Endgames Case Report

Early morning headache with vomiting in a 5 year old boy

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3315 (Published 29 May 2013) Cite this as: BMJ 2013;346:f3315
  1. Benjamin R T Jones, fifth year medical student1,
  2. Shelley A Renowden, consultant neuroradiologist2,
  3. Stephen P Lowis, MacMillan consultant in paediatric and adolescent oncology 3,
  4. Kathreena M Kurian, consultant neuropathologist, honorary senior lecturer4
  1. 1Bristol University Medical School, University of Bristol, Bristol BS8 1TH, UK
  2. 2Department of Neuroradiology, Frenchay Hospital, Bristol BS16 1LE, UK
  3. 3Department of Paediatric Haematology, Oncology, and BMT, Bristol Royal Hospital for Children, Bristol, UK
  4. 4Brain Tumour Research Group, Department of Neuropathology, Frenchay Hospital, Bristol, UK
  1. bjones7392{at}gmail.com

A 5½ year old boy presented with a 10 day history of progressively worsening early morning headache, with vomiting and subsequent development of slurred speech. Before this presentation his development had been normal, with no delay in developmental milestones or abnormality in vision. He was referred to the emergency department for an urgent magnetic resonance imaging (MRI) scan, which showed a tumour arising from the fourth ventricle with a maximum dimension of 3 cm. There was slight dilation of the fourth ventricle, but no hydrocephalus or obvious disease in the spine or leptomeninges.

He underwent craniotomy and gross total excision of the mass. Cytological examination of the cerebrospinal fluid showed no malignant cells. Histological examination of the tumour showed that it was a medulloblastoma, with large pale nuclei (high nuclear to cytoplasmic ratio), cell-cell wrapping, and a high mitotic rate. There were several foci of apoptosis but no sheets of necrosis. Molecular analysis of the tumour showed that the c-Myc and N-Myc genes were amplified. Chemotherapy was started in accordance with Children Cancer and Leukaemia Group guidelines. This involves high dose intensity chemotherapy followed by craniospinal hyperfractionated accelerated radiotherapy.

Questions

  • 1 What is the differential diagnosis for his initial presenting symptoms of early morning headache with vomiting?

  • 2 What tumours may occur in a child of this age, at this site?

  • 3 What do the histology and immunohistochemistry results suggest?

  • 4 How would you manage this patient?

  • 5 What are the long term complications of neurosurgery, chemotherapy, and radiotherapy in children?

Answers

1 What is the differential diagnosis for his initial presenting symptoms of early morning headache with vomiting?

Short answer

Although relatively short, the history of early morning vomiting and slurred speech suggests a neurological cause. Differential diagnoses include raised intracranial pressure, migraine, and viral meningitis. Lack of meningism or signs of sepsis suggest that raised intracranial pressure is the most likely cause.

Long answer

A 10 day history of early morning headache and vomiting is more likely to have a neurological cause rather than a gastrointestinal one, although gastrointestinal causes should also be included in the differential diagnosis. A neurological cause is supported by the absence of other gastrointestinal symptoms and development of dysarthria, which suggests cerebellar involvement. Possible diagnoses include raised intracranial pressure, migraines, and viral meningitis.

Visual assessment and ophthalmoscopy should be performed at presentation.

A diagnosis of viral meningitis is less likely because of the patient’s age and the absence of signs of meningism. Bacterial meningitis is not commonly associated with vomiting. Although migraines are common in children and can vary greatly in their presentation, a migraine would be unlikely to last for 10 days.

There are four main causes of increased intracranial pressure in children:

  • Hydrocephalus

  • Cerebral oedema

  • Intracranial bleeding

  • Tumour.

A history of just 10 days is unusual for a primary tumour of the central nervous system; a history of progressive deterioration over a longer period—weeks or months—would be expected. Similarly, hydrocephalus was not present on imaging, although he had a history of early morning vomiting. A meta-analysis found that the most common presenting symptoms of posterior fossa tumours in children are nausea and vomiting (75%), headache (67%), abnormal gait and coordination (60%), and papilloedema (34%).1 The median interval between the development of symptoms and presentation ranged from one to 27 months, with individual patients presenting with an interval between zero and 154 months. Ophthalmoscopy can show nystagmus associated with cerebellar tumours and papilloedema with raised intracranial pressure.

2 What tumours may occur in a child of this age, at this site?

Short answer

Medulloblastoma, pilocytic astrocytoma, ependymomas, and atypical teratoid rhabdoid tumour account for most cerebellar tumours in children. Most posterior fossa tumours that arise in the vicinity of the fourth ventricle in children are medulloblastomas. MRI and MRI spectroscopy do not reliably differentiate between these two options.

Long answer

The differential diagnosis for posterior fossa tumours in childhood includes pilocytic astrocytoma, medulloblastoma , ependymomas, and atypical teratoid rhabdoid tumour.

Pilocytic astrocytoma is the most common brain tumour in children, accounting for about 40% of such tumours. These tumours have a peak incidence at 5-15 years of age, compared with 2-6 years for medulloblastoma. Pilocytic astrocytomas are benign tumours that, unlike medulloblastoma and ependymomas, are associated with a prolonged clinical history. On imaging, pilocytic astrocytomas usually look like a cyst with an avidly enhancing nodule. The cyst wall occasionally enhances. Enhancement tends to be homogeneous, and there is little or no surrounding oedema.

Medulloblastomas are highly malignant tumours, typically with a rapid growth rate; they account for about 20% of brain tumours in children. Most arise from the roof of the fourth ventricle or inferior vermis and are midline lesions. Ninety percent of medulloblastomas are dense on computed tomography and they may show calcification. MRI usually shows a solid mass, but small intratumoral cysts or necrosis can be seen. Almost all medulloblastomas enhance homogeneously with contrast and show restricted diffusion. A proportion (20-30%) show leptomeningeal enhancement, indicating dissemination at presentation.

Ependymomas are less common (comprising 10% of paediatric brain tumours) and present at a median age of 5 years. They arise from within the ventricle itself and may extend inferiorly through the fourth ventricular foramina and foramen magnum. They may be associated with head tilt as the child tries to reduce pressure on the upper cervical cord. Imaging commonly shows a lesion arising from the floor of the fourth ventricle. These tumours often show heterogeneous enhancement and sometimes haemorrhage.

Atypical teratoid rhabdoid tumour is indistinguishable from medulloblastoma on imaging but tends to occur in children younger than 3 years old. This tumour is highly invasive and may show contiguous spread even through the dura. It is the most common malignant tumour in infants.

3 What do the histology and immunohistochemistry results suggest?

Short answer

The histological features suggest that this is a medulloblastoma, subtype large cell/anaplastic. These generally have a poor prognosis compared with classic medulloblastomas (intermediate prognosis) and desmoplastic variants (best prognosis). High amplification of the Myc oncogene is also associated with an adverse prognosis.

Long answer

The histological features suggest that this is a medulloblastoma, subtype large cell/anaplastic. The 2007 World Health Organization classification recognises four distinct histological subgroups of medulloblastoma: classic (66%), desmoplastic (15%), large cell (15%), and anaplastic (2-4%).2 Desmoplastic tumours usually carry the most favourable prognosis, whereas the large cell/anaplastic variants typically have an unfavourable prognosis.

More robust markers of prognosis have recently been developed. Molecular profiling has identified at least four main subgroups of medulloblastoma, which require different types of treatment. Although the molecular classification system overlaps with the histopathological one, it can identify good and poor risk disease that would otherwise be missed. For example, overexpression of the gene encoding β catenin characterises the Wnt subgroup with classic histology, for which conventional treatment is highly likely to provide a cure. Mutations affecting the Shh (sonic hedgehog) pathway characterise many desmoplastic types of tumour, which carry a good prognosis in infants. Group 3 tumours overexpress genes involved in retinal development and often have amplification of Myc.3 These tumours are often metastatic and have a worse prognosis than other groups. Lastly, group 4 tumours, which are typically seen in boys age 7 years, have classic histology, carry isochromosome 17q, and have an intermediate prognosis.4

4 How would you manage this patient?

Short answer

Medulloblastoma is treated with surgery, radiotherapy, and chemotherapy. Many children are left with serious disability, and systematic rehabilitation services should be offered, including physiotherapy, speech and language therapy, and educational support. Endocrine deficiency is inevitable after craniospinal radiotherapy and will require close endocrinology follow-up. Replacement of growth hormone is most often required, but gonadotrophin, cortisol, and thyroid hormone are also often needed. After treatment, regular follow-up and MRI are needed for a minimum of five years to look for evidence of treatment side effects and relapse.

Long answer

Medulloblastoma is treated with surgery, radiotherapy, and chemotherapy.

Surgical resection of the tumour greatly improves prognosis, and complete removal of the tumour should always be attempted. A large residual mass should never be left unless further surgery is deemed too hazardous. Second-look surgery may be necessary, but the advent of intraoperative MRI should mean that it will be used less often.

Craniospinal radiotherapy is recommended for all patients, unless there is a high risk of severe neurocognitive side effects. It may be difficult to balance the risks against the benefits, but craniospinal radiotherapy is generally not given to infants and very young children. Even in older children, the need to reduce radiation doses is recognised, and a total craniospinal dose of 23.4 Gy is currently used in standard risk patients, rather than the 36 Gy dose used previously.

Conversely, patients with high risk disease need more intensive radiotherapy. A larger dose, which may be further intensified using accelerated frequency dosing and hyperfractionation, has been reported to increase the possibility of cure.5

Chemotherapy is recommended for all patients. Conventional treatment using vincristine, lomustine, and cisplatin combined with radiation leads to a five year event-free survival of 82% and overall survival of 86%.6 This is not the case for high risk disease, however, and a variety of strategies—using hyperfractionated radiotherapy; intensified chemotherapy, sometimes with double cycles of high dose therapy; and autologous stem cell reconstitution (autograft)—have been adopted. To date, no single strategy has proved to be significantly better than any other, although the approach reported by the Milan group is the current recommended strategy in the UK.5

Patients are monitored closely during and after treatment for any side effects or complications. Because of the relatively high rate of relapse, follow-up imaging of the brain and spine is generally recommended every three months for the first two years. MRI of the brain should be performed every four months for the third year, every six months until the fifth year, and then annually, although local protocols vary. Rehabilitation services should be offered, including speech and language therapy, physiotherapy, and educational support.

5 What are the long term complications of neurosurgery, chemotherapy, and radiotherapy in children?

Short answer

Long term complications of neurosurgery, chemotherapy, and radiotherapy include motor, sensory, and cognitive defects; endocrine sequelae; and neuropsychological and behavioural problems. These can affect academic achievement, problem solving, independent living, and quality of life in general.

Long answer

Long term complications of the tumour and of neurosurgery, chemotherapy, and radiotherapy affect many aspects of health.

In the immediate postoperative period, the “posterior fossa syndrome” is reported in 25-30% of patients. Typically, a patient may make an initial good recovery from surgery but will then become quiet, introverted, and less responsive. Some children are seriously distressed even with minimal disturbance; others become mute and immobile. Such symptoms may last for a few days to several months. Most children recover, but the process may be profoundly difficult for children and their carers.7 8

After surgery, children commonly experience residual ataxia and cranial nerve palsies, which may cause severe disability. Improvement may take several years, emphasising the need for early and systematic rehabilitation.

Chemotherapy will cause acute side effects, including immunosuppression and infection, nausea and vomiting, and weight loss. Vincristine often causes peripheral neuropathy, which exacerbates the difficulties for a child with ataxia. Cisplatin commonly causes a high tone sensorineural hearing loss, which is made more severe by damage to the cochlear as a result of irradiation to the posterior fossa, and it is common to omit cisplatin in later cycles of chemotherapy for this reason. Lomustine may cause profound myelosuppression and carries a risk of damage to fertility and of a second primary cancer.

Radiotherapy has many sequelae, but the neurocognitive effects are most important, particularly in younger children. Neuropsychological outcome data for a cohort of children treated for standard risk medulloblastoma reported the greatest loss in children under 7 years at diagnosis.9 A mean loss of 2.4 IQ points per year from onset of irradiation was seen during follow-up of these young children. This probably results in substantial limitation of abilities in later life for many children, although survivors may remain within the normal range.

Neuroendocrine deficiencies—particularly growth hormone and thyroid stimulating hormone, but also corticotrophin and gonadotrophin—probably result from irradiation of the hypothalamic-pituitary axis. Such deficits can be replaced but require close monitoring and early intervention.

The many and varied after effects of the tumour and treatment often affect many aspects of later life, and it is a principal goal of current research protocols to reduce such effects. Clearer stratification of risk should allow treatment to be reduced in “good risk” patients. Sadly, for patients such as our case, with high risk disease, further intensification is needed.

Patient outcome

Our patient was treated with chemotherapy and hyperfractionated radiotherapy according to current UK guidelines. He had no residual tumour and did not receive high dose therapy. Six months after the end of treatment, he had some unsteadiness of gait, a right sided hemiparesis, and some difficulty speaking, but these have largely resolved. He tolerated consolidation chemotherapy well with few complications, and between cycles he was active—playing football and tennis. He has good hand to eye coordination and is reaching out to objects and drawing. He has slight hearing impairment but shows normal speech development.

Subsequent MRI scans have shown no signs of relapse of the tumour one year from the end of treatment.

Notes

Cite this as: BMJ 2013;346:f3315

Footnotes

  • Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following interests: None.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Parental consent obtained.

References