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Young Man With a History of Vague Headaches Ascribed to Sinusitis


A 37-year-old man found unresponsiveat home with erratic respiration andurinary incontinence was brought tothe emergency department (ED). Accordingto his family, the patient hadbeen complaining of headaches, vertigo,and mild neck pain for 2 months.During that time, a CT scan of thesinuses revealed chronic sinusitis; thepatient had completed a course ofprednisone, naproxen, and meclizinewithout symptomatic improvement.The day before he was brought to theED, he had presented to a differenthospital with the same complaints andwas given a prescription for antibioticsfor a presumed sinus infection. He haddiet-controlled hypercholesterolemiaand did not smoke.

A 37-year-old man found unresponsiveat home with erratic respiration andurinary incontinence was brought tothe emergency department (ED). Accordingto his family, the patient hadbeen complaining of headaches, vertigo,and mild neck pain for 2 months.During that time, a CT scan of thesinuses revealed chronic sinusitis; thepatient had completed a course ofprednisone, naproxen, and meclizinewithout symptomatic improvement.The day before he was brought to theED, he had presented to a differenthospital with the same complaints andwas given a prescription for antibioticsfor a presumed sinus infection. He haddiet-controlled hypercholesterolemiaand did not smoke.In the ED, the patient's temperaturewas 38.8C (102F); heart rate,120 beats per minute. He had nonreactivepupils, papilledema, no cornealor conjunctival reflex, diffuse rhonchi,tachycardia, and no gag reflex. Abdominalfindings were unremarkable.On painful stimulation, decorticateposturing was noted. He had bilateralupgoing plantar responses.A CT scan of the head showeda 3-cm low-attenuation mass in theright parietal lobe with surroundingedema, increased density of subarachnoidspace, and evidence of transtentorialherniation (Figure 1). Immediatecraniotomy (for decompression)and biopsy of the lesion were performed,and the patient was admittedto the ICU. A smear of the brain biopsyspecimen showed no white bloodcells or pathogens.A chest radiograph revealed aright lower lobe infiltrate. Clindamycinwas initiated for possible aspirationpneumonia. Pyrimethamine andacyclovir were started for possible toxoplasmosisand herpes simplex virusinfection, respectively.A repeated CT scan of the headrevealed blood within the mass withsurrounding edema, which extendedinto the temporal and occipital lobes(Figures 2 and 3). A midline shiftand a new area of infarct involvingthe left superior cerebellar and rightoccipital lobes were also noted. Intravenousmannitol and methylprednisolonewere started for the edema.Results of enzyme-linked immunosorbentassay testing for HIVand Toxoplasma antibodies (IgG andIgM) were negative. Pyrimethaminewas discontinued. The patient's urinaryoutput subsequently increasedtremendously. Serum and urinalysisconfirmed diabetes insipidus.Despite aggressive treatment, thepatient's health worsened. His familyrequested "comfort measures only,"and he died shortly thereafter.The cytology report revealed ahypervascular tumor, excessive necrosis,and marked atypia; normalbrain tissue is shown for comparison

(Figure 4) Glioblastoma multiformewas the postmortem diagnosis.GLIOBLASTOMAMULTIFORME: AN OVERVIEW
Glioblastoma multiforme--themost aggressive variant of astrocytoma--is a rare cause of headache.The prognosis is poor. Mean survivalafter diagnosis is 8 to 10months; after 2 years, the survivalrate is 10%.1 Glioblastoma multiformeis characterized by a high malignancyrate, extensive infiltration,and large growth before causingsymptoms. The onset is relativelyrapid and is heralded by seizures,headaches, and focal neurologicdeficits.Epidemiology and pathology
Astrocytic tumors--the most commontype of brain tumor--are classifiedas astrocytomas, brain stemgliomas, and pilocytic astrocytomas.Astrocytomas are subdivided intolow-grade astrocytomas, anaplasticastrocytomas, and glioblastoma multiforme(increasing grades of pathologicanaplasia). About 40% to 50%of primary CNS tumors are gliomas.Approximately 50% of gliomas areglioblastoma multiforme, and 7% arelow-grade astrocytomas and anaplasticastrocytomas.Astrocytic tumors can be dividedinto grades I through IV; gradeI is the most benign, and grade IV is the most malignant. The WorldHealth Organization has classifiedglioblastoma multiforme as a gradeIV astrocytoma (Table 1).2 GradesI and II astrocytomas have a relativelybenign appearance with homogeneousgrouping of cells and littleatypia or anaplasia. Grades III andIV astrocytomas have a greater degreeof anaplasia than the benignforms; however, they do not containfocal necrosis as seen with glioblastoma.Anaplastic astrocytomas representmore than 50% of all malignanttumors and are the third mostfrequent type of cancer in the 15- to34-year-old age group.1Approximately 60% of the primarybrain tumors diagnosed annuallyin the United States aregliomas.3 Men are affected moreoften than women, and there is ahigher incidence in whites. Theexact cause is unknown. Somegliomas occur as a late consequenceof radiation to the head or skull. Ionizingradiation--the only firmly establishedenvironmental risk factorfor brain tumors--and genetic predispositionaccount for only a fractionof cases.Characteristic histologic findingsof a glioblastoma multiforme includeabundant glial pleomorphism,numerous mitotic figures and giantcells, vascular hyperplasia, and focalareas of necrosis. This malignantneoplasm occurs most commonly inthe fifth through seventh decades oflife. It usually develops in the cerebralhemispheres and, rarely, in thecerebellum. The typical presentation is an irregularly shaped mass withcentral necrosis and extensive surroundingedema and mass effect.Table 2 lists differential diagnosticconsiderations. Metastasiswas less likely in the patient wehave described, because he wasyoung and had no history of a primarytumor. A brain abscess is typicallyidentified by a thin regularrim of enhancement around a centralcavity.Genetics
Certain genetic alterationscorrelate with progression ofastrocytic tumors from low to highgrade. Among the alterations mostcommonly found in low-grade astrocytomasare inactivation of p53 andoverexpression of PDGF-A and its receptor.Transition to a higher-gradeastrocytoma is associated with additionaldisruption of tumor-suppressorgenes, the p16/CDKNZA gene,the RB gene, and a putative tumorsuppressor on chromosome 19q.4SIGNS AND SYMPTOMS
Initial signs and symptoms ofglioblastoma multiforme include seizures,speech disturbances, a changein the pattern of headaches or an increasinglysevere headache, vomiting,nausea, visual disturbances, andweakness or sensory disturbances.The period between the onset ofsymptoms and presentation for medicalcare is usually short--less than3 months, as in this patient--unlessthe neoplasm develops from a lowergradeastrocytoma.Careful interviews with the patientor family members may lead tothe discovery of neurobehavioralsymptoms. Dementia may be considered,because elderly patientsmay present with memory loss. Occasionally,older patients presentwith a sudden onset of focal neurologicfindings that are believed to besecondary to a vascular event.In patients with glioblastomamultiforme, hemiparesis is seen in 61% to 83%, papilledema in 32% to66%, confusion in 18% to 40%, andaphasia in 25% to 32%.5,6 Commonpresenting symptoms of meningealinvolvement are back pain, with orwithout radicular involvement; mentalstatus changes; cranial nervepalsies; myelopathy or cauda equinasyndrome; and headache with symptomatichydrocephalus.Headache
In almost half of allpatients with brain tumors, headacheis a prominent presenting feature.7 Tension-type headaches aredescribed in about 25% of such patients.About 5% of patients haveheadaches that are clinically indistinguishablefrom migraines. Theclassic brain tumor headache--involvingprogressive headache andassociated nausea that develops inthe morning--affects only about15% to 17% of patients.7The most important distinguishingfeature of the classic braintumor headache is its associationwith other clinical features, such asseizures, personality changes, cognitivedysfunction, and focal neurologicabnormalities. Thus, the American AmericanAcademy of Neurology does notrecommend routine neuroimagingstudies in headache patients withnormal neurologic findings. However,neuroimaging is warranted forpatients with new-onset or progressiveheadaches, even without accompanyingfeatures, and for thosewho have a change in the characterof chronic headaches.In elderly patients, headachesare more likely to suggest a structuralpathology. Headache associatedwith a brain tumor has been linkedto intracerebral edema, elevated intracranialpressure, and midline shiftof various structures. These findingsare not well correlated with the sizeof the tumor.Seizure
In about 20% to 40%of affected patients, seizure is theinitial presenting symptom. Approximatelyhalf of patients with braintumors experience seizures duringtheir illness. Seizures associatedwith brain tumors are manifested bymotor, sensory, visual, or behavioralchanges. They may be either focalor generalized. The type and incidenceof the seizure depend on the location and size of the tumor.8THE WORKUP
An MRI of the brain--with andwithout contrast--is the preferreddiagnostic test for glioblastoma multiforme.9 Characteristically, thesetumors have low-signal intensity onT1-weighted images and high-signalintensity on T2-weighted images.The tumors usually enhance whencontrast is added. MRI is particularlyuseful in evaluating tumor extensionand subacute and chronic hemorrhagecollections. Gadoliniumenhancement is almost always presentand usually appears like a ringaround the tumor with thick and irregularwalls. MRI also helps distinguishthe tumor nidus from the surroundingedema.10When MRI is contraindicated orunavailable, CT may be used. On CTscans, glioblastoma multiforme typicallyappears as a variable, nonhomogeneoushypodense or isodensemass with surrounding edema. Thetumor tends to infiltrate along thewhite matter tracts. Frequently, it involvesthe corpus callosum, crossesthe midline, and produces the characteristic"butterfly" appearance.11,12Glioblastoma multiforme can bedifferentiated from a benign masslesion, brain abscess, or toxoplasmosiswith positron emission tomography,single-photon emission CT, ormagnetic resonance spectroscopy.However, when using functional neuroimaging,the definitive diagnosismust be confirmed with stereotacticor open brain biopsy.13MANAGEMENT
The treatment of malignantglioma is mostly palliative and consistsof pharmacologic therapy, surgery,radiotherapy, and chemotherapy.Seizures may be managed withan anticonvulsant, such as phenytoin,carbamazepine, or valproate.Peritumoral vasogenic edema istypically managed with corticosteroids.Intracranial pressure can bedecreased by elevating the head ofthe bed to greater than 30 degrees,by forcing hyperventilation, by restrictingfluid to less than 1 to 1.5 Lper day, and by using osmoticagents (mannitol, diuretics).After surgical resection of thetumor, external beam radiation therapyis often tried.14 Varying successhas been noted with stereotacticbrachytherapy,15 stereotactic radiosurgery,boron neutron capture therapy,and chemotherapy (carmustineor combinations of procarbazine, carmustine,and vincristine)16 followingsurgery and radiation therapy.Several promising agents, includingtemozolomide, topotecan, and paclitaxel,are under investigation forpossible use in the treatment ofgliomas.



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Dean BL, Drayer BP, Bird CR, et al. Gliomas:classification with MR imaging. Radiology. 1990;174:411-415.


Kieffer SA, Salibi NA, Kim RC, et al. Multifocalglioblastoma: diagnostic implications. Radiology.1982;143:709-710.


Byrne TN. Imaging of gliomas. Semin Oncol.1994;21:162-171.


Latchaw RE, ed. MR and CT Imaging of theHead, Neck and Spine. St Louis: Mosby Yearbook;1991:449-471.


Leibel SA, Scott CB, Pajak TF. The managementof malignant gliomas with radiation therapy:therapeutic results and research strategies. SeminRadiat Oncol. 1991;1:32-49.


Loeffler JS, Alexander E 3rd, Wen PY, et al. Resultsof stereotactic brachytherapy used in the initialmanagement of patients with glioblastoma. J NatlCancer Inst. 1990;82:1918-1921.


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