Long-Term Outcome of Schilder Disease Treated with Interferon-B Wei-Sheng Lin, MD,A Meng-Fai Kuo, MD, Phd,B Steven Shinn-Forng Peng, MD, Phd,C Pi-Chuan Fan, MD, Phdd

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Long-term Outcome of Schilder Disease Treated With Interferon-b Wei-Sheng Lin, MD,a Meng-Fai Kuo, MD, PhD,b Steven Shinn-Forng Peng, MD, PhD,c Pi-Chuan Fan, MD, PhDd

Schilder disease, also termed diffuse myelinoclastic sclerosis, is characterized abstract by a large demyelinating lesion involving 1 or both sides of the centrum semiovale of the cerebral hemispheres. It often presents with tumorlike features and poses a diagnostic challenge. Schilder disease can be monophasic or relapsing, and disease-modifying therapy for the latter scenario is largely empirical. Here, we report a 14-year-old girl with relapsing Schilder disease within 1 year after disease onset. She has been followed-up for nearly 10 years and remains in sustained remission ever since interferon-b therapy was prescribed after the second attack. In this case study, it is suggested that interferon-b may induce long-term remission in relapsing Schilder disease aDepartment of Pediatrics, National Taiwan University and is therefore worth considering in this regard. Hospital Yunlin Branch, Yunlin, Taiwan; bDivision of Neurosurgery, Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan; and cDepartments of Medical Imaging and dPediatrics, National Taiwan University Schilder disease, also termed diffuse was suggested that fingolimod and Hospital, College of Medicine, National Taiwan University, myelinoclastic sclerosis, is natalizumab should be avoided.8 Taipei, Taiwan characterized by a large demyelinating Because of the rarity and clinical Dr Lin reviewed the literature and drafted the initial lesion involving 1 or both sides of the heterogeneity of Schilder disease, it is manuscript; Ms Kuo and Mr Peng critically reviewed centrum semiovale of the cerebral virtually impossible to conduct and revised the manuscript; Dr Fan followed-up this hemispheres.1 The size of controlled therapeutic trials. Therefore, patient and reviewed and revised the manuscript critically; and all authors approved the final demyelinating lesion in Schilder disease anecdotal evidence and observational manuscript as submitted and agree to be 3 is at least 3 2 cm, and patients often studies are valuable. Here, we report accountable for all aspects of the work. a patient of relapsing Schilder disease present with tumorlike features DOI: https://doi.org/10.1542/peds.2019-0505 clinically and radiologically.2 Although with a 10-year follow-up in whom the Accepted for publication Aug 5, 2019 the pathogenesis of Schilder disease interferon-b therapy appears effective. remains incompletely understood, it is Address correspondence to Pi-Chuan Fan, MD, Department of Pediatrics, National Taiwan University usually considered to be a variant of Hospital, College of Medicine, National Taiwan 1 CASE REPORT multiple sclerosis (MS). Because of its University, No. 8, Zhongshan South Rd, Taipei 100, atypical presentations, Schilder disease A 14-year-old girl presented with Taiwan. E-mail: [email protected] 2–4 often poses a diagnostic challenge. weakness and incoordination of the PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, Its course can be monophasic or right hand for 1 month. The symptoms 1098-4275). relapsing, which is difficult to predict at disturbed her piano playing and Copyright © 2019 by the American Academy of the outset of the disease. Therefore, writing, whereas other aspects of daily Pediatrics whether and when disease-modifying activities were largely unaffected. On FINANCIAL DISCLOSURE: The authors have indicated therapy (DMT) is helpful remains to be examination, mouth angle deviation to they have no financial relationships relevant to this investigated. Furthermore, DMT of the right side was noted, particularly article to disclose. choice differs among various types of when she was smiling. Wrinkling of her FUNDING: No external funding. central nervous system (CNS) forehead was not impaired, indicating POTENTIAL CONFLICT OF INTEREST: The authors have demyelinating diseases. For instance, a central type facial nerve paresis. indicated they have no potential conflicts of interest interferon-b is used as the first-line Cranial computed tomography to disclose. DMT in pediatric MS, whereas it could disclosed a masslike lesion in the left aggravate neuromyelitis optica basal ganglia, with compression on the To cite: Lin W, Kuo M, Peng SS, et al. Long-term – spectrum disorder.5 7 For patients with left lateral ventricle (Fig 1 A and B). Outcome of Schilder Disease Treated With Interferon-b. Pediatrics. 2019;144(5):e20190505 tumefactive demyelinating lesions, it MRI of the brain revealed an ill-defined

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 144, number 5, November 2019:e20190505 CASE REPORT masslike lesion involving the left centrum semiovale, left basal ganglia, and left thalamus (Fig 1 C–F). A biopsy of the basal ganglion “tumor” was performed. The pathologic findings were characterized by perivascular lymphocytic and histiocytic infiltration in both gray and white matters. No tumor cells were identified. The pathologist concluded that an inflammatory process was favored. Periodic acid–Schiff stain, mucicarmine stain, and immunostain were negative for fungus, Cryptococcus, and cytomegalovirus, respectively. A cerebrospinal fluid (CSF) study revealed neither pleocytosis nor elevated protein level. A dual isotope nuclear medicine study revealed that the lesion was 201Tl avid, and the 18F-fluorodeoxyglucose uptake was relatively low. The radiologist concluded that viable tumor was favored. Although pathologic examination did not find evidence for tumor cells, the neurosurgeon still had concern about the possibility of a germ cell tumor. Therefore, a therapeutic trial of radiotherapy was instituted after discussion with the family. However, because the diagnosis was uncertain and demyelinating disease was also contemplated, radiotherapy was stopped after 14 fractions (25.2 Gy). The patient was clinically improving and was discharged. Follow-up MRI 2 months later revealed shrinkage of the mass lesion (Fig 2).

Eight months after hospital discharge, the patient presented with loss of the ability to understand written language, without gross motor impairment. Mental status examination revealed impaired judgment, attention, and calculation. MRI of the neural axis revealed FIGURE 1 enlarged extent of the previous Neuroimaging at presentation. A and B, Brain computed tomography without contrast shows an ill- masslike lesion in the left hemisphere deﬁned mass lesion involving left lenticulocapsular region, with perifocal edema and compression of the left lateral ventricle. C and D, Brain MRI without contrast reveals that the mass lesions also (Fig 3); no spinal lesion was noted. A involve the left corona radiata and centrum semiovale. E and F, Postcontrast heterogeneous en- CSF study revealed mild pleocytosis hancement is seen in the left basal ganglia. (8 white blood cells per mL), elevated protein level (158.7 mg/dL), as well

Downloaded from www.aappublications.org/news by guest on September 24, 2021 2 LIN et al cases have been reported.2,17,18 For those with a monophasic course, it couldbeeitherself-limitedor progressive.2,15 For those suffering from second or more demyelinating events, the subsequent events could still conform to Schilder disease,17 or they could convert to more typical MS in terms of clinical and radiologic pictures.18 The interval between the first and second attack was ∼10 months in our patient. This is similar to that in a recently reported case,17 whereas it is significantly shorter than that in another patient with recurrent Schilder disease in whom the interval between the first 2 episodes was ∼25 months.18 On the FIGURE 2 other hand, in a large cohort of 168 Noncontrast brain MRI 5 months after disease onset, revealing shrinkage of the mass lesion with patients with biopsy-proven negative mass effect. A, Axial view. B, Coronal view. tumefactive demyelinating lesions, including those with and without as elevated immunoglobulin G index event afterward, and MRI at 9 years conversion to MS at follow-up, the (0.81). No malignant cell was after disease onset revealed Kaplan-Meier estimate of the median identified in CSF cytology. Under the stationary findings (Fig 4). time to the second clinical episode was impression of Schilder disease, long (∼4.8 years), and the long-term methylprednisolone pulse therapy prognosis appeared better compared (1 g/day for 5 days) was provided, DISCUSSION to conventional MS.9 Because the followed by oral corticosteroid. Tumefactive lesions can be the initial natural history is unpredictable at the Clinical improvement was observed presentation of several CNS outset of the disease and a monophasic but appeared slow at follow-up visits. demyelinating diseases, including course is often anticipated, initiation of After discussion with the family, Schilder disease, MS, neuromyelitis DMT for Schilder disease is often b interferon- (Rebif) therapy was optica spectrum disorder, and acute delayed until the second or third 17,18 initiated 2 months after her hospital disseminated encephalomyelitis.9–13 demyelinating event occurs. discharge. Three months later, her Tumefactive demyelinating lesions of cognition improved further, and her the CNS are rare and diagnostically In addition to the timing of DMT fi ne motor function improved to the challenging.1,14 The clinical and commencement, the choice of DMT for degree that she could play the neuroradiologic features, including Schilder disease is also unresolved. saxophone but not the piano (because mass effect, perifocal edema, and The rarity and clinical heterogeneity of fi of residual ne motor dysfunction in increased intracranial pressure, could Schilder disease make controlled fi the right hand). She regained the mimic a brain tumor or other space- studies dif cult so that treatment is ability to play the piano in the occupying lesion, as illustrated in our largely empirical to date, borrowing ensuing year. Oral corticosteroid was case. Although pathology could be from the experience with management gradually tapered. Because helpful by revealing the evidence of of conventional MS. Although Schilder deterioration in learning, demyelination and ruling out other disease is usually viewed as a variant psychomotor slowing, and stuttering possibilities, the result of biopsy may of MS, several of its features had been noted during periods when be inconclusive or even misleading at distinguish it from typical MS. For the corticosteroid dose was reduced, times.3 Exclusion of diseases with example, MS is usually relapsing- the tapering schedule was extended, similar clinical or radiologic pictures, remitting, whereas Schilder disease is and the corticosteroid was ultimately such as adrenoleukodystrophy and often monophasic. CSF-restricted discontinued after 5 years of CNS lymphoma, is mandatory.1,9 oligoclonal bands are often noted in treatment. Her full-scale IQ (Wechsler MS, yet they are usually absent in Adult Intelligence Scale, Fourth The natural history of Schilder disease Schilder disease.16 These differences Edition) was 63 at 21 years old. There is monophasic in the majority of suggest the possibility of a unique was no more clinical demyelinating cases.15,16 Nevertheless, relapsing pathophysiological mechanism

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 144, number 5, November 2019 3 underlying Schilder disease, which may be relevant in terms of therapeutic consideration. It has been recognized that DMT for MS is not always appropriate for other CNS demyelinating conditions. For example, interferon-b is associated with serological and clinical deterioration in some cases with neuromyelitis optica,5,6 and it was advised that natalizumab and fingolimod should be avoided in patients with tumefactive lesions.8 Because Schilder disease often presents with tumefactive lesion, caution should be exercised in the use of drugs affecting lymphocyte trafficking, including natalizumab and fingolimod, in these patients. However, interindividual differences may well exist because natalizumab has been reported to lead to stabilization of both pediatric and adult patients with tumefactive MS, whereas interferon-b was not effective in the latter case.19,20 Reports on the treatment of Schilder disease have been limited. Acute treatment usually consists of high- dose systemic corticosteroid, which is FIGURE 3 often effective in controlling disease Noncontrast brain MRI at relapse, 11 months after disease onset. The white matter lesions are much activity. This is followed by a taper of more extensive posteriorly and cross the midline, and the splenium of the corpus callosum is also corticosteroid over a variable period. involved. A and C, Axial views at the level of basal ganglia and centrum semiovale, respectively. B and Plasma exchange has been considered D, Representative images in coronal view. a reasonable choice when the response of tumefactive lesions to corticosteroid is not satisfactory. Intravenous immunoglobulins have also been used more or less successfully as a rescue therapy.2,21 Therehavebeenscarcedataregarding DMT for Schilder disease. Interferon-b was considered after the third event in an earlier pediatric case.18 Rituximab was prescribed after the second demyelinating event in a recently reported case.17 Long-term effects of these medications, as well as other DMT choices for MS, remain to be determined in patients with Schilder disease.

CONCLUSIONS FIGURE 4 Noncontrast brain MRI at 9 years after disease onset, revealing residual lesion and encephalo- It is suggested in our case that malacia change in the left cerebral hemisphere. A, Axial view. B, Coronal view. interferon-b therapy may result in

Downloaded from www.aappublications.org/news by guest on September 24, 2021 4 LIN et al favorable long-term response in 6. Shimizu J, Hatanaka Y, Hasegawa M, and follow-up observations. J Neurol Schilder disease. More research is et al. IFNb-1b may severely exacerbate Sci. 2015;358(1–2):118–124 Japanese optic-spinal MS in clearly needed to inform the 14. Abdoli M, Freedman MS. Neuro- neuromyelitis optica spectrum. appropriate treatment strategy for oncology dilemma: tumour or Neurology. 2010;75(16):1423–1427 this rare condition. tumefactive demyelinating lesion. Mult 7. Wang KC, Lin KH, Lee TC, et al. Poor Scler Relat Disord. 2015;4(6):555–566 responses to interferon-beta treatment 15. Maras¸ Genç H, Kara B, Uyur YalçınE, in patients with neuromyelitis optica ABBREVIATIONS et al. Long-term clinical and radiologic and multiple sclerosis with long spinal follow-up of Schilder’s disease. Mult CNS: central nervous system cord lesions. PLoS One. 2014;9(6): Scler Relat Disord. 2017;13:47–51 CSF: cerebrospinalfluid e98192 DMT: disease-modifying therapy 8. Algahtani H, Shirah B, Alassiri A. 16. Hardy TA, Reddel SW, Barnett MH, et al. fl MS: multiple sclerosis Tumefactive demyelinating lesions: Atypical in ammatory demyelinating a comprehensive review. Mult Scler syndromes of the CNS. Lancet Neurol. – Relat Disord. 2017;14:72–79 2016;15(9):967 981 REFERENCES 9. Lucchinetti CF, Gavrilova RH, Metz I, 17. Dunn-Pirio AM, Eckstein C. Recurrent ’ 1. Poser CM, Goutières F, Carpentier MA, et al. Clinical and radiographic schilders disease. Mult Scler Relat – Aicardi J. Schilder’s myelinoclastic spectrum of pathologically confirmed Disord. 2018;26:8 10 diffuse sclerosis [published correction tumefactive multiple sclerosis. Brain. 18. Fitzgerald MJ, Coleman LT. Recurrent appears in Pediatrics. 1986;78(1):138]. 2008;131(pt 7):1759–1775 myelinoclastic diffuse sclerosis: a case – Pediatrics. 1986;77(1):107 112 10. Balloy G, Pelletier J, Suchet L, et al; report of a child with Schilder’s variant 2. Garell PC, Menezes AH, Baumbach G, Société Francophone de la Sclérose en of multiple sclerosis. Pediatr Radiol. – et al. Presentation, management and Plaques. Inaugural tumor-like multiple 2000;30(12):861 865 follow-up of Schilder’s disease. Pediatr sclerosis: clinical presentation 19. Nakamura M, Itani K, Miyake K, et al. Neurosurg. 1998;29(2):86–91 and medium-term outcome in 87 Natalizumab is effective for the patients. JNeurol. 2018;265(10): 3. Bacigaluppi S, Polonara G, Zavanone ML, treatment of relapsing-remitting 2251–2259 et al. Schilder’s disease: non-invasive tumefactive multiple sclerosis. Intern diagnosis? A case report and review. 11. Kuan YC, Wang KC, Yuan WH, Tsai CP. Med. 2017;56(2):211–214 Neurol Sci. 2009;30(5):421–430 Tumefactive multiple sclerosis in 20. Sandi D, Bereg E, Biernacki T, et al. 4. Kurul S, Cakmakçi H, Dirik E, Taiwan. PLoS One. 2013;8(7):e69919 Pediatric multiple sclerosis and Kovanlikaya A. Schilder’s disease: case 12. Roy U, Saini DS, Pan K, et al. fulminant disease course: features and study with serial neuroimaging. J Child Neuromyelitis optica spectrum approaches to treatment - a case Neurol. 2003;18(1):58–61 disorder with tumefactive report and review of the literature. J Clin Neurosci. 2018;53:13–19 5. Palace J, Leite MI, Nairne A, Vincent A. demyelination mimicking multiple Interferon Beta treatment in sclerosis: a rare case. Front Neurol. 21. Kraus D, Konen O, Straussberg R. neuromyelitis optica: increase in 2016;7:73 Schilder’s disease: non-invasive relapses and aquaporin 4 antibody 13. Jeong IH, Kim SH, Hyun JW, et al. diagnosis and successful treatment titers. Arch Neurol. 2010;67(8): Tumefactive demyelinating lesions as with human immunoglobulins. Eur 1016–1017 a first clinical event: clinical, imaging, J Paediatr Neurol. 2012;16(2):206–208

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Downloaded from www.aappublications.org/news by guest on September 24, 2021 Long-term Outcome of Schilder Disease Treated With Interferon-β Wei-Sheng Lin, Meng-Fai Kuo, Steven Shinn-Forng Peng and Pi-Chuan Fan Pediatrics originally published online October 29, 2019;

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