Neurologic Manifestations of Glioblastoma Multiforme

Updated: Oct 09, 2020
  • Author: ABM Salah Uddin, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA  more...
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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. GBM is divided into three subgroups based on isocitrate dehydrogenase 1 (IDH1) and IDH2 mutation status: IDH-mutant, IDH-wild-type and NOS (not otherwise specified). 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.




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]




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. Approximately three per 100,000 people develop the disease each year, [5] although regional frequency may be higher. [6] 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. [7]

The frequency of GBM in England doubled between 1995 and 2015. [8]


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. [5]

While GBM occurs in all age groups, its incidence is increasing in elderly patients. [5] 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.



With optimal treatment, the median survival of patients with glioblastoma is about 12 to 15 months. However, only 3–7% of patients survive for more than 5 years. [9] In the United States between 2012 and 2016, five-year survival was 6.8%. [9] The overall prognosis for GBM has changed little since the 1980s, despite major improvements in neuroimaging, neurosurgery, radiotherapy, and chemotherapy techniques. [10]  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.

  • An 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. [11]

  • 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. [12]

  • 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. [13]

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.