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Pediatric tumefactive demyelination: case series and review of the literature
Pediatric Tumefactive Demyelination: Case Series and Review of the Literature Laura C. McAdam, MSc, MD*, Susan I. Blaser, MD†, and Brenda L. Banwell, MD‡ Tumefactive demyelinating lesions may be misdiagnosed as brain neoplasms or abscesses. In this paper, we present four cases of pediatric tumefactive demyelination. Twelve cases of pediatric tumefactive demyelination previously reported in the English literature are also summarized. We describe the neuroimaging characteristics and clinical presentation of tumefactive demyelination and how these features may be used in differentiating demyelination from other mass lesions. © 2002 by Elsevier Science Inc. All rights reserved. McAdam LC, Blaser SI, Banwell BL. Pediatric tumefactive demyelination: Case series and review of the literature. Pediatr Neurol 2002;26:18-25.
Introduction Multiple sclerosis is a common demyelinating disease in adults with a prevalence of approximately 30 per 100,000 population in Canada [1]. Multiple sclerosis also occurs in children [1–3]. Approximately 4.4% of patients with multiple sclerosis present with their first episode of demyelination before their sixteenth birthday and 0.3% present before 10 years of age [1]. Several papers have reported the infrequent presentation, in adults and children, of a large focal area of demyelination surrounded by ring enhancement, often associated with mass effect on neighboring central nervous system structures [4 –19]. These lesions may resemble brain neoplasms or abscesses and have been termed tumefactive demyelinating lesions. Distinguishing tumefactive demyelinating lesions from malignancy or infection is critical for proper patient management and to avoid unnecessary medical or surgical interventions. Here, we present four children with tumefactive demyelinating lesions. We also review the previ-
From the *Department of Pediatrics, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada; †Department of Diagnostic Imaging and the ‡Department of Pediatrics (Neurology); University of Toronto; The Hospital for Sick Children; Toronto, Ontario, Canada.
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ously published cases of tumefactive multiple sclerosis lesions. We describe the use of magnetic resonance imaging to distinguish tumefactive demyelination from other lesions with similar imaging characteristics (Table 1).
Patient 1 A previously well 11-year-old Korean female presented with a 1-week history of bitemporal, frontal, and periorbital headache associated with nausea. She then experienced blurring of vision in the right and left eye, worsening over 3 days. On admission, magnetic resonance imaging (MRI) revealed patchy areas of increased signal along the intraorbital portion of both optic nerves, right greater than left. A second, small asymptomatic white matter lesion was noted in the anterior limb of the right internal capsule. Cerebrospinal fluid analysis revealed 20 leukocytes (89% lymphocytes), protein 0.21 g/L, glucose 3.0 mmol/L, an opening pressure of 5.8 cm H2O, and negative cultures. Visual-evoked potentials were low in amplitude, with poorly delineated morphology and delayed cortical responses. She was diagnosed with bilateral optic neuritis and treated with pulse IV methylprednisolone for 3 days, followed by a tapering dose of oral prednisone. Her eyesight improved rapidly to normal. However, shortly after completing prednisone, she again presented with reduced visual acuity, more in the left eye than right. The same treatment regimen was repeated. Three months after her initial presentation, she developed acute left-sided flaccid paralysis of the upper limb, and severe weakness of the left lower limb associated with hyperreflexia. Computed tomography (CT) demonstrated a right parietal lobe lesion of 3.5 cm with significant surrounding edema, causing a 7-mm deviation of midline structures to the left. MRI displayed the right frontoparietal lesion to be of increased signal on T2-weighted images. Gadolinium-enhanced T1-weighted images revealed faint rim enhancement. The findings were accentuated on fast fluid-attenuated inversion-recovery images (Fig 1A). In addition to the large lesion, there were also signal changes in the right fornix and posterior optic radiations (Fig 1B). She was treated with IV methylprednisolone for 5 days, after which she received a slow tapering dose of prednisone. Two months later she demonstrated only slight facial weakness, and trace weakness of the left shoulder girdle. Visual acuity was 20/20 bilaterally. She was diagnosed with clinically definite multiple sclerosis, and treatment with immunomodulatory therapy (interferon beta1a) was commenced. There is no family history of multiple sclerosis.
Communications should be addressed to: Dr. Banwell, Department of Pediatrics (Neurology); 6th Floor Gerrard Wing; University of Toronto; The Hospital for Sick Children; 555 University Avenue; Toronto, Ontario, Canada M5G 1X9. Received November 16, 2000; accepted June 6, 2001.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00322-8 ● 0887-8994/02/$—see front matter
Table 1.
Imaging characteristics of the differential diagnoses of tumefactive demyelination
Diagnosis
CT
T1-weighted MRI
Tumefactive demyelination
Plaque surrounded by an area of decreased attenuation precontrast May reveal patchy rim enhancement after contrast
Hypointense central area with thick surrounding band of moderately increased intensity Enhancement (when present) incomplete around lesion, often more intense on side facing the ventricle
Acute disseminated encephalomyelitis
Multiple areas of low density NOT a single focal lesion
Abscess
Low-density lesion with a thin wall of slightly increased density precontrast After contrast a thin ring of enhancing tissue (abscess wall and surrounding inflammatory tissue) Abscess rim thicker on side facing cortex
Lymphoma
Area of isodense to hyperdense signal before contrast enhancement Diffuse and prominent enhancement after contrast Presents in two forms in pediatric patients: TB meningitis and miliary TB Basal meningitis may lead to small vessel infarcts, as well as accumulation of purulent exudate within ventricles Miliary TB has tuberculomas, which are often multiple punctate high-density areas precontrast Demonstrate a ring of enhancement after contrast Small (⬍1 cm) parenchymal cysticerci lesions may be solid or cystic Solid lesions often heal to punctate calcifications Cystic foci commonly have a rim of enhancement after contrast Surrounding vasogenic edema occurs during death of scolyx Homogenous lesion, well circumscribed, associated with only mild surrounding edema Heterogeneity occurs if there are areas of necrosis or hemorrhage Higher grade astrocytomas generate more extensive vasogenic edema
Large asymmetric bilateral areas of hypointensity Lesions primarily subcortical 50% have involvement of deep nuclei Phlegmoneous stage demonstrates an area of heterogeneous hyperintensity precontrast Heterogeneous enhancement leading to an irregular appearance to the abscess rim in both the phlegmoneous stage and in a mature abscess after contrast Precontrast the mature abscess reveals central iso-hypointensity, wall is isointense to slightly hyperintense Tumor is of slightly hypointense signal Diffuse and prominent enhancement after contrast
Tuberculosis
Cysticercosis
Astrocytoma
T2-weighted MRI Tumefactive plaque is hyperintense and occasionally heterogeneous In the older child, other demyelinating lesions (when present) are preferentially located in the periventricular white matter in a pattern similar to adult MS In the younger child, other demyelinating lesions (if present) tend to be preferentially located in the subcortical white matter, and are often poorly defined Multiple large areas of hyperintensity typically involving white and gray matter Phlegmoneous stage has an area of heterogeneous hyperintensity Mature abscess has a hyperintense center with a hypointense abscess wall Abscess rim enhances after contrast
Tumor is of isointense to slightly hyperintense signal
Tuberculomas are isointense centrally with a surrounding rim of high signal intensity, which is further surrounded by a collar of hypointensity (edema) Small tuberculomas may demonstrate uniform enhancement
Granulomata are hypointense, but may be homogeneous or heterogeneous in intensity Large TB abscesses may reveal vasogenic edema that is hyperintense
Parenchymal cysticerci have a hypointense center surrounded by thick hyperintense enhancement, which may be further surrounded by a region of hypointensity (edema)
Parenchymal cysticerci have a hyperintense center precontrast surrounded by a thin rim of hypointensity, further surrounded by a hyperintense rim of vasogenic edema Scolyx may be occasionally visualized in some cysts
Isointense with gray matter May reveal enhancement, particularly high-grade gliomas May reveal areas of flow void (feeding vessels)
Solid portion of the tumor is hyperintense
Modified from: Barkovich JA, ed. Pediatric neuroimaging, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:23– 4. Neuroimaging characteristics of tumefactive demyelination are contrasted with imaging features of tumefactive lesions seen in CNS infection, or malignancies. Both CT and MRI features are described.
McAdam and Banwell: Pediatric Tumefactive Demyelination 19
Figure 1. (A) Axial fast fluid-attenuated inversion-recovery MRI (TR ⫽ 9002 ms, TE ⫽ 165 ms) of a tumefactive demyelinating lesion demonstrates abnormal signal intensity in the internal and external capsule, subinsular cortex, lateral thalamus, and posterior putamen association with mass effect. In addition, bilateral signal abnormality is seen in the fornical columns. (B) Axial gradient-recalled echo T1 image with gadolinium (TR ⫽ 9.1 ms, TE ⫽ 4.2 ms) demonstrates heterogeneous enhancement of the lesion.
Patient 2 A previously well 8-year-old female, born in Sri Lanka, presented with progressive bilateral visual loss over 4 days. For several months before presentation she suffered from increasingly frequent intermittent frontal headaches. Cerebrospinal fluid analysis revealed 33 leukocytes (76% monocytes), 14 erythrocytes, protein 0.31 g/L, and glucose 3.9 mmol/L.
Computed tomography scan revealed bilateral enlargement of the optic nerves, and diffuse abnormality of the white matter. T2-weighted MRI confirmed diffusely increased signal in the white matter bilaterally. T1-weighted images after administration of gadolinium displayed enhancement of the intraconal and intracanalicular segments of right optic nerve, and a single area of abnormal enhancement in left optic nerve (Fig 2). The diagnosis of bilateral optic neuritis and acute disseminated
Figure 2. (A) Axial T1-weighted fat-saturated contrast-enhanced image (TR ⫽ 500 ms, TE ⫽ 15 ms) demonstrates enhancement of the optic nerve and sheath complex, and the posterior sclera bilaterally, with the right side more affected than the left. (B) Axial proton density image (TR ⫽ 2800 ms, TE ⫽ 22 ms) demonstrates multiple regions of confluent white matter demyelination.
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Figure 3. (A) Axial-enhanced CT image demonstrating a demyelinating lesion with a thick irregular rim of enhancement. A collar of low density, consistent with vasogenic edema or partial demyelination, surrounds the demyelinating lesion. (B) Axial fast fluid-attenuated inversion-recovery MRI (TR ⫽ 9002 ms, TE 165 ms) demonstrates a large right-sided demyelinating lesion extending from the external to internal capsule, also involving the white matter of the frontoparietal lobe. This lesion is associated with mass effect on overlying cortex and slight impingement of the lateral ventricle. In addition, subcortical and periventricular demyelinating foci are noted in the left frontal and peritrigonal regions. encephalomyelitis was made. She was treated with IV methylprednisolone for 3 days, followed by a tapering dose of oral prednisone. Visual acuity improved with treatment. Two months later, she presented with right-sided head tilt, a resting tremor of the upper limbs, persistent dizziness, and unsteadiness of gait. Her parents found her emotionally labile with intermittent anger and agitation. MRI revealed interval improvement in the previously noted diffuse frontal, parietal, and temporal white matter lesions. However, new multifocal asymmetric white matter lesions were noted in the area surrounding the right basal ganglia, at the right pontomesencephalic junction, and in the left middle cerebellar peduncle. She was diagnosed with clinically definite multiple sclerosis, and treated with IV methylprednisolone for 3 days, after which she received an oral prednisone taper. There is no family history of multiple sclerosis. Two months later, she developed left optic neuritis. MRI demonstrated improvement in the frontal white matter signal, the right basal ganglia signal abnormality had resolved, and there was interval improvement in the left cerebellar peduncle lesion. Increased T2-weighted signal was noted in the right occipital region bordering the lateral ventricle, and in numerous other areas. Visual-evoked potentials revealed poorly defined and delayed responses on the left, and an abnormal p100 response in the right eye. After steroid therapy, interferon beta 1b was commenced. The patient continued interferon without side effects for more than 1 year, during which time she had a single attack consisting of right-sided optic neuritis. She was reluctant to have further injections and decided to discontinue interferon therapy. Two months after discontinuing interferon therapy, she presented with marked left-sided weakness. She had two seizures while in the hospital. Neuroimaging revealed a large area of high signal intensity on T2weighted images in the right periventricular white matter with extensive surrounding edema extending cephalad into the corona radiata and inferiorly into the white matter tracts, sparing the basal ganglia (Fig 3). There was mild mass effect. Multiple other white matter lesions were noted. She improved rapidly and completely with steroid therapy. Reinitiation of therapy with interferon is planned.
Patient 3 A previously well male, 5 years, 6 months of age, of Indian descent, moved to Canada 11⁄2 years before presentation. Shortly after returning from an extended visit to India, he presented with slowly progressive bilateral lower limb spasticity, urinary retention, weakness of the left arm, and a homonymous left-sided visual-field defect. Cranial CT demonstrated a ring-enhancing lesion in the right parietooccipital area. MRI of the spine revealed a ring-enhancing intramedullary lesion at C2 with edema and multiple lesions with increased T2-signal throughout the spinal cord (Fig 4A). Brain biopsy was performed to exclude tumor (with spinal metastasis) or neurocysticercosis infection. The biopsy specimen demonstrated demyelination, and the patient was tentatively diagnosed with acute disseminated encephalomyelitis. Steroid therapy resulted in complete remission of symptoms, and his neurologic examination returned to normal. One month later, the result of a serum immunoblot assay for neurocysticercosis became available and was positive. No immediate therapy was given, since the patient was clinically stable. Repeat imaging 5 months later revealed complete resolution of the cranial lesion, but persistence of the spinal lesions. Anticysticercal treatment with albendazole and dexamethasone was given for possible neurocysticercosis. Five months later, he presented with mild left-sided hemiparesis. While in the hospital, he had one brief focal seizure. A new 3– 4-cm cystic lesion in the right frontoparietal subcortical area was seen on a MRI. He was treated with steroids and albendazole for 4 weeks followed by a tapering dose of steroids. Nine months later he presented with headache, vomiting, and seizures. Imaging revealed a new ring-enhancing white matter lesion in the left frontoparietal area (Fig 4B). The diagnosis of neurocysticercosis was then dismissed based on the following: (1) the lesions were atypical for cysticercosis, (2) the cysticercosis immunoassay was repeated within 1 year and was negative, and (3) a third recurrence of neurocysticercosis is almost unheard of in someone outside of an endemic area. Albendazole
McAdam and Banwell: Pediatric Tumefactive Demyelination 21
Figure 4. (A) Sagittal T2-weighted fast spin-echo image (TR ⫽ 5700 ms, TE ⫽ 90 ms) demonstrates prominent abnormal signal in the cervical spinal cord from level of the synchondrosis to the body of C3, with faint signal abnormality extending cephalad to C1 and inferiorly to C4. (B) Axial T1-weighted image (TR ⫽ 680 ms, TE ⫽ 22 ms) demonstrates a large ring-enhancing lesion in the left occipital region, and a second area of enhancement in the right occipital region. Multiple small enhancing foci are present throughout the hemispheres (not displayed in this image). Note is made of an incidental right middle cranial fossa arachnoid cyst (arrow). therapy was withheld. He was diagnosed with clinically definite multiple sclerosis and treated with corticosteroids. There is no family history of multiple sclerosis. Two months later he presented with right facial droop and slurred speech. CT demonstrated a new 2-cm left frontal ring-enhancing lesion. He was treated with IV methylprednisone followed by a tapering dose of steroids. Five months later, he developed left hemiparesis, difficulty with speech, and pervasive fatigue. He responded well to steroids. Using CT, two large ring-enhancing lesions in the right hemisphere were found, increased in size compared with prior images. A new left frontal lobe ring-enhancing lesion was also noted. He was started on interferon beta 1a, without noteworthy side effects. Seven months later, he presented with decreased visual acuity, mild weakness in right arm, and a brief seizure. CT displayed improvement in the previously noted multiple ring-enhancing lesions, however, new lesions in the posterior right parietal lobe and in left parietooccipital region were evident. One month later, he developed a right foot-drop and right leg weakness followed by weakness in his left leg, left hemianopsia, and decreased visual acuity. MRI of the spine displayed a large demyelinating plaque extending from T2 to T7. He was admitted for IV methylprednisolone for 3 days. On day 2, he became less responsive, complained of headache, and had several episodes of vomiting. MRI revealed extensive white matter demyelination. Slow, but incomplete, improvement was evident with steroid therapy. The frequency and severity of clinical relapses, and the failure to document any reduction in central nervous system lesion load on MRI, prompted withdrawal of therapy with interferon beta 1a. He was commenced on treatment with subcutaneously administered glati-
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ramer acetate, 20 mg daily, which he has tolerated well. Amantadine was started to reduce clinically profound fatigue. The frequency and severity of the relapses, combined with significant residual visual loss (20/200), a dense homonymous visual-field deficit, mild weakness, and profound fatigue, led to a decision to treat with a 5-day course of IV cyclophosphamide combined with methylprednisolone and antinauseants. The treatment was well tolerated, and the expected leukopenia was achieved. Alopecia was minimal. One month later the patient reported marked improvement in function and wellbeing. On examination, vision improved markedly to 20/20, the visualfield deficit resolved, and he had no demonstrable weakness. He has been free of relapse for 6 months.
Patient 4 A 14-year-old white female of Irish decent (previously reported by Kumar et al. [4]) was well until she awoke with a headache, blurring of vision, and vomiting, which resolved over 24 hours. Similar symptoms recurred 1 month later. Five months later, she developed a headache, followed by blurring of vision and loss of consciousness. A generalized seizure lasting 2 minutes was then witnessed. One month later, she developed the same symptoms, followed by a generalized seizure lasting 2–3 minutes. A cranial CT demonstrated a right frontal lobe cystic lesion. MRI confirmed this finding (Fig 5A). Because of the history of new-onset, recurrent seizures, the lesion was thought to be a tumor, and the patient was transferred to our institution for surgery. Neurologic examination was normal. Family history revealed a grandmother with multiple sclerosis.
Figure 5. (A) Coronal T1-weighted image (TR ⫽ 12 ms, TE ⫽ 5 ms) of the demyelinating lesion displays asymmetric ring enhancement. The rim appears thicker and reveals more prominent enhancement on the side facing the lateral ventricle. (B) Coronal T1-weighted, gadolinium-enhanced image (TR ⫽ 600 ms, TE ⫽ 20 ms) highlights the smooth, regular contour of the abscess rim.
A right frontal craniotomy with gross total removal of the lesion was performed. There were no surgical complications, and she recovered well without sequelae. Pathologic studies revealed a demyelinating process with myelin loss, perivascular inflammatory cuffing, and gliosis. She remains well, without seizures or recurrent demyelination 4 years after her initial presentation. A recent MRI scan was normal, with no evidence of recurrent demyelination.
Discussion MRI characteristics of typical multiple sclerosis lesions have been well described by Patty et al. [20] and Fazekas et al. [21]. Typical multiple sclerosis plaques are ovoid in shape, sharply demarcated, and are located perpendicular to the long axis of the lateral ventricles. They have a low signal on T1-weighted images, and a high signal on T2-weighted images. CT scans may miss subtle demyelinating lesions, and thus MRI is the preferred imaging modality for the investigation of demyelination. There are reported cases of multiple sclerosis presenting with a large solitary mass lesion with a surrounding ring that enhances with contrast administration [4,5,18]. These lesions have been termed tumefactive demyelination. Differential diagnoses include cerebral tumors, abscesses, and parasitic foci. Pathologic studies of tumefactive lesions report large areas of confluent demyelination with an inflammatory cellular response, often associated with perilesional edema and mass effect on surrounding structures [22]. To date, there have been 12 reported cases in the English literature of tumefactive demyelinating lesions in children [5,12–18]. Eight of the 12 cases were in female
patients. The mean age of presentation was 11.2 years (11.4 years of age for females, and 10.3 years of age for males). Six patients were initially diagnosed with a brain neoplasm, and one was felt to have multiple abscesses. All lesions revealed ring enhancement, in 10 of 12 patients the lesions were associated with perilesional edema, and in four cases, lesions exhibited mass effect on neighboring structures. Seven patients underwent brain biopsy or resection of the entire lesion [12–17]. Pathologic studies confirmed demyelination in the seven cases biopsied. Three children received brain radiation [13,15], and six received steroids. Acute neurologic deficit, combined with the neuroradiologic appearance of a large mass lesion, is a cause for immediate medical attention. Distinguishing tumefactive demyelination from other etiologies is of critical importance to avoid unnecessary and invasive diagnostic interventions, and to prevent unwarranted toxic therapies. This is highlighted by the significant morbidity of several patients, including one child [15], treated with central nervous system radiation for presumed central nervous system malignancy. Pathologic specimens revealed demyelination, and four of five patients developed severe neurologic sequelae post radiation, suggesting that patients with demyelination may be selectively vulnerable to radiation-induced toxicity. The importance of accurate diagnosis is further highlighted by the death of one child after an attempted drainage of presumed abscess [14], in whom pathologic study confirmed multifoci of demyelination. Even in patients with established multiple sclerosis, the
McAdam and Banwell: Pediatric Tumefactive Demyelination 23
diagnosis of tumefactive demyelination can occasionally be difficult. Many multiple sclerosis patients receive treatment with corticosteroids and other immunosuppressant medications, and thus a new mass lesion with ring enhancement raises the possibility of opportunistic infection, abscess, or even neoplasm. Table 1 outlines various radiologic features of cerebral mass lesions that would be in the differential diagnosis of tumefactive demyelination. Although there is no one radiologically distinct imaging feature to distinguish a tumefactive demyelinating lesion from other lesions in the differential, there are several important features that would favor demyelination. Tumefactive demyelination is supported by the presence of demyelinating plaques elsewhere in the neuraxis, particularly those adjacent to the ventricular surface (Fig 3), and by enhancement limited to only one side of the lesion or preferential enhancement of the lesional rim facing the lateral ventricles (Fig 5A). In contrast, cerebral abscesses tend to have a thicker rind, the rim is more regular in contour, and rim enhancement is either uniform (Fig 5B), or concentrated at the region of the rim facing the overlying cortex. Because multiple sclerosis plaques may occur anywhere in the central nervous system, a search for other areas of demyelination should include MRI evaluation of the spine, or at least the cervical spinal cord, which is the spinal cord region in which multiple sclerosis plaques most commonly occur (Fig 4A). A history of prior transient neurologic events and clinical findings of neurologic deficit referable to separate areas of the central nervous system support the diagnosis of multiple sclerosis. In patients with no past clinical or MRI features of definite multiple sclerosis, but in whom the diagnosis of tumefactive demyelination is entertained, repeat fast fluid-attenuated inversion-recovery sequences may be performed during or shortly after completion of corticosteroid therapy. Although perilesional edema associated with tumor or abscess may respond to corticosteroid administration, a rapid reduction in the size of the tumefactive lesion associated with significant clinical improvement favors demyelination. Tumors or abscesses are unlikely to respond rapidly or completely. The development of new enhancing lesions also supports the diagnosis of multiple sclerosis. Rapid development of new lesions is unlikely in primary central nervous system malignancy or in patients who initially presented with a solitary central nervous system abscess. Exceptions to this include widespread metastatic tumors, the diagnosis for which should be suggested by the presence of a primary systemic tumor. Tumors known to metastasize to brain include lung, breast, and colon carcinomas, all of which are extremely rare in the pediatric population [23]. Primary pediatriconset central nervous system malignancies, which may be multifocal, include medulloblastoma and central nervous system lymphoma. Medulloblastomas are highly malignant, preferentially located in the cerebellar vermis with the potential to spread to adjacent structures, and may have
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drop metastasis to the spinal subarachnoid space. On CT, medulloblastomas are well circumscribed, and, unlike demyelination, are hyperdense or isodense [23]. Central nervous system lymphomas, which also may be multifocal, are often hyperdense on CT before contrast. On MRI, lymphomas are hypointense on T1-weighted images and isointense to slightly hyperintense on T2-weighted images. Lymphomas display diffuse and prominent enhancement with contrast on CT and MRI, rather than rim enhancement [23]. Follow-up imaging in adult patients with suspected multiple sclerosis typically includes T1-weighted, gadolinium-enhanced images to document recent perturbation of the blood– brain barrier associated with the development of new lesions. In pediatric patients, it may be preferential to use fast fluid-attenuated inversion-recovery sequences to document new areas of demyelination, because this avoids the need for IV line insertion and gadolinium administration. In addition, when imaging is for the purpose of rapid sequence follow-up, a brief MRI protocol using fast fluid-attenuated inversion-recovery sequences, rather than a lengthy complete protocol, may obviate the need for sedation in young or uncooperative patients. For initial evaluation of patients with acute tumefactive lesions, a full MRI protocol should be used. We have presented four cases of tumefactive demyelinating lesions, which developed during the course of relapsing remitting multiple sclerosis in three patients and as a monophasic event in one patient. It is important that a detailed history be obtained in all such patients, with attention to prior episodes of central nervous system demyelination, such as optic neuritis, acute disseminated encephalomyelitis, or transient neurologic deficits (for which the patient may not have sought medical assessment). Our cases, combined with those in the literature, highlight the importance of considering demyelination in the differential diagnosis of tumefactive lesions.
The authors acknowledge Ben Harito for his expert technical assistance in preparing the images and Ms. Marianne Sofronas for her secretarial support.
References [1] Sadovnick AD, Ebers GC. Epidemiology of multiple sclerosis: A critical overview. Can J Neurol Sci 1993;20:17–29. [2] Pinhas-Hamiel O, Barak Y, Siev-Ner I, Achiron A. Juvenile multiple sclerosis: Clinical features and prognostic characteristics. J Pediatr 1998;132:735–7. [3] Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: Clinical features of 149 cases. Mult Scler 1997;3:43– 6. [4] Kumar K, Toth C, Jay V. Focal plaque of demyelination mimicking cerebral tumor in a pediatric patient. Pediatr Neurosurg 1998;29:60 –3. [5] Gutling E, Landis T. CT ring sign imitating tumour, disclosed as multiple sclerosis by MRI: A case report. J Neurol Neurosurg Psychiatry 1989;52:903– 6. [6] Mastrostefano R, Occhipinti E, Bigotti G, Pompili A. Multiple
sclerosis plaque simulating cerebral tumor: Case report and review of the literature. Neurosurgery 1987;21:244 – 6. [7] Ernst T, Chang L, Walot I, Huff K. Physiologic MRI of a tumefactive multiple sclerosis lesion. Neurology 1998;51:1486 – 8. [8] Otsuka S, Nakatsu S, Matsumoto S, et al. Multiple sclerosis simulating brain tumor on computed tomography. J Comput Assist Tomogr 1989;13:674 – 8. [9] Khan OA, Bauserman SC, Rothman MI, Aldrich EF, Panitch HS. Concurrence of multiple sclerosis and brain tumor: Clinical considerations. Neurology 1997;48:1330 –3. [10] Kurihara N, Takahashi S, Furuta A, et al. MR imaging of multiple sclerosis simulating brain tumor. Clin Imaging 1996;20:171–7. [11] Paley RJ, Persing JA, Doctor A, Westwater JJ, Roberson JP, Edlich RF. Multiple sclerosis and brain tumor: A diagnostic challenge. J Emerg Med 1989;7:241– 4. [12] Case Records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 26-1998. A 15-year-old girl with hemiparesis, slurred speech, and an intracranial lesion [clinical conference]. N Engl J Med 1998;339:542–9. [13] Hunter SB, Ballinger WE, Jr., Rubin JJ. Multiple sclerosis mimicking primary brain tumor. Arch Pathol Lab Med 1987;111:464 – 8. [14] Giang DW, Poduri KR, Eskin TA, et al. Multiple sclerosis masquerading as a mass lesion. Neuroradiology 1992;34:150 – 4. [15] Peterson K, Rosenblum MK, Powers JM, Alvord E, Walker RW, Posner JB. Effect of brain irradiation on demyelinating lesions [see comments]. Neurology 1993;43:2105–12.
[16] Kepes JJ. Large focal tumor-like demyelinating lesions of the brain: Intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients [see comments]. Ann Neurol 1993;33:18 –27. [17] Rusin JA, Vezina LG, Chadduck WM, Chandra RS. Tumoral multiple sclerosis of the cerebellum in a child. Am J Neuroradiol 1995;16:1164 – 6. [18] Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology 1996;38:560 –5. [19] Morimoto T, Nagao H, Sano N, et al. A case of multiple sclerosis with multi-ring-like and butterfly-like enhancement on computerized tomography. Brain Dev 1985;7:43–5. [20] Paty DW, Oger JJ, Kastrukoff LF, et al. MRI in the diagnosis of MS: A prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1988;38: 180 –5. [21] Fazekas F, Offenbacher H, Fuchs S, et al. Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis. Neurology 1988;38:1822–5. [22] van der Valk P, De Groot CJ. Staging of multiple sclerosis (MS) lesions: Pathology of the time frame of MS. Neuropathol Appl Neurobiol 2000;26:2–10. [23] Barkovich JA. Intracranial, orbital and neck tumors of childhood. In: Barkovich JA, ed. Pediatric neuroimaging, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:443–580.
McAdam and Banwell: Pediatric Tumefactive Demyelination 25
Introduction Multiple sclerosis is a common demyelinating disease in adults with a prevalence of approximately 30 per 100,000 population in Canada [1]. Multiple sclerosis also occurs in children [1–3]. Approximately 4.4% of patients with multiple sclerosis present with their first episode of demyelination before their sixteenth birthday and 0.3% present before 10 years of age [1]. Several papers have reported the infrequent presentation, in adults and children, of a large focal area of demyelination surrounded by ring enhancement, often associated with mass effect on neighboring central nervous system structures [4 –19]. These lesions may resemble brain neoplasms or abscesses and have been termed tumefactive demyelinating lesions. Distinguishing tumefactive demyelinating lesions from malignancy or infection is critical for proper patient management and to avoid unnecessary medical or surgical interventions. Here, we present four children with tumefactive demyelinating lesions. We also review the previ-
From the *Department of Pediatrics, Foothills Hospital, University of Calgary, Calgary, Alberta, Canada; †Department of Diagnostic Imaging and the ‡Department of Pediatrics (Neurology); University of Toronto; The Hospital for Sick Children; Toronto, Ontario, Canada.
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ously published cases of tumefactive multiple sclerosis lesions. We describe the use of magnetic resonance imaging to distinguish tumefactive demyelination from other lesions with similar imaging characteristics (Table 1).
Patient 1 A previously well 11-year-old Korean female presented with a 1-week history of bitemporal, frontal, and periorbital headache associated with nausea. She then experienced blurring of vision in the right and left eye, worsening over 3 days. On admission, magnetic resonance imaging (MRI) revealed patchy areas of increased signal along the intraorbital portion of both optic nerves, right greater than left. A second, small asymptomatic white matter lesion was noted in the anterior limb of the right internal capsule. Cerebrospinal fluid analysis revealed 20 leukocytes (89% lymphocytes), protein 0.21 g/L, glucose 3.0 mmol/L, an opening pressure of 5.8 cm H2O, and negative cultures. Visual-evoked potentials were low in amplitude, with poorly delineated morphology and delayed cortical responses. She was diagnosed with bilateral optic neuritis and treated with pulse IV methylprednisolone for 3 days, followed by a tapering dose of oral prednisone. Her eyesight improved rapidly to normal. However, shortly after completing prednisone, she again presented with reduced visual acuity, more in the left eye than right. The same treatment regimen was repeated. Three months after her initial presentation, she developed acute left-sided flaccid paralysis of the upper limb, and severe weakness of the left lower limb associated with hyperreflexia. Computed tomography (CT) demonstrated a right parietal lobe lesion of 3.5 cm with significant surrounding edema, causing a 7-mm deviation of midline structures to the left. MRI displayed the right frontoparietal lesion to be of increased signal on T2-weighted images. Gadolinium-enhanced T1-weighted images revealed faint rim enhancement. The findings were accentuated on fast fluid-attenuated inversion-recovery images (Fig 1A). In addition to the large lesion, there were also signal changes in the right fornix and posterior optic radiations (Fig 1B). She was treated with IV methylprednisolone for 5 days, after which she received a slow tapering dose of prednisone. Two months later she demonstrated only slight facial weakness, and trace weakness of the left shoulder girdle. Visual acuity was 20/20 bilaterally. She was diagnosed with clinically definite multiple sclerosis, and treatment with immunomodulatory therapy (interferon beta1a) was commenced. There is no family history of multiple sclerosis.
Communications should be addressed to: Dr. Banwell, Department of Pediatrics (Neurology); 6th Floor Gerrard Wing; University of Toronto; The Hospital for Sick Children; 555 University Avenue; Toronto, Ontario, Canada M5G 1X9. Received November 16, 2000; accepted June 6, 2001.
© 2002 by Elsevier Science Inc. All rights reserved. PII S0887-8994(01)00322-8 ● 0887-8994/02/$—see front matter
Table 1.
Imaging characteristics of the differential diagnoses of tumefactive demyelination
Diagnosis
CT
T1-weighted MRI
Tumefactive demyelination
Plaque surrounded by an area of decreased attenuation precontrast May reveal patchy rim enhancement after contrast
Hypointense central area with thick surrounding band of moderately increased intensity Enhancement (when present) incomplete around lesion, often more intense on side facing the ventricle
Acute disseminated encephalomyelitis
Multiple areas of low density NOT a single focal lesion
Abscess
Low-density lesion with a thin wall of slightly increased density precontrast After contrast a thin ring of enhancing tissue (abscess wall and surrounding inflammatory tissue) Abscess rim thicker on side facing cortex
Lymphoma
Area of isodense to hyperdense signal before contrast enhancement Diffuse and prominent enhancement after contrast Presents in two forms in pediatric patients: TB meningitis and miliary TB Basal meningitis may lead to small vessel infarcts, as well as accumulation of purulent exudate within ventricles Miliary TB has tuberculomas, which are often multiple punctate high-density areas precontrast Demonstrate a ring of enhancement after contrast Small (⬍1 cm) parenchymal cysticerci lesions may be solid or cystic Solid lesions often heal to punctate calcifications Cystic foci commonly have a rim of enhancement after contrast Surrounding vasogenic edema occurs during death of scolyx Homogenous lesion, well circumscribed, associated with only mild surrounding edema Heterogeneity occurs if there are areas of necrosis or hemorrhage Higher grade astrocytomas generate more extensive vasogenic edema
Large asymmetric bilateral areas of hypointensity Lesions primarily subcortical 50% have involvement of deep nuclei Phlegmoneous stage demonstrates an area of heterogeneous hyperintensity precontrast Heterogeneous enhancement leading to an irregular appearance to the abscess rim in both the phlegmoneous stage and in a mature abscess after contrast Precontrast the mature abscess reveals central iso-hypointensity, wall is isointense to slightly hyperintense Tumor is of slightly hypointense signal Diffuse and prominent enhancement after contrast
Tuberculosis
Cysticercosis
Astrocytoma
T2-weighted MRI Tumefactive plaque is hyperintense and occasionally heterogeneous In the older child, other demyelinating lesions (when present) are preferentially located in the periventricular white matter in a pattern similar to adult MS In the younger child, other demyelinating lesions (if present) tend to be preferentially located in the subcortical white matter, and are often poorly defined Multiple large areas of hyperintensity typically involving white and gray matter Phlegmoneous stage has an area of heterogeneous hyperintensity Mature abscess has a hyperintense center with a hypointense abscess wall Abscess rim enhances after contrast
Tumor is of isointense to slightly hyperintense signal
Tuberculomas are isointense centrally with a surrounding rim of high signal intensity, which is further surrounded by a collar of hypointensity (edema) Small tuberculomas may demonstrate uniform enhancement
Granulomata are hypointense, but may be homogeneous or heterogeneous in intensity Large TB abscesses may reveal vasogenic edema that is hyperintense
Parenchymal cysticerci have a hypointense center surrounded by thick hyperintense enhancement, which may be further surrounded by a region of hypointensity (edema)
Parenchymal cysticerci have a hyperintense center precontrast surrounded by a thin rim of hypointensity, further surrounded by a hyperintense rim of vasogenic edema Scolyx may be occasionally visualized in some cysts
Isointense with gray matter May reveal enhancement, particularly high-grade gliomas May reveal areas of flow void (feeding vessels)
Solid portion of the tumor is hyperintense
Modified from: Barkovich JA, ed. Pediatric neuroimaging, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:23– 4. Neuroimaging characteristics of tumefactive demyelination are contrasted with imaging features of tumefactive lesions seen in CNS infection, or malignancies. Both CT and MRI features are described.
McAdam and Banwell: Pediatric Tumefactive Demyelination 19
Figure 1. (A) Axial fast fluid-attenuated inversion-recovery MRI (TR ⫽ 9002 ms, TE ⫽ 165 ms) of a tumefactive demyelinating lesion demonstrates abnormal signal intensity in the internal and external capsule, subinsular cortex, lateral thalamus, and posterior putamen association with mass effect. In addition, bilateral signal abnormality is seen in the fornical columns. (B) Axial gradient-recalled echo T1 image with gadolinium (TR ⫽ 9.1 ms, TE ⫽ 4.2 ms) demonstrates heterogeneous enhancement of the lesion.
Patient 2 A previously well 8-year-old female, born in Sri Lanka, presented with progressive bilateral visual loss over 4 days. For several months before presentation she suffered from increasingly frequent intermittent frontal headaches. Cerebrospinal fluid analysis revealed 33 leukocytes (76% monocytes), 14 erythrocytes, protein 0.31 g/L, and glucose 3.9 mmol/L.
Computed tomography scan revealed bilateral enlargement of the optic nerves, and diffuse abnormality of the white matter. T2-weighted MRI confirmed diffusely increased signal in the white matter bilaterally. T1-weighted images after administration of gadolinium displayed enhancement of the intraconal and intracanalicular segments of right optic nerve, and a single area of abnormal enhancement in left optic nerve (Fig 2). The diagnosis of bilateral optic neuritis and acute disseminated
Figure 2. (A) Axial T1-weighted fat-saturated contrast-enhanced image (TR ⫽ 500 ms, TE ⫽ 15 ms) demonstrates enhancement of the optic nerve and sheath complex, and the posterior sclera bilaterally, with the right side more affected than the left. (B) Axial proton density image (TR ⫽ 2800 ms, TE ⫽ 22 ms) demonstrates multiple regions of confluent white matter demyelination.
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Figure 3. (A) Axial-enhanced CT image demonstrating a demyelinating lesion with a thick irregular rim of enhancement. A collar of low density, consistent with vasogenic edema or partial demyelination, surrounds the demyelinating lesion. (B) Axial fast fluid-attenuated inversion-recovery MRI (TR ⫽ 9002 ms, TE 165 ms) demonstrates a large right-sided demyelinating lesion extending from the external to internal capsule, also involving the white matter of the frontoparietal lobe. This lesion is associated with mass effect on overlying cortex and slight impingement of the lateral ventricle. In addition, subcortical and periventricular demyelinating foci are noted in the left frontal and peritrigonal regions. encephalomyelitis was made. She was treated with IV methylprednisolone for 3 days, followed by a tapering dose of oral prednisone. Visual acuity improved with treatment. Two months later, she presented with right-sided head tilt, a resting tremor of the upper limbs, persistent dizziness, and unsteadiness of gait. Her parents found her emotionally labile with intermittent anger and agitation. MRI revealed interval improvement in the previously noted diffuse frontal, parietal, and temporal white matter lesions. However, new multifocal asymmetric white matter lesions were noted in the area surrounding the right basal ganglia, at the right pontomesencephalic junction, and in the left middle cerebellar peduncle. She was diagnosed with clinically definite multiple sclerosis, and treated with IV methylprednisolone for 3 days, after which she received an oral prednisone taper. There is no family history of multiple sclerosis. Two months later, she developed left optic neuritis. MRI demonstrated improvement in the frontal white matter signal, the right basal ganglia signal abnormality had resolved, and there was interval improvement in the left cerebellar peduncle lesion. Increased T2-weighted signal was noted in the right occipital region bordering the lateral ventricle, and in numerous other areas. Visual-evoked potentials revealed poorly defined and delayed responses on the left, and an abnormal p100 response in the right eye. After steroid therapy, interferon beta 1b was commenced. The patient continued interferon without side effects for more than 1 year, during which time she had a single attack consisting of right-sided optic neuritis. She was reluctant to have further injections and decided to discontinue interferon therapy. Two months after discontinuing interferon therapy, she presented with marked left-sided weakness. She had two seizures while in the hospital. Neuroimaging revealed a large area of high signal intensity on T2weighted images in the right periventricular white matter with extensive surrounding edema extending cephalad into the corona radiata and inferiorly into the white matter tracts, sparing the basal ganglia (Fig 3). There was mild mass effect. Multiple other white matter lesions were noted. She improved rapidly and completely with steroid therapy. Reinitiation of therapy with interferon is planned.
Patient 3 A previously well male, 5 years, 6 months of age, of Indian descent, moved to Canada 11⁄2 years before presentation. Shortly after returning from an extended visit to India, he presented with slowly progressive bilateral lower limb spasticity, urinary retention, weakness of the left arm, and a homonymous left-sided visual-field defect. Cranial CT demonstrated a ring-enhancing lesion in the right parietooccipital area. MRI of the spine revealed a ring-enhancing intramedullary lesion at C2 with edema and multiple lesions with increased T2-signal throughout the spinal cord (Fig 4A). Brain biopsy was performed to exclude tumor (with spinal metastasis) or neurocysticercosis infection. The biopsy specimen demonstrated demyelination, and the patient was tentatively diagnosed with acute disseminated encephalomyelitis. Steroid therapy resulted in complete remission of symptoms, and his neurologic examination returned to normal. One month later, the result of a serum immunoblot assay for neurocysticercosis became available and was positive. No immediate therapy was given, since the patient was clinically stable. Repeat imaging 5 months later revealed complete resolution of the cranial lesion, but persistence of the spinal lesions. Anticysticercal treatment with albendazole and dexamethasone was given for possible neurocysticercosis. Five months later, he presented with mild left-sided hemiparesis. While in the hospital, he had one brief focal seizure. A new 3– 4-cm cystic lesion in the right frontoparietal subcortical area was seen on a MRI. He was treated with steroids and albendazole for 4 weeks followed by a tapering dose of steroids. Nine months later he presented with headache, vomiting, and seizures. Imaging revealed a new ring-enhancing white matter lesion in the left frontoparietal area (Fig 4B). The diagnosis of neurocysticercosis was then dismissed based on the following: (1) the lesions were atypical for cysticercosis, (2) the cysticercosis immunoassay was repeated within 1 year and was negative, and (3) a third recurrence of neurocysticercosis is almost unheard of in someone outside of an endemic area. Albendazole
McAdam and Banwell: Pediatric Tumefactive Demyelination 21
Figure 4. (A) Sagittal T2-weighted fast spin-echo image (TR ⫽ 5700 ms, TE ⫽ 90 ms) demonstrates prominent abnormal signal in the cervical spinal cord from level of the synchondrosis to the body of C3, with faint signal abnormality extending cephalad to C1 and inferiorly to C4. (B) Axial T1-weighted image (TR ⫽ 680 ms, TE ⫽ 22 ms) demonstrates a large ring-enhancing lesion in the left occipital region, and a second area of enhancement in the right occipital region. Multiple small enhancing foci are present throughout the hemispheres (not displayed in this image). Note is made of an incidental right middle cranial fossa arachnoid cyst (arrow). therapy was withheld. He was diagnosed with clinically definite multiple sclerosis and treated with corticosteroids. There is no family history of multiple sclerosis. Two months later he presented with right facial droop and slurred speech. CT demonstrated a new 2-cm left frontal ring-enhancing lesion. He was treated with IV methylprednisone followed by a tapering dose of steroids. Five months later, he developed left hemiparesis, difficulty with speech, and pervasive fatigue. He responded well to steroids. Using CT, two large ring-enhancing lesions in the right hemisphere were found, increased in size compared with prior images. A new left frontal lobe ring-enhancing lesion was also noted. He was started on interferon beta 1a, without noteworthy side effects. Seven months later, he presented with decreased visual acuity, mild weakness in right arm, and a brief seizure. CT displayed improvement in the previously noted multiple ring-enhancing lesions, however, new lesions in the posterior right parietal lobe and in left parietooccipital region were evident. One month later, he developed a right foot-drop and right leg weakness followed by weakness in his left leg, left hemianopsia, and decreased visual acuity. MRI of the spine displayed a large demyelinating plaque extending from T2 to T7. He was admitted for IV methylprednisolone for 3 days. On day 2, he became less responsive, complained of headache, and had several episodes of vomiting. MRI revealed extensive white matter demyelination. Slow, but incomplete, improvement was evident with steroid therapy. The frequency and severity of clinical relapses, and the failure to document any reduction in central nervous system lesion load on MRI, prompted withdrawal of therapy with interferon beta 1a. He was commenced on treatment with subcutaneously administered glati-
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ramer acetate, 20 mg daily, which he has tolerated well. Amantadine was started to reduce clinically profound fatigue. The frequency and severity of the relapses, combined with significant residual visual loss (20/200), a dense homonymous visual-field deficit, mild weakness, and profound fatigue, led to a decision to treat with a 5-day course of IV cyclophosphamide combined with methylprednisolone and antinauseants. The treatment was well tolerated, and the expected leukopenia was achieved. Alopecia was minimal. One month later the patient reported marked improvement in function and wellbeing. On examination, vision improved markedly to 20/20, the visualfield deficit resolved, and he had no demonstrable weakness. He has been free of relapse for 6 months.
Patient 4 A 14-year-old white female of Irish decent (previously reported by Kumar et al. [4]) was well until she awoke with a headache, blurring of vision, and vomiting, which resolved over 24 hours. Similar symptoms recurred 1 month later. Five months later, she developed a headache, followed by blurring of vision and loss of consciousness. A generalized seizure lasting 2 minutes was then witnessed. One month later, she developed the same symptoms, followed by a generalized seizure lasting 2–3 minutes. A cranial CT demonstrated a right frontal lobe cystic lesion. MRI confirmed this finding (Fig 5A). Because of the history of new-onset, recurrent seizures, the lesion was thought to be a tumor, and the patient was transferred to our institution for surgery. Neurologic examination was normal. Family history revealed a grandmother with multiple sclerosis.
Figure 5. (A) Coronal T1-weighted image (TR ⫽ 12 ms, TE ⫽ 5 ms) of the demyelinating lesion displays asymmetric ring enhancement. The rim appears thicker and reveals more prominent enhancement on the side facing the lateral ventricle. (B) Coronal T1-weighted, gadolinium-enhanced image (TR ⫽ 600 ms, TE ⫽ 20 ms) highlights the smooth, regular contour of the abscess rim.
A right frontal craniotomy with gross total removal of the lesion was performed. There were no surgical complications, and she recovered well without sequelae. Pathologic studies revealed a demyelinating process with myelin loss, perivascular inflammatory cuffing, and gliosis. She remains well, without seizures or recurrent demyelination 4 years after her initial presentation. A recent MRI scan was normal, with no evidence of recurrent demyelination.
Discussion MRI characteristics of typical multiple sclerosis lesions have been well described by Patty et al. [20] and Fazekas et al. [21]. Typical multiple sclerosis plaques are ovoid in shape, sharply demarcated, and are located perpendicular to the long axis of the lateral ventricles. They have a low signal on T1-weighted images, and a high signal on T2-weighted images. CT scans may miss subtle demyelinating lesions, and thus MRI is the preferred imaging modality for the investigation of demyelination. There are reported cases of multiple sclerosis presenting with a large solitary mass lesion with a surrounding ring that enhances with contrast administration [4,5,18]. These lesions have been termed tumefactive demyelination. Differential diagnoses include cerebral tumors, abscesses, and parasitic foci. Pathologic studies of tumefactive lesions report large areas of confluent demyelination with an inflammatory cellular response, often associated with perilesional edema and mass effect on surrounding structures [22]. To date, there have been 12 reported cases in the English literature of tumefactive demyelinating lesions in children [5,12–18]. Eight of the 12 cases were in female
patients. The mean age of presentation was 11.2 years (11.4 years of age for females, and 10.3 years of age for males). Six patients were initially diagnosed with a brain neoplasm, and one was felt to have multiple abscesses. All lesions revealed ring enhancement, in 10 of 12 patients the lesions were associated with perilesional edema, and in four cases, lesions exhibited mass effect on neighboring structures. Seven patients underwent brain biopsy or resection of the entire lesion [12–17]. Pathologic studies confirmed demyelination in the seven cases biopsied. Three children received brain radiation [13,15], and six received steroids. Acute neurologic deficit, combined with the neuroradiologic appearance of a large mass lesion, is a cause for immediate medical attention. Distinguishing tumefactive demyelination from other etiologies is of critical importance to avoid unnecessary and invasive diagnostic interventions, and to prevent unwarranted toxic therapies. This is highlighted by the significant morbidity of several patients, including one child [15], treated with central nervous system radiation for presumed central nervous system malignancy. Pathologic specimens revealed demyelination, and four of five patients developed severe neurologic sequelae post radiation, suggesting that patients with demyelination may be selectively vulnerable to radiation-induced toxicity. The importance of accurate diagnosis is further highlighted by the death of one child after an attempted drainage of presumed abscess [14], in whom pathologic study confirmed multifoci of demyelination. Even in patients with established multiple sclerosis, the
McAdam and Banwell: Pediatric Tumefactive Demyelination 23
diagnosis of tumefactive demyelination can occasionally be difficult. Many multiple sclerosis patients receive treatment with corticosteroids and other immunosuppressant medications, and thus a new mass lesion with ring enhancement raises the possibility of opportunistic infection, abscess, or even neoplasm. Table 1 outlines various radiologic features of cerebral mass lesions that would be in the differential diagnosis of tumefactive demyelination. Although there is no one radiologically distinct imaging feature to distinguish a tumefactive demyelinating lesion from other lesions in the differential, there are several important features that would favor demyelination. Tumefactive demyelination is supported by the presence of demyelinating plaques elsewhere in the neuraxis, particularly those adjacent to the ventricular surface (Fig 3), and by enhancement limited to only one side of the lesion or preferential enhancement of the lesional rim facing the lateral ventricles (Fig 5A). In contrast, cerebral abscesses tend to have a thicker rind, the rim is more regular in contour, and rim enhancement is either uniform (Fig 5B), or concentrated at the region of the rim facing the overlying cortex. Because multiple sclerosis plaques may occur anywhere in the central nervous system, a search for other areas of demyelination should include MRI evaluation of the spine, or at least the cervical spinal cord, which is the spinal cord region in which multiple sclerosis plaques most commonly occur (Fig 4A). A history of prior transient neurologic events and clinical findings of neurologic deficit referable to separate areas of the central nervous system support the diagnosis of multiple sclerosis. In patients with no past clinical or MRI features of definite multiple sclerosis, but in whom the diagnosis of tumefactive demyelination is entertained, repeat fast fluid-attenuated inversion-recovery sequences may be performed during or shortly after completion of corticosteroid therapy. Although perilesional edema associated with tumor or abscess may respond to corticosteroid administration, a rapid reduction in the size of the tumefactive lesion associated with significant clinical improvement favors demyelination. Tumors or abscesses are unlikely to respond rapidly or completely. The development of new enhancing lesions also supports the diagnosis of multiple sclerosis. Rapid development of new lesions is unlikely in primary central nervous system malignancy or in patients who initially presented with a solitary central nervous system abscess. Exceptions to this include widespread metastatic tumors, the diagnosis for which should be suggested by the presence of a primary systemic tumor. Tumors known to metastasize to brain include lung, breast, and colon carcinomas, all of which are extremely rare in the pediatric population [23]. Primary pediatriconset central nervous system malignancies, which may be multifocal, include medulloblastoma and central nervous system lymphoma. Medulloblastomas are highly malignant, preferentially located in the cerebellar vermis with the potential to spread to adjacent structures, and may have
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drop metastasis to the spinal subarachnoid space. On CT, medulloblastomas are well circumscribed, and, unlike demyelination, are hyperdense or isodense [23]. Central nervous system lymphomas, which also may be multifocal, are often hyperdense on CT before contrast. On MRI, lymphomas are hypointense on T1-weighted images and isointense to slightly hyperintense on T2-weighted images. Lymphomas display diffuse and prominent enhancement with contrast on CT and MRI, rather than rim enhancement [23]. Follow-up imaging in adult patients with suspected multiple sclerosis typically includes T1-weighted, gadolinium-enhanced images to document recent perturbation of the blood– brain barrier associated with the development of new lesions. In pediatric patients, it may be preferential to use fast fluid-attenuated inversion-recovery sequences to document new areas of demyelination, because this avoids the need for IV line insertion and gadolinium administration. In addition, when imaging is for the purpose of rapid sequence follow-up, a brief MRI protocol using fast fluid-attenuated inversion-recovery sequences, rather than a lengthy complete protocol, may obviate the need for sedation in young or uncooperative patients. For initial evaluation of patients with acute tumefactive lesions, a full MRI protocol should be used. We have presented four cases of tumefactive demyelinating lesions, which developed during the course of relapsing remitting multiple sclerosis in three patients and as a monophasic event in one patient. It is important that a detailed history be obtained in all such patients, with attention to prior episodes of central nervous system demyelination, such as optic neuritis, acute disseminated encephalomyelitis, or transient neurologic deficits (for which the patient may not have sought medical assessment). Our cases, combined with those in the literature, highlight the importance of considering demyelination in the differential diagnosis of tumefactive lesions.
The authors acknowledge Ben Harito for his expert technical assistance in preparing the images and Ms. Marianne Sofronas for her secretarial support.
References [1] Sadovnick AD, Ebers GC. Epidemiology of multiple sclerosis: A critical overview. Can J Neurol Sci 1993;20:17–29. [2] Pinhas-Hamiel O, Barak Y, Siev-Ner I, Achiron A. Juvenile multiple sclerosis: Clinical features and prognostic characteristics. J Pediatr 1998;132:735–7. [3] Ghezzi A, Deplano V, Faroni J, et al. Multiple sclerosis in childhood: Clinical features of 149 cases. Mult Scler 1997;3:43– 6. [4] Kumar K, Toth C, Jay V. Focal plaque of demyelination mimicking cerebral tumor in a pediatric patient. Pediatr Neurosurg 1998;29:60 –3. [5] Gutling E, Landis T. CT ring sign imitating tumour, disclosed as multiple sclerosis by MRI: A case report. J Neurol Neurosurg Psychiatry 1989;52:903– 6. [6] Mastrostefano R, Occhipinti E, Bigotti G, Pompili A. Multiple
sclerosis plaque simulating cerebral tumor: Case report and review of the literature. Neurosurgery 1987;21:244 – 6. [7] Ernst T, Chang L, Walot I, Huff K. Physiologic MRI of a tumefactive multiple sclerosis lesion. Neurology 1998;51:1486 – 8. [8] Otsuka S, Nakatsu S, Matsumoto S, et al. Multiple sclerosis simulating brain tumor on computed tomography. J Comput Assist Tomogr 1989;13:674 – 8. [9] Khan OA, Bauserman SC, Rothman MI, Aldrich EF, Panitch HS. Concurrence of multiple sclerosis and brain tumor: Clinical considerations. Neurology 1997;48:1330 –3. [10] Kurihara N, Takahashi S, Furuta A, et al. MR imaging of multiple sclerosis simulating brain tumor. Clin Imaging 1996;20:171–7. [11] Paley RJ, Persing JA, Doctor A, Westwater JJ, Roberson JP, Edlich RF. Multiple sclerosis and brain tumor: A diagnostic challenge. J Emerg Med 1989;7:241– 4. [12] Case Records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 26-1998. A 15-year-old girl with hemiparesis, slurred speech, and an intracranial lesion [clinical conference]. N Engl J Med 1998;339:542–9. [13] Hunter SB, Ballinger WE, Jr., Rubin JJ. Multiple sclerosis mimicking primary brain tumor. Arch Pathol Lab Med 1987;111:464 – 8. [14] Giang DW, Poduri KR, Eskin TA, et al. Multiple sclerosis masquerading as a mass lesion. Neuroradiology 1992;34:150 – 4. [15] Peterson K, Rosenblum MK, Powers JM, Alvord E, Walker RW, Posner JB. Effect of brain irradiation on demyelinating lesions [see comments]. Neurology 1993;43:2105–12.
[16] Kepes JJ. Large focal tumor-like demyelinating lesions of the brain: Intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients [see comments]. Ann Neurol 1993;33:18 –27. [17] Rusin JA, Vezina LG, Chadduck WM, Chandra RS. Tumoral multiple sclerosis of the cerebellum in a child. Am J Neuroradiol 1995;16:1164 – 6. [18] Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology 1996;38:560 –5. [19] Morimoto T, Nagao H, Sano N, et al. A case of multiple sclerosis with multi-ring-like and butterfly-like enhancement on computerized tomography. Brain Dev 1985;7:43–5. [20] Paty DW, Oger JJ, Kastrukoff LF, et al. MRI in the diagnosis of MS: A prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1988;38: 180 –5. [21] Fazekas F, Offenbacher H, Fuchs S, et al. Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis. Neurology 1988;38:1822–5. [22] van der Valk P, De Groot CJ. Staging of multiple sclerosis (MS) lesions: Pathology of the time frame of MS. Neuropathol Appl Neurobiol 2000;26:2–10. [23] Barkovich JA. Intracranial, orbital and neck tumors of childhood. In: Barkovich JA, ed. Pediatric neuroimaging, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000:443–580.
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