Pathophysiology of Signs and Symptoms Associated with Brain Tumors

Parenchymal brain tumors produce symptoms by three mechanisms: (1) Tumor cell infiltration occurs along nerve fiber tracts in both the white matter and the cortex. Low-grade astrocytomas and oligodendrogliomas behave in this fashion, often producing seizures. (2) Tumor cells grow into a mass, displacing but not destroying the surrounding brain tissue. Metastatic brain tumors typically grow this way. The patient presents with symptoms and signs of an intracranial mass, which often resolve after treatment. (3) A combination of tumor cell infiltration and growth as a mass destroys the surrounding neuropil. Malignant gliomas behave in this fashion, producing symptoms and signs that may not improve after treatment. Although each mechanism takes place independently, considerable overlap occurs, and, as the tumors evolve, all three mechanisms come into play.

Tumors that arise outside of the parenchyma (e.g., meningiomas) rarely infiltrate into the neuropil; instead, they produce their effects by compression of the adjacent brain directly and by the production of cerebral edema. These tumors may present only as a mass, without focal symptoms, or may induce a seizure focus in the underlying brain. As the tumor grows, producing further brain compression, symptoms and signs of brain damage become evident. Resection, especially if carried out when the tumor is small, often restores the patient to a normal neurological state.

Intracranial neoplasms characteristically produce progressive symptoms. The rate of progression varies from an acute apoplectic onset (e.g., after hemorrhage into an intracranial neoplasm, or a seizure associated with cortical stimulation) to progressive mental deterioration. Thus, a patient with a low-grade glioma may have seizures for months to years, developing progressive neurological signs only late in the course of disease. By contrast, a patient with a malignant glioma may develop headaches and focal neurological signs over a few weeks. An acute hemorrhage into a malignant brain tumor may bring the patient to the hospital abruptly with little warning that an intracranial tumor has been developing. Similarly, it is not unusual for a patient to seek psychiatric help because of depression or change in work habits, only to be found to harbor a cerebral neoplasm. It is the progressive nature of the symptoms that alerts the clinician to suspect brain tumor.

Brain tumors produce generalized symptoms because of their expanding mass effect. They produce focal symptoms by direct compression on, or infiltration into, the surrounding neuropil.

Generalized symptoms from brain tumors are manifestations of increased intracranial pressure, a result of the expanding tumor volume and the associated edema. Tumors may obstruct the cerebrospinal fluid (CSF) pathways, producing hydrocephalus. As the mass enlarges, intracranial pressure rises; brain tissue may be displaced through the rigid intracranial dural passageways, producing various herniation syndromes. Cerebral dysfunction and headache ensues. Abrupt headache and worsening neurological signs may accompany sudden increases in intracranial pressure that last 5 to 20 minutes. These episodes of raised pressure have a characteristic appearance on recording of intracranial pressure leading to their name, plateau waves.³

The herniation syndromes are life-threatening. Because the skull is divided into compartments by the relatively inelastic dura, an expanding mass in one compartment forces brain tissue through the openings between compartments, tearing blood vessels and compressing the neuropil (Fig. 108-1).⁴ A unilateral cerebral mass may force the medial surface of the brain beneath the falx cerebri (cingulate herniation). Transtentorial and tonsillar herniation may occur because of displacement of brain tissue through, respectively, the tentorial notch and foramen magnum. Table 108-1 lists the pathogenesis and clinical manifestations of the herniation syndromes.⁴

TABLE 108-1 Herniation Syndromes

PATHOGENESIS	CLINICAL MANIFESTATION
CENTRAL HERNIATION
Lateral and Forward Shift of Diencephalon and Upper Midbrain
Diencephalic compression	Decreased state of consciousness, small pupils, Cheyne-Stokes respiration
Midbrain pontine compression	Midposition fixed pupils Loss of oculocephalic reflexes Abnormal motor signs Hyperventilation

Lower pons-medullary compression Tonsillar (Foramen Magnum) Herniation Posterior fossa mass pushes cerebellar tonsils through foramen magnum, compressing medulla Rapid loss of consciousness, stiff neck, vomiting, skew deviation of eyes, irregular respirations, death UNCAL HERNIATION Temporal Lobe Herniation through Tentorial Notch, Compressing Ipsilateral third nerve Third nerve palsy Posterior cerebral artery Homonymous hemianopia Midbrain   Opposite cerebral peduncle Ipsilateral hemiparesis

Adapted from Posner JB, Saper CB, Schiff N, Plum F. Plum and Posner’s Diagnosis of Stupor and Coma, 4th ed. New York: Oxford University Press, 2007.

The clinical manifestations of transtentorial herniation depend in part on the site of the mass lesion. Central herniation occurs when the mass effect is bilateral or becomes symmetrical, causing a downward shift of the diencephalon and upper brainstem. Uncal herniation occurs when the mass is unilateral, especially temporal, and the medial temporal lobe is displaced inferiorly and medially through the tentorial notch.

The clinical manifestations of the two herniation syndromes overlap, although there are differences in the specific nature and temporal sequence of individual symptoms. With central herniation, diencephalic compression produces decreased state of consciousness, small pupils, and respiratory abnormalities. With progression, the pupils become midposition and fixed, respirations are frequently Cheyne-Stokes; decorticate and decerebrate posturing follows; and progressive coma ensues. Ultimately, apnea, slow pulse, and raised blood pressure presage death. In uncal herniation, the ipsilateral third nerve may be compressed, leading to partial oculomotor palsy, with paresis of extraocular movement and a dilated pupil. The posterior cerebral artery may be compressed against the tentorium, producing a homonymous hemianopia. Further progression is identical to that of central herniation. Occasionally, the opposite cerebral peduncle may be compressed against the tentorium, producing an ipsilateral hemiparesis, one of the false localizing signs (i.e. neurological signs that incorrectly suggest a location of a specific lesion). They also include unilateral or bilateral lateral rectus palsy from sixth nerve compression. False localizing signs are more common in slowly growing neoplasms like meningiomas.

Although tonsillar herniation can be caused by supratentorial mass lesions, a more common cause is an expanding posterior fossa mass, which forces the cerebellar tonsils through the foramen magnum, compressing the medulla. The patient becomes obtunded, with headache, vomiting, stiff neck, and, occasionally, opisthotonos. Other signs include skew deviation of the eyes and other disconjugate eye movements, arterial hypertension, and syncope with cough or sudden postural change. Respiratory activity is irregular, and acute apnea may occur. Upward herniation may occur with rapidly expanding cerebellar masses, wherein the brainstem is forced upward through the tentorial notch. Lumbar puncture may produce tonsillar herniation acutely.

Cerebral edema accompanies growing brain tumors. It is produced mostly within a parenchymal brain tumor but also comes from the surrounding brain tissue as a result of the release of vasogenic permeability factors produced by the tumor, which act on brain capillaries.⁵ (The vascular permeability factor has been identified as vascular endothelial growth factor, which plays an important role in angiogenesis of tumors.⁶) Cerebral edema increases the total size of the mass. It is not unusual for a tumor of perhaps 20 g to produce a mass of nearly 100 mL because of the associated edema. Cerebral edema may also be produced by an extra-axial tumor, in which case the edema, also vasogenic in origin, comes only from the brain tissue itself.

Treatment of cerebral or cerebellar herniation includes corticosteroid hormones (e.g., dexamethasone, 10 mg intravenously, followed by oral divided doses of 16 mg/day), intravenous mannitol 25 to 50 g, and sometimes intubation and hyperventilation to reduce plasma carbon dioxide and thus reduce cerebral blood flow. Subsequent treatment depends on the site and nature of the tumor.

Focal symptoms occur as a direct effect of the tumor’s growth into the surrounding neuropil. As the tumor infiltrates along nerve fiber tracts or surrounds neurons (satellitosis), it ultimately interferes with neurological function. “Irritation” from the tumor on adjacent cortex may produce seizures. Seizures are a common manifestation of intracranial tumor, both generalized and focal. More commonly, the tumor produces loss of neurological function, manifested as weakness or sensory disturbances. Finally, the tumor itself may hemorrhage, producing acute headache and focal localizing signs. Tumors that are particularly likely to hemorrhage include glioblastomas and metastatic tumors from melanoma, choriocarcinoma, and testicular carcinomas.

Clinical Manifestations of Intracranial Tumors

The symptoms and signs of intracranial tumor depend on the size of the tumor, its location, and its rate of growth. Manifestations may be general or focal, or both. General manifestations include mental changes, headache, generalized convulsions, nausea, and vomiting. Examples of focal signs include focal seizures, weakness, sensory abnormalities, speech disturbances, and visual defects. It is important to recognize that general and focal manifestations overlap, as does their pathogenesis. Thus, although mental dullness often accompanies large masses, mental changes may occur with small focal tumors in the temporal lobe, or may be part of an aphasia syndrome. In addition to its size, the location of the tumor in the brain quantitatively influences signs and symptoms. Thus, a small tumor in the speech or visual association cortex may produce more signs than does a large frontal tumor. In addition, the character of an abnormality may differ according to whether it accompanies a generalized increase in intracranial pressure or is part of a specific focal dysfunction.

SOCIAL DISTURBANCES “PSYCHOLOGICAL” SYMPTOMS

Headache

Headache occurs from traction of basal meningeal structures and is worse the larger the mass, although even small tumors may produce such traction, especially meningiomas. The degree and intensity of headache also relate to the rapidity with which traction develops. A rapidly enlarging intracranial mass may produce sudden severe headache, whereas a slowly growing mass may become quite large without producing headache.

Headache occurs in about 50% of patients with brain tumor at some time during the course of the illness.⁸ Headache is more prominent and tends to occur earlier when the tumor produces increased intracranial pressure. Of special importance is a headache that has recently changed in character, for example, becoming more intense, frequent, or longer lasting. Although classic brain tumor–associated headaches are severe, often worse in the morning, all brain tumor patients do not have morning headaches, and in fact may have head pain at any time of day or night.⁸ The head pain from brain tumor is often intermittent and may be described as deep, aching, or pressure-like rather than the more characteristic throbbing pain of migraine. It is often aggravated by the Valsalva maneuver, as in coughing or straining, and frequently becomes worse through change of posture. The headache that occurs in the early morning hours appears to be related to the recumbent posture and is thought to be associated with increased intracranial pressure as a result of lying down.

Generalized Convulsions

Seizures occurring for the first time in adults are more likely to be due to focal cerebral disease, especially neoplasms, than are seizures that begin in childhood, which are more often part of the epilepsies that are characteristic of this age group.⁹ Intracranial tumors produce both generalized major motor convulsions and various forms of focal seizures. Petit mal epilepsy is probably never due to a neoplasm, but minor temporal lobe seizures (partial simple or complex) that resemble petit mal attacks may accompany temporal lobe tumors. Jacksonian seizures that progress from one body part to another usually imply a lesion of the motor or sensory cortex. Lesions of the temporal lobe characteristically give rise to partial complex (psychomotor) seizures that may be associated with olfactory hallucinations (uncinate fits), disorders of visual or auditory perception, episodes of déjà vu, or automatic behavior.

Seizures, both generalized and focal, occur in 25% to 50% of patients with cerebral tumors (Table 108-3).¹⁰ They are more likely to accompany slowly growing tumors than they are the more rapidly growing malignant neoplasms.¹¹ A review of data of the Brain Tumor Cooperative Group (BTCG) database revealed that seizures occurred as the initial manifestation of tumor in 50% of patients with anaplastic astrocytoma but in only 27% of patients with glioblastoma multiforme. Seizures have been reported to occur in 25% of patients with reported malignant gliomas.¹² Low-grade astrocytomas and oligodendrogliomas are more likely to present as seizures than are other tumors; indeed, a single seizure is now the most common presentation of a patient with a low-grade glioma diagnosed by magnetic resonance imaging (MRI). A syndrome of low-grade gliomas as a cause of chronic epilepsy has been recognized.¹³ Generalized seizures may occur with tumors in a variety of locations, whereas focal seizures are more common with tumors in the motor or sensory subcortical regions. Partial complex seizures are much more frequent with tumors of the temporal lobe than tumors located elsewhere in the brain. Seizures infrequently accompany infratentorial childhood brain tumors but occur in 22% of children younger than 14 years with supratentorial tumors and 68% of older teenagers with such tumors.¹⁴

Papilledema

Papilledema consists of swelling of the optic nerve head with engorgement of the retinal veins; it may be accompanied by hemorrhages into the nerve and adjacent retina. Its presence almost always indicates raised intracranial pressure. In the older literature, papilledema was a frequent finding in patients with brain tumors. Thus, Huber¹⁵ reported that of his 1166 patients with brain tumor, 59% had papilledema, and 41% did not. In recent years, the overall incidence of papilledema in patients with brain tumor has decreased; currently, fewer than 20% of such patients have papilledema, although it is more common with increased intracranial pressure.⁸ The reduced incidence appears to be related to earlier diagnosis, the initiation of corticosteroid hormones to control raised intracranial pressure, and the earlier specific therapy of the tumors.

Focal Manifestations of Intracranial Tumor

Focal clinical manifestations of intracranial tumor depend on which regions of nervous system are impaired and, by definition, vary with the location of the process (Table 108-4). Focal seizures may accompany tumor invasion of the cortex. A jacksonian seizure is most likely to occur with central-parietal tumors, whereas partial complex (psychomotor) seizures are usually associated with temporal lobe tumors.

TABLE 108-4 Focal Signs and Symptoms Accompanying Brain Tumors and Their Localization

SYMPTOMS AND SIGNS

LOCALIZATION

FOCAL SEIZURE Jacksonian Partial (psychomotor) seizure VISUAL DISTURBANCES Altered visual acuity Hemianopia or quadrantanopia Bitemporal field cut Diplopia, nystagmus LANGUAGE AND SPEECH DISTURBANCES Dysphasia or aphasia (expressive and receptive) Dysarthria HEARING DISTURBANCES Deafness, vertigo MOTOR DISTURBANCES Weakness Incoordination (clumsiness, dysmetria) SENSORY DISTURBANCES Dysesthesia Proprioception Numbness Cortical discrimination GAIT DISTURBANCES Weakness or sensory problems Ataxia Apraxia of gait URINARY DISTURBANCES Incontinence

Alteration of vision implies involvement of the visual apparatus, including a problem in the eye itself, the occipital cortex, or the oculomotor nerves. Visual loss may involve reduced visual acuity, the occurrence of field defects, or diplopia. Occipital lesions produce variously congruent homonymous hemianopias. Parietal lesions and temporal lobe lesions produce corresponding, variably congruent homonymous quadrantanopia. Tumors growing out of the sella turcica may compress the optic chiasm, inducing a corresponding bitemporal hemianopia, or a combination of partial bitemporal hemianopia and unilateral blindness. Pupillary abnormalities and oculomotor abnormalities may be caused by tumors growing in the base of the brain and involving the third cranial nerve, fourth nerve, or sixth nerve. As noted previously, a sixth nerve paresis may accompany mass lesions as a false localizing sign.

Hearing impairment may mean reduced auditory acuity or the occurrence of tinnitus and may be associated with vertigo. Hearing impairment is especially common in tumors that involve the eighth cranial nerve but may also accompany meningeal carcinomatosis and tumors of the fifth cranial nerve.

Speech disturbances include impaired spoken language and understanding speech and may be transient or progressive; expressive and receptive dysphasia progressing to aphasia occurs. Generally, tumors involving the dominant posterior-inferior frontal lobe produce an expressive aphasia; those involving posterior parietal or posterior temporal lobe produce mixed receptive-expressive aphasia. A speech disorder involving articulation, called dysarthria, can accompany tumors of the posterior fossa or cerebral hemisphere and is not unusual in meningeal carcinomatosis.

Motor signs include weakness, postural disturbances, incoordination, and tremor. Subcortical tumors of the hemispheres frequently produce weakness of the contralateral body side. Usually increased deep tendon reflexes and other evidence of increased tone are seen. The plantar response on the affected side may be extensor. Posterior fossa tumors may produce long-tract signs with accompanying weakness and incoordination. Cerebellar tumors frequently produce incoordination, difficulty in walking, and dysmetria (uncoordinated rapid alternating movements or point-to-point testing, e.g., “finger to nose”); the tone is often diminished.

Sensory disturbances include paresthesias (tingling sensations), numbness, or altered sensation (e.g., dysesthesia, burning sensation on touching) and imply lesions in the cerebral hemispheres or posterior fossa. Cortical (usually parietal lobe) disturbances include proprioception loss, sensory discrimination (two-point, graphesthesia), and astereognosis.

Gait disorders may accompany weakness, incoordination, or sensory disturbances and include falling and ataxia. Ataxia may accompany tumors in the posterior fossa or, occasionally, in the frontal lobes (apractic gait). Anosmia may be associated with infrafrontal meningiomas, which can compress the olfactory or first cranial nerve. Precipitate urination may be caused by bifrontal gliomas. Neuroendocrine disturbances frequently occur in pituitary and pineal tumors. As noted previously, cerebral hemorrhage into a tumor (usually choriocarcinoma), testicular tumors, melanomas, glioblastomas, and, less frequently, other tumors may also be associated with subarachnoid hemorrhage. Skull tumors, especially metastatic, may be associated with subdural collections of tumor and subdural effusions; the patient may present as if a chronic subdural hematoma were present. Meningeal carcinomatosis is frequently associated with multifocal neurological signs and symptoms, including cerebral, cranial nerve, and spinal cord and nerve disturbances.

Tumors of the cerebral hemispheres are characterized by progressive, focal neurological deficit, and commonly by generalized or focal convulsive seizures.

Karnofsky Performance Score

The clinical symptoms and signs reviewed alert the physician to the possibility of brain tumor and offer clues to its localization. The same clinical features may be used to follow the patients during treatment and may be combined to semiquantify their quality of life. In the early days of cancer chemotherapy, Karnofsky and Burchenal established criteria for patients’ performance status as one measure of the outcome of treatment.¹⁹ The Karnofsky performance score (KPS) quickly became a standardized tool for expressing such outcome and was adapted for brain tumor treatment studies. The KPS is a 10-grade scale describing the patient’s capabilities (Table 108-5). KPS scores of 80 to 100 apply to patients who can work or maintain a home. KPS scores of 50 to 70 apply to patients whose clinical status prevents them from working. KPS scores of 40 and below apply to patients who are disabled. A number of quality-of-life instruments have since been tested, adapted for brain tumors, and compared with the KPS.^20–22 Nevertheless, the KPS remains a mainstay of brain tumor studies.

TABLE 108-5 Karnofsky Performance Score for Brain Tumor Patients

SCORE	PATIENT STATUS
100	Normal, no complaints, no evidence of disease
90	Able to carry on normal activity, minor symptoms
80	Normal activity with effort, some symptoms
70	Cares for self, unable to carry on normal activity
60	Requires occasional assistance, cares for most needs
50	Requires considerable assistance and frequent care
40	Disabled, requires special care and assistance
30	Severely disabled, hospitalized, death not imminent
20	Very sick, active supportive treatment needed
10	Moribund, fatal processes are rapidly progressing

Paraneoplastic Disorders

The paraneoplastic neurological disorders consist of a diverse group of syndromes affecting the central nervous system, peripheral nervous system, muscle, and neuromuscular junctions that occur in patients with cancer but are not caused by direct invasion of the cancer into the nervous system.² The cause of these disorders has not been proved, although much evidence suggests an immunologic connection for many if not most of them. Thus, a number of antibodies have been found in the serum (and sometimes the CSF) of affected patients that react with internal neuronal antibodies (Table 108-6). Specific antigens have been identified for some of the antibodies, and for some, the gene defect has also been determined. Paraneoplastic neurological disorders are rare diseases, although their identification depends on the vigor with which a diagnosis is pursued. The associated cancers are often small at the onset of the neurological disorder and span the range of the common tumors, including small cell lung cancer, ovarian and breast cancer, and the lymphomas. However, within each category of cancer, the incidence of paraneoplastic disorder is still rare, especially for the specific disorders, such as paraneoplastic cerebellar degeneration. The incidence rises if one considers the nonspecific disorders such as sensorimotor peripheral neuropathy, which may accompany the cachexia of advanced cancer. Moreover, several of the specific disorders may occur in the absence of cancer.

This review concentrates on the specific paraneoplastic disorders, especially of the brain. Also included are functional impairment of the neuromuscular junction (Lambert-Eaton myasthenic syndrome), sensory neuronopathy, and the inflammatory myopathies. One entity, progressive multifocal leukoencephalopathy (PML), used to be included among the paraneoplastic disorders until it was shown to be caused by a virus. Clinically, PML may resemble one of the paraneoplastic disorders, but it is readily distinguished from them by MRI.