Approach to Malignant Brain Tumors in Children

Approach to Malignant Brain Tumors in Children 

Synopsis

Urgent Action

• Intracranial hypertension and acute brain herniation are considered neurologic emergencies that require immediate treatment to prevent irreversible damage or death 
  • Administer dexamethasone and consider cerebrospinal fluid drainage and other measures to relieve pressure; consider circulatory and ventilatory support 
• Prolonged seizures and status epilepticus in pediatric populations are considered medical emergencies 
  • Immediately begin supportive measures and medication to control seizures 

9 Interesting Facts of Approach to Malignant Brain Tumors in Children 

1. Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood
2. Common forms include medulloblastoma, high-grade glioma (eg, glioblastoma, anaplastic astrocytoma, diffuse intrinsic pontine glioma), and ependymomas
3. Symptoms and signs develop as a result of local invasion, compression of central nervous system structures, and increased intracranial pressure; may initially be subtle and nonspecific
4. Clinical presentation varies according to age of child and type and location of tumor; however, common findings associated with all ages and types of tumor include persistent or recurrent nausea and vomiting, motor abnormalities (eg, balance, gait, and coordination difficulties), and abnormal eye movements
   • Infants may present with enlarging head circumference (macrocephaly), lethargy, irritability, bulging fontanelle, or splayed sutures
   • Young children may be unable to articulate symptoms and may present with irritability, lethargy, and gait or coordination difficulties
   • Older children and adolescents typically complain of persistent or recurrent headache and may develop gait abnormalities or seizures; may have delayed puberty or slow growth
5. Diagnosis is based on history, physical examination (including thorough neurologic and visual examinations), and central nervous system imaging (MRI or CT scan)
6. Specific tumor type is confirmed on basis of immunohistopathologic examination of tissue obtained during tumor resection or by stereotactic biopsy guided by MRI or CT in the case of deep-seated tumors that are not amenable to open surgical approach
7. Management consists of surgery, with adjunctive radiation therapy and/or chemotherapy; optimal treatment varies according to tumor histopathology, biochemical/molecular characteristics, extent of disease at diagnosis, site of origin, age at diagnosis, and residual tumor burden after resection
8. Measures to address associated complications, such as raised intracranial pressure and seizures, are frequently required perioperatively
9. Prognosis varies widely according to tumor histopathology and other factors; survivors frequently have neurologic, endocrine, and cognitive complications resulting from the tumor itself and/or treatment

Pitfalls

• Avoid radiation therapy in children younger than 3 years, owing to detrimental effects of radiation to the developing central nervous system 

• Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood
  • Brain tumors are the second most common cancer and the most common cause of cancer death among children 
• There are more than 100 different histologic subtypes of childhood brain tumor with the incidence of each varying by age 
  • Common forms include medulloblastoma, high-grade glioma (eg, glioblastoma, anaplastic astrocytoma, diffuse intrinsic pontine glioma), and ependymomas 

Classification

• By cell of origin
  • Tumors of glial cell origin (gliomas)
    • Astrocytomas (astrocytes)
      • Tumors arising from astrocyte glial cells; the most frequent posterior fossa tumor in children, accounting for 10% to 20% of all childhood intracranial tumors 
    • Oligodendroglial tumors (oligodendrocytes)
      • Very rare; only 6% of cases are diagnosed in children or adolescents 
    • Mixed gliomas (cell types of origin include oligodendrocytes, astrocytes, and ependymal cells)
    • Mixed neuronal-glial tumors
  • Embryonal tumors
    • Medulloblastoma
      • Fast-growing, high-grade tumor derived from the cerebellum
      • Most common malignant brain tumor in children (accounts for 20% of all pediatric tumors) 
    • Ganglioneuroblastoma
      • Defined by the presence of only neuronal differentiation and the presence of neoplastic ganglion cells
    • Atypical teratoid/rhabdoid tumor
      • Rapidly growing, malignant tumor that typically arises in the cerebellum or brain stem
      • Approximately 10% of children with brain tumors have atypical teratoid/rhabdoid tumors 
  • Ependymomas
    • Brain tumors arising from neuroepithelial lining of the ventricles of the brain and the central canal of the spinal cord 
    • Account for approximately 5.5% of all childhood brain tumors 
  • Meningioma
    • Tumors derived from the covering of the brain and/or spinal cord 
    • Rare brain tumor in children; incidence before age 16 years ranges from 0.4% to 4.6% of all primary brain tumors in this group 
  • Pineal gland tumors
    • Account for 2.7% of all brain tumors in children (aged 1-12 years) 
  • Choroid plexus tumors
    • Rare central nervous system neoplasms that account for 1% to 4% of all pediatric brain tumors 
  • Tumors of sellar region
    • Include craniopharyngiomas, which account for about 6% of all intracranial tumors in children 
  • Germ cell tumors
    • Account for 0.5% of all primary brain tumors, with approximately 90% of cases occurring before age 20 years 
    • Include germinomas, embryonal carcinomas, and choriocarcinomas
  • Cranial and paraspinal nerve tumors
    • Include schwannomas, neurofibromas, and peripheral nerve sheath tumors
  • Mesenchymal nonmeningothelial tumors
    • Include hemangioblastomas and hemangiopericytomas
  • Melanocytic tumors
    • Include melanocytoma, malignant melanoma, and meningeal melanomatosis
  • Lymphomas and other hematopoietic neoplasms
• Based on anatomic location
  • Infratentorial (posterior fossa)
    • Cerebellar astrocytomas (pilocytic is most common; may also include fibrillary and, less frequently, high-grade)
    • Medulloblastomas (including classic, desmoplastic/nodular, extensively nodular, anaplastic, or large-cell variants)
    • Ependymomas (papillary, clear cell, tanycytic, or anaplastic)
    • Brain stem gliomas (diffuse intrinsic pontine gliomas and focal, tectal, and exophytic cervicomedullary gliomas are most frequently pilocytic astrocytomas)
    • Atypical teratoid/rhabdoid tumors
    • Choroid plexus tumors (eg, papillomas, carcinomas)
    • Rosette-forming glioneuronal tumors of the fourth ventricle
  • Supratentorial
    • Low-grade cerebral hemispheric astrocytomas (eg, grade 1 [pilocytic] astrocytomas, grade 2 [diffuse] astrocytomas)
    • High-grade or malignant astrocytomas (eg, anaplastic astrocytomas, glioblastomas [grade 3 or grade 4])
    • Mixed gliomas (low- or high-grade)
    • Oligodendrogliomas (low- or high-grade)
    • Cerebral neuroblastomas and pineoblastomas
    • Atypical teratoid/rhabdoid tumors
    • Ependymomas (anaplastic or RELA fusion positive)
    • Meningiomas (grades 1, 2, and 3)
    • Choroid plexus tumors (eg, papillomas, carcinomas)
    • Pineal region tumors (eg, pineocytomas, pineoblastomas, pineal parenchymal tumors of intermediate differentiation, papillary tumors of the pineal region) and germ cell tumors
    • Neuronal and mixed neuronal glial tumors (eg, gangliogliomas, desmoplastic infantile astrocytoma/gangliogliomas, dysembryoplastic neuroepithelial tumors, papillary glioneuronal tumors)
    • Other low-grade gliomas (eg, subependymal giant cell tumors, pleomorphic xanthoastrocytoma)
    • Metastasis (rare) from extraneural malignancies
  • Parasellar
    • Craniopharyngiomas
    • Diencephalic astrocytomas (central tumors involving the chiasm, hypothalamus, and/or thalamus) that are generally low-grade (including grade 1 [pilocytic] or grade 2 [diffuse] astrocytomas)
    • Germ cell tumors (germinomatous or nongerminomatous)
  • Spinal
    • Low-grade cerebral hemispheric astrocytomas (grade 1 [pilocytic] or grade 2 [diffuse])
    • High-grade or malignant astrocytomas (anaplastic astrocytomas and glioblastoma [grade 3 or grade 4])
    • Gangliogliomas
    • Ependymomas (often myxopapillary)
• Based on molecular genetics and histologic features
  • 2021 WHO Classification of Tumors of the Central Nervous System classifies tumor types and subtypes based on molecular parameters, in addition to histology and immunohistochemistry 
    • Pediatric tumors are now covered in a separate volume in fifth edition of WHO Classification of Tumors, which includes a specific chapter on pediatric central nervous system tumors
• By grade (WHO) 
  • Low grade
    • Grade 1
    • Grade 2
  • High grade
    • Grade 3
    • Grade 4

Clinical Presentation

History

• Symptoms develop as a result of local invasion, compression of central nervous system structures, and increased intracranial pressure; may initially be subtle and nonspecific
• Consider presence of brain tumor in children presenting with any of the following: 
  • Headache
    • New, persisting, or recurrent headache
    • Change in nature of headache in child with known migraine or tension headache
    • Persistent headaches on waking
    • Confusion or disorientation with headache
  • Nausea/vomiting
    • Persistent or recurrent nausea/vomiting, particularly on awakening
  • Visual symptoms
    • Reduced visual acuity
    • Abnormal eye movements
    • Proptosis
    • New onset squint
    • Diplopia
  • Motor symptoms
    • Regression in motor skills
    • Abnormal gait
    • Incoordination
    • Focal motor abnormalities
    • Swallowing difficulties
    • Isolated facial palsy
    • Subtle changes such as switched hand preference or loss of learned skills (eg, dexterity in computer games)
  • Polyuria and polydipsia (diabetes insipidus)
    • May be associated with secondary nocturnal enuresis
  • Growth failure
  • Delayed, arrested, or precocious puberty
  • Behavior changes
    • Lethargy in situations where child would normally be active
    • Declining school performance
    • Personality change
    • Delay in achieving developmental milestones
  • Seizures
  • Altered level of consciousness
• Symptoms vary according to age of child and type and location of tumor
  • Tumor location
    • Infratentorial (posterior fossa) tumors may present with nausea and vomiting, headache, abnormal gait, incoordination, abnormal eye movements, and lethargy
      • Brainstem tumors are associated with abnormal gait, incoordination, and cranial nerve palsies
    • Supratentorial tumors present with symptoms of raised intracranial pressure, headache, seizures, and focal neurologic signs
    • Midline tumors involving the parasellar region generally have nonspecific symptoms; most commonly include headache, abnormal eye movements, nausea and vomiting, reduced visual acuity, and growth failure
    • Spinal cord tumors cause back pain, spinal deformity, focal weakness or paresthesia, and abnormal gait or incoordination
  • Age of child
    • Infants may present with enlarging head circumference (macrocephaly), lethargy, irritability, bulging fontanelle, or splayed sutures
    • Young children may be unable to articulate symptoms and may present with irritability, lethargy, and gait or coordination difficulties
    • Older children and adolescents typically complain of persistent or recurrent headache and may develop gait abnormalities or seizures; may have delayed puberty or slow growth
  • Common symptoms associated with all ages and types of tumor include: 
    • Persistent or recurrent nausea and vomiting
    • Motor abnormalities (eg, balance, gait, and coordination difficulties)
    • Abnormal eye movements

Physical examination

• Physical and neurologic examination findings vary according to type and location of tumor
• Common findings include: 
  • Visual examination
    • Reduced visual acuity
    • Reduced visual fields
    • Bilateral papilledema
    • Abnormal eye movements/nystagmus
    • Exophthalmos
    • Nonconvergent squint
    • Optic atrophy
  • Motor examination
    • Focal motor weakness
    • Ataxia and gait abnormalities
    • Cranial nerve palsies
• Specific findings in infants may include:
  • Macrocephaly (measure head circumference)
  • Bulging fontanelles
  • Splayed sutures

Causes

• Exact cause of pediatric brain tumors is unknown; most tumors develop sporadically 
  • A small portion of pediatric brain tumors may be linked to a genetic syndrome or environmental exposure

Risk factors and/or associations

Age

• Incidence varies according to age and histologic type
  • Overall incidence rates by age group
    • Birth to 4 years: 6.3 per 100,000 
    • 5 to 9 years: 5.59 per 100,000 
    • 10 to 14 years: 5.94 per 100,000 
    • 15 to 19 years: 7.32 per 100,000 
• Histologic type varies by age
  • Among children from birth to age 14 years:
    • Pilocytic astrocytomas: 18.3%
    • Embryonal tumors: 12.3%
      • Medulloblastomas: 67.7%
      • Atypical teratoid/rhabdoid tumors: 17.1%
      • Primitive neuroectodermal tumors: 8.5%
    • Gliomas: 51.3%
    • Malignant gliomas (not otherwise specified): 14.8%
  • Incidence rates of pilocytic astrocytomas, malignant gliomas, ependymal tumors, choroid plexus tumors, and embryonal tumors decrease with increasing age
  • Among adolescents aged 15 to 19 years: 
    • Pituitary tumors: 33.1%
    • Pilocytic astrocytomas: 8.2%
    • Gliomas: 30.6%

Sex

• Overall, childhood brain tumors are more common in males, though this varies by histologic type 

Genetics

• Established familial cancer syndromes that increase brain tumor susceptibility include: 
  • Neurofibromatosis type 1 (NF1)
  • Neurofibromatosis type 2 (NF2)
  • Tuberous sclerosis (TSC1 or TSC2)
  • Li-Fraumeni syndrome (TP53 or CHEK2)
  • Nevoid basal cell carcinoma (PTCH)
  • Turcot syndrome (APC)
  • Cowden disease (PTEN)
  • Hereditary retinoblastoma (RB1)
  • Rubinstein-Taybi syndrome (CREBBP)
  • DICER1 syndrome (DICER1, DROSHA) 
  • Fanconi anemia (FANCA)
  • Lynch syndrome (MSH2, MLH1, MSH6, PMS2)
  • Ataxia-telangiectasia (ATM)
  • Melanoma-neural system tumor syndrome (CDKN2A)

Ethnicity/race 

• In the United States, White and Asian-Pacific Islander populations have a higher incidence than Black and American Indian/Alaskan Native populations
• Non-Hispanic populations have higher incidence than Hispanic populations

Other risk factors/associations 

• High-dose radiation therapy to head and neck for cancer or other conditions is an established risk factor
• No definitive evidence of other environmental risk factors; however, maternal dietary intake of nitrates and residential pesticide exposure may increase risk
• Exposure to CT increases brain tumor risk; magnitude of risk depends on cumulative radiation dose (number of scans and radiation dose)
  • 3-fold increase in risk of brain tumor was reported with cumulative radiation doses of 60 mGy in one study; however, uncertainty remains about the estimated magnitude of risk and absolute risk is small 
• Other radiographic imaging modalities have not been associated with increased risk of childhood brain tumors
• Nonchromosomal birth defects are associated with increased risk of childhood brain tumors 

Diagnostic Procedures

Primary diagnostic tools

• Suspect diagnosis based on history and physical examination, including thorough neurologic and visual examinations 
  • Central nervous system imaging (MRI or CT) is indicated in children with any of the following: 
    • Persistent headaches that wake child from sleep or occur upon waking, that occur in a child younger than 4 years, or that are associated with confusion or disorientation
    • Persistent nausea and/or vomiting upon waking
    • Visual manifestations
      • Papilledema
      • Optic atrophy
      • New-onset nystagmus
      • Reduction in visual acuity not caused by refractive error
      • Visual field reduction
      • Exophthalmos (proptosis)
      • New-onset paralytic squint
    • Motor symptoms
      • Abnormal gait
      • Focal motor weakness
    • New-onset seizures (not including febrile)
    • Altered consciousness
    • Macrocephaly
• Diagnosis is confirmed by identification of mass lesion on MRI or CT scan of brain and spine 
  • Other forms of imaging such as brain PET scans, MRI spectroscopy, and MRI perfusion scanning may provide information to supplement standard CT or MRI; however, these are not routinely used at all centers
  • Refer patients to pediatric neurosurgeon for further evaluation, tissue biopsy, and complete resection of lesion (when possible)
• Specific tumor type is confirmed on basis of immunohistopathologic examination of tissue obtained during tumor resection or by stereotactic biopsy guided by MRI or CT in the case of deep-seated tumors that are not amenable to open surgical approach 
• Lumbar puncture may be done to detect metastasis in tumors with a predisposition for leptomeningeal spread (eg, medulloblastomas, ependymomas, atypical teratoid/rhabdoid tumors, germ cell tumors) 
  • Contraindicated in patients with raised intracranial pressure owing to risk for herniation of brain
• Additional diagnostic evaluation may be required in some cases:
  • Test for serum and cerebrospinal fluid tumor markers α-fetoprotein and β-hCG, and evaluate pituitary and hypothalamic function in patients with germ cell tumors
  • Perform endocrine testing and formal vision examination, including visual field evaluation, in patients with craniopharyngioma
  • Consider renal ultrasonography to detect synchronous tumors in patients with atypical teratoid/rhabdoid tumors
• Additional imaging is not usually indicated unless there are symptoms or signs suggesting other organ involvement; common tumors rarely metastasize to bone, bone marrow, or other sites at time of diagnosis 

Imaging

• MRI of brain and spine (with and without contrast enhancement)
  • Gold standard for imaging tumors of brain and spine
  • Superior to CT for assessing anatomy; can provide information indicating tumor type
• CT brain and spine (with and without contrast enhancement)
  • Secondary imaging method; however, it is often the initial imaging study performed owing to wider availability and shorter study time (which may not require sedation)
  • Less sensitive than MRI, and normal findings do not completely exclude lesion

Procedures

• Insertion of hollow-bore needle between vertebral bodies into subarachnoid space to obtain a specimen of cerebrospinal fluid for cytologic analysis
• Patient is either in lateral recumbent position (preferable for measuring opening pressure) or sitting upright
• To evaluate for metastases in tumors with predisposition for leptomeningeal spread (eg, medulloblastomas, ependymomas, atypical teratoid/rhabdoid tumors, germ cell tumors) 
• Uncontrolled coagulopathy
• Skin infection at site of needle insertion
• Patient at risk for herniation of the brain
  • Best predictors of precipitating herniation (even with normal CT result) include:
    • Deteriorating level of consciousness (particularly to Glasgow Coma Scale score of 11 or less)
    • Brainstem signs (eg, pupillary changes, abnormal posturing, irregular respirations)
    • Very recent seizure
• Post–dural puncture headache
• Back pain (lower or upper)
• Radicular injury
• Epidural abscess
• Meningitis
• Diskitis
• Vertebral osteomyelitis
• Epidural hematoma
• Cerebral herniation
• Presence of tumor cells in fluid indicates metastasis of primary brain tumor

Differential Diagnosis

Most common

• Migraine and migraine variants
  • Primary headache disorder associated with sensitivity to light and accompanied by nausea and vomiting
  • Migraine variants occurring in childhood may present with cyclic vomiting or vertigo with only mild or absent headache
  • Similarly to malignant brain tumors, migraine can present with recurrent nausea and vomiting with or without headache
  • Migraines are often preceded by a prodrome and are accompanied by sensitivity to light and sound, which do not occur with brain tumors
  • Symptoms such as diplopia, paresthesias, dysarthria, altered vision, or focal motor weakness may be seen; however, these are fully reversible
  • Differentiated on basis of family history of migraine and characteristic signs and symptoms; may include neuroimaging to exclude brain tumor
• Tension-type headaches
  • Holocranial headache without nausea or vomiting; typically mild to moderate and does not worsen with activity
  • May involve photophobia and/or sensitivity to sound
  • Not associated with neurologic signs, nausea, or vomiting
  • Differentiated based on history and physical examination
• Idiopathic intracranial hypertension
  • Occurs most frequently in obese children
  • Similarly to malignant brain tumors, presents with headache, transient visual obscurations, and double vision; papilledema may develop
  • Presence of pulsatile tinnitus may be a differentiating feature
  • Differentiated based on history and lumbar puncture with cerebrospinal fluid analysis after CT or MRI excludes presence of a space-occupying lesion or other diagnosis
    • Lumbar puncture result demonstrates elevated opening pressure with normal cerebrospinal fluid analysis
• Brain abscess
  • Most common in children aged 4 to 8 years and in neonates
  • Associated with embolization due to congenital heart disease with right to left shunts (eg, tetralogy of Fallot), endocarditis, meningitis, sinusitis, chronic otitis media and mastoiditis, orbital cellulitis, dental infections, severe complicated pneumonia, penetrating head injuries, soft tissue infections involving the scalp or face, immunodeficient state, and ventriculoperitoneal shunt infections
  • Similarly to malignant brain tumors, may present with headache, behavioral changes, cranial nerve palsy, gait disorder, or seizures, depending on the location of the abscess; findings may be subtle for days or weeks
  • Fever and altered level of consciousness are frequently absent
  • Differentiated based on history, physical examination, and identification of abscess on CT scan; lumbar puncture is contraindicated

Treatment Goals

• Promptly relieve raised intracranial pressure if present
• Debulk or, when possible, completely remove tumor
• Prevent progression or recurrence

Admission criteria

Admission is required for surgical resection or management of complications associated with brain tumor

Criteria for ICU admission

• Raised intracranial pressure
• After craniotomy (for postoperative care)

Recommendations for specialist referral

• Refer to pediatric neurosurgeon for further evaluation, tissue biopsy, and complete resection of lesion (when possible) if mass lesion is identified on neuroimaging
• Refer for management at a center with pediatric specialists who have expertise in the care of patients with these diseases (eg, neurosurgeon, neuropathologist, radiation oncologist, pediatric oncologist, neuro-oncologist, neurologist, rehabilitation team, neuroradiologist, endocrinologist, psychologist) 

Treatment Options

Management consists of surgery, with adjunctive radiation therapy and/or chemotherapy depending on tumor type 

• Treatment may vary according to tumor histopathology, biochemical/molecular characteristics, extent of disease at diagnosis, site of origin, age at diagnosis, and residual tumor burden after resection
• Open surgical resection is preferred to obtain tissue for histologic diagnosis and to remove tumor bulk
  • Typically, near-total resection is performed, as complete resection is difficult to achieve without risking permanent neurologic deficits
  • Tumor resection can be maximized and damage to adjacent normal brain tissue may be minimized by use of preoperative stereotactic imaging techniques, intraoperative imaging, and intraoperative neurophysiologic monitoring
  • Sellar and suprasellar tumors (eg, craniopharyngiomas, pituitary adenomas) may be effectively resected via endonasal endoscopic skull base surgery 
• Chemotherapy and/or radiation therapy may be implemented to eradicate any residual tumor cells after surgery and to prevent recurrence
  • Radiation therapy is an effective adjunct to surgery but is generally avoided in children younger than 3 years owing to potential neurologic and cognitive sequelae; may be delayed until there is evidence of disease progression 
  • Postoperative chemotherapy can be used to delay, limit, and sometimes obviate the need for radiation therapy, particularly in younger children 
  • Optimal treatment regimens for specific tumors have not been established and enrollment in a clinical trial is encouraged

Measures to address associated complications are frequently required perioperatively 

• Raised intracranial pressure
  • Arrange for urgent surgical resection if causing a significant mass effect
  • Treat vasogenic tumor edema with corticosteroids
  • Apply general treatment of increased intracranial pressure
    • Maintain cerebral perfusion pressure and support airway
    • Avoid drugs that will increase intracranial pressure
    • Elevate head of bed and maintain head in midline position
    • Blunt noxious stimuli with appropriate analgesia
    • Administer mannitol or hypertonic saline
    • Consider hyperventilation to achieve mild to moderate hypocapnia, cooling to induce moderate hypothermia, and/or pentobarbital infusion
  • Drain cerebrospinal fluid to relieve obstructive hydrocephalus
    • Emergent external ventricular shunt or third ventriculostomy can be used before tumor resection to decrease intracranial pressure
    • Ventriculoperitoneal shunt may be inserted to drain excess cerebrospinal fluid and relieve intracranial pressure; usually performed at time of surgical resection of tumor
• Seizures
  • Institute standard anticonvulsant therapy (eg, phenytoin, carbamazepine, levetiracetam, gabapentin) for patients experiencing seizures
  • Be aware of potential for interaction between chemotherapy agents and anticonvulsants; some common anticonvulsants induce hepatic cytochrome P450, as well as increase clearance and decrease effectiveness of certain chemotherapy agents
  • Prophylactic anticonvulsants are not generally recommended
• Endocrine abnormalities
  • May require replacement of specific hormones

Drug therapy

• Corticosteroids
  • Dexamethasone 
    • Dexamethasone Sodium Phosphate Solution for injection; Infants, Children, and Adolescents: 1 to 1.5 mg/kg/dose IV initially, followed by 1 to 1.5 mg/kg/day IV in divided doses every 3 to 4 hours has been used in pediatric patients with severe head injury (n = 24, age 3 months to 14 years). 0.02 to 0.3 mg/kg/day or 0.6 to 9 mg/m2/day IV or IM given in 3 to 4 divided doses is the FDA-approved dosage range. Adjust to patient response.
• Anticonvulsants
  • Phenytoin
    • Cytochrome P450 enzyme inducer
    • Phenytoin Oral suspension; Children and Adolescents: 5 mg/kg/day PO (range: 4 to 8 mg/kg/day PO), divided into 2 or 3 doses per day. If the daily dose cannot be divided evenly, administer the larger dose in the evening. Usual Max: 300 mg/day PO; however, this dosage is sometimes exceeded in clinical practice with careful titration and monitoring. Data suggest the following maintenance doses are often required to maintain plasma concentrations in the therapeutic range: children younger than 3 years: 10 mg/kg/day PO; children 4 to 6 years: 7.5 mg/kg/day PO; children 7 to 9 years: 7 mg/kg/day PO; children and adolescents 10 to 16 years: 6 mg/kg/day PO. Consider at least a 25% reduction of the recommended starting maintenance dose in patients who are intermediate metabolizers of CYP2C9 and at least a 50% reduction of the recommended starting maintenance dose in patients who are poor metabolizers of CYP2C9.
  • Levetiracetam 
    • Does not affect cytochrome P450 isoenzymes
      • Levetiracetam Oral solution; Infants and Children 6 months to 3 years: Initially, 10 mg/kg/dose PO twice daily. Increase dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) to goal of 25 mg/kg/dose twice daily; dose may be reduced if not tolerated.
      • Levetiracetam Oral solution; Children and Adolescents 4 to 15 years: Initially, 10 mg/kg/dose PO twice daily. Increase dose every 2 weeks by 10 mg/kg/dose (i.e., 20 mg/kg/day) to goal of 30 mg/kg/dose twice daily; dose may be reduced if not tolerated.
• Hyperosmolar agents
  • Mannitol
    • Mannitol Solution for injection; Infants, Children, and Adolescents: 0.25 to 2 g/kg/dose IV every 6 to 8 hours as needed.
  • Hypertonic 3% saline
    • Continuous IV infusion dosage
      • Sodium Chloride Solution for injection; Infants, Children, and Adolescents: 0.1 to 1 mL/kg/hour continuous IV infusion. Treat to maintain ICP less than 20 mmHg, CPP between 40 and 50 mmHg, and serum osmolarity less than 320 to 360 mOsm/L. Avoid sustained (more than 72 hours) serum sodium above 160 mEq/L.

Monitoring

• Surveillance neuroimaging (MRI) and clinical assessments are recommended to monitor for progression or recurrence after treatment
• Optimal frequency and duration have not been established; may depend on tumor type and aggressiveness, extent of resection, and adjuvant therapy
• Long-term management may also require endocrine evaluation and vision, hearing, and neurocognitive assessments; requires a multidisciplinary approach
• Long-term follow-up guidelines for survivors of childhood malignancies are published by Children’s Oncology Group and International Late Effects of Childhood Cancer Guideline Harmonization Group 

Complications

• Acute complications
  • Seizures
  • Focal neurologic deficits
  • Raised intracranial pressure
  • Hydrocephalus
  • Acute brain herniation, causing permanent neurologic impairment or death 
• Late complications related to disease or treatment
  • Neurologic impairment (eg, paresis, ataxia, coordination deficits)
  • Cognitive impairment 
  • Neuropsychological and behavioral problems
  • Hearing loss
  • Ophthalmologic complications
  • Endocrine abnormalities (eg, growth hormone deficiency, precocious puberty, delayed puberty, hypothyroidism)
  • Overweight and obesity (secondary to underlying hypothalamic-pituitary dysfunction) 
  • Cerebrovascular complications (eg, stroke)
  • Secondary neoplasms (eg, meningioma; cavernomas; glioblastoma multiforme; acute lymphoblastic leukemia; cancers of the thyroid gland, cervix uteri, and salivary gland)
  • Recurrent disease

Prognosis

• Overall estimated 5- and 10-year relative survival rates are 73% and 69.5%, respectively (for patients aged 0-19 years) 
• However, prognosis varies widely according to tumor histopathology
  • 5-year survival rate is 97% for pilocytic astrocytoma and 18% for glioblastoma 
  • Prognosis for diffuse intrinsic pontine glioma is very poor 
• Other factors influencing prognosis include:
  • Age at diagnosis
    • 5-year survival rate is greater than 75% for medulloblastoma in children older than 5 years but is much lower in younger children 
  • Site of origin
  • Extent of disease at diagnosis
  • Biochemical/molecular tumor cell characteristics
  • Residual tumor burden after resection
• Survivors frequently have neurologic, endocrine, and cognitive complications resulting from tumor itself and/or treatment
  • Risk of complications is greater in patients who are younger at diagnosis (younger than 3 years), who have hydrocephalus, and/or who are treated with cranial radiation therapy
• Late mortality occurs in 15% to 25% of patients who survive beyond 5 years; typically caused by tumor progression, recurrence, or secondary tumors 

References

Stevens RD et al: Emergency neurological life support: intracranial hypertension and herniation. Neurocrit Care. 23(Suppl 2):S76-82, 2015