Neurologic Manifestations of Glioblastoma Multiforme 

Updated: Nov 09, 2015
Author: ABM Salah Uddin, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA 

Overview

Background

Glioblastoma multiforme (GBM) is the most common and most aggressive of the primary brain tumors. The current World Health Organization (WHO) classification of primary brain tumors lists GBM as a grade IV astrocytoma.[1] Astrocytoma is one of 3 distinct types of gliomas in the brain, although mixed cell types occur as well. GBMs are highly malignant, infiltrate the brain extensively, and at times may become enormous before turning symptomatic. See the image below.

T1-weighted axial gadolinium-enhanced MRI demonstr T1-weighted axial gadolinium-enhanced MRI demonstrates an enhancing tumor of the right frontal lobe. Image courtesy of George Jallo, MD.

 

Pathophysiology

GBM is an anaplastic, highly cellular tumor with poorly differentiated, round, or pleomorphic cells, occasional multinucleated cells, nuclear atypia, and anaplasia. Under the modified WHO classification, GBM differs from anaplastic astrocytomas (AA) by the presence of necrosis under the microscope. Variants of the tumor include gliosarcoma, multifocal GBM, or gliomatosis cerebri (in which the entire brain may be infiltrated with tumor cells). These variants, however, do not alter the prognosis of the tumor. Multifocal metastasis of GBM, including far distant spinal drop metastasis in patients treated with antiangiogenic chemotherapy[2] , is extremely rare but is increasing. Two reasons for the metastasis are an antiangiogenic therapy – induced activation of glioma invasion[3] and the fact that patients are living longer.[4]

Epidemiology

Frequency

Among primary brain tumors, malignant astrocytomas are the most common in all age groups. (However, among all brain tumors, metastases are the most common.) GBMs are the most common primary brain tumors in adults, accounting for 12-15% of intracranial tumors and 50-60% of primary brain tumors. Several authors have reported a true increase in the incidence of brain tumors, especially among the elderly, and many have attributed the observed changes to developments in diagnostic imaging or changes in the classification system.[5]

International incidence of GBM is similar to that of the United States.

Mortality/Morbidity

Morbidity is from the tumor location, progression, and pressure effects. The overall prognosis for GBM has changed little in the past 2 decades, despite major improvements in neuroimaging, neurosurgery, radiation treatment techniques, adjuvant chemotherapy, and supportive care. Few patients with GBM survive longer than 3 years and only a handful survive 5 years. Previously reported long-term survivors of GBM may be patients diagnosed with GBM who actually harbor low-grade glioma, pleomorphic xanthoastrocytoma, ganglioglioma, or other lesions. Occasional patients with a single necrotic, demyelinating plaque of multiple sclerosis also may be misdiagnosed with GBM, especially if only CT scans are obtained.

Race-, sex-, and age-related demographics

High-grade astrocytomas (HGAs) are slightly more common in whites than in blacks, Latinos, and Asians.

GBM is slightly more common in men than in women; the male-to-female ratio is 3:2.

While GBM occurs in all age groups, its incidence is increasing in elderly patients. A true increase in incidence of primary brain tumors exists, which cannot be explained by the aging population, better imaging techniques, or earlier detection at surgery.

 

Presentation

History

Glioblastoma multiforme (GBM), like other brain tumors, produces symptoms by a combination of focal neurologic deficits from compression and infiltration of the surrounding brain, vascular compromise, and raised intracranial pressure. Presenting features include the following:

  • Headaches (30-50%): Headaches are nonspecific and indistinguishable from tension headache. As the tumor enlarges, it may have features of increased intracranial pressure.

  • Seizures (30-60%): Depending on the tumor location, seizures may be simple partial, complex partial, or generalized.

  • Focal neurologic deficits (40-60%): As some patients with GBM survive longer, an increasing number of patients experience cognitive problems, neurologic deficits resulting from radiation necrosis, communicating hydrocephalus, and occasionally cranial neuropathies and polyradiculopathies from leptomeningeal spread.

  • Mental status changes (20-40%): With the advent of MRI, GBMs are increasingly diagnosed at an earlier stage and with subtle personality changes.

Physical

Physical findings depend on the location, size, and rate of growth of the tumor, as with any other CNS tumor. Tumors in less critical areas (eg, anterior frontal or temporal lobe) may present with subtle personality changes and memory problems. Similarly, motor weakness and sensory hemineglect are the hallmarks of tumors arising in the frontal or parietal lobes and thalamic regions. Sensory neglect is more prominent in right hemispheric lesions. Note the following:

  • Seizures are a common presentation of small tumors in the frontoparietal regions (simple motor or sensory partial seizure) and temporal lobe (simple or complex partial seizure).

  • Occipital lobe tumors may present with visual field defects. Although these tumors are less frequent than tumors originating at other sites, patients generally are unaware of the slow onset of a cortically based hemianopsia.

  • Brainstem GBMs are rare in adults. However, they may present with bilateral crossed neurological deficits (eg, weakness on one side with contralateral cranial nerve palsy). Alternatively, they may present with rapidly progressive headache or altered consciousness.

Causes

The etiology of GBM is unknown. However, at least 2 genetic pathways have been delineated in its development: de novo (primary) glioblastomas and secondary glioblastomas. De novo glioblastomas are most common. De novo GBM develops in older patients and demonstrates a high rate of epidermal growth factor receptor (EGFR) overexpression, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutations, and p16INK4A deletions. In contrast, secondary GBM develops in younger patients and develops from a malignant transformation of a previously diagnosed low-grade tumor. TP53 and retinoblastoma gene (RB) mutations are more common in the development of secondary glioblastomas.

Several genetic disorders are associated with increased incidence of gliomas (eg, tuberous sclerosis, neurofibromatosis type 1 and type 2, Turcot syndrome, Li-Fraumeni syndrome). An association exists between ionizing radiation and astrocytomas. Children who receive low-dose intracranial radiation have a 2.6-fold increase in prevalence of astrocytomas, and prophylactic whole-brain radiation therapy in patients with acute lymphocytic leukemia increased the incidence of astrocytomas 22-fold.

Other suspected risk factors, such as electromagnetic radiation and cellular telephone use, are yet to be substantiated by large epidemiologic studies. However, researchers reviewed 16 published studies that looked at cell phone use and the risk of brain cancers and concluded that using cell phones for more than 10 years gives a consistent pattern of increased risk of at least 2 types of brain cancer such as acoustic neuroma and gliomas. The risk is significantly higher for the ipsilateral exposure (tumor on the same side of the brain as cell phone exposure).[6]

 

DDx

 

Workup

Laboratory Studies

Routine laboratory workup results often are negative, but excluding a metabolic or infective process is important in an otherwise healthy patient who presents with new-onset seizures or mental status changes for the first time.

Imaging Studies

The preferred workup is diagnostic neuroimaging studies; MRI with and without contrast is the most sensitive and specific study. These tumors characteristically have low-signal intensity on T1-weighted images and high-signal intensity on T2-weighted images. With contrast, the tumors usually enhance. The enhanced T1-weighted images typically have a central hypodensity surrounded by a thick enhancing rim of tumor. See the images below.

T1-weighted axial gadolinium-enhanced MRI demonstr T1-weighted axial gadolinium-enhanced MRI demonstrates an enhancing tumor of the right frontal lobe. Image courtesy of George Jallo, MD.
T2-weighted image demonstrates notable edema and m T2-weighted image demonstrates notable edema and midline shift. This finding is consistent with a high grade or malignant tumor. Image courtesy of George Jallo, MD.

CT scan can be ordered with or without contrast when MRI is contraindicated or unavailable. Consider the following:

  • On CT scan, GBMs have a variable, inhomogeneous hypodense or isodense appearance with surrounding edema.

  • GBMs tend to infiltrate along the white matter tracts and frequently involve and cross the corpus callosum.

  • Approximately 4-10% of GBMs and 30-50% of AAs do not enhance, while a significant percentage of low-grade gliomas do not enhance.

Other Tests

Functional neuroimaging such as positron emission tomography (PET scan), single-photon emission computed tomography (SPECT), or MR spectroscopy may help differentiate the tumor from other benign mass lesions, brain abscess, or toxoplasmosis. However, the definitive diagnosis is confirmed by stereotactic or open brain biopsy. See the image below.

Magnetic resonance spectroscopy is representative Magnetic resonance spectroscopy is representative of a glioblastoma multiforme.

Consider the following:

  • Functional imaging is commonly used to differentiate between treatment-related radiation necrosis and tumor recurrence.

  • Functional imaging is also used in defining the margins of the tumor for surgical resection and planning for the radiation fields.

  • Additionally, functional imaging may be helpful in determining the most abnormal region of the tumor to improve the diagnostic accuracy in case a small biopsy sample is taken.

Histologic Findings

High-grade astrocytomas (HGAs) are extremely heterogenous tumors characterized by varying degrees of increased cellularity, pleomorphism, mitoses, endothelial proliferation, and necrosis. See the image below.

Histopathologic slide demonstrating a glioblastoma Histopathologic slide demonstrating a glioblastoma multiforme.

Staging

Many different grading systems exist for gliomas. The current WHO classification of gliomas is based on the presence or absence of 4 histologic criteria: (1) nuclear atypia, (2) mitoses, (3) endothelial proliferation, and (4) necrosis. Grade I tumors have none of the criteria, grade II have at least 1, grade III have at least 2, and grade IV (GBM) have at least 3 or 4 criteria present. Prominent microvascular proliferation and/or necrosis must be one of the criteria for GBM.

 

Treatment

Medical Care

Although the prognosis of glioblastoma multiforme (GBM) is uniformly poor, treating patients in an attempt to improve the quality of life is worthwhile. The current standard of care includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy with temozolomide. However, continuous supportive care is a major component of the medical treatment of primary brain tumors.

Surgical Care

In GBM, surgery is always an incomplete debulking, since it is a highly infiltrating tumor and cannot be resected completely. The extent of surgical resection depends on location and eloquence of the brain areas. However, a recent trial using 5-aminolevulinic acid showed a significantly higher rate of complete resection (65% gross total resection) of enhancing tumor on postoperative MRI performed within 72 hours of surgery versus 35% in the conventional surgery arm. Further analysis of the data has demonstrated that patients who underwent gross total resection, regardless of the treatment arm, had superior survival to those who received subtotal resection.[7, 8]

  • After surgery, combination of radiation therapy (RT) with temozolomide followed by adjuvant temozolomide therapy remains the most effective adjuvant therapy for the treatment of patients with HGA/GBM. In a phase 3 clinical trial organized by European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada showed modest improvement of overall survival 14.6 months compared with 12 months in the RT arm.[9] The standard of care for RT in GBM is focal, fractionated external beam RT. New techniques and technologies continue to be evaluated, but none has clearly shown to be superior to standard EBRT. Different methods of administering radiation therapy are available.

  • External beam radiation therapy (EBRT)

    • The standard dose of external beam radiotherapy is 60 Gy in single daily fractions of 1.7-2 Gy, 5 times a week. This is applied to a limited field that includes the enhancing volume on CT scans with a 2-3 cm margin or a 1-2 cm margin beyond T2-weighted MR images.

    • Approximately 50% of AAs and 25% of GBMs decrease in size following radiotherapy. This response usually occurs by the end of treatment.

  • Stereotactic brachytherapy

    • In patients who have recurrence after conventional radiotherapy, repeat resection of the tumor and brachytherapy may be indicated. Excellent candidates are patients with unifocal, well-defined, supratentorial tumors less than 5 cm in diameter that do not involve the corpus callosum, brain stem, or ependymal surfaces.

    • Brachytherapy involves using stereotactic techniques to accurately place catheters containing radioactive isotopes within brain tumors, without tumoricidal effect to normal brain tissues.

    • Typically, brachytherapy delivers an additional 50-60 Gy of radiation, bringing the total dose of radiation up to 110-120 Gy.

  • Stereotactic radiosurgery

    • Stereotactic radiosurgery is a technique used to treat small (< 4 cm), radiographically well-defined lesions with a single high-dose fraction of ionizing radiation in stereotactically directed narrow beams.

    • Radiosurgery has the advantage over brachytherapy in being noninvasive, allowing treatment of patients with tumors in surgically inaccessible or eloquent areas of the brain or serious coexisting medical illnesses.

    • Preliminary results are promising.

    • Stereotactic radiosurgery has largely supplanted brachytherapy because of the invasive risks of the latter procedure.

  • Boron neutron capture therapy (BNCT)

    • This modality of treatment is still investigational, not widely available, and costly. The value still is not proven.

    • Recently, Hatanaka treated patients with intra-arterial polyhedral borane anion and focused thermal neutron irradiation and reported a 5-year survival rate of 50% with few complications.[10]

    • Boron neutron capture therapy for newly diagnosed or recurrent high-grade gliomas still is being evaluated.

  • Chemotherapy probably has a modest but significant effect in prolonging survival when administered with concurrent radiation therapy after surgery.

    • Current recommendations include maximal safe surgical resection followed by concurrent radiation and chemotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide.

    • A phase III randomized trial combining low-dose chemotherapy using the oral alkylating agent temozolomide concurrently with radiation, followed by an additional 6 months of adjuvant temozolomide showed statistically significant survival benefit over radiation alone. The median survival was 14.6 months with radiation therapy plus temozolomide and 12.1 months with radiation therapy alone. The treatment was well tolerated with minimal additional toxicity.[9]

    • Another phase III randomized trial that included 240 patients compared surgery with implantation of polymer wafers with BCNU (Gliadel wafers) into the tumor bed demonstrated significant prolongation of survival compared with a placebo wafer. Both groups received radiation therapy. The median survival was 13.9 months in the group treated with Gliadel wafers and 11.6 months in the group treated with placebo.[11]

    • A safety and efficacy study by Darakchiev et al, using adjunct combination therapy with BCNU wafers and permanent iodine-125 seeds, resulted in favorable survival in patients with recurrent GBM. The median survival was 69 weeks and the median progression-free survival was 47 weeks. The incidence of brain necrosis appeared to be higher than with either therapy alone. However, the necrosis was manageable with surgery or hyperbaric oxygen therapy and did not affect the survival.[12]

    • Stupp et al reported the final results of the randomized phase III trial for patients with glioblastoma who were treated with adjuvant temozolomide and radiation with a median follow-up of more than 5 years. Stupp et al previously reported improved median and 2-year survival when temozolomide was added to radiation therapy in glioblastoma.[9] Survival in the combined therapy group (ie, temozolomide and radiation) continued to exceed that of radiation alone throughout the 5-year follow-up (p< 0.0001). Survival of patients who received adjuvant temozolomide with radiotherapy for glioblastoma is superior to radiotherapy alone across all clinical prognostic subgroups.

    • A posthoc analysis in a subset of patients in a phase III trial, patients whose tumors had methylation of the promoter region of the methylguanine methyltransferase (MGMT) gene survived longer and derived greater benefit from the addition of temozolomide therapy to RT than those whose tumors were not methylated.[13]

  • Extensive research is taking place on newer therapeutic options (eg, immunotherapy, antiangiogenesis[14] , biologic therapy, growth factor and second messenger inhibition, gene therapy). These options are beyond the scope of this section. Interested readers are encouraged to read standard neuro-oncological textbooks, journals, and other sources (see References).

  • For tumor recurrence, various conventional chemotherapeutic agents, including nitrosoureas, BCNU and CCNU, and chemotherapies such as cisplatin, carboplatin, etoposide, are used. Selected patients may benefit from tumor resection. Patients with recurrent GBM are encouraged to participate in approved clinical trials to develop effective regimens.

  • A phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma (RESCUE study) concluded that for patients with recurrent GBM, rechallenging with 50 mg/m2/d continuous dose-intense temozolomide is a valuable option. Patients with recurrence after a treatment-free interval or patients experiencing progression during the first 6 cycles of conventional adjuvant temozolomide therapy benefit the most.[15, 16]

  • Probably the most important part of the management of patients with GBM is compassionate and effective supportive care.

    • This care includes treatment of cerebral edema with a potent glucocorticosteroid. Dexamethasone is most commonly used because of its potent impact on edema and minimal mineralocorticoid effects. Steroid therapy often requires prophylactic use of H-2 blockers to prevent gastrointestinal side effects.

    • Seizures are a major concern with supratentorial tumors. Although seizures are less common with GBM than the low-grade glioma, treatment with appropriate anticonvulsant is uniformly recommended for a documented seizure. However, the use of a prophylactic anticonvulsant is controversial. A 2009 prospective study strongly concluded that the use of prophylactic AEDs in glioma is not justified, as patients without epilepsy and not taking AEDs never developed seizures.[17] Careful consideration is required in selecting an effective AED with minimal side effects and without cytochrome P450 enhancing activity because enzyme inducers can increase the metabolism and clearance of some chemotherapeutic agents.

    • Thromboembolic disease is also a major concern for patients with primary brain tumors. Although the incidence of thromboembolic disease has been reported to be as high as 35-40% during the course of the GBM, prophylactic use of anticoagulation has not been recommended because of increased risk of intracranial hemorrhage.

    • Besides the symptoms of seizures, headache, and mental status changes, many patients have neurologic deficits and require physical, occupational, and speech therapy. Frequently, patients require emotional and psychological support and benefit from help provided by support groups, local workers, psychiatrists, and organizations such as Brain Tumor Society or National Brain Tumor Foundation.

Consultations

Treatment of GBM is largely a multispecialty team approach. Therefore, neurology, neurosurgery, neuro-oncology, radiation oncology, psychiatry, and social service consultations should be obtained.

 

Medication

Medication Summary

The goals of pharmacotherapy for glioblastoma multiforme (GBM) are to reduce morbidity and to prevent complications.

Alkylating agents

Class Summary

This oral alkylating agent has been approved for newly diagnosed GBM and recurrent anaplastic astrocytomas.

Temozolomide (Temodar)

Oral alkylating agent converted to MTIC at physiologic pH; 100% bioavailable; approximately 35% crosses blood-brain barrier. Indicated for GBM combined with radiotherapy. Significant overall survival was demonstrated in patients treated with temozolomide and radiation compared with radiotherapy alone.

Cytotoxic agents

Class Summary

Local chemotherapy with carmustine (BCNU) wafers (Gliadel wafers) significantly prolongs survival in patients with newly diagnosed primary malignant glioma.

Carmustine

Gliadel is a small wafer that contains the chemotherapeutic drug carmustine, or BCNU. The wafer is designed to release the drug slowly over a period of 2-3 wk after placed in tumor bed. Up to 8 Gliadel wafers are implanted in the cavity, slowly delivering BCNU directly to tumor site.

 

Follow-up

Further Outpatient Care

After the initial successful therapy, observe the patient regularly as an outpatient with neurologic examination and repeat MRI scans every 2 months with the chemotherapy cycles; continue every few months to follow tumor recurrence.

Further Inpatient Care

After the initial definitive treatment (surgical debulking) of glioblastoma multiforme (GBM), the patient may need further inpatient care during the ongoing radiation therapy. Chemotherapy usually is performed on an outpatient basis. Continuing outpatient follow-up care is necessary if the patient develops neurological deterioration such as acute motor weakness or depression of consciousness from the effects of therapy, increased intracranial pressure from vasogenic edema, or acute hydrocephalus from ventricular obstruction. Appropriate intervention depends on the nature of the problem (eg, steroid therapy for edema, shunting for hydrocephalus).

Inpatient & Outpatient Medications

No specific medications are recommended for GBM. However, as mentioned previously, patients may need symptomatic therapy with steroids or anticonvulsants.

Transfer

Transfer requirements depend on the tumor location and its response to treatment. If the tumor is in a noneloquent area and no neurological deficit is present after treatment, the patient remains fully ambulatory. However, other patients may require assistance, such as a 3-pronged cane or a wheelchair, depending on the residual neurological deficit.

Complications

During continuing follow-up care, monitor the patient closely and treat appropriately any complications that may develop. These may be caused by ongoing treatment, such as radiation necrosis and chemotherapy-induced neuropathy, or by progression of the disease, such as recurrence or leptomeningeal spread.

Prognosis

With optimal treatment, the median survival of patients with glioblastoma is about 12 months. However, only 3-5% of patients survive for more than 3 years. The overall prognosis for GBM has changed little since the 1980s, despite major improvements in neuroimaging, neurosurgery, radiotherapy, and chemotherapy techniques.[18] Although histologic grading remains the most important prognostic factor, other important prognostic factors include age at diagnosis and Karnofsky performance status (KPS). Consider the following:

  • Various studies demonstrated that patients with GBM who are younger than 40 years have an 18-month survival rate of 50%, while those aged 40-60 years have an 18-month survival rate of 20% and those older than 60 years have a rate of only 10%. In some series, age appears to be an even more important prognostic factor than histology.

  • The survival of patients with GBM decreases as KPS decreases. Patients with a KPS of more than 70 have an 18-month survival rate of 34%, while those with a KPS of less than 70 have an 18-month survival rate of 13%.

  • Additional factors such as extent of surgical resection, seizures as the initial presentation, and tumor location with superficial tumors have been variably associated with outcome.

  • A recent animal study in rats investigated the use of monoclonal antibodies 8H9 as interstitial infusion showed significant volumetric response and prolonged survival (54 d for untreated rats vs 120 d for treated rats) as a potential target therapy for high-grade gliomas.[19]

  • A study by Wang et al demonstrated that overexpression of EphA7 was predictive of adverse outcomes in patients with primary and recurrent glioblastoma multiforme, independent of microvascular density (MVD) expression. Moreover, high density of both MVD and EphA7 expression predicted the disease outcome more accurately than EphA7 alone.[20]

  • A study by Liang et al demonstrated that nuclear FABP7 was preferentially expressed in infiltrative gliomas only and associated with poor prognosis in EGFR-overexpressing glioblastoma. The study suggested that FABP7 immunoreactivity could be used to monitor the EGFR-overexpressed GBM progression.[21]

Studies are focusing attention on identifying molecular markers similar to anaplastic oligodendroglioma to predict response or resistance to specific treatments. One such interest is the expression of MGMT (O6 -methylguanine–DNA methyltransferase) gene. The protein product of this gene, 06 alkyl guanine DNA-alkyl-transferase (AGAT), is shown to be a major mechanism for tumor resistance to alkylating agents. Recent clinical trials for malignant gliomas now often include determination of MGMT expression status. Several other molecular markers, such as epidermal growth factor receptor, platelet-derived growth factor receptor, vascular endothelial growth factor receptor, loss of chromosome 10, mutation or loss of the p53 gene, expression of the YKL-40 gene, loss or mutation of PTEN gene, are being investigated.

Studies are also focusing on new targets such as receptor blockade. Glutamatergic system alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-blocker talampanel, may be beneficial in this disease. In a recent study, talampanel was added to the standard radiation and temozolomide in adults with newly diagnosed glioblastoma to estimate the overall survival as well as talampanel toxicity as a secondary measure. The study concluded that talampanel was well tolerated and compared with European Organization for Research and Treatment of Cancer (EORTC) data, median survival seemed superior (20.3 vs 14.6 mo, respectively). Therefore, talampanel can be added to radiation therapy and temozolomide without significant additional toxicity.

Patient Education

During the course of diagnosis, treatment, and follow-up care, educate the patient and family about the course and prognosis of the tumor to help them cope with the physical and emotional burden. Set this goal during discussion with the patient in the presence of family members, nurses, physicians, social services, and spiritual services. In addition, frequent contacts, regular follow-up care, and involvement of support groups are necessary.

For patient education resources, see the Cancer Center and Brain Cancer.