J Stroke Cerebrouasc Dis 1994;4:42-45 is> 1994 National Stroke Association
Glioblastoma Multiforme Presenting with Recurrent Neurological Deficits: Transient Ischemic Attacks or Tumor Attacks "Iaher AI-Tweigeri, M.D., 1,5Ashfaq Shuaib, M.D., FRCPC, 2Fareed Denath, M.B. Ch.B., FF Rad, 3Lee C. Ang, M.B., MRC Path, FRCPC, 4,sMoe Khan, M.D., FRCSC, and 1Rita M. Bourgault, RET
Transient ischemic attacks result from the temporary focal interruption of blood flow to the brain. We present three patients with glioblastoma multiforme and recurrent speech arrests or right-sided numbness. The clinical diagnosis of "transient ischemic attack" was made in each patient. This diagnosis remained unchanged for months to 2 years after initial presentation and investigations. The correct diagnosis was made with a brain biopsy in two patients and as a result of additional investigations in the third patient. It is important to remember brain tumor in the differential diagnosis of patients presenting with recurrent brief neurological symptoms. Key Words: Transient ischemic attacks-Glioblastoma multiforme-Tumor.
Transient ischemic attacks (TlAs) are brief focal neurological deficits that are generally secondary to carotid artery disease (1) (artery-to-artery emboli) or emboli arising from within the heart (1,2). Partial seizures can present with recurrent attacks of focal neurological symptoms and can be mistaken for TIAs (3-5). Other conditions that can be confused with TIAs include migraine with aura (6), migraine aura without headache (7), small intracerebral and subdural hemorrhages, multiple sclerosis (8), or intracranial tumors (9). Primary brain tumors rarely present with transient focal neurological symptoms. In one recent series, From the Departments of IMedicine (Neurology), 2Radiology (Neuroradiology), 3pathology (Neuropathology), and 4Neurosurgery, and Sthe Saskatchewan Stroke Research Centre, Saskatoon, Saskatchewan, Canada. Address correspondence and reprint requests to Dr. A. Shuaib at Department of Medicine, College of Medicine and The Royal University Hospital, Saskatoon, Saskatchewan, Canada S7N OXO. 42
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less than 2% of patients (10 of 685) presented with such symptoms (10). Recurrent symptoms are extremely uncommon. The underlying etiology in such cases is uncertain and can be secondary to concomitant carotid artery disease, alteration of regional blood flow or metabolism, direct compression of cerebral blood vessels, or effects of brain edema (11). In this communication, we report three patients who presented with recurrent transient neurologic events suspected to be ischemic. Months to 2 years later, further investigations and/or biopsy revealed the correct diagnosis.
Case Reports Patient 1 This 68-year-old woman was initially seen in the Stroke Clinic in April 1991 with complaints of intermittent right arm and leg numbness. Individual episodes would last for less than 5 min and would
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develop suddenly without warning. There were no precipitating factors, and symptoms occurred at any time of the day or night. There were no additional symptoms, such as weakness or speech difficulties. Risk factors for stroke included a 10-year history of controlled hypertension, and a strong family history of vascular disease at an early age. The patient was admitted for investigation of possible TIAs. All studies, including carotid Doppler, echocardiography, and contrast-infused cranial computed tomography (CT), were normal (Fig. 1, top scans). The patient was discharged on aspirin, 1,300 mg/day, with a diagnosis of TIA etiology uncertain. For the next 2 years, the patient continued to have intermittent numbness over the right arm and leg, and the symptoms were no different from the initial complaints. Eighteen months after onset of symptoms, reinvestigation with carotid Doppler and echocardiography once again failed to show any abnormalities. A sudden onset of right-sided hemiparesis and aphasia resulted in a third hospitalization. This time repeat cranial CT revealed a large left frontoparietal tumor with a central region of necrosis (Fig. 1, middle and bottom scans). During surgery, the tumor was easily visualized and debulked. Histological evaluation revealed a highly cellular tumor with marked degree of anaplasia and mitotic figures. There was a fibrillary background compatible with astrocytic differentiation. Marked endothelial proliferation and areas of tumor necrosis and pseudopalisading were noted. These findings were typical of glioblastoma multiforme.
Patient 2 This 56-year-old physician developed a 3-min episode of speech difficulty that resolved spontaneously. During the episode, the patient was unable to speak, but his comprehension appeared to be normal. During the episode, the patient was fully aware of his surroundings and very disturbed about his speech difficulty. The onset and resolution were sudden, and no associated neurological difficulties were experienced. Examination within hours showed no systemic or neurological abnormalities. He was able to fully recall the entire episode without difficulty. Unenhanced cranial CT exhibited no abnormalities. Contrast-enhanced CT showed two small enhancing lesions in the left frontal and parietal regions felt to be compatible with small cerebral infarctions. Carotid ultrasound examination was normal. A cardiac source was suspected, since the patient had suffered two separate myocardial infarctions but had normal carotid
ultrasound. Transthoracic echocardiography was normal, but transesophageal echocardiography showed a small thrombus in the left atrium. The patient was anticoagulated with warfarin. Three weeks later, the patient developed additional recurrent short-lived speech difficulties. These were identical to the initial episode. He was adequately anticoagulated at this time. Electroencephalography showed focal spikes from the left temporal area. These episodes were believed to be secondary to focal seizures and responded well to oral anticonvulsants. Twomonths after initiation of the anticonvulsant therapy, transient speech difficulties recurred. The speech difficulties lasted only a few seconds. These occurred two or three times per day and were most evident at breakfast and supper. Repeat examination showed no change. Cranial CT with contrast medium infusion showed an increase in the size of the cortical lesion. MRI confirmed this finding. The lesion was subsequently biopsied because of its increasing size. Microscopic examination showed a highly cellular tumor with frequent mitosis typical of glioblastoma multiforme. Tumor necrosis (pseudopalisading), giant cells, and vascular endothelial proliferation were noted.
Patient 3 This 63-year-old woman was evaluated for several episodes of speech arrest. These episodes would last for 2-3 min during which she was unable to speak. Her comprehension would be normal, however, and she experienced no other neurological or systemic problems. There were no risk factors for stroke. Evaluation on the neurology service showed no abnormalities. The patient was admitted for cerebral arterial angiography with a diagnosis of TIAs. Angiography showed no abnormalities, and the patient was discharged. In the 2 months after discharge, the episodes of speech arrest increased in frequency and duration. The patient was readmitted for further evaluation and investigations. Examination showed no speech or cognitive deficits. Motor examination showed a mild right arm drift. The remainder of the examination was entirely normal. Cranial CT showed a large hypodense lesion with irregular regions of enhancement in the left frontoparietal region. The features were characteristic of an anaplastic highgrade malignancy. Microscopic examination of the brain biopsy specimen revealed necrosis with pseudopalisading, vascular endothelial proliferation, abundant mitotic figures, and pleomorphism. These findings were typical for glioblastoma multiforme.
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T. AL-TWEIGERI IT AL.
Figure 1. N?rmal CT (con!,ast:injused) examin~tion in P~tient 1 atthetimeofpresentation (left) andrepeat CTstudy 2 years later witha large left-hellllsphere necrotic lesion very suggestive of a high-grade tumor (right).
Discussion Two patients presented with recurrent short-lived speech difficulties, whereas the third patient had recurrent episodes of right-sided numbness. Examination between the episodes continued to be normal for several months to 2 years. Features such as headache, evolving focal signs, or cognitive deficits, typically seen with rapidly enlarging intracranial lesions, were conspicuously absent. In all patients, the clinical diagnosis of TIAs remained unchanged for months after completion of the initial evaluation. The initial evaluation included CT, carotid Doppler, and echo cardiography in the first patient, CT in the second, and arterial angiography in the third patient. Despite the diagnosis of high-grade brain tumor, the exact mechanism of the focal symptoms remains ~ifficu.lt .t? prove in. the patients. In the second patient, initial evaluation suggested a cardiac source. Transesophageal echocardiography revealed a thrombus in the left atrium. It is therefore difficult to know whether the initial symptoms were directly related to the brain tumor or secondary to emboli from the heart. In addition, the abnormal EEG and the reo sponse to anticonvulsants were consistent with a diagnosis of focal epilepsy, suggesting an alternate mechanism for the symptoms. It is possible that focal symptoms in patients with brain neoplasms may be related to local metabolism disturbances in the region of the tumor or hemodynamic factors developing secondary to the biological activity of the fast growing tumor. It is interesting to note that the majority of patients with ischemic symptoms and brain tumors reported by Kondziolka et a1. (10) also had glioblastomas or other high-grade tumors. ~pisodes of
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Reports of brain tumors presenting as "ischemic stroke" are rare. Fisher and Recht (11) reported three patients with pure motor weakness whose initial diagnosis of "lacunar stroke" was changed after CT. In Weisberg and Nice's series, the misdiagnosis of stroke was made in 13 patients with brain tumors. In their series, 12 of 13 patients presented with "stroke in evolution." Intermittent symptoms, similar to our patients, have been reported with meningiomas (13) and, similar to our patients, were also mistaken for cerebral infarction. Finally, Ross's report included three patients with brain tumors and transient "tumor" attacks. Two of the patients showed papilledema on examination, and the third case showed focal abnormalities (9). Focal seizures or Leao's spreading depression were felt to be two likely mechanisms that could explain the symptoms. Contrary to other reports in the literature, in which diagnosis was easily established at the time of presentation, in at l~ast two of our patients, despite detailed investigations, the correct diagnosis remained elusive for months after presentation. In summary, most patients with transient focal neurological symptoms have TIAs. Occasionally, the sy~ptoms may be secondary to a small underlying mahgnancy that can be missed on initial investigations (including CT or MRI). It is important to consider central nervous system tumors in the differential ~iagn~sis .ofpatients with TIAs to avoid unnecessary investigations for an ischemic etiology. Acknowledgment: This work was done at the Clinical Investigative Stroke Unit of the Royal University Hospital, Saskatoon, Saskatchewan, Canada. Doris Kanigan helped with the preparation of the manu-
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script, and Debbie Shul did histological preparations of brain sections in all patients.
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5. Fisher CM. Transient ischemic attacks of obscure nature: the question of non-convulsive seizure paralysis. Call J Neural Sci 1978;5:267-73.
6. Headache Classification Committee of the International Headache Society. Classification, diagnostic criteria for headache disorders, cranial neuralgias and facial pain . Cephalalgia 1988;8:27-68 . 7. Fisher CM. Late life migraine accompaniments as a cause of unexplained transient ischemic attacks . Call J Neurol Sci 1980;7:9-17. 8. Twomey JA, Espir MLE. Paroxysmal symptoms as the first manifestations of multiple sclerosi s. J Neurol Neurosurg Psychiatry 1980;43:296-304. 9. Ross RT. Transient tumor attacks. Arch Neural 1983; 40:633-6. 10. Kondziolka 0, Bernstein M, Resch L, Tator CH. Brain tumors presenting as TIA and strokes. Call J Neural Sci 1986;13:195-6. 11. Fisher M, Recht LD. Brain tumor presenting with acute pure motor hemiparesis. Stroke 1989;20:288-91. 12. Weisberg LA, Nice CN. Intracranial tumors simulating the presentation of cerebrovascular disease. Am J Med 1977;63:517-24. 13. Daly DO, Svien HJ, Yoss RE. Intermittent cerebral symptoms with meningiomas. Arch Neurol 1961;5: 287-93.
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Glioblastoma multiforme presenting with recurrent neurological deficits: Transient ischemic attacks or tumor attacks.
Transient ischemic attacks result from the temporary focal interruption of blood flow to the brain. We present three patients with glioblastoma multif...