Background Multiple sclerosis is an inflammatory demyelinatingdisease of the central nervous system and is the most commoncause of neurologic disability in young adults. Despite antiinflammatoryor immunosuppressive therapy, most patients have progressiveneurologic deterioration that may reflect axonal loss. We conductedpathological studies of brain tissues to define the changesin axons in patients with multiple sclerosis.
Methods Brain tissue was obtained at autopsy from 11 patientswith multiple sclerosis and 4 subjects without brain disease.Fourteen active multiple-sclerosis lesions, 33 chronic activelesions, and samples of normal-appearing white matter were examinedfor demyelination, inflammation, and axonal pathologic changesby immunohistochemistry and confocal microscopy. Axonal transection,identified by the presence of terminal axonal ovoids, was detectedin all 47 lesions and quantified in 18 lesions.
Results Transected axons were a consistent feature of the lesionsof multiple sclerosis, and their frequency was related to thedegree of inflammation within the lesion. The number of transectedaxons per cubic millimeter of tissue averaged 11,236 in activelesions, 3138 at the hypocellular edges of chronic active lesions,875 in the hypocellular centers of chronic active lesions, andless than 1 in normal-appearing white matter from the controlbrains.
Conclusions Transected axons are common in the lesions of multiplesclerosis, and axonal transection may be the pathologic correlateof the irreversible neurologic impairment in this disease.
Multiple sclerosis is a disease of the central nervous systemcharacterized by multicentric inflammation and destruction ofmyelin. The primary cause of multiple sclerosis is unknown.Environmental risk factors1 and multiple genetic loci2,3,4 contributeto susceptibility to the disease. The onset of the symptomsof multiple sclerosis is often associated with breakdown ofthe blood–brain barrier, as visualized by magnetic resonanceimaging.5,6 Inflammatory mediators block nerve conduction atthe nodes of Ranvier,7 and soluble and cellular effector mechanismsdestroy myelin.8,9 The intensity of this process, its resolution,and possibly remyelination determine the severity and durationof the clinical symptoms and recovery after each exacerbation.Acute relapses respond well to corticosteroid therapy,10 providingfurther evidence that inflammation is central to the diseaseprocess.
In more than 50 percent of patients with multiple sclerosis,steadily progressive clinical deterioration develops after a10-to-15-year relapsing–remitting disease course.11 Thischronic progressive stage of the disease is much less responsiveto antiinflammatory-drug therapy. Although it was formerly assumedthat axons were spared from the destructive process, recentstudies indicate that axonal injury in multiple sclerosis maycause permanent neurologic dysfunction. Neurologic disabilityin patients with multiple sclerosis has been correlated withatrophy in the spinal cord,12 cerebellum,13 and cerebral cortex,14and the neuronal marker N-acetyl aspartate is decreased in multiple-sclerosislesions according to magnetic resonance spectroscopy.14,15,16,17In patients with relapses, reduced N-acetyl aspartate is restrictedto the area of the lesion, whereas patients with chronic progressivemultiple sclerosis have reduced N-acetyl aspartate even in normal-appearingwhite matter.18 This observation suggests the spread of axonalpathologic changes, wallerian degeneration, or both.19,20
Axonal pathologic changes in multiple sclerosis were mentionedby Charcot21 and have been reported in an experimental modelof immune-mediated demyelination.22 Few studies have rigorouslycharacterized axonal pathologic changes in the brains of patientswith multiple sclerosis. A recent study reported axonal accumulationof the amyloid precursor protein in multiple-sclerosis lesionsand raised the possibility of irreversible axonal damage.23Using three-dimensional imaging of brain sections, we have attemptedto identify the pathologic changes in axons in multiple sclerosis.
Methods
Tissue
We studied tissue from the brains of 11 patients with multiplesclerosis (age at death, 18 to 62 years; 8 women and 3 men).Forty-seven demyelinated lesions were identified, and each wascharacterized as active or chronic active, as described previously.24Active lesions contained abundant and evenly distributed major-histocompatibility-complex(MHC) class II–positive cells throughout the lesion andmyelin-protein–positive inclusions within the macrophages.In chronic active lesions, MHC class II–positive cellswere abundant at the edges of lesions and less frequent in thecenter. On the basis of these criteria, 14 active and 33 chronicactive lesions were identified.
Immunocytochemistry
The tissue was fixed in 4 percent paraformaldehyde, protectedin 70 percent sucrose, placed on the stage of a sliding microtome,and frozen. Free-floating sections (30 µm thick) werecut without exposure to solvents or other embedding mediums.Sections were rinsed in phosphate-buffered saline four timesfor 5 minutes each, microwaved twice for 5 minutes each in 10mM citrate buffer (pH 6.0), incubated in 3 percent hydrogenperoxide and 10 percent Triton X-100 for 30 minutes, and immunostainedby the avidin–biotin complex procedure and with diaminobenzidine,as described previously.24 Sections for confocal microscopywere pretreated as described above, incubated with two primaryantibodies, and then incubated with fluorescein-conjugated andTexas red–conjugated secondary antibodies (Jackson Laboratories,West Grove, Pa.), as described previously.25
Antibodies
The following well-characterized primary antibodies were used:mouse anti–MHC class II and rabbit anti–myelin basicprotein (Dako, Carpinteria, Calif.), mouse anti–proteolipidprotein (gift from Nigel Groom), rabbit antiferritin (SigmaImmunochemicals, St. Louis), and mouse anti–nonphosphorylatedneurofilament (SMI-32) (Sternberger Monoclonals, Baltimore).
Confocal Microscopy
Sections were analyzed on a Leica Aristoplan laser scanningmicroscope (Leitz Wetzlar, Heidelberg, Germany). Individualconfocal optical sections represented 0.5-µm axial resolution.The entire thickness of the section was scanned. The imagespresented here consist of 16 to 32 optical sections combinedto form a "through-focus" image. Fluorescence was collectedindividually in the green (fluorescein) and red (Texas red)channels to eliminate "bleed-through" from either channel. Theyellow is a result of stacking multiple images and not of colocalizationof antigens.
Quantification of Terminal Swellings
Tissue from five brains, which included 5 active and 13 chronicactive lesions, was selected for quantitative analysis of axonaltransection. Sections immunostained with nonphosphorylated-neurofilamentantibodies and diaminobenzidine were used for quantification.Only swellings at the terminal ends of axons, as verified bymoving the plane of focus up and down through the section, werecounted. To eliminate regional variations in the distributionof terminal-axon ovoids, all areas of multiple-sclerosis lesionswere analyzed. The tissue volume (in cubic millimeters) wascalculated by multiplying the total two-dimensional area ofthe grid that was analyzed by the thickness of the section (30µm). Terminal ovoids in multiple-sclerosis lesions, 10microscopical fields of normal-appearing white matter in multiple-sclerosisblocks, and 20 microscopical fields of white matter from controlbrains were quantified. The data were compared by the Wilcoxonrank-sum test and mixed-model analysis.
Results
Axonal Pathologic Changes in Multiple-Sclerosis Lesions
Axonal pathologic changes, demyelination, and inflammation werestudied in serial sections of individual multiple-sclerosislesions immunostained with antibodies to proteolipid protein,MHC class II molecules, and nonphosphorylated neurofilament(SMI-32) (Figure 1A, Figure 1B, and Figure 1C). Proteolipidprotein is the major structural protein of central nervous systemmyelin,26 and its absence in white matter indicates areas ofdemyelination. MHC class II molecules are expressed by activatedmonocytes and microglia concentrated in and around multiple-sclerosislesions,24 and their abundance and distribution have been usedto characterize different stages of demyelinating lesions.23,27,28Nonphosphorylated neurofilaments are abundant in neuronal cellbodies and dendrites.29,30,31 Neurofilaments in healthy myelinatedaxons are heavily phosphorylated and not stained by SMI-32 antibodies.29SMI-32 immunoreactivity in normally myelinated regions of thebrain provides a sensitive marker for demyelination or axonalpathologic changes. SMI-32 immunoreactivity was rare in normal-appearingwhite matter from control brains (data not shown). In contrast,all 47 multiple-sclerosis lesions analyzed contained abundantSMI-32–positive axons.
Figure 1. Serial Sections of Multiple-Sclerosis Lesions Immunostained for Myelin (Panel A), MHC Class II (Panel B), and Nonphosphorylated Neurofilaments (Panel C).
This figure shows an active multiple-sclerosis lesion characterized by loss of myelin (Panel A), myelin debris within the demyelinated area (Panel A, arrowheads), even distribution of numerous MHC class II–positive cells throughout the demyelinated area (Panel B), and abundant expression of nonphosphorylated neurofilaments within the lesion (Panel C). The scale bars in Panels A and B represent 400 µm; the scale bar in Panel C represents 235 µm.
Figure 1A, Figure 1B, and Figure 1C shows a lesion classifiedas active because of the absence of proteolipid-protein immunoreactivity(Panel A) and the abundance and even distribution of MHC classII–positive cells (Panel B) throughout the demyelinatedarea. The acuteness of the demyelination is also indicated bythe detection of proteolipid-protein–positive myelin debriswithin the lesion (Figure 1A, arrowheads). Abundant SMI-32 immunoreactivitywas detected within the area of demyelination (Figure 1C). Thisstaining appeared as thin lines and small dots, which representdemyelinated axons viewed in longitudinal and transverse orientation,and as larger ovoids that may represent damaged axons.
Several patterns of SMI-32 staining were detected in and nearmultiple-sclerosis lesions, and these patterns varied on thebasis of lesion activity. In active lesions, small-diameteraxons and large ovoids (Figure 2A) were distributed randomlythroughout the demyelinated area. In chronic active lesions,SMI-32–positive axons and ovoids were concentrated atthe actively demyelinating edges (Figure 2B). Both were lessabundant than those found in active lesions, and the ovoidswere of smaller diameter. The centers of chronic active lesionscontained fewer SMI-32–positive axons and ovoids thanthe borders (data not shown).
Figure 2. Patterns of Axonal Pathologic Changes in Multiple-Sclerosis Lesions.
In active lesions (Panel A), SMI-32–positive ovoids and axons are abundant. At the edges of chronic active lesions (Panel B), nonphosphorylated-neurofilament–positive axons and ovoids are less abundant and the ovoids are smaller. Most nonphosphorylated-neurofilament–positive axons in multiple-sclerosis lesions have a normal appearance (Panels A and B). Some have discontinuous staining for nonphosphorylated neurofilaments (Panel C), which is characteristic of axonal degeneration. Other axons have constrictions, dilatations, or large swellings (Panel D). The scale bars in Panels A and B represent 60 µm; the scale bars in Panels C and D represent 52 µm.
Individual axons displayed several patterns of SMI-32 immunoreactivity.Most abundant were continuous lines of SMI-32 immunoreactivity(Figure 2A and Figure 2B), which indicated intact demyelinatedaxons. Some axons contained discontinuous lines of SMI-32–positivedots (Figure 2C). These staining patterns are consistent withaxonal degeneration distal to the sites of transection. Otheraxons showed dramatic changes in caliber, including alternatingconstrictions and dilatations or single swellings that extendedfrom a thin axon (Figure 2D).
Axonal Transection in Multiple-Sclerosis Lesions
The most striking axonal alterations in multiple-sclerosis lesionswere ovoids of intense SMI-32 staining. These structures resembledterminal axonal ovoids or end bulbs that resulted from axontransection.32,33,34,35 To confirm this interpretation, sectionswere stained with SMI-32 and fluorescence-labeled antibodiesand examined by confocal microscopy, and computer-based three-dimensionalreconstructions of entire ovoids were generated. Figure 3A showsan active lesion with many axonal ovoids. On the basis of three-dimensionalanalysis, the vast majority of ovoids retained only a singleaxonal connection (Figure 3A, arrows). Axonal ovoids with dualaxonal connections were rare (Figure 3A, arrowhead). This analysisestablished that the majority of SMI-32–positive axonalswellings were terminal ends of axons.
Figure 3. Confocal Microscopical Images of Axonal Changes in Multiple-Sclerosis Lesions.
Nonphosphorylated neurofilaments are green in all panels. Red indicates myelin in Panels B and C and macrophages or microglia in Panels D and E. Panels A and D show the centers of active lesions. Panels B, C, and E show the edges of active lesions. Panel A shows "stacked images" of terminal axonal ovoids with single axonal connections (arrows), an axonal ovoid with dual axonal connections (arrowhead), and many normal-appearing axons. Panel B shows three large, nonphosphorylated-neurofilament–positive axons undergoing active demyelination (arrowheads). One axon ends in a large terminal ovoid (arrow). Panel C shows some axons (green) terminating at the ends of normal-appearing myelin internodes (arrow), and many axons that express nonphosphorylated neurofilaments surrounded by normal-appearing myelin (arrowheads). In Panels D and E, macrophages (red in Panel D) and microglia (red in Panel E) surround and engulf terminal axonal swellings (large arrows) but have no consistent association with normal-appearing axons (arrowheads) or swellings in nontransected axons (Panel E, small arrow). The scale bar in Panel A represents 64 µm; the scale bars in Panels B, C, D, and E represent 45 µm.
Axonal Transection in Relation to Demyelinating Activity in Multiple-Sclerosis Lesions
Inflammatory demyelination is the pathologic hallmark of multiplesclerosis. The relation between SMI-32–positive terminalovoids and active demyelination was studied by confocal microscopy.Figure 3B shows the distribution of SMI-32 (green) and myelinbasic protein (red) at the edge of a chronic active lesion.Three large-diameter axons are intensely stained by SMI-32 antibodies.The irregular and discontinuous distribution of myelin basicprotein immunoreactivity around these axons indicates ongoingdemyelination. The two lower, large-diameter fibers had normal-appearingaxonal cylinders, whereas the upper fiber terminated in a largeovoid (Figure 3B, arrow). Figure 3C is another confocal imageof myelin basic protein (red) and SMI-32 (green) staining atthe border of a lesion. Many SMI-32–positive, myelin basicprotein–negative fibers extended into normal-appearingwhite matter, where they remained SMI-32–positive butwere surrounded by normal-appearing myelin internodes (Figure 3C,arrowheads). Occasionally, an SMI-32–positive axonthat was surrounded by normal-appearing myelin terminated ina swelling (Figure 3C, arrow). Confocal analysis of these andsimilar fibers provided additional evidence that most SMI-32–positiveovoids were terminal ends of axons.
Cells of monocyte origin are effectors in tissue destructionand phagocytosis in multiple-sclerosis lesions. To study theassociation between macrophages or microglia and terminal axonalovoids, sections were immunostained for SMI-32 and ferritin(a marker for cells of monocyte origin) and analyzed by confocalmicroscopy. In the center of an active lesion (Figure 3D), phagocyticmacrophages were abundant and were closely associated with orpartially surrounded terminal axonal ovoids (Figure 3D, arrows).Normal-appearing SMI-32–positive axons (Figure 3D, arrowheads)were not surrounded by phagocytic macrophages. At the bordersof chronic active lesions (Figure 3E), the majority of ferritin-positivecells (red) were process-bearing microglia. SMI-32–positiveaxons (green) were abundant; most had a normal appearance andno consistent association with activated microglia (Figure 3E,arrowheads). However, two terminal axonal swellings were engulfedby activated microglia (Figure 3E, large arrows), whereas aswelling with dual axonal connections was not ensheathed bymicroglia or their processes (Figure 3E, small arrow).
Quantification of Axonal Transection
The results described above established a strong qualitativecorrelation between axonal pathologic changes and areas of demyelinationin 47 lesions from 11 patients with multiple sclerosis. To determinethe quantitative relation between axonal transection and regionsof demyelination and inflammation, we counted the number ofSMI-32–positive terminal axonal swellings in 5 activeand 13 chronic active lesions selected from five well-preservedbrains of patients with multiple sclerosis. Transected axonswithin chronic active lesions were counted in the cores andat the edges of the lesions. The clinical features of the fivepatients are shown in Table 1. One had acute progressive diseasewith a course of only 2 weeks; another had primary progressivedisease with a 5-year course; and three had secondary progressivedisease with durations ranging from 7 to 27 years.
Table 1. Clinical Features of Patients with Multiple Sclerosis Whose Brain Tissue Was Used for Quantitative Studies.
The average number of SMI-32–positive terminal ovoidsper cubic millimeter of tissue was 17 in 11 areas of normal-appearingwhite matter from brains of patients with multiple sclerosisand less than 1 in 5 blocks from four control brains (Table 2).The average number of terminal axonal ovoids per cubic millimeterof tissue was 11,236 in active lesions, 3138 in the demyelinatingborders of chronic active lesions, and 875 in their inactivecenters. All multiple-sclerosis lesions contained significantlymore terminal axonal ovoids than did normal control tissue.Active lesions contained significantly more terminal ovoidsthan the edges or cores of chronic active lesions, and terminalovoids were significantly more numerous at the edges of chronicactive lesions than in their cores. All lesion areas containedsignificantly more terminal ovoids than nonlesion areas in sectionsof brains of patients with multiple sclerosis. These resultsestablish that axonal transection is a consistent and abundantfeature of multiple-sclerosis lesions and that its incidenceis related to the degree of inflammation.
Table 2. Distribution and Number of Transected Axons in Multiple-Sclerosis Lesions.
Discussion
These results establish that axonal transection is a consistentconsequence of demyelination in the brains of patients withmultiple sclerosis. The use of 30-µm-thick sections andcomputer-based three-dimensional reconstruction identified thevast majority of axonal ovoids as terminal ends of axons. Thenumber of terminal axonal ovoids per cubic millimeter of tissueaveraged 11,236 in active lesions, 3138 at the edges of chronicactive lesions, 875 at the centers of chronic active lesions,and less than 1 in white matter from control brains. These resultsare consistent with and extend those of a recent report describingamyloid precursor protein–positive axonal swellings in10-µm-thick paraffin sections of multiple-sclerosis lesions.23Since many multiple-sclerosis lesions have volumes of severalcubic centimeters, these data establish axons as a major diseasetarget in patients with multiple sclerosis.
The finding of extensive axonal transection in multiple-sclerosislesions has important clinical and therapeutic implications.Historically, it has been assumed that the disease process inmultiple sclerosis spares axons. Major therapeutic and researchefforts have been directed toward limiting immune-mediated damageto myelin and promoting remyelination. The treatment of multiplesclerosis remains unsatisfactory, with chronic disease progressionbeing the principal clinical challenge. This report and recentresults from magnetic resonance imaging studies indicate a needfor noninvasive techniques that monitor axonal pathologic changesin patients with multiple sclerosis. The development of neuroprotectivetherapies should become an objective of multiple-sclerosis research.It will be of particular interest to define the consequencesin terms of axonal injury of therapy with high-dose pulsed corticosteroids,commonly used to treat relapses,10 and interferon beta, whichis indicated for patients with relapsing–remitting disease.36,37
The findings in this study provide an additional rationale forearly treatment with drugs that reduce inflammation, since axonaltransection is irreversible and is most abundant in areas ofinflammation. However, the effects of specific antiinflammatorystrategies on axonal integrity will need careful evaluation.Ultimately, neuroprotective factors may be one element of aneffective, comprehensive therapeutic strategy for multiple sclerosis.
Axonal transection was abundant in active and chronic activelesions from patients with durations of clinical disease rangingfrom 2 weeks to 27 years. During relapsing–remitting stagesof the disease, the restoration of conduction along demyelinatedaxons, redundant neuronal pathways, or axonal sprouting maycompensate for the destruction of axons. Our results suggestthat a threshold of axonal loss is eventually reached beyondwhich patients have progressive neurologic deterioration. Ifaxonal pathologic changes begin at the onset of disease, asour data suggest, aggressive early treatment with neuroprotectiveagents should be considered.
Axonal destruction in multiple-sclerosis lesions could resultfrom direct immunologic attack on axons, from soluble inflammatorymediators, or from secondary effects of chronic demyelination.A specific immune attack on axons seems unlikely, because mostaxons survive the demyelinating process and have no consistentassociation with cells of monocytic origin. Since the greatestdegree of axonal transection occurred in areas of active demyelinationand inflammation, we consider it most likely that demyelinatedaxons are vulnerable to inflammatory environments and that axonaltransection is caused by proteolytic enzymes, cytokines, oxidativeproducts, and free radicals produced by activated immune andglial cells.38,39,40
The possibility that chronic demyelination may lead to axonaldegeneration was also supported by the finding of terminal axonalovoids in the centers of chronic active lesions. Myelinationprovides an extrinsic trophic signal to axons that increasesaxonal caliber,41,42 and the loss of this effect can resultin axonal degeneration. Although the precise nature of thistrophic effect is unknown, degeneration and atrophy have beendescribed in mouse axons that are normally myelinated but aredeficient in the myelin-associated glycoprotein.43 As a memberof the immunoglobulin gene superfamily that is localized exclusivelyin the adaxonal membrane of central nervous system myelin,44myelin-associated glycoprotein may directly or indirectly bepart of a ligand system that modulates the maturation and survivalof myelinated axons.
Neurofilaments are the principal constituent of the axonal cytoskeleton,45and their phosphorylation states are dynamically regulated bymyelination, demyelination, and intrinsic axonal pathologicchanges. Developmentally, myelination increases neurofilamentphosphorylation, which in turn increases the lateral extensionof neurofilament side arms.46,47 This increases neurofilamentspacing, axonal caliber, and axonal conduction velocity.42,48In animal models, demyelination or dysmyelination causes decreasedneurofilament phosphorylation, reduced axonal caliber, and anincrease in nonphosphorylated neurofilament epitopes.49,50 Therefore,it was expected that SMI-32 immunoreactivity would be increasedin multiple-sclerosis lesions and that most SMI-32–positiveaxons would appear normal. In addition to axonal transection,two patterns of axonal pathologic changes were identified. DiscontinuousSMI-32 staining similar to that described in axonal degeneration(Figure 2C) provided additional evidence of axonal transectionin multiple-sclerosis lesions. Other axons had significant alterationsin caliber (Figure 2D) and represented damaged axons that retainedactive-transport systems and connection to neuronal perikarya.
Axons distant from multiple-sclerosis lesions also displayedalterations in neurofilament phosphorylation. Although mostappeared normally myelinated, some ended in terminal ovoids.This finding is consistent with the results of magnetic resonancespectroscopy studies that detected reduced N-acetyl aspartatein regions where there were no visible lesions.20 Reduced N-acetylaspartate may therefore reflect potentially reversible axonaldysfunction due to demyelination,51 as well as irreversibleaxonal degeneration distal to sites of transection. Since myelinensheathment governs the activity of the axonal kinases andphosphatases that regulate neurofilament phosphorylation, myelinationmay also modulate the activity of aspartoacylase, the enzymethat hydrolyzes N-acetyl aspartate to aspartate and acetate.N-Acetyl aspartate–derived acetate can be used to makeacetyl coenzyme A.52N-Acetyl aspartate may therefore be partof an energy-storage system in axons that helps meet the energydemands of saltatory conduction. In the absence of myelination,axonal energy demands may be reduced and N-acetyl aspartatelevels diminished. The results of this study highlight the considerableimportance of clarifying the implications of reduced N-acetylaspartate in multiple-sclerosis lesions, and they stress theneed to develop or improve noninvasive methods of monitoringand treating axonal pathologic changes in patients with multiplesclerosis.
Supported by a grant from the National Institutes of Health(R01 NS35058), the Norwegian Research Council, the MultipleSclerosis Society of Norway, and the Rebekka Ege Hegermann Foundation,Bergen, Norway.
We are indebted to Karen Toil for typing the manuscript andto Jeff Cohen for helpful comments.
Source Information
From the Departments of Neurosciences (B.D.T., J.P., R.M.R., R.R., L.B.) and Neurology (R.M.R., R.R.), Lerner Research Institute, and the Mellen Center for Multiple Sclerosis Research (R.M.R., R.R.), Cleveland Clinic Foundation, Cleveland; and the Department of Pathology, Haukeland Hospital, Bergen, Norway (S.M.).
Address reprint requests to Dr. Trapp at the Department of Neurosciences, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195.
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