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February 27, 2007; 68 (9) Views & Reviews

Gray matter involvement in multiple sclerosis

Istvan Pirko, Claudia F. Lucchinetti, Subramaniam Sriram, Rohit Bakshi
First published February 26, 2007, DOI: https://doi.org/10.1212/01.wnl.0000250267.85698.7a
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Abstract

Gray matter (GM) involvement is detected even in the earliest stages of multiple sclerosis (MS), and GM atrophy occurs at a faster rate than white matter (WM) atrophy early in the disease course. Studies published to date establish that 1) GM involvement and in particular cortical demyelination can be extensive in MS; 2) GM pathology may occur in part independently of WM lesion formation; 3) a primarily GM-related process may be the earliest manifestation of MS; 4) GM involvement is associated with physical disability, fatigue, and cognitive impairment in MS; and 5) GM disease might help explain the observed dissociation between markers of inflammatory demyelination (relapses, WM gadolinium enhancement, WM lesion burden) and disease progression. It remains likely that GM damage is related to WM damage. However, continued studies of GM pathology as well as neuronal and axonal involvement in MS and related experimental models are necessary to better understand the etiology and pathogenesis of the degenerative components.

Most therapeutic, diagnostic, and research efforts have concentrated on the white matter (WM) pathology in multiple sclerosis (MS); yet features including physical disability, seizures, cognitive impairment, and fatigue have also been linked to gray matter (GM) involvement. It has been known since the late 19th century that MS affects both WM and GM.1 In 1962, a large pathologic case series examined 32 MS brains and concluded that 26% of all brain lesions were located in GM, including 17% at the gray–white junction, 4% in deep GM nuclei, and 5% in the cortical mantle.2 Because of recent advances in imaging techniques including MRI and PET,3 GM involvement is again receiving considerable attention. We review the current understanding of MS in light of imaging and neuropathologic data suggesting GM involvement.

Neuropathologic studies of GM involvement.

Although MS is generally considered a disease of WM, pathology can also be found in the deep cerebral nuclei2,4 and cerebral cortex.2,5–10 Cortical MS plaques may be abundant in some patients with MS (figure 1). One study6 detected 478 cortical lesions in 12 postmortem brains of patients with MS. By careful histologic analysis, the investigators proposed seven morphologic subtypes of cortical plaques based on the cortical layers involved. Seventy-eight percent of these lesions also involved the subcortical WM.

Figure

Figure 1. Cortical plaques in progressive forms of multiple sclerosis (MS). Cortical demyelination and diffuse white matter inflammation are hallmarks of primary progressive MS (PPMS) and secondary progressive MS (SPMS). (A and D) Schematic lesion maps based on whole hemispheric sections from two archival progressive MS cases. Case A (PPMS): A 37-year-old man with history of gradually progressive left greater than right hemiparesis, sphincter dysfunction, and dysarthria, requiring wheelchair within 6 years of disease onset. Patient died at age 72 of aspiration pneumonia and acute myocardial infarction. Case D (SPMS): A 33-year-old woman initially presented with diplopia and hemiataxia that partially recovered following short course of corticosteroids. Subsequent course characterized by gradually progressive dysarthria, dysphagia, ophthalmoplegia, and limb and gait ataxia, requiring wheelchair within 7 years of disease onset. She also developed a focal seizure disorder 4 years prior to death and died at age 46 of aspiration pneumonia. (B and C) Subpial cortical demyelination is demonstrated in Case A at low (B) and high (C) magnification. (E) Extensive subpial demyelination involving multiple gyri is illustrated in Case D at low magnification. (F) Meningeal inflammation may be prominent, often in close proximity to areas with subpial cortical demyelination. Proteolipid protein immunocytochemistry; green = focal demyelinated plaques in the white matter; orange = cortical demyelination; blue = demyelinated lesions in the deep gray matter.

Another classification system has been proposed8 featuring three patterns of cortical demyelination: Type I lesions are contiguous with subcortical WM lesions; type II lesions are small, confined to the cortex, and often perivascular; type III lesions extend from the pial surface to cortical layers 3 or 4. When this classification system was applied to biopsy samples from patients with early stage MS, 37% revealed clear evidence of cortical demyelination.10

Cortical lesions fundamentally differ from WM plaques. They are thought to be less inflammatory with a dominant effector cell population of ramified microglia.8 One study7 reported that cortical lesions contained demyelination, however, with no increase in lymphocyte count or altered distribution of lymphocyte subsets compared with controls. The authors concluded that the demyelination in cortical MS lesions may be independent of T-cell-mediated inflammation. However, the chronic autopsy samples analyzed were likely biased toward a chronic “burnt-out” stage of plaque formation. A recent analysis of biopsy samples from newly diagnosed cases demonstrated that cortical lesions contained numerous infiltrating immune cells.10

The demyelinated cortex contains apoptotic neurons.8 Cortical demyelination could therefore influence neuronal, dendritic, and axonal function and neuronal viability, which may be relevant to disease progression. Such involvement may partially explain the disconnection between clinical findings and lesional WM abnormalities on MRI scans.3 Besides demyelination, the cerebral cortex of patients with MS may also be affected by tissue loss and atrophy, particularly in areas adjacent to severe WM pathology. Neurons in such lesions may show signs of retrograde damage, including central chromatolysis. Axonotmesis as a result of inflammation in MS lesions can lead to retrograde neuronal degeneration and apoptosis.11 Quantitative MRI indicates that cortical atrophy occurs early in the disease course and is related to physical disability and cognitive impairment.12–22 Furthermore, degeneration of cortical neurons could contribute to the depletion of neuronal metabolites as detected by MRS in the normal-appearing WM (NAWM) and GM, as discussed later.

A recent pathologic study5 investigated the role of cortical demyelination in all clinical MS subtypes. Cortical demyelination and diffuse axonal injury in NAWM were hallmarks of progressive forms of MS. Demyelination was mainly seen in the subpial layer of the cortex and was associated with inflammatory infiltrates in the surrounding meninges. Diffuse inflammation was also observed throughout the WM of progressive cases and was associated with microglial activation. However, there was only a marginal correlation between focal WM lesion load and diffuse WM injury or GM pathology. These observations suggest there may be three basic pathologic processes in MS. The hallmark of acute or relapsing MS is focal inflammatory demyelinated WM lesions, whereas chronic progressive MS additionally includes diffuse damage in NAWM and cortical demyelination. These three pathologic processes occur in parallel as well as independent from one another, as supported by the lack of correlation between WM lesion load and diffuse damage in NAWM or cortical demyelination. These pathologic observations appear consistent with MRI studies showing dissociation between WM lesion load and diffuse global pathology.3 Although GM involvement is classically explained as secondary to WM lesions leading to axonal damage, Wallerian degeneration,4,23,24 and neuronal loss, a recent histopathologic study5 suggested a dissociation between inflammatory demyelination and neurodegeneration. This is further supported by MRI studies suggesting that cortical atrophy appears early in the disease process,12,15,16,18,21 and may occur independent of WM pathology and MS relapses. These observations raise the possibility that the earliest pathologic events in MS may in some cases be concentrated in the cortical GM. It is theoretically possible that the inflammatory demyelinating features of MS WM lesions are triggered by this early GM-based process, as seen in some viral models of MS.25

Neuroimaging studies of GM involvement.

Detection of cortical lesions.

Advanced MRI techniques have far greater sensitivity than conventional MRI for the detection of GM lesions in MS (figures 2 and 3).9,26,27 One group27 demonstrated more than 800 cortical/juxtacortical lesions in 84 patients with MS that were detected by fast fluid-attenuated inversion recovery (FLAIR) but largely undetected by conventional T1- or T2-weighted images (figure 2). In a postmortem tissue–MRI correlation study, T2-weighted images captured only 3% of cortical lesions, whereas FLAIR captured 5%.9 The MRI detectability for mixed cortical–subcortical lesions was better: 22% on T2-weighted and 41% on FLAIR images; 13% of deep gray lesions were identified on T2 studies, 38% by FLAIR. By comparison, 63% of WM lesions were identified on T2-weighted images and 71% by FLAIR. A novel three-dimensional double inversion recovery sequence (three-dimensional DIR) is more sensitive in visualizing cortical plaques than FLAIR or conventional methods (figure 3).26 In a pilot study of 10 patients, three-dimensional DIR depicted more intracortical lesions (80 lesions) than both T2-weighted images (10 lesions) and FLAIR (31 lesions).26 In vivo and ex vivo MRI was used to study cortical lesions in MS.6 The in vivo component determined that 70% of enhancing cortical lesions were visible on T2-weighted images. Ex vivo investigation revealed that only 40% of histologically identified lesions were captured by MRI, including 53% of juxtacortical lesions and 14% of cortical lesions. Higher-field MRI systems (3 T or higher) will likely result in increased detectability of both cortical and WM lesions.

Figure

Figure 2. Fluid-attenuated inversion recovery (FLAIR) vs T2-weighted MRI detection of cortical and juxtacortical lesions in a 38-year-old woman with relapsing–remitting multiple sclerosis, disease duration of 12 years, and mild to moderate physical disability (Expanded Disability Status Scale score 4). (Top) Fast FLAIR images; (bottom) corresponding fast spin echo T2 images. Although some of the cortical and juxtacortical lesions are visible on T2 images, the FLAIR images show all of them more crisply and enable the visualization of lesions that would remain undetected.

Figure

Figure 3. Intracortical and mixed gray matter/white matter lesions in multiple sclerosis (MS). Top row shows zoomed views of bottom row axial MRI scans: short echo time (A) and long echo time (B) T2-weighted images showing hyperintense lesions within or in the proximity of the cortical gray matter; the images provide little information about whether lesions are juxtacortical, mixed gray matter/white matter lesions, or purely intracortical. (C) Multislab three-dimensional fluid-attenuated inversion recovery image showing only a subset of the lesions. (D) Multislab three-dimensional double inversion recovery image9,26 allowing for superior depiction of MS lesions in and around the cortex (arrows) and a better distinction between intracortical and mixed gray matter/white matter lesions (compared with the more conventional techniques).

Topography of GM atrophy.

Atrophy is widespread in MS, affecting all areas of the brain.28 With use of MRI segmentation, prominent GM atrophy can be detected in patients with MS (figures 4 through 6). Several groups have assessed the loss of GM vs WM brain volume and have documented selective GM atrophy (figure 6).12–16,18 Other groups have shown that atrophy affects both GM and WM compartments to a similar degree21 or preferentially the WM.22 Heterogeneity of patient populations, small sample sizes, and differences in acquisition and postprocessing techniques may partially explain the conflicting conclusions of these studies.

Figure

Figure 4. MRI detection of cortical thinning in multiple sclerosis (MS) using a surface reconstruction with three-dimensional rendering.17 The average statistical map of five subjects with secondary progressive MS was compared with the average map of seven control subjects. Cortical thinning is displayed on views of folded (left) and inflated (right) brains. Dark gray areas on the right image correspond to sulci, and lighter gray areas correspond to gyri. These maps demonstrate areas with highly significant differences in cortical thickness in the MS group where statistical significance represents the dynamic range of thinning. The color scale shows the dynamic range of thinning. Blue represents a statistically significant thickening of the cortex. Full yellow corresponds to a statistically significant cortical thinning with a p value of 0.001 that relates to at least 0.4 mm of cortical thinning.

Figure

Figure 5. Caudate atrophy in multiple sclerosis (MS). One study23 tested whether caudate atrophy occurs in MS and whether it correlates with conventional MRI or clinical markers of disease progression. Caudate nuclei of 24 patients with MS and 10 age-matched healthy control subjects were traced, normalized, reconstructed, and visualized from high-resolution MRI scans. Normalized bicaudate volume was 19% lower in patients with MS vs controls (p < 0.001), an effect that persisted after adjusting for whole-brain atrophy (p < 0.008). Caudate volume did not correlate with global T2-hyperintense or T1-hypointense lesion load (both p > 0.05). Inferolateral three-dimensional reconstructed views of bilateral caudate nuclei from five representative patients with MS (green) and age-matched control subjects (red), after normalizing for intracranial volume. Ages of patients and respective controls from left to right are 26, 33, 38, 40, and 50 years. Gradations on rulers represent 5 mm. The caudates from the MS group appeared not only smaller in volume but also dysmorphic. The anterior and medial aspects of the caudates were especially affected, and the tails were smaller.

Figure

Figure 6. MRI-based quantification of global gray vs white matter volume. Representative sections from a three-dimensional T1-weighted gradient echo MRI protocol and resulting gray, white, and CSF tissue compartments after automated processing by SPM99 for a patient with multiple sclerosis (MS). Images are 1) raw T1-weighted image (upper left); 2) white matter (upper right); 3) gray matter (lower left); and 4) CSF segmented images (lower right). Note the misclassification of MS white matter lesions as gray matter. This procedure can be used to quantify the volumes separately or determine residual or proportion-based measures of normalized whole-brain atrophy. Applying this method, one group14 studied 41 patients with MS and 18 age/sex-matched healthy control subjects. Patients with MS had lower global gray matter (–3.9%, p = 0.003) and total parenchymal volume (–3.8%, p = 0.003), but only a trend for lower global white matter volume (–3.7%, p = 0.052) relative to normal control subjects. Gray matter atrophy was most closely related to clinical status as compared with all other MRI measures (table).

View this table:

Table Correlations between MRI measures (atrophy and lesion loads) and physical disability in patients with multiple sclerosis

As discussed above, histologic data suggest that GM lesions may have less inflammation than WM lesions. In a 3-year longitudinal study,12 patients with early RRMS had large decreases in global GM but small increases in global WM brain volume, whereas those with clinically isolated demyelinating syndromes (CISs) had decreases in GM volume but no changes in WM volume. At the same time, both groups had substantial increases in WM lesions, suggesting that WM volume loss was offset by inflammation- and edema-related increases in tissue bulk. This increase in global WM volume may mask ongoing atrophy while the GM is relatively devoid of inflammation. Taken together, these data suggest that GM volume loss may be a more sensitive marker of early disease progression in MS than measures of WM volume loss.

There is mounting evidence that neocortical atrophy occurs early in the disease process.15,17,19 Cortical thickness measurements in 20 patients with MS showed a significantly lower average cortical width (2.3 vs 2.48 mm) (figure 4).17 Atrophy was detected in the frontal and temporal cortex in early MS and in the motor cortex in patients with more advanced disease. Atrophy of the deep gray nuclei also occurs in MS and is disproportionate to the amount of global atrophy.23,29 Volume loss of the thalamus4,29 and the caudate nucleus23 has been documented using MRI segmentation (figure 5). In the thalamus, there is substantial neuronal loss, depletion of neuronal metabolites, and a 22% loss of neuronal density.4 These observations are consistent with PET data demonstrating hypometabolism of the brain affecting cortical and subcortical GM more than WM.30

With use of voxel-based morphometry (VBM) from MRI scans, a recent study31 of 51 patients with RRMS and 34 control subjects showed that GM volume was significantly decreased in the frontotemporal cortex, precuneus, anterior cingulate gyrus, postcentral gyrus, and caudate nuclei bilaterally. These results suggest that in RRMS, GM reduction preferentially involves frontotemporal and deep central GM. Another VBM study also reported significant volume reduction in temporal and prefrontal cortex.32 VBM will likely emerge as an important tool in understanding the topography, time course, and clinical relevance of GM involvement in MS.

Advanced MRI techniques.

A wide range of newer MRI methods provide increased sensitivity for GM disease compared with conventional methods. Proton MRS, diffusion imaging, and magnetization transfer imaging can detect GM involvement in patients with MS. N-Acetyl-aspartate (NAA) peaks on MRS are thought to represent axonal and neuronal integrity. Whole-brain NAA was, on average, 22% lower (range: +8 to −63%) in 71 patients with RRMS as compared with control subjects and appeared to be dependent on GM damage.33 A longitudinal study of GM in RRMS showed periodic peaks consistent with the breakdown of myelin-associated macromolecules.34 These abnormal MRS peaks had a time course similar to that of evolving WM lesions but without associated alterations in choline and NAA. This pattern may reflect the histologic finding that cortical lesions are characterized by demyelination and microglial activation. Reduced NAA that parallels neuronal loss and atrophy has also been documented in deep central gray structures.4

Magnetization transfer MRI provides additional evidence of GM damage. In normal-appearing GM and WM as well as in overt lesions, the magnetization transfer ratio is typically decreased. Such decreases are seen in patients at the earliest stage of disease, including in both cortical and subcortical GM areas.35,36 However, not all studies have shown magnetization transfer ratio decreases in GM.37

Diffusion MRI typically shows increased diffusivity and decreased anisotropy in WM lesions and NAWM.38–41 A diffusion tensor MRI study38 reported decreased anisotropy and increased diffusivity in NAWM and increased anisotropy in the basal ganglia and thalamus. This unexpected increase in anisotropy may be related to damage to corticosubcortical connections, which unmasks the intrinsic connections among the basal ganglia nuclei, resulting in increased tissue organization. Furthermore, the lack of correlation between anisotropy and diffusivity in the basal ganglia suggests that these two measures may be sensitive to different pathologic aspects of MS involvement of the deep GM. Diffusivity is increased in both nonlesional WM and GM in patients with progressive forms of MS.41 However, GM changes appear to be more sensitive to disease progression than WM changes.41

Newer MRI techniques allow relatively rapid measurement of T1 relaxation time in voxels of interest, allowing the assessment of region-specific T1 maps. In one study, T1 relaxation times in the thalamus and the putamen were significantly higher in patients with RRMS than normal control subjects.42 The investigators found a significant correlation between fatigue severity and the thalamic T1 relaxation time (r = 0.418; p = 0.014). Moreover, patients with fatigue had T1 relaxation time prolongation in the thalamus compared with those without fatigue.

T2 hypointensity in GM.

T2 hypointensity is commonly detected in the cortical and subcortical GM in patients with RR- or SPMS (figure 7).43,44 T2 hypointensity is a more reliable predictor of disability, cognitive impairment, and clinical course than are conventional MRI WM lesion measures.43,44 T2 hypointensity is also an independent predictor of brain atrophy.45 It probably reflects pathologic iron deposition, as has been described in neurodegenerative diseases. However, paramagnetic substances other than iron could also be responsible for T2 hypointensity such as other metals or an increase in cellular density or tissue compactness related to macrophage and microglial infiltration.46 Iron deposition may be purely a disease epiphenomenon. If so, T2 hypointensity may serve as an effective means to monitor the neurodegenerative component of the disease in GM. It is also possible that iron directly contributes to the pathogenesis of MS by promoting the production of free radicals, oxidative stress, lipid peroxidation, and neurotoxicity in GM. If iron plays a direct role in pathogenesis, a range of new therapies may become available to target GM damage.

Figure

Figure 7. T2 hypointensity and brain atrophy in multiple sclerosis (MS). Fast spin echo T2-weighted images are shown of a 43-year-old man with relapsing–remitting MS (disease duration of 4 years, mild to moderate physical disability, Expanded Disability Status Scale score 3.5) (A through E) and an age-matched healthy subject (F through J). In the patient with MS, note the bilateral hypointensity of various gray matter areas (arrows), including the red nucleus (A), thalamus (B and C), lentiform nucleus (B and C), caudate (D), and rolandic cortex (E) compared with the healthy subject. The patient also has brain volume loss compared with the control subject (note prominence of ventricular and subarachnoid spaces). The T2 hypointensity most likely represents pathologic iron deposition.

Functional imaging evidence of GM involvement.

High-resolution fluorodeoxyglucose PET in 25 patients with MS showed a 9% reduction in whole-brain glucose metabolism (p < 0.05).47 Hypometabolism was most dramatic in cortical structures. This may represent direct GM involvement or indirect involvement via diaschisis or both mechanisms. GM metrics derived from PET or SPECT have shown moderate correlations with relapse rate,48 physical disability,48 cognitive impairment,30,48 depression,49 and fatigue,50 suggesting the clinical relevance of GM damage.

fMRI maps the brain areas activated during a task paradigm. fMRI frequently shows cortical adaptation and cortical reorganization in patients with MS, which is clearly a GM-related process and suggests GM plasticity.51–53 In a study of patients with CIS with a minimal MRI lesion load and mean disease duration of 6 months, greater activation in the right frontopolar cortex, the bilateral lateral prefrontal cortices, and the right cerebellum was seen while performing a cognitive attentional/working memory paradigm as compared with control subjects.52 This argues for compensatory cortical reorganization at the earliest stage of MS, even when the WM T2 lesion load is low. In patients with MS and fatigue, fMRI showed reduced activation of the movement associated cortical/subcortical network.53 Fatigue severity correlated with the reduction in thalamic and cerebellar activation, highlighting the clinical relevance of GM dysfunction in patients with MS.53 However, although fMRI changes reflect functional adaptation, they do not necessarily serve as direct evidence for GM pathology.

Clinical relevance of GM involvement.

Clinical features suggesting GM involvement.

MS includes clinical manifestations that are characteristic of GM involvement, such as seizures and cognitive dysfunction. According to a meta-analysis of 29 published studies of patients with MS and epilepsy, the prevalence of 2.9% represented a three- to sixfold increase compared with the seizure prevalence in the general population.54 There is a correlation between seizures and cortical/juxtacortical MS lesions.55 Cognitive impairment is a common and disabling manifestation of MS and has clinical features suggesting a contribution from GM.20,29,56–58 MS fatigue has been linked to subcortical GM pathology in a range of imaging studies.42,50,53 However, clearly WM involvement also impacts these clinical manifestations of MS, as the correlations between GM disease and clinical status remain only moderate to strong at best.20,29

Cognitive impairment is related to GM involvement.

Imaging data suggest that neuropsychologic impairment in MS is related, in part, to atrophy of GM regions.19,20,29,32,57 GM atrophy has been associated with impairments in verbal memory, euphoria, and disinhibition.19,20,29,32 In a study of 41 patients, neocortical atrophy was associated with impairment in verbal memory (r = 0.51, p = 0.02), verbal fluency (r = 0.51, p = 0.01), and attention/concentration (r = 0.65, p < 0.001).19 A recently published study suggests that WM volume loss is most closely associated with processing speed and working memory, whereas GM volume is most closely linked to verbal memory, euphoria, and disinhibition.20 Another study showed a moderate to strong relationship between thalamic atrophy and impairment in numerous cognitive domains (r = 0.5 to 0.7, p < 0.005) to a stronger extent than was seen for conventional WM lesion measures in 31 patients with MS.29 Cortical and juxtacortical lesions have also been linked to cognitive impairment.58 In addition, PET has linked GM hypometabolism with cognitive impairment in patients with MS.30 These studies uniformly suggest that GM involvement is associated with cognitive dysfunction in MS.

Physical disability is related to GM involvement.

MRI markers of GM involvement correlate better with measures of physical disability than do conventional MRI WM lesion markers in patients with MS.14,44 Historically, the most commonly used functional outcome scale in MS is the Expanded Disability Status Scale (EDSS).59 Several studies have demonstrated that imaging markers of GM damage are associated reasonably well with clinical disability in many14,15,17,28,44,48,61 but not all studies.22,31 The correlation between T2 lesion volume (which is almost exclusively WM based) and EDSS score ranges from 0.17 to 0.60 in cross-sectional studies and from 0.18 to 0.72 in longitudinal studies,62 suggesting a weak to moderate correlation with disability. T1-hypointense WM lesion load shows a better correlation with disability: In cross-sectional studies, the correlation is 0.46 to 0.74; in longitudinal studies, it is 0.46 to 0.52.62 In one study14 (figure 6, table), GM atrophy was selected in regression modeling as most closely related to neurologic disability measured by EDSS score and 25-ft timed walk as compared with WM atrophy and conventional T1-hypointense and T2-hyperintense WM lesion measures. A study of patients with PPMS or RRMS showed that MRI-based neocortical volume correlated with EDSS scores across all of the patients, but the strength of the correlation was stronger (p < 0.05) in the patients with PPMS (r = −0.64, p < 0.0001) than those with RRMS (r = −0.27, p = 0.04).15

Clinicopathologic significance of GM involvement.

The extensive cortical damage observed predominantly in progressive forms of MS suggests that GM involvement may be an important pathologic correlate of irreversible disability. Furthermore, early cortical involvement seen on imaging studies raises the intriguing possibility that the GM may represent the primary and initial target of the disease process, leading to axonal degeneration and subsequent demyelination (the “inside-out” model of MS).25 One of the most important questions regarding GM involvement is whether it is a consequence of WM demyelination with secondary axonal damage leading to neuronal loss in GM structures or whether the GM, in particular neurons, are a direct target of the disease process. Emerging histopathologic and neuroimaging studies support the concept that GM pathology occurs in part independently of WM lesions and may precede WM pathology. It is hotly debated whether a primary neuronal or axonal process could lead to WM demyelination as opposed to WM demyelination leading to secondary axonal and neuronal damage.

Imaging and MRS studies have suggested that brain damage in MS may be mediated by two independent events: an inflammatory reaction, which drives the formation of WM lesions, and neurodegeneration, which is responsible for diffuse and progressive brain damage. However, from the pathologic perspective, neurodegeneration is defined as degeneration of nervous system cells (neurons or glia) due to a genetic, metabolic, or toxic effect. Inflammatory diseases are distinguished from neurodegenerative diseases by the fact that inflammation is thought to drive this destruction. In contrast to classic neurodegenerative diseases, all MS lesions, regardless of the stage and type of the disease, are associated with inflammation. The apparent lack of correlation between early clinical or neuroimaging markers of inflammation and subsequent disease progression do not necessarily imply the two processes are completely dissociated. It is likely that the inflammatory response is both qualitatively and quantitatively different during the early vs late phases of the disease as well as within areas of GM and WM damage. However, regardless of the course, phase, or site of the disease, neurodegeneration in MS appears to occur on a background of inflammation. The presence of GM damage does not exclude the possibility that it is mediated by inflammatory processes (e.g., an infectious agent). The focus on the neurodegenerative aspects may underestimate the pathogenic importance of persistent global inflammation in contributing to ongoing tissue injury. Although the inflammatory response is a key feature of MS pathology, what drives the inflammatory response remains to be determined.

Future directions.

Because the immunopathogenic mechanisms underlying GM damage in MS are unknown, it is uncertain whether they are limited by currently available disease-modifying therapies. It is also unknown if GM involvement has any relationship with the proposed classification of WM MS lesion subtypes.63 Focal new WM lesions are associated with blood–brain barrier damage, inflammation, and acute axonal injury both in the lesion and distal to the lesion site due to Wallerian degeneration. This type of injury is likely to be limited by immunomodulatory and immunosuppressant drugs. However, diffuse global brain injury including GM involvement is likely associated with a compartmentalized inflammatory response that occurs typically behind an intact blood–brain barrier in the absence of ongoing focal WM demyelination. The limited benefit of anti-inflammatory or immunomodulatory therapy in the chronic slowly progressive phase of MS may in part be explained by the compartmentalization of this inflammatory reaction in the CNS. Additional studies examining mechanisms underlying GM damage are needed to better understand the pathogenesis of disease initiation, evolution, and progression, in the hope of ultimately developing more effective therapeutic strategies.

Acknowledgment

The authors thank Ms. Sophie Tamm for assistance with manuscript preparation, Dr. J.J.G. Geurts and colleagues (VU University Medical Center, Amsterdam, the Netherlands) for providing figure 3, and Dr. M. Sailer, (Department of Neurology, Otto-von-Guerricke University Magdeburg, Germany) for providing figure 4.

Footnotes

  • Disclosure: The authors report no conflicts of interest.

    Received January 13, 2006. Accepted in final form September 16, 2006.

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