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Show lOUl7Ul1 of Clinical Neuro-ophlhalmology 13(2): 105-112, 1993. Glioblastoma Multiforme Masquerading as Pseudotumor Cerebri Case Report Maryam Aroichane, M.D., Neil R. Miller, M.D., and Eric R. Eggenberger, D.O. © 1993 Raven Press, Ltd., New York A 16-year-old girl developed headaches and bilateral papilledema while taking minocycline for acne. The initial neuro-ophthalmologic evaluation was normal except for enlarged blind spots au. An MRI scan demonstrated subtle abnormalities. A lumbar puncture was entirely normal except for an increased opening pressure. A tentative diagnosis of pseudotumor cerebri was made and the patient was treated with Diamox. A second MRI was unchanged, and a lumbar puncture performed while the patient was taking Diamox was entirely normal. The patient subsequently lost vision in both eyes, and a third MRI now revealed a supracellar enhancing mass. Biopsy and subtotal resection of the mass showed it to be a glioblastoma multiforme. This case emphasizes pitfalls in the diagnosis of pseudotumor cerebri. Careful followup and a high index of suspicion in pseudotumor cerebri syndromes are essential. Key Words: Pseudotumor cerebri-Glioblastoma multiforme- Papilledema-Cerebrospinal fluid cytopathology- Cerebrospinal fluid protein-Minocycline. From the Neuro-Ophthalmology Unit, The Johns Hopkins Medical Institution, Baltimore, Maryland, U.S.A. Address correspondence to Dr. Neil R. Miller, Maumenee 6-109601 North Broadway, Baltimore, MD 21205, U.S.A. 105 Pseudotumor cerebri (PTC) is a condition characterized by elevated intracranial pressure, normal cerebrospinal fluid composition, and normal neuroimaging studies (1). Additionally, most patients have papilledema. Although PTC is often idiopathic, certain drugs, such as tetracycline and its analogs, can be associated with this condition (27). We report a case of glioblastoma multiforme that initially mimicked minocycline-induced pseudotumor cerebri. CASE PRESENTATION A 16-year-old girl presented to her pediatrician with complaints of daily, right-sided headaches of 12-months' duration associated with a 5-week history of intermittent, horizontal, binocular diplopia. Although sinus radiographs reportedly were consistent with sinusitis, a course of amoxicillin only transiently improved her symptoms, and she sought the opinion of an ophthalmologist. She was referred for neuro-ophthalmologic consultation after the general ophthalmologic examination revealed bilateral optic disc swelling. The patient's past medical history was significant for acne treated with the tetracycline analog, minocycline, and a topical vitamin A preparation (Retin-A). She also had suffered from seasonal allergies treated with the antihistamine agents astemizole (Hismanal) and terfenadine (Seldane). Neuro-ophthalmologic examination revealed best corrected visual acuity of 20/15 00 and 20/20 OS. Near vision was J-l OU. Color vision utilizing Hardy-Rand-Rittler (HRR) pseudoisochromatic plates was 9.5/10 00 and 10/10 OS. Kinetic perimetry was normal; however, static perimetry revealed enlarged blind spots OU and a slight reduc- 106 M. AROICHANE ET AL. tion in the mean deviation 00 (Fig. 1). Pupils were normal without a relative afferent defect. A small esophoria of approximately 4 prism diopters was noted at distance and near. Corneal and facial sensation were normal bilaterally. Slit-lamp biomicroscopy was unremarkable au. Ophthalmoscopy revealed bilateral, hyperemic swollen discs, right greater than left (Fig. 2). No spontaneous venous pulsations were observed in either eye. An MRI was performed, which some neuroradiologists considered normal; however, others thought that there was subtle nonenhancing diffuse enlargement of both thalami, the optic chiasm, and the infundibulum (Fig. 3). A lumbar puncture revealed acellular cerebrospinal fluid (CSF) with an opening pressure of 340 mm of water. The protein concentration was less than 10 mg%, and the glucose was normal. Cytopathologic examination of the CSF revealed no malignant cells. The patient was placed on acetazolamide (Oiamox) 250 mg q.i.d. and she stopped using both minocycline and Retin-A. Her headaches improved, but 2 weeks after beginning therapy, she developed paresthesias. Accordingly, the Oiamox was decreased to 250 mg t.i.d. Repeat neuro-ophthalmologic examination and cerebral MRI 5 weeks later, were unchanged. A second lumbar puncture now revealed acellular CSF with an opening pressure of 185 mm of water, a protein concentration of 29 mg% and normal glucose. CSF cytopathologic examination was again negative for tumor cells. At 8 weeks after the initial presentation, the pa-tI :::::;;;::-·~-:-~-:-~-:-:-:-·:1:r..~ ·~ ~..: ·~·;··j·=).;..:.::;;:; : : ; ~ ~ ~ :::.; ~ : ~: ~ ; ~ ~ ~ ~ ~ ~ ; I . ~ : ~ : : ; ; : ~ : ~ : :: ; . : : .. ..- .....-..:. - ..-_- ..... ·······.1! · -- _- .. . ::::::::::: .. : ":1:::::', . ~ ~ :~ :.;::~.: .: :. :::::::: ~ t: :.:.::~ :::~ ~ ;~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ;~ ~ : • ..-:..~.-:.. 1 • _•.•••••••••••.•.• Ft-i__: '--1:;I-::._··:::·::-fu:-,~;-+~~_·~-~:_:-'-:'+-1.->-._.:_::--1:1_>_~'_::_::_~~+;-~~-~~_:~-~:-+1 :~;·:;j.f::~·:· :::;:'.':::':,:,,::.:.'::..:~~::: . . I .. - - • • - . . ..• • . --i:::::::.' - • • • 1 • • -; . tient returned with complaints of visual loss as. Additionally, she related a several-month history of amenorrhea. Examination now revealed best corrected visual acuity of 20/25-2 00 and 20/80 as. Color vision was 10/10 00 and 9/10 as, but there was a mild left relative afferent pupillary defect, and static perimetry demonstrated bitemporal hemianopic visual field defects (Fig. 4). The papilledema was unchanged. The patient was admitted to the hospital and a third MRI with gadolinium (Gd-OTPA) was performed. This revealed a large supracellar mass with diffuse involvement of the diencephalon and optic chiasm. The mass showed irregular enhancement following administration of Gd-OTPA (Fig. 5). The patient was placed on dexamethasone and scheduled for surgery. While awaiting surgery, she experienced an episode of bradycardia and hypotension accompanied by worsening headache. An emergency computed tomographic (CT) scan revealed subarachnoid and intraventricular blood caused by hemorrhage within the tumor. An emergency right pterional craniotomy was performed, and the tumor was partially resected. Histopathologic examination revealed abnormal cells with prominent nuclei, vascular endothelial proliferation, pseudopalisading, and areas of necrosis characteristic of glioblastoma multiforme (Fig. 6). The glial fibrillary astrocytic protein (GFAP) stain was positive (Fig. 7). The patient developed hydrocephalus in the postoperative period and underwent placement of a ventriculoperitoneal shunt. She was subsequently treated with chemotherapy consisting of os . . ·····1·-·::::::::::::::·· ::::::::~;t·:;:;;;;;;:;;;:: ·::::1·-·:::::: II+ OD FIG. 1. Static perimetry (24-2 strategy) at presentation shows enlarged blind spots OD and OS. I Clin Neuro-ophthalmol, Vol. 13, No.2, 1993 GLIOBLASTOMA MULTIFORME AND PTC 107 FIG. 2. Bilateral optic disc swelling worse in the right eye. carmustine (BCNU) and cisplatin and with hyperfractionated radiation therapy. Despite treatment, a follow-up MRI 2 months after surgery demonstrated tumor extension into the corpus callosum and both frontal lobes with edema and mass effect. DISCUSSION This case, in which a glioblastoma multiforme simulated pseudotumor cerebri (PTC), is noteworthy from several standpoints. First, the patient was a 16-year-old girl. PTC typically occurs in young women; however, the peak incidence of glioblastoma multiforme occurs between the fourth and sixth decades with a male predominance (1). In one study of patients with glioblastoma, less than 3% of patients were children (8). The second aspect concerns the presence of increased intracranial pressure. When associated with glioblastoma multiforme, the intracranial hypertension can be caused by several mechanisms, including the tumor's critical mass, obstruction of I Clill N,·l/rtJ-0l'lttlU1ll11ol. Vol. 13, No.2. 1993 108 A c M. AROICHANE ET AL. ,B FIG. 3. A: Axial T2-weighted image showing apparent enlargement of both thalami, left greater than right. No abnormal high signals are noted. B: Coronal T1-weighted image shows apparent enlargement of thalami and a diffusely enlarged optic chiasm and infundibulum. C: Coronal T1-weighted image with GdOTPA of same region as in B shows no evidence of enhancement. the intracranial venous outflow and blockage of the CSF pathways (9). Frankel and German (10) reviewed the results of 122 lumbar punctures in 219 cases of glioblastoma multiforme and found that 80% had increased intracranial pressure. In our patient, the diagnosis of PTC was supported by the finding of a normal CSF pressure at the time of the second lumbar puncture. The third aspect of this unusual case was the normal CSF protein concentration. The concentration of protein in the CSF in patients with PTC is, by definition, normal. It may even be low, suggesting an increased rate of CSF absorption in patients with this syndrome (9). In contrast, CSF analyses /1.·!/I1 N,·/lr,,-,'/,htllllll//ol. Vol. 13. No.2. 1993 in glioblastoma multiforme typically reveal an increased CSF protein level (11). Merritt and Fremont- Smith (12) found that 68% of patients with hemispheric glioma had CSF protein content greater than 45 mg/dL. Similarly, Frankel and German (10) found that CSF protein content was increased in 76% of patients with glioblastoma multiforme. The increase in CSF protein concentration with CNS tumor correlates with disruption of the blood-brain barrier caused by changes in endothelial cell permeability (9). In patients with suspected neoplasm, when neuroimaging is negative, the increased CSF protein content is an early and sensitive indicator of increased endothelial cell perme- GLIOBLASTOMA MULTIFORME AND PTC 109 OD FIG. 4. Static perimetry (24-2 strategy) 8 weeks after initial presentation shows an incomplete bitemporal field defect. ability associated with eNS neoplasms and absolutely eliminates the diagnosis of PTe (9). Nevertheless, the findings of Merritt and FremontSmith (12), Frankel and German (10), and others (9) indicate that about 20 to 30% of patients with glioblastoma multiforme have a normal eSF protein concentration. The fourth aspect is related to the patient's acellular eSF noted on two different occasions. The eSF in patients with glioblastoma multiforme often shows a mild pleocytosis of 10 to 100 cells (1,9). Frankel and German found that 46% of the lumbar punctures in glioblastoma multiforme showed abnormal cell counts (10). In addition, the eSF cytopathologic examination in patients with glioblastoma multiforme often demonstrates malignant cells (9,11). In previous reports, the incidence of positive eSF cytopathology in cases of glioblastoma multiforme has ranged from 17% to 37.2% (13-18). Nevertheless, Bischoff (13) reported a false negative rate of eSF cytopathology in 9 of 20 (45%) cases of glioblastoma multiforme. This high vari- A B FIG. 5. MRI performed 8 weeks after initial presentation: A:.Coronal T1-wei.ghted image shows a large heterogeneous hypointensity in the diencephalon. B: Coronal T1-welght~d Image with Gd-DTPA of the same. region as In B shows a marked irregular hyperintense signal involving the diencephalon. The leSion IS compressing the optiC chiasm. JClIIl NellrO-0l'hthalmol, Vol. 13, No.2. 1993 110 M. AROICHANE ET AL. FIG. 6. Histopathologic examination of the biopsy specimen demonstrates abnormal cells with prominent nuclei, pseudopalisading and areas of necrosis. (Hematoxylin and eosin, 100X.) ability among the different series may reflect the differences and difficulties in processing of CSF cytopathologic examination. Diagnosis of primary brain tumors based on CSF cytopathology has been challenging because of the low-yield processing techniques, the relatively small amount of CSF that is often obtained, the fragile character of the malignant cells, and low number of cells often FIG. 7. Glial fibrillary astrocytic protein stain (GFAP) of specimen shows diffuse staining in many cells. Vascular endothelial cell proliferation is evident. (GFAP, 100x.) , C/ill Neuro-ol'htIUllmol. Vol. 13, No.2, 1993 GLIOBLASTOMA MULT/FORME AND PTC 111 present (19). Neoplastic cell dissemination into the eSF is dependent upon tumor type and location (20,21). Brain tumors invading the ventricular system or the subarachnoid space are more likely to be detected with eSF sampling than are hemispheric infiltrative tumors such as low-grade astrocytoma (9). Glioblastoma multiforme has a high propensity to exfoliate malignant cells into the eSF by direct extension to the pia or the ependyma of the lateral and third ventricles (19,22-25). Onda described two types of eSF dissemination of glioblastomas: type A consists of extensive CSF seeding with only slight intraparenchymal invasion at the primary site. Type B, which is compatible with this case, consists of a diffusely infiltrating tumor at the primary site with only slight eSF seeding (21). Thus, eSF cytopathology cannot be used to rule out the presence of a malignancy. The completely normal eSF findings (excluding the increased opening pressure of the first lumbar puncture) on two different occasions in this patient with glioblastoma multiforme is very unusual. Frankel and German (10) found that only 6% of the cases showed normal values for all the parameters including intracranial pressure, eSF protein content, and cell count. They stressed the fact that in glioblastoma multiforme, the eSF is almost always abnormal in some respect. The final interesting aspect of this case report concerns the neuroimaging studies. Usually, the Tl-weighted MRI appearance of a glioblastoma multiforme is characterized by poorly circumscribed heterogeneous hypointensity. On T2weighted image, glioblastoma multiforme exhibits hyperintense signal that develops in almost all cases (26). The presence of hemosiderin or evidence of previous hemorrhage helps to distinguish glioblastoma multiforme from an anaplastic astrocytoma. One of us (N.R.M) has seen another patient who presented initially with enlargement of the thalami and was found subsequently to have a diffuse anaplastic astrocytoma. However, in that case, the eSF protein concentration was abnormal. This case illustrates the fact that even patients who seem to fulfill the criteria for PTe may have another process that is responsible for their increased intracranial pressure. 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