Sci. Aging Knowl. Environ., 24 August 2005
Vol. 2005, Issue 34, p. dn2
[DOI: 10.1126/sageke.2005.34.dn2]

NEURODEGENERATIVE DISEASE CASE STUDIES

Brain Tumor-Associated Dementia

James McC. Noble, Peter Canoll, and Lawrence S. Honig

The authors are at Columbia University College of Physicians and Surgeons, in the Departments of Neurology (J.M.N., L.S.H.) and Pathology (P.C.), and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain (L.S.H.) and Gertrude H. Sergievsky Center (L.S.H.), New York, NY 10032, USA. E-mail: jnoble{at}neuro.columbia.edu(J.M.N.); lh456{at}columbia.edu(L.S.H.)

http://sageke.sciencemag.org/cgi/content/full/2005/34/dn2

Abstract: In this case study, we describe a patient with a dementia due to a brain tumor. This unusual cause of dementia illustrates the importance of a thorough evaluation of anyone who experiences relatively sudden changes in cognitive functions. The disorder had features common to other dementias but also had some unusual attributes that made a diagnosis of neurodegenerative disease less likely. Common features included intellectual decline involving difficulties in word-finding, the occurrence of paraphasia, poor concentration, disorientation in familiar environments, problems performing routine complex tasks, and elements of social withdrawal. Unlike more common degenerative dementias, however, there was no marked memory involvement. In addition, the onset of illness was rapid and associated with headaches, incontinence, and some gait and motor dysfunction.

Introduction Back to Top

Dementia is a condition in which there is progressive deterioration of intellectual capacity. Typically, it involves impairment of various cognitive capacities, including memory (forgetfulness, misplacing objects, inability to recall recent events), language (difficulty finding words or understanding written or spoken speech), visuospatial functions (difficulty navigating), and behavior. Whereas a large number of conditions can cause dementia, the most common cause is Alzheimer's disease, which is a slow, insidious disorder, often occurring among the elderly, most commonly marked by memory impairment, frequently with prominent loss of awareness and insight. Atypical dementias include those that present earlier in life (e.g., before age 60) and with more rapid deterioration, or involve nonmemory functions more than memory.

Mr. G. was a 75-year-old left-handed man who presented for neurological evaluation because his family had noticed a marked change in behavior over 3 months. He exhibited mental slowness, problems finding words, and difficulties in naming common objects. He was also having some minor problems remembering things. At times he was disoriented and confused. For example, if he were driving and saw an exit sign, he would think to himself, "What does that mean?" His family had also expressed concern about his driving abilities when they noticed that he was "weaving." Over the past 3 months, he had become much quieter and less energetic, a dramatic change from his usual personality, and had developed marked urinary incontinence, which had never before been a problem. Over the past 2 weeks, he had had frequent headaches centered at the forehead, although he had never had headaches before in his life. He had experienced some minor, but noticeable, changes in his agility when walking, which were accompanied by leg pains. He also reported generalized body aches, fatigue, low energy levels, palpitations, ankle swelling, and shortness of breath. These symptoms were of concern in that they represented a significant change in a variety of brain functions and suggested a dementia involving confusion, as well as language, personality, and behavior changes. However, the fact that memory complaints were not as prominent as other changes, the occurrence of new headaches, the involvement of gait and continence problems, and the rapidity of these changes, suggested the possibility of an expansive structural brain lesion.

Medical History Back to Top

Past medical history revealed that Mr. G. was a generally healthy person who had had asthma as a child and some mild angina and high cholesterol levels in adulthood. Past surgical history included a tonsillectomy during childhood and bilateral cataract removals during the past 10 years. He had not had any changes in weight over the past year, and a recent routine general medical examination had not detected anything unusual. Mr. G. was not taking any medications regularly other than an over-the-counter sleep aid.

Social History Back to Top

Mr. G. had a bachelor's degree, was retired, and lived alone. He had no history of tobacco smoking or excessive alcohol consumption.

Family History Back to Top

Mr. G.'s father died at age 49 of obstructive lung disease due to tobacco smoking. His mother died at age 76 of a brain tumor. One of his six siblings had died of a brain tumor at age 80, whereas two others died of lung cancer at ages 59 and 79.

Neurological Examination Back to Top

Mr. G. exhibited problems with naming and finding words, which affected his performance in some aspects of the mental status examination. Overall, Mr. G. appeared disoriented. He was able to correctly state the current month, date, year, and season but struggled to come up with the correct day of the week. He was able to state the city, county, and floor of the hospital where the tests were being conducted but was unable to recall the correct name of the institution or its street address. At first he stated the name of another hospital (a semantic paraphasia), and then a word that resembled the name of the institution but was actually the name of a type of food (a phonemic paraphasia). Attention and concentration were somewhat variable. He displayed some lapses in concentration during the examination but had little difficulty spelling a five-letter word backward. He made two errors when serially subtracting 7 from 100, showing mild problems in arithmetic ability. His language functions were impaired; specifically, speech production was slow, with prominent difficulties in finding words. Although the patient could name simple objects, such as a watch, pen, or necktie, he was unable to name parts of these objects. He would call a pen clip "the thing that holds the pen" (a circumlocution) and the knot of a necktie "the wedge" (a paraphasia), and he could not name a watchband. On the other hand, his comprehension was relatively intact, as he was able to follow complex commands. He could also read and write normally. Memory testing showed that he was able to register and repeat three words but that he could recall only two of the three after a 5-minute delay. He had no difficulty with a test that required him to perform a sequential set of hand movements. His score on a mental status screening instrument, the Folstein Mini-Mental Status Examination was 27/30, which in this high-functioning man was consistent with cognitive impairment but not in itself diagnostic of dementia.

Examination of cranial nerve function showed normal vision and movements of the eyes, symmetric facial movements, and no difficulty with speech articulation. Motor examination revealed normal muscle bulk and tone throughout but slightly better fine finger movements on the left side, indicating minor motor incoordination on the right. Testing of strength revealed subtle weakness of the muscle groups in the right arm as compared with the left. Rapidly alternating movements and finger-to-nose-to-finger movements were slow. Similarly, gait was slow and somewhat unstable. Sensory examination did not reveal any abnormalities. Reflex examination showed an asymmetry of the deep tendon reflexes in the arms, whereby reflexes were slightly more brisk on the right arm than on the left, although the reflexes were symmetrical in the legs. No pathological plantar reflexes or frontal release reflexes were detected.

Diagnostic Imaging Back to Top

Because of the medical history of recent changes in mental behavior, computerized tomography (CT) of Mr. G.'s brain was promptly performed. It showed a large, irregularly shaped left frontal mass, about 4 cm in diameter, containing an asymmetrically placed apparently cystic center (Fig. 1). The white matter surrounding the mass looked abnormal, and this appearance extended anteriorly and posteriorly nearly throughout the entire left hemisphere, with some possible mild involvement of the right hemisphere. The lesion also showed signs of being an expansile mass, with effacement of the left anterior ventricular horn and a shift of the left hemisphere across the midline into the right side of the brain, which is characteristic of pressure from a growing lesion.



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Fig. 1. CT of the brain. These noncontrast images show four axial sections of the brain from the level of the midbrain up to the level of the lateral ventricles. A left frontal mass about 4 cm in diameter is evident, with a cystic center (arrowheads demarcate the posterior margin) likely representing necrosis and surrounding edema (single arrow). Two adjacent dense satellite areas are present, one of them abutting the ventricular system. Tumor mass effect has caused shift of left hemispheric brain tissue (on the right of the slices) over the midline into the left.

 

Hospital Course Back to Top

Mr. G. was admitted to the hospital, directly from the outpatient area, for evaluation and treatment of the brain mass. The symptoms and signs observed on examination were consistent with the brain mass being responsible for the dementing illness of relatively recent onset. The anti-inflammatory glucocorticoid drug dexamethasone was delivered to reduce the effects of the tumor mass on the brain, including edema. Electroencephalography (EEG) was used to determine whether there were signs of epileptiform activity. The tracings showed abnormal, low-frequency waveforms over the front of the left hemisphere, consistent with the presence of a subcortical lesion, but no activity suggesting ongoing seizures was detected. Magnetic resonance imaging (MRI) of the brain was performed to further clarify the nature of the lesion. The results confirmed the existence of a left frontal brain mass (Fig. 2) with maximum dimensions of about 4.9 cm. Use of the intravenous contrast imaging agent gadopentetate dimeglumine showed evidence for abnormal, enhanced signal at the rim of the mass and some focal enhancement of the mass surrounded by hypointense areas. Since normal brain tissue does not show any enhanced signal with gadopentetate infusion, the findings indicated breakdown of the blood-brain barrier at the periphery of the mass. Areas of hyperintense signal, likely representing edema, were detected in the white matter of the left frontal lobe, extending posteriorly and within the left internal capsule and the fornices. In addition, the contrast images showed a small focal area of abnormal enhancement in the right basal ganglia and some hyperintensity in the white matter of the right hemisphere, suggesting the possible involvement of both cerebral hemispheres. The overall appearance of the brain suggested the presence of an expansile neoplasm, with associated focal necrosis forming a cyst and more widespread tumor-cell infiltration and extensive edema. Although a neoplasm was the most likely explanation for these observations, a brain infection, with abscess formation, could not be entirely excluded.



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Fig. 2. MRI of the brain. Axial brain sections at the level of the lateral ventricles show an abnormal mass in the left hemisphere (right side of the images). (A) T1-weighted image reveals a left frontal brain mass of maximum dimension 4.9 cm. T1-weighted images show brighter signal in regions with shorter proton spin-lattice relaxation times and less intense signal in areas with longer spin-lattice relaxation times, such as a cystic area with high water content. (B) When gadopentetate penetrates brain tissue, due to a breakdown of the blood-brain barrier, it causes T1-shortening, or brighter signal. The T1-weighted image after gadopentetate dimeglumine infusion shows bright signal enhancement, which is abnormal, on the rim of the mass (arrowhead). These findings are consistent with a neoplasm with focal necrosis. (C) Fluid attenuation inversion recovery sequence--an MRI sequence that shows areas of increased water fluid content in the tissue as bright signal but suppresses signal for actual fluid collection--shows the right frontal mass (arrowhead) surrounded by white matter signal hyperintensity (arrows), likely representing edema, which is present within the fornices, the left caudate, and the internal capsule. Additional findings included a small focal area of abnormal enhancement in the right basal ganglia and hyperintensity in the right hemispheric white matter, suggesting possible involvement of the contralateral cerebral hemisphere.

 
Surgical biopsy of the brain was performed to allow definitive diagnosis of the lesion and, if it were indeed a tumor, to ascertain the histological type for subsequent prognosis and treatment considerations. Microscopic examination of a frozen section obtained during the operation revealed a high-grade glial neoplasm, resulting in an intraoperative diagnosis of glioblastoma multiforme (GBM). Standard tumor resection was then performed to remove the bulk of the tumor but spare the important speech and language cerebral structures--although these areas had shown some possible tumor involvement by imaging studies. The definitive pathology on the biopsy tissue confirmed the diagnosis of GBM.

After surgery, the patient experienced complete relief from headaches but transient worsening of language abilities and right-sided movements. Over several days, these functions improved to baseline. This indicated that vital functioning brain structures had not been lost, but the surgery had provided little relief of symptoms, despite some relief of the mass effect. After a 7-day hospitalization, Mr. G. was discharged home with 24-hours-per-day health care. To treat the remaining brain tumor, a course of fractionated radiotherapy was directed to the tumor bed. The treatment was administered 5 days per week for a period of 4 weeks. Despite these efforts, there was continued decline in cognitive abilities, prompting readmission of the patient to the hospital. At this time, the patient suddenly deteriorated further to a state of unresponsiveness. A new CT brain imaging study was performed on an emergency basis and revealed the development of hydrocephalus. To treat this condition, a ventriculoperitoneal shunt was put in place, which resulted in considerable improvement.

Mr. G. was transferred to a rehabilitation facility for recovery. However, he developed swelling of the right leg; ultrasonographic imaging revealed a deep venous thrombosis. As a result, anticoagulation therapy was started and a filter was placed in the inferior vena cava to reduce the chance of pulmonary emboli. Radiotherapy to the brain tumor was restarted, but cognitive and functional abilities continued to decline, as exhibited by growing confusion, disorientation, and memory and language problems. Because of the markedly progressive disease and dire prognosis, radiotherapy was discontinued before the scheduled completion. Supportive and palliative care was subsequently administered. The patient died 10 weeks after the initial diagnosis of his brain tumor.

Pathology Back to Top

An autopsy, limited to the brain, was performed. The fresh brain weighed 1305 grams, which is normal. The brain was bisected in the midsagittal plane, and a large, partially necrotic and hemorrhagic mass involving the septum and hypothalamus was seen in the midsagittal view (Fig. 3A). The left hemisphere was examined pathologically, whereas the right hemisphere was frozen for biochemical research. The sulci and gyri were of normal size and configuration, except in the left frontal area, where there was a small depression of the surface of the brain and evidence of old blood products in an area consistent with the location of the brain tumor resection surgery (seen in the fixed brain in Fig. 3B). The leptomeninges over the cerebrum and base of the brain showed normal translucency. The blood vessels at the base of the brain showed a normal adult configuration of the circle of Willis and mild atherosclerosis.



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Fig. 3. Gross pathology of the left hemibrain. The midsagittal view (A) shows a large tumor in the septum and hypothalamus, which is outlined by arrows. The lateral view of the brain (B) shows sulci and gyri of normal size and configuration, except in the left frontal area. Here, there was a small depression of the surface with evidence of old blood products at the site of the surgical resection (indicated by a blue arrow). The coronal section in (C) shows a necrotic focus (blue arrow) in the subcortical white matter, which corresponds to the site of the surgical resection and is surrounded by an area of abnormal softening and tan discoloration extending into the caudate nucleus. This area was contiguous with a large, partially necrotic tumor involving the septum and hypothalamus (red arrows). The temporal lobe also showed evidence of tumor infiltration with blurring of the gray-white junction (white arrow).

 
The brain was serially sectioned in the coronal plane. These sections revealed a normal ventricular system and a cortical gray mantle of normal thickness and distribution. There was a focus of necrosis in the frontal lobe white matter at the site of surgical resection, which was surrounded by an area of abnormal softening and discoloration extending into the caudate nucleus. This area was contiguous with the necrotic mass in the septum, which extended into the hypothalamus and basal forebrain (Fig. 3C). There was also evidence of infiltration of the tumor into the temporal lobe with blurring of the gray-white junction (Fig. 3C). Sections of the midbrain, pons, medulla, and cerebellum showed no unusual features.

Microscopic examination of the grossly normal-appearing brain sections revealed normal cerebral cortex, without any signs of the neurofibrillary tangles or neuritic plaques typically seen in Alzheimer's disease, or the Lewy bodies seen in Parkinson's disease or dementia with Lewy bodies, other common causes of dementia (see Honig Case Study, Constantino Case Study, and Posner Case Study.)

Microscopic examination of the tumor at the site of the initial resection showed a highly cellular glial neoplasm surrounding large areas of necrosis (Fig. 4A). Glioma cells infiltrated the cerebral cortex and subcortical white matter of the frontal lobe (Fig. 4B), septum, basal forebrain, caudate nucleus, putamen, insular cortex, lenticular nucleus, and hypothalamus. The tumor cells were highly pleomorphic, having markedly atypical nuclei and abundant eosinophilic cytoplasm (Fig. 5A). Numerous mitotic figures were observed, and vascular proliferation was prominent within the neoplasm (Fig. 5B). In summary, this tumor showed all the histologic hallmarks of GBM and displayed extensive infiltration of glioma cells throughout the left frontal cortex and subcortical structures.



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Fig. 4. Low magnification micrographs of the brain tumor stained with hematoxylin and eosin. (A) A highly cellular region of tumor (T) surrounds a large area of necrosis (N). (B) Tumor cells can be seen diffusely infiltrating the frontal cortex and accumulating under the pial surface (P).

 


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Fig. 5. High-magnification micrograph of the brain tumor section stained with hematoxylin and eosin. (A) A region of vascular proliferation (VP) is seen in the brain tumor. (B) Tumor cells are highly pleomorphic, with markedly atypical nuclei and abundant eosinophilic (pink) cytoplasm.

 

Discussion Back to Top

The presenting symptoms described in this case study consisted predominantly of changes in language ability, including a decreased proficiency in recalling names and reduced verbal skills. Changes in these cognitive functions are consistent with the involvement of left-hemispheric structures, since most people (even those who are left-handed) have left-hemispheric dominance of language. Other notable cognitive changes were mild difficulties in arithmetic, a function also generally localized to the left cerebral hemisphere. Findings of mild right-sided motor weakness and loss of coordination, and increased right arm reflexes, also point to left-hemispheric dysfunction. The relative preservation of memory and visuospatial functions was due to the sparing of the temporal lobes (memory) and posterior regions, especially the right hemisphere (visuospatial functions). Symptoms of decreased energy and changes in personality are common in processes affecting the frontal lobes. Other symptoms, including confusion, disorientation, and episodic incontinence, do not typically localize to specific brain regions but are associated with increased intracranial pressure (in this case, from the expansile nature of the tumor) and disruption of cerebrospinal fluid flow pathways. The most notable feature of the patient's medical history was the relatively recent onset of symptoms, over only a 3-month period. Overall, the observed symptoms and other signs were consistent with a rapidly progressing process that affected the left hemisphere more than the right one and predominantly involved the frontal brain regions.

Rapidly progressive dementia should always receive prompt evaluation because it is more likely that the active process is not one of the slowly degenerative brain disorders such as Parkinson's disease, Lewy body dementia, or Alzheimer's disease. Brain disorders showing rapid progressive deterioration include disorders due to infection and inflammation, neoplasm (as in this case), and, more rarely, degenerative disorders such as Creutzfeldt-Jakob disease, or cerebrovascular disorders such as multiple recurrent strokes, hemorrhages, or vasculitis. Clues as to the diagnosis may be obtained through the medical history, but neuroimaging is typically required to determine the diagnostic category of the disorder. In this case, CT and MRI revealed the presence of a large mass in the brain, which appeared distinct from brain tissue but also appeared to infiltrate neighboring tissue, cause breakdown of the blood-brain barrier, and cause surrounding edema. The findings were most consistent with a brain tumor. Brain tumors may present with a dementia syndrome that includes changes in personality and memory, speech and language disorders, and confusion, as was found in this case. However, it is also often the case that tumors will present with epileptic seizures, headaches, and obvious motor changes such as weakness of a limb.

Glial neoplasms comprise approximately 80% of all malignancies of the central nervous system and can be divided into tumors of astrocytic and oligodendroglial origin. The astrocytic lineage tumors fall into one of four histologic grades based on different pathological hallmarks (Fig. 6). Glioblastoma is distinguished from other astrocytomas by markedly increased mitotic activity, endothelial proliferation, and necrosis--although lower grade glial tumors may also display hypercellularity and cellular atypia. Glioblastoma typically presents de novo, in other words, in the absence of known prior tumor. However, GBM may also arise from known lower grade (for example, grade II or grade III anaplastic astrocytomas); in such cases, it is referred to as "secondary glioblastoma."



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Fig. 6. Grading scheme showing the classification of astrocytic glial tumors.

 
GBM is the most common primary brain tumor in adults, constituting more than half of all astrocytic tumors. It has an incidence of approximately 3 new cases per 100,000 people per year. The diagnosis is typically made between the fifth and eighth decades of life, with increasing incidence among the elderly. The disease shows a mild predominance (3:2) among males. A family history of similar tumors occurs in about 1% of cases. In the case described in this report, there was a history of both brain tumors and other tumors among first-degree relatives. This might indicate a genetic single-locus disorder, a broader genetic susceptibility, or an unknown common environmental factor predisposing to cancer. A number of genetic loci have been associated with a familial propensity for astrocytic tumors. Some of these loci are associated only with particular types of early age-of-onset tumors, such as the low-grade gliomas found in neurofibromatosis I and the giant cell astrocytomas found in tuberous sclerosis. However, other genetic disorders may be associated with higher grade neoplasms that occur during adulthood. For example, Turcot syndrome and Li-Fraumeni syndrome, each linked to several known genetic loci, are characterized by an increased incidence of astrocytic brain tumors and other systemic tumors. Some of these syndromes are due to germline mutations in the p53 tumor suppressor gene (see Campisi Perspective).

Although GBM may present with multiple centers of brain tumor, it commonly exhibits a dominant, single central mass. There typically is extensive infiltration of tumor cells throughout the ipsilateral hemisphere of the brain, and often contralaterally. Although tumor cells show a wide distribution in the brain, complete contiguity of tumor-involved areas may not be evident pathologically. In general, the widespread involvement is thought to be due to cell migration rather than to separately originating neoplasms. Tumor cells seem to migrate along white matter tracts in the brain and are frequently noted in the corpus callosum, the structure through which they apparently migrate to the opposite side of the brain from where they originated. Perivascular infiltration may also provide a mechanism for rapid migration distally along blood vessels. Subpial locations of tumor cells may indicate migration of cells along the brain surface or extensive distal migration through the parenchyma.

Glioblastoma is among the most malignant human neoplasms, with the majority of patients living less then 2 years after initial diagnosis. Prognosis in GBM depends primarily on age, with older patients, especially those 60 and older, having a worse prognosis. Other factors include the patient's functional neurological status (the more functional patients having a better prognosis) and residual tumor burden after initial surgery (the more intracranial tumor remaining, the worse the prognosis). Most patients over 60 years of age do not survive more than a year after diagnosis.

Treatment initially consists of surgery, both to provide tissue for diagnosis and to decrease tumor burden in the brain. Whereas the patient benefits more from removing most of the tumor, it is not possible to perform complete resections because of the widespread migration of tumor cells, even if these cells are not visible intraoperatively or on radiological studies. Furthermore, surgery is limited by the need to preserve brain function and not resect functionally important structures, even if these have tumor involvement. Because there are still tumor cells present after resection, radiation therapy is usually begun several weeks after resection, and it has been shown to be of modest benefit. At one time, therapy typically involved radiation of the entire brain, but present techniques consist of local radiotherapy to the region of the tumor mass, because local growth is the most frequent recurrence. Radiation is usually delivered as fractionated therapy, consisting of doses of 20 cGy per day for 3 to 5 days per week for up to 6 weeks, with total local doses of about 600 Gy. This regimen is usually accomplished with external beam radiation from a linear accelerator, although in some cases other types of focal external therapy or internal brachytherapy, which entails local intralesional placement of a radiation source, may be performed. Radiation therapy is often well tolerated systemically, but side effects to nonbrain structures can lead to visual problems, erosive skin or mucosal changes, and swallowing difficulties. In addition, radiation-induced necrosis of tumor tissue can also occur and become symptomatic in the short term. Long-term effects of radiation may include demyelination necrosis of normal brain tissue and vascular changes leading to strokes--although they may not occur during the average life span of the GBM patient.

Symptomatic treatment of GBM with corticosteroids, as was done in the case described here, results in palliation by reducing edema and the effects of the tumor mass on the brain, as well as by alleviating some of the side effects of radiation-induced tumor necrosis. However, progressive tumor growth and edema eventually overcome the beneficial effects of the steroids, leading to escalating steroid dosing, which is accompanied by other side effects, including weight gain, diabetes, candidiasis, and, sometimes, agitation and insomnia. The tumor growth may occlude cerebrospinal fluid pathways, resulting in hydrocephalus, as in this case, and surgical remediation through shunting may provide a marked immediate benefit.

Chemotherapy for astrocytic lineage tumors, which includes the use of antimetabolites, antimitotic or alkylating agents, antiangiogenesis agents, immune-activating substances, growth factor inhibitors, hormonal agents, and others, shows modest benefits. A decade ago, the most common chemotherapy, referred to as PCV, consisted of a combination of orally delivered procarbazine and lomustine (both compounds that act by alkylating DNA) and intravenously administrated vincristine (a microtubule-affecting drug). These drugs are typically given in a specific dosage pattern repeated in 6-week cycles. They often result in major systemic toxicity, including nausea, vomiting, fatigue, decreased blood counts, and increased susceptibility to mouth sores and systemic infections. More recently, oral chemotherapy with temozolomide (Temodar), often used concomitantly with radiotherapy, has shown some efficacy in prolonging survival. This drug also causes nausea and vomiting, but it is tolerated better than PCV. Other established therapies include intralesional administration of the nitrosourea compound BCNU (Gliadel wafer) in the tumor bed after surgery for recurrences. Various new investigational chemotherapies include the delivery of intralesional therapies, such as gene therapies, vaccines, interleukin-13, and others; topoisomerase-I inhibitors, such as irinotecan (Camptosar); antiangiogenesis agents, including thalidomide; hormonal antagonists, such as tamoxifen; epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib; and immunotherapies.

Prolonged survival in cases of GBM is extremely rare, despite use of multiple treatment modalities. Typically, the patient suffers from continued tumor growth, both in total mass and in infiltration throughout the brain. Seizures are a frequent occurrence in GBM and can be treated with anticonvulsant medications; however, prophylaxis with these medications in the absence of known seizures has not proven to be useful. GBM is associated with a systemic hypercoagulable state, despite the fact that metastases outside the central nervous system are extremely rare. The basis of this hypercoagulable state is unknown, but it may lead to deep venous thrombosis, as reported in this case, and pulmonary emboli. Death may occur from pulmonary emboli or, more commonly, from progressive tumor growth, which leads to increased intracranial pressure and, sometimes, hemorrhages within the tumor, and ultimately brain herniation leading to brainstem dysfunction.


August 24, 2005

Abbreviations: Alzheimer's disease. A neurodegenerative disease characterized by progressive and irreversible loss of brain functions, prominently including loss of memory, and also involving other cognitive functions such as language and visuospatial abilities. Characteristic changes observed in the brain include the accumulation of extracellular amyloid plaques in cerebral cortex, neurofibrillary degeneration in neurons, and loss of neuronal synapses and ultimately neuronal cells. • Astrocytoma. A primary tumor of the central nervous system composed of neoplastic glial cells that are thought to be related to cells of the astrocytic lineage. • Astrocytic. A term that pertains to astrocytes, one of the major non-neuronal cells of the central nervous system, whose role includes metabolic and physiologic support of neurons. An astrocyte is a comparatively large and branched neuroglial cell. • Atherosclerosis. A condition characterized by lipid deposits and fibrosis of the inner layer of the medium and large arteries. • Basal forebrain. An evolutionarily ancient, deep part of the brain, consisting of several discrete groups of neurons that make connections with much of the cerebral cortex. • Basal ganglia. The basal ganglia (consisting of caudate nucleus, putamen, globus pallidus, and nucleus accumbens) are deeply located groups of neurons that are involved in the programming, timing, maintenance, and execution of body posture and movements. • Blood-brain barrier. A naturally occurring barrier created by brain capillaries and astrocytes, through the formation of tight cell-to-cell contacts. It prevents many substances from leaving the blood and crossing the capillary walls into the brain tissues. • Caudate nucleus. A nucleus (group of neurons) that is part of the basal ganglia in each cerebral hemisphere. • Cellular atypia. An uncharacteristic appearance of the cell, suggesting the possibility that it may be malignant. • Cerebral cortex. The neuron-rich mantle of gray matter forming the outer layer of the cerebral hemispheres, which is folded into ridges (gyri) and furrows (sulci). The cortex is involved in cognition, memory, consciousness, behavioral reactions, and speech. Deficits associated with lesions of the cerebral cortex depend on the specific area(s) affected. • Cerebellum. The large brain mass that lies below the posterior part of the cerebrum and behind the brainstem. Integrating information from the cerebrum and peripheral parts of the body, the cerebellum plays a role in coordinating voluntary movement, controlling muscle tone, and maintaining balance. Symptoms of cerebellar lesions include motor coordination, tremors, disturbances of gait and balance, slurred speech, and nystagmus. • Cerebrum. The largest part of the brain in higher mammals, consisting of the cerebral hemispheres and connecting structures. It is the seat of conscious mental processes. • Circle of Willis. A group of large arteries at the base of the brain that interconnect to form a "circle" and provide the blood supply for most of the brain. • Computerized tomography. Radiographic study in which a three-dimensional body structure is imaged through a series of plane cross-sectional images (also called computed tomography.) • Corpus callosum. A large, thick plate of nerve fibers forming the major connection between the two cerebral hemispheres. • Cranial nerve. Any of the 12 paired nerves that arise from the lower surface of the brain, with one of each pair on each side. The nerves pass through openings in the skull to the periphery of the head and body. • Creutzfeldt-Jakob disease. A less common dementia that is rapidly progressive and caused by accumulation of abnormal prion proteins causing a "spongy" degeneration of brain tissue. • Cystic center. A tissue region having the appearance of a closed sac, containing fluid instead of cellular tissue. • Dementia. A type of disorder in which there is loss of cognitive and intellectual capacities characterized by impairments in memory, attention, orientation, language, judgment, motor and spatial skills, emotional behavior, and personality. Dementia is most commonly caused by neurodegenerative conditions in which neuronal cell functions, connections, or integrity are progressively lost. • Edema. Swelling caused by abnormal excess accumulation of fluid in a tissue. • Electroencephalography. A technique used to detect and record summated electrical brain activity. • Emboli. Abnormal particles circulating in the blood. • Eosinophilic. Staining readily with the dye eosin--usually referring to cell or tissue elements, which have proteinaceous material. • Epileptiform activity. Brain potentials (waves) seen on electroencephalography that resemble those seen in epilepsy, which is a disorder marked by excessive, synchronized electrical discharges of neurons causing convulsions or changes in behavior. • Fornices. A body of nerve fibers lying beneath the corpus callosum connecting the hippocampus with other parts of the brain. • Frontal lobe. The most anterior regions of the cerebral hemispheres, which include areas that control movement of the body, speech, and behavior. Damage to the frontal lobes may be marked by deficits in motor function, language use, abstract and creative thinking, problem solving, concentration, judgment and impulse control, and changes in behavior and personality. • Frontal release reflexes. Certain reflexes, such as involuntary sucking, that may occur in infancy but recur in adults in whom the frontal lobes of the brain are impaired. • Glioblastoma multiforme. The most malignant form of astrocytic tumors. The histologic features include marked nuclear atypia, high mitotic rate, microvascular proliferation, and areas of necrosis, often surrounded by pallisading tumor cells. • Gray mantle. The portion of the brain that appears gray in unstained specimens and contains nerve cell bodies, astrocytes, and nerve cell connections (synapses). • Gyri. A gyrus is a convolution of the surface of the cerebrum, separated from other gyri by grooves or furrows known as sulci. • Hydrocephalus. An abnormal increase in the relative amount of cerebrospinal fluid within the cranial cavity, causing expansion of the cerebral ventricles and compression of brain tissue. • Hypercellularity. The presence of an abnormal excess of cells. • Hypercoagulable state. A state in which there is an abnormal tendency of blood to clot (undergo thrombosis). • Hypothalamus. A group of neurons lying below the thalamus and involved in autonomic regulation. • Inferior vena cava.. The large vein in the lower trunk formed by the union of the two common iliac veins returning blood to the right atrium of the heart from the lower body. • Internal capsule. A layer of white matter that consists largely of fibers passing to and from the cerebral cortex and that lies internal to the lentiform nucleus. • Insular cortex. An area of cerebral cortex overlying the basal ganglia and covered by the frontal and temporal lobes. • Lenticular nucleus. A group of neurons in the basal ganglia in each cerebral hemisphere, also called the lentiform nucleus. • Leptomeninges. The delicate membranes of connective tissue that cover the brain and spinal cord, consisting of pia and arachnoid. • Lewy bodies. Intracytoplasmic inclusions, mostly consisting of the protein alpha-synuclein, which were originally identified within certain brainstem neurons of patients with Parkinson's disease. Lewy bodies may also occur in a more widespread distribution in patients with the neurodegenerative dementing disorder referred to as dementia with Lewy bodies. • Li-Fraumeni syndrome. A rare familial syndrome characterized by a high risk of developing various cancers and associated with mutations in the p53 tumor suppressor gene. • Magnetic resonance imaging. A noninvasive diagnostic technique that produces computerized images of internal body tissues. Images are created by the nuclear magnetic resonance of atoms within the body, induced by the application of radio waves. • Medulla. The lowest portion of the brainstem (also known as the medulla oblongata). • Mini-Mental Status Examination. One of several standardized, commonly used, quick "screening" assessment measures of a person's thinking and memory function. The test includes measures of orientation to time (e.g., the date) and place (e.g., the address), concentration, language and drawing skills, and short-term memory. • Neuritic plaques. Abnormal degenerative extracellular structures consisting of {beta}-amyloid protein deposits and surrounding distorted abnormal nerve fibers. • Neurofibrillary tangles. Abnormal degenerative intracellular structures, seen frequently in Alzheimer's disease and principally consisting of filamentous deposits of a hyperphosphorylated form of the microtubule-associated protein tau. • Neurofibromatosis I. A disorder of skin and nervous system tissue inherited as an autosomal dominant trait and characterized by certain skin conditions and benign tumors of peripheral nerves and brain. • Oligodendroglial. A term that pertains to oligodendroglia, a class of neuroglial cells principally located in the white matter that form the myelin of nerve fibers in the central nervous system. • Paraphasia. A word substitution in which the wrong word is involuntarily used. • Plantar reflexes. Reflex movements of the toes upon stimulation of the sole of the foot. Abnormal responses suggest disruption of cerebral control. • Pons. The middle portion of the brainstem, lying between midbrain and medulla. • Putamen. A group of neuronal cells in the basal ganglia. • Septum. A thin area of brain tissue, including neuronal cells, that lies between the two lateral ventricles. • Subpial. Brain tissues situated immediately below the pia, the innermost layer of the leptomeninges. • Sulci. Furrows on the surface of the brain separating adjacent convolutions. • Temporal lobe. The lower lateral portions of the cerebral hemispheres, which have prominent involvement in the encoding and retrieval of memory. In most persons, right temporal lobe damage may result in greater impairment of memory for visual material, while left temporal lobe damage may result in greater impairment of memory for verbal material. • Tendon reflexes. These are reflexes, like a knee jerk, in which a muscle group contracts involuntarily in response to a sudden stretch of its tendon caused by the tap of an examiner's rubber hammer. • Thrombosis. The formation or presence of a blood clot, often in a blood vessel. • Tuberous sclerosis. An inherited disorder of the skin and nervous system that may include epilepsy and mental retardation, certain skin conditions, and benign tumors of the brain, kidney, retina, and heart. • Tumor suppressor gene. A gene (such as the p53 gene) that acts in normal cells to inhibit unrestrained cell division. When it is inactivated (for example, by mutation) the cell is at increased risk of becoming malignant. • Turcot syndrome. A rare inherited disorder characterized by both benign growths (adenomatous polyps) in the mucous lining of the gastrointestinal tract and tumors of the central nervous system. • Ultrasonographic imaging. Examination of deep body structures by forming images based on the penetration or reflection of high frequency sound waves above the range of human hearing. • Vasculitis. Inflammation of blood vessels. • Ventricular horn. A region of the lateral ventricle, a normal fluid-filled cavity in the brain. • Ventriculoperitoneal shunt. A surgically placed tube with an in-line valve providing for drainage of fluid from the ventricle of the brain to the peritoneal cavity. • White matter. The portion of the brain and spinal cord that appears white in unstained specimens and occurs in the more central (nonsurface) regions of the brain. It does not contain neuron cell bodies but rather is composed of myelinated axons and supporting cells (predominantly oligodendrocytes and astrocytes).

Suggested ReadingBack to Top

  • V. P. Collins, Brain tumours: Classification and genes. J Neurol. Neurosurg. Psych. 75 Suppl. 2, ii2-ii11 (2004). [Abstract]
  • L. M. DeAngelis, Brain tumors. New Engl. J. Med. 344, 114-123 (2001). [Abstract]
  • S. A. Grossman, J. F. Batara, Current management of glioblastoma multiforme. Semin. Oncol. 31, 635-644 (2004). [Abstract]
  • A. Merlo, B. Bettler, Glioblastomas on the move. Sci. STKE 2004, pe18 (2004). [Abstract]
  • P. Kleihues, W. K. Cavanee, Eds., Tumors of the Nervous System: Pathology and Genetics; The World Health Organization Classification of Tumors (IARC Press, Lyon, France, 2000).
  • H. Ohgaki, P. Kleihues, Epidemiology and etiology of gliomas. Acta Neuropathol. 109, 93-108 (2005). [Abstract]
Citation: J. M.. Noble, P. Canoll, L. S. Honig, Brain Tumor-Associated Dementia. Sci. Aging Knowl. Environ. 2005 (34), dn2 (2005).








Science of Aging Knowledge Environment. ISSN 1539-6150