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© 2003 American Society for Clinical Oncology Long-Term Neurological Outcome of Childhood Brain Tumors Treated by Surgery Only
From the Pediatric Clinic II and the Department of Growth and Reproduction, Juliane Marie Center, Clinic of Neurosurgery, Neurocenter, The University Hospital, H:S Rigshospitalet, Copenhagen 2100, Denmark. Address reprint requests to Kjeld Schmiegelow, PhD, Pediatric Clinic II, Juliane Marie Center, H:S Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark; email: kschmiegelow{at}rh.dk.
Purpose: To evaluate the pattern of neurological late effects in patients who have received surgery only for a brain tumor in childhood and to identify possible risk factors for neurological sequelae. Patients and Methods: The medical, histologic, and operative records were reviewed for 65 consecutive patients operated for a benign brain tumor from 1970 to 1997, and all patients were re-examined after a median length of follow-up of 10.7 years. Thirty-four patients had posterior fossa tumors, 22 patients had cerebral hemisphere tumors, and nine patients had midline tumors. Results: At the time of follow-up, 20 patients (31%) had no neurological deficits, 22 patients (34%) had minor deficits that did not interfere with their daily life activities, and 23 patients (35%) had moderate or severe deficits such as severe ataxia, spastic paresis, seriously reduced vision, or epilepsy with more than two seizures per year. Fourteen of the 31 patients (45%) registered with ataxia preoperatively had recovered fully. Six of seven patients had persistence of a pre- or postoperatively developed hemiparesis. Thirteen of 23 patients had persistence of cranial nerve deficits that developed second to surgery. Fifty-five percent of the 18 patients with seizures at diagnosis were seizure-free at follow-up. At follow-up both ataxia and hemiparesis were significantly more frequent among females (P = .02 and P = .03, respectively). Conclusion: In patients who received operation as the only treatment for their brain tumor, there was a good chance of total or partial recovery of preoperative and postoperative neurological deficits, although only one third of the patients will have no long-term neurological deficits.
INTRACRANIAL TUMORS are second only to leukemia as the most frequent cancer in childhood.1,2 The overall 5-year survival of children who have brain tumors and who are younger than 15 years of age at diagnosis has increased from 35% in the early 1960s to almost 60% in the late 1980s.3 For some subgroups such as cerebellar astrocytomas, the outcome is even better, with a survival rate that has improved from approximately 40% to more than 90%.4,5,6 These improvements partly reflect a decrease in the peri- and postoperative mortality from almost 30% to less than 5% because of better peri- and postoperative intensive care, better surgical techniques, and the development of computed tomography and magnetic resonance scanning techniques.2,4–10 The improved survival rates have increased the clinical effect of the late effects to the disease itself and to the treatment. However, the focus has mainly been on the neurological and neuropsychological late effects of chemotherapy and radiotherapy.11–13 This has lead to the skewed impression that the majority of patients with benign tumors who have received surgery only will have no or only minor late effects of their disease and treatment. As part of a large multidisciplinary Danish study on children with brain tumors, the aims of this investigation were to evaluate the extent of neurological late effects in patients who had received surgery only for a brain tumor in childhood and to identify possible risk factors for neurological sequelae such as sex, age at diagnosis, tumor localization, histology, duration of preoperative symptoms, presence of hydrocephalus, extent of tumor resection, operative and postoperative complications, and time period of operation.
We performed a follow-up investigation of all the surviving persons in the eastern part of Denmark (which includes about half the population in Denmark = 2.5 million) who were diagnosed with a brain tumor between January 1, 1970, and March 1, 1997, before the age of 15 years; had received surgery including a biopsy only; and were more than 1 year from the end of treatment. Patients were excluded if, at the time of follow-up (between September 1998 and September 1999), they had emigrated or had a residence in the Faroe Islands or Greenland (n = 7). The study was approved by the Ethical Committee of Copenhagen and Frederiksberg counties, and all patients who participated gave their written consent (approval no. 01–339/96). Of 83 patients who were eligible for the study, 78% (28 males and 37 females) participated. At diagnosis, the median age of the participants was 8.2 years (75% range, 3.3 to 13.2 years), and the median age at follow-up was 19.2 years (75% range, 8.9 to 32.2 years). The median length of follow-up was 10.7 years. There were no significant differences between those who participated in the study and those who declined with respect to age, sex, histologic diagnoses, or localization of the tumors. All tumors were benign. Astrocytomas of World Health Organization grade 1 and 2 were found in 51 patients (78%), craniopharyngiomas were found in three patients (5%), and miscellaneous tumors (eg, hamartoma, meningioma, choroid plexus papilloma, and teratoma) were found in 11 patients (17%). Thirty-four (52%) of the tumors were localized to the posterior fossa, 22 tumors were localized (34%) to the hemispheres, and nine tumors (14%) were supratentorial midline tumors. Fifty of the patients had a complete tumor resection (eight of which occurred by a second craniotomy) as judged during surgery by the surgeon or after a postoperative scan; 12 patients had a partial tumor resection, including five patients who had a second craniotomy, and three patients had a biopsy only. The median duration of symptoms before the diagnosis was 6 months (75% range, 0.5 to 13.7 months). For tumors localized in the hemispheres, the median duration of symptoms was 9.5 months; for the midbrain tumors, median duration of symptoms was 6 months; and for the posterior fossa tumors, median duration of symptoms was 3.5 months. These differences were only borderline significant (supratentorial tumors v infratentorial tumors, P = .06). Eighteen of 28 patients with hydrocephalus had shunts inserted before the tumor surgery. In addition, three patients developed hydrocephalus postoperatively and had shunts inserted. Four of these 21 patients had their shunts removed within 14 days of the operation because of infection, and four had their shunts removed later for other reasons. Thus, 13 patients had shunts at the follow-up investigation. The medical, histologic, and operative records were reviewed, and the patients were interviewed and had a thorough physical and neurological examination carried out by the same two physicians (S.S. and M.S.). The neurological examination included all 12 cranial nerves, sensibility to touch, agnosia, dysdiadochokinesia, ataxia (finger to nose and heel to knee), Romberg’s test, walking on a line, on heels and toes, standing on one leg for balance, strength examinations, and reflexes. The overall neurologic outcome (level of performance) was graded according to the Bloom’s scale,14 to which we added the presence of epilepsy. The classifications of this scale are as follows: score I: no disability, active life; no abnormal neurological signs. Score II: Mild disability, active life; minor deficits not interfering with everyday life, such as ocular paresis, discrete reduced field of vision, or strabismus; limited intension tremor, mild ataxia, or reduced strength of limbs not interfering with walking ability or manual work; or the presence of epilepsy with fewer than three seizures per year. Score III: Partial disability not preventing self-care but including deficits that interfere with normal everyday life, such as severe ataxia (eg, change of hand preference, not being able to drink without spilling, or not being able to ride a bicycle), spastic paresis of an arm or a leg, seriously reduced vision (ie, blindness of one or both eyes or severely reduced field of vision including no central vision of one or both eyes), or epilepsy with more than two seizures per year; the patient may have impaired intellect, but he or she is capable of being taught a trade. Score IV: Severe disability but capable of limited self-care such as self-feeding and dressing, or institutionalized and incapable of self-care.
Statistics
The clinical signs and symptoms preoperatively, postoperatively, and at the time of follow-up are given in Tables 1  and 2. At the time of diagnosis, all patients had symptoms and signs of increased intracranial pressure and/or neurological symptoms directly related to the tumor. Twenty-five patients (38%) developed one or more new neurological deficits postoperatively.
Only 20 patients (31%) had no neurological deficits at the time of follow-up (modified Bloom’s score I). Twenty-four patients had only one neurological deficit or symptom including epilepsy (n = 6), visual deficits (n = 6), loss of sensibility (n = 1), or motor deficits (n = 11) (Fig 1 ). Finally, 21 patients had two or more deficits and/or symptoms. The supra- and infratentorial tumors did not differ significantly in their distribution of either Bloom’s modified score (P = .18) or the unmodified Bloom’s score (P = .75) (Table 3). Bloom’s modified score at follow-up was significantly related to sex (P = .001, trend analysis) and to the level of consciousness at diagnosis (fully awake v unconscious/somnolent; P < .001), with the 37 females and the four patients who were unconscious/somnolent on admittance having the poorer outcome. The sex difference in the modified Bloom’s score was most pronounced for the 25 patients 10.0 to 14.9 years of age at diagnosis (number of patients with score I/II/III/IV: girls one/five/six/zero v boys seven/five/zero/one, respectively; P = .001). Specifically, among patients with infratentorial tumors, the frequency of Bloom’s score III/IV was higher for females than for males (10 of 22 v two of 12, P = .02), whereas no significant difference was found for patients with supratentorial tumors (females seven of 15 v males four of 16, P = .23). These differences reflected a higher frequency of ataxia and hemiparesis among females. In contrast, duration of symptoms before diagnosis, age at diagnosis, the presence of hydrocephalus at diagnosis, having a shunt inserted, the surgical time period (1970 to 1983 v 1984 to 1997), achieving a total tumor resection, having a second craniotomy, or duration of follow-up were not significantly related to Bloom’s score.
Ataxia Twenty-eight of the 31 patients with ataxia preoperatively had infratentorial tumors; 23 of the 31 patients were still ataxic postoperatively. Three additional patients were found to be ataxic postoperatively, and all were patients with posterior fossa tumors. At follow-up, 22 patients had ataxia, of which 17 were recorded to have ataxia at diagnosis. For two of these 22 patients, the presence of ataxia was not recorded in either their surgical or their preoperative medical records. Thus, the ataxia had disappeared in only 45% of the patients (14 of 31) who had ataxia at diagnosis. The risk of persistent ataxia was not related to the time period of surgery (1970 to 1983 v 1984 to 1997) or to whether a total tumor resection was done. At follow-up, ataxia was more commonly found among females than males (P = .018), in patients with infratentorial tumors (P < .001), and in those with hydrocephalus at diagnosis (P = .001). The frequency of ataxia was significantly higher among females than males when only patients with infratentorial tumors (16 of 22 v four of 12; P = .03) or patients with hydrocephalus at diagnosis (13 of 18 v three of 10; P = .05) were analyzed. The predominance of females with ataxia was not significantly related to age at diagnosis or to the time of operation. The higher incidence of ataxia at follow-up among females was most significant among children 10.0 to 14.9 years of age at diagnosis; six of 12 females versus only one of 13 males had ataxia (P = .03).
Hemiparesis
Cranial Nerve Palsies
Epilepsy
Major differences in the incidence of neurological deficits at follow-up of children with brain tumors have been reported.2,7,9,10,16–23 These differences reflect the variations in tumor histology, degree of malignancy, localization, treatment modalities, type of study (retrospective v cross-sectional), and scoring method used. This population-based study with a high participation rate (78%) shows that even among patients who have received surgery only for their brain tumors, a large proportion will persist in having significant neurological sequelae, and only 31% will be free of neurological deficits. More specifically, we found that a major part of cranial nerve palsies developed after recovery from surgery, especially sixth and seventh cranial nerve palsies,20 whereas affection of the optical nerve, ataxia in patients with infratentorial tumors, and hemiparesis tended to persist at follow-up. These overall results coincide well with the results found by others, who by the use of similar scoring systems, found moderate to severe neurological deficits in 21% to 45% of the patients.7,8,10,20,22,24 In this study, 65% of the patients were classified in group I/II at follow-up according to the modified Bloom’s score; that is, with no or only minor deficits. In comparison, others have reported no or only minor neurological deficits in up to 86% to 100% of patients,16,17,19,23 but the inclusion of epilepsy significantly influences the scoring because seizures may be the only neurological symptom in patients who have had supratentorial tumors.25 If we did not include epilepsy in the Bloom’s score, 73% of the entire group and 84% of the patients with supratentorial tumors would be in group I and II. In addition, the fraction of patients with supratentorial tumors will influence the incidence of persistent moderate to severe neurological deficits. Thus, the study by Gilles et al8 showed a lower percentage of neurological deficits in children with supratentorial tumors than among those with infratentorial tumors. Similarly, other investigations2,7,9,10,18,20–22 have reported that the frequency of patients with no or minor deficits varies between 55% and 80%, with a tendency toward a higher percentage if the cohorts include supratentorial tumors. Many of the previous studies of children with brain tumors do not describe in detail the actual pre- and postoperative neurological deficits and those that persist at follow-up (ie, the likelihood for recovery) or attempt to identify factors related to the chance of total recovery.8,10,20,23,24 Thus, no previous study has so clearly identified female sex to be a risk factor for hemiparesis and ataxia, especially in infratentorial tumors. Why ataxia and, thereby, worse Bloom’s scores are specifically more common in females is not easily explained. Thus, and in contrast to Pencalet et al,10 we did not find any significant influence of the time period of surgery, duration of symptoms, age at diagnosis, or presence of hydrocephalus on Bloom’s score either for the entire group or for the subgroups of supra- and infratentorial tumors. Further research is needed to explore to what extent the inferior outcome, especially in girls older than 10 years at diagnosis, reflects biologic differences or whether the outcome differences are second to differences in rehabilitation and physical activity. Overall, our frequency of postoperative complications in patients is in the high end of that previously reported for patients with brain tumors, which could be because our investigation covers a time span of 25 years.20,26,27 Accordingly, cranial nerve palsies and hemiparesis were more frequent in the early operative era. Another important parameter explaining a higher complications rate than that previously reported for benign brain tumors could be that this study includes both supra- and infratentorial tumors, because complications are more often seen among supratentorial tumors.8 Among patients with supratentorial benign tumors and preoperative seizures, our 65% likelihood (95% confidence interval, 42% to 87%) of no (n = 10) or only rare (n = 1) seizures postoperatively is somewhat although not significantly lower than the 75% to 85% likelihood previously reported by others using Engel’s surgical seizure outcome classification.25,28–31 Several of these investigators have reported that total tumor resection, age, and early surgery after the start of seizures are important prognostic factors for obtaining a seizure-free outcome.25,29–31 Our data support the hypothesis that total tumor resection is an important prognostic factor for freedom of seizures, although the difference did not reach significance. Brain mapping during surgery, electrocorticoencephalography, and stereotactic surgery (not used in this material) could improve the outcome of children with epilepsy at diagnosis.32 In conclusion, only one third of patients with benign brain tumors who received surgery only survive with no neurological deficits or symptoms, another third will have a partial recovery of their pre- and postoperative deficits and symptoms, and the last third of the patients will continue to have severe neurological disabilities that demand continuous follow-up and both physical and social support. To allow comparison of different surgical approaches as well as to explore the efficacy of preventive and therapeutic measures, there is a strong need for the development of an international neurological scoring system, which covers all types of brain tumors regardless of localization.
We thank Peter Uldall for his helpful comments about this article.
Supported by The Ville Heise Foundation (grant M1-96), The Haensch Foundation, and the Fraenkel Foundation.
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14. Bloom HJ, Wallace EN, Henk JM: The treatment and prognosis of medulloblastoma in children: A study of 82 verified cases. Am J Roentgenol 105:43–62, 1969 15. Siegel S, Castellan NJ: Nonparametric Statistics for the Behavioral Sciences. Singapore, McGraw-Hill, 1988 16. Gjerris F: Clinical aspects and long-term prognosis of intracranial tumours in infancy and childhood. Dev Med Child Neurol 18:145–159, 1976[Medline] 17. Palma L, Russo A, Mercuri S: Cystic cerebral astrocytomas in infancy and childhood: Long-term results. Childs Brain 10:79–91, 1983[Medline] 18. Mercuri S, Russo A, Palma L: Hemispheric supratentorial astrocytomas in children: Long-term results in 29 cases. J Neurosurg 55:170–173, 1981[Medline] 19. Garcia DM, Latifi HR, Simpson JR, et al: Astrocytomas of the cerebellum in children. J Neurosurgery 71:661–664, 1989[Medline] 20. Cochrane DD, Gustavsson B, Poskitt KP, et al: The surgical and natural morbidity of aggressive resection for posterior fossa tumors in childhood. Pediatr Neurosurg 20:19–29, 1994[Medline] 21. Li FP, Winston KR, Gimbrere K: Follow-up of children with brain tumors. Cancer 54:135–138, 1984[CrossRef][Medline] 22. Hayostek CJ, Shaw EG, Scheithauer B, et al: Astrocytomas of the cerebellum: A comparative clinicopathologic study of pilocytic and diffuse astrocytomas. Cancer 72:856–869, 1993[CrossRef][Medline] 23. Slavc I, Salchegger C, Hauer C, et al: Follow-up and quality of survival of 67 consecutive children with CNS tumors. Childs Nerv Syst 10:433–443, 1994[CrossRef][Medline] 24. Zarbock G, Matthes-Martin S, Schulte FJ: Quality of life and symptoms of residual damage in cerebellar tumors in children and adolescents. Klin Padiatr 201:337–345, 1989[Medline] 25. Iannelli A, Guzzetta F, Battaglia D, et al: Surgical treatment of temporal tumors associated with epilepsy in children. Pediatr Neurosurg 32:248–254, 2000[CrossRef][Medline] 26. Voth D, Schwarz M, Geissler M: Surgical treatment of posterior fossa tumors in infancy and childhood: Techniques and results. Neurosurg Rev 16:135–143, 1993[CrossRef][Medline] 27. Albright AL, Wisoff JH, Zeltzer PM, et al: Effects of medulloblastoma resections on outcome in children: A report from the Children’s Cancer Group. Neurosurgery 38:265–271, 1996[CrossRef][Medline] 28. Engel J, van Ness PC, Rasmussen TB, et al: Outcome with respect to epileptic seizures, in Engel J (ed): Surgical Treatment of Epilepsies. New York, NY, Raven Press, 1993, pp 609–621
29. Khajavi K, Comair YG, Wyllie E, et al: Surgical management of pediatric tumor-associated epilepsy. J Child Neurol 14:15–25, 1999 30. Packer RJ, Sutton LN, Patel KM, et al: Seizure control following tumor surgery for childhood cortical low-grade gliomas. J Neurosurg 80:998–1003, 1994[Medline] 31. Hirsch JF, Sainte RC, Pierre-Kahn A, et al: Benign astrocytic and oligodendrocytic tumors of the cerebral hemispheres in children. J Neurosurg 70:568–572, 1989[Medline] 32. Berger MS, Ghatan S, Haglund MM, Dobbins J, Ojemann GA: Low-grade gliomas associated with intractable epilepsy: Seizure outcome utilizing electrocorticography during tumor resection. J Neurosurg 79:62–69, 1993[Medline] Submitted August 1, 2002; accepted December 14, 2002. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test including analysis for trend, Fisher’s exact test, and Spearman rank order correlation analyses were applied to compare distribution of parameters between subgroups and correlation between parameters (rS is the correlation coefficient).
