intracranial tumors in children in the first five years of ... ·...
TRANSCRIPT
Intracranial tumors in children in the first 5 years of life
• Clinical presentation and diagnostic delay • A single institution consecutive series of 70 patients treated at the Oslo University Hospital, Rikshospitalet
Authors: Lene Skarfoss Pernes & Linda Karin Eiken Sommerfelt
Supervisors: Tryggve Lundar & Finn Wesenberg
Faculty of Medicine
University of Oslo, Norway.
May 2013
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Preface We are two female students who study medicine at the University of Oslo. We are now in our fourth year and paediatrics has not yet been a subject of study, but still this is a field of our interest. As part of the study programme, a written assignment is mandatory. After doing some research, we soon got in contact with our two supervisors, Tryggve Lundar and Finn Wesenberg, which have their specialties in respectively neurosurgery and paediatrics. Discussing different topics with them made us realize that research on children with brain tumors is an important and interesting field and that literature most often includes those below the age of 16, looking at this group as a whole. Because of differences in both psychological and physical development within different age groups, we thought it would be interesting to learn more about the youngest children, those below the age of five. Some earlier studies have found that the youngest children do have a different clinical picture than the older children, but little research has been done to verify this. In our research process, we soon found the Head Smart campaign done in the United Kingdom. This is a campaign started to increase awareness around brain tumor symptoms, because they have found a diagnostic delay in this patient group in the UK. These findings made us wonder if there is a corresponding diagnostic delay in Norway. To find out more about this, we have studied 70 journals as a consecutive series from the neurosurgical department at Oslo University Hospital, Rikshospitalet from 2005 through 2011, which makes a representative and unique series and gives some expected and other more surprising results. Contributing to increase the awareness around symptoms in children with brain tumor is our main purpose with writing this student assignment. We hope that our findings can be used to enlighten health care professionals in the primary health care.
The following story is a true story, which demonstrates the importance of awareness around symptoms and diagnostics in children with brain tumor. It also shows how easy a diagnostic delay gets prolonged, unless one is aware of brain tumor as a differential diagnosis.
Mari was a healthy little girl with normal development in the first year of life. She started walking with good balance and developed language as expected for her age. Fifteen months old her mother noticed that her balance was impaired, and at 18 months her general health was deteriorating. She started vomiting daily and the ER doctor diagnosed her with gastroenteritis. Her symptoms remained the same and one month later more than 20 ER doctors had given her the same diagnosis: gastroenteritis. Finally, a doctor referred her to the children’s clinic at the local hospital. It was decided to take a CT caput in anaesthesia, but due to public holidays and summer vacation, this was postponed with two months. At clinical examination, unsteadiness was observed, but no other focal neurological signs were found. CT caput and later MRI, showed an enormous cystic tumor in the right cerebellar hemisphere. It turned out to be a pilocytic astrocytoma with good prognosis.
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The tumor was surgically removed. Mari recovered well and is today a 20-‐year-‐old student, practising extreme sports as a hobby. Control MRI shows a great resection cavity with no sign of residual tumor or recurrence.
MRI scan Control MRI showing a great resection cavity with no sign of tumor tissue.
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Table of contents
Preface .................................................................................................................................. 2 Abstract ................................................................................................................................. 5
Acnowledgements ............................................................................................................. 6
Introduction ........................................................................................................................ 7 Material and methods ...................................................................................................... 9 Statistical methods .................................................................................................................... 9
Clinical results ................................................................................................................. 10 Histology, age and localization ............................................................................................ 10 Treatment ................................................................................................................................... 13 Prognosis .................................................................................................................................... 13 Symptoms and signs ................................................................................................................ 15 Symptoms and signs in general ....................................................................................................... 15 Symptoms and signs relative to age .............................................................................................. 18 Macrocephaly .......................................................................................................................................... 19 Symptoms and signs relative to the localization of the tumor .......................................... 20
Cause of referral to further investigation/hospital ...................................................... 21 Instance of referral and involved specialties ................................................................. 22 Diagnostic delay time ............................................................................................................. 23 Symptoms related to the diagnostic delay time ....................................................................... 24
Discussion ......................................................................................................................... 26 Strengths and weaknesses .................................................................................................... 26 The strength of the study ................................................................................................................... 26 The weakness of the study ................................................................................................................ 26
Histology, age and localization ............................................................................................ 27 Treatment ................................................................................................................................... 27 Prognosis .................................................................................................................................... 27 Symptoms and signs ................................................................................................................ 28 Diagnostic delay ....................................................................................................................... 30
Conclusion ......................................................................................................................... 32
List of included tables and figures ............................................................................ 33
References ........................................................................................................................ 34
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Abstract Background: Intracranial brain tumor in children is a rare but severe diagnosis. In children under the age of 15, it covers 1/3 of all cancers. The symptomatology is complex and the time to diagnosis can often be prolonged as the symptoms may mimic other less severe conditions in children. Misinterpretations can lead to a prolonged diagnostic delay time (DDT) and affect the prognosis. A study done in Britain showed that it did exist a prolonged DDT, which initiated the Head Smart campaign. The purpose of our study was to discover if the same delay was present in Norway, and to look at the symptomatology in these children. As younger children often have a different clinical presentation, a topic less immersed in earlier literature, this review is concerning children below five years of age.
Methods: The study is done as a retrospective consecutive study of the children below five years of age present in the protocol of surgery at the neurosurgical department at Oslo University Hospital, Rikshospitalet in the period from 2005 through 2011. In total 70 patients primarily treated for intracranial brain tumor in the infra-‐ and supratentorial compartment were included. Information was systematically gathered from the electronic journal system.
Results: In the material, there were 36 girls and 34 boys. Twenty-‐one children were diagnosed in their first year of life, 13 in their second, 13 in their third, 11 in their fourth and 12 in their fifth. Forty-‐six of the tumors were supratentorial and 24 were infratentorial. In the first year of life, 90% had a supratentorial tumor. Twenty-‐five were high-‐grade tumors, PNET being most frequent, 45 were low-‐grade, astrocytomas being most frequent. The five-‐year overall survival was 90% among the low-‐grade tumors and 58% among the high-‐grade ones. The median DDT was 8,1 weeks among the low-‐grade tumors and 4,5 weeks among the high-‐grade ones. Distribution of symptoms were: nausea and vomiting (57%), unsteadiness and poor coordination (36%), headache (30%), decreased general state (27%), seizures (24%), decreased well-‐being (17%), altered level of consciousness (13%), other symptoms (3%). Distribution of signs were: Abnormal eye movements (27%), other neurological signs (19%), macrocephaly (17%), bulging of the fontanelle and splayed sutures (17%), squint (16%), cranial nerve palsy (14%), paretic limbs and focal motor weakness (11%), reduced visual aquity (10%), other signs (10%), head tilt (9%), other visual/eye related signs (9%), no eye contact (7%), nutritional problems (3%).
Conclusion: Brain tumor in children below the age of five gives a heterogenous clinical picture with a wide range of symptoms. The DDT among these 70 patients is at level with the rest of Europe and not prolonged as seen in the UK.
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Acnowledgements We would like to address great gratitude to our supervisors for their time, help and encouragement during the process. Due to our regular lunchmeetings, we have been able to keep a steady progress and to work purposefully towards our target. In addition, we would like to thank Marius Eiken Sommerfelt for all technical assistance.
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Introduction This student assignment is done as a cooperation between pediatric oncology and neurosurgery in children. We are both interested in pediatrics and wanted to do a study in this field. Contacting our supervisors gave us the chance to write about brain tumors in young children, a topic which we soon wanted to learn more about.
Brain tumor in children is fortunately rare, but is one of the most common cancers among children. Cancer in the CNS covers alone approximately 1/3 of all cancers in children under the age of 15 (1). In Norway the incidence of brain tumors is 4,2 per 100 000 children under the age of 15 (2), that is to say about 40 new cases each year (2,3). Of these, about 13 children are under the age of 5 (1;2). About 60% of these patients are treated at Oslo University Hospital, Rikshospitalet.
Brain tumors in children has been subject of research earlier, but most often in children 0-‐16 years of age as a whole. Brain tumors are a very heterogeneous group and it’s therefore interesting to look at the variation in clinical presentation. We wanted to learn more about the youngest children under the age of five because we suspected that the symptomatology, localization, degree of malignancy and histology could be varying with age, especially within this youngest group because the children are at such different stages in development. Through our supervisors, we got to learn about the HeadSmart campaign in the UK. This is a campaign started to “enhance the awareness of symptoms of brain tumors in children and young people”(4) because it was discovered a prolonged time to diagnosis in these patients in the UK, compared to other parts of Europe and in North America. Hearing about the HeadSmart campaign made us wonder if there is a corresponding diagnostic delay when it comes to brain tumors in children in Norway as found in the UK. The research question that we wanted to answer included the following items:
• How is the distribution regarding age, localization and histology among these patients and how is age, localization and histology related to diagnostic delay time (DDT)?
• What is the diagnostic delay time among children with brain tumors in Norway and what factors have an impact on the DDT?
• Which clinical presentation do these children have?
Diagnostic delay time of an illness is defined as the time period between symptom onset and diagnosis. This time can be prolonged, and this is often seen in young patients with brain tumor because the symptoms often mimic other diseases and easily can be misinterpreted. The diagnostic delay time is divided in parent's delay and doctor's delay, the parent's delay time is the time from symptom onset to the first contact with a doctor. Doctor's delay time is the time from the first contact with the patient to diagnosis. The diagnostic delay time can be expected and unavoidable, but sometimes too much time has been used to either contact a doctor or to make the necessary examinations, and the diagnostic delay time gets prolonged. In this assignment we haven’t separated the diagnostic delay time in parent's delay and doctor's delay, because the information about this was insufficient in our information sources.
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The purpose of investigating these questions was first of all to find out if there is a prolonged diagnostic delay time in this group of patients compared to other countries. If there is, maybe a campaign like the HeadSmart is needed in Norway to enlighten doctors and parents? Second, we wanted to learn about the clinical presentation in this age group, to find out if there is a distinction between the youngest children and the older within this group. Finding out this could be helpful in diagnosing children.
To find answers to these questions, we have studied 70 patients treated at Oslo University Hospital, Rikshospitalet in the seven year period from 2005 through 2011. We will present the group of patients and the methods we have used in Material and methods.
Before we started to go through the cases, we didn’t know much about neither pediatric oncology nor neurosurgery, but we nevertheless had a few expectations to what we would find in this patient group. These expectations might have affected our interpretation of the data that we have found and should therefore be mentioned. We expected that the children younger than 12 months would have a different clinical presentation than the older children. This is linked to the closure of the fontanelles and the brain’s development and stages at different age levels. We also expected to find a prolonged diagnostic delay time, as seen in the UK. These expectations arose talking about and discussing this patient group with our supervisors, which both have a substantial clinical experience in this field. Their expectations became ours.
In the following we will present our methods and findings in the chapters Methods and materials, Clinical results, Discussion and Conclusion in that order.
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Material and methods The material presented consists of 70 consecutive patients below five years of age primarily treated for intracranial brain tumor at the Oslo University Hospital, Rikshospitalet, from 2005 through 2011. They are registered from the protocol of surgery at the department of neurosurgery. They represent all intracranial tumors in this age group, localized in the supratentorial and infratentorial compartment. Tumors of the spinal cord and cranium were excluded. Included in the study are two children with diffuse pontine glioma, in whom no surgery has been performed. The other 68 patients all had their primary surgery between 01.01.2005 and 31.12.2011.The children were followed until death or until 31.12.12.
In two of the patients, the diagnosis is based on clinical history, and typical MRI findings considered to be conclusive for the very severe diagnosis of diffuse pontine glioma. No biopsy has been taken because it would be dangerous and harmful to the child and have no impact on either treatment or prognosis, therefore these two have tumors of uncertain histological origin. In the other 68 the diagnosis is based on verified histological examinations from biopsies taken.
We started out by collecting data. Under guidance from our experienced supervisors we found a wide range of parameters to systematically search for. We decided on looking at the symptoms the children presented with, divided into localized and general symptoms, and including clinical signs found during examination by the neurosurgeon when they were admitted. Furthermore we looked at the main reason they had been admitted to the department of neurosurgery. To get a deeper understanding of the diagnostic delay time we tried to find out how long the symptoms had been present before their guardian contacted a doctor (parent’s delay), and the time span from the first doctor consult to the admittance at hospital for detailed investigation and diagnosis (doctor’s delay). We also registered from what institution they where admitted, other institutions and specialties involved in the process, and former symptomatic diagnosis given prior to the brain tumor diagnosis. Finding these data on clinical presentation and time line, we wanted to see this in context with specific diagnosis and prognosis among these children, therefore we collected data on histological diagnosis, detailed localization of the tumor, the grade of malignancy and the treatment they received, both surgically and medically. Status of last MRI taken and how many who were dead and alive where also included.
We systematically read through the journals of the selected patients and later used the data collected as our work tool. When uncertain factors evolved we consulted each other first, and if the insecurity remained we consulted our main supervisor in whom have first-‐hand experience with these patients.
Statistical methods SPSS software, version 18.0, was used to create a Kaplan Meier Curve (5).
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Clinical results In the following section we will present the results of our study starting out with histology and localization, followed by treatment and prognosis. Then comes a presentation of the symptoms and signs, the cause of referral and the instance of referral. The section will finish up with a review on diagnostic delay. When presenting our results we have chosen some overall guidelines to refer to. First of all we have divided the children into three groups after their age at the time of diagnosis. The first group includes children less then 12 months and consists of 21 children, the second group is children aged 12 to 23 months consisting of 13, and the last group is children from 24 to 59 months, counting 36 in total. The reason for putting together the children in the third, fourth and fifth year of life are due to the fact that their symptomatology is expected to be more alike. For the record the distribution is 13 in the third year of life, 11 in the fourth year of life and 12 in the fifth year of life, as shown in figure 1.
The average age at the time of diagnosis was 27,03 months in the material. In addition we divided the localization into two groups being supratentorial and infratentorial, having 46 in the group first mentioned and 24 in the second group. All together there are a total of 36 girls and 34 boys. 11 boys and 10 girls in the first age group, 5 boys and 8 girls in the second group, and 18 boys and 18 girls in the last group.
Figure 1 The distribution of age in children age 0-‐4 years with CNS tumor treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011.
Histology, age and localization The histological diagnoses are divided in high-‐grade and low-‐grade tumors, where the low-‐grade ones are tumors with WHO grade 1 and 2, and the high-‐grade ones are WHO grade 3 and 4. The World Health Organization adopted in 1993 a new classification of neoplasms in the central nervous system and this is used world wide to ensure a common understanding when it comes to communicating in this field (6). To make it easier for the reader, we will only use the terms high-‐grade and low-‐grade.
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13 13 11 12
0
5
10
15
20
25
0 1 2 3 4
PaFe
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Age (years)
Age distribuFon
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Forty-‐five patients (64,3%) had a low-‐grade tumor (WHO classification 1 or 2). Twenty-‐five patients (35,7%) had a high-‐grade tumor (WHO classification 3 or 4).
The most common tumor among the low-‐grade ones was astrocytoma in which stood for 27 of the tumors (38,6%). Four of these were fibrillary astrocytomas (WHO grade 2), while the rest were WHO grade 1. The second most common tumor was low-‐grade plexus tumor, which five patients had (7,1%). Four patients (5,7%) had a low-‐grade glioma. Next, two patients (2,9%) had respectively chraniopharyngioma, teratoma, epidermoid cyst and ganglioglioma. One patient (1,4%) had a cavernous hemangioma.
Among the high-‐grade tumors, the largest group was the primitive neuroectodermal embriogenic tumor (PNET) that stood for 14 (20%) of the tumors. Of these 14, four of them were atypical teratoid rhabdoid tumors (ATRTs). Five (7%) of the patients had ependymomas. Three of these were anaplastic, and two were none-‐anaplastic. We had three (4,3%) high-‐grade gliomas in our review. Of these, two were pontine gliomas with uncertain histology because they haven’t been taken a biopsy of, and one was a grade 3 oligoastrocytoma. There was one case (1,4%) of respectively high-‐grade plexus tumor, germinal cell tumor and glioblastoma.
HISTOLOGY
Supratentorial Infratentorial
Low-‐grade High-‐grade Low-‐grade High-‐grade
Astrocytoma 17 PNET 8 Astrocytoma 10 PNET 6
Plexus tumor 4 Glioma 1 Plexus tumor 1 Glioblastom 1
Chraniopharyngioma 2 Ependymoma 3 Epidermoid 2 Glioma* 2
Teratoma 2 Germinalcell tumor 1 Ependymoma 2
Ganglioglioma 2 Plexus tumor 1
Cavernous hemangioma 1
Glioma 4
Table 1 Histology, localization and tumor grade in 70 children age 0-‐4 years, treated at the Oslo University Hospital, Rikshospitalet, 2005-‐2011. *These are the two pontine gliomas.
Looking into the histology and distribution in the three age groups, it varied relative to age. The high-‐grade tumors PNETs was clearly more frequent in the age group 24-‐59 months, 10 (27,8%) of the patients in this group had PNET, in comparison only two had it in both of the youngest age groups. In the youngest group, 9,5% had PNET, while in those 12-‐23 months, 15,4% had PNET. The high-‐grade tumors ependymomas were found only in the two youngest groups. Three patients (14,3%) had it in those younger than 12 months, and two (15,4%) was in the group 12-‐23 months. The most frequent tumors, the low-‐grade astrocytomas, were frequent in all three age groups. There were 10 (47,6 %) in the youngest group. In those 12-‐23 months four (30,8%) had astrocytoma and in the children 24-‐59 months 13 (36,1%) children had this tumor.
Other tumors than those mentioned made 28,6 % in the youngest group. In the children 12-‐23 months other tumors represented 38,5 %. Finally in the oldest group, other tumors totaled up to 36,1 %.
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Germinal cell tumors, epidermoid tumors, glioblastomas and cavernous hemangioma were only observed above the age of two years. Ganglioglioma and chraniofaryngeoma were not found in those 12-‐23 months. Ependymomas and teratomas were only found in those younger than two years of age. The distribution is shown in table 2.
HISTOLOGY RELATIVE TO AGE <12 months 12-‐23 months ≥24 months Total
Astrocytoma 10 47,6 % 4 30,8 % 13 36,1 % 27 38,6 %
Plexus tumor 1 4,8 % 3 23,1 % 2 5,6 % 6 8,6 %
Chraniopharyngeoma 1 4,8 % 0 0,0 % 1 2,8 % 2 2,9 %
Teratoma 1 4,8 % 1 7,7 % 0 0,0 % 2 2,9 %
Epidermoid cyst 0 0,0 % 0 0,0 % 2 5,6 % 2 2,9 %
Ganglioglioma 1 4,8 % 0 0,0 % 1 2,8 % 2 2,9 %
Cavernous hemangioma 0 0,0 % 0 0,0 % 1 2,8 % 1 1,4 %
PNET 2 9,5 % 2 15,4 % 10 27,8 % 14 20,0 %
Glioma 2 9,5 % 1 7,7 % 4 11,1 % 7 10,0 %
Ependymoma 3 14,3 % 2 15,4 % 0 0,0 % 5 7,1 %
Germinalcell tumor 0 0,0 % 0 0,0 % 1 2,8 % 1 1,4 %
Glioblastoma 0 0,0 % 0 0,0 % 1 2,8 % 1 1,4 %
Table 2 Histology relative to age in 70 children age 0-‐4 years, treated at the Oslo University Hospital, Rikshospitalet, 2005-‐2011.
The distribution between infratentorial and supratentorial tumors was markedly uneven, shown in table 3.
Figure 2 Age groups and localization in 70 children age 0-‐4 years, treated at the Oslo University Hospital, Rikshospitalet, 2005-‐2011.
The grade of the tumors varied with their localization. Of the 46 supratentorial tumors 32 (69,6%) of them were low-‐grade. Only 14 (30,4%) were high-‐grade. Among the infratentorial tumors 13 (54,2%) were low-‐grade and 11 (45,8 %) were high-‐grade.
The grade of the tumors also varied between the age groups. Among those less than 12 months, five (23,8%) had a high-‐grade tumor and 16 (76,2%) had a low-‐grade. In
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0 5 10 15 20 25 30 35 40
<12 months 12-‐23 months ≥24 months
PaFe
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Age and localizaFon
Infratentorial
Supratentorial
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the age group 12-‐23 months, four patients (30,8%) had a high-‐grade tumor and nine (69,2%) a low-‐grade one. For the children between 24 months and four years, 16 (44,4%) had a high-‐grade tumor. Twenty patients (55,6%) had a low-‐grade tumor. This is shown in table 3.
GRADE AND AGE
Age group High-‐grade Low-‐grade Total
<12 months 5 23,8% 16 76,2% 21 30,0%
12-‐23 months 4 30,8% 9 69,2% 13 18,6%
≥24 months 16 44,4% 20 55,6% 36 51,4%
Table 3 Tumor grade relative to age in 70 children age 0-‐4 years, treated at the Oslo University Hospital, Rikshospitalet, 2005-‐2011.
Treatment We have looked at what kind of treatment the 70 patients received. Different treatments are available when it comes to brain tumors, these are surgical resections, intracranial shunts, cytostatic drugs, radiation and symptomatic treatment. Symptomatic treatment wasn’t well documented in the journals, much because it often were given at the patients’ local hospitals.
All the patients received some kind of surgery, except the two with pontine gliomas. The 68 patients were divided in three different groups considering what surgical treatment they had. These groups were only biopsy, partial resection and gross total resection. Gross total resection is defined as removal of more than 90% of the tumor. In some journals the surgeon didn’t explicitly mention this, but through an interpretation of the surgery description together with control MRI taken after surgery, we have managed to decide which ones that had a gross total resection and which ones didn’t. Tumor resection was done in 61 (90%) patients. Of these, 36 (53%) were considered gross total resections, while the other 25 (37%) were considered partial resections. In seven patients (10%) there were only taken biopsies and no further resection was done.
Sixty-‐eight patients underwent primary surgical resections during this seven year period, equaling to a number of 9,7 surgeries each year. Twenty-‐four out of the 68 patients had a second resection when this was indicated. Further three out of these had a third resection. In total the number of surgical resections was 95.
Twenty-‐six patients (37%) did get an intracranial shunt. Thirty-‐five (50%) had chemotherapy, and 11 (16%) underwent radiation therapy.
Prognosis The prognosis and the relation to diagnostic delay is important concerning whether there is an actual need for improvement in diagnosis of brain tumor in children, and if early diagnosis have impact on the prognosis of the child. In our study we have 54 survivors as far as to 31.12.12. Of these patients 40 have low-‐grade tumor, and 14 have high-‐grade tumor. Sorted by findings on the last MRI pictures taken 25 have no signs of tumor on the MRI, 23 have a steady residue, and 6 patients have findings consistent with progressive disease.
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Sixteen patients died in total. Eleven of these had tumor with high grade of malignancy, while 5 were diagnosed with a low-‐grade tumor. This outcome is as expected. Out of the five dead patients with low-‐grade tumor one died for reasons not related to the brain tumor. One was born with a great tumor taking up most space in the cranium, two had a difficult treatable tumor with a complicated localization (one of them was pilomyxoid). The last one died from unknown reasons. The last MRI findings among the dead patients showed 14 with disease in progression, one with no signs of tumor and one with a steady residue.
The mortality in the different age groups was respectively 28,6% in the first year of life, 23,1% in the second year of life, and 19,5% in the children 24-‐59 months. This implies a trend with higher mortality among the youngest ones. Of the living patients 38 have a supratentorial tumor and 16 have an infratentorial tumor. Of the dead patients eight had a supratentorial tumor and eight had an infratentorial tumor. Thus the mortality is markedly higher among those with infratentorial tumor (33%), compared to those with supratentorial tumor (17%).
Of the patients who died the average symptom interval was 8,9 weeks, missing information on one patient. To comparison the average time to diagnosis among the living was 19,2 weeks, also in this group missing information on one patient. The median time from surgery to time of death was 10,05 months (range 0,07 months to 37,4 months), with an average of 13,9 months. This was 12,5 months in the first and the third group relative to 18, 5 months in the second group.
As all the children are included from 2005 through 2011 some have longer time of observation than others, differing from at least one year (from 01.01.2012 to 31.12.2012) but counting up to eight years (from 01.01.2005 to 31.12.2012). The median time for observation among the high-‐grade tumors was 2 years 2 months and 5 days (range 4 months 2 days to 4 years 5 months 12 days), being relatively short. Among the low-‐grade tumors the median observation time was 4 years 19 days (range 2 days to 7 years 11 months 6 days). The 5-‐year survival rate for the low-‐grade tumors is 90% whilst for the high-‐grade tumors it is 58%. This is to be illustrated by the Kaplan Meier curve, demonstrating a marked difference between the two groups. Not included in the Kaplan Meier curve is the two children with diffuse pontine glioma. The 5-‐year overall survival is 78% estimated, data not shown.
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Figure 3 A Kaplan Meier curve showing survival rate over time in 68 children age 0-‐4 years treated at the neurosurgical department, Oslo University Hospital, Rikshospitalet, 2005-‐2011. Green line shows children with low-‐grade tumors, blue line shows children with high-‐grade tumors.
Symptoms and signs
Symptoms and signs in general We have recorded all major symptoms presented in the journals in our study. The symptoms are divided into anamnestic findings (symptoms), findings during the clinical examination (signs), and findings on MRI, including hydrocephalus.
In our material the top ranking symptom overall is nausea and vomiting with a total incidence of 57%. Thereafter comes unsteadiness and poor coordination with 37%, followed by headache at 30%. 27% had a situation with decreased general state. Seizures were present in 24% of the cases. 17% of the children showed signs of decreased well being. As much as 13% were present with altered state of consciousness. A few patients had sleep related problems numbering up to 3%.
The sign with highest occurrence among the patients were abnormal eye movements with a total of 27%. Included in the group abnormal eye movements are nystagmus, gaze palsy, gaze deviation, and sunsetting of the eyes. Squinting was present in 16% of the children. Thirteen percent showed signs of cranial nerve palsy, facial nerve palsy being fairly most common with 6% steadily followed by speech problems at 4%. Three percent had newly acquired drooling and 1% presented with retardation in language and hearing, also being included in this group. Ten percent had reduced visual acuity at the time of diagnosis, many of them had been followed
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by an ophthalmologist. Furthermore, 9% had other visual or eye related signs including anisocoria (4%), photophobia (3%), and exophthalmia (1%). As much as 5 (7%) of the children were described to not be giving eye contact and having a wandering gaze, at least one of these had affected consciousness at entry to the hospital. It can be discussed in this section whether some of the signs of eye affection should be featured under the heading of cranial nerve palsy but for sake of the overview we have kept the signs from the visual system as an own heading.
Motor symptoms in terms of focal motor weakness and paretic limbs were present with a total of 11%. This group is divided into paraplegia, hemiplegia, hemiparesis, monoparesis, and retardation in gross motor function. Nineteen percent had other neurologic signs including involuntary movements (9 %), spasticity (9 %) and fasciculations (1 %). Another 9% had a typical head tilt, some being an actual head tilt, others being referred to as torticollis, both kinds treated by a physiotherapist.
Macrocephaly was present in 17% (see discussion of this subject later). Seventeen percent also had bulging of the fontanelle and splayed sutures, often clinical signs of hydrocephalus. Hydrocephalus was diagnosed on MRI in 26 (37%) of the children.
Finally two children (3%) had nutritional problems or feeding problems, one in which had failure to thrive. Other signs have been reported posing 10% in total and distributed as follows; newly acquired incontinence (4%), signs of affected hormone status resulting in a diagnosis of endocrinopathy (3%), and stiff neck in two children (3%) hence at least one of these was diagnosed with meningitis and had their intracranial tumor diagnosed as a incidental MRI finding during that period of sickness.
The distribution of symptoms and signs relative to age and localization is shown in detail in table 4. Due to many subgroups a simplified version of symptoms and signs, compiling the subgroups, is shown in table 5.
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Table 4 Symptoms and signs relative to age and localization in 70 children with CNS tumor treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Showing the relative number of children in each group and the total in percentage.
SYMPTOMS <12M 12-‐23M ≥24M TOTAL TOTAL # INFRA SUPRA
Nausea and vomiting 7 6 27 57 % 40 19 21 Unsteadiness and poor coordination 1 5 19 36 % 25 17 8 Headache 0 1 20 30 % 21 14 7 Decreased general state 6 3 10 27 % 19 7 12 Seizures 4 2 11 24 % 17 2 15 Decreased state of well-‐being 5 4 3 17 % 12 6 6 Altered level of consciousness 4 2 3 13 % 9 0 9 Others: sleep-‐problems 0 0 2 3 % 2 1 1 SIGNS
Abnormal eye movements 11 2 6 27 % 19 5 14 o Nystagmus 5 1 2 11 % 1 7 o Gaze palsy 1 0 2 4 % 2 1 o Gaze deviation 2 0 2 6 % 0 4 o Sunsetting of the eyes 3 1 0 6 % 2 2 Other neurologic signs 5 2 6 19 % 13 4 9 o Involuntary movements 2 1 3 9 % 2 4 o Fasciculations 0 0 1 1 % 0 1 o Spasticity 3 1 2 9 % 2 4 Macrocephaly 9 2 1 17 % 12 3 9 Bulging fontanelle and splayed sutures 12 0 0 17 % 12 2 10 Squint 2 2 7 16 % 11 3 8 Cranial nerve palsy 0 2 8 14 % 10 6 4 o Speech difficulty 0 1 2 4 % 3 0 o Facial nerve palsy 0 0 4 6 % 1 3 o Drooling 0 1 1 3 % 1 1 o Retardation in language and hearing 0 0 1 1 % 1 0 Paretic limbs/ focal motor weakness 1 2 5 11 % 8 3 5 o Paraplegia 0 1 0 1 % 1 0 o Hemiplegia 0 1 1 3 % 1 1 o Hemiparesis 0 0 2 3 % 0 2 o Monoparesis 1 0 1 3 % 0 2 o Gross motor retardation 0 0 1 1 % 1 0 Reduced visual acuity 3 0 4 10 % 7 1 6 Other signs 2 0 5 10 % 7 3 4 o Incontinence 0 0 3 4 % 3 0 o Endocrinopathies 0 0 2 3 % 0 2 o Stiff neck 2 0 0 3 % 0 2 Head tilt 0 1 5 9 % 6 4 2 Other visual/eye-‐related signs 2 2 2 9 % 6 4 2 o Exophthalmia 1 0 0 1 % 0 1 o Anisocoria 0 1 2 4 % 3 0 o Photophobia 1 1 0 3 % 1 1 No eye contact 5 0 0 7 % 5 0 5 Nutritional problems/poor feeding 2 0 0 3 % 2 0 2
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Table 5 Symptoms and signs relative to age and localization in 70 children with CNS tumor treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Subgroups are compiled and the distribution is shown in percentage.
Symptoms and signs relative to age As we expected the symptoms and signs are differing between the groups, some symptoms only being present in the first year of life, others only in the elderly children. This can partly be explained by the lack of ability to express oneself at a younger age. The children more than two years of age can to a greater extent explain themselves and their sufferings, whilst it among the younger ones are observation of the child and its behavior that will at first give the parents/guardians a clue that something is wrong. Also their anatomy and physiology plays an important role concerning the symptomatology, especially keeping in mind the closing of the sutures and fontanelles within 18 months of age as well as the development of the brain in different stages.
Nausea, vomiting and headache are all present to a greater extent in the group of children 24-‐59 months. Nausea and vomiting were present in 27 patients in this group, against seven in the first group and six in the second group. No headache was reported in the first group, one patient in the second group complained about “the heart in the head” being interpreted as pulsatile headache, whilst 20 of those 24-‐59 months complained about pain in the head, in which equals to more than 95% of those with-‐ headache. Decreased state of well being and altered consciousness were more evenly divided among the age groups. In total twelve patients were observed to have a decreased wellbeing, with five being below twelve months.
When it comes to unsteadiness and poor coordination this was mostly reported in the children 24-‐59 months in which all of them were walking at the time of diagnosis, with 19 out of 25 patients being in this group. In the first group one child
SYMPTOMS <12M 12-‐23M ≥24M TOTAL TOTAL # INFRA SUPRA
Nausea and vomiting 33% 46% 75% 57 % 40 79% 46% Unsteadiness and poor coordination 5% 38% 53% 36 % 25 71% 17% Headache 0% 8% 56% 30 % 21 58% 15% Decreased general state 29% 23% 28% 27 % 19 29% 26% Seizures 19% 15% 31% 24 % 17 8% 33% Decreased state of well-‐being 24% 31% 8% 17 % 12 25% 13% Altered level of consciousness 19% 15% 8% 13 % 9 0% 20% Others: sleep-‐problems 0% 0% 6% 3 % 2 4% 2% SIGNS
Abnormal eye movements 53% 15% 17% 27 % 19 21% 30% Other neurologic signs 24% 15% 17% 19 % 13 17% 20% Macrocephaly 43% 15% 3% 17% 12 13% 20% Bulging fontanelle and splayed sutures 57% 0% 0% 17 % 12 8% 22% Squint 10% 15% 19% 16 % 11 13% 17% Cranial nerve palsy 0% 15% 22% 14 % 10 25% 9% Paretic limbs/ focal motor weakness 5% 15% 14% 11 % 8 13% 11% Reduced visual acuity 14% 0% 11% 10 % 7 4% 13% Other signs 10% 0% 14% 10 % 7 13% 9% Head tilt 0% 8% 14% 9 % 6 17% 4% Other visual/eye-‐related signs 10% 15% 6% 9 % 6 17% 4% No eye contact 24% 0% 0% 7 % 5 0% 11% Nutritional problems/poor feeding 10% 0% 0% 3 % 2 0% 4%
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was reported with an increased tendency to fall over on the side from sitting position. Five patients were from the second group and had mainly stagnation or retardation compared to their achieved walking and coordination abilities at that time. Focal motor weakness and paretic limbs also were more frequent in the third group with 63% of those with this symptom. Eighty percent with cranial nerve palsy were present in the third group, 20% in the second group and none among the youngest ones.
Seizures also turned out to be most frequent in the group 24-‐59 months, found in 11 patients, which equals to 65%. Sleep-‐related problems were reported in two children in the age group 24-‐59 months.
Affection of the eyes, including among more visual acuity, eye movements, and pupil reaction were present in all age groups. Abnormal eye movements (in terms of nystagmus, gaze palsy, gaze deviation and sunsetting of the eyes) were most common in the youngest, whilst squinting and reduced vision were more frequent in the older children. Signs of no eye contact with the child were only reported among the youngest ones.
Other neurologic signs were relatively well divided between the groups, some more in the first group. None in their first year of life were observed with head tilt, only one in the second year, and the last five patients in their third/fourth/fifth year of life. Nutritional problems were only present in the first year of life, including poor feeding and failure to thrive. Other signs reported were more or less evenly divided between the groups.
Macrocephaly The word macrocephaly describes a condition with a head larger than normal. In this study the term macrocephaly is used to describe increased head circumference due to crossing of the percentiles on the percentile form. Increased head circumference is an important factor in diagnosis of brain tumor in the youngest children. In this paper macrocephaly has been assigned as a symptom, but it may in other cases be considered more as an objective measuring.
In the study the occurrence of increased head circumference totals to twelve patients (17%) divided as listed; nine in the first group, two in the second group and one in the third group. Known from physiology is that the sutures and the fontanelle closes during the first year of life, or at least upon 18 months of living, giving expansive masses in the brain more room for growing without noticing during the first year. After the closure of the sutures symptoms of increased intracranial pressure will have an earlier onset. The children in their first year of life in Norway are closely monitored and after recommendations given from the Norwegian Ministry of Health in 1998 (7) measuring is done before departure from the maternity ward and at the appointments at the local health care stations being seven in the first year of life at the following times: one week, six weeks, three months, five months, six months, ten months and twelve months, and then once between 15 and 18 months. If a child switches his or her percentile by one or two and have no clinical findings they are to be measured for control after four weeks, if they switches his or her percentile by three and/or have clinical findings they are to
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be referred for further investigation to a pediatrician. Unfortunately it is known from clinical practice that this isn’t always a followed procedure, and that delay from the health care station is responsible for some of the doctor´ s delay in children with brain tumor in Norway.
Of the nine children in the first year of life reported with macrocephaly seven of them had a head circumference percentile of more than 97,5%, one had exact 97,5% and one had 90%. In the group one patient had a percentile of 97,5% without it being reported anywhere about macrocephaly. Of these nine patients two were referred to the hospital due to other symptoms. In the second year of life one patient had just turned one year, and both parents also had big heads, therefore they had awaited the situation, even though the child by the time of diagnosis had crossed the whole percentile form. Another child had a circumference of more than 97,5% but it had just slightly been increasing. In the last group one two year old child was reported with a percentile of more than 97,5% that had been followed at the health care station from six months of age, steadily increasing. It is important to emphasize that it has to be an abnormal increase of the percentile over a given time for macrocephaly to be a warning sign. Some children may be born with a large head circumference without it being abnormal, but then again other children can be born with a large head circumference due to the whole cranium being filled with tumor masses, a state called oncocephalus.
Symptoms and signs relative to the localization of the tumor The following section will review the variation of the symptoms differing between the supratentorial and infratentorial tumors. When it comes to supratentorial tumors there are some signs and symptoms that are only present in this group, these being altered level of consciousness, no eye contact and sleep related problems. Among the infratentorial tumors there are no signs and symptoms only present in this group.
Seizures of epileptic origin due to intracranial pathology were present in 17 patients. Eighty-‐eight percent of these occurred in children with supratentorial tumors compared to 12% among the children with infratentorial tumors. Because supratentorial tumors are much more common this implies that 33% of those with supratentorial tumors experienced seizures compared to 8% among those with infratentorial tumor.
Abnormal eye movements were also overrepresented in this group, with 74% in the supratentorial group relative to 26% in the infratentorial group. The same applies for squinting with 73% supratentorial relative to 27% infratentorial.
Of other symptoms being mainly present among the supratentorial tumors comes macrocephaly (75%), bulging of the fontanelle and splayed sutures (83%), in comparison it was respectively 25% and 17% in the infratentorial group. Paretic limbs were distributed with 63% in the supratentorial group relative to 37% in the other group.
Ten children had cranial nerve palsy. This implies that six out of 24 (25%) with an infratentorial tumor had this symptom while only four out of 46 (9%) with a
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supratentorial tumor had it, demonstrating that cranial nerve affection is more common among the infratentorial tumors. Of those with head tilt 17% had an infratentorial tumor, compared to only 4% in the supratentorial group. Headache and unsteadiness were symptoms also more frequent in the infratentorial group. 67% of the patients with headache had an infratentorial tumor, the same applies for unsteadiness with the number being 68%.
Nausea and vomiting were symptoms more evenly distributed, with a few more patients in the supratentorial group. Other less specific symptoms include decreased state of well being and decreased general state, which shows fairly good distribution between the groups. The same applies for other neurologic signs, other visual/eye-‐related signs and other signs in general, and also sleep related problems.
Cause of referral to further investigation/hospital It is in our interest to review for what reasons these children were admitted to the hospital, giving important information on what health care professionals should be aware of concerning suspicion of brain tumor in younger children. Some children presents with a complex clinical picture and an advanced state of the disease, while others in a less dramatic way for example are admitted from the health care station due to an increase in the head circumference. A significant number also present with symptoms related to vision or eye motility. We have assigned all the children to a cause of referral, that cause is based on the major symptom or the symptom that provoked a further referral, as stated in the journals. See table 6 for an overview.
In the first year of life, five were referred for increase in head circumference, five with problems related to vision, two with newly arisen epileptic seizures and three with altered level of consciousness. One had incidental findings on MRI taken for other reasons, two for other reasons not specified, and the last three were a mix of the reasons mentioned above.
Of the children in the group 12-‐23 months the cause of referral varied a lot, having two with a decrease in general state and well-‐being, two with signs of increased intracranial pressure (ICP), two with random MRI findings, one with altered level of consciousness, one with head tilt, one with focal neurologic findings, one with increased unsteadiness, one with epileptic seizure, one with increased head circumference and one with a mixture of the above.
Among the children aged 2-‐4 years the cause of referral were more definite. The main reason for referral in this group was symptoms of increased ICP, meaning nausea, vomiting and headache for instance, with 11 out of 36 in which equals to more than 30% of the group. Following with 11,1% were seizures, and also the combination of increase in unsteadiness and progressive symptoms related to intracranial pressure. Three patients were referred due to problems related to vision and eye motility, two due to alteration in consciousness, two with unsteadiness, two with head tilt, two with paretic limbs and one with decrease in general state and well being, four with a combination of the above, and one for non-‐specific reasons.
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CAUSE OF REFERRAL <12 M 12-‐23 M ≥24 M TOTAL Epilepsy/seizures 2 1 4 7 Signs of increased ICP* 0 2 11 13 Altered level of consciousness 3 1 2 6 Unsteadiness 0 1 2 3 Vision/eye motility 5 0 3 8 Head tilt 0 1 2 3 Paretic limbs/focal motor weakness 0 1 2 3 Decreased general state 0 2 1 3 Increased head circumference 5 1 0 6 Increased ICP and unsteadiness 0 0 4 4 Unsteadiness and vision/eye motility 0 0 2 2 Unsteadiness and epilepsy 0 0 1 1 Decreased general state and increased ICP 1 1 1 3 Increased head circumference and increased ICP 1 0 0 1 Increased head circumference and epilepsy 1 0 0 1 Random findings 1 2 0 3 Other 2 0 1 3 TOTAL 21 13 36 70
Table 6 Cause of referral in 70 children age 0-‐4 years treated for intracranial tumor at Oslo University Hospital, Rikshospitalet, 2005-‐2011. * Signs that may indicate increased ICP, in this context meaning headache, nausea, and vomiting.
Instance of referral and involved specialties Another point of interest is other specialties that have been involved in the course of illness, and other diagnoses that have been given to the children prior to the brain tumor diagnosis. Some of the diagnostic delay, both parents delay and doctors delay, can be related to misinterpretations of the first signs and symptoms.
The authority of referral seems quite well divided between the general practitioner (18,6%), the emergency room (17,1%) and the local hospital (20%). Of the 70 patients information is missing in 16 of the cases (22,9%). Further we have 8,6% referred from an ophthalmologist, 7,1% from the health care station, 2,9% from the prehospital service, 1,4% from a center of epilepsy, and finally 1,4% from a specialist in ear, nose and throat diseases.
The numbers of contacts with the health care system was relatively high, many of the children had been in touch with several different specialists and doctors before they got admitted to further investigation, brain MRI and so on. In total it was 102 contacts with the health care system, local hospital in front responsible for almost 40% of the contacts. A pediatrician saw most children, to be mentioned some were referred to gastroenterological or neurological examinations. Two children were assessed by an orthopedic surgeon.
Fourteen children had seen an ophthalmologist and twelve had been in touch with the emergency room, but number of visits for each child is unknown, meaning this number could be higher. Experience in this field implies that these children often have been back and forth with their problem several times before a CNS tumor was suspected. Concerns from the health care station had been posted in eight cases. Two children had been evaluated for their epileptic disease as new seizures had
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arisen. Another five children had been referred to a specialist in ear, nose and throat diseases. Four had been offered treatment with a physiotherapist, one with habilitation services, and one with an ortoptist. One contact has been made with the social services.
The last data gathered concerning the matter is diagnoses given prior to the brain tumor diagnosis, important because the symptoms for brain tumor may in many cases be misinterpreted with other less severe diseases in childhood. The study shows that 25 patients got other symptomatic diagnoses, this being more than one third of the children. The diagnosis ranking highest is gastroenteritis. Other diagnoses given are epilepsy, torticollis and sinusitis. In two children diagnosed with meningitis, a brain tumor was diagnosed on the MRI. One child was given the symptomatic diagnosis of dehydration. Another two patients have been given diagnoses related to problems with vision and eye motility. Finally we got seven children with other diagnoses not specified.
Diagnostic delay time The diagnostic delay time is, as defined above, the time period between symptom onset and diagnosis. It can be divided in a doctor’s delay time and a parent’s delay time, but as mentioned earlier, we have only managed to quantify this time seen as a whole. The median diagnostic delay time that we have found among these 70 patients was eight weeks. The 25 % percentile was two weeks, and the 75 % percentile was as much as 21 weeks.
When taking a look at the diagnostic delay time related to the three different age groups, we have found that there were differences between the groups. In the group younger than 12 months we found that the median value was three weeks, in the group between 12 and 24 months it was 11 weeks, and in the group more than 24 months of age the median value was eight weeks, as in the material seen as a whole.
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Figure 4 Individual diagnostic delay time and age distribution in 70 patients below five years treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011.
Comparing the low-‐grade tumors with the high-‐grade ones we found that among the high-‐grade tumors the median diagnostic delay time was 4,5 weeks with a range from 0,14-‐76 weeks, while it was 8,1 weeks with a range from 0-‐128 weeks among the low-‐grade ones.
Figure 5 Individual diagnostic delay time and tumor grade in 70 patients below five years treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011.
Supratentorial tumors had a median diagnostic delay time of seven weeks with a range from 0-‐128 weeks. The infratentorial ones had a median value of eight weeks with a range from 0,71-‐76 weeks.
Symptoms related to the diagnostic delay time To get an impression of how the symptoms had an impact on the diagnostic delay time we gave each patient a symptom score, where each symptom present at the time of diagnosis gave one point. This resulted in a mean symptom score of 3,6, and a median value of 4 points (range 0-‐12). Further the diagnostic delay time (DDT) was divided in groups including the following; DDT less than one week, DDT between one
3 11 8
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sFc de
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e (w
eeks)
DiagnosFc delay and age distrubuFon Median
<12 months 12 -‐ 23 months ≥24 months
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Diagno
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High-‐grade Low-‐grade
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week and one month, DDT between one month and three months, DDT between three and six months, DDT between six months and one year, and finally DDT more than one year.
Ten children got a diagnosis within one week of time. The average symptom score was 2,2 points, and the median score was 2 (range 0-‐4). Two of them had no symptoms and their tumor was a random finding. One presented with seizures only, and one was reported with abnormal eye movements only. Three of the patients had an altered level of consciousness, and in addition signs of increased ICP, cranial nerve palsy or other neurologic signs. The last four all had a mixture of symptoms, but common for all of them were either abnormal eye movements or squinting.
In the children who got their diagnosis between one week and three months there is huge variation. What is repeatedly seen is that out of those presenting with few symptoms, seizures and macrocephaly are significant symptoms. Further, those with many symptoms have a mixture that almost always includes unspecific symptoms and signs, such as decreased general state, decreased state of well being, nausea/vomiting, and some also with altered level of consciousness.
The group which had a diagnostic delay time between six months and one year included ten children, with an average of 3,6 symptoms each, median score was 3 (range 1-‐9). Two of them presented with eight or more symptoms at the time of diagnosis, both with unspecific symptoms and signs such as decreased general state and decreased state of well being, as well as signs of increased ICP. Four children presented with only one symptom, three of them being seizures, and the last one being macrocephaly. In these cases with seizures the children were under assessment for epilepsy. Out of the ten children six of them were reported with some kind of affection of the eye movements, vision or other eye/vision-‐related symptoms, among other symptoms as well.
Six children had more than one year in diagnostic delay time. The average symptom score in this group was 2,8 symptoms, and the median value was 3 (range 1-‐4) symptoms. Out of these six patients, none had more than four symptoms, two of them had four symptoms, two of them had three symptoms, and two of them had one symptom. The two children with one symptom both reported with paretic limb as their main problem, and were referred due to abnormal gait. Two of the children showed symptoms related to increased intracranial pressure with headache, nausea/vomiting, and unsteadiness. One of these also had seizures, the other one macrocephaly and involuntary movements. The last two had visual trouble with reduced acuity and squinting. One of these presented with unsteadiness in addition and was referred because of that. The other one had developed endocrinopathy at the time of diagnosis.
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Discussion
Strengths and weaknesses
The strength of the study The major strength of our study is the consecutive series of patients over 7 years. We concluded that 70 patients would make a representable group. All patients have been identified from the protocol of surgery and no one has been excluded. This study is seen as a project of quality control within the field of treatment. By keeping the project anonymous and inside the Oslo University Hospital we also kept within the limits for consent, not having to gather consent from each parent.
The reason for choosing patients from 2005 and up had to do with the availability of electronic journals. Further back the journals are kept in a paper archive, not easily available and if so, a time-‐consuming process to access. Keeping to the electronic journals made the project manageable for us, considering time available and workload. We used the collected data as a systematic work tool to gather the same information from each patient. Also our supervisors functioned as a quality control, remembering each of these patients and holding first hand information on their cases. Therefore they could easily correct us in our work by ruling out the misinterpretations along the way.
The weakness of the study Our study is done retrospective and the data are collected from the electronic journals documented in the database of patients used at the Oslo University Hospital, the journal system called Docu Live. To complement the information we have used PasDoc, a program mainly containing lab results and radiological reports. Docu Live contains among other things all reports from the departments of neurosurgery and pediatrics, entry reports, descriptions of performed surgical procedures, nursing reports, multidisciplinary reports, and medical curves, providing several separate sources of information. There is also a section for reports and notes sent from the local hospitals, general practitioners and other health institutions, but some of this information might be missing or incomplete.
The method used is qualitative, and depends on our interpretation of the information in these journals, and again on the doctor’s interpretation of the situation at the admission to the hospital. Some journals are more complete than others, some didn’t contain all the information we were looking for. It varied what each doctor had emphasized in the interview, and some of the journals lacked information on certain things, milestones in development among others. Also the information written in a journal is secondhand information, neither the patients nor their parents have been consulted. When it comes to information about the symptoms and timeline, we have to keep in mind that some of the journals might have been done or redone after the MRI results were available, thus the interview done could be influenced by this result, and leading questions might have been asked. It’s easier to see the symptoms and their onset in retrospect, both from a doctor's and from a parent’s point of view, than it is to see them before you know the diagnosis.
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Histology, age and localization In this study 31% of the patients who had surgery, were under the age of 12 months, 19% were in the second year of life, and 50% were 2-‐4 years. The group including children in their first year of life is the largest 12-‐month group, considering that the last group represents a 3-‐year period. In a previous study from our institution from 1990, Lundar et al found 26% of the children to be in their first year of life (8). This could imply that the incidence in this group is somewhat increased because of a higher occurrence, or that young children are diagnosed at an earlier age than before, due to better knowledge and equipment, or access to such. We found interesting numbers when it comes to localization relative to age. In the first year of life 90% of the tumors were supratentorial. In the other two groups the distribution was more even, but with a small majority of supratentorial tumors in both. In the same study as mentioned above, Lundar et al found that 54% of the tumors were supratentorial, but this was in the age group 0-‐19 years of age. This may indicate that the localization differs with age.
When it comes to histological groups, we found that astrocytoma was the most common tumor, standing for 38,6% of the patients. This is correlating with earlier reports. In the same study as referred to earlier, astrocytomas made 32%. In the article “Classification, incidence and survival analyses of children with CNS tumors diagnosed in Sweden 1984-‐2005” by Lannering et al. astrocytomas made as much as 44,6% of the material (9).
Treatment In our material the total number of primary surgeries was 68 during a seven-‐year period, equaling to 9,7 per year. In the previous study done at the same institution, considering patients over a five-‐year period in the same age group, only 27 primary resections were done (8), which equals to 5,4 each year. This is showing a marked increase in the number of tumors in small children.
Prognosis The Kaplan Meier curve shows a five-‐year survival rate of 90% in the low-‐grade tumors, and 58% among the high-‐grade tumors. This is in accordance with what is known from literature regarding treatment and prognosis. Low-‐grade tumors do have better treatment results and lower mortality than high-‐grade tumors (9). Our study shows distinct trends in survival rate, but it is important to keep in mind that the time of observation is relatively short. Further we found that children in the first year of life had the worst outcome out of the three groups, with almost 30% mortality. The five-‐year survival rate in children below fifteen years of age with CNS tumor in Norway is 77,1% (15).
A Swedish study done on classification, incidence and survival analyses of children with CNS tumors found that children in the first year of life had an inferior prognosis compared to older children. Five-‐year survival rate in the first year of life was 58%, and for the children between one and five years of age it was 74%. The youngest children who died all died within five years from the time of diagnosis. Older children in comparison had a higher initial survival rate but continued to die after ten and fifteen years. Overall five-‐year survival rate in CNS tumors in children up to fifteen
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years was 76%. The study made detailed distinctions between the histological groups, but here to be illustrated by the OS (overall survival) at 10 years of respectively low-‐grade astrocytoma being 90% and of PNET/medulloblastoma being 53% (38% < 12 months), showing the same trends as in Norway regarding the tumor grade. The five-‐year survival rate in general and the higher mortality among the youngest children are then showing the same trends in Scandinavian countries (H).
Symptoms and signs The clinical presentation of patients with CNS tumors is an already illuminated field in the literature. The Head Smart Campaign aims at decreasing the symptom interval in children with brain tumor in Britain by making a guideline to diagnosis, focusing on the symptoms that potentially can indicate a brain tumor. It is important to highlight the fact that the initial symptoms of brain tumor often mimic those of other childhood conditions (10). The literature to this day has not emphasized the differences that exist within the younger age groups, this being the main reason why we chose to work on that subject.
The symptoms and signs are known by clinicians to show some variation with age, due to the children being in different stages of development extending from closure of the fontanelles in the first year of life to the late/early onset of puberty in teenagers (10). Also the children are in different stages of neurological development, especially concerning the development of the brain system and function. A childhood CNS tumor can also present with different clinical pictures varying with the localization and the biology of the tumor (11).
Our findings in general corresponds fairly well with the systematic review and meta-‐analyses from recent years on the subject of brain tumor in children below five years of age, done by Wilne, Collier et al. published in Lancet Oncology in 2007 (12). In this study symptoms and signs in children below four years have been reviewed. However no detailed information on the age groups is available. They reported a high tendency of macrocephaly, followed by nausea and vomiting, irritability, lethargy and abnormal gait as the most frequent symptoms and signs in that order.
Children in the first year of life is often a diagnostic challenge as their symptoms can be masked for a long time by their great ability to adaption, as well as their lack of ability to express discomfort. Splayed sutures and bulging of the fontanelle (as signs of head enlargement), together with macrocephaly, are important signs to look for if suspecting a CNS tumor (12), and must be seen as a possible warning sign and thus as an indication for further investigation. Macrocephaly is however less common in older children, as the closure of the fontanelles takes place between 12-‐18 months (12). Children with an increased ICP or a state of hydrocephalus may present with altered level of consciousness (13).
Headache may be a cardinal symptom of a brain tumor. This symptom cannot be diagnosed in children in their first year of life (12), and this is confirmed in our study. But one third of the youngest did have nausea and vomiting, being one of the major symptoms. Of other less specific signs the youngest children often show signs of discomfort and decreased well being (13). Children in their second year of life are
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much alike the youngest ones on this matter, not having headache, but nausea, vomiting, and decreased well being.
In the group with children aged 2 to 4 years of age three fourth of the children had nausea and vomiting. More than half of the children also had headache. In the systematic review mentioned earlier headache was only present in 10% of the patients below the age of four, in comparison we have an incidence of 30%, but with 95% of these being more than 24 months of age. Headache, nausea and vomiting are symptoms that may be caused by increased intracranial pressure due to occlusion of the drainage of cerebrospinal fluid, which is more common in infratentorial than supratentorial tumors (13). Headache was, in our study, present to a much greater extent in the infratentorial group. Headache is overall recognized as the most common symptom in children with brain tumor, if all ages are considered (12).
Visual symptoms are a common presenting symptom in children with brain tumor, almost one out of three children having an abnormality of visual field or acuity at the time of diagnosis (12). Reduced visual acuity may be due to increased ICP with papilledema, lesions along the optic pathway, or might also be because of a brainstem lesion (12). Reduced visual acuity, squinting, other visual signs, and most frequent of all being abnormal eye movements, were all present in our study with good distribution between the age groups. A total of 27% presented with abnormal eye movement, 58% of these being in the first year of life. This confirms what is recommended in the national guidelines made in Britain where assessment of the visual system is recommended in the investigation of a child with potential brain tumor (11). In Norway all four-‐year-‐old children are having a visual examination at the health care station. This is to assure proper investigation if visual symptoms are found and also if necessary to assure the right action to be taken regarding facilitation when starting school (7).
Seizures were present to less extent among the ones in their first and second year of life, in which corresponds to literature (11;12). In our study 65% of the children with seizures were > 24 months of age. Also 24% were under 12 months, being in line with literature but different from our expectations, as we expected more seizures in the first year of life. Compared to the absolute number of children in each group this implies that 28% of those 24-‐59 months had seizures, relative to 19% in those less than twelve months and 15% in the age group 12-‐23 months.
The systematic review found an incidence for this symptom at 10% in children below four years of age. Seizures were present in 24% of the children in total in our study, and almost 90% of these had a supratentorial tumor. In earlier literature it is described that tumors in the cerebral cortex often gives epileptic seizures, but also that more than 50% are presenting with seizures as their initial symptom (12;13), something that differs from our findings.
Abnormal gait and unsteadiness are early clinical signs in children with affection of the cerebellar structures or the motor nerve pathways in the CNS (13). In our study we had a total of 36% with this sign, more than three/fourth of these children were more than two years of age, verifying that this sign is being more frequent in the older children (12). Further the infratentorial tumors made out 68% of them, also
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confirming that this sign is more common in tumors from that region. Paretic limbs and focal motor weakness may also be seen in children with affection of the same structures (13), but in our study no huge difference with either age or localization has been seen. Head tilt may be seen in children with an infratentorial tumor, as a reflectory position to avoid ailments from the region (4). Torticollis can be seen as a sign of a tumor in the cerebellar hemisphere, with affection of the nervus accessories (CN XI) (13). Patients with head tilt and torticollis often are treated by a physiotherapist before getting their diagnosis. Increased awareness that this may be a symptom of brain tumor can be useful to pick up on these children and their diagnosis earlier.
Diagnostic delay It is important to diagnose brain tumors early, because in many cases the symptoms can progress rapidly and give an emergency presentation, resulting in an increase of the perioperative morbidity. Also, progressive symptoms can result in more permanent neurological damage. The diagnostic delay time we have found within our group of patients has, as mentioned under Clinical Results, a median value of eight weeks. Compared to the UK this value is lower, as they have found it to be 12-‐13 weeks in their material (4). Our findings on DDT are matching other European countries (12).
The range in the diagnostic delay time was wide, from 0-‐128 weeks. Zero weeks occurred when the brain tumor was an incidental finding. A couple of the children had a head CT done after head trauma, and a tumor was found incidentally. A prolonged diagnostic delay time was e.g. found in children who had an increase in head circumference, but were not referred from the health care station when crossing two percentiles, as they should, but maybe weeks later.
In high-‐grade tumors we found the diagnostic delay time to have a median value of 4,5 weeks compared to 8,1 weeks in the low-‐grade ones. This difference can be explained by the fact that high-‐grade tumors, being more aggressive, will within a shorter period of time give more severe illness. The high-‐grade tumors seem, from these numbers, easier to catch. As high-‐grade tumors will do more harm in the same period of time, these are also the most important to diagnose early.
There are a number of reasons why the diagnostic delay time sometimes is prolonged in children with brain tumors. Some of the symptoms are not specific, and are misinterpreted both by parents and healthcare professionals. An example is nausea and vomiting, in which presents in the same way as gastroenteritis, the main difference being that gastroenteritis will shortly pass. If the symptoms last longer than expected one should investigate the possibility of increased ICP. Another sign that might be misinterpreted is an epileptic seizure. A brain tumor is a rare cause of such a seizure, but it is an important cause to exclude for obvious reasons. Therefore, in Norway, the standard is to take an MRI picture of patients with a first time epileptic seizure, not only to exclude brain tumors but also to look for other specific causes in the brain (14). This practice has hopefully resulted in improved diagnosis. Children with eye and vision problems also on occasion have a brain tumor. As such a cause would be rare, it would be exaggerated to take a MRI of
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every child presenting with for instance strabismus, but ophthalmologic evaluation should take place and one should be aware of other symptoms and signs from the central nervous system and investigate further if such signs are present.
A brain tumor may occlude the drainage of cerebrospinal fluid and lead to hydrocephalus and a head circumference increasing more rapidly than expected in the youngest children, and increasing ICP in the older children. Both hydrocephalus and a rapidly growing cranium can have other causes, but it is still important to diagnose high ICP, as it can lead to neurological damage and even death. This is the reason why health care stations in Norway follow up newborns until they are 15-‐18 months old, with measurements of the head circumference. This has been done since the 1950s.
In 2010 the latest national guidelines for weighing and measuring at the health care stations and at the school health care facilities were published. It contains extensive guidelines and recommendations for when to take measure of the head circumference, when to perform a control measure and when to refer for further investigation. It also contains a guide on how to actually perform the measuring. This system will catch up on around 300-‐400 children each year that have a condition causing hydrocephalus, in which only a few of them have a brain tumor, but one child having an undiscovered hydrocephalus is one too many and it is a goal to discover them all. In Norway we have had cases where the measurements have been done, but the data haven’t been plotted in the curve (Lundar personal information). Without plotting the data, the measurement doesn’t give any valuable information, as most values may seem within the normal range. It is of great significance to see if percentiles have been crossed, as children should follow their percentile even though they get older, taller and longer. This is a perfect example of a type of doctor’s delay that easily can be avoided.
At Rikshospitalet they have in the last few years seen that more children in their first year of life are diagnosed with brain tumors, compared to earlier years. It seems that the number is increasing, but this is most likely explained by extended use of MRI, and also by health care stations who refers patients more often than earlier, maybe due to better knowledge around the importance of head measurements. MRI pictures are taken more often today to investigate neurological symptoms, but it’s also taken more often in general, leading to incidental findings that cause more young children to get an earlier diagnosis than before. This increase in incidence of children with CNS tumors is the same as described in other countries, related to improved diagnostics, rather than a real increase in incidence. This is consistent with what other Nordic and European countries reports (9).
Improvement in diagnostics is still required though, even if the median symptom interval found is eight weeks, the range is wide reaching up to 128 weeks, in which of course is an unacceptable amount of time. This indicates that it should be an increased awareness of CNS tumors in health care centers and in the general population.
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Conclusion The distribution regarding age, localization and histology among our group of patients is similar to previous presentations. In the first year of life however, 90% of the tumors were in the supratentorial compartment, which is different from previous reports. There was no big difference in diagnostic delay time regarding localization of the tumor. Children with high-‐grade tumors have a shorter diagnostic delay time than those with low-‐grade tumor. Furthermore it may seem like children in their first year of life have a shorter diagnostic delay time than the older ones.
Diagnostic delay is present in Norway, contributing to a prolonged time to diagnosis for children with brain tumor, though it isn’t present to such extent as in Britain. It is roughly equivalent to other European countries (12). Several factors have an impact on the diagnostic delay time, e.g. the clinical presentation, tumor grade, age, and the actions taken by parents and doctors when symptoms are present. The diagnostic delay time can be reduced by enlightenment around the subject, but it is important to keep in mind that brain tumor in children is rare, and that making too much attention around the subject also may serve to frighten parents. The clinical presentation in our study confirms the symptomatology that is seen in the literature. Brain tumors often give a heterogeneous presentation, therefore it is important to be aware of symptoms that can be misinterpreted with other less severe conditions in children. Certain symptoms and signs are important to be aware of, such as seizures, increased head circumference and persistent headache, nausea and vomiting, together with newly acquired symptoms from the visual pathways and other parts of the nervous system. In Norway the system of measuring head circumference need to be followed as in the written procedures, together with the assessment of the visual system in all four-‐year olds to discover a potential underlying and treatable cause of visual affection. By shortening the diagnostic delay time the morbidity and mortality can hopefully be reduced.
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List of included tables and figures Tables Table 1 Histology, localization and tumor grade in 70 children age 0-‐4 years, treated
at the Oslo University Hospital, Rikshospitalet, 2005-‐2011. Table 2 Histology relative to age in 70 children age 0-‐4 years, treated at the Oslo
University Hospital, Rikshospitalet, 2005-‐2011. Table 3 Tumor grade relative to age in 70 children age 0-‐4 years, treated at the Oslo
University Hospital, Rikshospitalet, 2005-‐2011. Table 4 Symptoms and signs relative to age and localization in 70 children with CNS
tumor treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Showing the relative number in each group, and the total in percentage.
Table 5 Symptoms and signs relative to age and localization in 70 children with CNS
tumor treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Subgroups are compiled, and the distribution is shown in percentage.
Table 6 Cause of referral in 70 children below five years treated for intracranial
tumor at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Figures Figure 1 The distribution of age in children below five years with CNS tumor treated
at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Figure 2 Age groups and localization in 70 children age 0-‐4 years, treated at the Oslo
University Hospital, Rikshospitalet, 2005-‐2011. Figure 3 A Kaplan Meier curve showing survival rate over time in 68 children age 0-‐4
years treated at the neurosurgical department, Oslo University Hospital, Rikshospitalet, 2005-‐2011. Green line shows children with low-‐grade tumors, blue line shows children with high-‐grade tumors.
Figure 4 Individual diagnostic delay time and age distribution in 70 patients below
five years treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011. Figure 5 Individual diagnostic delay time and localization distribution in 70 patients
below five years treated at Oslo University Hospital, Rikshospitalet, 2005-‐2011.
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