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Concurrence of multiple sclerosis, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity in the same patient: A challenging diagnosis
Multiple Sclerosis and Related Disorders 40 (2020) 101945
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Case report
Concurrence of multiple sclerosis, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity in the same patient: A challenging diagnosis
T
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Hussein Algahtania, , Bader Shirahb, Mohamed Tashkandic, Alaa Samkarid a
King Abdulaziz Medical City / King Saud bin Abdulaziz University for Health Sciences, Jeddah 12723,21483, Saudi Arabia King Abdullah International Medical Research Center / King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia c King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia d Department of Pathology and Lab Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia b
A R T I C LE I N FO
A B S T R A C T
Keywords: Multiple sclerosis Oligodendroglioma Autosomal recessive cerebellar ataxia with spasticity GBA2 Saudi Arabia
Multiple sclerosis (MS) has been described in several case reports to coexist with brain tumors. This unusual concurrence has been the subject of research projects with a common question of whether these pathological entities share common roots. However, no clear association has proved that either of them could provoke the other, and mere chance is the only acceptable explanation. Along all reported cases, oligodendroglioma has been rarely reported to coexist with MS. In this paper, we report a unique case with a triad of MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity and discuss possible theories that might have attributed to these three conditions. To our knowledge, this is the first case ever to have these three conditions present in one patient. The most likely explanation is believed to be that this patient was unfortunate to have three unrelated diseases.
1. Introduction
2. Case report
Multiple sclerosis (MS) has been described in several case reports to coexist with brain tumors (Plantone et al., 2015). This unusual concurrence has been the subject of research projects with a common question of whether these pathological entities share common roots. However, no clear association has proved that either of them could provoke the other, and mere chance is the only acceptable explanation (Plantone et al., 2015; Green et al., 2001). Along all reported cases, oligodendroglioma has been rarely reported to coexist with MS. The first reported case of MS with pure oligodendroglioma was in 1967, and only 9 cases were published since then (Green et al., 2001; Carvalho et al., 2014; Barnard and Jellinek, 1967; Giordana et al., 1981; Rao et al., 1986; Khan et al., 1997; de la Lama et al., 2004; Shirani et al., 2018). In this paper, we report a unique case with a triad of MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity and discuss possible theories that might have attributed to these three conditions.
A 23-year-old female presented to the emergency department with one episode of tonic-clonic seizure with tongue biting, uprolling of the eye, and urinary incontinence. She was not known to have epilepsy or any other neurological diseases. In the emergency department, the patient was treated aggressively for her seizure and was fully investigated including electroencephalogram (EEG) and neuroimaging of the brain. Computed tomography (CT) scan of the brain showed a left frontal hypodensity with local mass effect. Magnetic resonance imaging (MRI) of the brain showed a 5.6 cm cortical-based tumor arising from the left superior and part of the middle frontal gyri and surrounded by vasogenic edema. Few variable-sized foci of high signal intensity in fluid-attenuated inversion recovery (FLAIR) sequences were seen in the periventricular white matter of the right frontal and left occipital lobes and in the subcortical white matter of the right parietal lobe. Only the latter showed enhancement in the post-contrast images with no diffusion or restriction (Fig. 1). These multifocal areas were initially thought to represent areas of multifocal gliomatosis and less likely to be demyelinating lesions. Retrospectively, the patient gave a history of repeated episodes of neurological dysfunction with motor, sensory, and
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Corresponding author. E-mail addresses: [email protected], [email protected] (H. Algahtani).
https://doi.org/10.1016/j.msard.2020.101945 Received 23 July 2019; Received in revised form 28 November 2019; Accepted 10 January 2020 2211-0348/ © 2020 Elsevier B.V. All rights reserved.
Multiple Sclerosis and Related Disorders 40 (2020) 101945
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Fig. 1. MRI of the brain showing a large cortical-based tumor seen arising from the left superior and part of the middle frontal gyri with surrounding vasogenic edema. It measures approximately 5.6 × 4.8 cm in anteroposterior and transverse diameters, respectively. It shows heterogeneous signal intensity in T1 and T2 weighted images, with peripheral areas of diffusion restriction. A central area of faint enhancement is seen in the post-contrast images, which corresponds to the central area of increased perfusion in the MRP. The surrounding vasogenic edema is causing mild mass effect on the anterior horn of the left lateral ventricle, with subfalcine herniation of approximately 5 mm. The vasogenic edema is compressing the corpus callosum, with no invasion or involvement. The MR spectroscopy evaluation of the lesion showed increased choline/creatinine ratio, reduction in NAA, and peak of lactate. Few variable-sized foci of high signal intensity in T2/FLAIR sequences are seen in the periventricular white matter of the right frontal and left occipital lobe with another one seen in the subcortical white matter of the right parietal lobe. Only the latter lesion shows enhancement in the post-contrast images, with no diffusion restriction seen.
(WHO grade III) (Louis et al., 2016). The patient was discharged home in good condition with the final diagnosis of oligodendroglioma. Six months later, on routine MRI follow-up, new white matter lesions consistent with dissemination in time and space and with a demyelinating disease were detected (Fig. 4). Therefore, an urgent neurology consultation was recommended. On reviewing her family history, one sister was diagnosed with autosomal-recessive cerebellar ataxia with spasticity. Upon admission, full MS workup was done including cerebrospinal fluid (CSF) analysis, serum aquaporin-4 antibody titer, serum anti-myelin oligodendrocyte glycoprotein antibody (AntiMOG) titer, whole spine MRI, and MRI spectroscopy. CSF analysis revealed positive oligoclonal bands (positive in the CSF and negative in the serum) and increased immunoglobulin G index. Other investigations were within normal limits, except for the previously demonstrated demyelinating lesions on MRI. Due to the history of repeated episodes of neurological deficit involving multiple parts of the neuraxis (motor, sensory, and visual) and due to the MRI and CSF findings, the patient was diagnosed with MS relapsing-remitting form due to evidence of dissemination in time and space. An intravenous injection of methylprednisolone (1000 mg) was therefore administered for five days. Three months after treatment, a repeat MRI of the brain showed a stable number of the demyelinating plaque with regression of enhancement of one of the lesions denoting regression of disease activity (Fig. 5). The patient was offered to start on disease-modifying therapy, but she elected not to do so until she recovers from her brain surgery and finishes her chemotherapy and radiation therapy.
visual impairment that last few weeks and recover spontaneously. In addition, she described walking difficulty and imbalance since the age of 9 years, which is there all the time and gradually progressive, causing intermittent falls. Clinically, the patient was conscious, oriented to time, place, and person with normal elements of higher mental function. She was dysarthric with cerebellar scanning speech and florid cerebellar signs including dysmetria, dysdiadokinesia, and impaired tandem gait. In addition, she had pyramidal weakness of the right side (4/5) with hyperreflexia and positive Babinski sign. After stabilization of her condition with no recurrence of her seizures (using valproic acid 500 mg once daily and levetiracetam 1500 mg twice daily), she underwent left frontal craniotomy for tumor excision. Microscopic examination of the cortical-based tumor showed a moderately cellular infiltrated glial tumor. There was no evidence of endothelial proliferation or necrosis. The tumor cells were round to oval and hyperchromatic with clear perinuclear halo. Delicate vascularity was present in the background and rare microcalcification was noted. Immunohistochemistry (IHC) staining showed focally positive mini-gemistocytes for glial fibrillary acidic protein (GFAP) in the cytoplasm, while the tumor cells were negative. IHC was also negative for isocitrate dehydrogenase 1 (IDH1), p53, synaptophysin, and neuronal nuclei antibody. Alpha thalassemia/mental retardation x-linked was normal. Ki-67 level was estimated to be moderate to high (>20%) (Fig. 2). Molecular analysis was indicated for further assessment. A mutation in the IDH2 gene at codon 172 and 1p/19q co-deletion was detected (Fig. 3). These findings concur with anaplastic oligodendroglioma 2
Multiple Sclerosis and Related Disorders 40 (2020) 101945
H. Algahtani, et al.
Fig. 2. Histopathology sections showing: A) Brain parenchyma with moderately cellular infiltrated glial tumor. The tumor cells are round to oval, hyperchromatic with perinuclear clear halo. There is no evidence of endothelial proliferation or necrosis. Delicate vascularity in the background (H&E 20X), B) In focal areas, the tumor appears hypercellular with brisk mitosis (H&E 40X), C) GFAP (6F2): Tumor cells are negative. There are focally positive mini-gemistocytes (arrows), D) ATRX (Polyclonal): Normal, E) P53 (D0-7): Negative, and F) Ki-67 (MIB-1): Moderate proliferative index (15-20%).
epidemiology of the co-existence of MS and brain tumors. However, early diagnosis of such cases is possible because patients with MS have more frequent neuroimaging than the general population. Several studies have shown that the incidence of cancer is less in patients with MS with the only exception being brain and genitourinary tract tumors (Bahmanyar et al., 2009). The distribution of brain tumors in patients with MS are located mostly in the frontal and temporal lobes with equal incidence (Green et al., 2001). Unfortunately, brain tumors might be misdiagnosed as tumefactive demyelinating lesions on MRI in patients with MS or in patients presenting for the first time with no previous history of demyelinating disease. These lesions tend to occur in the frontal and parietal lobes and are typically well-circumscribed and supratentorial (Algahtani et al., 2017; Hardy and Chataway, 2013). Therefore, it is crucial to consider brain tumors in tumefactive MS lesions due to overlapping MRI features with other differential diagnoses (Algahtani et al., 2017; Hardy and Chataway, 2013).
Due to a positive family history of autosomal-recessive cerebellar ataxia with spasticity in her sister and significant findings of cerebellar dysfunction on physical examination, targeted mutation sequencing was done for her and the rest of her family. Sequence analysis revealed a homozygous mutation (c.2618G>A, p.Arg873His) in the GBA2 gene consistent with the diagnosis of autosomal recessive cerebellar ataxia with spasticity. MRI of the brain showed mild to moderate cerebellar atrophy (Fig. 6). 3. Discussion MS has been rarely reported to have a causal relationship with brain tumors (Plantone et al., 2015). The first ever reported case of a patient with MS and glioma was by Schere in 1938 (Scherer, 1938). There is no enough valid data to determine the true incidence of brain tumors in patients suffering from MS. It might be difficult to estimate the
Fig. 3. Glioma FISH for 1p/19q deletion A) Nuclei with 1R2G have loss of 1p; FISH probes: TP73[1p36.3](R) and APL2[1q25](G). B) Nuclei with 1R2G have loss of 19q; FISH probes: D19S221[19p13.2](G) and EHD2[19q13.3](R). Abbreviations: FISH, fluorescence in situ hybridization; G, green; R, red. 3
Multiple Sclerosis and Related Disorders 40 (2020) 101945
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Fig. 4. MRI of the brain showing postsurgical changes in the form of gliosis and encephalomalacia with a minimal marginal enhancement of surgical cavity with blood products seen at the surgical cavity. There is an area of gliosis seen around the surgical cavity and left periventricular area and shows no restriction. There are multiple bilateral enhancing white matter high signal intensity lesions noted at the supratentorial periventricular and subcortical white matter, the largest seen at the right inferofrontal gyrus measures around 0.6 × 1 cm. Those lesions show interval progression in number in comparison to previous studies in the right periventricular as well as subcortical areas. No clear restriction on diffusion-weighted images. These new disseminated (in space and time) white matter lesions are consistent with a demyelinating disease (multiple sclerosis).
Fig. 5. MRI of the brain showing a stable appearance of the previously seen supratentorial juxtacortical, callosal septal, and periventricular demyelinating plaque with no restricted diffusion or new lesions. The previously seen enhanced subcortical plaque demonstrates no significant enhancement suggestive of the regression of disease activity. No new demyelinating plaques noted.
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Fig. 6. MRI of the brain showing mild to moderate cerebellar atrophy.
association with their disease (Del Valle et al., 2002). Upon reviewing the literature, only nine cases have been published since 1967 following the first reported case of MS and pure oligodendroglioma (Table 1). The mean age of MS diagnosis is 33 years, and the mean age of oligodendroglioma diagnosis is 44 years (Bondy et al., 2008; Howard et al., 2016). All previous cases had the tumor diagnosis years after the initial manifestations of MS or as an incidental finding on MRI during the first MS symptoms. Our case, on the other hand, presented first as a space-occupying lesion that resulted in a seizure episode while the MS lesions were an incidental finding on MRI. As a result, one might question the hypothesis that the increased proliferation during remyelination processes could predispose to neoplastic transformation. Alternatively, the presence of oligodendroglioma could lead to an autoimmune demyelinating disease. However, this could not apply for cases that developed oligodendroglioma years after the initial presentation of MS. In addition, the multifocality of MS in our case makes it unlikely to have been initiated by the tumor. The unique part of this case is that our patient had autosomal recessive cerebellar ataxia with spasticity. This disorder belongs to a large group known as inherited ataxias with more than 20 known forms of inherited cerebellar diseases (Fogel and Perlman, 2007). Clinical manifestations usually present during childhood as balance dysfunction, incoordination, and dysarthria (Fogel and Perlman, 2007; Hammer et al., 2013). Several homozygous mutations have been previously identified to lead to autosomal recessive cerebellar ataxia with spasticity in the GBA2 gene (Hammer et al., 2013). The one present in our case is on exon 17 that results in the substitution of arginine by histidine at residue 873 (c.2618G>A). This shift is predicted to alter protein structure (Algahtani et al., 2019; Hammer et al., 2013). GBA2 gene encodes for β-glucosidase 2, which cleaves glucosylceramide into glucose and ceramide within the endoplasmic reticulum (Boot et al., 2007; Yildiz et al., 2006). Ceramide can be then utilized for sphingomyelin generation, a component of myelin sheaths and normal cell membranes (Kitatani et al., 2008). Non-functional copies of the GBA2 gene would lead to accumulation glucosylceramide within the endoplasmic reticulum (Yildiz et al., 2006). In putting MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity together, the most likely explanation is believed to be that this patient was unfortunate to have three unrelated diseases. It is not known that a defect in β-glucosidase 2 enzyme activity would lead to demyelinating disease. Ceramide could be generated through another pathway involving the condensation of L-serine and palmitoyl-CoA (Hannun and Obeid, 2008). This rebuts the idea of reduced ceramide generation through β-glucosidase 2 would lead to less myelin production, thus a demyelinating disease. Also, the theories that were discussed regarding the possible association of MS with oligodendroglioma are yet to be proven. Further research is still required to identify such possible pathological mechanisms.
Oligodendroglioma is a tumor that originates from glial cells. They were originally described by Baily and Bucy back in 1929 (Baily and Bucy, 1929). The incidence of oligodendroglioma is relatively rare as they account for approximately 5% of glial tumors and 2.5% of all primary brain tumors (Bondy et al., 2008). Although MS is more common in females, the concurrence of MS and oligodendroglioma occurs almost equally in males and females with a male to female ratio of 1.1:1 (Bondy et al., 2008). Such distribution is most likely a result of a combination of a female predominance in MS (2-2.5:1) and a male predominance in oligodendroglioma (1.5-2:1) (Bondy et al., 2008; Howard et al., 2016). Classically, seizures tend to be the typical clinical presentation of oligodendroglioma (Wieshmann et al., 2015). On microscopy, nuclear features are the primary key for distinguishing oligodendroglia phenotype (Wesseling et al., 2015). The combination of round nuclei and perinuclear halo are the main features that result in “fried-egg” appearance of oligodendrocytes histology (Wesseling et al., 2015). A section of tumor cells might show a gliofibrillary phenotype with positive staining for GFAP in the cytoplasm (Kros et al., 1997; Kros et al., 1990). The molecular profile also plays a major role in diagnostic and prognostic data (Wesseling et al., 2015). For example, non-balance translocation in chromosome 1 and 19 results in complete codeletion of 1p and 19q (Griffin et al., 2006). Furthermore, IDH mutations are another molecular marker for oligodendroglioma and were identified in diffuse grade II and III gliomas in both astrocytic and oligodendroglial cell type (Wesseling et al., 2015; Yan et al., 2009). IDH2 mutation in oligodendroglioma, as in our case, is a rare variant that encodes for mitochondrial nicotinamide adenine dinucleotide phosphate (NADP+)-dependent IDH (Hartmann et al., 2009). IDH2 is known to be involved in the regulation of oxidative respiration (Reitman and Yan, 2010). The overall prognosis is better in pure oligodendroglioma than other gliomas including astrocytoma (Hartmann et al., 2010). Although several theories have been proposed for the unusual concurrence of MS and oligodendroglioma, none have been proven yet, and mere chance is the only acceptable explanation (Plantone et al., 2015; Green et al., 2001). It is possible to hypothesize that MS lesions can undergo neoplastic transformation due to the increased proliferative ratio that is induced by the remyelination process. This increase in proliferation results in more DNA double strand breaks, thereby increasing the chance of chromosomal aberrations (Aplan, 2006). In fact, all tumors with 1p/19q codeletion tend to have a pro-neural expansion profile (Wesseling et al., 2015). This supports the hypothesis that these tumors result in bipotential progenitor cell that is able to give rise to neurons and oligodendrocytes (Ducray et al., 2008). It is also possible to contemplate that viral infections might act as a neoplastic agent in oligodendroglioma (Plantone et al., 2015). Postmortem examination of patients with MS and glioblastoma multiforme have shown molecular evidence of human poliovirus JC virus in 5
6
26
23 44
de la Lama et al., 2004
Carvalho et al., 2014 Shirani et al., 2018
37 9 months after MS Dx
37
43
65
42
44?
50
51
23
Age at tumor Dx
RRMS N/A
RRMS
RR/SC MS
N/A
PPMS
N/A
RRMS
N/A Multipe FLAIR white matter lesions in periventricular, juxtacortical and subcortical areas
N/A
N/A
N/A
Focal non-enhancing T2 hyperintensities superior to LV and posterior to splenium of CC Nodular areas of T2 bright white matter lesions up to 1 cm in diameter close to LV and in CC N/A
Few foci of T2 are seen in the periventricular white matter of the right frontal and left occipital, and in the subcortical white matter of the right parietal lobe Multiple T2 bright lesions in periventricular white matter
N/Aa
RRMS
MS MRI findings
MS course
Left frontal lobe Right frontal lobe
Right temporal lobe+ metastasis to right cerebellar hemisphere Subcortical right frontal lobe
Diffuse across CC (right>left)
Anterior CC, bilateral frontal lobes
Right temporal lobe
Right temporoparietal junction
Right posterior parietal lobe
Left superior part of the middle frontal gyri
Tumor location
Unclear grade oligodendroglioma, not contiguous with MS lesions Oligodendroglioma with spotty calcification, ring lesions, contiguous with MS plaques Polymorphic oligodendroglioma with mitotic figures and central necrosis Tumoural proliferation with homogeneous nuclei and clear cytoplasms, not contiguous with MS plaques. grade C oligodendroglioma (Smith classification) Grade II oligodendroglioma (WHO classification) Grade II oligodendroglioma (WHO classification)
Grade II oligodendroglioma (WHO classification)
Monomorphic neoplasm composed of oligodendrocytes, GFAP positive, and CD68 negative Microcystic low grade oligodendroglioma
Anaplastic oligodendroglioma (WHO grade III)
Histopathology
Abbreviations: CC, corpus callosum; FLAIR, fluid-attenuated inversion recovery; LV, left ventricle; N/A, not available; PPMS, primary progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SCMS, secondary progressive multiple sclerosis; WHO, world health organization. a Multiple sclerosis was an incidental finding on MRI and treatment was immediately initiated after the diagnosis was made.
28
Barnard and Jellinek, 1967
44?
Case2
N/A
34
Case1
Green et al., 2001
Rao et al., 1986
43
Khan et al., 1997
34
23
Current case
Giordana et al., 1981
Age at MS Dx
Author
Table 1 Reported cases of MS with pure oligodendroglioma
H. Algahtani, et al.
Multiple Sclerosis and Related Disorders 40 (2020) 101945
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in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J. Neuropathol. Exp. Neurol. 65 (10), 988–994. Hammer, M.B., Eleuch-Fayache, G., Schottlaender, L.V., et al., 2013. Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am. J. Hum. Genet. 92 (2), 245–251. Hannun, Y.A., Obeid, L.M., 2008. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat. Rev. Mol. Cell Biol. 9 (2), 139–150. Hardy, T.A., Chataway, J., 2013. Tumefactive demyelination: an approach to diagnosis and management. J. Neurol. Neurosurg. Psychiatry 84 (9), 1047–1053. Hartmann, C., Hentschel, B., Wick, W., et al., 2010. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 120 (6), 707–718. Howard, J., Trevick, S., Younger, D.S., 2016. Epidemiology of multiple sclerosis. Neurol. Clin. 34 (4), 919–939. Khan, O.A., Bauserman, S.C., Rothman, M.I., Aldrich, E.F., Panitch, H.S., 1997. Concurrence of multiple sclerosis and brain tumor: clinical considerations. Neurology 48 (5), 1330–1333. Kitatani, K., Idkowiak-Baldys, J., Hannun, Y.A., 2008. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 20 (6), 1010–1018. Kros, J.M., van den Brink, W.A., van Loon-van Luyt, J.J., Stefanko, S.Z., 1997. Signet-ring cell oligodendroglioma–report of two cases and discussion of the differential diagnosis. Acta Neuropathol. 93 (6), 638–643. Kros, J.M., Van Eden, C.G., Stefanko, S.Z., Waayer-Van Batenburg, M., van der Kwast, T.H., 1990. Prognostic implications of glial fibrillary acidic protein containing cell types in oligodendrogliomas. Cancer 66 (6), 1204–1212. Louis, D.N., Perry, A., Reifenberger, G., et al., 2016. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 131 (6), 803–820. Plantone, D., Renna, R., Sbardella, E., Koudriavtseva, T., 2015. Concurrence of multiple sclerosis and brain tumors. Front. Neurol. 6, 40. Rao, T.V., Mushtaq, S., Dasetal, S., 1986. Multiple sclerosis and diffuse oligodendroglioma. NIMHANS J. 4 (2), 105–110. Reitman, Z.J., Yan, H., 2010. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J. Natl. Cancer Inst. 102 (13), 932–941. Scherer, H., 1938. La `glioblastomatose en plaques’: sur les limites anatomiques de la gliomatose et des processus sclerotiques progessifs. J. Belg. Neurol. Psychiat. 38, 1–17. Shirani, A., Wu, G.F., Giannini, C., Cross, A.H., 2018. A case of oligodendroglioma and multiple sclerosis: Occam's razor or Hickam's dictum? BMJ Case Rep. Wesseling, P., van den Bent, M., Perry, A., 2015. Oligodendroglioma: pathology, molecular mechanisms and markers. Acta Neuropathol. 129 (6), 809–827. Wieshmann, U.C., Milinis, K., Paniker, J., et al., 2015. The role of the corpus callosum in seizure spread: MRI lesion mapping in oligodendrogliomas. Epilepsy Res. 109, 126–133. Yan, H., Parsons, D.W., Jin, G., et al., 2009. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360 (8), 765–773. Yildiz, Y., Matern, H., Thompson, B., et al., 2006. Mutation of beta-glucosidase 2 causes glycolipid storage disease and impaired male fertility. J. Clin. Invest. 116 (11), 2985–2994.
4. Conclusion To our knowledge, this is the first case ever to have MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity in one patient. The most likely explanation is believed to be that this patient was unfortunate to have three unrelated diseases. Declaration of Competing Interest The authors declare that they have no conflicts of interest. References Algahtani, H., Shirah, B., Alassiri, A., 2017. Tumefactive demyelinating lesions: a comprehensive review. Mult. Scler. Relat. Disord. 14, 72–79. Algahtani, H., Shirah, B., Ullah, I., Al-Qahtani, M.H., Abdulkareem, A.A., Naseer, M.I., 2019. Autosomal recessive cerebellar ataxia with spasticity due to a rare mutation in GBA2 gene in a large consanguineous Saudi family. Genes Dis. Aplan, P.D., 2006. Causes of oncogenic chromosomal translocation. Trends Genet. 22 (1), 46–55. Bahmanyar, S., Montgomery, S.M., Hillert, J., Ekbom, A., Olsson, T., 2009. Cancer risk among patients with multiple sclerosis and their parents. Neurology 72 (13), 1170–1177. Baily, P., Bucy, P.C., 1929. Oligodendrogliomas of the brain. J. Pathol. Bacteriol. 32, 735–751. Barnard, R.O., Jellinek, E.H., 1967. Multiple sclerosis with amyotrophy complicated by oligodendroglioma. History of recurrent herpes zoster. J. Neurol. Sci. 5 (3), 441–455. Bondy, M.L., Scheurer, M.E., Malmer, B., et al., 2008. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113 (7 Suppl), 1953–1968. Boot, R.G., Verhoek, M., Donker-Koopman, W., et al., 2007. Identification of the nonlysosomal glucosylceramidase as beta-glucosidase 2. J. Biol. Chem. 282 (2), 1305–1312. Carvalho, A.T., Linhares, P., Castro, L., Sá, M.J., 2014. Multiple sclerosis and oligodendroglioma: an exceptional association. Case Rep. Neurol. Med. 2014, 546817. de la Lama, A., Gómez, P.A., Boto, G.R., et al., 2004. Oligodendroglioma and multiple sclerosis. A case report. Neurocirugia (Astur) 15 (4), 378–383. Del Valle, L., Delbue, S., Gordon, J., et al., 2002. Expression of JC virus T-antigen in a patient with MS and glioblastoma multiforme. Neurology 58 (6), 895–900. Ducray, F., Idbaih, A., de Reyniès, A., et al., 2008. . Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. Mol. Cancer 7, 41. Fogel, B.L., Perlman, S., 2007. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 6 (3), 245–257. Giordana, M.T., Mauro, A., Soffietti, R., Leone, M., 1981. Association between multiple sclerosis and oligodendroglioma. Case report. Ital. J. Neurol. Sci. 2 (4), 403–409. Green, A.J., Bollen, A.W., Berger, M.S., Oksenberg, J.R., Hauser, S.L., 2001. Multiple sclerosis and oligodendroglioma. Mult. Scler. 7 (4), 269–273. Griffin, C.A., Burger, P., Morsberger, L., et al., 2006. Identification of der(1;19)(q10;p10)
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Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard
Case report
Concurrence of multiple sclerosis, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity in the same patient: A challenging diagnosis
T
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Hussein Algahtania, , Bader Shirahb, Mohamed Tashkandic, Alaa Samkarid a
King Abdulaziz Medical City / King Saud bin Abdulaziz University for Health Sciences, Jeddah 12723,21483, Saudi Arabia King Abdullah International Medical Research Center / King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia c King Saud bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia d Department of Pathology and Lab Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia b
A R T I C LE I N FO
A B S T R A C T
Keywords: Multiple sclerosis Oligodendroglioma Autosomal recessive cerebellar ataxia with spasticity GBA2 Saudi Arabia
Multiple sclerosis (MS) has been described in several case reports to coexist with brain tumors. This unusual concurrence has been the subject of research projects with a common question of whether these pathological entities share common roots. However, no clear association has proved that either of them could provoke the other, and mere chance is the only acceptable explanation. Along all reported cases, oligodendroglioma has been rarely reported to coexist with MS. In this paper, we report a unique case with a triad of MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity and discuss possible theories that might have attributed to these three conditions. To our knowledge, this is the first case ever to have these three conditions present in one patient. The most likely explanation is believed to be that this patient was unfortunate to have three unrelated diseases.
1. Introduction
2. Case report
Multiple sclerosis (MS) has been described in several case reports to coexist with brain tumors (Plantone et al., 2015). This unusual concurrence has been the subject of research projects with a common question of whether these pathological entities share common roots. However, no clear association has proved that either of them could provoke the other, and mere chance is the only acceptable explanation (Plantone et al., 2015; Green et al., 2001). Along all reported cases, oligodendroglioma has been rarely reported to coexist with MS. The first reported case of MS with pure oligodendroglioma was in 1967, and only 9 cases were published since then (Green et al., 2001; Carvalho et al., 2014; Barnard and Jellinek, 1967; Giordana et al., 1981; Rao et al., 1986; Khan et al., 1997; de la Lama et al., 2004; Shirani et al., 2018). In this paper, we report a unique case with a triad of MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity and discuss possible theories that might have attributed to these three conditions.
A 23-year-old female presented to the emergency department with one episode of tonic-clonic seizure with tongue biting, uprolling of the eye, and urinary incontinence. She was not known to have epilepsy or any other neurological diseases. In the emergency department, the patient was treated aggressively for her seizure and was fully investigated including electroencephalogram (EEG) and neuroimaging of the brain. Computed tomography (CT) scan of the brain showed a left frontal hypodensity with local mass effect. Magnetic resonance imaging (MRI) of the brain showed a 5.6 cm cortical-based tumor arising from the left superior and part of the middle frontal gyri and surrounded by vasogenic edema. Few variable-sized foci of high signal intensity in fluid-attenuated inversion recovery (FLAIR) sequences were seen in the periventricular white matter of the right frontal and left occipital lobes and in the subcortical white matter of the right parietal lobe. Only the latter showed enhancement in the post-contrast images with no diffusion or restriction (Fig. 1). These multifocal areas were initially thought to represent areas of multifocal gliomatosis and less likely to be demyelinating lesions. Retrospectively, the patient gave a history of repeated episodes of neurological dysfunction with motor, sensory, and
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Corresponding author. E-mail addresses: [email protected], [email protected] (H. Algahtani).
https://doi.org/10.1016/j.msard.2020.101945 Received 23 July 2019; Received in revised form 28 November 2019; Accepted 10 January 2020 2211-0348/ © 2020 Elsevier B.V. All rights reserved.
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Fig. 1. MRI of the brain showing a large cortical-based tumor seen arising from the left superior and part of the middle frontal gyri with surrounding vasogenic edema. It measures approximately 5.6 × 4.8 cm in anteroposterior and transverse diameters, respectively. It shows heterogeneous signal intensity in T1 and T2 weighted images, with peripheral areas of diffusion restriction. A central area of faint enhancement is seen in the post-contrast images, which corresponds to the central area of increased perfusion in the MRP. The surrounding vasogenic edema is causing mild mass effect on the anterior horn of the left lateral ventricle, with subfalcine herniation of approximately 5 mm. The vasogenic edema is compressing the corpus callosum, with no invasion or involvement. The MR spectroscopy evaluation of the lesion showed increased choline/creatinine ratio, reduction in NAA, and peak of lactate. Few variable-sized foci of high signal intensity in T2/FLAIR sequences are seen in the periventricular white matter of the right frontal and left occipital lobe with another one seen in the subcortical white matter of the right parietal lobe. Only the latter lesion shows enhancement in the post-contrast images, with no diffusion restriction seen.
(WHO grade III) (Louis et al., 2016). The patient was discharged home in good condition with the final diagnosis of oligodendroglioma. Six months later, on routine MRI follow-up, new white matter lesions consistent with dissemination in time and space and with a demyelinating disease were detected (Fig. 4). Therefore, an urgent neurology consultation was recommended. On reviewing her family history, one sister was diagnosed with autosomal-recessive cerebellar ataxia with spasticity. Upon admission, full MS workup was done including cerebrospinal fluid (CSF) analysis, serum aquaporin-4 antibody titer, serum anti-myelin oligodendrocyte glycoprotein antibody (AntiMOG) titer, whole spine MRI, and MRI spectroscopy. CSF analysis revealed positive oligoclonal bands (positive in the CSF and negative in the serum) and increased immunoglobulin G index. Other investigations were within normal limits, except for the previously demonstrated demyelinating lesions on MRI. Due to the history of repeated episodes of neurological deficit involving multiple parts of the neuraxis (motor, sensory, and visual) and due to the MRI and CSF findings, the patient was diagnosed with MS relapsing-remitting form due to evidence of dissemination in time and space. An intravenous injection of methylprednisolone (1000 mg) was therefore administered for five days. Three months after treatment, a repeat MRI of the brain showed a stable number of the demyelinating plaque with regression of enhancement of one of the lesions denoting regression of disease activity (Fig. 5). The patient was offered to start on disease-modifying therapy, but she elected not to do so until she recovers from her brain surgery and finishes her chemotherapy and radiation therapy.
visual impairment that last few weeks and recover spontaneously. In addition, she described walking difficulty and imbalance since the age of 9 years, which is there all the time and gradually progressive, causing intermittent falls. Clinically, the patient was conscious, oriented to time, place, and person with normal elements of higher mental function. She was dysarthric with cerebellar scanning speech and florid cerebellar signs including dysmetria, dysdiadokinesia, and impaired tandem gait. In addition, she had pyramidal weakness of the right side (4/5) with hyperreflexia and positive Babinski sign. After stabilization of her condition with no recurrence of her seizures (using valproic acid 500 mg once daily and levetiracetam 1500 mg twice daily), she underwent left frontal craniotomy for tumor excision. Microscopic examination of the cortical-based tumor showed a moderately cellular infiltrated glial tumor. There was no evidence of endothelial proliferation or necrosis. The tumor cells were round to oval and hyperchromatic with clear perinuclear halo. Delicate vascularity was present in the background and rare microcalcification was noted. Immunohistochemistry (IHC) staining showed focally positive mini-gemistocytes for glial fibrillary acidic protein (GFAP) in the cytoplasm, while the tumor cells were negative. IHC was also negative for isocitrate dehydrogenase 1 (IDH1), p53, synaptophysin, and neuronal nuclei antibody. Alpha thalassemia/mental retardation x-linked was normal. Ki-67 level was estimated to be moderate to high (>20%) (Fig. 2). Molecular analysis was indicated for further assessment. A mutation in the IDH2 gene at codon 172 and 1p/19q co-deletion was detected (Fig. 3). These findings concur with anaplastic oligodendroglioma 2
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Fig. 2. Histopathology sections showing: A) Brain parenchyma with moderately cellular infiltrated glial tumor. The tumor cells are round to oval, hyperchromatic with perinuclear clear halo. There is no evidence of endothelial proliferation or necrosis. Delicate vascularity in the background (H&E 20X), B) In focal areas, the tumor appears hypercellular with brisk mitosis (H&E 40X), C) GFAP (6F2): Tumor cells are negative. There are focally positive mini-gemistocytes (arrows), D) ATRX (Polyclonal): Normal, E) P53 (D0-7): Negative, and F) Ki-67 (MIB-1): Moderate proliferative index (15-20%).
epidemiology of the co-existence of MS and brain tumors. However, early diagnosis of such cases is possible because patients with MS have more frequent neuroimaging than the general population. Several studies have shown that the incidence of cancer is less in patients with MS with the only exception being brain and genitourinary tract tumors (Bahmanyar et al., 2009). The distribution of brain tumors in patients with MS are located mostly in the frontal and temporal lobes with equal incidence (Green et al., 2001). Unfortunately, brain tumors might be misdiagnosed as tumefactive demyelinating lesions on MRI in patients with MS or in patients presenting for the first time with no previous history of demyelinating disease. These lesions tend to occur in the frontal and parietal lobes and are typically well-circumscribed and supratentorial (Algahtani et al., 2017; Hardy and Chataway, 2013). Therefore, it is crucial to consider brain tumors in tumefactive MS lesions due to overlapping MRI features with other differential diagnoses (Algahtani et al., 2017; Hardy and Chataway, 2013).
Due to a positive family history of autosomal-recessive cerebellar ataxia with spasticity in her sister and significant findings of cerebellar dysfunction on physical examination, targeted mutation sequencing was done for her and the rest of her family. Sequence analysis revealed a homozygous mutation (c.2618G>A, p.Arg873His) in the GBA2 gene consistent with the diagnosis of autosomal recessive cerebellar ataxia with spasticity. MRI of the brain showed mild to moderate cerebellar atrophy (Fig. 6). 3. Discussion MS has been rarely reported to have a causal relationship with brain tumors (Plantone et al., 2015). The first ever reported case of a patient with MS and glioma was by Schere in 1938 (Scherer, 1938). There is no enough valid data to determine the true incidence of brain tumors in patients suffering from MS. It might be difficult to estimate the
Fig. 3. Glioma FISH for 1p/19q deletion A) Nuclei with 1R2G have loss of 1p; FISH probes: TP73[1p36.3](R) and APL2[1q25](G). B) Nuclei with 1R2G have loss of 19q; FISH probes: D19S221[19p13.2](G) and EHD2[19q13.3](R). Abbreviations: FISH, fluorescence in situ hybridization; G, green; R, red. 3
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Fig. 4. MRI of the brain showing postsurgical changes in the form of gliosis and encephalomalacia with a minimal marginal enhancement of surgical cavity with blood products seen at the surgical cavity. There is an area of gliosis seen around the surgical cavity and left periventricular area and shows no restriction. There are multiple bilateral enhancing white matter high signal intensity lesions noted at the supratentorial periventricular and subcortical white matter, the largest seen at the right inferofrontal gyrus measures around 0.6 × 1 cm. Those lesions show interval progression in number in comparison to previous studies in the right periventricular as well as subcortical areas. No clear restriction on diffusion-weighted images. These new disseminated (in space and time) white matter lesions are consistent with a demyelinating disease (multiple sclerosis).
Fig. 5. MRI of the brain showing a stable appearance of the previously seen supratentorial juxtacortical, callosal septal, and periventricular demyelinating plaque with no restricted diffusion or new lesions. The previously seen enhanced subcortical plaque demonstrates no significant enhancement suggestive of the regression of disease activity. No new demyelinating plaques noted.
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Fig. 6. MRI of the brain showing mild to moderate cerebellar atrophy.
association with their disease (Del Valle et al., 2002). Upon reviewing the literature, only nine cases have been published since 1967 following the first reported case of MS and pure oligodendroglioma (Table 1). The mean age of MS diagnosis is 33 years, and the mean age of oligodendroglioma diagnosis is 44 years (Bondy et al., 2008; Howard et al., 2016). All previous cases had the tumor diagnosis years after the initial manifestations of MS or as an incidental finding on MRI during the first MS symptoms. Our case, on the other hand, presented first as a space-occupying lesion that resulted in a seizure episode while the MS lesions were an incidental finding on MRI. As a result, one might question the hypothesis that the increased proliferation during remyelination processes could predispose to neoplastic transformation. Alternatively, the presence of oligodendroglioma could lead to an autoimmune demyelinating disease. However, this could not apply for cases that developed oligodendroglioma years after the initial presentation of MS. In addition, the multifocality of MS in our case makes it unlikely to have been initiated by the tumor. The unique part of this case is that our patient had autosomal recessive cerebellar ataxia with spasticity. This disorder belongs to a large group known as inherited ataxias with more than 20 known forms of inherited cerebellar diseases (Fogel and Perlman, 2007). Clinical manifestations usually present during childhood as balance dysfunction, incoordination, and dysarthria (Fogel and Perlman, 2007; Hammer et al., 2013). Several homozygous mutations have been previously identified to lead to autosomal recessive cerebellar ataxia with spasticity in the GBA2 gene (Hammer et al., 2013). The one present in our case is on exon 17 that results in the substitution of arginine by histidine at residue 873 (c.2618G>A). This shift is predicted to alter protein structure (Algahtani et al., 2019; Hammer et al., 2013). GBA2 gene encodes for β-glucosidase 2, which cleaves glucosylceramide into glucose and ceramide within the endoplasmic reticulum (Boot et al., 2007; Yildiz et al., 2006). Ceramide can be then utilized for sphingomyelin generation, a component of myelin sheaths and normal cell membranes (Kitatani et al., 2008). Non-functional copies of the GBA2 gene would lead to accumulation glucosylceramide within the endoplasmic reticulum (Yildiz et al., 2006). In putting MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity together, the most likely explanation is believed to be that this patient was unfortunate to have three unrelated diseases. It is not known that a defect in β-glucosidase 2 enzyme activity would lead to demyelinating disease. Ceramide could be generated through another pathway involving the condensation of L-serine and palmitoyl-CoA (Hannun and Obeid, 2008). This rebuts the idea of reduced ceramide generation through β-glucosidase 2 would lead to less myelin production, thus a demyelinating disease. Also, the theories that were discussed regarding the possible association of MS with oligodendroglioma are yet to be proven. Further research is still required to identify such possible pathological mechanisms.
Oligodendroglioma is a tumor that originates from glial cells. They were originally described by Baily and Bucy back in 1929 (Baily and Bucy, 1929). The incidence of oligodendroglioma is relatively rare as they account for approximately 5% of glial tumors and 2.5% of all primary brain tumors (Bondy et al., 2008). Although MS is more common in females, the concurrence of MS and oligodendroglioma occurs almost equally in males and females with a male to female ratio of 1.1:1 (Bondy et al., 2008). Such distribution is most likely a result of a combination of a female predominance in MS (2-2.5:1) and a male predominance in oligodendroglioma (1.5-2:1) (Bondy et al., 2008; Howard et al., 2016). Classically, seizures tend to be the typical clinical presentation of oligodendroglioma (Wieshmann et al., 2015). On microscopy, nuclear features are the primary key for distinguishing oligodendroglia phenotype (Wesseling et al., 2015). The combination of round nuclei and perinuclear halo are the main features that result in “fried-egg” appearance of oligodendrocytes histology (Wesseling et al., 2015). A section of tumor cells might show a gliofibrillary phenotype with positive staining for GFAP in the cytoplasm (Kros et al., 1997; Kros et al., 1990). The molecular profile also plays a major role in diagnostic and prognostic data (Wesseling et al., 2015). For example, non-balance translocation in chromosome 1 and 19 results in complete codeletion of 1p and 19q (Griffin et al., 2006). Furthermore, IDH mutations are another molecular marker for oligodendroglioma and were identified in diffuse grade II and III gliomas in both astrocytic and oligodendroglial cell type (Wesseling et al., 2015; Yan et al., 2009). IDH2 mutation in oligodendroglioma, as in our case, is a rare variant that encodes for mitochondrial nicotinamide adenine dinucleotide phosphate (NADP+)-dependent IDH (Hartmann et al., 2009). IDH2 is known to be involved in the regulation of oxidative respiration (Reitman and Yan, 2010). The overall prognosis is better in pure oligodendroglioma than other gliomas including astrocytoma (Hartmann et al., 2010). Although several theories have been proposed for the unusual concurrence of MS and oligodendroglioma, none have been proven yet, and mere chance is the only acceptable explanation (Plantone et al., 2015; Green et al., 2001). It is possible to hypothesize that MS lesions can undergo neoplastic transformation due to the increased proliferative ratio that is induced by the remyelination process. This increase in proliferation results in more DNA double strand breaks, thereby increasing the chance of chromosomal aberrations (Aplan, 2006). In fact, all tumors with 1p/19q codeletion tend to have a pro-neural expansion profile (Wesseling et al., 2015). This supports the hypothesis that these tumors result in bipotential progenitor cell that is able to give rise to neurons and oligodendrocytes (Ducray et al., 2008). It is also possible to contemplate that viral infections might act as a neoplastic agent in oligodendroglioma (Plantone et al., 2015). Postmortem examination of patients with MS and glioblastoma multiforme have shown molecular evidence of human poliovirus JC virus in 5
6
26
23 44
de la Lama et al., 2004
Carvalho et al., 2014 Shirani et al., 2018
37 9 months after MS Dx
37
43
65
42
44?
50
51
23
Age at tumor Dx
RRMS N/A
RRMS
RR/SC MS
N/A
PPMS
N/A
RRMS
N/A Multipe FLAIR white matter lesions in periventricular, juxtacortical and subcortical areas
N/A
N/A
N/A
Focal non-enhancing T2 hyperintensities superior to LV and posterior to splenium of CC Nodular areas of T2 bright white matter lesions up to 1 cm in diameter close to LV and in CC N/A
Few foci of T2 are seen in the periventricular white matter of the right frontal and left occipital, and in the subcortical white matter of the right parietal lobe Multiple T2 bright lesions in periventricular white matter
N/Aa
RRMS
MS MRI findings
MS course
Left frontal lobe Right frontal lobe
Right temporal lobe+ metastasis to right cerebellar hemisphere Subcortical right frontal lobe
Diffuse across CC (right>left)
Anterior CC, bilateral frontal lobes
Right temporal lobe
Right temporoparietal junction
Right posterior parietal lobe
Left superior part of the middle frontal gyri
Tumor location
Unclear grade oligodendroglioma, not contiguous with MS lesions Oligodendroglioma with spotty calcification, ring lesions, contiguous with MS plaques Polymorphic oligodendroglioma with mitotic figures and central necrosis Tumoural proliferation with homogeneous nuclei and clear cytoplasms, not contiguous with MS plaques. grade C oligodendroglioma (Smith classification) Grade II oligodendroglioma (WHO classification) Grade II oligodendroglioma (WHO classification)
Grade II oligodendroglioma (WHO classification)
Monomorphic neoplasm composed of oligodendrocytes, GFAP positive, and CD68 negative Microcystic low grade oligodendroglioma
Anaplastic oligodendroglioma (WHO grade III)
Histopathology
Abbreviations: CC, corpus callosum; FLAIR, fluid-attenuated inversion recovery; LV, left ventricle; N/A, not available; PPMS, primary progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SCMS, secondary progressive multiple sclerosis; WHO, world health organization. a Multiple sclerosis was an incidental finding on MRI and treatment was immediately initiated after the diagnosis was made.
28
Barnard and Jellinek, 1967
44?
Case2
N/A
34
Case1
Green et al., 2001
Rao et al., 1986
43
Khan et al., 1997
34
23
Current case
Giordana et al., 1981
Age at MS Dx
Author
Table 1 Reported cases of MS with pure oligodendroglioma
H. Algahtani, et al.
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4. Conclusion To our knowledge, this is the first case ever to have MS, oligodendroglioma, and autosomal recessive cerebellar ataxia with spasticity in one patient. The most likely explanation is believed to be that this patient was unfortunate to have three unrelated diseases. Declaration of Competing Interest The authors declare that they have no conflicts of interest. References Algahtani, H., Shirah, B., Alassiri, A., 2017. Tumefactive demyelinating lesions: a comprehensive review. Mult. Scler. Relat. Disord. 14, 72–79. Algahtani, H., Shirah, B., Ullah, I., Al-Qahtani, M.H., Abdulkareem, A.A., Naseer, M.I., 2019. Autosomal recessive cerebellar ataxia with spasticity due to a rare mutation in GBA2 gene in a large consanguineous Saudi family. Genes Dis. Aplan, P.D., 2006. Causes of oncogenic chromosomal translocation. Trends Genet. 22 (1), 46–55. Bahmanyar, S., Montgomery, S.M., Hillert, J., Ekbom, A., Olsson, T., 2009. Cancer risk among patients with multiple sclerosis and their parents. Neurology 72 (13), 1170–1177. Baily, P., Bucy, P.C., 1929. Oligodendrogliomas of the brain. J. Pathol. Bacteriol. 32, 735–751. Barnard, R.O., Jellinek, E.H., 1967. Multiple sclerosis with amyotrophy complicated by oligodendroglioma. History of recurrent herpes zoster. J. Neurol. Sci. 5 (3), 441–455. Bondy, M.L., Scheurer, M.E., Malmer, B., et al., 2008. Brain tumor epidemiology: consensus from the Brain Tumor Epidemiology Consortium. Cancer 113 (7 Suppl), 1953–1968. Boot, R.G., Verhoek, M., Donker-Koopman, W., et al., 2007. Identification of the nonlysosomal glucosylceramidase as beta-glucosidase 2. J. Biol. Chem. 282 (2), 1305–1312. Carvalho, A.T., Linhares, P., Castro, L., Sá, M.J., 2014. Multiple sclerosis and oligodendroglioma: an exceptional association. Case Rep. Neurol. Med. 2014, 546817. de la Lama, A., Gómez, P.A., Boto, G.R., et al., 2004. Oligodendroglioma and multiple sclerosis. A case report. Neurocirugia (Astur) 15 (4), 378–383. Del Valle, L., Delbue, S., Gordon, J., et al., 2002. Expression of JC virus T-antigen in a patient with MS and glioblastoma multiforme. Neurology 58 (6), 895–900. Ducray, F., Idbaih, A., de Reyniès, A., et al., 2008. . Anaplastic oligodendrogliomas with 1p19q codeletion have a proneural gene expression profile. Mol. Cancer 7, 41. Fogel, B.L., Perlman, S., 2007. Clinical features and molecular genetics of autosomal recessive cerebellar ataxias. Lancet Neurol. 6 (3), 245–257. Giordana, M.T., Mauro, A., Soffietti, R., Leone, M., 1981. Association between multiple sclerosis and oligodendroglioma. Case report. Ital. J. Neurol. Sci. 2 (4), 403–409. Green, A.J., Bollen, A.W., Berger, M.S., Oksenberg, J.R., Hauser, S.L., 2001. Multiple sclerosis and oligodendroglioma. Mult. Scler. 7 (4), 269–273. Griffin, C.A., Burger, P., Morsberger, L., et al., 2006. Identification of der(1;19)(q10;p10)
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