impaired balance.

Physical, quality of life, and social outcomes in survivors, overall and by balance impairment are provided in Table 2. Survivors with impaired balance, on average, had weaker lower extremity muscles and less ankle range of motion, scored lower on the sit and reach test, took longer to complete the TUG, had slower gait speed over 50 feet, walked a shorter distance in 6 min, performed worse in the physical performance test and scored higher on the mTNS. Impaired deep tendon reflexes, hearing loss, cognitive deficits, and lower scores on the physical component summary scale of the SF-36 were also more common among survivors with impaired balance. Additionally, survivors with impaired balance were less likely to go to college, be employed, live independently, have a driver’s license, or participate in any physical activity over the past month. Examinations of the contribution of sensory systems to overall balance indicated that survivors had the most difficulty employing vestibular processes to maintain upright posture.

Table 2.

Physical, quality of life and social outcomes for adult survivors of childhood CNS malignancies with and without impaired balance

	Total (n=329)		Impaired Balance (n=158)		Intact Balance (n=171)		P Value
	Mean (SD)	Impaired % (CI)	Mean (SD)	Impaired % (CI)	Mean (SD)	Impaired % (CI)
Motor Function
Muscle Strength
Quadriceps 60°/s (Nm)	151.5 (51.4)	38.8 (33.2–44.4)	136.4 (47.2)	50.4 (42.6–59.6)	163.7 (51.5)	29.5 (22.5–36.5)	<0.001
Dorsiflexion 90°/s (Nm)	22.9 (8.9)	37.2 (31.7–42.7)	21.5 (8.5)	44.6 (36.2–53.2)	24.0 (9.1)	31.3 (24.2–38.41	0.02
Plantar Flexion 90°/s (Nm)	46.6 (26.6)	32.4 (27.1–37.8)	40.1 (23.1)	42.3 (34.7–51.6)	51.7 (28.0)	24.5 (17.9–31.2)	<0.001
Range of Motion
Active dorsiflexion (°)	8.0 (7.3)	17.4 (13.3–21.5)	7.1 (7.9)	20.5 (14.3–26.7)	8.9 (6.6)	14.6 (9.3–19.9)	0.03
Active plantar flexion (°)	54.3 (7.8)	21.7 (17.2–26.2)	53.0 (9.0)	30.8 (23.9–38.2)	55.4 (6.3)	13.5 (8.3–18.6)	0.004
Flexibility
Sit and reach distance (cm)	19.0 (11.6)	26.0 (21.2–30.8)	16.5 (11.4)	36.9 (29.4–44.6)	21.2 (11.4)	16.5 (10.9–22.1)	<0.001
Mobility
Timed Up and Go	7.2 (5.4)	39.6 (34.2–45.0)	8.8 (7.5)	57.9 (50.8–66.6)	5.8 (1.5)	24.0 (17.6–30.4)	<0.001
Gait Speed (m/s)	1.5 (0.3)	48.9 (43.3–54.4)	1.4 (0.4)	68.3 (60.7–76.0)	1.6 (0.3)	32.8 (25.7–39.8)	<0.001
6-min walk	519.2 (107.7)	35.5 (30.2–40.9)	478.8 (112.3)	52.2 (43.8–60.6)	551.9 (91.9)	22.0 (15.8–28.3)	<0.001
Physical Performance Test	24.8 (4.7)	47.5 (42.1–53.0)	22.7 (5.7)	68.0 (60.6–75.3)	26.6 (2.2)	29.2 (22.4–36.1)	<0.001
Sensory Organization Test
Composite score	69.51 (14.93)	48.0 (42.6–53.4)	54.88 (10.73)	100.0	80.46 (4.80)	0.0	<0.001
Somatosensory ratio	0.97 (0.03)	23.7 (19.1–28.3)	0.97 (0.04)	36.7 (29.2–44.2)	0.97 (0.03)	11.7 (7.3–17.6)	0.04
Vision ratio	0.88 (0.12)	24.0 (19.4–28.6)	0.81 (0.15)	46.8 (39.1–54.6)	0.93 (0.06)	2.9 (0.4–5.5)	<0.001
Vestibular ratio	0.68 (0.13)	38.6 (33.3–43.7)	0.58 (0.10)	76.6 (70.0–83.2)	0.76 (0.09)	3.5 (0.8–6.3)	<0.001
Sensory Impairments
Visual Impairment (n)							1.00
Yes	16	4.9 (2.5–7.2)	8	5.0 (1.6–8.5)	8	4.7 (1.5–7.8)
No	313		123		162
Hearing Loss (n)							<0.001
Yes	115	35.0 (29.8–40.1)	92	58.2 (50.5–65.9)	23	13.5 (8.3–18.6)
No	214		66		147
Sensory Neuropathy (n)							0.07
Yes	52	16.0 (12.0–20.0)	28	18.2 (12.1–24.2)	24	14.0 (8.8–19.2)
No	273		125		146
Impaired Tendon Reflexes (n)							0.002
Yes	114	34.8 (29.6–39.9)	69	44.0 (36.2–51.7)	45	26.3 (19.7–32.9)
No	214		88		125
mTNS	2.8 (3.3)	29.6 (24.7–34.6)	3.8 (3.7)	41.8 (34.0–49.7)	2.0 (2.6)	18.7 (12.9–24.6)	<0.001
Intelligence Quotient (IQ)
Overall IQ (%)	44.2 (11.3)	24.1 (19.4–28.8)	39.5 (11.1)	37.5 (29.8–45.2)	48.6 (9.7)	12.0 (7.1–16.9)	<0.001
Quality of Life
Physical Components	49.0 (10.9)	20.8 (16.3–25.3)	45.0 (12.0)	32.9 (25.3–40.5)	52.7 (8.3)	9.9 (5.3–14.5)	<0.001
Mental Component	48.8 (12.0)	19.2 (14.8–23.6)	49.1 (12.5)	19.2 (12.8–25.6)	48.4 (11.5)	19.1 (13.1–25.2)	0.63
Social Outcomes
Education Level (n) (%)							<0.001
<High school Grad	34 (10.7)		21 (13.7)		13 (7.9)
High school grad	126 (39.6)		80 (52.3)		46 (27.9)
>High school grad	158 (49.7)		52 (34.0)		106 (64.2)
Employment (n) (%)							<0.001
Employed/student	153 (53.1)		44 (32.1)		109 (72.2)
Unemployed	135 (46.9)		93 (67.9)		42 (27.8)
Living Status (n) (%)							<0.001
Non-independent	167 (52.5)		97 (63.8)		70 (42.2)
Independent	151 (47.5)		55 (36.2)		96 (57.8)
Driver License (n) (%)							<0.001
Yes	218 (68.3)		76 (48.7)		142 (87.1)
No	101 (31.7)		80 (51.3)		21 (12.9)
Sedentary Behavior (n) (%)							0.02
Yes	58 (20.9)		37 (27.0)		21 (15.0)
No	219 (79.1)		100 (73.0)		119 (85.0)

The cutoff ratios for reporting an impaired somatosensory, visual, and vestibular system are 0.94, 0.78, and 0.58, respectively.

Peripheral neuropathy is indicated based on a score equal or greater than 4.

Deficits in muscle strength, range of motion, sit and reach, gait speed, 6 min-walk and physical performance test are indicated with a score more than 1.3 standard deviation below height, weight, age, and sex-specific values.

Reduced quality of life is indicated based on a score ≤40.

IQ deficits is indicated by z scores lower than 1.3 standard deviation below the mean, which is representative of lowest 10% on a normal distribution curve.

Visual impairment: Participants are characterized as having a chronic visual system deficit if they are diagnosed with reduced visual acuity in one or both eyes ≥Grade 3.

Hearing loss: Participants are classified as having a hearing loss if they are diagnosed with an auditory impairment ≥Grade 2.

Sensory neuropathy: A sensory subscale score of ≥3 on mTNS test is considered impaired

Impaired tendon reflexes: A reflex subscale score ≥2 on mTNS is considered impaired.

Table 3 shows the associations of demographic, anthropometric, treatment, and tumor-related factors with impaired balance, overall and by sensory system. In models adjusted for age and sex, an infratentorial tumor location, higher doses of radiation to the posterior fossa, higher body fat percentage, and shunt placement were associated with risk of impaired balance. Impaired ability to use somatosensory information to maintain balance was related to an infratentorial tumor location. A higher vincristine dose was associated with impaired ability to process visual information to maintain balance. An infratentorial tumor location, a longer time post completion of treatment, shunt placement, and higher doses of radiation to the occipital area were associated with impaired ability to use vestibular information to maintain balance.

Table 3.

Anthropometric, treatment and tumor-related associations for risk of impaired balance among childhood CNS tumor survivors

	SOT Composite Impairment		Somatosensory Impairment		Visual Impairment		Vestibular Impairment
	OR (95% CI)	P Value	OR (95% CI)	P Value	OR (95% CI)	P Value	OR (95% CI)	P Value
Female vs Male	1.70 (0.81–3.55)	0.16	1.18 (0.55–2.54)	0.67	1.21 (0.59–2.47)	0.61	1.59 (0.85–2.98)	0.15
Age	1.01 (0.96–1.06)	0.74	0.98 (0.93–1.04)	0.47	1.02 (0.97–1.08)	0.37	0.96 (0.90–1.03)	0.28
Survivorship Duration	-		-		-		1.10 (1.02 –1.19)	0.01
Percent Body Fat	1.05 (1.01–1.10)	0.02	1.04 (0.99–1.09)	0.08	-		-
Weight	-		-		0.99 (0.97–1.00)	0.12	-
Infratentorial vs Supratentorial	3.95 (2.00–7.63)	<0.001	2.66 (1.39–5.10)	0.003	-		5.92 (2.86–12.25)	<0.001
Shunt Placement	3.45 (1.77–6.73)	<0.001	-		-		2.07 (1.05–4.07)	0.04
Posterior Fossa Radiation (Gy)	1.02 (1.01–1.04)	<0.001	-		1.01 (0.99–1.02)	0.12	1.01 (1.00–1.03)	0.05
Occipital/Parietal Radiation (Gy)	-		-		-		1.02 (1.00–1.04)	0.03
Vincristine Dose	-		-		1.03 (1.00–1.05)	0.02	-
Cisplatin Dose	-		-		1.00 (1.00–1.00)	0.51	-
R Squared	0.28		0.05		0.06		0.28

Table includes information on only those participants who had the SOT assessment.

Factors were chosen based on elastic net results.

Models are adjusted for age at assessment and sex.

OR indicates odds ratio; CI indicates confidence interval.

Associations between physical and cognitive measures and impaired balance, overall and by sensory system are presented in Table 4. Female sex, peripheral neuropathy, hearing loss, poor flexibility, and cognitive deficit were associated with impaired balance. Sensory neuropathy was associated with difficulty using somatosensory information; knee extensor weakness and cognitive deficit were associated with difficulty utilizing visual information; and peripheral neuropathy, hearing loss, and cognitive deficit were associated with difficulty utilizing vestibular information to maintain balance. In adjusted models, balance impairment was associated with limitations in physical performance, mobility, endurance, and non-independent living, even after accounting for cognitive deficits (Table 5).

Table 4.

Associations of sensory and functional factors and risk of impaired balance among childhood CNS tumor survivors

	Impaired SOT Composite		Somatosensory System Impairment		Visual System Impairment		Vestibular System Impairment
	OR (95% CI)	P Value	OR (95% CI)	P Value	OR (95% CI)	P Value	OR (95% CI)	P Value
Female vs Male	2.80 (1.52 –5.17)	0.001	1.82 (0.96 –3.44)	0.07	1.28 (0.63–2.64)	0.50	1.61 (0.83–3.13)	0.16
Age	0.97 (0.92 –1.02)	0.27	0.97 (0.92 –1.03)	0.33	1.02 (0.97–1.08)	0.46	0.99 (0.93–1.04)	0.59
Peripheral Neuropathy	2.36 (1.23 – 4.50)	0.01	-		-		2..00 (0.99–4.03)	0.05
Sensory Neuropathy	-		2.28 (1.03 – 5.02)	0.04	-		-
Impaired Sit and Reach	2.00 (1.03 –3.89)	0.04	-		-		-
Dorsiflexion Weakness	-		-		-		1.58 (0.83–3.01)	0.16
Quadriceps Weakness	-		-		2.65 (1.31–5.36)	0.01	-
Hearing Loss	11.14 (5.60 –22.18)	<0.001	1.73 (0.88 – 3.40)	0.11	1.92 (0.91–4.06)	0.09	9.56 (4.85–18.84)	<0.001
Cognitive Deficit	2.22 (1.05–4.70)	0.04	-		3.18 (1.50–6.77)	0.003	3.41 (1.64–7.09)	0.001
R Squared	0.28		0.03		0.11		0.28

Table includes information on only those participants who had the SOT assessment.

Factors were chosen based on elastic net results.

Models are adjusted for age at assessment and sex.

OR indicates odds ratio; CI indicates confidence interval.

Table 5.

Associations among balance impairment and impaired physical performance, mobility limitation, sedentary behavior dependent living and diminished quality of life in childhood CNS tumor survivors

	Impaired Physical Performance		Mobility Limitation		Diminished Walking Endurance
	OR (95% CI)	P Value	OR (95% CI)	P Value	OR (95% CI)	P Value
Age	0.99 (0.95–1.04)	0.75	1.01 (0.96–1.05)	0.98	0.98 (0.93–1.02)	0.32
Female vs Male	0.20 (0.10–0.42)	<0.001	0.62 (0.32– 1.19)	0.15	0.65 (0.34–1.24)	0.19
Percent Body Fat	1.10 (1.05–1.15)	<0.001	1.06 (1.02–1.10)	0.003	1.07 (1.03–1.12)	0.001
Cognitive Deficit	7.92 (3.56–17.62)	<0.001	3.94 (2.06–7.60)	<0.001	1.57 (0.83–2.98)	0.17
Impaired Balance	3.57 (2.04–6.27)	<0.001	2.58 (1.51–4.38)	0.001	2.93 (1.70–5.03)	<0.001
R Squared	0.27		0.17		0.13
	Sedentary Behavior		Non-independent Living		Diminished Quality of Life
	OR (95% CI)	P value	OR (95% CI)	P value	OR (95% CI)	P value
Age	1.01 (0.96–1.07)	0.68	0.87 (0.82 –0.91)	<0.001	1.11 (1.05 –1.18)	<0.001
Female vs Male	0.73 (0.33 – 1.59)	0.42	1.11 (0.58 – 2.13)	0.75	1.21 (0.52 – 2.84)	0.66
Percent Body Fat	1.04 (0.99 – 1.09)	0.08	1.02 (0.98 – 1.05)	0.41	1.02 (0.97 – 1.07)	0.52
Cognitive Deficit	2.12 (1.03– 4.38)	0.04	4.21 (2.08– 8.54)	<0.001	3.45 (1.62– 7.34)	0.001
Impaired Balance	1.38 (0.69 – 2.72)	0.36	2.03 (0.96 – 4.28)	0.013	1.93 (0.92 – 4.02)	0.08
R Squared	0.05		0.19		0.12

Table includes information on only those participants who had the SOT assessment.

Models are adjusted for age at assessment, sex, percentage body fat and cognitive deficit.

Impaired balance: Sensory organization test scores <70%.

Impaired physical performance: Physical performance test scores that are more than 1.3 standard deviation below height, weight, age, and sex-specific scores.

Diminished quality of life: Physical component summery scores ≤40.

Discussion

Through comprehensive clinical neurosensory and functional assessments, we provide novel data about the prevalence and secondary consequences of balance impairment in a large well characterized cohort of long-term survivors of childhood CNS tumors. Study results indicate that balance impairment and associated physical performance and mobility limitations are common problems in young adults previously treated for cancers of the CNS during childhood. An infratentorial tumor location, intraventricular shunt placement surgery, radiation to the posterior fossa area, obesity, peripheral neuropathy, impaired low back and hamstring flexibility, hearing loss and global cognitive deficits were identified as risk factors for impaired balance. These data can be used by clinicians to help identify those at highest risk for impaired balance as well as guide the development of interventions for potentially modifiable impairments.

Over 48% of survivors in this study had impaired balance. This is similar to the percentage (50%) of balance impairment reported in a group of younger (N=41, male=58%, 6–17 years of age) CNS tumor survivors [33], but less than the 70% reported in a group (N=30, male=50%, 4–18 years of age) of posterior fossa tumor survivors [34]. Our findings support an association between infratentorial tumor location, radiation to posterior fossa, and impaired balance. When photon beam radiation therapy is applied to treat tumors located in the posterior fossa, centrally located supratentorial structures, such as the splenium of the corpus callosum, pulvinar of the thalamus that have a role in regulation of balance and coordination [35–38], and parieto-insular vestibular cortex (PIVC) which has a central role in integrating vestibular, visual, and somatosensory information [39], receive radiation doses similar to tumor doses (Supplemental Figure 1). Thus, potential radiation damage to these structures can negatively impact balance. In our study, intraventricular shunt placement was also associated with balance impairment. While the initial presence of hydrocephalus can result in impaired balance due to injury to brain structures associated with balance control [40], surgery for shunt placement, a known risk factor for hearing loss [41], may also interfere with vestibular function. Greater fat mass in this population can also increase the risk of balance impairment. This same association has been observed in young adults [42, 43] and the elderly [44]. We speculate that greater fat mass reduces efficiency in ability to control the center of mass within the base of support.

While survivors with impaired balance were younger at diagnosis and longer post-diagnosis than the survivors without balance impairment, age at diagnosis, and time since diagnosis were not independent predictors of impaired balance. This is consistent with two previous studies that reported no effect of age at diagnosis [45, 46]. However, we did find an association between longer time since diagnosis and impaired vestibular information processing. This suggests that survivors’ ability to process vestibular information may diminishes over time, maybe due to the late effects of chemotherapy agents on vestibular function, increasing dependence on somatosensory and visual information to maintain balance. However, the effect of normal aging on vestibular function cannot be excluded, as naturally those further away for diagnosis are also older. Interestingly, occipital/parietal radiation dose was also associated with impaired vestibular information processing, rather than with impaired visual information processing. This may seem counterintuitive; however, it is structurally possible. Efferent fibers of the superior vestibular nuclei project to the contralateral ventral thalamus and then to Brodmann area 2 (primary somatosensory cortex) in the intraparietal sulcus and the PIVC. Thus, damage to any of these cortical structures could lead to disruption of the vestibular signal. We also found an association between vincristine and impaired visual information processing. Vincristine is a known peripheral neurotoxin, and potentially can cause optic neuropathy [47]. Interestingly, in our elastic net model, no association between cumulative dose of individual chemotherapy agents and impaired balance was found. However, our results show survivors with peripheral neuropathy are twice as likely to have impaired balance in comparison to those without peripheral neuropathy. This may imply that a combination of chemotherapy agents can have enhanced neurotoxic effects, leading to higher chances for interruption in the integrity of peripheral nervous system and associated balance impairment.

An association between impairment in using visual information for maintaining balance and quadriceps weakness was also observed. We speculate that this may be because the inability to use visual cues makes movement uncomfortable, decreasing physical activity participation, and over time, resulting in muscle weakness. Survivors with cognitive deficits also had problems using visual cues. CNS centers that process visual information are also involved with cognitive processes such as visual memory [48]. We also observed an association between the presence of a cognitive deficit and impaired balance determined with the SOT composite score. Higher level CNS function is required for processing of sensory information; thus, it is possible that cognitive impairment can lead to inefficient processing of sensory information resulting in greater challenges to maintaining balance. We also found that limited hamstring, and lower back flexibility and hearing loss were significant predictors of impaired balance. These relationships are noteworthy as they identify additional factors that should be considered in a rehabilitation program to address balance in survivors.

When we examined the different sensory systems that contribute to balance in survivors of childhood CNS tumors, we found that almost 24% of survivors had difficulties using somatosensory information, 24% had difficulties using visual information, and over 38% had difficulties using vestibular information. When the support surface is stable, and the environment is such that the individual can adequately use vision, individuals will rely on their somatosensory and visual systems to maintain their balance. However, when walking on a dimly lit unpaved sidewalk or a uneven grass surface at night adequate vestibular processing is required to maintain balance [49]. This ability allows individuals to adapt to conditions and reduce their overall fall risk. Those with problems in vestibular processing, like many survivors, need to be educated on the risks associated with negotiating unpredictable surfaces and/or environments where their vision is compromised. Survivors with these limitations should consider avoiding walking on uneven surfaces and in dimly lit areas and making modifications to their home environment to improve lighting and minimize unstable surfaces.

The high rate of impaired balance among our survivors who were on average 18 years post diagnosis indicates that, contrary to previous speculations [50], balance impairments in survivors do not resolve over time and continue to affect survivors’ lives. This is concerning, as among the survivors with impaired balance, mobility limitations, and physical performance impairments were frequent. Because physical performance limitations reduce access to physical environment in this population [51], balance impairments may also contribute to social dependence in adult survivors of brain tumors [52]. Our work suggests that even after adjusting for cognitive functioning, impaired balance can double the risk of having a non-independent lifestyle. This highlights the importance of addressing balance impairment in survivors. We are not aware of any published study that has examined the effect of balance training in adult survivors of CNS tumors; however, exercise programs that include balance specific exercises improve balance performance in groups of adult cancer patients or survivors with signs and symptoms of peripheral neuropathy [53, 54]. Given that in our study peripheral neuropathy is identified as a significant predictor for impaired balance, the use of rehabilitation interventions to address balance impairment in CNS tumor survivors is promising and should be encouraged.

The results of our analyses should be considered in the context of potential study limitations. First, not everyone who received treatment for a CNS tumor at St. Jude participated in the study. If those who agreed were in better or worse health than those who did not agree to participate, study results could have been different. Additionally, this study used only the SOT, which quantifies balance through evaluations of anterior-posterior sway during quiet standing. More dynamic balance assessments like gait may provide additional information regarding balance in adult survivors of childhood CNS malignancies. Also, the Wechsler Abbreviated Scale of Intelligence test used in this study, similar to other neurocognitive tests, may be racially biased; however, the importance of this is unknown [55]. Although the racial distribution of whites and african-americans survivors in our study is similar to the distribution in the United States, we do not know what effect this potential bias may have on our estimates. Another limitation of current study is that we were unable to determine if these adult survivors received rehabilitation services in the past. Patients with identified balance problems would have received occupational and physical therapy services while on the hospital campus with subsequent referral to school and or community services. However, whether or not they received services is unknown. Previous interventions may have positively influenced balance and functional outcomes, and therefore prevalence of balance impairment in our survivors may be underestimated. Future studies should compare the prevalence of balance impairment in survivors who received rehabilitation services to those who did not receive services. Finally, some participants were not able to complete the functional tests due to health conditions that precluded testing, potentially affecting our results.

Nevertheless, these results indicate that almost half of young adult CNS tumor survivors have a balance impairment, which may be multifaceted, and associated with mobility and physical performance limitations. Given that survivors of pediatric CNS malignancies are at risk for the accelerated aging [56, 57] and its consequences, such as loss of flexibility and strength, it is important that survivors are referred to rehabilitation services early in survivorship. Those with risk factors for developing impaired balance; an infratentorial tumor, peripheral neuropathy, impaired flexibility, cognitive deficits, and hearing loss, should be closely monitored. While evaluating balance in survivors, the underlying reasons for the impaired balance should be identified and rehabilitation techniques aimed to improve those impaired systems should be offered. Addressing the balance impairment can affect survivors’ day to day life and enable them to be more prepared for challenges associated with aging when physiologic reserve naturally declines.