Glioblastoma Multiforme

Glioblastoma multiforme is a high-grade astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma, an aggressive brain tumor arising from astrocytes, with an unknown cause and a poorly understood link to risk factors. There are two main types: primary, a more aggressive form seen more commonly in older patients, and secondary, developing from lower-grade astrocytomas and seen more commonly in younger patients. Glioblastomas most commonly present with headache, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and neurologic deficits. MRI is the gold standard diagnostic tool, and surgical resection combined with radiation and chemotherapy is the treatment of choice. Prognosis is extremely poor, with survival of only 1–5 years in patients receiving aggressive treatment and only 3 months in patients who do not undergo treatment.

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Overview

Definition

Glioblastoma multiforme (GBM) is an aggressive, rapidly progressive type of brain tumor arising from astrocytes:

  • Classified by the WHO as a grade IV astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma (a high-grade malignant glioma)
  • Glial cells are supportive tissues within the brain and nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System.
  • Neuroepithelial tumors are those involving the brain parenchyma.
  • Astrocytomas, including GBMs, are graded but not staged.

Classification of nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System tumors

Table: Classification of nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System tumors
Categories Specific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including GBM
  • Oligodendroglioma Oligodendroglioma Oligodendrogliomas are malignant CNS tumors arising from neural glial cell precursors. Oligodendrogliomas often arise in the frontal lobes of the brain and have a generally favorable prognosis when compared to other gliomas. Oligodendrogliomas are the 3rd most common CNS tumor. The most frequent presenting symptom is a seizure. Oligodendroglioma
  • Ependymoma Ependymoma Ependymomas are glial cell tumors arising from CSF-producing ependymal cells lining the ventricular system. Ependymomas most commonly occur within the posterior fossa in contact with the 4th ventricle, or within the intramedullary spinal cord. Ependymoma and choroid-plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma Craniopharyngioma Craniopharyngiomas are rare squamous epithelial tumors with a solid and/or cystic structure that arise from the remnants of Rathke's pouch along the pituitary stalk, in the suprasellar region. Craniopharyngiomas are histologically benign but tend to invade surrounding structures; thus, they should be treated as low-grade malignancies. Craniopharyngioma
  • Pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas
  • Pinealoma/pinealoblastoma
Primary CNS lymphoma Primary CNS lymphoma
Metastasis to the brain (5× more common than primary brain tumors) Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma Acoustic neuroma Acoustic neuroma, also referred to as vestibular schwannoma, is a benign tumor arising from Schwann cells of the vestibular component of the cranial nerve VIII. Acoustic neuroma forms within the internal auditory meatus and extends into the cerebellopontine angle. Acoustic Neuroma
  • Neuroblastoma Neuroblastoma Neuroblastoma is a malignancy that arises from the neural crest cell derivatives along the sympathetic chain (neuroblasts) and is most commonly located in the adrenal medulla. The tumor often presents in childhood with a flank mass that crosses the midline. Neuroblastoma

Epidemiology

  • Most common malignant brain tumor 
  • Incidence: 
    • 3 per 100,000 population
    • Accounts for 23% of all primary brain tumors.
    • 60% of all astrocytomas are grade IV (GBM) at diagnosis.
  • Age:
    • Can occur in any age group 
    • Peak incidence: 45–70 years of age
    • Mean age at diagnosis: approximately 55–60 years
  • Sex: more common in men than in women
  • Race/ethnicity: does not appear to affect incidence
  • Mortality: GBM has a poor survival rate 
    • 40% mortality in the 1st year after diagnosis 
    • 17% in the 2nd year after diagnosis

Classification

The 2 main types of glioblastoma are:

  • Primary glioblastoma:
    • A more aggressive form of GBM arising de novo (without progressing from a lower-grade astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma)
    • More common than secondary GBM
    • Typically seen in older patients (> 50 years)
    • Patients present with a short clinical history and no evidence of a preexisting lesion.
  • Secondary glioblastoma:
    • A slower-growing form of GBM that develops from a lower-grade astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma (e.g., grade II or III) over 1–10 years (mean, 5).
    • Typically seen in younger patients (< 45 years)
    • Patients present with longer-term symptoms and evidence of a preexisting lesion.

Pathophysiology

Risk factors

The cause of glioblastomas is unclear and it is difficult to determine a single cause. The risk factors that appear to contribute to glioblastoma include:

  • Previous exposure to therapeutic radiation
  • Genetic associations:
    • Li-Fraumeni syndrome (p53 germline mutations)
    • Lynch syndrome Lynch syndrome Lynch syndrome, also called hereditary non-polyposis colorectal cancer (HNPCC), is the most common inherited colon cancer syndrome, and carries a significantly increased risk for endometrial cancer and other malignancies. Lynch syndrome has an autosomal dominant inheritance pattern involving pathogenic variants in one of the mismatch repair (MMR) genes or epithelial cell adhesion molecule (EpCAM). Lynch syndrome
    • Constitutional mismatch repair–deficiency syndrome
  • Large studies have not consistently shown that cell phone use is a risk factor.

Pathogenesis

Several genetic mutations are associated with astrocytomas:

  • Loss of heterozygosity on chromosome 10q:
    • Occurs in 60%–90% of GBMs (in both primary and secondary)
    • Specific for GBM (rarely found in lower-grade astrocytomas) → a diagnostic marker of GBM
    • Loss of heterozygosity plus 1 or 2 additional mutations are likely key players in the development of GBM.
  • Activating mutations in the telomerase reverse transcriptase (TERT) promoter:
    • TERT is a catalytic subunit in telomerase → activating mutations allow tumor cells to become “immortal.”
    • Diagnostic marker for GBM
  • Activating mutations in epidermal growth factor receptor (EGFR):
    • EGFR helps control cell proliferation → activating mutations contribute to ↑ proliferation
    • Diagnostic marker of GBM
  • Mutations in isocitrate dehydrogenase (IDH):
    • IDH:
      • Catalyzes the reversible oxidative decarboxylation of isocitrate → α-ketoglutarate (α-KG) in the tricarboxylic acid (TCA) cycle 
      • A primary producer of nicotinamide adenine dinucleotide phosphate (NADPH) in most tissues, especially the brain
      • Also involved in mitigating oxidative damage
    • Mutations lead to production and buildup of a 2-hydroxyglutarate (2-HG):
      • 2-HG inhibits enzymatic function of α-KG–dependent dioxygenases, which are involved in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure demethylation.
      • ↑ 2-HG causes epigenetic dysregulation → can lead to tumor development
  • Methylation (i.e., silencing) of the O-6-methylguanine- DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure methyltransferase (MGMT) promoter:
    • MGMT is an enzyme involved in DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair (including DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure repair after alkylating-agent chemotherapy).
    • MGMT methylation at the promoter region:
      • Silences expression of the gene
      • May occur during tumor development → prevents repair of DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage
      • Improves chemotherapy responsiveness and overall survival (independent of other risk factors) 
  • Inactivating p53 mutations 
  • Overexpression of platelet-derived growth factor alpha (PDGF-α): common in secondary GBM

Pathophysiology

  • Location: GBMs usually arise in the cerebral hemispheres (i.e., parenchyma).
    • Common locations:
      • Frontal lobe
      • Temporal lobe
    • Less common locations:
      • Brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem
      • Cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum
      • Spinal cord
  • Regional effects on brain parenchyma include:
    • Compression
    • Invasion
    • Destruction
  • ↑ Intracranial pressure ( ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)) may be due to:
    • Direct mass effect
    • Edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema in surrounding brain tissue
    • ↑ Blood volume
    • ↑ CSF volume/hydrocephalus
  • Disruptions of normal parenchymal functions are due to:
    • Hypoxia
    • Competition for nutrients
    • Release of metabolic end products:
      • Free radicals
      • Altered electrolytes Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
      • Neurotransmitters
    • Release and recruitment of cellular mediators (e.g., cytokines)

Clinical Presentation

Onset

  • 50% of the cases present with a short clinical history unless they develop from a lower-grade astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma
  • The clinical symptoms progress over days to weeks.
  • Signs and symptoms vary according to the location of the tumor. 

Signs and symptoms

Many generalized symptoms are due to increases in ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP). Symptoms may include:

  • General (symptoms that can occur with tumors in any location):
    • Headache, usually in the morning (50%–60% of patients)
    • Nausea and/or vomiting 
    • Cognitive difficulties: 
      • Memory problems
      • Mood or personality changes
    • Papilledema
  • Focal (symptoms that occur because of tumors in specific locations):
    • Seizures (20%–50% of patients) 
    • Aphasia 
    • Visual field deficits
    • Motor weakness
    • Hemiparesis
    • Sensory abnormalities

Diagnosis

Diagnosis of glioblastomas is based mainly on imaging after the clinical presentation and a careful history and exam raise suspicion for a brain tumor. A biopsy is required to confirm the diagnosis. Laboratory studies are not helpful in diagnosing GBMs.

Imaging

  • MRI:
    • Gold standard imaging method for diagnosis
    • Should be ordered with and without contrast
    • T1-weighted images show a hypointense, irregularly shaped, ring-enhancing mass with an area of central clearing (indicating central necrosis).
    • T2-weighted images show a hyperintense, irregularly shaped lesion, with a broad surrounding zone of edema.
  • CT:
    • Indicated in patients with a contraindication to MRI or in the acute setting (e.g., to rule out hemorrhage or stroke)
    • Lesions appear hypointense in comparison to adjacent brain tissue.
    • Midline shift is present because of moderate to severe edema.

Biopsy

A histopathologic specimen obtained through biopsy is required for definitive diagnosis. Findings include:

  • Areas of necrosis (key diagnostic feature differentiating GBM from grade III astrocytomas)
  • Areas of microvascular proliferation
  • Irregular and elongated astrocytic cells with eosinophilic and hyperchromatic nuclei
  • Marked nuclear pleomorphism and atypia
  • Multiple mitotic figures
  • Key molecular tests to perform on biopsy specimen:
    • Immunohistochemical staining for IDH and p53 mutations
    • Methylation assays or PCR to assess MGMT promoter methylation status

Management and Prognosis

The main approach to management is surgical intervention, followed by radiation and chemotherapy. No treatment is curative, and prognosis remains poor, even with aggressive treatment.

Management challenges

Challenges that hinder the management of glioblastomas are:

  • Location of the tumor
  • Poorly defined tumor margins make complete resection complicated.
  • Limited ability of medications to cross the blood–brain barrier
  • Disrupted blood supply within the tumor, making drug delivery even less effective
  • Neurotoxicity of treatments
  • Tumor-induced seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures

Primary management

  • Surgical intervention:
    • Goal is maximal resection.
    • Effects of surgical resection:
      • Reduced tumor burden (which also makes radiation and chemotherapy more effective)
      • Relief of ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP)
      • Improvement in both survival and quality of life
    • Preoperative imaging is important to determine the location and extent of the tumor.
  • Radiation therapy:
    • Improves survival rates
    • Starts after surgery
  • Chemotherapy:
    • Primary agent used: temozolomide: 
      • Alkylating agent Alkylating Agent Alkylating agents are cell cycle-independent antineoplastic drugs that work primarily by binding alkyl groups to various parts of DNA. The overall action produces cross-linking of DNA, leading to inhibition of DNA replication and DNA damage. Alkylating Agents and Platinum
      • Given after surgery for 6 cycles
    • Other chemotherapeutic agents include:
      • Carmustine polymer wafers (implanted at the time of surgical resection)
      • Cisplatin
      • Tyrosine kinase inhibitors: erlotinib, gefitinib
      • Bevacizumab + irinotecan (for recurrent GBM)
  • Alternative electric field therapy (the Optune device):
    • Uses low-intensity, intermediate-frequency, alternating electric fields to selectively target actively dividing cells 
    • Indications:
      • Can be used in combination with temozolomide as initial therapy
      • Recurrent GBM

Supportive management

  • Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis) prophylaxis: in nonambulatory and hospitalized patients
  • Anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs therapy: in patients with a history of seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures (prophylactic anticonvulsant therapy remains controversial)
  • Corticosteroids (e.g., dexamethasone): may be used for their antiinflammatory properties to reduce tumor mass effect and swelling

Prognosis

  • Without therapy, patients usually do not survive beyond 3 months.
  • Patients treated with optimal therapy have a median survival of 12‒15 months:
    • 1 year survival rate: 38%–50%
    • 5 year survival rate: 5%–10% 
  • Factors affecting prognosis:
    • Age
    • MGMT methylation and IDH mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations status
    • Level of functional capacity
    • Extent of resection achieved with surgery

Differential Diagnosis

For patients who present with neurologic findings, the following conditions should be considered in the differential diagnosis for glioblastoma multiforme.

Other brain tumors

  • Anaplastic astrocytoma Astrocytoma Astrocytomas are neuroepithelial tumors that arise from astrocytes, which are star-shaped glial cells (supporting tissues of the CNS). Astrocytomas are a type of glioma. There are 4 grades of astrocytomas. Astrocytoma: grade III astrocytomas that typically progress to secondary GBM within 2 years. Clinical presentation is similar to that of GBM. Diagnosis is made on imaging and biopsy, with the key difference being that anaplastic astrocytomas lack necrosis and microvascular proliferation. Management is surgical resection with radiation and chemotherapy. 
  • Oligodendroglioma Oligodendroglioma Oligodendrogliomas are malignant CNS tumors arising from neural glial cell precursors. Oligodendrogliomas often arise in the frontal lobes of the brain and have a generally favorable prognosis when compared to other gliomas. Oligodendrogliomas are the 3rd most common CNS tumor. The most frequent presenting symptom is a seizure. Oligodendroglioma: CNS tumor arising from oligodendrocytes. Oligodendroglioma Oligodendroglioma Oligodendrogliomas are malignant CNS tumors arising from neural glial cell precursors. Oligodendrogliomas often arise in the frontal lobes of the brain and have a generally favorable prognosis when compared to other gliomas. Oligodendrogliomas are the 3rd most common CNS tumor. The most frequent presenting symptom is a seizure. Oligodendroglioma most commonly develops in the cerebral hemisphere, usually the frontal lobe, and presents similarly to GBM. A key test differentiating oligodendrogliomas from GBM is testing a biopsy specimen for a 1p/19q codeletion, which will typically be present in oligodendrogliomas but absent in GBMs. Management involves surgical resection possibly accompanied by radiation and/or chemotherapy. 
  • Primary CNS lymphoma: rare variant of non- Hodgkin lymphoma Hodgkin lymphoma Hodgkin lymphoma (HL) is a malignancy of B lymphocytes originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, splenomegaly and hepatomegaly. Hodgkin Lymphoma involving the brain, leptomeninges, eyes, or spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord, without evidence of systemic disease. Immunodeficiency, including HIV infection HIV infection Human immunodeficiency virus (HIV), a single-stranded RNA virus belonging to the Retroviridae family, is the etiologic agent of acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus is a sexually transmitted or blood-borne infection that attacks CD4+ T lymphocyte cells, macrophages, and dendritic cells, leading to eventual immunodeficiency. HIV Infection and AIDS, is a primary risk factor. Clinical presentation depends on the location of the tumor and is similar to that of GBM. The diagnosis is made with imaging (typically MRI), biopsy, and potentially CSF evaluation. Management typically involves chemotherapy, potentially whole-brain radiation, and, in patients with HIV/AIDS, antiretroviral therapy Antiretroviral therapy Antiretroviral therapy (ART) targets the replication cycle of the human immunodeficiency virus (HIV) and is classified based on the viral enzyme or mechanism that is inhibited. The goal of therapy is to suppress viral replication to reach the outcome of undetected viral load. Anti-HIV Drugs.
  • Metastatic tumor: neoplastic cells that have spread to the brain from primary tumors elsewhere in the body. Metastatic tumors are the most common neoplasms in the brain. Neuroimaging often shows multiple foci of the carcinoma, suggesting an origin outside the brain. Clinical presentation depends on the primary tumor and location and extent of brain metastasis. Treatment is directed at the underlying neoplasm and may involve surgical resection, radiation therapy, and chemotherapy.

Nonneoplastic processes

  • Intracranial hemorrhage: life-threatening bleeding within the cranium; second most common cause of stroke. Bleeding may be due to hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension, ruptured aneurysms, or bleeding vascular malformations. Patients usually present with signs of increased ICP ICP Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP) and/or neurologic findings. Diagnosis is by clinical presentation and imaging (often a CT scan in an acute care setting). Management involves urgent medical and surgical treatment.
  • Encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis: inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation of the brain parenchyma due to infection. Encephalitis Encephalitis Encephalitis is inflammation of the brain parenchyma caused by an infection, usually viral. Encephalitis may present with mild symptoms such as headache, fever, fatigue, and muscle and joint pain or with severe symptoms such as seizures, altered consciousness, and paralysis. Encephalitis presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in muscles and joints, fatigue, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. The condition is diagnosed by imaging, CSF analysis, lab tests, and EEG. Management is supportive and involves antiinflammatory drugs and, if the etiology is viral, antivirals.
  • Brain abscess Brain abscess Brain abscess is a life-threatening condition that involves the collection of pus in the brain parenchyma caused by infection from bacteria, fungi, parasites, or protozoa. The most common presentation is headache, fever with chills, seizures, and neurological deficits. Brain Abscess: collection of pus within the brain that develops in response to an infection or trauma that clinically presents with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, nausea, and vomiting. Brain abscess Brain abscess Brain abscess is a life-threatening condition that involves the collection of pus in the brain parenchyma caused by infection from bacteria, fungi, parasites, or protozoa. The most common presentation is headache, fever with chills, seizures, and neurological deficits. Brain Abscess is diagnosed by clinical presentation, laboratory testing, and brain imaging. Management includes antibiotic therapy, and surgery to drain the abscess.

References

  1. Prabhu, V. C. (2021). Glioblastoma multiforme. American Association of Neurological Surgeons. Retrieved May 21, 2021, from https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme
  2. Bruce, J. N., Kennedy, B. C. (2019). Glioblastoma multiforme. Medscape. Retrieved May 21, 2021, from https://emedicine.medscape.com/article/283252-overview
  3. Hanif, F., et al. (2017). Glioblastoma multiforme: A review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 18(1), 3–9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563115/
  4. Dietrich, J. (2021). Clinical presentation, diagnosis, and initial surgical management of high-grade gliomas. In Eichler, A. F. (Ed.), UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/clinical-presentation-diagnosis-and-initial-surgical-management-of-high-grade-gliomas
  5. Batchelor, T. (2021). Initial treatment and prognosis of newly diagnosed glioblastoma in adults. In Eichler, A. F. (Ed.), UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/initial-treatment-and-prognosis-of-newly-diagnosed-glioblastoma-in-adults 

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