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Overview
Background
Brainstem gliomas are tumors that occur in the region of the brain referred to as the brain
stem, which is the area between the aqueduct of Sylvius and the fourth ventricle. Although
various systems are used to classify these tumors, the authors have divided brainstem gliomas
into 3 distinct anatomic locations—diffuse intrinsic pontine,[3] tectal, and cervicomedullary.
Intrinsic pontine gliomas carry a grave prognosis. Longer survival is associated with the
tectal and cervicomedullary gliomas. Tumors also are characterized on the basis of site of
origin, focality, direction and extent of tumor growth, degree of brainstem enlargement,
degree of exophytic growth, and presence or absence of cysts, necrosis, hemorrhage, and
hydrocephalus.[4]
Pathophysiology
These tumors have a predilection to originate from the left side. Most are located in the pons;
however, medulla and midbrain may be involved as well. Brainstem gliomas are highly
aggressive brain tumors. Anatomic location determines the pathophysiological manifestation
of the tumor. With tectal lesions, hydrocephalus may occur as a result of fourth ventricular
compression. With pontine and cervicomedullary lesions, cranial nerve or long tract signs are
observed commonly.
Histopathologically, brainstem gliomas can range from WHO Grade 1 to 4. Grade 1 is the
juvenile pilocytic astrocytoma, Grade 2 is the diffuse astrocytoma, Grade 3 is the anaplastic
astrocytoma, and grade 4 is the glioblastoma multiforme. The grading is based on the
presence of nuclear atypia, vascular proliferation, mitoses, and necrosis. Typically, the
necrosis is seen in Grade 4 (glioblastoma multiforme).
Brainstem gliomas have been reported to make up 2.4% of all intracranial tumors in adults
and 9.4% of intracranial tumors in children. Brainstem gliomas account for approximately
10-20% of all childhood brain tumors. The incidence in adults is lower than that in children
younger than 16 years. A tendency for brainstem gliomas to follow a more indolent course in
adults than in children has been noted; in adults, these tumors are more likely to be low grade
and remain localized.
Mortality/Morbidity
Sudden death can result from increased intracranial pressure and subsequent cerebral
herniation. This may be a consequence either of edema induced by the tumor or of
hemorrhage into the neoplasm.
Epidemiology
Race-, sex-, and age-related demographics
CNS tumors vary in incidence by age, sex, ethnic group, and country, and also over time.
How much of this variation is due to artifactual influences or etiologic differences has been
the subject of many debates.
Some reports have suggested a slight male preponderance, whereas others have failed to
observe any sex predilection.
Bimodal age distribution has been noted, with a peak incidence in the latter half of the first
decade of life and a second peak in the fourth decade. Approximately three fourths of patients
are younger than 20 years.
Neoplasms of the brain stem have been identified in children younger than 1 year.
Presentation
History
Common presenting symptoms include double vision, weakness, unsteady gait, difficulty in
swallowing, dysarthria, headache, drowsiness, nausea, and vomiting. Rarely, behavioral
changes or seizures may be seen in children. Older children may have deterioration of
handwriting and speech.
Pontine lesions usually present with any or all of the above signs and symptoms, depending
on location and extension. Midbrain and lower brainstem/upper spinal cord signs and
symptoms may be seen with extension of the neoplasm to involve these structures.
In infants and children presenting with failure to thrive, pontine glioma should be considered
in the differential diagnosis.
Physical
Common clinical findings can be summarized as constituting a triad of cranial nerve deficits,
long tract signs, and ataxia (of trunk and limbs). Papilledema may be seen.
Sixth and seventh cranial nerves are involved commonly. Facial sensory loss and a primary
position, upbeating nystagmus may be seen. Involvement of cranial nerve III or IV suggests a
mesencephalic component.
Cervicomedullary lesions may present with sensory loss of the face (involvement of the
trigeminal nucleus), dysphagia and/or dysphonia from lower cranial nerve involvement
(commonly IX and X), long tract signs, and ataxia. Downbeating nystagmus and
oculomyoclonus often are seen with medullary involvement.
Causes
Thus far, no genetic or molecular markers have been recognized for brainstem gliomas.
In children irradiated for tinea capitis, an increased incidence of CNS tumors, especially
meningiomas, gliomas, and nerve sheath tumors, has been reported. No specific reference is
made in these reports to tumors of the brain stem. Radiotherapy-induced neoplasms tend to
be more aggressive in their natural history than their de novo counterparts.
Differential Diagnoses
Brain Metastasis
Glioblastoma Multiforme
Low-Grade Astrocytoma
Meningioma
Neurosarcoidosis
Pediatric Ependymoma
Pediatric Medulloblastoma
Tolosa-Hunt Syndrome
Vascular Surgery for Arteriovenous Malformations
Workup
Laboratory Studies
Lab studies of blood chemistry and related body fluids are not helpful as a rule, though
cerebrospinal fluid (CSF) examination is often important for differential diagnosis. The
protein content of CSF may be elevated. Because of the risk of increased intracranial pressure
due to obstructive hydrocephalus, caution in clinical and imaging assessment prior to lumbar
puncture is stressed.
Imaging Studies
MRI
MRI of the head is the diagnostic test of choice. MRI can differentiate vascular
malformations and other processes that can be misdiagnosed as a brainstem glioma on CT
scan.[6]
The typical MRI appearance of a brainstem glioma is an expansile, infiltrative process with
low-to-normal signal intensity on T1-weighted images and heterogeneous high-signal
intensity on T2-weighted images, with or without contrast enhancement (see the images
below).
MR spectroscopy has been used to help distinguish between tumor and nontumor lesions in
the brain. An elevated choline peak suggests neoplasm.
MRI can delineate the extent of infiltration of the leptomeninges and the surrounding
structures.
High midbrain tumors, especially those arising in the tectum, are typically low-grade lesions
by histologic criteria. They commonly appear hypointense on T1 and hyperintense on T2
images even without contrast enhancement.
CT scan
Although CT imaging is an appropriate choice when MRI is not available, the appearance of
brainstem gliomas is variable on CT scan, and the sensitivity of and characterization of
tumors by CT are poorer.
Other Tests
Procedures
Typically, biopsy is not required for diagnosis of diffuse intrinsic pontine or tectal gliomas,
and cannot be recommended routinely; diagnosis can be made by MRI alone. Especially in
clinical trials, however, biopsy of diffuse intrinsic pontine gliomas can be used to ascertain
biological characteristics of the tumor, which may enhance understanding and targeting of
treatments.
Tissue confirmation is frequently not feasible with infiltrating, expansile tumors unless an
exophytic component exists. Even then, a biopsy cannot always be obtained.
Histologic Findings
The histopathology is variable; most gliomas in the brain stem are fibrillary, pilocytic
astrocytomas, or the more malignant glioblastoma multiforme. Hemorrhage and necrosis are
associated with the more malignant forms. Cysts may be seen with either the high- or low-
grade forms.
Treatment
Medical Care
Treatment of brainstem gliomas has been frustrating; at this point, new therapies have yielded
little benefit over conventional treatment with radiotherapy alone.
Adjuvant chemotherapy is not used in children because efficacy has not been proven. Data
have suggested that preradiation chemotherapy may improve survival in pediatric diffuse
intrinsic brainstem gliomas.[2] Its efficacy in adults is similarly unproven, and at present,
postradiotherapy adjuvant chemotherapy cannot be recommended. The effectiveness of
combined radiotherapy and chemotherapy (typically temozolomide) has not been thoroughly
evaluated. The effectiveness of chemotherapy at relapse is uncertain, but it may benefit some
patients.
Chemotherapy options, when considered for use in brainstem gliomas, may include
conventional agents such as temozolomide and carboplatin/vincristine. Antiangiogenesis
agents have been used with success in supratentorial glioblastomas. These include
thalidomide and bevacizumab. Bevacizumab is a VEGF receptor inhibitor, approved as
monotherapy for recurrent glioblastoma multiforme in May 2009.[7] Drugs (such as erlotinib)
targeted against EGFR, when present, have been modestly effective in supratentorial
glioblastoma. If chemotherapy is desired adjuvantly or concurrently with radiotherapy,
particularly in the pediatric population, the physician should consider entrance into a clinical
trial.
Focal radiotherapy is the cornerstone of treatment of brainstem gliomas and can improve or
stabilize the patient's condition.[1] The conventional dose of radiotherapy ranges from 54-60
Gy, with doses up to 72 Gy given with hyperfractionation. At present, no benefit has been
demonstrated with doses greater than 72 Gy; however, this therapy has not demonstrated
efficacy in children.
Surgical Care
Typically, surgery is not required for treatment of diffuse intrinsic pontine gliomas or tectal
gliomas.
Ancillary Procedures
Patients with difficulties in swallowing and diminished gag reflex may need feeding by
gastrostomy, such as percutaneous esophagogastrostomy (PEG).
Those patients who have had multiple upper respiratory infections, pneumonia, or altered
voice may need postoperative ventilatory assistance.
Consultations
Neuro-oncologist: The neuro-oncologist should be the primary physician supervising the care
of these patients. If a neuro-oncologist is not available, a medical oncologist with expertise
in treating brain tumors may be consulted for guidance. Otherwise, the patient should be
referred to a reputable institution that specializes in the care of patients with CNS
neoplasms.
Neurosurgeon: The treating neurosurgeon should have significant experience in resection of
CNS neoplasms.
Radiation oncologist
Neuropathologist
Neuroradiologist
Neuropsychologist for pretreatment and posttreatment evaluations, when clinically
indicated
Rehabilitation medicine specialist
Medication
Medication Summary
Corticosteroids
Class Summary
These agents have anti-inflammatory properties and cause profound and varied metabolic
effects. Corticosteroids modify the body's immune response to diverse stimuli.
Dexamethasone (Decadron)
Follow Up
Further Outpatient Care
Typically, patients are monitored for worsening signs/symptoms. Admission to the hospital
may be required to enable therapeutic intervention and stabilization.
Complications
Prognosis
Pontine tumors are the most common variety of brainstem tumor. They also carry the worst
prognosis; in children, the median survival duration is 9-12 months even with treatment.
Kaplan et al reported a 37% survival rate at 1 year, 20% at 2 years, and 13% at 3 years, with a
median survival of 10 months. Only 9 of 119 patients in their study were alive for more than
3 years after diagnosis.[8]
Squires et al, in a study of 12 children with midbrain tectal tumors, reported a median
survival duration of more than 50 months.[9]
Poor prognostic indicators include (1) age younger than 2 years, (2) multiple brainstem signs,
(3) cranial nerve palsies, (4) diffuse intrinsic lesions of the pons, (5) short duration of signs
and symptoms prior to the time of diagnosis, and (6) high-grade histology on tumor biopsy.
The limited available data suggest that adults fare better than children with brainstem
gliomas.
Grigsby et al reported a 10-year disease-free survival rate of 15.4% for adult patients with
gliomas involving the midbrain, thalamus, or hypothalamus, and 29.6% for adults with
pontine or medullary tumors. However, thalamic/hypothalamic neoplasms are not included
historically in the classification of brainstem tumors. [10]
Landolfi et al studied 19 adults with brainstem gliomas, which included 13 diffuse intrinsic
pontine, 4 cervicomedullary, and 2 tectal gliomas. They noted a trend that higher Karnofsky
performance status conferred a better prognosis. Other factors did not affect survival.
Median survival duration of patients in this study was 54 months, with a 5-year survival rate
of 45%. [11]
Hamilton et al studied 16 adults with focal midbrain gliomas; they reported a median
survival of 84 months. This indolent growth pattern is in marked contradistinction to the
natural history of this disease in children. This is also the reverse of the usual behavior of
hemispheric gliomas in which children typically fare better than older patients. [12]
Kesari et al reported on 101 adult patients with brainstem glioma. The overall survival for all
patients at 5 and 10 years was 58% and 41%, respectively. The median survival was 85
months. They identified 4 factors that were significantly associated with survival in adults
with brainstem gliomas. These factors included ethnicity, tumor location, age at diagnosis,
and tumor grade. [13]
No explanation has been identified for the better outcome in adults; however, the possibility
of prolonged survival with limited neurologic impairment must be recognized when
counseling adults with brainstem gliomas.
Patient Education
Patients and families of patients acquire information from multiple sources, including, but not
limited to, physician, patients, support groups, pharmaceutical companies, and the Internet.
Physicians should be aware of this and have an open, informative relationship with their
patients, empowering patients to become active members of the team with regard to the
decision-making process involving their care.
Hyperosmolar agents
Class Summary
These agents may reduce ICP and cerebral edema by creating an osmotic gradient across an
intact blood-brain barrier. As water diffuses from the brain into the intravascular
compartment, ICP decreases.
Mannitol (Osmitrol)
May reduce subarachnoid space pressure by creating osmotic gradient between cerebrospinal
fluid in arachnoid space and plasma. Not for long-term use.