Patients suffering from malignant glioma may present with symptoms arising due to an increase in intracranial pressure and compression or destruction of brain tissue. In this context, headaches, nausea, and vomiting, as well as, seizures may be experienced. Furthermore, neurological deficits like aphasia, visual impairment, and progressive cognitive decline may be observed. Motor deficits are common and may range from mild gait disturbances to hemiparesis. Additionally, patients may not be able to control micturition and defecation and may suffer from incontinence. Psychiatric symptoms associated with aggressive brain tumors comprise of mood swings, an altered mental status,and personality changes. In most cases, symptoms worsen progressively within a few months, although complaints like headaches, nausea and vomiting may tend to follow diurnal patterns. Specific neurological deficits may imply the involvement of specific regions of the brain.

Gliomas rarely metastasize outside the central nervous system. The one exception of this rule is gliosarcoma, a rare variant of glioblastoma, which spreads hematogenously in about 11% of affected individuals [11]. Metastases are most commonly detected in lungs (72%), liver (41%) and lymph nodes (18%). They may interfere with organ function and cause local mass effects. Additionally, tumor thrombi may provoke thromboembolic events. Of note, any type of malignant glioma is histopathologically characterized by prominent neoangiogenesis and infiltrative growth that may compromise intracranial vessels. In these patients, thromboembolism may also be observed and presumably results from thrombus formation due to vascular anomalies and endothelial lesions.

• Nausea

  Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. [ncbi.nlm.nih.gov]

  General symptoms include headache, confusion, change in personality, nausea, loss of balance or coordination, memory loss, blurred vision or other visual abnormalities, and slurred speech. [britannica.com]

  Some of the most common are headaches, usually worse in the morning nausea and vomiting changes in your ability to talk, hear, or see problems with balance or walking problems with thinking or memory muscle jerking or twitching numbness or tingling in [icd9data.com]

  In this context, headaches, nausea, and vomiting, as well as, seizures may be experienced. Furthermore, neurological deficits like aphasia, visual impairment, and progressive cognitive decline may be observed. [symptoma.com]

• Vomiting

  Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules. [ncbi.nlm.nih.gov]

  Astroctyoma symptoms Headache Seizure Behavioural changes Ependymoma symptoms Increased head size Irritability Vomiting Inability to sleep Nausea Vomiting Headache Oligodendroglioma symptoms Headache Seizure Behavioral changes Weakness on one side of [news-medical.net]

  Some of the most common are headaches, usually worse in the morning nausea and vomiting changes in your ability to talk, hear, or see problems with balance or walking problems with thinking or memory muscle jerking or twitching numbness or tingling in [icd9data.com]

  In this context, headaches, nausea, and vomiting, as well as, seizures may be experienced. Furthermore, neurological deficits like aphasia, visual impairment, and progressive cognitive decline may be observed. [symptoma.com]

  Some common symptoms include headache, frequent vomiting without cause, seizures, memory loss, confusion, personality changes, balance and walking problems, speech issues, vision difficulties, and other symptoms. [nicklauschildrens.org]

• Hypertension

  Anterior Chamber Brain and Optical Pathway Choroid Congenital Syndromes, Malformations and Abnomalities Conjunctiva Cornea Glaucomas, Ocular Hypertension Hypertensive Retinopathy Iris and Ciliary Body Lacrimal System Lens Lids Neuro-Ophthalmology Optic [atlasophthalmology.net]

  […] clouding of the consciousness, with rapidly evolving intracranial hypertension despite partial removal of the tumor. [scielo.br]

  Case Presentation A 69-year-old woman, with a history of medication for hypertension, was referred to our hospital because of gait disturbance. [hindawi.com]

  Intracranial involvement may be associated with intracranial hypertension as well as decreased function of the hypothalamus and pituitary gland. [eyewiki.aao.org]

  It has been associated with neutropenia (decreased immunity), hypertension, and thromboembolism (blood clots). Hormone Treatments Hormonal treatments may be needed to counteract the effects of hormone-producing pituitary tumors. [neurology.about.com]

• Back Pain

  A 45-year-old woman visited our hospital with low back pain and radiating leg pain. [kiss.kstudy.com]

• Strabismus

  Their placement along the optic nerve, however, can cause vision loss (depending on the location of the tumor) or strabismus (“crossed eyes”). Hormonal disturbance might also occur, causing developmental delay(s), early puberty, and other symptoms. [abta.org]

  Retinal Perforations, Breaks Surgical Procedures and Postoperative Cases Toxic Retinopathies; see also Light Toxicitiy Trauma (Injury) Tumors, Neoplasma Vascular Diseases (see also: Systemic Immunologic Diseases) Sclera Strabismus, Ocular Motility Disorders [atlasophthalmology.net]

  Shipman, Acute V Pattern Esotropia Without Abduction Deficit, Secondary to a Posterior Fossa Pilocytic Astrocytoma, Journal of Pediatric Ophthalmology & Strabismus, 46, 4, (235), (2009). Mark W. Kieran, Susan N. [doi.org]

• Diplopia

  Pontine gliomas Involvement of cranial nerve III or IV – A mesencephalic component Hydrocephalus – Tumors in periaqueductal or fourth ventricle outflow locations Patients with tectal lesions may present with the following: Headache, nausea, and vomiting Diplopia [emedicine.medscape.com]

• Urinary Incontinence

  Common signs and symptoms of gliomas include: Headache Nausea or vomiting Confusion or a decline in brain function Memory loss Personality changes or irritability Difficulty with balance Urinary incontinence Vision problems, such as blurred vision, double [mayoclinic.org]

  A 74-year-old man complaining of gait disturbance, urinary incontinence, and memory disturbance underwent ventroperitoneal (VP) shunt under the impression of obstrctive hydrocephalus that occurred secondarily to a tumor in the pineal gland. [kiss.kstudy.com]

• Seizure

  Partial seizure control (PSC) was defined as a reduction of >50% in the number of seizures, with the steroid dose stable or reduced, and no modification of anti-convulsant treatment; complete seizure control (CSC) was defined as absence of seizures in [annonc.oxfordjournals.org]

  A person can have a seizure and not have a seizure disorder. Seizures are fairly common. The chance of having a seizure in your lifetime is almost 10%; and many times the cause of a seizure is never determined. [medicinenet.com]

• Headache

  This report describes two patients who presented with headache and signs of multifocal neurological disease. One of the patients had neurofibromatosis type I. [ncbi.nlm.nih.gov]

  Astroctyoma symptoms Headache Seizure Behavioural changes Ependymoma symptoms Increased head size Irritability Vomiting Inability to sleep Nausea Vomiting Headache Oligodendroglioma symptoms Headache Seizure Behavioral changes Weakness on one side of [news-medical.net]

  In this context, headaches, nausea, and vomiting, as well as, seizures may be experienced. Furthermore, neurological deficits like aphasia, visual impairment, and progressive cognitive decline may be observed. [symptoma.com]

  General symptoms include headache, confusion, change in personality, nausea, loss of balance or coordination, memory loss, blurred vision or other visual abnormalities, and slurred speech. [britannica.com]

• Stroke

  China. 3 Center of Stroke, Beijing Institute for Brain Disorders, Beijing, P. R. China. 4 Beijing Key Laboratory of Translational Medicine for Cerebrovascular Diseases, Beijing, P. R. [ncbi.nlm.nih.gov]

  Kennedy was hospitalized with apparent stroke-like symptoms, Saturday morning, May 17, 2008. (AP Photo/Lisa Poole) less **FILE**Sen. [sfgate.com]

  If you think it's a stroke, dial 999 immediately and ask for an ambulance. [nhs.uk]

  Kennedy underwent surgery seven months ago at the same hospital to restore blood flow through a narrowed carotid artery in his neck and to prevent a possible stroke. He had no symptoms at the time, the hospital said. [nytimes.com]

• Personality Change

  Some common symptoms include headache, frequent vomiting without cause, seizures, memory loss, confusion, personality changes, balance and walking problems, speech issues, vision difficulties, and other symptoms. [nicklauschildrens.org]

  They may also manifest psychiatric symptoms like mood swings, an altered mental status, and personality changes. [symptoma.com]

  The most common, including glioblastoma symptoms are: Headaches Seizures Personality changes Weakness in the arms, face or legs Numbness Problems with speech Other symptoms include: Nausea and vomiting Vision loss Dizziness Glioblastoma symptoms and other [hopkinsmedicine.org]

  Other symptoms can include seizures, memory loss, physical weakness, loss of muscle control, visual symptoms, language problems, cognitive decline, and personality changes. These symptoms may change, according to which part of the brain is affected. [webmd.com]

• Confusion

  General symptoms include headache, confusion, change in personality, nausea, loss of balance or coordination, memory loss, blurred vision or other visual abnormalities, and slurred speech. [britannica.com]

  Some common symptoms include headache, frequent vomiting without cause, seizures, memory loss, confusion, personality changes, balance and walking problems, speech issues, vision difficulties, and other symptoms. [nicklauschildrens.org]

  Symptoms may include persistent and worsening headaches, seizures, nausea and vomiting; problems with vision, hearing, balance or movement; and sometimes confusion and memory loss. Low-grade gliomas may have minimal initial symptoms. [brighamandwomens.org]

  SM can sometimes be confused with skin infections and inadvertently treated with antibiotics, which can delay the diagnosis of a recurrent or metastatic disease [5]. [hindawi.com]

  […] by vomiting severe or frequent vomiting without other signs of gastrointestinal illness vision problems, such as double vision, blurry vision, or loss of vision difficulty walking or balancing seizures weight gain or loss premature puberty clumsiness confusion [danafarberbostonchildrens.org]

In general, diagnostic imaging is required to visualize brain tumors, to assess their precise localization and extension. Magnetic resonance imaging is most appropriate for such studies. In T1-weighted images, malignant gliomas present as well-defined, hypointense areas that often encompass necrotic regions. Ring-like enhancement may be observed after administration of gadolinium. In T2-weighted images, these tumors display as hyperintense lesions. These settings also allow for the depiction of cerebral edema, which usually surrounds the brain tumor in a penumbra-like pattern. Finally, brain edema may be observed in diffusion-weighted images that depict brain tumors as hypointense regions. In general, mixed signals may indicate tumor-associated hemorrhages. Increased glucose uptake may be demonstrated by means of positron emission tomography scans.

Distinguishing between different types of brain tumors and gliomas requires a thorough analysis of tissue specimens that may be obtained during surgery, biopsy or fine-needle aspiration. The former usually allows for a more reliable diagnosis in histopathological and immunohistochemical studies. Because malignant gliomas frequently encompass necrotic regions, analyses of small amounts of neoplastic tissue may pose a major challenge. Representative specimens should also be used for molecular analyses. It is to be expected that future therapies for malignant glioma will target dysregulated intracellular signaling pathways and in this context, the identification of gene defects underlying tumor growth is gaining importance.

Surgical resection of neoplastic tissue is the mainstay of glioblastoma therapy; it aims at reducing the number of tumor cells and relieving local mass effects as far as possible. In this context, it should be noted that margins observed in images obtained by magnetic resonance imaging do not necessarily correspond to the maximal extension of the tumor [12]. Unfortunately, greater safety margins come at the high cost of neurological deficits and poor quality of life. After surgery, patients generally undergo adjuvant radiotherapy (a total dose of 60 Gy divided in 30 fractions delivered over the course of six weeks) and receive temozolomide, a DNA-alkylating agent [13]. Radiotherapy and chemotherapy are first-line treatment options in cases of diffuse midline glioma. Here, surgery is rarely indicated.

Current research is focused on identifying modulators that may be applied in personalized therapy, i.e., the aim is to address molecular targets contributing to tumor growth in individual patients. So far, promising results have mainly been obtained in vitro. Drugs like bevacizumab have already been tested in humans but have yielded contradictory results [14]. Nowadays, bevacizumab is primarily used to treat glioma patients who develop recurrence. Immunotherapy and use of oncolytic virus therapy are also being tested, but require further improvements.

Symptomatic therapy should be offered to augment the quality of life, e.g., analgesics may relieve headaches, antiepileptic drugs are indicated in patients suffering from seizures, diuretics and corticosteroids may reduce cerebral edema, and anticoagulants may prevent thromboembolism. Despite all efforts, recurrence and progressive neurological decline are likely.

While tumor stages and grades affect the prognosis of most cancer patients, gliomas do not typically metastasize and thus, the respective tumor grade is the single most important prognostic factor. As has been indicated above, malignant gliomas exclusively correspond to WHO grade IV. They are associated with a poor to unfavorable prognosis and usually, lead to death within months after diagnosis. Median survival times of five and eight months have been reported for primary and secondary glioblastoma, respectively [4], and less than 3% of glioblastoma patients remain alive after five years [5]. For diffuse midline glioma H3 K27M mutant, median survival times may be a few months longer [10].

According to the current classification system of central nervous system tumors as proposed by the World Health Organization (WHO), highly malignant glioma may correspond to [1]:

• Glioblastoma, IDH-wildtype, and its subtypes giant cell glioblastoma, gliosarcoma and epithelioid glioblastoma (most common type of malignant glioma)
• Glioblastoma, IDH-mutant
• Diffuse midline glioma H3 K27M mutant

The majority of those tumors have astrocytic differentiation, but they may also contain oligodendroglial components, multinucleated giant cells, small cells, sarcomatous and gemistocytic cells [2].

Genetic analyses of malignant gliomas revealed the following [3] [4]:

• IDH1 and IDH2 encode for isocitrate dehydrogenase 1 and 2, respectively, which are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. Both depend on NADP and generate NADPH, but while IDH1 encodes for a cytosolic enzyme, isocitrate dehydrogenase 2 is encountered in mitochondria. Although the precise pathogenetic roles of dysfunctional isocitrate dehydrogenase 1 and 2 are not yet known, they may affect DNA methylation and render cells more sensitive to oxidative damage.
• EGF receptor (epidermal growth factor receptor) is commonly overexpressed in glioblastoma, IDH-wildtype. Furthermore, these tumors often test positive for mutations of PTEN (phosphatase and tensin homolog, a tumor suppressor protein affecting cell cycle progression and survival) and degenerated cells may have lost chromosome 10.
• Glioblastoma, IDH-mutant, frequently present mutations of TP53 (tumor protein 53, a tumor suppressor protein involved in DNA repair and cell cycle regulation) and lack of the long arm of chromosome 19.
• H3 K27M describes a somatic mutation of histone H3 caused by the replacement of lysine with methionine at position 27.

Further molecular features characteristic of individual types of malignant glioma are discussed elsewhere [1].

The causes of mutations promoting the development of malignant glioma remain largely unknown. Presumably, both genetic and environmental factors contribute to this process. With regards to the latter, therapeutic irradiation has been proven to increase a patient's risk of brain tumors. Such a role has also been suggested for occupational exposure to carcinogens, smoking and dietary factors, but scientific evidence has not yet been provided [5]. Additionally, patients suffering from hereditary disorders such as neurofibromatosis type 1, Turcot syndrome, or Li-Fraumeni syndrome have a higher risk of developing malignant gliomas.

Gliomas account for more than 70% of primary brain tumors, and the vast majority of those tumors are highly malignant glioblastomas [5]. For this type of malignant glioma, annual incidence rates of 3.2 per 100,000 inhabitants have been reported in the United States [6]. Of note, when these data were collected, diffuse midline glioma H3 K27M mutant had not yet been defined as an individual entity.

Glioblastomas are 3.5 times more common in Caucasians than in patients of African or Asian descent. Accordingly, lowest incidence rates are observed in sub-developed regions of Africa, Central and South East Asia, and Latin America [5]. To date, it is not known whether these differences are owing to a genetic predisposition of certain ethnicities, to life expectancy or environmental factors. It has to be noted that brain tumors may be underdiagnosed in poorly developed regions. Malignant gliomas may be diagnosed in patients of any age, but most frequently affect the elderly. However, younger individuals seem to be more prone to develop low-grade glioma that subsequently transform into IDH-mutant glioblastoma [4]. Diffuse midline glioma H3 K27M mutant is sometimes referred to as pediatric high-grade astrocytoma, but this tumor may also be diagnosed in adults [7].

As per definition, gliomas arise from glial cells. There are distinct types of glial cells in the central nervous system, namely microglia, astrocytes, oligodendrocytes and ependymal cells. Data on microglial neoplasms is scarce, and what has formerly been designated microglioma is now referred to as primary lymphoma of the central nervous system [8]. Presumably, microglia originate from hematopoietic stem cells. In contrast, other types of glia develop from neuroepithelial stem cells and thus, astroglioma, oligodendroglioma and ependymoma including mixed tumors and variants have previously been classified as tumors of neuroepithelial tissue by the WHO [9]. It is important to note that the current classification takes into account molecular parameters and distinguishes astrocytic, oligodendroglial, ependymal and other gliomas [1].

Besides molecular features, histopathological and immunohistochemical properties are of importance to relate glioma with a determined population of glial cells. Results obtained by these means also allow for tumor grading and thus directly affect the patient's prognosis as well as therapeutic options. In general, higher grades are associated with more destructive tumor growth, worse prognoses and the need for more aggressive treatment. To elaborate in detail, the following grades may be assigned:

• Grade I: slowly growing tumors, possibility of cure after surgical resection
• Grade II: infiltrative growth, increased likelihood of recurrence after surgery
• Grade III: mitotic figures and nuclear atypia indicate higher malignancy
• Grade IV: poorly differentiated, abundant mitotic figures and nuclear anomalies, marked angiogenesis, necrotic foci

Although grade III tumors definitely have malignant potential, the term malignant glioma is generally reserved for WHO grade IV tumors of neuroepithelial origin. These include variants of glioblastoma as indicated above as well as diffuse midline glioma H3 K27M mutant. Malignant gliomas may arise de novo, and these tumors are usually of type IDH-wildtype, or they may develop after transformation of low-grade tumors into neoplasms of higher malignancy. The latter may be referred to as secondary gliomas and are frequently of IDH-mutant type[1].

Although therapeutic irradiation has been identified as a risk factor for malignant glioma, reducing exposure is usually not an option in patients suffering from hematological malignancies. This situation may change as soon as alternative treatment options for those diseases become available. Otherwise, no specific measures can be recommended to prevent malignant glioma.

Malignant glioma is a highly malignant brain tumor characterized by rapid and infiltrative growth. Surgical resection of neoplastic tissue is the mainstay of therapy, but recurrence after surgery is likely. Additionally, patients may receive chemotherapy and irradiation, but malignant brain tumors are often refractory to these therapeutic approaches. Progressive destruction of brain tissue is associated with an irreversible exacerbation of symptoms within months, severely reduced life quality and eventually death. Median survival times are less than a year in pediatric and adult patients. While this applies to all types of malignant glioma, such tumors may originate from distinct populations of glial cells, and thus differ with regards to histopathological, immunohistochemical and molecular features.

The central nervous system essentially consists of neurons and glial cells, i.e., cells that fulfill a myriad of functions to maintain optimum conditions for neuron function and the conduction of action potentials. Tumors that arise from the glial cells are named glioma. Gliomas differ with regards to growth behavior; malignant gliomas are characterized by highly aggressive and invasive growth, which leads to a progressive destruction of brain tissue. Consequently, affected individuals suffer from neurological deficits like aphasia, visual impairment, and cognitive disorders. They may also manifest psychiatric symptoms like mood swings, an altered mental status, and personality changes. Most commonly, though, patients with malignant glioma have headaches, nausea, vomiting or migraine-like seizures, which are caused by local mass effects. Malignant gliomas may be diagnosed in pediatric and adult patients. With the exception of therapeutic irradiation used to treat other malignancies, the causes of tumor development are still unknown. Unfortunately, malignant gliomas are refractory to common therapies used in cancer patients. To date, surgery remains the mainstay of treatment, but a complete resection of the brain tumor is rarely feasible. Patients have to undergo radiotherapy and chemotherapy. Despite this, the median survival time is still less than a year.

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