JNS-13538; No of Pages 3 Journal of the Neurological Sciences xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the editor Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?
Keywords: Multiple sclerosis Pseudotumour Tumour-like Atypical Neuroinflammation
1. Case A 38-year-old female with a fifteen pack year smoking history woke with left lower limb focal motor seizures, weakness and gait disturbance. MRI of the brain showed an isolated, minimally-enhancing 1.5 cm, concentric lesion with surrounding oedema in the right superior frontal gyrus with a differential diagnosis including demyelination, glioma and infarction (Fig. 1A–C). She was commenced on carbamazepine CR 200 mg twice daily and tapering oral dexamethasone 4 mg twice daily and underwent stereotactic biopsy of the lesion a week later. Histopathology revealed increased foamy histiocytes, perivascular lymphoid cuffing, and areas of disproportionate myelin loss in some fragments consistent with demyelination, which together with the MRI appearance, favoured a diagnosis of BCS (Fig. 1G–I). Follow-up imaging one week after biopsy showed involution of the lesion without treatment and her leg weakness steadily improved and seizures resolved. MRI of the whole spine was normal. Six-months after her initial symptoms, she noticed incoordination of her left leg. Repeat MRI of the brain revealed a tumefactive periventricular white matter lesion in the left hemisphere with peripheral enhancement and perilesional vasogenic oedema consistent with tumefactive demyelination (Fig. 1D–F). Once again, there were no other lesions. Although assumed to be an incidental finding unrelated to her symptoms, she was treated with intravenous methylprednisolone 1 g daily for 3 days. CSF examination confirmed 8 unmatched oligoclonal bands not present in the serum. Repeat MRI of the whole spine was normal. Aquaporin 4 antibody, ANA, dsDNA, ANCA, ENA, lupus anticoagulant, anticardiolipin antibodies, serum paraproteins, ACE, ESR, CRP, treponemal serology, cryptococcal antigen and HIV were normal or negative. Visual evoked and somatosensory evoked potentials were normal. MRI of the brain 3 weeks later showed improvement in lesion size and enhancement. Disease modifying therapy with glatiramer acetate was commenced and she has had no further clinical or radiological relapses at 12 month follow-up. 2. Discussion Our patient underwent biopsy of a pseudotumoural, demyelinating concentric ring lesion in the right hemisphere consistent with BCS.
Given that there may be a better prognosis for patients who recover following a Baló lesion as a first demyelinating event compared to more conventional relapsing remitting MS [4], and that there was no initial supporting evidence of dissemination in space and time for a diagnosis of MS, disease modifying therapy was withheld until after the second lesion appeared. The patient's second episode of leg weakness was thought to be unrelated to the second lesion given its location in the ipsilateral cerebral hemisphere but clinical involvement of uncrossed corticospinal tract fibres, or decompensation of another contralateral pathway recruited after the first lesion, cannot be excluded. Evidence is lacking to guide appropriate therapy when MS is confirmed in the context of atypical demyelinating lesions, but initiation of a first line injectable such as glatiramer acetate or interferon beta appears reasonable [4,5], and glatiramer acetate was chosen with the patient in this case mainly due to its potentially favourable adverse effect profile. Experience with newer disease modifying therapies and atypical demyelinating lesions is particularly limited. An association between tumefactive demyelinating lesions and fingolimod has been noted in several case reports [6]. While this may reflect reporting bias, a cautious approach to the use of this agent in patients with large inflammatory demyelinating lesions is advised. If the effect is real, the mechanism of how fingolimod might trigger tumefactive lesions remains speculative. If, in susceptible individuals, a population of inhibitory immunoregulatory cells (e.g. CCR7neg T cells) were preferentially affected by fingolimod's action in reducing lymphocyte migration from peripheral lymph nodes, then failure of normal inhibitory mechanisms might be an explanation for the formation of large lesions [6]. Experience with natalizumab also remains limited but it has been used successfully in TD and BCS in case reports [7,8]. To our knowledge, this is the first case of a Baló lesion and a tumefactive demyelinating lesion being reported in the same patient, a phenomenon certainly not reported in large series of patients in which the radiology and pathology of tumefactive demyelination have been assessed [2,3,9]. It is interesting that both of these lesions developed without evidence of other more typical demyelinating lesions. There is no consensus definition as to how many concentric rings are required for a lesion to be considered BCS but some authors have suggested the use of the term “Baló-like lesions” to describe a concentric demyelinating lesion with ≥2 alternations on any MRI sequence [10]. BCS was originally described in post-mortem studies as a relentlessly progressive and fatal form of demyelination but studies in the MRI era have shown that Baló or Baló-like lesions can be associated with a more favourable prognosis. Hence, BCS appears to be defined by a wide spectrum of clinical severity [5]. It may be that some tumefactive lesions start out with a Baló appearance but that the alternating ring appearance is lost with time [11]. Thus, we cannot completely exclude that the second lesion in our patient did not develop into a tumefactive lesion after beginning as BCS. However, the lesions of BCS can hold their characteristic appearance for at least a year [12], and the second lesion appeared within only 6 weeks of the patient's last MRI scan.
http://dx.doi.org/10.1016/j.jns.2014.11.024 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Hardy TA, et al, Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.11.024
2
Letter to the editor
Fig. 1. Magnetic resonance imaging showing (A) axial fluid attenuated inversion recovery (FLAIR) image and (B) inset of a concentric Baló lesion in the right parietal lobe. (C) Sagittal T2 image of the Baló lesion. (D) Axial FLAIR image and (E) inset of a tumefactive demyelinating lesion occurring in the same patient in the left parietal lobe 6 months later. (F) Sagittal FLAIR image of the tumefactive lesion. Histopathology of the Baló lesion shows (G) parenchymal rarefaction with perivascular inflammation, gliosis and macrophage infiltration (H&E). (H) LFB/PAS stain shows near absence of myelin with some myelin fragments in macrophages. (I) NFP stain shows relatively preserved axons.
Whether BCS and TD truly represent variants of each other or of more conventional multiple sclerosis is unclear and there is variability in the literature about what constitutes BCS or TD [4,5]. The pathology of Baló lesions and TD is generally similar to conventional demyelinating lesions [1]. Many otherwise typical cases of acute MS have small lesions at post-mortem that exhibit a partial concentric ring pattern (“partial Baló” lesions) [13], and so BCS may reflect an uncommon subtype of typical MS pathology. Smaller, more typical white matter lesions may accompany or can develop following either Baló or tumefactive lesions and a more typical MS course is common in this context. In due course it may be that some unification of these diagnoses is possible, but more research is needed. The co-existence of a Baló lesion and a tumefactive demyelinating lesion in our patient argues for at least a partly shared immunopathogenesis for these two subtypes of demyelination. Although our patient is yet to develop more typical demyelinating lesions, the presence of positive unmatched oligoclonal bands in the CSF likely increases her risk of developing typical relapsing remitting MS [5].
Author contributions TAH and MHB conceived the idea for the manuscript. TAH drafted the manuscript. All authors revised the manuscript critically for important intellectual content and gave final approval of the version to be published.
Study funding This work received no specific funding.
Conflict of interest The authors report no disclosures relevant to the manuscript.
References [1] Hu W, Lucchinetti CF. The pathological spectrum of CNS inflammatory demyelinating diseases. Semin Immunopathol Nov 2009;31(4):439–53. [2] Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain Jul 2008;131(Pt 7):1759–75. [3] Altintas A, Petek B, Isik N, Terzi M, Bolukbasi F, Tavsanli M, et al. Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study. Mult Scler Oct 2012;18(10):1448–53. [4] Hardy TA, Chataway J. Tumefactive demyelination: an approach to diagnosis and management. J Neurol Neurosurg Psychiatry Sep 2013;84(9):1047–53. [5] Hardy TA, Miller DH. Baló's concentric sclerosis. Lancet Neurol Jul 2014;13(7): 740–6. [6] Pilz G, Harrer A, Wipfler P, Oppermann K, Sellner J, Fazekas F, et al. Tumefactive MS lesions under fingolimod: a case report and literature review. Neurology Nov 5 2013; 81(19):1654–8. [7] Seifert CL, Wegner C, Sprenger T, Weber MS, Brück W, Hemmer B, et al. Favourable response to plasma exchange in tumefactive CNS demyelination with delayed B-cell response. Mult Scler Jul 2012;18(7):1045–9. [8] Berghoff M, Schlamann MU, Maderwald S, Grams AE, Kaps M, Ladd ME, et al. 7 tesla MRI demonstrates vascular pathology in Balo's concentric sclerosis. Mult Scler Jan 2013;19(1):120–2. [9] Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology Aug 1996;38(6):560–5. [10] Seewann A, Enzinger C, Filippi M, Barkhof F, Rovira A, Gass A, et al. MRI characteristics of atypical idiopathic inflammatory demyelinating lesions of the brain: a review of reported findings. J Neurol Jan 2008;255(1):1–10. [11] Kastrup O, Stude P, Limmroth V. Balo concentric sclerosis: evolution of active demyelination demonstrated by serial contrast enhanced MRI. J Neurol 2002;247: 811–4. [12] Ng SH, Ko SF, Cheung YC, Wong HF, Wan YL. MRI features of Balo's concentric sclerosis. Br J Radiol Apr 1999;72(856):400–3. [13] Barnett MH, Henderson AP, Prineas JW. The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult Scler Apr 2006; 12(2):121–32.
Please cite this article as: Hardy TA, et al, Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.11.024
Letter to the editor
3
Todd A. Hardy⁎ MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW, Australia Neuroimmunology Clinic, Concord Repatriation General Hospital, Sydney, NSW, Australia Corresponding author at: MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW 2050, Australia. Tel.: +61 2 93510730. E-mail address: [email protected].
Benjamin P. Jonker Department of Neurosurgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia Brain & Mind Research Institute, University of Sydney, NSW, Australia
Heidi N. Beadnall MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW, Australia Ian J. Sutton Department of Neurology, St Vincent's Hospital, Sydney, NSW, Australia
Michael H. Barnett MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW, Australia Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia Brain & Mind Research Institute, University of Sydney, NSW, Australia
Armin Mohamed Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
3 September 2014 Available online xxxx
Michael E. Buckland Brain & Mind Research Institute, University of Sydney, NSW, Australia Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Please cite this article as: Hardy TA, et al, Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.11.024
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the editor Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?
Keywords: Multiple sclerosis Pseudotumour Tumour-like Atypical Neuroinflammation
1. Case A 38-year-old female with a fifteen pack year smoking history woke with left lower limb focal motor seizures, weakness and gait disturbance. MRI of the brain showed an isolated, minimally-enhancing 1.5 cm, concentric lesion with surrounding oedema in the right superior frontal gyrus with a differential diagnosis including demyelination, glioma and infarction (Fig. 1A–C). She was commenced on carbamazepine CR 200 mg twice daily and tapering oral dexamethasone 4 mg twice daily and underwent stereotactic biopsy of the lesion a week later. Histopathology revealed increased foamy histiocytes, perivascular lymphoid cuffing, and areas of disproportionate myelin loss in some fragments consistent with demyelination, which together with the MRI appearance, favoured a diagnosis of BCS (Fig. 1G–I). Follow-up imaging one week after biopsy showed involution of the lesion without treatment and her leg weakness steadily improved and seizures resolved. MRI of the whole spine was normal. Six-months after her initial symptoms, she noticed incoordination of her left leg. Repeat MRI of the brain revealed a tumefactive periventricular white matter lesion in the left hemisphere with peripheral enhancement and perilesional vasogenic oedema consistent with tumefactive demyelination (Fig. 1D–F). Once again, there were no other lesions. Although assumed to be an incidental finding unrelated to her symptoms, she was treated with intravenous methylprednisolone 1 g daily for 3 days. CSF examination confirmed 8 unmatched oligoclonal bands not present in the serum. Repeat MRI of the whole spine was normal. Aquaporin 4 antibody, ANA, dsDNA, ANCA, ENA, lupus anticoagulant, anticardiolipin antibodies, serum paraproteins, ACE, ESR, CRP, treponemal serology, cryptococcal antigen and HIV were normal or negative. Visual evoked and somatosensory evoked potentials were normal. MRI of the brain 3 weeks later showed improvement in lesion size and enhancement. Disease modifying therapy with glatiramer acetate was commenced and she has had no further clinical or radiological relapses at 12 month follow-up. 2. Discussion Our patient underwent biopsy of a pseudotumoural, demyelinating concentric ring lesion in the right hemisphere consistent with BCS.
Given that there may be a better prognosis for patients who recover following a Baló lesion as a first demyelinating event compared to more conventional relapsing remitting MS [4], and that there was no initial supporting evidence of dissemination in space and time for a diagnosis of MS, disease modifying therapy was withheld until after the second lesion appeared. The patient's second episode of leg weakness was thought to be unrelated to the second lesion given its location in the ipsilateral cerebral hemisphere but clinical involvement of uncrossed corticospinal tract fibres, or decompensation of another contralateral pathway recruited after the first lesion, cannot be excluded. Evidence is lacking to guide appropriate therapy when MS is confirmed in the context of atypical demyelinating lesions, but initiation of a first line injectable such as glatiramer acetate or interferon beta appears reasonable [4,5], and glatiramer acetate was chosen with the patient in this case mainly due to its potentially favourable adverse effect profile. Experience with newer disease modifying therapies and atypical demyelinating lesions is particularly limited. An association between tumefactive demyelinating lesions and fingolimod has been noted in several case reports [6]. While this may reflect reporting bias, a cautious approach to the use of this agent in patients with large inflammatory demyelinating lesions is advised. If the effect is real, the mechanism of how fingolimod might trigger tumefactive lesions remains speculative. If, in susceptible individuals, a population of inhibitory immunoregulatory cells (e.g. CCR7neg T cells) were preferentially affected by fingolimod's action in reducing lymphocyte migration from peripheral lymph nodes, then failure of normal inhibitory mechanisms might be an explanation for the formation of large lesions [6]. Experience with natalizumab also remains limited but it has been used successfully in TD and BCS in case reports [7,8]. To our knowledge, this is the first case of a Baló lesion and a tumefactive demyelinating lesion being reported in the same patient, a phenomenon certainly not reported in large series of patients in which the radiology and pathology of tumefactive demyelination have been assessed [2,3,9]. It is interesting that both of these lesions developed without evidence of other more typical demyelinating lesions. There is no consensus definition as to how many concentric rings are required for a lesion to be considered BCS but some authors have suggested the use of the term “Baló-like lesions” to describe a concentric demyelinating lesion with ≥2 alternations on any MRI sequence [10]. BCS was originally described in post-mortem studies as a relentlessly progressive and fatal form of demyelination but studies in the MRI era have shown that Baló or Baló-like lesions can be associated with a more favourable prognosis. Hence, BCS appears to be defined by a wide spectrum of clinical severity [5]. It may be that some tumefactive lesions start out with a Baló appearance but that the alternating ring appearance is lost with time [11]. Thus, we cannot completely exclude that the second lesion in our patient did not develop into a tumefactive lesion after beginning as BCS. However, the lesions of BCS can hold their characteristic appearance for at least a year [12], and the second lesion appeared within only 6 weeks of the patient's last MRI scan.
http://dx.doi.org/10.1016/j.jns.2014.11.024 0022-510X/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Hardy TA, et al, Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.11.024
2
Letter to the editor
Fig. 1. Magnetic resonance imaging showing (A) axial fluid attenuated inversion recovery (FLAIR) image and (B) inset of a concentric Baló lesion in the right parietal lobe. (C) Sagittal T2 image of the Baló lesion. (D) Axial FLAIR image and (E) inset of a tumefactive demyelinating lesion occurring in the same patient in the left parietal lobe 6 months later. (F) Sagittal FLAIR image of the tumefactive lesion. Histopathology of the Baló lesion shows (G) parenchymal rarefaction with perivascular inflammation, gliosis and macrophage infiltration (H&E). (H) LFB/PAS stain shows near absence of myelin with some myelin fragments in macrophages. (I) NFP stain shows relatively preserved axons.
Whether BCS and TD truly represent variants of each other or of more conventional multiple sclerosis is unclear and there is variability in the literature about what constitutes BCS or TD [4,5]. The pathology of Baló lesions and TD is generally similar to conventional demyelinating lesions [1]. Many otherwise typical cases of acute MS have small lesions at post-mortem that exhibit a partial concentric ring pattern (“partial Baló” lesions) [13], and so BCS may reflect an uncommon subtype of typical MS pathology. Smaller, more typical white matter lesions may accompany or can develop following either Baló or tumefactive lesions and a more typical MS course is common in this context. In due course it may be that some unification of these diagnoses is possible, but more research is needed. The co-existence of a Baló lesion and a tumefactive demyelinating lesion in our patient argues for at least a partly shared immunopathogenesis for these two subtypes of demyelination. Although our patient is yet to develop more typical demyelinating lesions, the presence of positive unmatched oligoclonal bands in the CSF likely increases her risk of developing typical relapsing remitting MS [5].
Author contributions TAH and MHB conceived the idea for the manuscript. TAH drafted the manuscript. All authors revised the manuscript critically for important intellectual content and gave final approval of the version to be published.
Study funding This work received no specific funding.
Conflict of interest The authors report no disclosures relevant to the manuscript.
References [1] Hu W, Lucchinetti CF. The pathological spectrum of CNS inflammatory demyelinating diseases. Semin Immunopathol Nov 2009;31(4):439–53. [2] Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain Jul 2008;131(Pt 7):1759–75. [3] Altintas A, Petek B, Isik N, Terzi M, Bolukbasi F, Tavsanli M, et al. Clinical and radiological characteristics of tumefactive demyelinating lesions: follow-up study. Mult Scler Oct 2012;18(10):1448–53. [4] Hardy TA, Chataway J. Tumefactive demyelination: an approach to diagnosis and management. J Neurol Neurosurg Psychiatry Sep 2013;84(9):1047–53. [5] Hardy TA, Miller DH. Baló's concentric sclerosis. Lancet Neurol Jul 2014;13(7): 740–6. [6] Pilz G, Harrer A, Wipfler P, Oppermann K, Sellner J, Fazekas F, et al. Tumefactive MS lesions under fingolimod: a case report and literature review. Neurology Nov 5 2013; 81(19):1654–8. [7] Seifert CL, Wegner C, Sprenger T, Weber MS, Brück W, Hemmer B, et al. Favourable response to plasma exchange in tumefactive CNS demyelination with delayed B-cell response. Mult Scler Jul 2012;18(7):1045–9. [8] Berghoff M, Schlamann MU, Maderwald S, Grams AE, Kaps M, Ladd ME, et al. 7 tesla MRI demonstrates vascular pathology in Balo's concentric sclerosis. Mult Scler Jan 2013;19(1):120–2. [9] Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology Aug 1996;38(6):560–5. [10] Seewann A, Enzinger C, Filippi M, Barkhof F, Rovira A, Gass A, et al. MRI characteristics of atypical idiopathic inflammatory demyelinating lesions of the brain: a review of reported findings. J Neurol Jan 2008;255(1):1–10. [11] Kastrup O, Stude P, Limmroth V. Balo concentric sclerosis: evolution of active demyelination demonstrated by serial contrast enhanced MRI. J Neurol 2002;247: 811–4. [12] Ng SH, Ko SF, Cheung YC, Wong HF, Wan YL. MRI features of Balo's concentric sclerosis. Br J Radiol Apr 1999;72(856):400–3. [13] Barnett MH, Henderson AP, Prineas JW. The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult Scler Apr 2006; 12(2):121–32.
Please cite this article as: Hardy TA, et al, Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.11.024
Letter to the editor
3
Todd A. Hardy⁎ MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW, Australia Neuroimmunology Clinic, Concord Repatriation General Hospital, Sydney, NSW, Australia Corresponding author at: MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW 2050, Australia. Tel.: +61 2 93510730. E-mail address: [email protected].
Benjamin P. Jonker Department of Neurosurgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia Brain & Mind Research Institute, University of Sydney, NSW, Australia
Heidi N. Beadnall MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW, Australia Ian J. Sutton Department of Neurology, St Vincent's Hospital, Sydney, NSW, Australia
Michael H. Barnett MS Australia Clinic, Brain & Mind Research Institute, University of Sydney, NSW, Australia Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia Brain & Mind Research Institute, University of Sydney, NSW, Australia
Armin Mohamed Department of Neurology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
3 September 2014 Available online xxxx
Michael E. Buckland Brain & Mind Research Institute, University of Sydney, NSW, Australia Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Please cite this article as: Hardy TA, et al, Baló's concentric sclerosis and tumefactive demyelination: A shared immunopathogenesis?, J Neurol Sci (2014), http://dx.doi.org/10.1016/j.jns.2014.11.024
