Department of Health and Human Services, National Institutes of Health, Bethesda, Maryland

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1 J Neurosurg 55: , 1981 Primary demyelinating the corpus callosum disease simulating glioma of Report of three cases KENNETH G. RIETH, M.D., GIOVANNI DI CHIRO, M.D., LAURENCE D. CROMWELL, M.D., PAUL E. MCKEEVER, M.D., PAUL L. KORNBLITH, M.D., CONRAD V. KUFTA, M.D., AND A. BERNARD PLEET, M.D. Department of Health and Human Services, National Institutes of Health, Bethesda, Maryland ~/ Computerized tomography (CT) has made it easier to distinguish tumoral from nontumoral diseases of the central nervous system. In the presence of mass effect, however, this distinction may be difficult or impossible to make. Primary demyelinating disease may occasionally present as a focal cerebral mass. The authors report three cases of primary demyelinating disease of the brain involving the corpus callosum and periventricular white matter and associated with mass effect, which proved difficult to differentiate from infiltrating "butterfly" gliomas. KEY WORDS 9 demyelinating disease 9 multiple sclerosis central nervous system 9 brain tumor computerized tomography 9 T HE computerized tomography (CT) findings in primary demyelinating processes of the central nervous system (CNS) have been described, 1-3'5-7'9'1~ including the CT appearance of multiple sclerosis, the most common of the demyelinating diseases. The CT findings in multiple sclerosis include: 1) focal areas of low attenuation in the white matter; 5'1~ 2) areas of normal or low attenuation in the white matter with focal contrast enhancement seen in the active phase of the disease; 1'3'1~ and 3) localized or diffuse cerebral atrophy) '6'9'1~ It should be noted that, particularly in the early stages of the disease, normal CT scans are frequently encountered. Focal cerebral space-occupying lesions in demyelinating disease are unusual, but have been reported in patients with progressive multifocal leukoencephalopathy, 8'11 adrenoleukodystrophy, a and recently in a patient with multiple sclerosisj 3 In the presence of a mass lesion, it may be difficult to differentiate demyelinating disease from a neoplasm. We present three cases of primary demyelinating disease involving the corpus callosum and periventricular white matter as- sociated with mass effect and contrast enhancement which were essentially indistinguishable from infiltrating "butterfly" gliomas. Case 1 Case Reports In this 42-year-old white woman, multiple sclerosis had been diagnosed in Symptomatology had been characterized by bilateral lower extremity paresthesias. After multiple relapses, the patient's condition had been stable since In January, 1978, the patient presented with progressive, persistent, rightsided headaches leading to confusion and increasing somnolence. Neurological examination revealed decreased attention and short-term memory, a left temporal field cut, and decrease in position sense. Cerebrospinal fluid (CSF) analysis showed elevated protein (80 mg/100 ml) and glucose (77 mg/100 ml), normal immunoglobulin G value, and 16 white blood cells (15 lymphocytes). Radionuclide brain scan demonstrated increased 620 J. Neurosurg. / Volume 55 / October, 1981

2 Demyelinating disease simulating glioma uptake in the centroparietal region, and CT (Fig. 1 left) showed a deep bilateral lesion in the white matter, involving the posterior corpus cauosum, and characterized by low attenuation with mass effect and contrast enhancement. Cerebral arteriographic studies, including bilateral carotid and vertebral artery examinations, failed to show abnormal vascularity. Mainly because of the CT findings, cerebral surgical exploration was seriously considered. Following a 10-day course of steroids, analysis of the CSF was normal for protein and glucose. A repeat radionuclide brain scan was normal, and a control CT study showed improvement. Two months later, a repeat CT scan revealed no evidence of mass or enhancement (Fig. 1 right). Case 2 This 23-year-old white woman developed frontal headaches and photophobia, and became quiet and withdrawn. The neurological examination demonstrated a flat affect with inappropriate response. Frontal signs, including glabeuar, snout, and rooting reflexes, were detected. Hoffman and Babinski reflexes were also evident. Computerized tomography (Fig. 2 left pair) demonstrated a large, asymmetrical, periventricular mass lesion involving the corpus callosum with peripheral contrast enhancement. The differential diagnosis included "butterfly" glioma of the corpus callosum, and a biopsy was performed. The pathological fmdings from the brain biopsy were equivocal: "possible lowgrade glioma; demyelinating disease cannot be excluded." A repeat CT scan after 6 weeks of steroid therapy showed less mass effect and contrast enhance- FIG. 1. Case 1. Computerized tomography scans after contrast-medium infusion. Left: An enhancing lesion can be seen in the corpus callosum and periventricular white matter, with some compression of the lateral ventricles. An edematous area surrounds the lesion. Right: Follow-up scan after 2 months of steroid therapy shows no contrast enhancement or mass effect. The ventricles are slightly larger than in the first scan. ment (Fig. 2 right pair), despite the fact that the clinical improvement was minimal. A radionuclide scan at this time was positive, with increased uptake bifrontally. Cerebral angiography demonstrated an avascular mass lesion involving the corpus callosum. Repeat brain biopsy, 10 weeks after initial surgery, confirmed a primary demyelinating process. The neuropathological findings included marked demyelination in the white matter with sparing of the cortical neurons and axons. Intense active gliosis was present in the region of demyelination. Macrophages contained myelin debris, periodic acid-schiff (PAS)-positive granules, and lipid droplets (Fig. 3). Steroid FIo. 2. Case 2. Computerized tomography (CT) scans after contrast medium infusion. Left Pair: Extensive areas of hypodensity are seen bifrontrally, greater on the left. There is compression of the frontal horns and marked peripheral enhancement. The CT appearance is that encountered in "butterfly gliomas" of the corpus callosum. Right Pair: Following biopsy and 6 weeks of steroid therapy, scans show less mass effect and peripheral enhancement. J. Neurosurg. / Volume 55 / October,

3 K. G. Rieth, et al. FIG. 3. Case 2. A 1-# thick plastic section of cerebral tissue from a brain biopsy. Loss of myelin around the axons is extensive (arrows). Macrophages containing round, lucent lipid droplets predominate in the parenchyma and in the perivascular space. Reactive astrocytes are present (arrowhead). Toluidine blue, x FIG. 4. Case 2. Follow-up scans showing marked improvement. The areas of hypodensity and mass effect have essentially disappeared. Also, the enhancement is no longer evident. Mild enlargement of the ventricles has occurred. therapy was continued, and the last follow-up CT scans 14 weeks later showed return toward normality (Fig. 4). Case 3 This 38-year-old man had a progressive CNS disease, manifested by increasing leg weakness and spasticity as well as bladder and bowel incontinence since Previous CSF studies were negative, and CT had shown only generalized atrophy. The patient presented at this time with generalized seizures which were increasing in frequency. He had also developed a fever. Physical examination revealed a slightly febrile (99.2~ lethargic, but arousable patient. Cranial nerves were normal. A spastic quadriparesis with decreased muscle mass was present, with ankle clonus and extensor plantar response bilaterally. Analysis of the CSF showed elevated protein with normal IgG. Glucose was normal and no abnormal cellularity was noted. Computerized tomography revealed a large bilateral lesion in the frontal lobes with involvement of the corpus callosum and an enhancing rim (Fig. 5). The possibility of brain abscess was considered, and treatment of the patient with antibiotics was initiated. Needle biopsy of the brain was reported to show a demyelinating process with no evidence of tumor or abscess. Following discharge, the patient was stable, taking Dilantin (phenytoin) for control of seizures. Four months later, he died from aspiration pneumonia. Neuropathological fmdings at autopsy revealed cerebral demyelination in the occipital and frontal lobes with degeneration of some of the spinal cord tracts. Bilateral adrenal atrophy led to consideration of adrenoleukodystrophy or adrenomyeloneuropathy. Additional studies, however, including histochemis- 622 J. Neurosurg. / Volume 55 / October, 1981

4 Demyelinating disease simulating glioma FIG. 5. Case 3. Postcontrast computerized tomography scans demonstrate peripheral enhancement of bilateral white matter hypodense lesions in the frontal area. There is deformity of the frontal horns secondary to involvement of the corpus callosum. try, electron microscopy, and review of adrenal material, did not support these diagnoses. Search for CNS viral inclusions was negative. The final diagnostic impression was that of multiple sclerosis. Discussion With the introduction of CT, it has become easier, in many instances, to distinguish tumoral from nontumoral disease of the CNS. With the newer generation scanners we are able to clearly differentiate white from gray matter. Certain patterns of contrast enhancement are quite characteristic for specific pathological processes. Primary demyelinating disease of the CNS generally does not produce focal or diffuse mass lesion. This feature has been used to distinguish demyelinating processes from brain tumors, as well as from inflammatory disease. If, however, areas of demyelination and associated inflammatory cellular response are marked and confluent, this may result in a focal space-occupying lesion often associated with contrast enhancement due to loss of integrity of the bloodbrain barrier. These fmdings may be hard to differentiate from those encountered in tumor and pure inflammatory lesions. Progressive multifocal leukoencephalopathy may present as a cerebral expanding lesion, a'11 Also, in adrenoleukodystrophy, inflammatory zones may be found in association with large areas of gliosis and astrocytosis, and may result in a mass effect. 4'8'12 Recently, mass effect and peripheral contrast enhancement have been demonstrated on CT in a patient with multiple sclerosis. 13 In this case, in contrast to our patients, the corpus callosum was not involved. Our three cases appear to represent slightly different manifestations of primary demyelinating disease. Both progressive multifocal leukoencephalopathy and adrenoleukodystrophy were excluded by neuropathological studies in Cases 2 and 3 and by the history in Case 1. The most instructive feature of our cases is the importance of considering primary demyelinating disease in the differential diagnosis of cerebral mass lesions involving and infiltrating the corpus callosum. When associated with mass effect and contrast enhancement on CT, a diagnosis of brain tumor or abscess may be considered, and inappropriate treatment instituted. Even brain biopsy, which was performed in two of our cases and seriously contemplated in a third (Case 1), may give equivocal results. In cases such as these, conservative management with steroid therapy and serial control CT scans may be the best means of substantiating a diagnosis of demyelinating disease. Acknowledgments The authors would like to thank Drs. Alan Rabson and Jos~ Costa for their consultation, Ms. Mary Bowling and Ruby Howard for their help with paraffin sections and special stains, Ms. Mary Greenwood for providing superb electron microscopy and plastic light microscopic sections, and Mrs. Colleen E. Bidle for her invaluable editorial assistance. References 1. Aita JF, Bennett DR, Anderson RE, et al: Cranial CT appearance of acute multiple sclerosis. Neurology 28: , Cala LA, Mastaglia FL: Computerised axial tomography in multiple sclerosis. Lancet 1:689, Cole M, Ross RJ: Plaque of multiple sclerosis seen on computerized transaxial tomogram. Neurology 27: , 1977 J. Neurosurg. / Volume 55 / October,

5 K. G. Rieth, et al. 4. Eiben RM, Di Chiro G: Computer assisted tomography in adrenoleukodystrophy. J Comput Assist Tomogr 1: , Gyldensted C: Computer tomography of the brain in multiple sclerosis. A radiological study of 110 patients with special reference to demonstration of cerebral plaques. Aeta Neurol Seand 53: , Gyldensted C: Computer tomography of the cerebrum in multiple sclerosis. Neuroradiology 12:33-42, Haughton VM, Ho KC, Williams AL, et al: CT detection of demyelinated plaques in multiple sclerosis. Am J Roentgenol 132: , Heinz ER, Drayer BP, Haenggeli CA, et al: Computed tomography in white-matter disease. Radiology 130: , Huckman MS, Fox JH, Ramsey RG: Computed tomography in the diagnosis of degenerative diseases of the brain. Semin Roentgenoi 12:63-75, Lane B, Carroll BA, Pedley TA: Computerized cranial tomography in cerebral diseases of white matter. Neurology 28: , Preskoru SH, Watanabe I: Progressive multifocal leukoencephalopathy: cerebral mass lesions. Surg Neuroi 12: , Schaumburg HH, Powers JM, Raine CS, et al: Adre- noleukodystrophy. A clinical and pathological study of 17 cases. Arch Neurol 32: , van der Velden M, Bots GTAM, Endtz LJ: Cranial CT in multiple sclerosis showing a mass effect. Surg Neurol 12: , Weinstein MA, Lederman R J, Rothner AD, et al: Interval computed tomography in multiple sclerosis. Radiology 129: , 1978 Manuscript received March 18, Address for Dr. Di Chiro: Neuroradiology and Computed Tomography Section, NINCDS, NIH, Bethesda, Maryland Address for Drs. Cromwell, Kornblith, and Kufta: Department of Radiology, University of Washington School of Medicine, Seattle, Washington Address for Dr. McKeever: Surgical Neurology Branch, NINCDS, NIH, Bethesda, Maryland Address for Dr. Pleet: Department of Neurology, Uniformed Services University of Health Sciences, Bethesda, Maryland Address reprint request to: Kenneth G. Rieth, M.D., Diagnostic Radiology Department, Building 10, Room 6S21 l, NIH, The Clinical Center, Bethesda, Maryland J. Neurosurg. / Volume 55 / October, 1981