2004; 13: 108–112 doi:10.1016/S1059-1311(03)00083-9 View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector as the presenting symptom of brain tumours in children

KHALID IBRAHIM & RICHARD APPLETON

The Roald Dahl EEG Unit, Department of Neurology, Royal Liverpool Children’s NHS Trust (Alder Hey), Liverpool, UK

Correspondence to: Dr Richard E. Appleton, F.R.C.P.C.H., Consultant Paediatric Neurologist, The Roald Dahl EEG Unit, Department of Neurology, Royal Liverpool Children’s NHS Trust (Alder Hey), Liverpool L12 2AP, UK. E-mail: [email protected]

Seizures were the presenting clinical symptom in 10 (12%) of 81 consecutive children with a primary brain tumour treated in a tertiary paediatric oncology unit over 5 years. Nine patients experienced partial seizures, and in seven a waking electroen- cephalogram showed focal or lateralising abnormalities. Astrocytoma was the most common tumour histology. The delay in tumour diagnosis from the onset of seizures ranged from 2 weeks to 2 years with a mean of 6 months. Complete resection of the tumour was the only treatment in three patients and four underwent resection followed by radiotherapy and/or chemotherapy. Two patients died. Three patients became seizure free receiving no antiepileptic medication and the remaining five showed a 50Ð80% reduction in seizures between 2 and almost 5 years following treatment. © 2003 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved.

Key words: children; brain tumours; seizures; outcome.

INTRODUCTION examined the frequency of as the initial pre- sentation of a brain tumour in children have reported , , Brain tumours are one of the most common solid a wide range of rates, from 7Ð16%4 5 8Ð11 to as high tumours in children, with an incidence of approx- as 40%12. imately 1Ð5 per 100 0001. In the UK, the annual The purpose of this retrospective study is to review incidence in children under 15 years is 3 per 100 000 the detailed seizure history of a population of children (350 cases annually)2. Presentation is usually with with brain tumours. symptoms and signs of raised with or without evidence of cranial nerve dysfunc- tion, reflecting the fact that most brain tumours in METHODS children over 4 years of age are sited infratentori- ally and specifically within the posterior fossa or The case notes were reviewed retrospectively of all brainstem2Ð5. Supratentorial tumours are more com- children aged 1 month to 15 years presenting with a mon in children under 4 years of age and in adults. primary brain tumour to a regional paediatric oncology Although cognitive or behavioural difficulties may unit in a tertiary care Children’s Hospital over 5 years. also be presenting features of brain tumours that are Children with secondary (metastatic) brain disease and located supratentorially (typically within the frontal or with a haematological malignancy were excluded from temporal lobes), seizures are a relatively uncommon this review. The paediatric oncology unit serves a total presentation of brain tumours. Previous studies have population of 2.8 million and is the only paediatric primarily focused on specific epilepsy populations unit in the region that manages and co-ordinates the and the proportion of epilepsy being caused by brain care of children with brain tumours. tumours, where the reported frequency is 0.2Ð6%, Information was collected on the following: sex, age depending on the type of seizure6, 7. Studies that have at onset of seizures, age at diagnosis of brain tumour,

1059–1311/$30.00 © 2003 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved. Seizures as the presenting symptom of brain tumours in children 109 type or types of seizures, additional neurological, subsequent temporal lobectomy revealed a low-grade cognitive or behavioural symptoms or signs at time glioma. of seizure onset, electroencephalographic (EEG) find- The mean age at onset of seizures was 5.7 years ings, magnetic resonance imaging (MRI) findings, and the mean age at diagnosis of the tumour was 6.1 histology of the tumour, treatment of the tumour, years years. The duration of epilepsy prior to the diagnosis of follow-up and seizure outcome (seizure frequency of the tumour ranged from 1 to 2 weeks (Patients 4 at latest follow-up compared to seizure frequency at and 7, respectively) to 2 years with a mean of 0.5 time of tumour diagnosis). years in the remaining eight patients. The longest Surface (scalp) EEG was undertaken in either period of active epilepsy prior to the diagnosis of a the waking or drowsy (following sleep deprivation) tumour was 2 years (Patient 6) whose initial (com- state with a Micromed ‘Brain Quick’ 32 System 98 puterised tomography [CT]) brain scan performed using the international 10Ð20 electrode placement 3 months after seizure onset was reported to be with referential and bipolar montages and reported normal. by one paediatric neurologist/neurophysiologist. Seizures were occurring at least weekly in all 10 In-depth EEG monitoring and intra-operative electro- patients prior to the diagnosis of the tumour; in 7 the corticography (ECOG) were not undertaken in any seizures were occurring at least once daily, including patient. in Patient 6, where seizures had been occurring for 2 MRI was undertaken using a Philips 0.5T Gyroscan years prior to the diagnosis of the tumour. NT 5 scanner, with axial and coronal views employ- Six patients were receiving one, and three pa- ing T1, T2 and FLAIR sequences with and without tients, two drugs at the time the tumour was diag- gadolinium and interpreted by two paediatric neuro- nosed. Monotherapy included carbamazepine (three radiologists. patients), vigabatrin (two patients) and lamotrigine (one patient). Dual therapy included one patient with each of the following combinations: carbamazepine+ RESULTS phenytoin, carbamazepine + vigabatrin and vigabat- rin + clobazam. One family declined any medication Eighty-one patients were diagnosed with a primary after the first AED proved ineffective and prior to brain tumour between January 1996 and December treatment of the tumour (Patient 7). 2000. Ten of the 81 patients (12.3%) presented with No patient had developed any new neurological epilepsy. The tumour was sited supratentorially in deficit following . Pre- and post-operative vi- all 10 patients. Demographic, treatment and seizure sual field examination was not performed routinely outcome details are demonstrated in Table 1. Neuro- and it is therefore not possible to comment on whether logical examination was normal in 7 of the 10 pa- surgery may have caused any new or additional visual tients; 1 patient had a slight hemiparesis and another field defects. patient demonstrated behavioural changes (impulsiv- Resection of the tumour was undertaken in seven ity and disinhibition) that had ante-dated the seizures patients, in whom it was radical in five (Patients 3, 5, by a number of months. One patient had precocious 7, 9 and 10). Patients 2 and 4 required additional re- puberty and one patient each had tuberous sclerosis sections because of persistent clinical seizures rather (TS) and neurofibromatosis (NF). The patient with than because of tumour recurrence. The diagnosis TS (Patient 3) demonstrated developmental delay at was made by high resolution MRI without histolog- the time infantile spasms and partial seizures were ical diagnosis in Patient 1; in Patient 6, histology diagnosed at 13 months of age; the patient with NF was confirmed by biopsy with no resection due to (Patient 10) already showed global developmental tumour location. Resection was considered inap- delay and abnormal visual behaviour when infantile propriate in Patient 8 in view of the biopsy-proven spasms were diagnosed at 6 months of age. Patient 3 histological diagnosis of a high-grade and malignant became seizure free on vigabatrin and re-presented at tumour. 8.5 years with complex partial and secondarily gen- At the time of the latest follow-up, three patients had eralised tonicÐclonic seizures. Repeat MRI showed a remained seizure free and receiving no AED between subependymal giant cell astrocytoma (SEGA). Patient 2 and 3.5 years after treatment of the tumour. Two pa- 10 presented at 6 months of age with infantile spasms tients died, both with persisting seizures at the time of and MRI showed an optic nerve glioma involving the death. The remaining five children continue to expe- optic chiasm and an enlarged, dysplastic-looking left rience seizures but in all there has been a 50 to 80% temporal lobe. Complex partial and secondarily gen- reduction in seizure frequency, particularly secondar- eralised seizures developed and were resistant to all ily generalised tonicÐclonic seizures. Three of these antiepileptic drugs (AEDs). Sequential MRI revealed five patients are receiving one, and the remaining two progressive expansion of the left temporal lobe and a patients, two AEDs. 110 K. Ibrahim & R. Appleton # # # # # urrent seizure (no anti-epileptic medication) (no anti-epileptic medication) (no anti-epileptic medication) months Ð Died aged 5 yrs 3.4 Seizure free 1.8 Seizure free 3.6 Every 2Ð3 3) 2) × × 2) 2) × × Resection 4.7 Weekly Nil Ð Died aged 9.5 yrs Resection 2.2 Every 2Ð3 weeks Nil 3.2Resection ( Monthly Resection (temporal lobe chemotherapy) chemotherapy ( Resection radiotherapy chemotherapy Resection ( Chemotherapy 2.8 Seizure free chemotherapy ( dysembryoblastic neuroepithelial tumour; = Astrocytoma (grade 2, left temporal lobe) Astrocytoma (anaplastic, left frontal lobe) DNET (right temporal lobe) SEGA Resection 4.2 Weekly Hypothalamic hamartoma Oligodendroglima (grade 2, left frontal lobe) Optic nerve glioma; left temporal glioma parietal lobe) (grade 1, left temporal lobe) (grade 2, right temporal lobe) sharp wave frontotemporal spike spike spike temporal spike spike spike subependymal giant cell astrocytoma; DNET = hypsarrhythmia. Tuberous sclerosis Right frontal Neurofibromatosis Hyps; left = simple partial; SEGA = ∗ not done; Hyps = (CP; SGTC) CP normal; ND = 10.0 Infantile spasms; secondarily generalised tonic-clonic; SP = ∗ seizures (years) tumour (years) at time of seizure onset follow-up status primitive neuroectodermaltumour; N = complex partial; SGTC = seizures persist but > 50% reduction in seizure frequency of all compared to seizure frequency prior to tumour diagnosis. presented at 13 months with infantile spasms; re-presented at 9 years with partial and secondarily generalised seizures. 9. (M) 1.1 1.3 SP; CP; SGTC None Left temporal 8. (F) 8.5 8.6 SP; CP Behaviour change Left 5. (M)7. 3.1 (F) 3.8 6.9 6.9 SP; SGTC None CP None Right temporal ND PNET (right Table 1: Demographic features of the 10Patient patients no. (sex) Age at1. onset of Age (M) at diagnosis2. of Seizure (F) types(s) Neurological/physical3. 7.9 signs EEG findings (F)4. 12.7 Tumour type (F) 8.0 1.1 (9) Tumour treatment 13.06. 1.4 Years of (F) C CP; gelastic 5.7 1.4 Myoclonic Early precocious puberty None Left temporal 7.7 SP; CP; SGTC10. (M) Minimal right hemiparesis Left frontal CP NCP 0.6∗ # None 0.7 Astrocytoma Infantile spasms N Astrocytoma PNET Seizures as the presenting symptom of brain tumours in children 111

DISCUSSION and brain tumours have reasonably suggested that the presence of focal neurological signs may contribute to Approximately one in nine (12%) of our patients an earlier diagnosis of the tumour. In our series, 6 of presented with seizures as the first symptom of an the 10 patients had neither focal neurological signs nor underlying brain tumour. This is similar5, 8Ð10 or al- a history of either cognitive or behavioural difficulties. most identical11 to previous paediatric studies, but In children with supratentorial tumours and particu- almost one half of adult studies9, 12. The study by larly in those with tumours of the temporal lobes, fo- Low et al. reported a very high incidence of seizures cal neurological abnormalities and fundoscopic signs (49 of 123 children, 40%) but it was unclear whether of increased intracranial pressure usually develop late. this related to the initial presenting symptom or to Behavioural and cognitive difficulties, additional fea- all patients who experienced a seizure at any time tures of tumours within the cerebral hemispheres, may during their study13. The increased rate in adults is also be identified—and taken seriously—only after likely to reflect the fact that proportionately, most many months. brain tumours in adults are supratentorial and sited The EEG may clearly be useful in suggesting a struc- in the cerebral hemispheres. Most of the tumours in tural abnormality, particularly in children with simple our series were low-grade gliomas or astrocytomas, and complex partial seizures; however, the correlation tumours that are commonly seen in children and between focal EEG findings and structural lesions is which are recognised to cause seizures2, 8, 14, 15. One neither close nor consistent19. Previous reports have patient each had a dysembryoplastic neuroepithelial shown that focal or lateralising abnormalities occur tumour (DNET), primitive neuroectodermal tumour in between 808,8215 and 92%5 of children who have (PNET) and oligodendroglioma, tumour types that seizures and brain tumours within the cerebral hemi- are also known to cause epilepsy. Somewhat surpris- spheres. At least one report has suggested that the ingly, neither DNETs nor PNETs were found to be initial EEG, as distinct from repeated EEGs, may be associated with epilepsy in an earlier and slightly of no localising value in adult patients with chronic larger paediatric series15, in contrast to a very recent epilepsy due to slow growing brain tumours20.Seven series of 23 patients with intractable epilepsy caused of the patients (70%) in the present series had focal by brain tumours11, in which DNETs accounted for EEG changes, which together with the partial semiol- 9 of 23 tumours. Tumour series reported prior to ogy of the seizures, would have resulted in early neu- 1973/1974 would not have included PNETs, as this roimaging based on the local guidelines of when to type was only introduced to tumour classifications undertake brain scans in children with epilepsy. These after this time16; previously, these tumours were usu- guidelines, in common with international guidelines21, ally labelled ‘cerebral neuroblastomas’. Although also recommend that MRI should be undertaken in all there is some debate as to whether DNETs should be children with infantile spasms. Adherence to our lo- regarded as a tumour, the most recent World Health cal neuroimaging guidelines may be one explanation Organisation (WHO) classification includes them for the relatively early identification of the tumours in in the category of ‘neuronal and mixed neuroglial our patients. tumours’17, 18. Few previous reports have evaluated the long-term The two children with a neurocutaneous syndrome seizure outcome in children with brain tumours. Of (TS and NF) developed characteristic tumour types the 15 patients reported by Patel et al.15, 80% showed known to occur in these disorders. The presentation a ‘very significant’ improvement in seizure frequency, with seizures of the patient with TS who developed with 8 becoming seizure free and 4 experiencing only a SEGA was atypical; the more usual presentation ‘rare’ seizures, based on the Engel classification22.In of this tumour is with symptoms and signs of hy- the earlier study of Sjors et al.8, which did not state drocephalus. The course of the patient with NF was the duration of follow-up, 8 of the 10 patients who sur- also atypical, firstly in terms of the initial presentation vived were seizure free, 5 on antiepileptic medication. with infantile spasms and secondly with the subse- Eight of our patients survived, of whom three became quent development and rapid growth of the temporal seizure free and receiving no antiepileptic medication glioma. and the remaining 5 showed a reduction in seizure Most of the patients were found to have a brain tu- frequency of between 50 and 80% at the time of the mour within 3 or 4 months of the onset of seizures. most recent follow-up (approximately 2Ð5 years after This is considerably shorter than has been found in the diagnosis of the tumours). There may be a number previous studies, where the lag time between seizure of reasons for the relatively poor seizure outcome in onset and tumour diagnosis has been as short as 3 our patients compared to earlier studies8, 15, including weeks and as long as almost 10 years, but typically tumour histology, the extent of surgical resection and with a mean duration of 1Ð3 years4, 5, 8, 9, 15. Previous late complications of chemotherapy and radiotherapy. studies that have evaluated the relationship of epilepsy The duration of seizures is unlikely to have been a 112 K. Ibrahim & R. Appleton contributory factor as the delay in diagnosis of the 2. Pizer, B. and May, P. Paediatric surgical oncology. 8: Central tumour was considerably shorter in our patients than tumours in children. European Journal of 8, 14 Surgical Oncology 1997; 23: 559Ð564. in earlier studies . It is likely that intra-operative 3. Koos, W. T. and Miller, M. H. Intracranial Tumors of Infants EEG monitoring with ECOG may have allowed a and Children. St. Louis, MO, C.V. Mosby, 1971. more precise surgical resection that could have poten- 4. Edgeworth, J., Bullock, P., Bailey, A., Gallagher, A. and tially influenced seizure outcome. It is also possible Crouchman, M. Why are brain tumours still being missed? Archives of Disease in Childhood 1996; 74: 148Ð151. that lesionectomy (resecting only the macroscopically 5. Backus, R. E. and Millichap, J. C. The seizure as a mani- visible limits of the tumour) may not be as effective festation of intracranial tumor in childhood. Pediatrics 1962; as a more radical resection that removes not only the 29: 978Ð984. tumour but also any additional epileptogenic tissue 6. Williams, B. A., Abbott, K. J. and Manson, J. I. Cerebral 11 tumors in children presenting with epilepsy. Journal of Child around the tumour . Unfortunately, the numbers of Neurology 1992; 7: 291Ð294. , , patients in the present, and previous8 11 15, studies 7. Aicardi, J. , 2nd edn. New York, Raven are too small to try and correlate seizure outcome Press, 1994. 8. Sjors, K., Blennow, G. and Lantz, G. Seizures as the present- with tumour histology, delay in tumour diagnosis, ing symptom of brain tumors in children. Acta Paediatrica extent of tumour resection or additional treatments 1993; 82: 66Ð70. (radiotherapy and chemotherapy). The influence on 9. Liigant, A., Haldre, S., Oun, A. et al. Seizure disorders in long-term seizure outcome of some of these factors patients with brain tumors. European Neurology 2001; 45: 46Ð51. could potentially only be clarified by national or even 10. Ferris, R. C., Nathwani, A. and Kennedy, C. R. Presenting international collaborative studies. features of brain tumours (abstract). Developmental Medicine and Child Neurology 2003; 45 (Suppl. 93): S15. 11. Kim, S.-C., Wang, K.-C. and Cho, B.-K. Intractable epilepsy associated with brain tumors in children: surgical modality CONCLUSION and outcome. Child’s Nervous System 2001; 17: 445Ð453. 12. Cascino, G. D. Epilepsy and brain tumours. Epilepsia 1990; Seizures are an uncommon presentation of brain tu- 37 (Suppl. 3): S37ÐS44. mours in children, occurring in approximately 10% 13. Low, N. L., Correl, J. W. and Hammill, J. F. Tumours of the cerebral hemispheres in children. Archives of Neurology of cases and are rarely accompanied by focal neu- 1965; 13: 547Ð554. rological signs, particularly in older children. The 14. Capra, M. and Hewitt, M. Brain tumours in childhood. Current semiology of the seizures are typically partial and Paediatrics 1998; 8: 88Ð91. the presence of focal or lateralising EEG abnor- 15. Patel, H., Garg, B. P., Salanova, V., Boaz, J. C., Luerson, T. G. and Kalsbeck, J. E. Tumor-related epilepsy in children. malities which do not suggest one of the idiopathic Journal of Child Neurology 2000; 15: 141Ð145. partial epilepsy syndromes, should lead to early 16. Hart, M. N. and Earle, K. M. Primitive neuroectodermal consideration of neuroimaging, specifically with tumors of the brain in children. Cancer 1973; 32: 890Ð897. 17. Schiffer, D. Brain Tumours. Biology, Pathology, and Clinical MRI. References. Berlin, Springer, 1997: p. 270. 18. Raymond, A. A., Halpin, S. F. S., Alsanjari, N. et al. Dysem- bryoplastic neuroepithelial tumours: features in 16 patients. ACKNOWLEDGEMENTS Brain 1994; 117: 461Ð475. 19. Gibbs, J., Appleton, R. E., Carty, H., Beirne, M. and Acomb, B. Focal electroencephalographic abnormalities and comput- The authors are grateful to Mrs Pat McCarrick for her erised tomographic findings in children with seizures. Journal assistance in the preparation of this manuscript and to of Neurology, , and Psychiatry 1993; 56: 369Ð Dr Barry Pizer for comments and advice. 371. 20. Hughes, J. R. and Zak, S. M. EEG and clinical changes in patients with chronic seizures associated with slow-growing brain tumors. Archives of Neurology 1987; 44: 540Ð543. REFERENCES 21. ILAE Neuroimaging Commission. ILAE Neuroimaging Com- mission recommendations for neuroimaging of patients with epilepsy. Epilepsia 1997; 38 (Suppl. 10): 1Ð2. 1. Walker, A. E., Robins, M. and Weinfeld, F. Epidemiology of 22. Engel, J. Outcome with respect to epileptic seizures. In: Sur- brain tumours: the national survey of intracranial neoplasms. gical Treatment of the (Ed. J. Engel Jr). New York, Neurology 1985; 35: 219Ð226. Raven Press, 1987: pp. 553Ð571.