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review by Hare and Woolf of 432 pediatric brain tumors seen at the - Brainstem glioma (05)
Neurological Institute of New York included only 7 tumors of the - Brainstem glioma (06)
brainstem (Hare and Woolf 1934). In a study evaluating diffuse pontine - Brainstem glioma (07)
gliomas in children, Bailey was one of the first authors to draw - Brainstem glioma (08)
attention to the high frequency of misdiagnosis in this population
- Brainstem glioma (09)
(Bailey 1935). Guillain and colleagues and Globus and colleagues were
- Brainstem glioma (10)
the first to document in detail brainstem tumors affecting the course of
- Brainstem glioma (11)
the aqueduct of Sylvius (Guillain et al 1936; Globus et al 1945). In a
- Brainstem glioma (12)
later review, Guillain was one of the first to document the behavior of
- Brainstem glioma (13)
exophytic brainstem tumors, in a review of 250 intracranial neoplasms
(Guillain et al 1945). The first author to study a population of adult Patient Handouts
patients with brainstem gliomas was White, who evaluated a series of - Brain anatomy
44 patients accumulated over 31 years at the Neurological Institute in - Brain basics
New York (White 1963). The mean age of the patients was 42 years - Brain tumors
(range 17 to 68 years); most of those studied pathologically had - Brain tumors:
astrocytic tumors of various grades. The clinical presentation and symptoms and
course of patients in this adult brainstem glioma series was similar to a diagnosis
comparable series of pediatric patients studied earlier at the - Brain tumors: tumor
types
Neurological Institute.
Web Resources
Clinical manifestations Clinical Trials
The clinical evolution and neurologic findings of adult patients with
- NIH: Gliomas
brainstem gliomas are similar to those seen in children and adolescents
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(White 1963; Tokuriki et al 1986; Maria et al 1993a; Freeman and
- Other articles on this
Farmer 1998; Selvapandian et al 1999; Donaldson et al 2006). The
topic
length of time from onset of symptoms to diagnosis ranges from 2 to
PubMed
10 months in most cases (median 4 to 5 months) and depends on the
- Other articles on this
location of the tumor within the brainstem, the severity of initial
topic
symptoms, and the rapidity of progression of disease. In general, the
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most common initial neurologic complaints consist of gait
- About Web Resources
abnormalities, visual disturbances, weakness, and headache (White
1963; Tokuriki et al 1986; Grigsby et al 1989b; Packer et al 1992;
Maria et al 1993a; Schild et al 1998; Selvapandian et al 1999;
Guillamo et al 2001). Gait disturbance occurs in 40% to 80% of
patients and is caused by weakness or spasticity from pyramidal tract
dysfunction, ataxia, or a combination of these factors. In the study by
White, 77% of an adult cohort of 44 patients complained of gait
disturbance, and in the study by Tokuriki and colleagues, 42% of adult
patients had a similar complaint (White 1963; Tokuriki et al 1986).
Visual disturbances, which develop in 20% to 70% of patients, usually
manifest as diplopia (horizontal more common than vertical). In the
study by White, diplopia was the second most common complaint
(White 1963). Headache and focal weakness develop in 15% to 55% of
adult patients (White 1963; Tokuriki et al 1986; Grigsby et al 1989b).
The headaches can be caused by several mechanisms, including
expansion of the brainstem with traction on surrounding meninges and
varying degrees of hydrocephalus. These headaches often occur in the
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suboccipital region, but their location can vary and may extend into the
upper cervical area. In some patients, there may be a periorbital
component of headache pain. Focal weakness can involve the face as
well as 1 or more limbs and is usually asymmetric. Other common
symptoms that developed in 15% to 40% of patients included
dysarthria, focal numbness of the face or body, dysphagia, nausea and
emesis, hearing loss, vertigo, tinnitus, and personality changes (White
1963; Tokuriki et al 1986; Schild et al 1998; Selvapandian et al 1999).
Dysarthria developed in 40% of patients in the study by White and was
usually caused by disturbance of cerebellar function or corticobulbar
pathways. Focal numbness was described by 35% of patients and
ranged from hemisensory loss to numbness in 1 section of a limb.
Dysphagia was a complaint in 10% to 30% of patients. The level of
swallowing dysfunction can vary from slight difficulty handling liquids or
solids to gross aspiration. Similar to other brain tumor patients, this
group may also underestimate their level of swallowing difficulty
(Newton et al 1994). Nausea, emesis, and other related symptoms
such as gastroesophageal reflux were present in 10% to 30% of
patients and, in rare cases, can be the sole presenting complaint
(White 1963; Wood et al 1985; Tokuriki et al 1986; Mahony et al 1987;
Frank et al 1989; Grigsby et al 1989b; Mann et al 1998). These
symptoms are probably caused by tumor-related compression of the
vomiting center in the floor of the fourth ventricle, nucleus ambiguus,
and dorsal vagal motor nucleus (Frank et al 1989; Mann et al 1998). It
is not uncommon for patients with this type of "gastrointestinal"
presentation to be extensively worked up for gastrointestinal problems
(eg, barium swallow, upper gastrointestinal series, endoscopy), often
delaying the necessary neurologic evaluation and diagnosis. Treatment
of the tumor may result in improvement of these "gastrointestinal"
symptoms (Wood et al 1985; Frank et al 1989). Mann and colleagues
reported a 30-year-old man who developed unremitting emesis over a
21-month period (Mann et al 1998). A complete gastrointestinal workup
was negative and neurologic function was normal. An MRI scan
revealed a small enhancing brainstem tumor in the low midbrain. The
emesis responded dramatically to dexamethasone. Alterations in
personality are well documented in children with brainstem gliomas and
can occur in adults as well; they were present in 15% to 18% of the
patients studied by White (White 1963; Packer et al 1992; Maria et al
1993a).
At the time of diagnosis, the most common neurologic signs of
brainstem gliomas in adults are pyramidal tract and cerebellar
dysfunction, cranial nerve palsies, nystagmus, and gait difficulty (White
1963; Tokuriki et al 1986; Grigsby et al 1989b; Packer et al 1992;
Maria et al 1993a; Schild et al 1998; Selvapandian et al 1999;
Guillamo et al 2001). In 65% to 75% of patients, pyramidal tract
damage is noted, with contralateral weakness in an upper motor neuron
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pattern (White 1963; Tokuriki et al 1986). Over half of these cases will
have hemiparesis or hemiplegia; monoparesis and tetraparesis are
much less common. Two thirds of all patients have associated extensor
plantar responses and asymmetric reflexes. Cerebellar involvement
manifests as gait ataxia, limb dysmetria, or dysarthria in 65% to 80%
of patients, most often caused by damage to corticopontocerebellar
pathways or the cerebellar peduncles (White 1963; Tokuriki et al
1986). Cerebellar dysfunction contributes to the high incidence of
nystagmus in this population and is noted in approximately 80% of all
patients (Miller 1988). The nystagmus is usually horizontal (65% to
70%) and gaze-evoked, less often during primary position.
Infrequently, patients have vertical or rotary nystagmus.
Cranial nerve signs occur in the majority of patients (White 1963;
Tokuriki et al 1986). In general, abnormalities of the lower cranial
nerves (cranial nerves VIII through XII) are more common in adults
than children and are usually caused by medullary tumors (Tokuriki et
al 1986). The most frequent cranial nerve sign is palsy of cranial nerve
VII, manifested by facial weakness in 50% to 80% of patients. Facial
weakness is usually unilateral, but can be bilateral (5% to 7% of
cases). Dysfunction of cranial nerves V (sensory), VI, IX, and X are
next most common, each occurring in 45% to 55% of patients. Facial
sensory loss is ipsilateral and variable in severity and can involve any
or all of the trigeminal divisions depending on the region of tumor
growth. Bulbar dysfunction caused by palsy of cranial nerves IX and X
can range from mild palatal weakness to frank dysphagia, dysarthria,
and aspiration. Decreased hearing is found in 40% to 45% of patients
and can be caused by disturbance of the cochlear nuclei, trapezoid
body, or other structures along the cranial nerve VIII pathways.
Dysfunction of cranial nerves III, V (motor), XI, or XII can be noted in
20% to 30% of patients, whereas palsy of cranial nerve IV is rare.
Other neuro-ophthalmological cranial nerve signs include papilledema,
gaze paralysis (mainly horizontal), and anisocoria, each noted in
approximately 25% of patients in the study by White (White 1963).
Disturbances of sensation are found in 35% to 55% of patients and
usually present as a hemisensory deficit.
Unusual or rare neurologic signs and symptoms that may seem
unrelated to a brainstem neoplasm can develop, such as isolated
inability to sneeze, unilateral astereognosis, symptomatic cataplexy,
isolated knee pain, and pathological emotions (eg, laughter, lability
due to pseudobulbar palsy) (Feinsod et al 1980; Martin et al 1991;
Rutka et al 1991; D'Cruz et al 1994). Uncommon neuro-ophthalmologic
abnormalities can also occur, including relative afferent pupillary
defects, upbeat nystagmus, fatigable ptosis, and false-positive
edrophonium testing for cranial nerve palsies (Gilman et al 1977; Miller
1988; Dirr et al 1989; King et al 1991; Ragge and Hoyt 1992). Facial
myokymia and hemifacial spasm, which typically occur secondary to
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Clinical vignette
A 31-year-old woman with an unremarkable past medical history
initially presented with diplopia. A workup consisting of several
noncontrast CT scans of the brain and a neurologic examination was
essentially normal. The neurologic symptoms progressed over the next
5 months, prompting a second opinion and an enhanced MRI scan of
the brain. The MRI demonstrated an enhancing mass in the left pons,
compatible with brainstem glioma. A biopsy revealed fibrillary
astrocytoma grade II. Postoperatively the patient did well except for
loss of hearing on the left side. No further treatment was offered at
this point. Her neurologic status deteriorated further with significant
weakness and spasticity on the right side, gait instability, and
dysphagia. A follow-up MRI scan 6 months later showed further growth
of the tumor. A second surgery was then performed that removed
tissue that was of higher grade-fibrillary astrocytoma grade III. After
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Etiology
The cells of origin of most brainstem gliomas are transformed
astrocytes. In rare cases, these tumors can occur after transformation
of oligodendroglial cells or ependymal cells or from mixtures of
neoplastic astrocytes and neurons (ganglionic cells; ie, ganglioglioma).
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Epidemiology
The exact incidence and prevalence of brainstem gliomas in adults is
unknown. In children they make up 10% to 20% of pediatric primary
brain tumors (Newton 1994; Freeman and Farmer 1998; Donaldson et
al 2006). Furthermore, approximately 70% to 75% of these neoplasms
develop by 20 years of age (Maria et al 1993a). By comparison, the
incidence in the adult population is estimated to be 9 to 10 times lower
than that in children, roughly 0.5% to 2.0% (White 1963; Tokuriki et al
1986; Linstadt et al 1991; Newton 1994). In a study by Gibbs
examining 1383 primary intracranial tumors in patients aged 16 to 70
years, only 1% were located within the pons or midbrain (Gibbs 1932).
Tokuriki and colleagues reviewed 3044 adult primary brain tumors over
a 35-year period (Tokuriki et al 1986). Intrinsic tumors of the
brainstem were found in 16 cases, an incidence of only 0.52%.
However, in smaller series of brainstem glioma patients, the proportion
of adults may be larger, ranging from 10% to 35% (White 1963;
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Prevention
There are no known measures to prevent the development of a
brainstem glioma in de novo patients or in those at risk from
associated disorders (eg, neurofibromatosis type 1).
Differential diagnosis
The differential diagnosis of brainstem gliomas in adults consists of
other mass lesions or disease processes that can present with a
progressive brainstem syndrome and includes other neoplasms,
parasitic cysts, viral and postviral brainstem encephalitis, infarction,
tuberculoma, demyelinating syndromes, vascular malformations,
abscesses, radionecrosis, and chronic meningitis of various etiologies
(Frank et al 1988; Franzini et al 1988; Abernathy et al 1989; Smith
1990; Maria et al 1993a; Rajshekhar and Chandy 1995; Lakhan and
Harle 2009). Neoplastic considerations include metastases to the
brainstem or posterior fossa, as well as primary brain tumors of the
posterior fossa or skull base such as meningioma, acoustic
schwannoma, dermoid cyst, medulloblastoma, ependymoma, and
epidermoid cyst. Infectious considerations include parasitic cysts from
cysticercosis, which have a predilection for the fourth ventricular
region, tuberculomas or pyogenic abscess formation of the posterior
fossa, viral encephalitis involving the brainstem, and chronic meningitis
with basilar exudate (eg, tuberculosis, cryptococcus neoformans).
Demyelinating syndromes refer mainly to multiple sclerosis, which
often presents with multifocal brainstem signs and symptoms, and to
postinfectious brainstem encephalitis, which is considered to be an
autoimmune-mediated demyelinating process following viral exposure.
In a recent case report, a 48-year-old woman demonstrated a
progressive brainstem syndrome, along with encephalopathy and
hallucinations (Lakhan and Harle 2009). She was thought to have an
acute demyelinating encephalopathy or collagen vascular disease, and
she was treated with plasmapheresis, without benefit. At autopsy, a
large brainstem glioma was noted, which involved the pons, medulla,
and cerebellum. Cerebrovascular processes include brainstem infarction
(although these tend to occur rather acutely), hemorrhage, and various
vascular malformations (ie, arteriovenous malformation, capillary
telangiectasia, cavernous angioma) that can become symptomatic
because of mass effect or spontaneous hemorrhage.
Although CT and MRI will usually help to discriminate between
brainstem glioma and other disease processes within the posterior
fossa, they are not 100% sensitive or specific and may lead on
occasion to false-positive or false-negative diagnoses (Frank et al
1988; Franzini et al 1988; Abernathy et al 1989; Rajshekhar and
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Diagnostic workup
In patients with neurologic signs and symptoms suggestive of a
brainstem glioma, neuroimaging with CT or MRI is the most critical
diagnostic test. These studies should be performed with and without
contrast media for the most accurate visualization of the mass, to
assess the relationship of the mass to other posterior fossa anatomy,
and to assist in differential diagnosis. The appearance of brainstem
gliomas in adults on CT or MRI is similar to that in children. In general,
both CT and MRI demonstrate enlargement and asymmetry within the
brainstem, most commonly the pons, with minimal edema formation
around the tumor (Tokuriki et al 1986; Shibamoto et al 1989; Smith
1990; Packer et al 1992; Maria et al 1993a; 1993b; Donaldson et al
2006). However, MRI has been shown to be superior to CT for
diagnosing brainstem gliomas, with a sensitivity and specificity for
pathology approaching 100% (Bradac et al 1985; Hueftle et al 1985;
Lee et al 1985; Packer et al 1985; Zimmerman et al 1985; Raffel et al
1988; Barkovich et al 1990; Smith 1990; Packer et al 1992; Maria et al
1993a; 1993b; Bognar et al 1994; Fischbein et al 1996). This
improvement in diagnostic accuracy is due to several factors, including
a lack of bone artifact in the posterior fossa, increased sensitivity to
intratumoral water content, and the multiplanar capability of MRI,
especially the midsagittal view. In 10% to 20% of cases, MRI will
detect tumors that are not discernible by CT, especially small, focal
tumors or those that occur within the midbrain. This is important for
patients who have hydrocephalus on CT, but with no evidence on the
scan for an intrinsic brainstem tumor. All of these patients should be
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studied with MRI because some of them will harbor neoplasms that
might benefit from earlier diagnosis and treatment (Raffel et al 1988).
The anatomical configuration within the brainstem, extent of
infiltration, presence of an exophytic component or leptomeningeal
seeding, and degree of enhancement are visualized in more detail with
MRI (Bradac et al 1985; Hueftle et al 1985; Lee et al 1985; Packer et
al 1985; Zimmerman et al 1985; Donahue et al 1998). Despite these
advantages, MRI is similar to CT in its inability to consistently
differentiate between neoplastic and benign lesions or to correlate the
appearance of a given lesion with a specific pathologic diagnosis. In
addition, recent data would suggest that even with MRI, there is
significant interobserver variability in the measurement of diffuse
brainstem gliomas. Because of this variability, the authors suggest that
for clinical trial purposes, the measurements of brainstem gliomas
should be made by a single neuroradiologist (Hayward et al 2008).
When using MRI for the initial assessment of brainstem gliomas, it is
recommended that T1- and T2-weighted nonenhanced imaging, as well
as T1-weighted gadolinium-enhanced imaging, be performed in both
the axial and midsagittal planes (Barkovich et al 1990; Packer et al
1992; Donaldson et al 2006). Doing this will provide the most
information on the size, extent, and other characteristics of the tumor
necessary for treatment decisions such as extent of surgery and design
of radiation ports, and for detailed comparison at follow-up. On
nonenhanced T1-weighted images, brainstem gliomas generally
demonstrate hypointense signal compared to normal white matter
(Hueftle et al 1985; Lee et al 1985; Packer et al 1985; Zimmerman et
al 1985; Barkovich et al 1990; Packer et al 1992; Maria et al 1993a).
On proton density and T2-weighted images, increased signal intensity
is usually noted within the mass. Because the degree of
peritumoral edema is typically insignificant in these tumors, the extent
of abnormal T2-weighted signal is believed to represent bulky tumor
and any associated infiltration. Following administration of gadolinium,
T1-weighted images show variable amounts of enhancement, with
patterns similar to that seen on CT: negligible, ring-enhancing,
partial/focal, and diffuse. The exophytic components of tumors
are usually found in the basilar subarachnoid spaces or cerebellopontine
angles, and they frequently enhance in a diffuse fashion. Disturbance
or encasement of the basilar artery by exophytic tumor in the
prepontine cistern is clearly seen on MRI. Additional features that
can demonstrate enhancement and suggest more aggressive behavior
are subpial extension, subependymal extension, ill-defined tumor
margins, necrosis, and the presence of daughter nodules (Maria et al
1993a; 1993b). The presence of acute or old hemorrhage within tumor
is easily determined by MRI, although it is uncommon at presentation,
occurring in approximately 6.25% of cases as reported in a recent
paper (Broniscer et al 2006). However, symptomatic hemorrhage is
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Management
The role of surgical therapy is more limited for patients with
brainstem gliomas than for patients with tumors at other sites because
of the intrinsic risks of aggressive surgery in this location (Packer et al
1992; Maria et al 1993a; Mursch et al 2005; Donaldson et al 2006).
This is especially true for more diffuse and infiltrative tumors. Despite
these restrictions and limitations, surgical intervention is still an
important aspect of management for many patients with brainstem
neoplasms. The morbidity and mortality associated with surgery of the
brainstem have been substantially reduced over the past 15 to 20 years
due to improved neuroimaging with MRI, advances in microsurgical
instrumentation and technique, use of intraoperative real-time
ultrasound and evoked potential monitoring, application of the CO2
laser and ultrasonic aspirator, and improvements in both open and
stereotactic approaches to the brainstem (Albright and Sclabassi 1985;
Fasano et al 1986; Hood et al 1986; Pimenta et al 1986; Abernathy et
al 1989; Hood and McKeever 1989; Epstein and Wisoff 1990; Rusyniak
et al 1992; Rajshekhar and Chandy 1995). In addition, the application
of computerized 3-D surgical navigation systems for removal of
brainstem tumors has further improved the ability to resect with
minimal morbidity (Wang et al 2000). The ability of MRI to more
accurately define the anatomy and infiltrative extent of brainstem
tumors improves the ability of the neurosurgeon to decide if surgery is
feasible and, more importantly, if it is appropriate (Epstein and Wisoff
1990; Packer et al 1992). By MRI classification, tumors most amenable
to surgical intervention include focal lesions of the midbrain or pons,
cystic astrocytomas without cyst wall enhancement, cervicomedullary
neoplasms, and the exophytic components of tumors (Epstein and
Wisoff 1988; 1990; Giunta et al 1989; Barkovich et al 1990; Bricolo et
al 1991; Packer et al 1992; Pollack et al 1993; Freeman and Farmer
1998; Selvapandian et al 1999; Wang et al 2000; Yeh et al 2002).
Real-time ultrasound imaging has been reported by many authors as an
excellent method during surgery to verify tumor location, depth, and
boundaries (Fasano et al 1986; Rusyniak et al 1992). Variations in
echogenicity allow for differentiation of solid tumor from areas of
calcification, cyst, and edema. Similarly, the use of evoked potentials
(auditory or somatosensory) during surgery allows for real-time
monitoring of potential damage to the brainstem and often decreases
morbidity (Albright and Sclabassi 1985; Fasano et al 1986; Epstein and
Wisoff 1990; Rusyniak et al 1992). Significant improvements in
computerized CT- and MRI-guided stereotactic techniques have also
contributed to the reduction of surgical morbidity and mortality
associated with brainstem tumors. In the majority of reports, surgical
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patients with brainstem gliomas. The earliest study was from Edwards
and colleagues, who evaluated 19 adults as part of a larger cohort in a
phase I-II trial of 100 cGy twice a day to a total dose of 7200 cGy
(Edwards et al 1989). After the completion of radiotherapy, the
majority of patients had stable disease as indicated by MRI, whereas
less than a third showed reduction in tumor volume. The median
survival was 7.6 months, with a median time to tumor progression of
5.5 months. In the study by Linstadt and colleagues, 14 adult patients
were treated with hyperfractionated radiation (100 cGy twice a day) to
a median dose of 7200 cGy (Linstadt et al 1991). All but 1 patient
improved or remained neurologically stable following treatment. The
3-year actuarial survival rate was 59%, with a projected median
survival in excess of 5 years. However, there were no glioblastoma
multiforme patients in this cohort; most had moderately anaplastic
astrocytomas. Shrieve and colleagues analyzed the results of a cohort
that included 45 adult patients who received between 6600 and 7800
cGy of hyperfractionated radiotherapy (Shrieve et al 1992). The
median survival was 15.8 months, with 1- and 2-year survival rates of
68% and 53%, respectively. Survival was not significantly different for
patients who received doses greater than 7200 cGy and those with
doses less than or equal to 7200 cGy. When comparing these results
with their previous experience in adult brainstem glioma patients using
conventional radiotherapy, there was a trend toward improved outcome
with hyperfractionation (p = 0.08). Their conclusion was that
hyperfractionated radiotherapy was an effective treatment for adults
with brainstem gliomas and that 7200 cGy was the preferred dosage. In
a review of patients who had received 7800 cGy of hyperfractionated
radiotherapy, Prados and colleagues included 45 adults (Prados et al
1995). Tumor size, as indicated by CT or MRI, decreased in 30%, was
stable in 39.5%, and increased in 29.6%. The median survival of the
adult patients was 16.1 months, with a median time to tumor
progression of 11.4 months. The median survival was almost identical
to that reported by Shrieve and colleagues using 7200 cGy, prompting
the authors to conclude that hyperfractionated radiation therapy to
7800 cGy did not improve survival and was associated with greater
toxicity. Several studies in adults and children suggest that
hyperfractionated protocols do not impart a survival advantage over
conventional radiation treatment (Botturi and Fariselli 1998; Freeman
and Farmer 1998; Schild et al 1998; Mandell et al 1999; Hargrave et al
2006). In a pediatric study by Mandell and colleagues, 132 children with
diffuse brainstem tumors were randomized to receive either
conventional (180 cGy/day, 5400 cGy total) or hyperfractionated (117
cGy twice per day, 7020 cGy total) irradiation over 6 weeks in
combination with cisplatin chemotherapy (Mandell et al 1999). The
median time to progression was 6 months for conventional therapy and
5 months for hyperfractionated treatment. Similarly, median survival
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was 8.5 months for conventional therapy and 8 months for patients
receiving hyperfractionation. In a study from the Mayo Clinic, 40
patients (median age 29.5 years) with brainstem tumors were reviewed
for response to irradiation; 9 of the patients received hyperfractionated
therapy (Schild et al 1998). No survival advantage could be
demonstrated in the cohort treated with hyperfractionated radiotherapy.
In an attempt to improve efficacy of radiotherapy, several
investigators have begun to use radiosensitizers. Marcus and colleagues
added etanidazole, a hypoxic-cell sensitizer, to 66 Gy of
hyperfractionated irradiation in a phase I study of 18 children with
brainstem glioma (Marcus et al 2003). The maximum tolerated dose of
etanidazole was 42 mg/m2, with cutaneous rash as the dose-limiting
toxicity. A similar phase I study by Sanghavi and colleagues used
topotecan in combination with conventional radiotherapy for 17 children
with brainstem tumors (Sanghavi et al 2003). Topotecan is a
topoisomerase I inhibitor that is known to convert sublethal radiation-
induced DNA damage into lethal double-strand DNA breaks. The
maximum tolerated dose of topotecan was 0.40 mg/m2 per day during
radiotherapy, with neutropenia as the dose limiting toxicity. A
subsequent phase II study of topotecan and concomitant irradiation
used the same dosing schedule in a series of 32 patients with
malignant diffuse brainstem gliomas (Bernier-Chastagner et al 2005).
In 40% of the cohort, partial responses were noted. However, the
responses were short-lived, and the 12-month survival rate was only
25.5%. In addition, the overall median survival was only 8.3 months,
similar to other studies of radiation therapy alone. The authors
concluded that the addition of topotecan could not be recommended.
Another recent approach has been to add weekly RMP-7 (300 ng/kg)
and intravenous carboplatin (35 mg/m2 per day) during the course of
irradiation in a phase I trial of newly diagnosed brainstem glioma
patients (Packer et al 2005). RMP-7 is a bradykinin analog that
transiently increases permeability across the blood-brain barrier and
may allow higher concentrations of carboplatin to reach tumor cells.
The treatment was relatively well tolerated, but no conclusions could be
drawn regarding efficacy of the protocol, although the estimated
median survival of the cohort was more than 11 months. A similar
phase II study using a different dosing regimen of RMP-7 (600 ng/kg)
and intravenous carboplatin (target AUC of 3.5 mg per min/ml per day)
was applied to 12 patients with brainstem and other high-grade gliomas
(Warren et al 2006). Although the regimen was relatively well tolerated
except for hematological toxicity, none of the brainstem glioma
patients responded.
Although brachytherapy has demonstrated improved survival for
patients with supratentorial gliomas, few authors have applied this
technique to brainstem tumors because of the inherent dangers of
radiation exposure in this location. Mundinger and colleagues have used
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survival was 20.7 months. A recent report describes the use of Gamma
Knife as the primary method of treatment in 20 patients with focal
brainstem lesions (Yen et al 2007). There were 4 complete responses
and 12 partial responses/minor responses during a mean follow-up
period of 78.0 months. The remaining patients were stable or clinically
improved.
A recent report by Combs and colleagues described the results of
using fractionated stereotactic radiosurgery in a cohort of 85 patients
with brainstem gliomas (Combs et al 2009). The median age at
primary diagnosis was 26 years of age, with only 31 patients under 18
years of age. A median dose of 54 cGy was administered in 1.8 Gy
fractions to a median target volume of 101 mL. The median
progression-free survival (PFS) was 52 months, with PFS rates at 12
and 24 months of 70% and 63%, respectively. Radiosurgery was well
tolerated and did not appear to have a dose-response relationship in
this group of patients.
Patients who are suspected of having leptomeningeal metastasis from
a brainstem glioma should be evaluated on an individual basis and, if
clinically indicated, undergo an evaluation of CSF (including cytology
and tumor markers such as beta-glucuronidase and beta2-
microglobulin), MRI of the spine with gadolinium, and myelography
(Packer et al 1983; 1992). In patients without evidence of infection,
abnormal levels of tumor markers can improve diagnostic sensitivity.
Patients with proven leptomeningeal seeding should then be considered
for craniospinal axis irradiation and intrathecal chemotherapy. Typical
doses for craniospinal axis irradiation are 3000 to 3500 cGy. In patients
with clinical and imaging evidence for focal bulky involvement by
leptomeningeal tumor, radiation can be administered to a localized
field with generous margins, using doses of 3500 to 4500 cGy.
Over the past 2 decades, chemotherapy has had little impact on the
overall survival of patients with brainstem gliomas (Packer et al 1992;
Maria et al 1993a; Freeman and Perilongo 1999; Donaldson et al 2006;
Hargrave et al 2006). The vast majority of data regarding
chemotherapy are from the pediatric literature, as summarized by
Maria and colleagues (Maria et al 1993a). A compilation of 18 studies
using various chemotherapy regimens for brainstem tumors in children
encompasses 261 patients. Of this cohort, 48 patients (18.4%)
responded, including 21 with partial responses and 27 with stable
disease; there were no complete responses. The most effective single
agents were carboplatin and cyclophosphamide. Unfortunately, all of
the responses were brief, as tumors rapidly progressed through
chemotherapy. A phase III trial of irradiation with or without adjuvant
lomustine, vincristine, and prednisone was reported by Jenkin and
colleagues (Jenkin et al 1987). The overall 5-year survival rate was
20% for both groups, suggesting that chemotherapy did not
significantly affect outcome. In the study by Levin and colleagues, 28
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Pregnancy
Pregnancy does not affect the clinical behavior of brainstem gliomas.
Anesthesia
Several anesthetic concerns specific to brainstem gliomas are not
typically encountered with other brain tumors. In rare patients,
especially adults, tumors may involve regions within the medulla or
pons that affect respiration and blood pressure control (Rodriguez et al
1982; Hsu et al 1984; Tobias and Heideman 1991; Valente et al 1993).
Apnea, hypoventilation, and hyperventilation may occur when a
brainstem tumor damages the lower brainstem pathways and nuclear
regions responsible for respiratory control (Rodriguez et al 1982; Kuna
et al 1991; Tobias and Heideman 1991; Valente et al 1993). The
alterations in PaO2, PaCO2, and pH caused by these respiratory
conditions may affect the approach to anesthesia. Abnormal blood
pressure control, especially orthostatic hypotension and secondary
cardiac syncope, can also develop in these patients due to disturbances
of central autonomic control and the afferent arc of the baroreceptor
reflex (Hsu et al 1984). In those patients particularly at risk, cardiac
pacing should be considered.
In addition, concerns regarding the presence or absence of elevated
intracranial pressure during the induction, maintenance, and emergence
from anesthesia are common to surgical therapy of any brain tumor
(LaSala et al 1991). In patients with brainstem gliomas who have
elevated intracranial pressure, care should be taken with
premedications to avoid agents that produce excessive sedation and
ventilatory depression, as these could exacerbate intracranial pressure.
Hypotonic fluids should also be avoided whenever possible. During the
induction and maintenance of anesthesia, agents should be chosen that
minimize hypertension, cerebral vasodilation, chest wall rigidity, and
hypercapnia (LaSala et al 1991).
The author would like to thank Dr. Carl Boesl for his efforts in
preparing the neuropathological slides and Mr. David Carpenter for
expert editorial assistance.
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ICD codes
ICD-9:
Malignant neoplasm of brain stem: 191.7
ICD-10:
Malignant neoplasm of brain stem: C71.7
OMIM
Glioma of brain, familial: #137800
Associated disorders
Medullary astrocytoma
Midbrain astrocytoma
Neurofibromatosis type 1
Pilocytic brainstem glioma
Pontine astrocytoma
Related summaries
Brainstem gliomas in childhood
Cerebellar astrocytoma
Low-grade gliomas (astrocytomas)
Malignant astrocytomas
Neurofibromatosis type 1
Neurofibromatosis type 1 and intracranial neoplasms of childhood
Pilocytic astrocytoma in adults
Differential diagnosis
other mass lesions or diseases
progressive brainstem syndrome
other neoplasms
parasitic cysts
viral brainstem encephalitis
postviral brainstem encephalitis
infarction
tuberculoma
demyelinating syndromes
vascular malformations
abscesses
radionecrosis
chronic meningitis
metastases to brainstem or posterior fossa
primary brain tumors of posterior fossa or skull base
meningioma
acoustic schwannoma
dermoid cyst
medulloblastoma
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ependymoma
epidermoid cyst
viral encephalitis involving brainstem
chronic meningitis with basilar exudate
tuberculosis
cryptococcus neoformans
multiple sclerosis
postinfectious brain encephalitis
brainstem infarction
brainstem metastases
hemorrhage
vascular malformations
arteriovenous malformation
capillary telangiectasia
cavernous angioma
nonneoplastic lesion
nonspecific chronic inflammation
granulomatous inflammation
epidermoid cyst
pyogenic abscess
cryptococcal abscess
cysticercosis
encephalitis
posterior fossa metastases
Demographics
For more specific demographic information, see the Epidemiology,
Etiology, and Pathogenesis and pathophysiology sections of this clinical
summary.
Age
19-44 years
45-64 years
65+ years
Population
None selectively affected.
Occupation
None selectively affected.
Sex
male=female
Family history
family history may be obtained
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Heredity
heredity may be a factor
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