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. Author manuscript; available in PMC: 2019 Aug 1.
Published in final edited form as: Pediatr Blood Cancer. 2018 May 9;65(8):e27063. doi: 10.1002/pbc.27063

Neurologic impairments from pediatric low-grade glioma by tumor location and timing of diagnosis

Zsila Sadighi 1, Elizabeth Curtis 1, Jennifer Zabrowksi 1, Catherine Billups 2, Amar Gajjar 3, Raja Khan 1, Ibrahim Qaddoumi 3
PMCID: PMC6310055  NIHMSID: NIHMS949735  PMID: 29741274

Abstract

Background

The neurologic outcomes of low-grade gliomas (LGGs) according to tumor location and duration of presenting symptoms remain poorly characterized in children.

Procedure

We retrospectively reviewed neurologic impairments in 246 pediatric patients with LGGs (88 with optic pathway and midline tumors, 56 with posterior fossa tumors, 52 with cerebral hemisphere tumors, 35 with brainstem tumors and 15 with spinal cord tumors) who were treated at St. Jude Children’s Research Hospital between 1995 and 2005. We compared neurologic impairments (defined by Common Terminology Criteria for Adverse Events, version 4.03) by tumor location and prediagnosis symptom interval (PSI) (≥ 3 months or < 3 months) at first and last patient visits.

Results

The median age of diagnosis was 7.1 years; median PSI was 2.1 months; and median time to last follow-up was 11.6 years. LGGs in the cerebral hemispheres resulted in significantly fewer neurologic impairments, compared with that of other locations at baseline (P < 0.001) and at last follow-up (P < 0.001). In all patients, PSIs greater than 3 months resulted in a significantly higher incidence of ataxia and dysmetria at last follow-up (41.6%, P = 0.003). Greater PSI was also significantly associated with worsening lower extremity motor weakness from cerebral hemisphere tumors; dysmetria from optic pathway and midline tumors; eye and visual dysfunction from posterior fossa tumors; and ear and vestibular disturbances from brainstem tumors (P ≤ 0.05).

Conclusion

Neurologic impairment in pediatric LGGs varies by tumor location, and PSIs greater than 3 months affect some functionally important neurologic outcomes.

Keywords: low-grade glioma, neurologic outcomes, pediatric brain tumors, prediagnosis symptom interval

INTRODUCTION

Brain tumors are the most common solid tumors of childhood and are the leading cause of disease-related pediatric mortality.1 Low-grade gliomas (LGGs) comprise a large and heterogeneous group of brain tumors that vary in location, treatment, histology, and outcome. These tumors have higher survival rates than do other brain tumors,2,3 but recurrence may occur in 50% of cases with incomplete surgical resection, thus resulting in long-term neurologic morbidity.4 LGGs in the cerebellum account for 15% to 25% of central nervous system (CNS) tumors. Hemispheric, midline structure, optic pathway, spinal cord, and brainstem LGGs also account for a considerable number of CNS tumors.5–7 Children with LGG may experience long-term neurologic impairments, including ataxia, visual impairment, eye movement disorders, hemiplegia, seizures, hearing loss, cranial nerve deficits, and cognitive dysfunction.8–11 Such long-term neurologic deficits vary by LGG location, with 30% occurring in the infratentorial region of the brain and 73% occurring in the supratentorial region.9 Diagnosis of childhood brain tumors is delayed when compared with that of other childhood cancers.12–15 Delayed diagnosis, measured by prediagnosis symptom interval (PSI), is associated with lower tumor grade, older age, and progressive disease.16 Here, we characterized neurologic impairments in pediatric patients with LGG according to tumor site and timing of diagnosis.

METHODS

Participants

All patients with LGG who were treated at St. Jude Children’s Research Hospital (St. Jude) between January 20, 1995, and December 28, 2005, were eligible for this retrospective study and included if baseline and long-term neurologic assessments were available. Diagnosis of LGG was confirmed by pathology reports. If tumor biopsy information was unavailable, diagnosis was confirmed by imaging and clinical reports. The 2007 World Health Organization Classification of Tumors of the Central Nervous System criteria for LGG was used.17 Patients with neurofibromatosis type I were excluded. Symptom duration was based on reports in the initial history and abstracted via chart review. If a patient did not provide a specific date of symptom onset, the most conservative date was used. For example, if only the month was given, the last day of the month was used. If the patient used seasonal terms (i.e., summer, winter, fall, or spring), the last day of the month for each season (i.e., August, February, November, or April) was used. If a patient provided only a year, then December 31 of that year was used. The date of diagnosis was defined as the date of the first computed tomography or magnetic resonance imaging report after initial presentation. Therefore, the PSI was defined as the period from symptom onset to the first imaging report. In the case of multiple symptoms, the patient’s longest PSI was used.16

Standard protocol approvals, registrations, and patient consents

This study was approved by the institutional review board at St. Jude as a retrospective chart review under the classification of exempt research and waived the requirement for informed consent for this study.

Data collection

Scale scores and adverse event grades were determined from reports collected during the first and last patient visits at St. Jude. Relevant clinical information included birth date, sex, race, age at diagnosis, histologic diagnosis, description of symptoms, duration of symptoms, and treatment history. Neurologic impairment was assessed with the Modified Rankin Scale (MRS), which assigns scores from 0 (no symptoms) to 6 (death), and the Karnofsky Performance Status scale (KPS), which assigns scores from 0 (death) to 100 (normal activity), at first and last visits.18,19 Neurologic severity was scored with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03), which assigns scores from 1 (absent) to 5 (death), by a board-certified pediatric neurologist (ZS). Neurologic impairments determined with CTCAE criteria included facial sensory and motor disorders, lower cranial nerve palsies, eye and visual dysfunction, disorders of the ear and vestibular apparatus, motor weakness, movement disorders, ataxia and dysmetria, speech disorders, sensory disorders, apraxia, headache, cognitive dysfunction, sleep disturbances, urinary disturbances, gastrointestinal disturbances, and autonomic dysfunction. Indicators for the presence of neurologic impairments at first and last visits were obtained for seizure, endocrine dysfunction, history of posterior fossa (PF) syndrome, stroke, and hydrocephalus (Supplementary Table S1). The incidence of each neurologic outcome by time point (first and last visit) and tumor site group was classified as positive for toxicity, if the CTCAE grade was 1 or higher or if the indicator was yes for yes or no outcomes. Tumor location information was obtained from radiology reports. Tumor site groups included spinal cord, PF, brainstem, optic pathway and midline, and the cerebral hemispheres. If the tumor involved multiple locations or was metastatic, the tumor’s origin (per imaging report) was used.

Statistical analyses

Continuous variables were compared among the three tumor site groups with Kruskal–Wallis tests. We used χ2 tests to compare the proportions of patients with worsening MRS and KPS scores by tumor site group. Continuous variables were compared among PSI groups (< 3 months versus ≥ 3 months) by Wilcoxon rank-sum tests. Incidence of neurologic impairment was calculated for all patients and by tumor site group, in which neurologic dysfunction was present in patients with a CTCAE grade 1 or greater. Fisher exact tests were used to compare the incidence of neurologic impairments for each PSI group. Proportions of patients who experienced worsening neurologic impairments from the first to last visits were calculated and compared among PSI groups with Fisher exact tests. We compared the incidence of neurologic impairments at last follow up among prior treatment regimens such as radiation therapy, chemotherapy, radiation therapy and chemotherapy, or neither chemotherapy or radiation therapy (i.e., surgery only) with χ2 tests. Data were considered statistically significant when P ≤ 0.05. All tests were two-sided, and no adjustments were made for multiple comparisons.

RESULTS

Patient characteristics

We included 246 patients in this analysis (88 with optic pathway and midline, 56 with PF, 52 with cerebral hemisphere, 35 with brainstem, and 15 with spinal cord tumors) (Table 1). The median age at cancer diagnosis was 7.1 years (range, 0.1–20.7 years), and the median time to last follow-up was 11.6 years (range, 0.1–21.4 years). The time between the first and last visits did not differ among the tumor site groups (P = 0.68). The median times to last follow-up by tumor site group were 12.0, 11.8, 11.2, 11.4, and 10.6 years for cerebral hemisphere, optic pathway and midline, PF, brainstem, and spinal cord LGGs, respectively.

TABLE 1.

Patient characteristics (n = 246)

Site Group All Patients
(n = 246)
Brainstem
(n = 35)		 Cerebral
(n = 52)		 Optic pathway/
midline (n = 88)		 Posterior
fossa (n = 56)		 Spinal cord
(n = 15)
n % n % n n % n % n %
Sex
  Female 13 37.1 24 46.2 46 52.3 29 51.8 8 53.3 120 48.8
  Male 22 62.9 28 53.8 42 47.7 27 48.2 7 46.7 126 51.2
Race
  White 25 71.4 40 76.9 67 76.1 44 78.6 15 100.0 191 77.6
  Black 5 14.3 12 23.1 13 14.8 10 17.9 0 0.0 40 16.3
  Other 4 11.4 0 0.0 6 6.8 2 3.6 0 0.0 12 4.9
  Unknown 1 2.9 0 0.0 2 2.3 0 0.0 0 0.0 3 1.2
Age at diagnosis (years)
  Median 6.4 – 9.0 – 6.6 – 7.2 – 8.8 – 7.1 –
  Minimum 0.1 – 0.4 – 0.3 – 0.6 – 2.1 – 0.1 –
  Maximum 16.0 – 20.7 – 17.8 – 17.5 – 17.0 – 20.7 –
Histology
  Pilocytic astrocytoma 23 65.7 10 19.2 55 62.5 50 89.3 9 60.0 147 59.8
  Ganglioglioma 1 2.9 7 13.5 6 6.8 4 7.1 2 13.3 20 8.1
  Fibrillary astrocytoma 2 5.7 6 11.5 6 6.8 0 0.0 0 0.0 14 5.7
  Oligodendroglioma 0 0.0 13 25.0 0 0.0 0 0.0 1 6.7 14 5.7
  Astrocytoma, NOS 4 11.4 4 7.7 4 4.5 0 0.0 0 0.0 12 4.9
  Pleomorphic xanthoastrocytoma 0 0.0 10 19.2 1 1.1 0 0.0 0 0.0 11 4.5
  Glioma, optic 0 0.0 0 0.0 8 9.1 0 0.0 0 0.0 8 3.3
  Glioma, NOS 4 11.4 0 0.0 3 3.4 0 0.0 0 0.0 7 2.8
  Pilomyxoid astrocytoma 1 2.9 0 0.0 4 4.5 2 3.6 0 0.0 7 2.8
  Other 0 0.0 2 3.8 1 1.1 0 0.0 3 20.0 6 2.4
Grade
  I 28 80.0 20 38.5 73 83.0 53 94.6 13 86.7 187 76.0
  II 7 20.0 32 61.5 15 17.0 3 5.4 2 13.3 59 24.0
Therapy
  Chemotherapy only 1 2.9 2 3.8 14 15.9 2 3.6 2 13.3 21 8.5
  Chemotherapy and RT 11 31.4 6 11.5 32 36.4 4 7.1 6 40.0 59 24.0
  RT only 16 45.7 4 7.7 25 28.4 3 5.4 3 20.0 51 20.7
  No chemotherapy or RT 7 20.0 40 76.9 17 19.3 47 83.9 4 26.7 115 46.7
GTR 0 0.0 25 48.1 8 9.1 38 67.9 3 20.0 74 30.1
Duration of symptoms/PSI (months)
  Median 2.7 – 1.3 – 1.8 – 3.5 – 4.2 – 2.1 –
  Minimum 0.0 – 0.0 – 0.0 – 0.0 – 0.1 – 0.0 –
  Maximum 58.7 – 107.7 – 99.4 – 128.6 – 131.1 – 131.1 –
  < 3 months 19 54.3 35 67.3 52 59.1 27 48.2 6 40.0 139 56.5
  ≥ 3 months 16 45.7 17 32.7 36 40.9 29 51.8 9 60.0 107 43.5
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GTR, gross total resection; NOS, not otherwise specified; PSI, prediagnosis symptom interval; RT, radiation therapy

The most prevalent histology was pilocytic astrocytoma (59.8%). One hundred twenty-six (51.2%) patients were male, and 191 (77.6%) were white. Seventy-four patients (30.1%) received gross total resections of their tumors. Twenty-one patients (8.5%) received chemotherapy, and 59 (24.0%) also received radiation therapy. Fifty-one (20.7%) patients received only radiation therapy, and 115 (46.7%) received neither chemotherapy nor radiation therapy following surgery. The median PSI was 2.1 months (range, < 1–131.1 months) for all patients. The distribution of PSI as a continuous variable did not differ among tumor site groups (P = 0.22). The median PSI for LGGs in the cerebral hemispheres was 1.3 months (range, 0–107.7 months), and 35 (67.3%) had “short PSIs” (i.e., < 3 months), whereas 17 (32.7%) had “long PSIs” (i.e., ≥ 3 months). The median PSI for optic pathway and midline LGGs was 1.8 months (range, 0–99.4 months), and 52 (59.1%) had short PSIs, whereas 36 (40.9%) had long PSIs. The median PSI for brainstem tumors was 2.7 months (range, 0–58.7 months), and 19 (54.3%) had short PSIs. The median PSI for PF tumors was 3.5 months (range, 0–128.6 months), and 27 (48.2%) had short PSIs. The median PSI for spinal cord tumors was 4.2 months (range, 0.1–131.1 months), and six (40.0%) had short PSIs (Table 1).

Presenting symptoms at diagnosis

The most commonly reported symptoms before diagnosis in all patients were headache (38.2%), nausea and vomiting (31.3%), motor weakness (22.8%), and eye and visual dysfunction (25.2%) (Supplementary Table S2). Before diagnosis the most commonly reported symptoms by site group were the following: (1) seizures (57.7%), headache (34.6%), and nausea and vomiting (21.2%) in the cerebral hemisphere; (2) eye and visual dysfunction (44.3%), headache (36.4%), and nausea and vomiting (33.0%) in the optic pathway or midline; (3) motor weakness (40.0%) in the spinal cord; (4) nausea and vomiting (45.7%), motor weakness (45.7%), and headache (31.4%) in the brainstem; and (5) headache (58.9%), nausea and vomiting (35.7%) and motor weakness (26.8%) in the PF.

Incidence of baseline and long-term neurologic impairments by location

Significant differences in the number of neurologic impairments at the first and last visits were present by tumor site group (Supplementary Table S3). Patients with cerebral hemisphere LGG had the lowest median number of neurologic impairments (two impairments) at baseline, compared with those of the PF (three impairments), optic pathway and midline (four impairments), spinal cord (four impairments), and brainstem (six impairments) (P < 0.001). The number of impairments for cerebral hemisphere and PF tumors was also lower at last follow-up (three impairments), compared with that of the other site groups (five impairments for optic pathway/midline and spinal cord and eight impairments for brainstem tumors) (P < 0.001). In all patients, the most common neurologic impairments at the first visit were eye and visual dysfunction (41.6%), motor weakness (40.6%), ataxia and dysmetria (28.3%), and headache (26.4%). The most common neurologic deficits at the last visit were eye and visual dysfunction (46.3%), motor weakness (42.3%), cognitive dysfunction (37.3%), ataxia and dysmetria (30.8%), endocrine dysfunction (28.3%), and headache (26.0%).

The median MRS score was 1 (range, 0–5) for all patients at first visit and 2 (range, 0–5) at last follow-up (Supplementary Table S3). Baseline and last follow-up MRS scores were significantly different among tumor site groups (P < 0.001 for both time points). Patients with spinal cord, PF, and brainstem LGGs had the lowest median baseline MRS scores. The proportion of patients whose MRS scores worsened over time were not different among tumor site groups (P = 0.16). The proportion of patients whose MRS scores worsened over time did not differ by PSI among the site groups (P ≥ 0.67) except for PF tumors, in which short PSIs were marginally associated with worsening MRS (P = 0.053). The median KPS score for all patients was 90 (range, 40–100) at baseline and 80 (range, 20–100) at last follow-up (Supplementary Table S3). Baseline and last follow-up KPS scores were significantly different for tumor site groups (P = 0.003 and P < 0.001, respectively). Patients with brainstem and cerebral hemisphere LGG had the highest baseline KPS scores.

Combining all tumor locations, we compared the incidence of neurologic impairments at last evaluation by prior treatment regimen (Supplementary Table S4). The incidence of facial sensory and motor disorder, lower cranial nerve palsies, eye and visual dysfunction, motor weakness, ataxia and dysmetria, endocrine dysfunction, stroke, hydrocephalus, sleep disturbances, and urinary dysfunction were significantly different in each treatment group (P = 0.001, < 0.001, < 0.001, < 0.001, 0.047, < 0.001, 0.025, 0.026, 0.019, and < 0.001, respectively). Patients who were treated with chemotherapy and radiation had higher incidences of facial motor and sensory disorder (27.1%), lower cranial nerve palsies (28.8%), eye and visual dysfunction (62.7%), motor weakness (67.8%), sleep disturbances (33.9%), and urinary dysfunction (20.3%), when compared with the other treatment groups. The radiation only group had higher incidences of ataxia and dysmetria (41.2%) and endocrine dysfunction (52.9%), when compared with the other treatment groups. Those who received chemotherapy only had higher incidences of stroke (9.5%) and hydrocephalus (14.3%).

Incidence of baseline and long-term neurologic impairments by location and PSI

The distribution of total neurologic impairments by time point, PSI, and tumor site were overall not significantly different (Table 2). In all tumor sites combined, the incidence of ataxia and dysmetria was significantly higher at last follow-up in patients with long PSIs (22.8% short PSI versus 41.6% long PSI; P = 0.003). Long PSIs of brainstem LGG were associated with increased ear and vestibular dysfunction at last follow-up (25.0% long PSI versus 0.0% short PSI; P = 0.039). The incidence of motor weakness for cerebral hemisphere tumors was significantly different by PSI at the first visit (34.3% short PSI versus 5.9% long PSI; P = 0.039), but not at the last follow-up.

TABLE 2.

Incidence of neurologic impairments by site group, time point, and PSIa (< 3 months versus ≥ 3 months)

PSI Brainstem Cerebral
hemisphere		 Optic
pathway/midline		 Posterior Fossa Spinal cord All patients
Baseline
(%)		 LFU
(%)		 Baseline
(%)		 LFU
(%)		 Baseline
(%)		 LFU
(%)		 Baseline (%) LFU
(%)		 Baseline
(%)		 LFU
(%)		 Baseline
(%)		 LFU
(%)
< 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo		 < 3
mo		 ≥ 3
mo
Facial sensory and motor disorder 52.6 43.8 52.6 25.0 0.0 5.9 0.0 5.9 9.6 8.3 15.4 19.4 11.1 10.3 7.4 10.3 0.0 0.0 0.0 0.0 12.9 13.1 14.4 14.2
Lower cranial nerve palsies (IX–XII) 21.1 43.8 42.1 31.3 0.0 11.8 2.9 0.0 9.6 2.8 9.6 13.9 7.4 6.9 3.7 13.8 0.0 0.0 0.0 0.0 8.0 11.3 10.9 13.2
Eye and visual dysfunction 47.4 56.3 63.2 50.0 14.3 29.4 34.3 29.4 61.5 69.4 71.2 72.2 18.5 41.4 14.8 34.5 0.0 0.0 0.0 0.0 36.7 48.1 46.8 45.8
Ear and vestibular dysfunction 5.3 12.5 0.0* 25.0* 0.0 11.8 11.4 11.8 5.8 0.0 7.7 11.1 7.4 3.4 14.8 20.7 0.0 0.0 0.0 11.1 4.3 4.8 8.7 16.2
Motor weakness 57.9 56.3 73.7 62.5 34.3* 5.9* 34.3 35.3 36.5 28.6 34.6 38.9 29.6 55.2 29.6 34.5 100.0 77.8 83.3 77.8 40.6 40.6 41.0 43.9
Movement disorders 5.3 18.8 5.3 18.8 2.9 0.0 0.0 5.9 1.9 8.3 3.8 13.9 3.7 3.4 11.1 3.4 0.0 11.1 0.0 0.0 2.9 7.5 4.3 9.4
Ataxia and dysmetria 36.8 43.8 52.6 68.8 8.6 0.0 11.4 11.8 15.4 11.1 17.3 33.3 63.0 69.0 29.6 55.2 0.0 0.0 0.0 11.1 26.3 31.0 22.8* 41.6*
Sensory disorder 5.3 0.0 5.3 6.3 2.9 11.8 8.6 11.8 2.0 0.0 3.8 8.3 3.7 6.9 0.0 6.9 66.7 44.4 50.0 33.3 5.9 7.8 6.6 10.9
Headache 10.5 37.5 15.8 25.0 22.9 17.6 22.9 35.3 30.8 33.3 21.2 30.6 29.6 31.0 40.7 27.6 0.0 11.1 16.7 11.1 24.5 29.0 24.5 28.0
Cognitive dysfunction 21.1 18.8 42.1 43.8 20.0 17.6 37.1 35.3 17.3 25.0 38.5 33.3 7.4 27.6 40.7 37.9 0.0 11.1 16.7 22.2 15.8 22.4 38.4 35.8
Seizure 10.5 6.3 10.5 12.5 74.3 88.2 31.4 35.3 3.8 8.3 11.5 19.4 3.7 6.9 3.7 3.4 0.0 11.1 0.0 11.1 22.3 20.6 14.4 15.9
Endocrine dysfunction 0.0 6.3 47.4 43.8 2.9 0.0 14.3 0.0 7.7 11.1 36.5 41.7 0.0 0.0 14.8 10.3 0.0 0.0 66.7 33.3 3.6 4.7 29.7 26.4
Hydrocephalus 5.3 25.0 5.3 0.0 0.0 0.0 0.0 0.0 50.0 50.0 15.4 16.7 3.7 3.4 0.0 0.0 0.0 0.0 0.0 0.0 20.3 21.7 6.5 5.7
Sleep 0.0 6.3 15.8 18.8 0.0 0.0 31.4 23.5 7.7 0.0 23.1 33.3 0.0 3.4 0.0 10.3 0.0 0.0 0.0 11.1 2.9 1.9 18.7 21.7
Urinary 0.0 6.3 5.3 12.5 0.0 0.0 0.0 5.9 1.9 2.8 9.6 11.1 3.7 3.4 0.0 0.0 0.0 11.1 0.0 44.4 1.4 3.7 4.3 10.3
Autonomic 21.1 18.8 10.5 18.8 25.7 25.0 34.3 18.8 25.5 22.2 41.2 30.6 3.7 10.3 11.1 10.3 0.0 0.0 0.0 11.1 19.7 17.1 27.7 20.0
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LFU, last follow-up; mo, months; PSI, prediagnosis symptom interval

a

Impairments < 10% for all site/PSI groups were excluded.

*

P ≤ 0.05.

The only neurologic impairment that significantly worsened for all tumor sites combined with long PSIs was dysmetria (P < 0.001) (Table 3). For cerebral hemispheric tumors, motor weakness (lower extremity) significantly worsened over time in patients with long PSIs (P = 0.031). Optic pathway and midline tumors with long PSIs had significantly worsened dysmetria over time (P = 0.007). In brainstem tumors with long PSIs, ear and vestibular apparatus disturbances (P = 0.039) significantly worsened over time. In PF tumors with long PSIs, eye and visual dysfunction significantly worsened over time (P = 0.021). Patients with short PSIs and brainstem tumors experienced significantly worsened vagal nerve deficits over time (P = 0.049) (Table 3).

TABLE 3.

Worsening of neurologic impairments by PSI group and locationa

PSI Brainstem Cerebral
hemisphere		 Optic
pathway/midline		 Posterior fossa Spinal cord All patients
< 3 mo ≥ 3 mo < 3 mo ≥ 3 mo < 3 mo ≥ 3 mo < 3 mo ≥ 3 mo < 3 mo ≥ 3 mo < 3 mo ≥ 3 mo
Facial sensory and motor 36.8 12.5 0.0 5.9 9.6 19.4 7.4 6.9 0.0 0.0 10.1 11.2
CN IX–XII 42.1 31.3 2.9 0.0 9.6 13.9 3.7 13.8 0.0 0.0 10.8 13.1
CN IX 31.6 6.3 0.0 0.0 1.9 2.8 0.0 0.0 0.0 0.0 5.0 1.9
CN X 26.3* 0.0* 0.0 0.0 1.9 5.6 0.0 0.0 0.0 0.0 4.3 1.9
Eye and visual dysfunction 57.9 43.8 28.6 17.6 59.6 50.0 7.4* 34.5* 0.0 0.0 38.8 35.5
Ear and vestibular dysfunction 0.0* 25.0* 11.4 5.9 7.7 11.1 7.4 20.7 0.0 11.1 7.2 15.0
Motor weakness (overall) 68.4 50.0 25.7 35.3 26.9 36.1 29.6 24.1 66.7 22.2 34.5 33.6
Motor weakness (LE) 26.3 43.8 5.7* 29.4* 13.5 16.7 11.1 13.8 16.7 22.2 12.9 22.4
Movement disorder 5.3 18.8 0.0 5.9 3.8 13.9 11.1 3.4 0.0 0.0 4.3 9.3
Ataxia 36.8 25.0 11.4 5.9 9.6 13.9 11.1 17.2 0.0 11.1 13.7 15.0
Dysmetria 10.5 37.5 2.9 11.8 1.9* 19.4* 3.7 17.2 0.0 0.0 3.6* 18.7*
Speech disorder 5.3 0.0 0.0 0.0 1.9 0.0 0.0 0.0 0.0 0.0 1.4 0.0
Sensory disorder 5.3 6.3 8.6 11.8 1.9 8.3 0.0 6.9 33.3 11.1 5.0 8.4
Seizures 0.0 12.5 5.7 0.0 9.6 16.7 0.0 0.0 0.0 0.0 5.0 7.5
Cognitive dysfunction 31.6 37.5 34.3 29.4 34.6 30.6 37.0 31.0 16.7 11.1 33.8 29.9
Stroke 0.0 0.0 0.0 0.0 1.9 5.6 0.0 3.4 0.0 0.0 0.7 2.8
Hydrocephalus 5.3 0.0 0.0 0.0 5.8 2.8 0.0 0.0 0.0 0.0 2.9 0.9
Sleep disturbances 15.8 18.8 31.4 23.5 21.2 33.3 0.0 6.9 0.0 11.1 18.0 20.6
Urinary 5.3 12.5 0.0 5.9 9.6 11.1 0.0 0.0 0.0 33.3 4.3 9.3
Gastrointestinal 5.3 0.0 0.0 5.9 0.0 2.8 0.0 0.0 0.0 11.1 0.7 2.8
Autonomic 10.5 18.8 20.0 11.8 26.9 25.0 11.1 10.3 0.0 11.1 18.7 16.8
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CN, cranial nerve; LE, lower extremity; mo, months; PSI, prediagnosis symptom interval

a

The percentage of patients who had worsening neurologic impairments from first to last visit for each PSI and tumor site group are indicated in each cell.

*

P ≤ 0.05.

DISCUSSION

We conducted the first and largest known study of long-term neurologic impairments in pediatric patients with LGG with respect to tumor location and timing of diagnosis. A previous study of delayed diagnosis of pediatric LGG by Arnautovic et al., demonstrated that increased PSIs are associated with lower tumor grade, older age, and disease progression, yet did not address neurological outcomes.16 We found that the incidence of neurologic impairments varied by tumor location and that long PSIs particularly affected the long-term incidence of ataxia and dysmetria.

Our findings are in agreement with reports that children with LGG commonly exhibit signs of increased intracranial pressure before diagnosis and that localized symptoms, such as focal neurologic deficits, seizures, and endocrinopathies, are dictated by tumor location.20,21 The frequencies of neurologic impairments at first and last visits (i.e., three and four, respectively) were similar to those reported in another study, with at least one long-term impairment occurring in 85% of patients and a minimum of three occurring in 28%.22 Of the five tumor site groups, cerebral hemisphere LGGs resulted in the fewest number of neurologic impairments at first and last visits, and brainstem tumors resulted in the highest numbers. We found no differences among tumor sites for worsening functional outcome, as measured by MRS. We observed higher incidences of worsening KPS scores over time in brainstem (57.1%), cerebral hemisphere (46.2%), and optic pathway and midline tumors (53.4%), as compared with those in PF (30.4%) and spinal cord (26.7%).

The most common long-term neurologic deficits observed in our study were similar to those reported in other studies, such as visual and motor deficits.22–24 For all patients, we found that long PSIs were associated with a higher incidence of long-term ataxia and dysmetria, and long PSIs were associated with ear and vestibular dysfunction specifically in patients with brainstem LGG. The only specific neurologic impairment that worsened over time for all patients with long PSIs was dysmetria. We found that long PSIs were associated with worsened ear and vestibular dysfunction in brainstem tumors; lower extremity motor weakness in cerebral hemisphere tumors; eye and visual dysfunction in PF tumors; and dysmetria in optic pathway and midline tumors. Long PSIs were reported for pediatric patients with spinal cord LGGs, of whom 83% experienced morbidity and 35% required orthopedic interventions for severe kyphoscoliosis at long-term follow-up.25 Of the 15 patients with spinal cord tumors in our study, 13 (86.7%) had scoliosis and seven (46.7%) required rod placement, but their neurologic deficits did not significantly worsen over time, regardless of PSI length. This could be due to functional compensation by neural plasticity in children with spinal cord LGGs.26

The strengths of our study include the presence of similar demographic data in our study as those in other large population-based studies. We also used increments of 3 months for PSI intervals, which were similarly reported by others.24,27 Our study included a higher proportion of patients with supratentorial LGG, which was similarly reported by other population-based studies of LGG. A relatively low incidence of spinal cord LGGs has been reported in other studies as well.28,29 We found that receiving both chemotherapy and radiation therapy was a risk factor for higher rates of long-term facial motor and sensory disorder, lower cranial nerve palsies, eye and visual dysfunction, motor weakness, sleep disturbances, and urinary dysfunction. Patients who received radiation had higher rates of long-term ataxia and dysmetria and endocrine disturbances, whereas higher rates of long-term stroke and hydrocephalus occurred in those treated with chemotherapy. This is consistent with other reports of radiation as an independent risk factor for endocrine dysfunction, but our findings highlight other neurologic deficits arising from radiation, chemotherapy, or both treatments, which have not been extensively described before.23

We report that stroke and hydrocephalus were more prevalent at long-term follow-up in the chemotherapy only group. However, the chemotherapy group consisted of only 21 patients, of which two (9.5%) had strokes. These two patients had optic pathway/midline LGG. Three (14.2%) of the 21 patients treated with chemotherapy only also had hydrocephalus. These three patients had optic pathway/midline LGG. The higher prevalence of stroke and hydrocephalus in patients treated with chemotherapy only is most likely attributed to the small number of patients in this group. Although the Childhood Cancer Survivor Study reported a cumulative incidence of late-occurring strokes in brain tumor survivors to be higher in those treated with radiation therapy, strokes occurred in survivors who did not receive radiation as well (2.69% radiation vs. 1.04% non-radiation).30 Risk factors for stroke typically include younger age at tumor diagnosis, radiation therapy, and neurofibromatosis type I.31,32 However, optic pathway/midline tumor location may also associate with risk of stroke.33

We were unable to compare specific chemotherapy regimens or radiation doses because of variability in the patient population and tumor locations. The retrospective nature of our study constitutes another weakness, in which data were collected from charts containing examinations and reports by various physicians. However, these data were reviewed by a board-certified neurologist who independently scored the neurologic impairments in a PSI interval–blinded manner. St. Jude is a referral center; therefore, referral bias may have also been introduced in our study cohort.

Although pediatric patients with LGG have high rates of survival, long-term neurologic morbidity persists and varies by tumor location. Prevention of delayed diagnosis is encouraged to prevent disease progression. Because neurologic deficits negatively affect physical function, academic performance, and quality of life34–37 and some long-term deficits are associated with long PSIs, we propose that earlier diagnoses of pediatric LGGs will prevent development of some neurologic deficits and improve the quality of life of survivors. This is specifically evidenced by the success of a quality-improvement campaign, known as HeadSmart: Be Brain Tumour Aware, that was initiated in 2011 in the United Kingdom.38 After its launch, the campaign facilitated a remarkable reduction in the PSIs associated with pediatric brain tumors in the United Kingdom.38 It augmented professional and public awareness of the presenting symptoms of brain tumors in children and created guidelines for seeking medical attention, with improved referral times for diagnostic neuroimaging.39 Although it is unclear whether such a methodology would be successful in the United States health care system, it is worthy of future investigation with prospective studies on survival and neurologic outcomes.

Supplementary Material

Supp TableS1

SUPPLEMENTARY TABLE S1 Neurologic impairments assessed

AE, adverse eevent; CN, cranial nerve; CTCAE, Common Terminology Criteria for Adverse Events (version 4.03); NS, nervous system

Supp TableS2

SUPPLEMENTARY TABLE S2 Presenting symptoms in prediagnosis symptom intervala

aSymptoms reported in < 10% of all patients were excluded. These comprised musculoskeletal (scoliosis, torticollis, and back/neck pain), constitutional (decreased appetite/energy, dizziness, drowsiness, fatigue, fever, irritability, low weight, night sweat, poor growth/weight gain, weakness, and weight loss), personality and behavior, facial motor, gastrointestinal, sensory, tremor, incidental (post head trauma), developmental regression, sleep, precocious puberty, speech, hearing, and academic performance symptoms.

Supp TableS3

SUPPLEMENTARY TABLE S3 Incidence of neurologic impairments by site group and time pointa

LFU, last follow-up; PFS, posterior fossa syndrome

aAll data are % incidence unless otherwise stated.

bScored from 0 (no symptoms) to 6 (death).

cScored from 0 (death) to 100 (normal activity).

Supp TableS4

SUPPLEMENTARY TABLE S4 Incidence of neurologic impairments at last evaluation by treatment groupa

aAll data are % incidence unless otherwise stated.

PFS, posterior fossa syndrome; RT, radiation therapy

Acknowledgments

The authors thank Nisha Badders, PhD, ELS, (St. Jude) for editing the manuscript.

FUNDING

This study was funded, in part, by a Cancer Center Support grant (CA21765) and a Pediatric Oncology Program Support grant (CA02394) from NCI, as well as by ALSAC.

Abbreviations

CNS

central nervous system

CTCAF

Common Terminology Criteria for Adverse Events

KPS

Karnofsky Performance Status

LGG

low-grade glioma

MRS

Modified Rankin Scale

PF

posterior fossa

PSI

prediagnosis symptom interval

St. Jude

St. Jude Children’s Research Hospital

Footnotes

CONFLICT OF INTEREST

The authors declare no conflicts of interest.

References

  • 1.Ullrich NJ. Neurologic sequelae of brain tumors in children. J Child Neurol. 2009;24:1446–1454. doi: 10.1177/0883073809342491. [DOI] [PubMed] [Google Scholar]
  • 2.Ater JL, Zhou T, Holmes E, et al. Randomized study of two chemotherapy regimens for treatment of low-grade glioma in young children: a report from the Children's Oncology Group. J Clin Oncol. 2012;30:2641–2647. doi: 10.1200/JCO.2011.36.6054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Gajjar A, Sanford RA, Heideman R, et al. Low-grade astrocytoma: a decade of experience at St. Jude Children's Research Hospital. J Clin Oncol. 1997;15:2792–2799. doi: 10.1200/JCO.1997.15.8.2792. [DOI] [PubMed] [Google Scholar]
  • 4.Palma L, Guidetti B. Cystic pilocytic astrocytomas of the cerebral hemispheres. Surgical experience with 51 cases and long-term results. J Neurosurg. 1985;62:811–815. doi: 10.3171/jns.1985.62.6.0811. [DOI] [PubMed] [Google Scholar]
  • 5.Choi GH, Oh JK, Kim TY, et al. The clinical features and surgical outcomes of pediatric patients with primary spinal cord tumor. Childs Nerv Syst. 2012;28:897–904. doi: 10.1007/s00381-012-1718-8. [DOI] [PubMed] [Google Scholar]
  • 6.Kutluk T, Varan A, Kafali C, et al. Pediatric intramedullary spinal cord tumors: a single center experience. Eur J Paediatr Neurol. 2015;19:41–47. doi: 10.1016/j.ejpn.2014.09.007. [DOI] [PubMed] [Google Scholar]
  • 7.Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009;24:1397–1408. doi: 10.1177/0883073809342005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Yule SM, Hide TA, Cranney M, Simpson E, Barrett A. Low grade astrocytomas in the West of Scotland 1987-96: treatment, outcome, and cognitive functioning. Arch Dis Child. 2001;84:61–64. doi: 10.1136/adc.84.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Aarsen FK, Paquier PF, Reddingius RE, et al. Functional outcome after low-grade astrocytoma treatment in childhood. Cancer. 2006;106:396–402. doi: 10.1002/cncr.21612. [DOI] [PubMed] [Google Scholar]
  • 10.Due-Tonnessen BJ, Helseth E, Scheie D, Skullerud K, Aamodt G, Lundar T. Long-term outcome after resection of benign cerebellar astrocytomas in children and young adults (0–19 years): report of 110 consecutive cases. Ped Neurosurg. 2002;37:71–80. doi: 10.1159/000065108. [DOI] [PubMed] [Google Scholar]
  • 11.Beebe DW, Ris MD, Armstrong FD, et al. Cognitive and adaptive outcome in low-grade pediatric cerebellar astrocytomas: evidence of diminished cognitive and adaptive functioning in National Collaborative Research Studies (CCG 9891/POG 9130) J Clin Oncol. 2005;23:5198–5204. doi: 10.1200/JCO.2005.06.117. [DOI] [PubMed] [Google Scholar]
  • 12.Edgeworth J, Bullock P, Bailey A, Gallagher A, Crouchman M. Why are brain tumours still being missed? Arch Dis Child. 1996;74:148–151. doi: 10.1136/adc.74.2.148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Flores LE, Williams DL, Bell BA, O'Brien M, Ragab AH. Delay in the diagnosis of pediatric brain tumors. Am J Dis Child. 1986;140:684–686. doi: 10.1001/archpedi.1986.02140210082031. [DOI] [PubMed] [Google Scholar]
  • 14.Pollock BH, Krischer JP, Vietti TJ. Interval between symptom onset and diagnosis of pediatric solid tumors. J Pediatr. 1991;119:725–732. doi: 10.1016/s0022-3476(05)80287-2. [DOI] [PubMed] [Google Scholar]
  • 15.Saha V, Love S, Eden T, Micallef-Eynaud P, MacKinlay G. Determinants of symptom interval in childhood cancer. Arch Dis Child. 1993;68:771–774. doi: 10.1136/adc.68.6.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Arnautovic A, Billups C, Broniscer A, Gajjar A, Boop F, Qaddoumi I. Delayed diagnosis of childhood low-grade glioma: causes, consequences, and potential solutions. Childs Nerv Syst. 2015;31:1067–1077. doi: 10.1007/s00381-015-2670-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109. doi: 10.1007/s00401-007-0243-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke. 1988;19:604–607. doi: 10.1161/01.str.19.5.604. [DOI] [PubMed] [Google Scholar]
  • 19.Mor V, Laliberte L, Morris JN, Wiemann M. The Karnofsky Performance Status Scale. An examination of its reliability and validity in a research setting. Cancer. 1984;53:2002–2007. doi: 10.1002/1097-0142(19840501)53:9<2002::aid-cncr2820530933>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  • 20.Sridhar K, Sridhar R, Venkatprasanna G. Management of posterior fossa gliomas in children. J Pediatr Neurosci. 2011;6:S72–77. doi: 10.4103/1817-1745.85714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Sievert AJ, Fisher MJ. Pediatric Low-Grade Gliomas. J Child Neurolog. 2009;24:1397–1408. doi: 10.1177/0883073809342005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Turner CD, Chordas CA, Liptak CC, et al. Medical, psychological, cognitive and educational late-effects in pediatric low-grade glioma survivors treated with surgery only. Pediatr Blood Cancer. 2009;53:417–423. doi: 10.1002/pbc.22081. [DOI] [PubMed] [Google Scholar]
  • 23.Armstrong GT, Conklin HM, Huang S, et al. Survival and long-term health and cognitive outcomes after low-grade glioma. Neuro Oncol. 2011;13:223–234. doi: 10.1093/neuonc/noq178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Ehrstedt C, Kristiansen I, Ahlsten G, et al. Clinical characteristics and late effects in CNS tumours of childhood: Do not forget long term follow-up of the low grade tumours. Eur J Paediatr Neurolog. 2016;20:580–587. doi: 10.1016/j.ejpn.2016.04.009. [DOI] [PubMed] [Google Scholar]
  • 25.Scheinemann K, Bartels U, Huang A, et al. Survival and functional outcome of childhood spinal cord low-grade gliomas. J Neurosurg Pediatr. 2009;4:254–261. doi: 10.3171/2009.4.PEDS08411. [DOI] [PubMed] [Google Scholar]
  • 26.Duffau H. Diffuse low-grade gliomas and neuroplasticity. Diagn Interv Imaging. 2014;95:945–955. doi: 10.1016/j.diii.2014.08.001. [DOI] [PubMed] [Google Scholar]
  • 27.Wilne S, Collier J, Kennedy C, et al. Progression from first symptom to diagnosis in childhood brain tumours. Eur J Pediatr. 2012;171:87–93. doi: 10.1007/s00431-011-1485-7. [DOI] [PubMed] [Google Scholar]
  • 28.Krishnatry R, Zhukova N, Guerreiro Stucklin AS, et al. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: a population-based study. Cancer. 2016;122:1261–1269. doi: 10.1002/cncr.29907. [DOI] [PubMed] [Google Scholar]
  • 29.Bandopadhayay P, Bergthold G, London WB, et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer. 2014;61:1173–1179. doi: 10.1002/pbc.24958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Bowers DC, Liu Y, Leisenring W, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006;24:5277–5282. doi: 10.1200/JCO.2006.07.2884. [DOI] [PubMed] [Google Scholar]
  • 31.Merchant TE, Conklin HM, Wu S, Lustig, Xiong X. Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol. 2009;27:3691–3697. doi: 10.1200/JCO.2008.21.2738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Grill J, Couanet D, Cappelli C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol. 1999;45:393–396. doi: 10.1002/1531-8249(199903)45:3<393::aid-ana17>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  • 33.Bowers DC, Mulne AF, Reisch JS, et al. Nonperioperative strokes in children with central nervous system tumors. Cancer. 2002;94:1094–1101. [PubMed] [Google Scholar]
  • 34.Ness KK, Morris EB, Nolan VG, et al. Physical performance limitations among adult survivors of childhood brain tumors. Cancer. 2010;116:3034–3044. doi: 10.1002/cncr.25051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Sato I, Higuchi A, Yanagisawa T, et al. Impact of late effects on health-related quality of life in survivors of pediatric brain tumors: motility disturbance of limb(s), seizure, ocular/visual impairment, endocrine abnormality, and higher brain dysfunction. Cancer Nurs. 2014;37:E1–E14. doi: 10.1097/NCC.0000000000000110. [DOI] [PubMed] [Google Scholar]
  • 36.Lieu JE. Speech-language and educational consequences of unilateral hearing loss in children. Arch Otolaryngol Head Neck Surg. 2004;130:524–530. doi: 10.1001/archotol.130.5.524. [DOI] [PubMed] [Google Scholar]
  • 37.Martin HC, Sethi J, Lang D, Neil-Dwyer G, Lutman ME, Yardley L. Patient-assessed outcomes after excision of acoustic neuroma: postoperative symptoms and quality of life. J Neurosurg. 2001;94:211–216. doi: 10.3171/jns.2001.94.2.0211. [DOI] [PubMed] [Google Scholar]
  • 38.HeadSmart Be Brain Tumour Aware. A new clinical guideline from the Royal College of Paedatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children--"Be Brain Tumour Aware". Neuro Oncol. 2016;18:445–454. doi: 10.1093/neuonc/nov187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Wilne S, Koller K, Collier J, Kennedy C, Grundy R, Walker D. The diagnosis of brain tumours in children: a guideline to assist healthcare professionals in the assessment of children who may have a brain tumour. Arch Dis Child. 2010;95:534–539. doi: 10.1136/adc.2009.162057. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supp TableS1

SUPPLEMENTARY TABLE S1 Neurologic impairments assessed

AE, adverse eevent; CN, cranial nerve; CTCAE, Common Terminology Criteria for Adverse Events (version 4.03); NS, nervous system

NIHMS949735-supplement-Supp_TableS1.docx (15.8KB, docx)
Supp TableS2

SUPPLEMENTARY TABLE S2 Presenting symptoms in prediagnosis symptom intervala

aSymptoms reported in < 10% of all patients were excluded. These comprised musculoskeletal (scoliosis, torticollis, and back/neck pain), constitutional (decreased appetite/energy, dizziness, drowsiness, fatigue, fever, irritability, low weight, night sweat, poor growth/weight gain, weakness, and weight loss), personality and behavior, facial motor, gastrointestinal, sensory, tremor, incidental (post head trauma), developmental regression, sleep, precocious puberty, speech, hearing, and academic performance symptoms.

NIHMS949735-supplement-Supp_TableS2.docx (13.4KB, docx)
Supp TableS3

SUPPLEMENTARY TABLE S3 Incidence of neurologic impairments by site group and time pointa

LFU, last follow-up; PFS, posterior fossa syndrome

aAll data are % incidence unless otherwise stated.

bScored from 0 (no symptoms) to 6 (death).

cScored from 0 (death) to 100 (normal activity).

NIHMS949735-supplement-Supp_TableS3.docx (16.4KB, docx)
Supp TableS4

SUPPLEMENTARY TABLE S4 Incidence of neurologic impairments at last evaluation by treatment groupa

aAll data are % incidence unless otherwise stated.

PFS, posterior fossa syndrome; RT, radiation therapy

NIHMS949735-supplement-Supp_TableS4.docx (14.2KB, docx)

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