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. 2006 Aug 4;16(3):202–208. doi: 10.1111/j.1750-3639.2006.00018.x

Spinal Cord Gray Matter Demyelination in Multiple Sclerosis—A Novel Pattern of Residual Plaque Morphology

Christopher P Gilmore 1,✉, Lars Bö 2,3, Trudy Owens 4, James Lowe 5, Margaret M Esiri 6, Nikos Evangelou 1
PMCID: PMC8095912  PMID: 16911477

Abstract

The extent and pattern of gray matter (GM) demyelination in the spinal cord in multiple sclerosis (MS) has not been examined in detail. Human autopsy material was obtained from 36 MS cases and 12 controls. Transverse sections were taken from five levels of the spinal cord (upper cervical, lower cervical, upper thoracic, lower thoracic and lumbar levels) and the extent of GM and white matter (WM) demyelination evaluated using proteolipid protein immunohistochemistry (IHC). The proportion of the GM that was demyelinated (33%) was significantly greater than the proportion of demyelinated WM (20%) (P < 0.0001). Similarly, demyelination was more extensive in the GM than in the WM at each of the five cord levels. The extent of GM demyelination was not significantly different between the five cord levels while WM demyelination was greatest at the upper cervical level. Morphologically, the borders of a proportion of the GM plaques show a strict respect for the GM/WM boundary. We demonstrate that extensive demyelination occurs in the GM of the spinal cord in MS. Myelin protein IHC reveals a novel pattern of residual plaque morphology challenging previous work suggesting that MS plaques display a total disregard for anatomical boundaries.

INTRODUCTION

The spinal cord is a common site for pathology in multiple sclerosis (MS). Involvement of this clinically eloquent area contributes substantially to motor, sensory and sphincter disturbance in both relapsing and progressive forms of the disease.

The topographic distribution of MS plaques in the spinal cord has been examined using histochemical staining techniques 11, 29. These studies suggest that plaques predominantly involve the white matter (WM), although they frequently impinge on the gray matter (GM), displaying a total disregard for anatomical boundaries, including the GM/WM boundary 11, 29, 31. However, spinal cord GM lesions have not been examined in detail.

The “gold standard” technique for detecting GM demyelination is myelin protein immunohistochemistry (IHC), which has been used to demonstrate that the cerebral cortex is a predilection site for MS plaques (4). In this study we use myelin protein IHC to assess the extent and pattern of GM demyelination in the spinal cord in MS. Further, we compare the utility of a conventional myelin stain (Luxol fast blue, LFB) with IHC in detecting myelin loss in this area.

MATERIALS AND METHODS

Clinical material.  Human autopsy material was obtained from 36 pathologically confirmed cases of MS and 12 controls. This material was derived from the neuropathology department, Oxford Radcliffe NHS Trust. The cases were selected at random from a collection of 55 MS cases and 33 controls studied previously 7, 8, 9, 16. The MS patients (16 men, 20 women) were aged 32–79 years (mean 59 years, median 58 years) with a disease duration of 2–43 years (mean 16 years, median 15 years). We do not have detailed clinical information regarding clinical disability or MS subtype. As reported previously, the majority of patients are likely to have had secondary progressive MS (9). The controls (six men, six women), aged 33–77 years (mean 59 years, median 63 years), had no clinical or pathological evidence of spinal cord disease. The local research ethics committee approved the study.

Preparation of the sections.  For each of the MS and control cases 6 µm formalin‐fixed paraffin‐embedded transverse sections were taken from five predetermined levels of the spinal cord (upper cervical, lower cervical, upper thoracic, lower thoracic and lumbar levels).

Immunohistochemistry.  Sections were stained for proteolipid protein (PLP) using the EnVision method (DAKO EnVision kit, Dako, Glostrup, Denmark). Sections were deparaffinated in a series of xylene, 100% alcohol, 96% alcohol, 70% alcohol and water, washed with phosphate‐buffered saline (PBS), and incubated with the primary antibody for 60 minutes at room temperature. After washing in PBS the sections were incubated for 30 minutes with the pre‐diluted Envision‐HRP complex and washed again in PBS. The sections were then developed for 10 minutes with diaminobenzidine (dilution 1:50), washed in tap water and dehydrated in alcohol 70% to 100%, and xylene. The primary antibody used was mouse anti‐myelin PLP (IgG2a, clone number plpc1, dilution 1:3000, MCA839G, Serotec Ltd., Oxford, UK).

Histochemical staining.  In order to compare LFB‐ and PLP‐staining for detecting GM demyelination in the spinal cord, 30 sections were stained with Luxol fast blue Cresyl Violet using a protocol described previously (25).

Measurement of GM and WM lesions.  The PLP‐stained sections were scanned in a slide scanner (Nikon Super Coolscan 4000, Nikon UK Ltd., Kingston upon Thames, UK) to produce a digital image. Using these images the MS lesions were manually outlined using image analysis software (“AnalySIS Pro” running SIS software, Olympus UK Ltd., Southall, UK). Lesions were defined as sharply demarcated areas, characterized by either complete myelin loss or markedly reduced myelin density in comparison to comparable anatomical areas in the control cases (Figure 1D–K). Areas of demyelinated GM and WM were measured separately. In addition, the cross‐sectional areas of the spinal cords and the cross‐sectional GM areas were measured in order to calculate the proportion of GM that was demyelinated (PGMd) and the proportion of WM that was demyelinated (PWMd). The PLP‐stained sections, examined via microscopy (10x, Leitz Dialux 20EB microscope, Leica Microsystems, Wetzler, Germany), were used as a reference to help identify the MS lesions and the GM boundaries.

Figure 1.

Figure 1

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Paraffin sections from control (A–C) and multiple sclerosis (MS) spinal cords (D–K), immunohistochemically stained with anti‐proteolipid protein antibody. A. Staining in the non‐diseased cord demonstrating a paucity of myelin in the gray matter (GM) commissure (solid box, shown at higher magnification in panel B) and the Substantia Gelatinosa (dashed box, panel C). D,E. The GM/white matter (WM) boundary (black line) and MS lesions (shaded) are outlined; this section contains one pure GM lesion and one mixed GM/WM lesion. F–K. Higher magnification images demonstrating areas of completely demyelinated GM (F), markedly reduced myelin density in the GM (G), myelinated GM (H), completely demyelinated WM (I), markedly reduced myelin density in the WM (J) and myelinated WM (K). The scale bars in B and C represent 500 µm; in F–K they represent 50 µm.

Statistical analysis.  Paired t‐tests were used to compare PGMd with PWMd. Correlations between PGMd and PWMd were assessed using Spearman’s ranked test. Multiple regression analyses were used to examine the influence of age, sex and cord location on PGMd and PWMd (“Stata” version 9, StataCorp, College Station, TX, USA).

RESULTS

PLP Immunohistochemistry.  The distribution of myelin in the GM of the non‐diseased human spinal cord has been described using histochemical staining (32). Consistent with this study we found considerable regional variation in myelin density within the GM, with a paucity of myelinated fibres in the Substantia Gelatinosa of the dorsal horns and in the GM commissure (Figure 1A–C). By examining a large amount of control tissue (60 sections from 12 cases) we were able to define the “normal limits” of myelin staining density within these areas. No demyelinated lesions were detected in the GM or WM of the control cases.

Lesion counts.  In the 150 sections studied from the 36 MS cases, 262 demyelinated lesions were detected in the WM and 194 lesions were detected in the GM. Eighty‐six of the 262 WM lesions (33%) were restricted to the WM and did not impinge on the GM. 43 of the 194 GM lesions (22%) were restricted to the GM and did not involve the WM. It has previously been reported that the vast majority of lesions in this spinal cord material are inactive (8). In keeping with this we observed evidence of ongoing demyelination (ie, macrophages containing LFB‐ or PLP‐inclusions) in only four lesions (two WM lesions and two mixed GM/WM lesions).

Demyelination is more extensive in the GM than the WM of the spinal cord.  PGMd (mean 33.3%) was significantly greater than PWMd (19.7%) (P < 0.0001). Similarly, when the five cord levels were analysed separately, PGMd was greater than PWMd at the upper cervical (P = 0.0247), lower cervical (P = 0.0751), upper thoracic (P = 0.0001), lower thoracic (P = 0.0003) and lumbar (P = 0.0021) levels (Figure 2). There was a significant correlation between PGMd and PWMd (r = 0.8316, P < 0.0001).

Figure 2.

Figure 2

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Bar chart of proportion of gray matter (GM) and white matter (WM) that is demyelinated at different levels of the spinal cord. UC = upper cervical; LC = lower cervical; UT = upper thoracic; LT = lower thoracic; Lum = lumbar. Values represent mean ± standard error.

PWMd was highest at the upper cervical level (31.8%). To examine this further PWMd was regressed on the cord level controlling for sex, age and disease duration. In comparison with the upper cervical level, PWMd was significantly reduced at the lower thoracic (coefficient of regression = −0.1514, P = 0.036, that is, controlling for other variables, PWMd was on average 15% greater at the upper cervical than the lower thoracic level) and lumbar (coefficient of regression = −0.2163, P = 0.001) levels. In addition, there was a trend towards significant reductions at the lower cervical (coefficient of regression = −0.1391, P = 0.054) and upper thoracic (coefficient of regression =−0.1421, P = 0.053) levels.

In comparison to the upper cervical cord, and controlling for other variables, cord level did not appear to have a significant influence on PGMd (lower cervical coefficient of regression = −0.1771, P = 0.079, upper thoracic coefficient of regression =−0.0326, P = 0.759, lower thoracic coefficient of regression = −0.0765, P = 0.471, lumbar coefficient of regression =−0.1420, P = 0.198).

The relative volumes of WM and GM vary between the different levels of the spinal cord. We control for this variation by assessing the proportion of the tissue that is demyelinated, rather than the absolute area. We note that the absolute area of demyelinated WM was greater than the area of demyelinated GM, simply reflecting the substantially greater volume of WM in the cord.

Influence of age, sex and disease duration on extent of demyelination.  Age (coefficient of regression = −0.0095, P < 0.001) appeared to have a significant influence on PWMd, with younger patients having greater WM demyelination. There was a trend for gender to influence PWMd, with demyelination being more extensive in men (coefficient of regression = 0.0870, P = 0.055). Disease duration did not significantly influence PWMd (coefficient of regression = 0.0034, P = 0.140).

Both age (coefficient of regression =−0.0087, P = 0.001) and gender (coefficient of regression = 0.1326, P = 0.043) appeared to have a significant influence on PGMd, while disease duration did not (coefficient of regression = 0.0047, P = 0.225).

Lesion morphology.  A large number of WM lesions show a similar morphology to those described previously using conventional staining techniques 11, 29. Predilection sites include the central portion of the posterior columns and the lateral columns, where the plaques frequently have a wedge‐shaped outline in transverse section and impinge on the GM (Figure 3A–C).

Figure 3.

Figure 3

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Paraffin sections from multiple sclerosis (MS) spinal cords stained with anti‐proteolipid protein (PLP) antibodies (A–E, H–J) and Luxol fast blue (LFB) (F, G, K). A–C. Many MS plaques show a similar morphology to those described previously using conventional staining techniques. The principal predilection sites for white matter (WM) plaques are the central portion of the posterior columns (A) and wedge‐shaped plaques in the lateral columns which frequently extend laterally to the pial surface of the cord and medially to the gray matter (GM), displaying a complete disregard for the GM/WM boundary (B). C. In a number of cases lesions show a striking symmetry about the midline. A proportion of mixed GM/WM (D,F) and pure GM lesions (H,J,K) appear to “expand” within the GM while maintaining a strict respect for the GM/WM boundary. D,F. Lesion morphology demonstrated using both PLP‐ and LFB‐staining. E,G. Higher magnification images from panels D and F (boxes) demonstrate complete demyelination of the GM commissure with sparing of the adjacent WM. H. Lesion involving the entire right anterior horn, respecting the GM/WM boundary, and extending to the contra‐lateral GM horn via the GM commissure. I. High magnification image from panel H (box). J,K. The GM lesion on the left respects the GM/WM boundary. The dashed lines represent the GM/WM boundaries. Scale bars (E, G, I) represent 150 µm.

Within the GM, plaques showed no obvious preponderance for any particular region; lesions frequently involved the anterior horns, posterior horns and the GM commissure, often in combination. In a number of cases a proportion of the border of the GM plaque maintains a strict respect for the GM/WM boundary. This pattern of residual plaque morphology, which has not been described previously, was observed in both mixed GM/WM lesions and pure GM lesions (Figure 3D–K).

The sensitivity of Luxol fast blue for detecting GM demyelination.  For a number of the PLP‐stained sections (n = 30), adjacent sections were stained with LFB to evaluate the utility of this stain for detecting GM demyelination in the spinal cord. These sections were selected to include a range of patterns of demyelination as demonstrated using the PLP staining. Lesion morphology was more readily appreciated using myelin protein IHC, which provided greater contrast between the myelinated and demyelinated tissue. However, all of the areas of GM demyelination were detected by thorough examination of the LFB‐stained sections at high magnification, particularly when informed by the PLP‐stained sections (Figure 4).

Figure 4.

Figure 4

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Paraffin sections from MS spinal cords stained with anti‐proteolipid protein (PLP) antibodies (A,C,E,G,I) alongside adjacent sections stained with Luxol fast blue (B,D,F,H,J respectively). Lesion morphology is more readily appreciated using immunohistochemistry, with the PLP‐stained sections demonstrating greater contrast between the myelinated and demyelinated gray matter (GM). C,D. Higher magnification images from panels A and B (boxes). E,F. Pure GM plaque, also shown at high magnification (G,H). I,J. Demyelination of the GM commissure is more clearly delineated using PLP‐staining. Scale bars (C,D,G,H) represent 500 µm.

DISCUSSION

We use myelin protein IHC to assess the extent and pattern of GM demyelination in the spinal cord in MS. The percentage of demyelinated GM was greater than the percentage of demyelinated WM, further challenging the view that MS is a predominantly WM disease. Our results suggest that GM demyelination in the spinal cord (mean 33.3%, median 17.2%) is at least as extensive as reported for the cerebral cortex (mean 26.5%, median 14%) (4).

The cervical cord is often described as a predilection site for MS plaques. Oppenheimer reported that approximately 90% of sections from the upper and lower cervical cord show MS lesions, in comparison with 46% of thoracic and 41% of lumbar cord sections 11, 29. The cross‐sectional area of the spinal cord is greatest at the lower cervical level; by correcting for this (ie, by considering the proportion of demyelinated WM) our results suggest that the lower cervical cord is no more of a predilection site for WM demyelination than the thoracic or lumbar levels. We find no significant difference in the extent of GM demyelination between cord levels.

Our results suggest that gender influences the extent of both WM and GM demyelination with more extensive demyelination being evident in men. There is little evidence suggesting differences in MRI lesion loads in the brain between male and female MS patients. In a study of secondary progressive MS, Li et al reported that male patients had greater T2 lesion loads than female patients, although women showed a greater accumulation of gadolinium‐enhancing lesions over the subsequent 3 years (24). MS tends to run a more aggressive course in male patients (36) and there is some evidence from post‐mortem studies that axonal loss in the spinal cord is more severe in males (13). However, interpretation of our finding is limited; because of a lack of clinical information the multiple regression analysis does not control for MS clinical subtype, which has been reported to influence lesion load in imaging studies (28).

MS patients that die soon after diagnosis, or at a younger age, may tend to have more aggressive disease. This may explain our observation that age appears to influence the extent of WM and GM demyelination, whereas disease duration does not. It is less likely that spinal cord lesion load reaches a plateau after a short time period following which disease duration has little influence on demyelinated area; longitudinal imaging studies indicate that T2 lesion load measures in the brain increase over time, even between 10 and 14 years disease duration (6). An additional consideration when interpreting post‐mortem studies is that plaques may have undergone several phases of evolution (ie, demyelination, remyelination and repeated demyelination). This may be particularly relevant in cases with long disease durations. Consistent with our finding that younger patients show more extensive myelin loss, Tedeschi et al report that a younger age of onset is associated with an increased WM lesion load on brain imaging (34).

There are limitations to using single sections to examine lesion topology and it is possible that a proportion of “pure” GM lesions expand into the WM as the plaque extends in cranial and caudal directions. However, our study suggests that the majority of GM lesions in the spinal cord are mixed GM/WM lesions. In contrast the majority of cortical lesions lie entirely within GM (4). In keeping with these observations we find a strong correlation between the degree of GM and WM demyelination in the spinal cord, while there is no such correlation in the forebrain (21).

Many MS plaques are seen on the course of small veins and venules (11). However, we demonstrate that in a number of cases a proportion of the border of the GM plaque maintains a strict respect for the GM/WM boundary. This pattern of plaque morphology, which has not been described previously, does not occur in a purely “perivenular” distribution. These plaques show similarities to the type IV lesions of the cerebral cortex, the borders of which correspond exactly to the GM/WM boundary, without involvement of the subcortical WM (4). The majority of MS plaques in our series are likely to be longstanding lesions. It is therefore unclear whether the pattern of residual plaque morphology that we observe at autopsy reflects the morphology of the demyelinating lesion per se, or demyelination with subsequent remyelination of the WM, but not the GM, portion of the lesion.

There may be differences in the glial‐cell environment between GM and WM which predispose to extensive GM demyelination with sparing of the adjacent WM. For example, there are phenotypical differences between inflammatory cells in WM lesions and those in the GM; the majority of MHC class II‐positive cells in active WM plaques are macrophages, while those in cortical GM lesions have the morphology of microglia (30). There are also phenotypical differences between astrocytes in WM and GM (17) and it is possible that there are similar differences related to the oligodendrocyte‐myelin complex. There is evidence that the topography of lesions in experimental autoimmune encephalomyelitis is determined, in part, by the target auto‐antigen. T cells that recognize myelin basic protein or PLP induce disease predominantly affecting areas with thick myelin sheaths, while myelin associated glycoprotein‐ or myelin oligodendroglia glycoprotein‐induced disease primarily involves areas containing numerous thin myelin sheaths 1, 22. Interestingly, T cells specific for glial fibrillary acidic protein or the non‐myelin auto‐antigen S100β, a calcium binding protein expressed and secreted by astrocytes, mediate inflammation which is more pronounced in the GM than the WM 1, 19.

There is evidence that the drainage pathway of interstitial fluid from cortical GM is different to that from the subcortical WM, prompting suggestions that type IV lesions may be generated by a myelinotoxic factor in the interstitial fluid 4, 37. Similarly, Gay has suggested that a myelinolytic antigen may circulate within the Virchow–Robin spaces and the cerebrospinal and extracellular fluid compartments of the central nervous system, mediating demyelination in perivascular, periventricular and subpial locations (14). Interstitial fluid drainage pathways have not been studied in detail in the spinal cord; if there are differences between the GM and WM in terms of the clearance of interstitial fluid, along with any associated myelinotoxic agents, one may expect a proportion of MS plaques to respect the GM/WM boundary as observed in our study.

Alternatively, the GM may have a relatively poor ability to remyelinate in comparison to the WM, due to numerical or functional differences in oligodendrocyte precursors between GM and WM. Although LFB‐staining may reveal remyelinated plaques by demonstrating abnormally thin myelin sheaths, remyelination is more reliably assessed using electron microscopy or Toluidine blue‐stained resin sections. Therefore, while the WM immediately adjacent to the GM plaques appears normal on the LFB‐ and PLP‐stained sections (Figure 3), we acknowledge that the possibility of remyelination in these areas cannot be ruled out. There is evidence that GM lesions show a reduced number of inflammatory cells in comparison to WM plaques 3, 18, 30, although this has not been demonstrated in the spinal cord specifically. The induction of acute inflammation stimulates remyelination in animal models of chronic demyelination (12). Animal studies also suggest that both macrophages and lymphocytes facilitate remyelination 2, 20. Weerth et al have suggested that the complement factor C5 promotes remyelination following inflammatory‐mediated injury, demonstrating that C5‐deficient mice with chronic experimental autoimmune encephalomyelitis show a reduced ability to remyelinate in comparison with control animals (35). Brink et al report that GM MS lesions in the cortex show markedly reduced complement deposition in comparison to WM lesions (5). It is therefore interesting to speculate that the GM environment may be less conducive to remyelination than the WM in MS.

While GM demyelination was more readily appreciated using myelin protein IHC, these plaques were also detected by LFB‐staining. This is not the case in the cerebral cortex where a proportion of GM plaques are not detectable using conventional histochemical staining, even when inspected alongside the corresponding IHC‐stained sections (4). This may reflect, in part, differences in myelin density between the GM of the spinal cord and that of the cerebral cortex. Furthermore, identification of the GM portion of the mixed GM/WM lesions is aided by following the plaque border from the WM portion of the plaque into the GM.

The clinical significance of cortical lesions is uncertain, largely because they are grossly underestimated by conventional MRI 15, 18, 27. They may contribute to a range of symptoms including cognitive dysfunction, seizures, fatigue and depression 10, 23, 33. Kutzelnigg et al have recently suggested that cortical demyelination may be a pathological correlate of disease progression (21). Similarly, it is possible that GM plaques in the spinal cord have substantial functional consequences, contributing to motor, sensory and bladder dysfunction. Animal studies demonstrate that GM‐specific injuries in the spinal cord can result in substantial deficits, including paraplegia and pain syndromes, even in the absence of damage to the WM tracts 26, 38.

CONCLUSION

We demonstrate extensive GM demyelination in the spinal cord in MS, with a proportion of plaques showing a distinct morphology which has not been described previously. A greater understanding of these lesions may provide important clues regarding the pathogenesis of MS plaques and mechanisms of disability in MS.

ACKNOWLEDGMENTS

The study was supported by generous funding from the MS society of Great Britain and Northern Ireland (grant number 801/03, N.E.).

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