International Journal of Neuroscience, 2014; Early Online: 1–8 Copyright © 2014 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2014.946563
ORIGINAL ARTICLE
Eccentric development of Balo’s concentric sclerosis: detected by magnetic resonance diffusion-weighted imaging and magnetic resonance spectroscopy Int J Neurosci Downloaded from informahealthcare.com by University of Washington on 11/19/14 For personal use only.
Feng Chen,1,2,∗ Tao Liu,3∗ Jianjun Li,2 Zengbao Xing,2 Shixiong Huang,3 Guoqiang Wen,3 and Guangming Lu1 1
Department of Medical Imaging, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China; 2 Departments of Radiology, People’s hospital of Hainan Province, Haikou 570311, China, and; 3 Departments of Neurology, People’s hospital of Hainan Province, Haikou 570311, China Background: The concentricity of BCS has captured wide attention; the findings of the current study may provide useful information on the centrifugal pathogenesis of BCS. Objective: This study aims to evaluate the performance of MRI, DWI and MRS in elucidating the pathogenesis of Balo’s lesions expanding. Methods: Six clinically diagnosed BCS cases were reviewed, and the findings obtained by MRI, DWI and MRS were analyzed. DWI data were available for six patients, with the DWI and ADC imaging locations being central and peripheral layers of the index lesion. At TE 144ms, we calculated metabolite ratios of MRS at different depths of the demyelinating lesions and compared with the lesion on the opposite normal side for two patients. Results: The ADC values of 18 typical concentric lesions revealed that the central lesion had the highest ADC value, followed by the internal ring, and the outermost layer had the lowest ADC value. The reduction in NAA/Cr and the increase in Cho/Cr were more evident in the central lesion than in the internal and outermost ring. Conclusion: The findings of DWI and MRS indicate Balo’s concentric rings develop gradually and centrifugally. Of course, this hypothesis remains to be proved by further experimental studies. KEYWORDS: Balo’s concentric sclerosis, diffusion-weighted imaging, magnetic resonance imaging, spectroscopy, pathogenesis
Introduction The dominant characteristics of Balo’s concentric sclerosis (BCS), a disease of brain white matter demyelinating, are lesions of alternating demyelinated and myelinated bands in the white matter [1,2]. Magnetic resonance imaging (MRI), if done at the start of this disease, enables the antemortem diagnosis of BCS, and therefore is of vital significance. Most studies focused on evaluating the performance of MRI in elucidating the pathogenesis of BCS. Despite the heavy attention to the concentricity of the lesions, the pathological mechanism underlying is far from clear. Instead of arising simultaneously, Balo’s concentric rings develop gradually and
Received 8 June 2014; revised 12 July 2014; accepted 16 July 2014 ∗
These authors contributed equally to this article. Correspondence: Guangming Lu, Department of Medical Imaging, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China. E-mail: [email protected]
centrifugally. Some researchers hold tissue preconditioning and outward expansion of BSC lesions to be the mechanism; however, other authors believe that the mechanism should be simultaneous multiple layers of ring enhancement or serpentine ring enhancement [3–5]. The present paper presented six cases clinically diagnosed with BCS through clinical findings and imaging. The findings of the current study may provide useful information on the centrifugal pathogenesis of BCS by combining MR diffusion weighted imaging (DWI) and magnetic resonance spectroscopy (MRS).
Materials and Methods Subjects This study was approved by the Human Research Committee of People’s Hospital of Hainan Province, and informed consent was obtained from every participant. Six 1
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F. Chen et al.
patients were enrolled in the Department of Neurology in our hospital for treatment from May 2005 to June 2013. The patients were diagnosed with BCS on the basis of clinical signs and symptoms of BCS, concentric rings on MR images, and absence of other neurologic diseases. The clinical data included a detailed history of existing symptoms, relevant past history and laboratory findings.
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MRI acquisition All the cases had undergone conventional MR imaging, including T1- and T2-weighted sequences images on a 1.5T clinical MRI scanner (Signa 1.5 T Twinspeed/Excite II, GE Company, USA). An eight-pathway head coil was used for MR scanning. The parameters used for conventional MR were as follows: axial T1 fluid-attenuated inversion recovery (FLAIR) sequence (TR = 1800 ms, TE = 24 ms, TI = 750 ms) T1WI, T2 FLAIR sequence (TR = 8002 ms, TE = 129 ms, TI = 2000 ms) T2WI, and fast recovery fast spin echo (TR = 3600 ms, TE = 102 ms) T2WI; matrix 128 × 128, FOV 24 cm × 24 cm, number of excitations 1, thickness of horizontal surface scanning layer 6 mm, and interval 2 mm. All patients were injected intravenously with 0.1 mmol/kg of gadopentetate meglumine, after which T1-enhanced scanning was carried out. The parameters of DWI data in 6 patients were as follows: The sequence was a single shot spin-echo EPI with TR 6000 ms, TE 75 ms, number of excitations 1 and matrix 128 × 128. Diffusion gradient field was applied in three vertical directions. Two diffusion gradients were used each time (b = 0 s/mm2 and b = 1000 s/mm2 ). Pixel was used as the unit to calculate the apparent diffusion coefficient (ADC) of each pixel point, producing ADC parametric image. 18 Lesions with typical concentric structures were selected. The central lesion, the internal ring, and the outermost layer were selected as regions of interest to record the ADC values respectively. The central area was regarded as the central lesion, the part of lesion displayed hypointense signal on T1WI, T2flair, DWI and hyperintense signal on T2WI and ADC images. The demyelinated areas that had the slightly high signal on T2WI, T2flair, DWI signal ring and slightly low signal on T1WI, ADC was adjacent to the central lesion as the internal ring. The corresponding area of the ring-enhanced lesion on enhanced T1WI as the outermost layer. ADC values in all regions of interest were calculated (Formulated in fig. 4, 8, 9 and 12). 3D multiple voxel 1H-MRS examination was performed in two patients. For 3D1 H-MRS, point sequence analysis (TR = 1000 ms, TE = 144 ms) was used to record the spectrum, with a transmitting frequency of 10, a phase of 10, a layer thickness of 10 mm, an interval of 10 mm, a vision of 16, and an average
water suppression of 98.6%. MRS data were sent to advantage work station. ADW 4.0 software and Functool 2 package were used to determine the aspartate/creatinine (NAA/Cr) and choline/creatinine (Cho/Cr) ratios in all regions of interest, respectively. The central lesion, the internal ring, and the outermost layer were selected as regions of interest to record NAA/Cr and Cho/Cr ratios. The ratios were compared with the contralateral normal side.
Statistics Statistical analyses were conducted by means of the Statistical Package for the Social Sciences (SPSS), version 16.0 (SPSS, Inc., Chicago, USA). ANOVA was used to compare differences of ADC values with different layers in concentric lesion. Due to multiple comparisons, significance was considered as the nominal p value < 0.01.
Results Clinical findings Six patients (3 males and 3 females) conclusively diagnosed with BCS were included. The clinical characteristics at presentation, investigation, and outcome at last follow-up are summarized in Table 1. The patients range in age from 21–45 years, with the mean being 35.8 ± 8.6 years. Two patients exhibited acute clinical onset of the disease, and 4, subacute. The presentation was polysymptomatic with the commonest presentation weak in six patients (100%) and aphasia in three (50%). None had antecedent febrile illness or recent vaccination. All the patients were negative in terms of vasculitis workup and retroviral serology. CSF routine and biochemical examinations were performed in all six patients, of whom four were normal, one exhibited increased leukocyte, and one showed increased protein. CSF analyses were negative for oligoclonal bands in all the cases. Visual evoked potentials were prolonged in three patients. After MRI scan had been finished, six patients were all treated with steroids while one patient was treated with immunoglobulin after steroid therapy. No patients had taken MS disease modifying therapies. Three patients made a complete recovery, two achieved a significant improvement, and one had an unsatisfactory recovery at last follow-up because of progressive course.
Imaging findings Conventional MRI, Gd-contrast enhanced MRI scanning, and DWI were carried out in all 6 patients. Multiple lesions were found, with a total of 55 lesions. Out of the 6 patients, ring or semi-ring enhancements were International Journal of Neuroscience
MRI in Balo’s concentric sclerosis Table 1.
Clinical characteristics, MRI findings, and outcome of BCS cases.
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Case (No.) Age(y)/sex 1
21/F
2
45/M
3
35/M
4
38/F
5
43/M
6
33/F
Onset symptoms
Investigations
Hemiparesis, right facial palsy
OCB absent, VEP normal, 35 white blood cells/ml in CSF Hemiparesis, agitation, OCB absent, VEP gross cognitive prolonged latencies impairment Sensory aphasia, OCB absent, VEP headache, memory normal impairment, quadriparesis Asymmetrical limb OCB absent, VEP weakness, numbness, prolonged dysarthria, dysphagia latencies, elevated protein (280 mg/dl) in CSF Hemiparesis, acute OCB absent, VEP Broca aphasia prolonged latencies Hemiparesis, numbness, acute Broca aphasia
OCB absent, VEP normal,
observed in 18 lesions through T1 enhanced scanning. Cranial MRI results showed that lesions mostly involved bilateral frontal and parietal lobes, corona radiata, and centrum ovale. Two cases involved posterior limb of internal capsule, 1 case involved left part of pons, and 1 case involved the right temporal pole. Characteristic lesions that favor MS include Dawson Fingers, ovoid lesions, corpus callosum lesions were not found. Typical MRI changes consist of concentric rings or a whorled appearance correspond with BCS were observed in all 6 cases (Figure 1A–B, 2A, 3A). The T1WI image of a typical concentric lesion showed hypointensity or isointensity (Figure 3B). Meanwhile, the T2WI image showed rings with alternating hyperintensity and hypointensity (Figure 2A). The isointensity rings were enhanced on Gd-contrast MRI (Figure 1B, 2C, 3C, 3D). In three patients, after therapies respectively for about 2 weeks, 1 month and 1 year rechecking lesions showed that the focal lesion had remarkably smaller on final MR imaging (Figure 1F, 3I). DWI was available for review in all six cases. It revealed one to five distinct concentric zones of varying diffusion characteristics in typical concentric lesions. In concentric lesions, a zone of increased signal intensity peripherally located was found on DWI images, and low signal intensity was observed at the center of the lesions in these cases, as shown on DWI images. On ADC maps, a well-defined outer zone of restricted diffusion was observed in six patients. This peripheral zone on diffusion imaging corresponded to the peripherally en C
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Number of Time to first concentric MRI lesions examination
Time to follow-up
Outcome
3
1 week
3 years, 10 months
Normal speech, Regained working ability
2
5 days
2 years, 11 months
Completely recovered
3
3 days
2 years, 8 months
Normal speech, return to physical work
1
1 week
2 months
Progressive disease. Patient died 2 months after onset symptoms
5
2 weeks
1 years, 2 weeks
4
1 month
1 years, 1 month
Slightly residual muscle strength, normal language Residual mild weakness, normal speech
hancing portion of the lesion on contrast-enhanced MR. In this type of concentric lesion, different layers showed different diffusion characteristics (Figure 1C, 1D, 2D, 2F, 3E). A gradual increase in the diffusion and facilitated diffusion in the center of the lesions were observed in all 18 lesions. The ADC maps (Figure 1E, 2E, 3F) of 18 typical concentric lesions revealed that the central lesion had the highest ADC value, followed by the internal ring. The outermost layer had the lowest ADC value. ANOVA was used to compare differences among the three groups. Significant differences were found among the three groups (F = 26.847, p = 0.000, Table 2). For Fig. 1, refer to case 6. 3D multiple voxel 1H-MRS was available for review in two patients. Regions of interest included four lesions with typical concentric pattern. MRS findings included lower NAA/Cr ratio and higher Cho/Cr ratio in the lesions compared with the normal contralateral mirror image voxel. The pattern of decreasing relative NAA/ Cr values on moving from periphery to the center was noted. The center of the lesions showed higher choline/Cr gradually diminished on moving toward the periphery of the lesions(Figure 3G, 3H).
Discussion BCS, which is a rare demyelinating disease, is a variant of multiple sclerosis [6], and has similar basic pathology to multiple sclerosis, only with a lamellar pattern as the
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Figure 1. (A) Axial T2-FLAIR shows concentric circle-like changes with alternating high and equal signals in bilateral corona radiata and left parietal. (B) Enhanced sagittal T1WI shows “C” shape and surrounding enhancement. (C) DWI shows alternating high and equal circular signals. (D) The green ROI shows slightly high signal ring on DWI as the internal ring adjacent to the central lesion. The red ROI shows the significantly high signal ring on DWI as the outermost ring. (E) ADC map shows the outermost ring having the lowest and the central lesion the highest ADC value. (F) After therapies for about 1 year rechecking T2-FLAIR, lesions were smaller obviously with unclear concentric performance. For fig. 1, refer to case 6.
exception [7]. BCS and MS like lesions are also known to coexist in the same patient [8]. The clinical course of BCS is highly variable. The common clinical features include headache, aphasia, hemiparesis, sensory disturbance, cognitive or behavioral dysfunction, and seizures. Traditionally, it has been considered to have a rapidly progressive fatal course, but with the advent of MRI, the mild and benign course has also been recognized [3,8–10]. Five cases of patients in this study had also benign courses with no relapse in the follow-up. The pathological characteristics observed are alternating rings of myelin preservation or remyelination and myelin loss, consistent with demyelination, which involve the cerebral hemispheres, cerebellum, brain stem, spinal cord and optic chiasm [11–13]. Formerly, the diagnosis of BCS was conducted on autopsy or histopathologically, based on the characteristic CNS lesions which consisted of concentric rings of demyelination alternating with myelinated white matter. Re-
cently, however, many patients are being diagnosed solely on the basis of characteristic MRI appearance without the need of biopsy and histopathological confirmation [3,8,9,14,15]. Characteristic MRI features include alternating bands of low and high signal in white matter as displayed on T2-weighted images, and the presence of concentric ring enhancement as displayed on postgadolinium T1-weighted images [3]. Mass effect and edema can also occur [15]. Diffusion-weighted findings with peripheral restricted diffusion has also been described [14]. In our case, the concentric pattern was seen on all MR sequence and even on T1-weighted image (Figure 3B) in which the perifocal edema had diminished similar to previously reported cases [4]. The contrast enhancement was heterogeneous in different rings or confined in the outermost ring (Figure 1B, 2C, 3C, 3D), which suggests that the active demyelinating in the concentric lesions takes place successively. These findings disagree with those reported by Kastrup et al. [5]. International Journal of Neuroscience
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MRI in Balo’s concentric sclerosis
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Figure 2. (A) Axial T2WI shows concentric circle–like changes with alternating high and equal circular signals
in bilateral frontal, parietal lobes. (B) The black ROI shows significantly high signal ring on T2WI as the central lesion, green ROI of slightly high T2WI signal as outermost ring, the red ROI region adjacent to the central lesion as internal ring with T2WI signal slightly higher than that of the outer ring and below the central lesion. (C) Enhanced T1WI shows circular and semi-circular enhancement on the edge of the lesions. (D) DWI shows alternating high and equal circular signals. (E) ADC map shows the outermost ring having the lowest and the central lesion the highest ADC value. (F) The green ROI on DWI as the outermost ring, red ROI as the central lesion, adjacent the central lesion as internal ring. For Fig. 2, refer to case 1.
The concentric pattern cannot always be observed if the MR imaging is not conducted in the early stage of the disease [16]. As far as the pathogenesis of this disease is concerned, there is much speculation, owing to the uniquely defining concentric pattern. One hypothesis is that the lesions begin at the central core, often a venule, from which the primary demyelination spreads out. Although the initial trigger of this disease remain unknown, it has been made clear that a centrifugally spreading band of lymphocytes or factors emanates from this initial site. The polarity of the demyelinating bands suggests that the demyelination is periodically reactivated and then fades in strength when it migrates from the center, rejuvenated on the arrival of the next bolus of activating substances. And the many cytokines, some undergoing periodic fluctuations in levels, are candidate modulators of immune activity [11]. However, this hypothesis is highly speculative. The data obtained by Chen et al. [13], who conducted serial C
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MR imaging for 5 patients with BCS, indicated that the concentric lesions did not occur simultaneously but developed gradually and centrifugally. These findings were not in agreement with those previously reported by Sekijima et al. [17]. It seems that Chen’s findings [13] are in gear with the preconditioning hypothesis made on the basis of pathological observation of upregulated protective factors in the outermost layers, findings which support a mechanism of tissue preconditioning and outward expansion of the concentric lesions. According to Stadelmann et al. [18], at the edge of active lesions, preconditioned oligodendrocytes, which express such protective proteins as hypoxia-inducible factor 1α and heat-shock protein 70, may be resistant to further damage at the edge of an expanding lesion and thus may cause the concentric preservation of myelin in BCS. Lucchinetti et al. [19] classified active MS lesions immunopathologically into four distinct subtypes. Pattern III shows unusual features where demyelination is
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Figure 3. (A) Axial T2-FLAIR shows concentric-like changes with alternating high and low signals in bilateral frontal lobe, centrum ovale, and left parietal lobe. (B) Axial T1WI shows a concentric circle–like shape with alternating equal and low signals. (C) Enhanced sagittal T1WI shows circular and semi-circular enhancement on the edge of the lesion. (D) Postcontrast T1WI image showing incomplete ring enhancement on the outermost ring (black arrowhead) and nonenhancement on the internal ring(white arrowhead). (E-G) Respectively shows Axial DWI, ADC map, TE 144ms Spectral analysis of regions of interest. (H).The reduction in N-acetyl aspartate/creatinine (NAA/Cr) and the increase in choline/creatinine (Cho/Cr) were more evident in the central lesion than in the internal and outermost ring. (I) After therapies for about 2 weeks rechecking T2-FLAIR, lesions were smaller obviously. For Fig. 3, refer to case 5.
not centered on inflamed vessels; instead, a rim of preserved myelin is observed around the vessels. Also it shows signs of distal oligodendrogliopathy with features of apoptosis. BCS lesion fits into pattern III(distal oligodendrogliopathy), characterized by microglial activation
and oligodendrocyte apoptosis. Recently, it is proposed that demyelination in these lesions resemble hypoxialike tissue injury is critical in Balo’s disease [18,20].This is supported by the diffusion-weighted finding with restricted diffusion in the periphery of the lesion [14]. International Journal of Neuroscience
MRI in Balo’s concentric sclerosis Table 2. ADC values of 18 typical concentric lesions (×10–3 mm2 /s).
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Concentric lesion (No.) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Central lesion
Internal ring
Outermost layer
1.51 1.29 1.42 1.26 1.75 1.81 1.37 2.10 1.72 1.18 1.72 1.48 1.90 1.87 1.69 1.33 1.84 1.48
1.27 1.45 1.10 1.65 0.981 0.887 1.35 1.52 1.33 1.28 1.39 1.38 1.49 1.56 1.61 1.02 1.59 1.25
0.863 1.24 0.968 1.41 0.94 1.32 1.02 0.858 0.795 0.658 1.33 0.942 0.953 1.08 1.23 0.856 1.12 0.952
Kavanagh et al. [15], in studying a case with Balo’s disease, also found alternating bands of restricted and unrestricted diffusion. Some researchers found increased diffusion in Balo’s lesions [21], but what Wiendl et al. [22] observed is markedly restricted diffusion on an ADC map of a very acute lesion the first day the neurological symptoms appeared, which, as exhibited on MRI, developed into Balo’s concentric lesions at day 14 after the onset of the disease. Such restricted diffusion shows that cytotoxic edema exists in acute inflammatory demyelinating lesions, which could be caused by myelin and oligodendroglia swelling, energy failure, and ischemia [23]. The diffusion analysis in our study, conducted in three regions of interest (Figure 1D, 2F, 3F), revealed a decreasing gradient of diffusion from the centre to the periphery of the lesion. This substantiates the hypothesis that outward expansion of the concentric lesions. Using serial proton MRS, some authors [3,24] found a decrease in the N-acetylaspartate (NAA)/creatine (Cr) ratio and an increase in the choline (Cho)/Cr ratio in BCS, which is in agreement with axonal loss, demyelination, and inflammatory cell infiltration, respectively, as seen in autopsied samples. Also, different microstructural changes were found at different depths of the lesion. NAA decreased in all the lesions. Additionally, the pattern of decreasing relative NAA values on moving from periphery to the center was noted. In the center of the lesions, the choline was higher and was observed to diminish gradually on moving towards the periphery of the lesions. In our series, differential changes of the typical spectroscopic pattern in metabolite peaks at pe C
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riphery and center of the lesions were observed. This observation is likely to indicate eccentric development of BCS. Berghoff et al. [25] found a pathological lactate peak of the lesion by using 3T MRS, which were suggestive of impaired aerobic metabolism in BCS. Balo’s concentric lesions are heterogeneous, which depends partly on the timing of MRI scanning, and Balo’s concentric rings already exist at the time of the first presentation in many MRI-confirmed cases. That Balo’s concentric rings expand outward gradually and stress proteins are induced in the outer, normalappearing white matter explain only a fraction of the cases with this condition or at the early stage of the disease. The findings of the current study may provide useful information on the centrifugal pathogenesis of BCS by combining MR-DWI and MRS. But this hypothesis is made on the basis of descriptive data and therefore remains to be proved by future experimental studies.
Declaration of Interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. The authors would like to thank the following funding sources: Hainan Natural Science Foundation 813201, Hainan Health Institution Project 2012PT06, Hainan Social Development Fundation SF201312, the National Natural Science Foundation of China 81260218, the National key clinical specialist construction Programs of China.
References 1. Yao DL, Webster HD, Hudson LD, et al. Concentric sclerosis (Balo): morphometric and in situ hybridization study of lesions in six patients. Ann Neurol 1994;35:18–30. 2. Kim MO, Lee SA, Choi CG, et al. Balo’s concentric sclerosis: a clinical case study of brain MRI, biopsy, and proton magnetic resonance spectroscopic findings. J Neurol Neurosurg Psychiatry 1997;62:655–658. 3. Karaarslan E, Altintas A, Senol U, et al. Balo’s concentric sclerosis: clinical and radiologic features of five cases. AJNR Am J Neuroradiol 2001;22:1362–1367. 4. Chaodong W, Zhang KN, Wu XM, et al. Balo’s disease showing benign clinical course and co-existence with multiple sclerosislike lesions in Chinese. Mult Scler 2008;14:418–424. 5. Kastrup O, Stude P, Limmroth V. Balo’s concentric sclerosis. Evolution of active demyelination demonstrated by serial contrast-enhanced MRI. J Neurol 2002;249:811–814. 6. Canellas AR, Gols AR, Izquierdo JR, et al. Idiopathic inflammatory-demyelinating diseases of the central nervous system. Neuroradiology 2007;49:393–409. 7. Nandini M, Gourie-Devi M, Shankar SK, et al. Balo’s concentric sclerosis diagnosed intravitam on brain biopsy. Clin Neurol Neurosurg 1993;95:303–309. 8. Li Y, Xie P, Fan X, et al. Balo’s concentric sclerosis presenting with benign clinical course and multiple sclerosis-like
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17. Sekijima Y, Tokuda T, Hashimoto T, et al. Serial magnetic resonance imaging (MRI) study of a patient with Balo’s concentric sclerosis treated with immunoadsorption plasmapheresis. Mult Scler 1997;2:291–294. 18. Stadelmann C, Ludwin S, Tabira T, et al. Tissue preconditioning may explain concentric lesions in Balo’s type of multiple sclerosis. Brain 2005;128:979–987. 19. Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717. 20. Lassmann H. Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci 2003;206:187–191. 21. Anschel DJ. Reply to the paper by Wiendl et al.: diffusion abnormality in Balo’s concentric sclerosis: clues for the pathogenesis. Eur Neurol 2006;55:111–112. 22. Wiendl H, Weissert R, Herrlinger U, et al. Diffusion abnormality in Balo’s concentric sclerosis: clues for the pathogenesis. Eur Neurol 2005;53:42–44. 23. Kira J. Astrocytopathy in Balo’s disease. Mult Scler 2011;17:771–779. 24. Chen CJ. Serial proton magnetic resonance spectroscopy in lesions of Balo concentric sclerosis. J Comput Assist Tomogr 2001;25:713–718. 25. Berghoff M, Schlamann MU, Maderwald S, et al. 7 Tesla MRI demonstrates vascular pathology in Balo’s concentric sclerosis. Mult Scler 2013;19:120–122.
International Journal of Neuroscience
ORIGINAL ARTICLE
Eccentric development of Balo’s concentric sclerosis: detected by magnetic resonance diffusion-weighted imaging and magnetic resonance spectroscopy Int J Neurosci Downloaded from informahealthcare.com by University of Washington on 11/19/14 For personal use only.
Feng Chen,1,2,∗ Tao Liu,3∗ Jianjun Li,2 Zengbao Xing,2 Shixiong Huang,3 Guoqiang Wen,3 and Guangming Lu1 1
Department of Medical Imaging, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China; 2 Departments of Radiology, People’s hospital of Hainan Province, Haikou 570311, China, and; 3 Departments of Neurology, People’s hospital of Hainan Province, Haikou 570311, China Background: The concentricity of BCS has captured wide attention; the findings of the current study may provide useful information on the centrifugal pathogenesis of BCS. Objective: This study aims to evaluate the performance of MRI, DWI and MRS in elucidating the pathogenesis of Balo’s lesions expanding. Methods: Six clinically diagnosed BCS cases were reviewed, and the findings obtained by MRI, DWI and MRS were analyzed. DWI data were available for six patients, with the DWI and ADC imaging locations being central and peripheral layers of the index lesion. At TE 144ms, we calculated metabolite ratios of MRS at different depths of the demyelinating lesions and compared with the lesion on the opposite normal side for two patients. Results: The ADC values of 18 typical concentric lesions revealed that the central lesion had the highest ADC value, followed by the internal ring, and the outermost layer had the lowest ADC value. The reduction in NAA/Cr and the increase in Cho/Cr were more evident in the central lesion than in the internal and outermost ring. Conclusion: The findings of DWI and MRS indicate Balo’s concentric rings develop gradually and centrifugally. Of course, this hypothesis remains to be proved by further experimental studies. KEYWORDS: Balo’s concentric sclerosis, diffusion-weighted imaging, magnetic resonance imaging, spectroscopy, pathogenesis
Introduction The dominant characteristics of Balo’s concentric sclerosis (BCS), a disease of brain white matter demyelinating, are lesions of alternating demyelinated and myelinated bands in the white matter [1,2]. Magnetic resonance imaging (MRI), if done at the start of this disease, enables the antemortem diagnosis of BCS, and therefore is of vital significance. Most studies focused on evaluating the performance of MRI in elucidating the pathogenesis of BCS. Despite the heavy attention to the concentricity of the lesions, the pathological mechanism underlying is far from clear. Instead of arising simultaneously, Balo’s concentric rings develop gradually and
Received 8 June 2014; revised 12 July 2014; accepted 16 July 2014 ∗
These authors contributed equally to this article. Correspondence: Guangming Lu, Department of Medical Imaging, Jinling Hospital, Nanjing Clinical School of Southern Medical University, Nanjing 210002, China. E-mail: [email protected]
centrifugally. Some researchers hold tissue preconditioning and outward expansion of BSC lesions to be the mechanism; however, other authors believe that the mechanism should be simultaneous multiple layers of ring enhancement or serpentine ring enhancement [3–5]. The present paper presented six cases clinically diagnosed with BCS through clinical findings and imaging. The findings of the current study may provide useful information on the centrifugal pathogenesis of BCS by combining MR diffusion weighted imaging (DWI) and magnetic resonance spectroscopy (MRS).
Materials and Methods Subjects This study was approved by the Human Research Committee of People’s Hospital of Hainan Province, and informed consent was obtained from every participant. Six 1
2
F. Chen et al.
patients were enrolled in the Department of Neurology in our hospital for treatment from May 2005 to June 2013. The patients were diagnosed with BCS on the basis of clinical signs and symptoms of BCS, concentric rings on MR images, and absence of other neurologic diseases. The clinical data included a detailed history of existing symptoms, relevant past history and laboratory findings.
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MRI acquisition All the cases had undergone conventional MR imaging, including T1- and T2-weighted sequences images on a 1.5T clinical MRI scanner (Signa 1.5 T Twinspeed/Excite II, GE Company, USA). An eight-pathway head coil was used for MR scanning. The parameters used for conventional MR were as follows: axial T1 fluid-attenuated inversion recovery (FLAIR) sequence (TR = 1800 ms, TE = 24 ms, TI = 750 ms) T1WI, T2 FLAIR sequence (TR = 8002 ms, TE = 129 ms, TI = 2000 ms) T2WI, and fast recovery fast spin echo (TR = 3600 ms, TE = 102 ms) T2WI; matrix 128 × 128, FOV 24 cm × 24 cm, number of excitations 1, thickness of horizontal surface scanning layer 6 mm, and interval 2 mm. All patients were injected intravenously with 0.1 mmol/kg of gadopentetate meglumine, after which T1-enhanced scanning was carried out. The parameters of DWI data in 6 patients were as follows: The sequence was a single shot spin-echo EPI with TR 6000 ms, TE 75 ms, number of excitations 1 and matrix 128 × 128. Diffusion gradient field was applied in three vertical directions. Two diffusion gradients were used each time (b = 0 s/mm2 and b = 1000 s/mm2 ). Pixel was used as the unit to calculate the apparent diffusion coefficient (ADC) of each pixel point, producing ADC parametric image. 18 Lesions with typical concentric structures were selected. The central lesion, the internal ring, and the outermost layer were selected as regions of interest to record the ADC values respectively. The central area was regarded as the central lesion, the part of lesion displayed hypointense signal on T1WI, T2flair, DWI and hyperintense signal on T2WI and ADC images. The demyelinated areas that had the slightly high signal on T2WI, T2flair, DWI signal ring and slightly low signal on T1WI, ADC was adjacent to the central lesion as the internal ring. The corresponding area of the ring-enhanced lesion on enhanced T1WI as the outermost layer. ADC values in all regions of interest were calculated (Formulated in fig. 4, 8, 9 and 12). 3D multiple voxel 1H-MRS examination was performed in two patients. For 3D1 H-MRS, point sequence analysis (TR = 1000 ms, TE = 144 ms) was used to record the spectrum, with a transmitting frequency of 10, a phase of 10, a layer thickness of 10 mm, an interval of 10 mm, a vision of 16, and an average
water suppression of 98.6%. MRS data were sent to advantage work station. ADW 4.0 software and Functool 2 package were used to determine the aspartate/creatinine (NAA/Cr) and choline/creatinine (Cho/Cr) ratios in all regions of interest, respectively. The central lesion, the internal ring, and the outermost layer were selected as regions of interest to record NAA/Cr and Cho/Cr ratios. The ratios were compared with the contralateral normal side.
Statistics Statistical analyses were conducted by means of the Statistical Package for the Social Sciences (SPSS), version 16.0 (SPSS, Inc., Chicago, USA). ANOVA was used to compare differences of ADC values with different layers in concentric lesion. Due to multiple comparisons, significance was considered as the nominal p value < 0.01.
Results Clinical findings Six patients (3 males and 3 females) conclusively diagnosed with BCS were included. The clinical characteristics at presentation, investigation, and outcome at last follow-up are summarized in Table 1. The patients range in age from 21–45 years, with the mean being 35.8 ± 8.6 years. Two patients exhibited acute clinical onset of the disease, and 4, subacute. The presentation was polysymptomatic with the commonest presentation weak in six patients (100%) and aphasia in three (50%). None had antecedent febrile illness or recent vaccination. All the patients were negative in terms of vasculitis workup and retroviral serology. CSF routine and biochemical examinations were performed in all six patients, of whom four were normal, one exhibited increased leukocyte, and one showed increased protein. CSF analyses were negative for oligoclonal bands in all the cases. Visual evoked potentials were prolonged in three patients. After MRI scan had been finished, six patients were all treated with steroids while one patient was treated with immunoglobulin after steroid therapy. No patients had taken MS disease modifying therapies. Three patients made a complete recovery, two achieved a significant improvement, and one had an unsatisfactory recovery at last follow-up because of progressive course.
Imaging findings Conventional MRI, Gd-contrast enhanced MRI scanning, and DWI were carried out in all 6 patients. Multiple lesions were found, with a total of 55 lesions. Out of the 6 patients, ring or semi-ring enhancements were International Journal of Neuroscience
MRI in Balo’s concentric sclerosis Table 1.
Clinical characteristics, MRI findings, and outcome of BCS cases.
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Case (No.) Age(y)/sex 1
21/F
2
45/M
3
35/M
4
38/F
5
43/M
6
33/F
Onset symptoms
Investigations
Hemiparesis, right facial palsy
OCB absent, VEP normal, 35 white blood cells/ml in CSF Hemiparesis, agitation, OCB absent, VEP gross cognitive prolonged latencies impairment Sensory aphasia, OCB absent, VEP headache, memory normal impairment, quadriparesis Asymmetrical limb OCB absent, VEP weakness, numbness, prolonged dysarthria, dysphagia latencies, elevated protein (280 mg/dl) in CSF Hemiparesis, acute OCB absent, VEP Broca aphasia prolonged latencies Hemiparesis, numbness, acute Broca aphasia
OCB absent, VEP normal,
observed in 18 lesions through T1 enhanced scanning. Cranial MRI results showed that lesions mostly involved bilateral frontal and parietal lobes, corona radiata, and centrum ovale. Two cases involved posterior limb of internal capsule, 1 case involved left part of pons, and 1 case involved the right temporal pole. Characteristic lesions that favor MS include Dawson Fingers, ovoid lesions, corpus callosum lesions were not found. Typical MRI changes consist of concentric rings or a whorled appearance correspond with BCS were observed in all 6 cases (Figure 1A–B, 2A, 3A). The T1WI image of a typical concentric lesion showed hypointensity or isointensity (Figure 3B). Meanwhile, the T2WI image showed rings with alternating hyperintensity and hypointensity (Figure 2A). The isointensity rings were enhanced on Gd-contrast MRI (Figure 1B, 2C, 3C, 3D). In three patients, after therapies respectively for about 2 weeks, 1 month and 1 year rechecking lesions showed that the focal lesion had remarkably smaller on final MR imaging (Figure 1F, 3I). DWI was available for review in all six cases. It revealed one to five distinct concentric zones of varying diffusion characteristics in typical concentric lesions. In concentric lesions, a zone of increased signal intensity peripherally located was found on DWI images, and low signal intensity was observed at the center of the lesions in these cases, as shown on DWI images. On ADC maps, a well-defined outer zone of restricted diffusion was observed in six patients. This peripheral zone on diffusion imaging corresponded to the peripherally en C
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Number of Time to first concentric MRI lesions examination
Time to follow-up
Outcome
3
1 week
3 years, 10 months
Normal speech, Regained working ability
2
5 days
2 years, 11 months
Completely recovered
3
3 days
2 years, 8 months
Normal speech, return to physical work
1
1 week
2 months
Progressive disease. Patient died 2 months after onset symptoms
5
2 weeks
1 years, 2 weeks
4
1 month
1 years, 1 month
Slightly residual muscle strength, normal language Residual mild weakness, normal speech
hancing portion of the lesion on contrast-enhanced MR. In this type of concentric lesion, different layers showed different diffusion characteristics (Figure 1C, 1D, 2D, 2F, 3E). A gradual increase in the diffusion and facilitated diffusion in the center of the lesions were observed in all 18 lesions. The ADC maps (Figure 1E, 2E, 3F) of 18 typical concentric lesions revealed that the central lesion had the highest ADC value, followed by the internal ring. The outermost layer had the lowest ADC value. ANOVA was used to compare differences among the three groups. Significant differences were found among the three groups (F = 26.847, p = 0.000, Table 2). For Fig. 1, refer to case 6. 3D multiple voxel 1H-MRS was available for review in two patients. Regions of interest included four lesions with typical concentric pattern. MRS findings included lower NAA/Cr ratio and higher Cho/Cr ratio in the lesions compared with the normal contralateral mirror image voxel. The pattern of decreasing relative NAA/ Cr values on moving from periphery to the center was noted. The center of the lesions showed higher choline/Cr gradually diminished on moving toward the periphery of the lesions(Figure 3G, 3H).
Discussion BCS, which is a rare demyelinating disease, is a variant of multiple sclerosis [6], and has similar basic pathology to multiple sclerosis, only with a lamellar pattern as the
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Figure 1. (A) Axial T2-FLAIR shows concentric circle-like changes with alternating high and equal signals in bilateral corona radiata and left parietal. (B) Enhanced sagittal T1WI shows “C” shape and surrounding enhancement. (C) DWI shows alternating high and equal circular signals. (D) The green ROI shows slightly high signal ring on DWI as the internal ring adjacent to the central lesion. The red ROI shows the significantly high signal ring on DWI as the outermost ring. (E) ADC map shows the outermost ring having the lowest and the central lesion the highest ADC value. (F) After therapies for about 1 year rechecking T2-FLAIR, lesions were smaller obviously with unclear concentric performance. For fig. 1, refer to case 6.
exception [7]. BCS and MS like lesions are also known to coexist in the same patient [8]. The clinical course of BCS is highly variable. The common clinical features include headache, aphasia, hemiparesis, sensory disturbance, cognitive or behavioral dysfunction, and seizures. Traditionally, it has been considered to have a rapidly progressive fatal course, but with the advent of MRI, the mild and benign course has also been recognized [3,8–10]. Five cases of patients in this study had also benign courses with no relapse in the follow-up. The pathological characteristics observed are alternating rings of myelin preservation or remyelination and myelin loss, consistent with demyelination, which involve the cerebral hemispheres, cerebellum, brain stem, spinal cord and optic chiasm [11–13]. Formerly, the diagnosis of BCS was conducted on autopsy or histopathologically, based on the characteristic CNS lesions which consisted of concentric rings of demyelination alternating with myelinated white matter. Re-
cently, however, many patients are being diagnosed solely on the basis of characteristic MRI appearance without the need of biopsy and histopathological confirmation [3,8,9,14,15]. Characteristic MRI features include alternating bands of low and high signal in white matter as displayed on T2-weighted images, and the presence of concentric ring enhancement as displayed on postgadolinium T1-weighted images [3]. Mass effect and edema can also occur [15]. Diffusion-weighted findings with peripheral restricted diffusion has also been described [14]. In our case, the concentric pattern was seen on all MR sequence and even on T1-weighted image (Figure 3B) in which the perifocal edema had diminished similar to previously reported cases [4]. The contrast enhancement was heterogeneous in different rings or confined in the outermost ring (Figure 1B, 2C, 3C, 3D), which suggests that the active demyelinating in the concentric lesions takes place successively. These findings disagree with those reported by Kastrup et al. [5]. International Journal of Neuroscience
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MRI in Balo’s concentric sclerosis
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Figure 2. (A) Axial T2WI shows concentric circle–like changes with alternating high and equal circular signals
in bilateral frontal, parietal lobes. (B) The black ROI shows significantly high signal ring on T2WI as the central lesion, green ROI of slightly high T2WI signal as outermost ring, the red ROI region adjacent to the central lesion as internal ring with T2WI signal slightly higher than that of the outer ring and below the central lesion. (C) Enhanced T1WI shows circular and semi-circular enhancement on the edge of the lesions. (D) DWI shows alternating high and equal circular signals. (E) ADC map shows the outermost ring having the lowest and the central lesion the highest ADC value. (F) The green ROI on DWI as the outermost ring, red ROI as the central lesion, adjacent the central lesion as internal ring. For Fig. 2, refer to case 1.
The concentric pattern cannot always be observed if the MR imaging is not conducted in the early stage of the disease [16]. As far as the pathogenesis of this disease is concerned, there is much speculation, owing to the uniquely defining concentric pattern. One hypothesis is that the lesions begin at the central core, often a venule, from which the primary demyelination spreads out. Although the initial trigger of this disease remain unknown, it has been made clear that a centrifugally spreading band of lymphocytes or factors emanates from this initial site. The polarity of the demyelinating bands suggests that the demyelination is periodically reactivated and then fades in strength when it migrates from the center, rejuvenated on the arrival of the next bolus of activating substances. And the many cytokines, some undergoing periodic fluctuations in levels, are candidate modulators of immune activity [11]. However, this hypothesis is highly speculative. The data obtained by Chen et al. [13], who conducted serial C
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MR imaging for 5 patients with BCS, indicated that the concentric lesions did not occur simultaneously but developed gradually and centrifugally. These findings were not in agreement with those previously reported by Sekijima et al. [17]. It seems that Chen’s findings [13] are in gear with the preconditioning hypothesis made on the basis of pathological observation of upregulated protective factors in the outermost layers, findings which support a mechanism of tissue preconditioning and outward expansion of the concentric lesions. According to Stadelmann et al. [18], at the edge of active lesions, preconditioned oligodendrocytes, which express such protective proteins as hypoxia-inducible factor 1α and heat-shock protein 70, may be resistant to further damage at the edge of an expanding lesion and thus may cause the concentric preservation of myelin in BCS. Lucchinetti et al. [19] classified active MS lesions immunopathologically into four distinct subtypes. Pattern III shows unusual features where demyelination is
F. Chen et al.
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Figure 3. (A) Axial T2-FLAIR shows concentric-like changes with alternating high and low signals in bilateral frontal lobe, centrum ovale, and left parietal lobe. (B) Axial T1WI shows a concentric circle–like shape with alternating equal and low signals. (C) Enhanced sagittal T1WI shows circular and semi-circular enhancement on the edge of the lesion. (D) Postcontrast T1WI image showing incomplete ring enhancement on the outermost ring (black arrowhead) and nonenhancement on the internal ring(white arrowhead). (E-G) Respectively shows Axial DWI, ADC map, TE 144ms Spectral analysis of regions of interest. (H).The reduction in N-acetyl aspartate/creatinine (NAA/Cr) and the increase in choline/creatinine (Cho/Cr) were more evident in the central lesion than in the internal and outermost ring. (I) After therapies for about 2 weeks rechecking T2-FLAIR, lesions were smaller obviously. For Fig. 3, refer to case 5.
not centered on inflamed vessels; instead, a rim of preserved myelin is observed around the vessels. Also it shows signs of distal oligodendrogliopathy with features of apoptosis. BCS lesion fits into pattern III(distal oligodendrogliopathy), characterized by microglial activation
and oligodendrocyte apoptosis. Recently, it is proposed that demyelination in these lesions resemble hypoxialike tissue injury is critical in Balo’s disease [18,20].This is supported by the diffusion-weighted finding with restricted diffusion in the periphery of the lesion [14]. International Journal of Neuroscience
MRI in Balo’s concentric sclerosis Table 2. ADC values of 18 typical concentric lesions (×10–3 mm2 /s).
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Concentric lesion (No.) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Central lesion
Internal ring
Outermost layer
1.51 1.29 1.42 1.26 1.75 1.81 1.37 2.10 1.72 1.18 1.72 1.48 1.90 1.87 1.69 1.33 1.84 1.48
1.27 1.45 1.10 1.65 0.981 0.887 1.35 1.52 1.33 1.28 1.39 1.38 1.49 1.56 1.61 1.02 1.59 1.25
0.863 1.24 0.968 1.41 0.94 1.32 1.02 0.858 0.795 0.658 1.33 0.942 0.953 1.08 1.23 0.856 1.12 0.952
Kavanagh et al. [15], in studying a case with Balo’s disease, also found alternating bands of restricted and unrestricted diffusion. Some researchers found increased diffusion in Balo’s lesions [21], but what Wiendl et al. [22] observed is markedly restricted diffusion on an ADC map of a very acute lesion the first day the neurological symptoms appeared, which, as exhibited on MRI, developed into Balo’s concentric lesions at day 14 after the onset of the disease. Such restricted diffusion shows that cytotoxic edema exists in acute inflammatory demyelinating lesions, which could be caused by myelin and oligodendroglia swelling, energy failure, and ischemia [23]. The diffusion analysis in our study, conducted in three regions of interest (Figure 1D, 2F, 3F), revealed a decreasing gradient of diffusion from the centre to the periphery of the lesion. This substantiates the hypothesis that outward expansion of the concentric lesions. Using serial proton MRS, some authors [3,24] found a decrease in the N-acetylaspartate (NAA)/creatine (Cr) ratio and an increase in the choline (Cho)/Cr ratio in BCS, which is in agreement with axonal loss, demyelination, and inflammatory cell infiltration, respectively, as seen in autopsied samples. Also, different microstructural changes were found at different depths of the lesion. NAA decreased in all the lesions. Additionally, the pattern of decreasing relative NAA values on moving from periphery to the center was noted. In the center of the lesions, the choline was higher and was observed to diminish gradually on moving towards the periphery of the lesions. In our series, differential changes of the typical spectroscopic pattern in metabolite peaks at pe C
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riphery and center of the lesions were observed. This observation is likely to indicate eccentric development of BCS. Berghoff et al. [25] found a pathological lactate peak of the lesion by using 3T MRS, which were suggestive of impaired aerobic metabolism in BCS. Balo’s concentric lesions are heterogeneous, which depends partly on the timing of MRI scanning, and Balo’s concentric rings already exist at the time of the first presentation in many MRI-confirmed cases. That Balo’s concentric rings expand outward gradually and stress proteins are induced in the outer, normalappearing white matter explain only a fraction of the cases with this condition or at the early stage of the disease. The findings of the current study may provide useful information on the centrifugal pathogenesis of BCS by combining MR-DWI and MRS. But this hypothesis is made on the basis of descriptive data and therefore remains to be proved by future experimental studies.
Declaration of Interest The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper. The authors would like to thank the following funding sources: Hainan Natural Science Foundation 813201, Hainan Health Institution Project 2012PT06, Hainan Social Development Fundation SF201312, the National Natural Science Foundation of China 81260218, the National key clinical specialist construction Programs of China.
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