Brain Tumors

Brain Tumors

Primary brain tumors are the most common solid neoplasms in children and are second only to leukemia in overall frequency during childhood. Brain tumors are the most common cause of cancer-related death and the second most common form of cancer in children.391 Recent advances in neuroimaging (higher resolution, diffusionweighted imaging, newer endoscopes and their surgical implementation to decrease complications) have led to greater survival and decreased morbidity in pediatric brain tumor patients.391 Our understanding of the molecular mechanisms involved in the pediatric brain tumors has also advanced.796 Surgery alone can be curative in a number of tumors, such as pilocytic astrocytomas, craniopharyngiomas, and choroid plexus tumors.391 Surgery in

combination with chemotherapy and radiation therapy can be curative in patients with primitive neuroectodermal tumors and ependymomas.391

Childhood brain tumors differ considerably from the adult variety in incidence, location, histology, morphology, and natural history. Common adult tumors such as meningiomas, schwannomas, pituitary tumors, and metastasis are rare in children. The predilection of adult neoplasms to affect the cerebral hemispheres differs markedly from childhood tumors, wherein approximately 50% of tumors in children older than 1 year are infratentorial. In one study,447 simple signal characteristics on diffusion weighted imaging correlate well with tumor grades in the pediatric population. Perinatal tumors are most often teratomas or tumors of neuroepithelial origin (astrocytoma, glioma, medulloblastoma, choroid plexus papilloma).421

There is concern that children with CNS tumors should be diagnosed sooner after the onset of symptoms.571 Although there is no real evidence that early diagnosis changes life expectancy, smaller tumors can be surgically resected with fewer complications, and gross total resection of several pediatric tumors has been linked to improved outcomes.571 There are several reasons why the diagnosis of a brain tumor can take several months from the onset of symptoms. Headache from migraines in children is at least 1,000 times more prevalent than headache caused by brain tumor. Furthermore, headaches from either increased intracranial pressure or migraine are associated with nausea and vomiting, and both can produce nocturnal distress.571

Finally, the ophthalmoscope (and the ophthalmologist) may be underutilized, so that papilledema is not detected in its early stages.571 Brain tumors often present with visual symptoms and/or educational problems or behavioral problems.945 The vast majority of children with brain tumors have additional neurological symptoms. Symptoms are often nonspecific, depending not only upon the localization of the tumor but the age of the child.728 Pediatric intracranial tumors may present with raised intracranial pressure, motor and visual system abnormalities, weight loss, macrocephaly, growth failure, or precocious puberty.945

Relevant initial history should inquire about early morning vomiting, poor balance (or wobbliness in an infant), motor dysfunction, disturbed vigilance, disturbed eye motility, and a change in growth or weight.728 In addition to neurologic assessment, a carefully taken history with questions about visual symptoms and or educational and behavioral difficulties is helpful in establishing the need for neuroimaging or other diagnostic evaluation. In a review of 200 consecutive children with brain tumors,945 the most frequent presenting complaint was headache (41%). Visual difficulties were noted in 10% and educational or behavioral problems in 10%. Additional neurologic signs were present in almost all cases, and 38% had papilledema. Approximately half of patients presenting with headache had visual complaints. The most common visual symptoms were diplopia (43%) and blurred vision (39%).945

Within the pediatric age group, the distribution of brain tumors differs between infants and older children. Although posterior fossa tumors are generally more common than supratentorial tumors in children, supratentorial tumors (suprasellar gliomas, teratomas, primitive neuroectodermal tumors, choroid-plexus tumors) predominate in infants. In the first 6 months of life, the tumors are more commonly supratentorial than infratentorial; in the second 6 months of life, the incidence is about equal in both locations, and thereafter, a posterior fossa predominance emerges. The younger the child, the more likely the tumor is to be supratentorial.

Brain tumors in infants have protean clinical manifestations that include irritability, listlessness, lethargy, vomiting,

failure to thrive, and hydrocephalus with increasing head circumference and bulging fontanelles.7,20,340,403 Focal neurologic deficits are generally absent because of the immaturity of the brain and the expansile nature of the cranium. Increased intracranial pressure is caused by obstruction of the ventricular system by the mass or, less commonly, by the sheer bulk of a supratentorial mass without ventricular obstruction.705 Vomiting is the most common presenting symptom of infants with brain tumors (as in all age groups). It may result from increased intracranial pressure or from neoplastic involvement of the floor of the fourth ventricle, where the vomiting center is located. In the absence of papilledema, such children may initially be misdiagnosed as having gastrointestinal disease.

Infants with cerebral hemispheric tumors and hemiparesis may be misdiagnosed as having static encephalopathy with hemiparetic cerebral palsy. Seizures are most commonly partial, with elementary symptoms with or without generalization, but infantile spasms may occur. In some infants with brain tumors, infantile spasms show a favorable response to adrenocorticotrophic hormone (ACTH) therapy prior to diagnosis of the tumors.760

Infants with midline tumors may show failure to thrive, endocrine dysfunction, and visual disorders. The diencephalic syndrome of Russell may also be found. This is characterized by profound failure to thrive despite good appetite. Affected children are alert and energetic despite severe emaciation. If the tumor involves the chiasm, decreased vision and nystagmus may be present.

Older children are more likely to show localizing neurological findings (cranial nerve palsy, hemiparesis, clumsiness, ataxia) and often present with recurrent headaches, nausea, vomiting, and visual complaints, which may be ascribed to nonspecific causes, delaying the diagnosis of underlying hydrocephalus and associated tumor. Tumors in the region of the hypothalamus often cause endocrine dysfunction (decreased appetite, failure to thrive), bitemporal hemianopia, or abnormal eye movements (seesaw nystagmus, spasmus nutans-like syndrome). Seizures are generally less common in children with posterior fossa tumors than in children with supratentorial tumors. In a study involving 3,291 children with brain tumors,343 supratentorial tumors were associated with seizures in 22% of children younger than 14 years of age and in 68% of older teenagers. Among children with infratentorial tumors, the prevalence of seizures was approximately 6% in all age groups. The tumor location with the highest incidence of seizures was the superficial cerebrum, with seizures occurring in more than 40% of cases.343 Headaches occur very frequently in children with brain tumors and are commonly, but not exclusively, associated with increased intracranial pressure.

A significant portion of the clinical signs and symptoms in children with brain tumors involves the visual system, either due to direct involvement of related structures in the neoplastic process or due to the mass effect of the tumor with associated hydrocephalus or secondary compression, deformation, or parenchymal shifts. Occasionally, children present initially to an ophthalmologist with visual signs and symptoms. Neuro-ophthalmologic evaluation is also a significant component of the clinical followup of these children.

Signs and symptoms of brain tumors can be nonlocalizing, falsely localizing, or localizing. Tumors are the most common cause of noncommunicating hydrocephalus (obstruction of cerebrospinal fluid [CSF] flow within the ventricular system) in children. The associated increased intracranial pressure gives rise to most of the nonlocalizing signs that include headache, papilledema, and sixth nerve palsy. This constellation of signs and symptoms does not provide specific clues regarding the tumor location. Falsely localizing signs are exemplified by the presence of bitemporal hemianopia in a child with posterior fossa tumor. The field defect results not from direct chiasmal infiltration but rather from compression by an enlarged third ventricle due to tumor-associated hydrocephalus. Once nonlocalizing and falsely localizing signs are excluded, the remaining symptoms and signs are generally related to the location of the tumor. The presence of alternating skew on lateral gaze in a child with brain tumor suggests a lesion in the lower brainstem or the cerebellum, such as a cystic cerebellar tumor or Chiari malformation.409,942

Acute changes in intracranial pressure associated with brain tumors may cause a variety of herniation syndromes characterized by displacement of brain tissue, either downward or, less commonly, upward. These syndromes include uncal, transtentorial, and falcial herniation. Uncal herniation results when a lateralized tumor in the frontal or temporal lobe causes a shift of structures through the tentorial notch into the midbrain. Pupillary-involving oculomotor palsy results from entrapment of the nerve by the herniated uncus on the free edge of the tentorium. Downward displacement of the cerebellar tonsils may result in compression of the medulla. Early signs of tonsilar herniation may include head tilt and a stiff neck, presumably arising from irritation of the cervical roots by the herniated mass.

Although children with posterior fossa tumors often develop paralytic strabismus, some may present with acute comitant esotropia.942 Therefore, the finding of comitancy in acute esotropia is no guarantee that there is no underlying intracranial mass. Acute comitant esotropia that does not fit the classic profile of accommodative esotropia should prompt a search for other neuro-ophthalmologic signs, such as papilledema or nystagmus. The failure to fuse despite satis-

factory postoperative ocular alignment in this setting should also raise concern about an underlying brain tumor.942 Acute comitant esotropia may also occur in the setting of a Chiari malformation.409 Associated gaze-evoked nystagmus or downbeat nystagmus in such a child should suggest this possibility. Acute comitant esotropia in children may also follow minor head trauma or be cryptogenic, and such cases generally lack associated neurologic findings, such as papilledema or nystagmus.186 Children with posterior fossa tumors rarely develop spasm of the near reflex221 or signs and symptoms reminiscent of myasthenia gravis.711,853 When successful treatment of brain tumors produces resolution of cranial nerve palsies, many patients are left with a comitant strabismus from longstanding disruption of fusion or from secondary extraocular muscle contracture.110 Conversely, brain tumors can produce cranial nerve palsies in children with preexisting strabismus. This possibility should be considered when a longstanding comitant strabismus is complicated by diplopia, incomitance, or other signs of extraocular muscle weakness.

Functional imaging techniques such as MR spectroscopy, perfusion imaging, diffusion imaging, and diffusion tensor imaging are increasingly used in the diagnosis and treatment of brain tumors in children.908 However, estimate of tumor size remains the primary imaging endpoint in the evaluation of response to treatment.908 Clinical outcome, measured not only by survival rates but also by the effects of disease and therapy on quality of life, has improved over the past two decades for some tumor types, most notably medulloblastoma and cerebellar astrocytoma.36,656

Suprasellar Tumors

Suprasellar tumors in children include optic pathway gliomas, craniopharyngiomas, germinomas, pituitary adenomas, and others.1a,521,763 Due to the proximity of these tumors to the various structures that comprise the anterior visual pathway, these tumors have a high propensity to cause various neuroophthalmologic symptoms and signs. These include optic atrophy, chiasmal syndrome, papilledema, spasmus nutans, seesaw nystagmus, and bobble-headed doll syndrome. Frisén and Jensen319 have recently found the optic chiasm to be surprisingly robust. Using sensitive perimetric techniques, they found an elevation of 6 mm necessary to produce a visual field defect in 50% of patients, and an additional elevation of 5 mm necessary to produce a visual field defect in 90% of patients.319 In adults with chiasmal syndrome, the findings of symptomatic visual loss, younger age, unilateral optic disc pallor, a relative afferent pupillary defect, and an absolute or complete visual defect, especially one worse inferiorly, is

suggestive of something other than pituitary tumor.587 However, these guidelines cannot be loosely applied to children, who tend to present with visual loss more readily from pituitary adenoma.519,926 The clinical and neuroimaging features of suprasellar tumors in the pediatric age group are detailed in Chap. 4.

Pituitary Adenomas

Most pediatric pituitary adenomas present after the onset of puberty with frequent headaches, changes in visual acuity, and, in girls, menstrual dysfunction. Most are secretory, with prolactinomas being most common.

Children younger than 17 years of age may be diagnosed during evaluations for delayed puberty.740 Pituitary adenomas in the prepubertal period may be more likely to exhibit extrasellar extension or invasiveness.

Pituitary adenomas in children may present with more severe visual loss and a have a greater likelihood of producing optic atrophy prior to presentation. Visual improvement after surgical decompression for pituitary adenomas in children may not be as high for children as in adults and may be more likely to be associated with optic atrophy. Octreotide, a synthetic somatostatin analog, can rapidly improve visual function in some patients with both secreting and nonsecreting pituitary macroadenomas that compress the anterior visual pathways.

Rathke Cleft Cysts

Rathke cleft cysts are benign epithelial lined intrasellar cysts that are believed to arise from remnants of Rathke’s pouch endoderm or neuroepithelium.506,821,964 They are small, asymptomatic, and reported to occur in 2–33% of routine autopsies.699 The most common presenting symptoms are visual impairment, hypothalamic dysfunction, hypopituitarism, and headache.278 Rathke cleft cysts are usually diagnosed in adults, and are frequently asymptomatic in childhood.278,911 MR imaging shows signal variability from hypointensity to hyperintensity on T1-weighted images, and hypointense T2-weighted images, with no enhancement of the cyst wall, no calcification, no solid matter in the cyst, and a “ledge sign” from the constraining effects of the posterior diaphragma sella.475

Rathke cleft cyst must be distinguished from craniopharyngioma and pituitary adenoma. It is thought that craniopharyngioma and Rathke’s cleft cysts have a common origin from the remnants of Rathke’s pouch but with a different histologic differentiation. Rathke cleft cysts are generally intrasellar but may show suprasellar extension. In contrast,

craniopharyngioma appears as a mixed cystic and solid suprasellar tumor. Rarely, chiasmal compression and optic atrophy can result, and surgical resection can produce improvement in the associated visual field defects.699 Rathke cleft cysts require a less aggressive treatment, have a lower incidence of recurrence, and a better visual prognosis. Visual defects, endocrine dysfunction, and headaches improve or resolve with treatment. Transsphenoidal drainage of the cyst with partial excision of the wall is generally effective.596 Rathke cleft cyst must also be distinguished from lymphocytic infundibulo-neurohypophysitis, which produces thickening of the pituitary infundibulum and the pituitary gland, and has been reported to cause recurrent optic neuropathy in a 13-year-old boy.13

Arachnoid Cysts

Arachnoid cysts comprise approximately 1% of nontraumatic intracranial masses.32,937 These cysts consist of clear fluid enclosed in reduplicated layers of arachnoid.726 Their MR signal characteristics are identical to those of cerebrospinal fluid.32 They may originate from maldevelopment of the leptomeninges in the prenatal or early postnatal period.496,726 The most common location for arachnoid cysts is in the middle cranial fossa, where they are generally asymptomatic.726 Aside from the well-known association of large arachnoid cysts with papilledema, obstruction of the cerebrospinal fluid pathway, or intracystic or subdural hematoma24 isolated cranial nerve palsies involving the oculomotor nerve,63,157,416,529 trochlear,645 and abducens nerve,581,772 have been reported. Symptomatic patients are generally treated with cystoperitoneal shunting. This procedure produces resolution of headaches, diplopia, and papilledema, but does not reverse head enlargement, mental retardation, or behavioral problems.24

Cavernous Sinus Lesions

Though rare in children, cavernous sinus lesions can represent a life-threatening condition.522 The finding of single or multiple nontraumatic ocular motor nerve palsies with ocular motor synkinesis, facial pain, or other trigeminal involvement suggests localization to the cavernous sinus. Lesions affecting the cavernous sinus in children include meningioma,939 lymphoma,171,446,518,773,799 rhabdomyosarcoma,522 giant aneurysm,322,469,648 and thrombosis.668 In cases of painful ophthalmoplegia, the diagnosis of Tolosa–Hunt syndrome should also be considered.233,866,962