Brain Neoplasms

Tumors of the brain produce neurologic manifestations through a number of mechanisms. Small, critically located tumors may damage specific neural pathways traversing the brain. Tumors can invade, infiltrate, or supplant normal parenchymal tissue, disrupting normal function. Because the brain dwells in the limited volume of the cranial vault, growth of intracranial tumors with accompanying edema may cause increased intracranial pressure. Tumors adjacent to the third and fourth ventricles may impede the flow of cerebrospinal fluid, leading to obstructive hydrocephalus. In addition, tumors generate new blood vessels (ie, angiogenesis), disrupting the normal blood-brain barrier and promoting edema.

Brain neoplasms. Colloid cyst of the third ventricle with obstructive hydrocephalus. Image courtesy of Peter Ferrera, MD.

The cumulative effects of tumor invasion, edema, and hydrocephalus may elevate the intracranial pressure (ICP) and impair cerebral perfusion. Intracranial compartmental rise in ICP may provoke shifting or herniation of tissue under the falx cerebri, through the tentorium cerebelli, or through the foramen magnum.

Slow-growing tumors, particularly tumors expanding in the so-called silent areas of the brain, such as the frontal lobe, may be associated with a more insidious clinical course. These tumors tend to be larger at detection.

Most primary brain tumors do not metastasize, but if they do metastasize, intracranial spread generally precedes distant dissemination.

Metastatic brain tumors from non-CNS primary tumors may be the first sign of malignancy, or they may herald a relapse. Nonetheless, the signs and symptoms of brain metastases simulate those of primary brain tumors.

Leptomeningeal infiltration may present with dysfunction of multiple cranial nerves.

Although few factors are unequivocally associated with an increased risk of brain cancer, most CNS neoplasms are thought to arise from individual cell mutations. A few inherited diseases, such as neurofibromatosis, tuberous sclerosis, multiple endocrine neoplasia (type 1), and retinoblastoma, increase the predilection to develop CNS tumors. Primary CNS lymphoma is a relatively frequent occurrence in HIV patients. A prior history of irradiation to the head for reasons other than treatment of the present tumor may increase the chance of primary brain tumor.

The most common tumors originating from the cerebellopontine angle are acoustic neuroma and meningioma.

Metastatic tumors reach the brain via hematogenous dissemination through the arterial system. Lung cancer—especially small cell lung cancer—is by far the most common solid tumor disseminating to the brain, followed by breast cancer, melanoma, and colon cancer. Less common sources of metastasis are testicular cancer and renal cell cancer. Prostate, uterine, and ovarian cancers are unlikely sources of brain metastasis.

The American Cancer Society estimates that 24,530 brain and other nervous system cancers will be diagnosed in 2021.[3]  Estimates of the annual incidence rate of primary brain tumors range from 7-19.1 cases per 100,000 population. Metastatic tumors to the brain are more common, with more than 200,000 patients per year in the United States with a new diagnosis of intracranial metastases. Pituitary adenomas are exceptionally common, and they are frequent incidental findings on autopsy. Autopsy series of patients with systemic cancer show that intracranial metastases are present in 18-24% of patients.

The International Agency for Research on Cancer of the World Health Organization estimates that in 2020, brain and nervous system cancers occurred in 168,346 men and 139,756 women worldwide.[4]  Differences are seen between ethnic groups within the same country, and a 3-fold difference in incidence has been reported between countries worldwide. Developed countries appear to have the highest rates, but this may reflect better registration systems.

Meningiomas and pituitary adenomas are slightly more common in women than in men. Males are more likely to be diagnosed with brain tumors than females, with a male-to-female ratio of 1.5:1.

In children, brain tumors are the most prevalent solid tumor, second only to leukemia as a cause of pediatric cancer. The incidence rate of primary CNS neoplasms is 3.6 cases per 100,000 children each year. Tumors in the posterior fossa predominate in preadolescent children, with the incidence of supratentorial tumors increasing from adolescence to adulthood. Low-grade gliomas, such as astrocytomas, are more common in younger people than in older people. High-grade gliomas, such as anaplastic astrocytoma and glioblastoma multiforme, tend to originate in the fourth or fifth decade or beyond.

Prognostic features include the following:

• Tumor resectability, tumor location, age of the patient, and tumor histology are the primary determinants of survival.

• Without radiation therapy, the mean life expectancy of a patient with brain metastases is 1 month. Radiation therapy may extend survival to 4-6 months.

• Patients with seizures secondary to a brain tumor generally experience obvious neurologic deterioration over a 6-month course.

• Most patients with brain metastases die from progression of their primary malignancy rather than from brain damage.

In a study of 69 pediatric brain tumor survivors, the patients showed deficits in executive function, memory, and attention. Whole-brain radiation therapy, tumor size, young age at diagnosis, and male gender were risk factors for late cognitive sequelae.[5]  Adult survivors of pediatric brain tumors have an increased risk of psychiatric illnesses, including depression, anxiety, suicidal ideation, schizophrenia and related psychoses, and behavioral problems.[6]

In the United States, brain and other nervous system cancers are expected to cause approximately 16,830 deaths in 2018.[3]  Brain tumors are the second most common cancer in children, comprising 15-25% of all pediatric malignancies. Perhaps no other cancer is as feared as brain tumor, since severe disability, including paralysis, seizures, gait disturbances, and impairment of intellectual capacity may occur.

Presenting complaints of patients with an intracranial neoplasm tend to be similar for primary brain tumors and intracranial metastases. Manifestations depend on the cause of the symptoms, which may comprise any of the following:

• Increased intracranial pressure (ICP)
• Direct compression of essential gray or white matter
• Shifting of intracranial contents
• Secondary cerebral ischemia

Symptoms may be nonspecific and include any of the following:

• Headache
• Altered mental status
• Ataxia
• Nausea
• Vomiting
• Weakness
• Gait disturbance

Central nervous system (CNS) neoplasms also may manifest as follows:

• Focal seizures
• Fixed visual changes
• Speech deficits
• Focal sensory abnormalities

Onset of symptoms usually is insidious. However, an acute episode may occur with bleeding into the tumor, or when an intraventricular tumor suddenly occludes the third ventricle.

In a United Kingdom study of 139 children with brain tumors, the median time from symptom onset to diagnosis of a brain tumor was 3.3 months. Head tilt, cranial nerve palsies, endocrine and growth abnormalities, and reduced visual acuity were associated with a longer delay in diagnosis. Headache was the most common initial manifestation, occurring in 55 patients (40%). By the time of diagnosis, patients had a median of six signs and/or symptoms.[7]

In a study from the United States, the mean time to diagnosis in the emergency department from onset of any symptom was 86.3 days, and 104.5 days for headache. Approximately 91% of cases were diagnosed by computed tomography scan, with 48% of tumors located in the posterior fossa. Headache, nausea/vomitting, and gait disturbance were the most common presenting symptoms.[8]

Although headache is the symptom customarily associated with an intracranial neoplasm, it often is a late complaint. In addition, headache usually is not an isolated finding, and headache is the worst symptom in only one half of patients.

Other features of headache from brain tumors are as follows:

• Most headaches in patients with brain tumors are nonspecific and resemble tension-type headaches[1, 2]

• In patients with a history of headache, a change in the headache pattern may be cause for concern

• New onset of headaches in middle-aged or older patients is worrisome

• The location of the headache reliably indicates the side of the head affected, but it does not indicate the precise site of the tumor.

• Headaches are more common with posterior fossa tumors

• Headache is a more frequent symptom of intracranial tumor in pediatric patients

Prevailing portrayals of tumor headache that are in fact inaccurate include the following:

• Pain that is worst in the early morning
• Vomiting (with or without nausea)
• Exacerbation with Valsalva maneuvers, bending over, or rising from a recumbent position

Manifestations of brain tumor may reflect the tumor site, as follows:

• Mental status changes, especially memory loss and decreased alertness, may be subtle clues of a frontal lobe tumor. Complaints may be as mundane as sleeping longer, appearing preoccupied while awake, and apathy.

• Temporal lobe neoplasms may lead to depersonalization, emotional changes, and behavioral disturbances.

• Vision, smell, and other sensory disturbances may be caused by a brain tumor.

• An acoustic neuroma may present as intermittent (then progressive) hearing loss, disequilibrium, and tinnitus.

• Symptoms of pediatric posterior fossa tumors include increased irritability, unsteadiness, ataxia, headache, vomiting, and progressive obtundation.

• Supratentorial tumors in children are more commonly associated with seizures, hemiparesis, visual field cuts, speech difficulties, and intellectual disturbance.

Pituitary adenomas may be divided into two broad categories: nonfunctional and hypersecretory. Nonfunctional pituitary adenomas remain asymptomatic until they are large enough to encroach the optic chiasm and disturb normal vision. Most hypersecretory pituitary adenomas secrete prolactin, with affected women noting an amenorrhea-galactorrhea syndrome. Men with prolactin-secreting pituitary adenomas more commonly complain of headache, visual problems, and impotence.

Seizures, focal or generalized, may be the earliest expression of a brain tumor. Depending on the rate of growth of the tumor, seizures may be present for months to years before a brain tumor is diagnosed. Seizures are common in patients with supratentorial meningioma, affecting anywhere from 10% to 50% of individuals with these lesions, and are frequently the presenting symptom.[9]   A Jacksonian pattern (ie, one in which a focal seizure begins in one extremity and then progresses until it becomes generalized) is distinctive in suggesting a focal structural lesion of the cortex. 

Any middle-aged or elderly patients presenting with a first seizure should have CNS tumor high in the differential diagnosis. Patients with a brain tumor may present with acute neurologic changes mimicking those associated with stroke.

No physical finding or pattern of findings unmistakably identifies a patient with a CNS neoplasm. Findings in these patients may include the following:

• Based on their location, intracranial tumors may produce a focal or generalized deficit, but signs may be lacking (especially if the tumor is confined to the frontal lobe) or even falsely localizing.

• Papilledema, which is more prevalent with pediatric brain tumors, reflects an increase in ICP of several days or longer. Papilledema usually does not cause visual loss. Not all patients with CNS tumors develop papilledema.

• Diplopia may result from displacement or compression of the sixth cranial nerve at the base of the brain.

• Impaired upward gaze, called Parinaud syndrome, may occur with pineal tumors.

• Tumors of the occipital lobe specifically (see the image below) may produce homonymous hemianopia or partial visual field deficits.

  Brain neoplasms. Occipital lobe glioblastoma with surrounding edema.

• Anosmia may occur with frontal lobe tumors.

• Brainstem and cerebellar tumors induce cranial nerve palsies, ataxia, incoordination, nystagmus, pyramidal signs, and sensory deficits on one or both sides of the body.

• Tumors in the region of the cerebellopontine angle may impair the functions of the three cranial nerves that traverse this region: facial, cochlear, and vestibular. Acoustic neuromas most commonly originate from the vestibular nerve (part of cranial nerve VIII).

Patients with cancer are predisposed to medical complications, including bleeding disturbances (hyperviscosity), metabolic disorders (hypercalcemia), and production of excessive hormones (syndrome of inappropriate antidiuretic hormone secretion). Therefore, with clinical suspicion of cancer, obtain routine laboratory studies on admission, including the following:

• Complete blood cell count (CBC)
• Coagulation studies
• Electrolyte levels
• Comprehensive metabolic panel

Obtain neuroimaging studies in patients with symptoms suggestive of an intracranial neoplasm (eg, acute mental status changes; new-onset seizures; focal, motor, or sensory deficits, including gait disturbance; suspicious headache; signs of elevated ICP, such as papilledema). Although some tumors exhibit a characteristic appearance, do not make an unequivocal diagnosis based solely on radiologic findings.

Diagnosis of a suspected brain tumor is dependent on appropriate brain imaging and histopathology. Gadolinium-enhanced magnetic resonance imaging (MRI) is the preferred modality because of its resolution and enhancement with contrast agents. If MRI cannot be performed (e.g., in patients with metallic implants, embedded devices, or claustrophobia), head and spine computed tomography (CT) is acceptable, although the resolution is not as high as MRI and it cannot adequately assess lesions in the posterior fossa and spine.[10]   

Drawbacks to MRI include incompatibility with certain medical equipment, longer imaging times (increased risk of motion artifact), and poor visualization of the subarachnoid space. Neither CT nor MRI can be used to differentiate tumor recurrence from radionecrosis.

Additional imaging such as magnetic resonance perfusion, magnetic resonance spectroscopy, or fluorodeoxyglucose positron emission tomography may be necessary for diagnosis and staging, and should be ordered only under the direction of the treating physician.[10]

Generally, care of patients with a brain tumor is multidisciplinary, requiring the involvement of a neurosurgeon, an oncologist, a radiologist, and an expert in radiation therapy. The patient's primary physician best manages coordination of consultants, but the responsible neurosurgeon should direct the treatment of specific postoperative complications or care. New occurrence of CNS tumor may require transfer to a facility with appropriate neurosurgical staff. 

Management varies greatly depending on tumor location, tissue type, and comorbid conditions. Surgical treatment options may include tumor removal or debulking, installation of a ventricular shunt, and placement of radioactive implants.

Prehospital care is supportive and directed to the presenting symptom complex. For example, treat seizures in the usual manner. Airway disturbance, breathing difficulty, signs of pronounced elevation in intracranial pressure (ICP), and notable impairment of consciousness may necessitate definitive airway control with endotracheal intubation and, possibly, hyperventilation.

Emergency department (ED) treatment of the patient with an intracerebral neoplasm depends on both the nature of the tumor and the general condition of the patient. Decisions regarding surgical resection, initiation of radiation treatment, and chemotherapy are beyond the scope of practice of the ED physician.

A common problem confronting the ED physician is a patient with a known brain neoplasm complaining of a headache or worsening other symptoms. This scenario always raises the possibility of tumor recurrence or worsening cerebral edema. Obtain a CT scan or MRI to rule out life-threatening events, such as hemorrhage or herniation.

Corticosteroids may dramatically reduce signs and symptoms related to cerebral edema. Affected patients may experience relief within the first few hours of steroid therapy.

Dexamethasone is the agent of choice because of its minimal salt-retaining properties. Recommended doses generally range from 4-24 mg daily. For patients with impaired consciousness or signs of increased intracranial pressure (ICP), 10 mg IV[11] or 10-24 mg IV are recommended as the first dose. Side effects, notably proximal muscle weakness, are dose-dependent. Often, corticosteroids can be tapered or discontinued after definitive therapy. The final dose of steroids should be the lowest necessary to control the patient's neurologic symptoms.

For patients with signs or symptoms of impending herniation and airway compromise, consider use of adjunctive medications for rapid-sequence intubation. These might include lidocaine and medication for rapid-onset neuromuscular blockade, with precautions to diminish fasciculations. Induction agents, such as thiopental, may be used.

After definitive control of the airway, consider gentle hyperventilation.

Discuss the use of mannitol with the appropriate consultant. Although mannitol may reduce transiently lower ICP, concern about rebound increases in ICP makes its use problematic.

Further inpatient care is complex and may involve multiple consultants, depending on the tumor type and overall prognosis. The admitting physician should coordinate oncologic or radiation oncology consultations. Radiation therapy for gliomas usually is performed on an outpatient basis.

Definitive diagnosis requires tissue biopsy performed by a qualified neurosurgeon. Neurosurgical options include resection or debulking and placement of a ventricular shunt with obstructive hydrocephalus.

Acute symptoms in a patient with a brain tumor, particularly when signs and symptoms resemble stroke, suggest the possibility of acute hemorrhage into a tumor. Brain neoplasms predisposed to hemorrhage include lung cancer, melanoma, and choriocarcinoma.

Lesions near the third ventricle can cause paroxysmal symptoms of headache, syncope, or mental status change. Additionally, vomiting, ataxia, memory changes, visual disturbances, or personality changes may occur.

Episodic increases in ICP secondary to pressure arising from blockage of cerebrospinal fluid outflow cause transient symptoms. Sudden death is a reported complication from obstruction of outflow drainage from the third ventricle. Sudden increases in ICP may lead to life-threatening brain herniation, which shifts the brain parenchyma in the direction of least resistance: caudally through the foramen magnum (posterior fossa tumors) or transtentorial apertures.

Some pituitary tumors are hormonally active and capable of producing acromegaly or galactorrhea. Pituitary apoplexy, an unusual complication arising from pituitary adenomas, describes hemorrhage into the tumor, leading to headache, deterioration of vision, oculomotor palsies, and shock secondary to acute adrenal insufficiency.

Although radiation therapy rarely causes acute toxicity with modern dosing schedules and concomitant use of steroids, subacute or chronic effects may occur, as follows:

• Subacute encephalopathy occurs 6-16 weeks after radiation therapy and is characterized by somnolence and headaches

• Chronic effects of prolonged radiation treatment tend to be more serious and range from impairment of intellectual capacity to complete incapacity

Class Summary

Steroids are thought to stabilize cell membranes and diminish the vasogenic edema associated with tumors.

Dexamethasone (Decadron)

Used in treatment of vasogenic cerebral edema; improves endothelial integrity.

Class Summary

These agents may reduce ICP and cerebral edema by creating an osmotic gradient across an intact blood-brain barrier. As water diffuses from the brain into the intravascular compartment, ICP decreases.

Mannitol (Osmitrol)

May reduce subarachnoid space pressure by creating osmotic gradient between cerebrospinal fluid in arachnoid space and plasma. Not for long-term use.