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(II-1) Tissue Changes in Specific Lesions
Considering the marked differences in mode of disposition, configuration and delimitation of multiple sclerosis spinal cord lesions as against those of the brain, the question arises as to whether spinal patches and cerebral plaques might not also differ in their tissue changes.
Currently both lesion types are referred to simply in the same clichéd histological terms. For the first time, in this book, the instructive original microscopical lesion accounts which unmistakably reflect the specific pictures of multiple sclerosis of the spinal cord and brain will be comparatively analyzed to bring into relief the histological features which distinguish spinal cord from cerebral lesion types.

(II-1-a) Histology of Flank-Lesions of the Spinal Cord
The brownish lesions shown in Plate I extend via a distinct greyish fringe zone. Figg. 1, 1' of Plate II show dark lesion cores encompassed by a differently colored tissue affection. Yet in describing their findings, neither Carswell nor Cruveilhier alerted the reader to the fact that, in the spinal cord, the lesions’ central and peripheral ranges were so different. In suggesting an even discoloration and scarring of all the involved parts, the changes were simply referred to, in the first instance, as "atrophy" and, in the second, as "grey [tissue] degeneration"(24,34)
Presented by Ernst Leyden in 1863, the first microscopical account of pathological findings corresponding specifically to Carswell's "remarkable spinal cord lesion" described only a non-specific nerve fiber degeneration (65). Leyden's specimen was subsequently subjected to Carl Frommann’s far more thorough microscopical analysis (50) and was found to exhibit a number of characteristic histological changes. In the meantime, Charcot's 1865 case report on spinal multiple sclerosis (26) had already indicated some new histological details.

Axons Bared of their Myelin Sheaths
In Charcot's report on that extensive affection of the spinal cord's flanks, which he intuitively considered identical to Carswell's and one of Cruveilhier's observations on spinal multiple sclerosis, an occurrence of denuded axons in multiple sclerosis was made mention of for the first time. In a microscopical study carried out with the assistance of Charles Jacques Bouchard (26), Charcot observed the following: The sclerosed parts consist of a tightly woven fibrillary connective tissue. Already outside their dense cores, the nerve fibers, i.e. both axons and myelin sheaths, appear to be wasting away. Towards the lesion centers this atrophy of nerve fibers is aggravated, until only a few thin, even strangled, axons with very scanty myelin-coverings can be detected. The patches' interiors harbor many amyloid (dead cell) bodies, some interstitial cell nuclei, and scarce "granulations of fat" (representative of agglomerates of degenerated myelin or myelin-stuffed scavenger cells).
Charcot concluded his descriptions: "In the outermost part of the [spinal cord's] lateral columns, where the nerve fibers are the most rarefied, one observes, here and there, axons which are completely devoid of their myelin [sheaths]. The spinal cord's central grey matter, nevertheless, does not show any perceptible alterations; all nerve cells encountered are in their normal state" (26).

Frommann: Primary Fiber Hypertrophy and Fibril Hyperplasy
The most exacting microscopic analysis ever made of the specific involvement of the spinal cord's sides was presented by C. Frommann in 1867. The results of his countless painstaking observations, illustrated in meticulous detail, can only be offered here in a very condensed form.
The specific patches' zonal differentiation: As the figures of Plate IX particularly well demonstrate, the microscopical picture of the distinctive spinal cord lesions presents various peculiarities: Not only do tissue changes extend beyond the directly visible lesion domains, but the structural changes within the individual patches also show a spatial gradation into different zones (Plate IX, figg. C and D). Rather than summarily rendering the modifications of the different tissue elements, Frommann carefully analyzed the ways in which every tissue component had been changed in each of the succeeding lesion zones. He reported the following: The lesion's basal, i.e. most lateral, zone (Plate IX , fig. F) extends for about one millimeter underneath the pia mater, the spinal cord's fibrous covering. Here the interstitial fibrous meshworks appear broadened and eventually tend to fuse. The changes extend first along fibrous septa and vessels -- main braces of the involved areas' mechanical framework – to subsequently encroach upon the nets of connective tissue fibers extending between the individual nerve fibers. Finally, this process is seen to advance upon and gradually occupy the nerve fibers' space.
In the basal lesion zone, with its shrunken and often grossly distorted connective tissue meshes, the nerve fibers have generally disappeared. A few axons are bared of their myelin sheaths, or invested with oversized ones. Figure F of Plate IX reveals that a mere swelling of myelin sheaths occurs side by side with a complete melting down of connective tissue structures to homogenized lumps or layers.
Plate IX, figg. C and D best demonstrate what Frommann described as the lesion's "second zone", the patch's densely fibrosed core. Here, except for a few thick-walled blood vessels that enter the cord's sides in deep-reaching tissue clefts, the picture of the cord's normal tissue fabric has been entirely effaced by a dense feltwork of very fine glia fibrils (very fine fibers of indigenous connective tissue), which are responsible for the patch's striking firmness. The dense fibrillary transformation of the lesion core is not really homogenous but interlaced with less severely fibrosed areas. Thus even fully scarred regions sometimes appear broken up by stripes of minimally altered tissue (Plate IX , fig. C) containing grouped axons and even whole nerve fibers.
Frommann's most interesting picture, however, presents the lesion's third zone, its zone of transition to normal tissue. The drawings of a lateral lesion’s deep – cf. Plate IX, fig. C -- and posterior front or, more precisely, fringe zone – cf. Plate IX , fig. D – illustrate how the changes typically advance: Out of the lesion core, consisting of a dense felt of very fine fibrils, issue numerous spiky, angulated, even barbed processes, evolving by way of a progressive broadening of already previously conspicuous connective tissue structures. The various peaks of the lesion’s advancing edge represent simply a fluid transition of such abnormally broadened fibrous structures into normally prominent ones.
In focussing as closely as possible on the minutiae in the changes of the different tissue elements, Frommann made several pioneering observations:
  1. Investigating the behavior of the (astro-)glia fibers (the connective tissue structures proper to the brain and spinal cord), he noted that the involved fibrous tracts develop at first a strikingly dense outline and abnormal breadth, to even more than a sixfold extent of their normal size.
  2. Once the structures have attained a certain thickness, tiny fibrils begin to form, at first inside their most condensed parts, and then to spread out of poorly delimited segments of the broadened fiber tracts’ edges.
  3. To Frommann's surprise, invasions of glia fibrils into the spaces of the nerve fibers were already traced before the nerve fibers or myelin sheaths were altered. Frommann therefore concluded that the initially perceptible hypertrophy and hyperplasy of the affected connective tissue structures had to represent the lesion cause. 
Conceiving of the lesion simply as an excessive overdevelopment of particular connective tissue structures appeared all the more justified in light of other findings, such as those testified to in figures E and F of Plate IX , namely accumulations of astroglia cell nuclei, a progressive outgrowth of new fibrils from sprawling fibrous structures, and even complete fusions of all sorts of connective tissue structures amidst, or directly adjacent to, not visibly altered nerve fibers and myelin sheaths. Curiously, old as well as newly formed glia structures could melt down, i.e. become affected by degenerative homogenizations, during any stage of their broadening or fibril formation.
Blood vessels played a curious role. Figures C and D of Plate IX show that especially the lesion's dense core tended to be broken through by strong blood vessels entering the spinal cord's sides in deep-reaching tissue clefts. Ruptured glia fibers or fibrils projected into part of these clefts. Frommann observed that the opening up of these clefts could only be understood as the effect of some mechanical impact.
An initial glia fibril formation, comparable to the one observed along broadened fibrous septa, also preferentially set out from definite lesion vessels, especially from the angles of their branchings. Along the affected vessels, newly formed fibrils frequently melted into circumferentially arranged layers of homogenized tissue, accumulating in definite directions off the vessel walls. Thus these vessel-based fibril growths and fusions tended overall to be contoured like mountain ranges.
Very early on in the progression of the affliction the small vessels pervading the patches' farthest extensions showed uneven thickenings of their walls and bizarre protrusions into their openings - some of which protrusions were bulky enough to block the vascular passage. Yet despite the frequency of these changes, not a single thrombosed vessel was found.
Regarding the nerve fibers, the losses of myelin-sheaths were very conspicuous. But also the axons showed manifold abnormalities, sometimes even within a not visibly altered myelin sheath. Gross axon swellings occurred, often in series along a nerve fiber's course. Elsewhere the axons -- as figure E of Plate IX demonstrates –- had perished in entire groups or rows. What was thus wasting away were both axons and myelin sheaths, the axons vanishing but more slowly.
Where lesions eventually had reached the spinal cord's central grey matter, nerve cell damages -- abnormal pigmentations, granulations, layered condensations of the cell periphery, wasted cells, dead cells -- were equally obvious.
Noticeably, even with severe tissue destructions, neither in the nervous tissue nor in its perivascular spaces were any fat granule cell (scavenger cell) accumulations or round cell (immunocyte) infiltrations to be traced.
As to the dynamics of the lesions’ spread, Frommann confirmed Carswell's conclusions that the specific changes had first involved the spinal cord's lateral periphery and from there gradually proceeded centrally (50). But the questions were apparently never addressed as to 1) why the lesion domains extend in this peculiar way, 2) why definite fibrous structures become primarily modified, and 3) why also the other tissue components undergo the changes detailed above.

Lauenstein's "Myelitic Softenings"
Findings recorded by Carl Lauenstein in 1877 illustrate spinal multiple sclerosis, in a peracutely lethal case, not with sclerosed patches, but with circumscribed softenings. A comparison of the lesion patterns presented in Plate I and Plate X , i.e. of Carswell's standard instance of multiple sclerosis and Lauenstein's instance of "myelitis", leaves no doubt as to formal identity of the former's scars and the latter's softenings. But as to histological characteristics, Lauenstein's specimen differed distinctly from that of Carswell: From the third cervical down to the first thoracic segment, the entire spinal cord appeared somewhat soft. Although the local blood vessels proved conspicuously engorged, there were no indications of their being otherwise affected. The actual tissue softening was limited to the spinal cord's most lateral parts. Here, both interstitial connective tissue structures and nerve fibers showed an abnormal coloring, the fibrous glia tracts appeared swollen, and their cells distinctly enlarged. Mainly in the surroundings of the lateral lesions' larger blood vessels, the tissue's continuity was interrupted by homogenously filled tissue clefts which were yet not directly continuous with the perivascular space.
Microscopically, the following observations were made: In the lateral lesions' central halves, all nerve fibers were abnormally intensely colored. Axons were hardly discernible from myelin sheaths and appeared at best as very fine points. The terminal lesion extensions were again chiefly characterized by axon swellings differing remarkably in intensity from region to region. Along the individual axons' courses, circumscribed balloonings and even corkscrew-like distortions -- see Plate X , lower right-hand corner -- tended to recur. However, the lack of a myelin sheath on a nerve fiber appeared to be due simply to the fact that the axon completely occupied the nerve fiber's space.
In addition, Lauenstein observed, outside of the actual flank lesions, a sporadic occurrence of swellings of definite clusters of axons or nerve cells distributed in a pattern of rounded dots shown on the spinal cord cross-sections of Plate X . Supposing that these foci had developed without a direct structural connection to the specific lateral lesions, they had to be considered the result of some complications such as ischemic events. At any rate, neither here nor in the specifically affected areas were any perivascular white blood cell immigrations or scavenging fat granule cell accumulations to be traced (64).

Dawson: Diverse Spinal Tissue Changes
In his monumental work on "disseminated sclerosis," James Walker Dawson did not refer to any of the specific observations of multiple sclerosis mentioned above. Among the nine specimens which Dawson described, there is only one in which the distinctive traits of both spinal and cerebral multiple sclerosis can be reliably identifed. For no obvious reason, Dawson's investigations concentrated mainly on this, his first, standard specimen. The results of these researches are of the utmost importance as they offer an unmatched opportunity for a direct comparison of the tissue changes of specific lesions of both spinal and cerebral multiple sclerosis.
In his attempt to elucidate and define the overall lesion nature, Dawson focussed primarily upon the development of histological changes. Curiously, although the damages to the spinal cord’s sides and its posterior flank appeared attributable to the same kind of injurious events, the respective tissue changes were in fact decidedly different.
The classic affection of the spinal cord’s sides was found to evolve as follows: In the lateral lesion domain any connective tissue formation, from fibrous septa, tracts and strands down to the finest interstitial meshworks, broadens, appears more and more condensed, and then bursts out in a feltwork of sprawling fibrils which subsequently tend to fuse. Amidst all these changes, the fiber and fibril-forming astroglia cells, as well as their processes, remain unusually prominent for long periods of time.
Simultaneous with the onset of the glia fibril formation in the affected zones, myelin sheaths and axons begin to dwindle away. These changes evoke the impression that the nerve fibers are being directly encroached upon and finally strangled by a circumferentially advancing fibril hyperplasy. The involved vessel walls also begin to thicken and condense, though at a slower pace. Throughout all of this only negligible perivascular inflammatory cell infiltrations, as well as fat granule (scavenger) cell developments, occur.
Prominent fibril formations also emerge preferentially from the local blood vessels' rather protractedly thickening walls. In their cross-sectional image, the perivascular fibril growths typically radiate in the form of a "corona ciliaris". Ultimately the ubiquitous sprawling of glia fibrils culminates in the formation of a dense fibrillary feltwork spreading throughout the entire affected area.
The lesions of the spinal cord's posterior flank, extending from its median and paramedian septa, show a different development. The onset of the injurious activities here is typically heralded by a swelling of only interstitial glia cells, followed soon by a comparable swelling of all other tissue elements. These tissue swellings are accompanied by plain vascular engorgements of a minor degree.
In the posterior lesions' marginal or transitional zones, the whole nerve fibers appear, from the outset, distinctly enlarged, and the myelin sheaths in the lesions' depth are often found to have broken apart. The axons, on the other hand, retain a swollen configuration, though entire groups of them may also break apart.
As a reaction to the injury throughout these posterior lesion areas, massive proliferations of both astroglial and scavenger cells arise. The scavenger cells' incorporation of debris quickly gives them the appearance of fat granule cells, and they leave the lesion site by way of neighboring perivascular spaces. In the typical posterior spinal lesions, an interstitial fibril formation and mild perivascular infiltration of lymphocytes, i.e. immunocytes, can only be traced from this stage on.
While studying the tissue changes of an unquestionable specimen of multiple sclerosis, Dawson, as previously Frommann, also discovered that it is not a breakdown of myelin sheaths but a swelling of interstitial tissue structures which first heralds spinal lesion developments. Similar to Frommann, Dawson again considered this initial hypertrophy and hyperplasy of local connective tissue structures to have been provoked by the causal agent itself (35).

(II-1-b) Histopathology of Cerebral Plaques
As to the distinctive lesions of the brain, it is extremely important to discover the cause(s) of their evenly affected lesion areas’ typically closed and rounded delimitations, which stand in stark contrast to the spinal patches' fraying out into irregular fringe zones. The fact that only the brain plaques appear so smoothly punched out obviously has a particular physical reason, and the most comprehensive and reliable information on this point was provided by Dawson.
The following is a summary of his standard account:
Regarding the primary histological changes, the cerebral plaque's domain does, as a whole, not differ essentially from the posterior spinal patch's border zone. Initially, everywhere in the lesion area, up into its outermost periphery, there is a swelling and massive proliferation of astroglial and scavenger cells. External to such a plaque border a few relatively small interstitial cells, each exhibiting a fairly round and dense nucleus, have begun to multiply. Yet there also are cerebral plaques whose entire domains are evenly marked; up to their outermost front; by an immediate destruction of nerve fibers, i.e. both axons and myelin-sheaths. Around corresponding lesions there is a scattering of fat granule cells rather than -– as in the posterior spinal lesion -- a swelling or hypertrophy of interstitial cells.
In the cerebral plaques themselves it is again the myelin sheaths which are commonly more affected. But also the axons show swellings, vesicular distensions, and even complete disintegrations throughout. In the brain lesions, the axons generally appear to be more severely damaged than those in the patches of the spinal cord. In keeping with this, both myelin sheaths and axons are, in the cerebral plaque domains, often broken up into fragments. Thereby globules and granules representing the axons' remains are still lined up in rows, or also scattered into neighboring tissue meshes. Occasionally, axon fragments appear amassed into greater clumps. or may already be found incorporated into scavenger cells.
Overall, the emergence of the cerebral plaques shows a distinct relationship to definite particularly conspicuous blood vessels, which appear –- often together with their perivascular spaces -- from the outset extraordinarily engorged and enlarged. And also in the brain the changes of the different local tissues regularly precede any degenerative and inflammatory changes of the walls of the lesion vessels themselves.
In the cerebral plaques, comparable to the subacute posterior spinal cord lesions, slight infiltrations by small round cells, of perivascular spaces and tissues are occasionally to be found. Because of their late and slight appearance, Dawson interpreted these reactions (and with this any local immunocytic activity) as being of a secondary nature, having been provoked by the perivascular accumulation of debris-laden scavenger cells (35).

(II-1-c) Spinal and Cerebral Multiple Sclerosis: The Same, and Yet Not the Same
The most important and characteristic feature of multiple sclerosis lesions, in Dawson's view, was the presence of densely ordered rows of large astroglial and fat granule cells in spaces normally occupied by nerve fibers. However, this lesion specification stood at variance with Dawson's own observation that there are not scavenger cells but rather a primary interstitial fibrosis in the classical lateral lesions of the spinal cord. Dawson considered that the lateral spinal cord patches' common lack of fat granules and small cell infiltrations might be attributable simply to a slighter degree of injury. The posterior spinal lesions and cerebral plaques were in fact marked by more massive devastations, but crudely broken-off myelin sheaths and rows of axon fragments also occurred in the lesions of the spinal cord’s sides.
One additional consistent histological lesion characteristic was the particularly intense scarring of the affected regions. The fibrotic connective tissue reaction was found to be more vigorous than that resulting from comparable central nervous damages of a different origin, not only in the spinal patches but also in the cerebral plaques. But contrary to the situation in the spinal cord's sides, in the brain and posterior spinal cord, the glia fibrils’ exuberant sprawling evolved only in the final lesion stage.

As to cerebral plaque development, Dawson's findings were quite revolutionary. Since Frommann the pathological changes in the spinal cord's sides had been thought to originate in a primary interstitial fibrosis. Dawson was the first investigator to show that, although related, the tissue changes in spinal and cerebral lesions do not necessarily evolve in the same way: In the brain the affection appears, microscopically, not to be marked by a primary fibrillary gliosis. Considering this plain fact, the nature and cause not only of cerebral multiple sclerosis but also of multiple sclerosis as a whole had to be envisaged from a new and different perspective.
Although Dawson noticed that also along the cerebral plaques' most prominent vessels the interstitial glia cells very early grew larger and proliferated vigorously, he emphasized that the fibrotic tissue transformation here only became evident after a distinct delay. He also discovered that, as Frommann had found in the spinal cord, firmly sclerosed zones in the brain tended to be preferentially perforated by large perivascular tissue defects. Entire branchings of lesion vessels coursed in wide, round perivascular hollows whose diameters, according to Dawson's illustrations, could reach a sevenfold width of the blood vessel they contained. But, especially regarding their tight and smooth circumvallation by densely compressed fiber layers, these yawning perivascular spaces stood in stark contrast to the vessel-related clefts or tissue lacerations entering the specifically affected cord sides.
As to the role of blood vessels in these lesion developments, Dawson's findings again underlined the fact that both the specific spinal patches and cerebral plaques first appeared near major vascular stems, and then advanced in the direction of the vascular periphery. But neither in the spinal cord nor the brain were the lesion vessels themselves ordinarily subject to more than rather protracted and not strictly lesion-related thickenings and degenerative scarrings of their walls.
Instead of demonstrating histological features peculiar to multiple sclerosis itself, Dawson's microscopical findings thus simply underscored the manifold, locally differing ways in which all the tissue constituents can become altered. Thereby, the histological manifestations of the cerebral plaques’ and spinal patches’ development were again found to differ in several important -- and yet widely neglected – respects, i.e. especially in the local vascular, perivascular, and connective tissue changes.

(II-2) Histological Lesion Categorizations
The name of a disease may rightly be expected to tell something definite about its nature and cause(s). Having reconsidered the macro- and microscopical post mortem evidence which reflects most clearly the distinctive traits of the classic standard examples of spinal and cerebral multiple sclerosis, we are left with the task of clarifying why and how this condition has come to be categorized not in macropathological but in histological terms, although it was at first clearly specified by the aforementioned naked-eye findings, i.e. on the basis of macroscopically unique lesion patterns.

(II-2-a) From "Atrophy" and "Grey Degeneration" to "Multiple Sclerosis"
Carswell did not directly say that his "peculiar diseased state" was characterized by its distinctive mode of involvement of the spinal cord's flanks alone. But his reference to solely non-specific lesion properties – by cataloguing the lesion simply as a kind of "atrophy" and describing it merely as consisting of a number of yellowish brown and semi-transparent, firmly consolidated areas – also did not really constitute a specification of multiple sclerosis in histological terms.
In the same way, Cruveilhier, in his second, more detailed topical report describing the lesion's preferential involvement of the spinal cord's sides and posterior flank, did not point to this lesion pattern's singularity. Instead, he indiscriminately referred to both his specific findings and a further number of essentially different cerebrospinal lesions -- in fact, to all the damages which Plate II illustrates -- simply as "grey degenerations".
Only Charcot's first specimen of multiple sclerosis, embodied by a spinal cord whose two sides were taken in by two long, boat-shaped patches (in which demyelinated axons had been found), was presented as a specific observation of "sclerosis of the lateral columns of the spinal cord" (26). The affection of the spinal cord’s sides by two symmetrical, inward-pointing, wedge-shaped scars was here, for the first time, defined as "sclerosis". And yet, although Charcot placed his case of lateral spinal cord sclerosis side by side with Carswell's and Cruveilhier's essentially identical observations, he also seems not to have been fully aware of the lesion pattern's specificity. He ultimately dubbed the condition rather ambiguously as "disseminated sclerosis in the form of circumscribed plaques", or "sclerosis in plaques" for short (26).
Ordenstein's 1867 thesis presented a specimen with clearly multiple sclerosis-specific lesions not only of the spinal cord (impressive sketches of its bilateral flank involvement are filed in Paris’ Bibliothèque Charcot) but also of the brain. Here, for the first time, this condition was spoken of simply as a multilocular scarring or hardening, and the peculiar pathology was designated as "multilocular sclerosis" or "multiple sclerosis" for short, mainly to stress the concurrence of cerebral and spinal affections -- traceable by clinicians (26).
The shorter name variant "multiple sclerosis" has meanwhile found general acceptance -- also in referring to lesions affecting either brain or spinal cord alone.

(II-2-b) Multiple Sclerosis: Primarily a Fibrous Overgrowth?
From Carswell's and Cruveilhier's lesion descriptions it was obvious that, in the specific lateral spinal patches' domain, the tissue had become firmly fibrosed, -- the nervous tissue had become widely substituted by dense connective tissue structures. But neither report revealed anything peculiar to the fibrosis itself.
Charcot, who first referred to the specific spinal cord injury simply and specifically as "sclerosis", merely noted that the lesion's greyness and translucency appeared, under the microscope, to be due to an increase in fibrillary connective tissue occupying the nerve fibers' spaces, giving the impression that, on account of its growth, the still existent nerve fibers had directly been forced apart.
Frommann's microscopic studies first provided actual proof of a primary hypertrophy and hyperplasy of fibrous structures evolving in, and progressively extending from, the initially affected stretches of the spinal cord's flanks. The fibrosis was traced to a sprawling of fibrils within and out of particular, primarily strengthened stretches of the lesion domains' connective tissue structures, and this fibril development even appeared to have advanced upon intact nerve fibers.
Beginning with Dawson, no single direct demonstration, but only three fragmentary documentations on the spinal cord’s specific flank affection (35,135,92), can be traced –- a trend coinciding with a luxuriant, still ongoing spread of ill-founded speculations on the essence and causation of (not only spinal) multiple sclerosis. Strasbourg psychiatrist M. Rosenfeld’s bold statement that it was by no means clear what was actually peculiar to multiple sclerosis and that it had never been shown how multiple sclerosis was to be differentiated from scars of a different nature (115) was discreetly passed over in silence.

(II-2-c) Multiple Sclerosis – The Prototypal Demyelination?
Modern authors commonly refer to multiple sclerosis as a “demyelinating disease”, characterized above all by a random destruction of myelin sheaths around preserved axons (86, 154, 116). Multiple sclerosis has even been hailed as the archetype of all demyelinating diseases and as the standard of reference by which all other primary myelin diseases are to be evaluated (110).
In thus conceiving of the disease simply as a multilocular, randomly distributed myelin destruction [of unknown cause], it has even been stated about its lesions that “the plaques are commonest in the white matter, for it is here that myelin is present in greatest amounts” (85).
However, the question immediately arises: How can the multiple sclerosis-specific fibrosing wedges extending into the spinal cord’s sides, and the compact plaques projecting off of the cerebral ventricles be reconciled with a lesion interpretation in terms of a systemic, randomly distributed myelin affection? To answer this question, the historical reasons for defining multiple sclerosis as a “demyelinating disease” must be detailed and explained.

Early Emphasis on the Significance of Demyelination
In 1868, Charcot presented a case in which brain and spinal cord specimens were said to have been affected by “multiple sclerosed plaques” - plaques which were thereafter microscopically specified through their lack of myelin (sheaths) or, more precisely, a “suffocating of the myelin [sheaths]” by connective tissue proliferations (27). Charcot’s co-worker Bouchard, eager to characterize multiple sclerosis in more distinctive histological terms, particularly emphasized that, in the demyelinated plaque centers, the axons had remained conserved. For Bouchard this explained the lack of secondary (nerve tract) degenerations in multiple sclerosis (15, 16). Fascinated by these microscopic findings, both researchers revealed nothing about the lesions’ additional properties, in particular their distribution patterns, and, in particular, whether they also corresponded to Carswell’s “peculiar diseased state”.
A further paper of Charcot’s, which is customarily quoted as having primarily determined the specifically demyelinating nature of multiple sclerosis, appeared half a year later (28). Forming a record of Charcot’s lecture on the subject of the condition’s histology, its text was soon directly incorporated into Charcot’s famous textbooks on neurology and so became part of the basic teachings on “multiple sclerosis” (29). Here Charcot made the abstract claim that a “permanent persistence of a certain number of axons amidst the most dense fibrillary tissue transformations constitutes a feature which appears peculiar to multiple sclerosis,” which statement was later qualified by the remark that “it [the survival of demyelinated axons] is certainly not to be observed, at least to the same degree, in the other forms of grey degeneration” (29) This particular “exclusive demyelination” was not found to be distinguished by any other peculiarities –- and the damage was said to be perfectly identical in appearance to the decay observed after the sectioning of a peripheral nervous trunk.
For Charcot the ultimate cause of multiple sclerosis was a “neoplastic” fibril formation. Relying heavily on his studies of Frommann, Charcot arrived at the conclusion that the observed fibrosis (in spinal multiple sclerosis) was “the initial and fundamental fact, the necessary antecedent of lesion development” (28,29). This fibrosis was supposedly set off by some “formative irritation” of the involved part’s connective tissue fabric. The reasons for these postulates, however, were not made plain. Since they were not provably derived from precisely specified findings, Charcot’s generalizations on multiple sclerosis thus appear hardly better founded than his and Bouchard’s earlier lesion characterizations. In the end, Charcot had to admit: “It remains to be determined which histological characteristics distinguish it [multiple sclerosis] from other forms of sclerosis of the nerve centers.” (28)
Although widely lauded as having established multiple sclerosis as the prototypal demyelinative disease, Charcot in fact provided no concrete evidence to prove that the causes of this particular kind of lesion actually lay in either some primary, or some specific, or at least some selective form of demyelination.

Establishment as a Myelin Affliction
The above-mentioned rather indefinite propositions apparently paved the ground for more decided articulations of the belief that multiple sclerosis merely constituted a primary cerebrospinal demyelination. It is revealing to trace how the breakthrough toward this new conception of multiple sclerosis was brought about.

Marie’s Mission
The first researcher to directly postulate that multiple sclerosis was characterized by selective demyelination was the progressive, somewhat impetuous Parisian neurologist Pierre Marie. In his 1892 “Lectures on the Diseases of the Spinal Cord” (82) he explicitly declared that, while the myelin sheaths dwindled in the course of the disease, the axons in the lesions of multiple sclerosis were ordinarily left intact. Marie even asserted that any axon loss in a (multiple sclerosis-) specific lesion had to be regarded as purely incidental, a mere accident. His evidence on the subject consisted solely of a few crude drawings of some gross damages to brain and spinal cord, evidence which, in its essence, corresponds neither to Carswell’s “peculiar diseased state” nor to the specifically related cerebral damage first demonstrated by Charcot. Nonetheless, Marie’s statement that selective myelin destruction “dominates, both in clinical and pathological respects, the entire history of this affection” (82) became accepted dogma.

Marburg Establishes Myelinolysis
In 1906, the Viennese neurologist Otto Marburg defined what he imagined multiple sclerosis to be directly in terms of a discontinuous (multifocal) myelin sheath destruction with initially absolute, and later relative, axon preservation (75). According to his established notion of these particularly acute kinds of “periaxial”, i.e. peri-axonal, myelin losses, multiple sclerosis commonly began to be conceived of as a "myelin disease". The experimental evidence for his thesis resulted from applying a lipid-splitting enzyme to a frog’s nerve, then observing the damages, which, according to Marburg, strikingly resembled those of multiple sclerosis. This led him to conclude that the process of multiple sclerosis revealed itself as a chemical lysis of the myelin sheath (75, 76). And this research into the cause of multiple sclerosis opened up a new, biochemical dimension.

Pette: Converting Multiple Sclerosis Into Multifocal Demyelination
The re-interpretation of multiple sclerosis as primary demyelination was promoted chiefly by the industrious and pragmatic neurologist Heinrich Pette of Hamburg, who first supported Marburg’s multiple sclerosis conception by declaring that mere “discontinuous demyelination [myelin loss of separate segments of an axon’s length] is so peculiar and unique an event as to justify the corresponding lesions’ being set apart as a distinct group of the acute inflammatory diseases of the central nervous system” (98).
Pette autocratically dictated that every cerebrospinal lesion development was marked only in its final stages by fibrosis and sclerosis. Demyelination, in contrast, was the cardinal, most reliable identifying characteristic of multiple sclerosis. This multiple sclerosis had in fact just one unique and fundamental feature, demyelination. Entirely taken in by the conception of (primary) demyelination, Pette even wrote that the typical myelin involvement of multiple sclerosis had already been documented by Cruveilhier.
In high-handedly denying the existence of any form of primary sclerosis, Pette discarded as invalid the entire histological evidence, from Frommann up to Dawson, on instances of multiple sclerosis characterized by a primary fibrosis of the spinal cord’s flanks. Pette even declared that findings of a massive sprawling of fibrous tissue excluded a diagnosis of multiple sclerosis (97, 98, 99, 100). Unacquainted with the post mortem observations by which multiple sclerosis had originally been specified, Pette in the end thus even denied the existence of any corresponding histological evidence.
Because it has never been substantiated by any concrete and specific specimens, it is no wonder that the concept of “demyelination” has always remained a dubious one: No single qualitative or quantitative criterion for reliably identifying a “primarily demyelinating lesion” has ever been presented. Even quite recently this indefiniteness of lesion categorization was confirmed by the statement that, to figure in the illustrious class of the “demyelinating diseases”, a pathological condition had to show demyelinations which were “predominant and not only prominent” (4).

(II-3) "Selective Demyelination": The Facts
A reconsideration of the original reasons for defining multiple sclerosis as "the prototypal demyelinating disease" shows that demyelination has never proved distinctive of any particular case or form of multiple sclerosis. Findings of demyelinated axons contributed, even less than the damaged areas' changes in color and consistency, to the identification of any multiple sclerosis-specific affection.
Because of their crucial importance, the prime histological features of the classical multiple sclerosis-specific observations will here be summarized. In the specifically involved parts of the spinal cord's flanks, a dwindling, or actual breakdown, of both axons and myelin sheaths takes place. Although preferentially the myelin sheaths tend to be injured -- some of the surviving axons appearing bared of part of their sheaths -- axons are more or less regularly lost as well. And axons, no less than myelin sheaths, are affected by swellings and various other changes, at times also in isolation (35, 50). In addition there are findings of myelin sheaths apparently simply squeezed out by their axons’ balloonings (64).
According to Dawson's observations, the proportions between the numbers of affected axons and myelin sheaths must vary enormously, depending also on the lesion locations. In the gradually extending patches of the spinal cord's sides, the axons seem to persist more frequently, while a more intense axon breakdown appears to be typical of the posterior damages to the spinal cord. In the cerebral plaques, both myelin sheaths and axons tend to be evenly injured throughout.
These observations show clearly that a principle sparing or consistent intactness of the axons is by no means a feature of multiple sclerosis. The manifold changes affecting not only the involved myelin sheaths, but also all other sorts of local tissue, show that it is grossly oversimplified to picture the process of multiple sclerosis merely as a "peeling off of the axons' myelin sheaths". The fact is that myelin sheaths in particular have never been shown to be altered in any way which might be considered multiple sclerosis-specific.

(II-3-a) Primary Demyelinations: A Commonplace Phenomenon
In light of what has been said above, there is little sense at all in upholding conjectures about the causes of "multiple sclerosis-specific demyelination". However, light can be shed on the reason(s) for the tendency of myelin sheaths to primarily fall prey to the process of multiple sclerosis, if comparable kinds of injury patterns, not only of the myelin sheaths but also of the other tissue elements – such as vessels, perivascular and other connective tissue structures -- are taken into consideration.
There has never been an objective evaluation, let alone a comprehensive survey of, any agents which might be capable of altering not only myelin sheaths and axons but also other cerebrospinal tissue elements in the way called attention to by Carswell's, Charcot's, Frommann's or Dawson's classical lesion characterizations. Instead, among the vast array of pathological conditions in which a prominent loss of myelin sheaths has been observed, the lesion damage of multiple sclerosis has, from the beginning, simply been compared to types of damage caused by blood-borne scatterings of tiny corpuscular agents or particles of inanimate matter.
The strikingly close analogies between the tissue changes of multiple sclerosis and those tissue changes resulting from diverse modes of plain mechanical trauma have gained remarkably little attention. Demyelinating brain lesions resulting from mechanical injuries have only in the past few decades been accordingly designated as "plaques simulatrices [of multiple sclerosis]", or as "false", "fool's" or "pseudo- [multiple sclerosis] plaques" (70, 72).
However, other comparable changes were already noted much earlier. Both in 1852 and 1855 Ludwig Türck observed that, where olfactory and optic nerves had been exposed to expansile processes, a glutting of fat globules, fat granules and fat granule cells indicated massive myelin decay, while the axons appeared rarefied in only one case of four (141, 143). In 1895 Bikeles noted that spinal cord concussion tends to damage and destroy myelin sheaths much more extensively, much earlier and more severely than it does axons (12).
In 1916, contemporaneous with Dawson's account on multiple sclerosis, Aubrey Mussen reported on several indirect war missile injuries to the spinal cord, comprising damages fairly remote from bullet or shrapnel impact. The recurrence of gross axon distortions and swellings along individual nerve fibers was deemed to be the most remarkable finding. But observations of swelling, squeezing out – as in Lauenstein's 1877 account -- or breakdown of myelin sheaths and of damages to their fibrous encasements were noted as well. Debris appeared incorporated by "myeloclasts", amoeboid scavenger cells, and it even turned up in endothelial cells, i.e. in cells of the blood vessels' inner linings (88).
The injuries were found to extend typically along particular fibrous septa, i.e. sheets of connective tissue, inserting radially into the spinal cord's periphery. Along their course, and deeper within the cord's substance, preferentially where septa and vessels met, there occurred gaping tissue clefts – closely resembling those which Frommann had illustrated in 1867 (50). Here injuries had, as in multiple sclerosis, obviously spread primarily by way of prominent strands of the spinal cord's mechanical framework.
The most striking aspect of the traumatized areas, in the second week after injury, was not so much the emergence of vascular congestion and marked proliferations of interstitial cells, but a very rarely observed phenomenon. Along altered stretches of the spinal cord's interstitial framework -- again mirroring Frommann's observations on spinal multiple sclerosis -- the following changes occurred: From previously ruptured or broadened stretches of the spinal cord's fibrous interstitial meshworks, there sprouted fine fibrils, which encroached upon the nerve fibers' circumferences. The latter tended to become replaced by a feltwork of sprawling, often interlaced fibrils, and the normal tissue structure was substituted by dense fibrillary scarring (88). On protruding intervertebral disks, circumscribed pressures of a minor degree were later observed to lead to a demyelination of the affected nervous tissue, just as already intimated by Türck in the 1850’s. Here again, together with the demyelinations, marked, co-extensive proliferations of the fiber-forming interstitial tissue emerged, culminating in the formation of dense fibrillary feltworks (73).
Since then, axon demyelination has been studied in minute detail by exposing nervous tissues to localized mechanical impacts (37, 52, 59). It has been demonstrated that, for compression to cause a peripheral nerve's demyelination, the tissue must be warped fairly energetically (89). But as for spinal bulb and spinal cord, a repetitive swashing with minor quantities of cerebrospinal fluid sufficed to cause the exposed parts' surface demyelination (19, 83). Because of their nonspecificity, the occurrence in multiple sclerosis of comparable changes will not be discussed here.
Sharply circumscribed areas of demyelination contiguous with the outside of arterial bends, i.e. of the tissue primarily exposed to local pulsatile impacts, have also been found in cases of arterial hypertension (163). This "status prae-cribrosus" most likely evolves into smooth periarterial hollows, which occasionally riddle the brain's substance in the form of a "status cribrosus" -- in close resemblance to Dawson's perivenous hollows of cerebral multiple sclerosis.
Of all the mechanically caused direct primary demyelinations referred to above none has ever been shown to differ, in any essential histological detail, from the primary demyelinations in specific pathological instances of multiple sclerosis. Not only as to the diversity of the ways in which the different tissue elements are changed but also regarding their manners of spread, the microscopic findings of multiple sclerosis and slighter mechanical traumata parallel each other to a remarkable extent.

The Myelin Sheaths’ Exceptional Mechanical Vulnerability
Neuropathologists have sometimes proposed that any edema, in fact any intense vascular seepage or leakage into some part of brain or spinal cord, whatever the causes, preferentially damages the myelin sheaths. One researcher even posited that there is no demyelination other than that attributable to perivascular edema (144). And yet the reasons for the particular vulnerability of myelin sheaths to such a "trivial" factor have scarcely ever been specifically addressed. This seems to be due to an insufficient awareness of the pathogenic implications of the utter delicacy of the tissue bridges joining –- in the brain and spinal cord alone -- a number of myelin sheaths individually to one particular oligodendrocyte. Each of these bridges constitutes a bottleneck in its myelin sheath's supply line. The particular frailness of a myelin sheath's connection to its nutritive center, the oligodendrocyte cell body, and the vital role played by the connection in the sheath's evolution and preservation, were not taken note of until quite recently -- although the myelin sheath's individuality apart from the nerve cell's axonal extension was already detected at the time of Carswell's first documentations of multiple sclerosis.
It was only at the beginning of this century that oligodendrocytes began to be differentiated from the other central nervous interstitial cells (36, 88). And even after it had been shown, in the early sixties, that myelin sheaths are formed, and their losses substituted for, by oligodendrocytes (20), it was still thought possible that mature myelin sheaths might persist independently of oligodendrocytes (21).
Not until 1980 was it pointed out that the frailness of the tissue bridges between oligodendrocytes and myelin sheaths might directly account for the brain and spinal cord tissues' special proclivity towards primary demyelinations. The occurrence of pure demyelinations in any form of cerebrospinal edema was then explained by the fact that whenever particular oligodendrocytes and their myelin sheaths were abnormally driven apart, and their connections broken, the myelin sheaths would presumably decay (25).
Both in peracute spinal multiple sclerosis and as a result of recent mechanical injuries to nervous tissues, it was eventually noted that a myelin sheath can also be damaged by being squeezed out between a massively swelling axon and the particular nerve fiber's unyielding fibrous encasement (64, 88, 89).

(II-3-b) Reverberations of a Histological Misspecification:
Demyelinated axons were first described not in multiple sclerosis but in tabes dorsalis, a common complication of syphilis in the form of a specific degeneration of the spinal cord's posterior nerve tracts (65) (Plate II , fig. 3). It was accordingly pointed out quite early that multiple sclerosis could not be identified simply by findings of axon segments bared of their myelin sheaths (43). Nevertheless, the continued emphasis, by several neurological celebrities, on the condition's specifically demyelinative nature, sufficed to establish multiple sclerosis as the main representative of the presumed class of "demyelinating diseases".

Blurred Lesion Identity
Since the distinctive macropathology of multiple sclerosis had never been defined in adequate terms, circumscribing it in terms of a "grey degeneration" (34), then later as a "[multilocular] sclerosis" (26), and eventually as a "[primary] demyelination" (82) made it easy to subsume under each of these designations other not properly identified cerebral and spinal lesions which happened to exhibit comparable tissue changes. The different kinds of damages thus designated by each of the given termini occasioned endless speculations as to the particular affection's cause. And the histological pseudo-specifications of multiple sclerosis spawned a number of other no less paradoxical disease conceptions.

Marburg's Sclerosing Inflammation
Otto Marburg's publications show what an extremely broad spectrum of essentially different pathological changes could become (mis-)identified as instances of "specifically demyelinating multiple sclerosis". Also presented as "sclerosing periaxial encephalomyelitis", i.e. as a scarring demyelinating cerebrospinal inflammation, Marburg's "multiple sclerosis" appeared simply as the main representative of a certain group of "non-purulent" conditions marked by "degenerative inflammatory foci, spread without any distinctive spatial distribution". The disease entity was said to be equally akin in nature to two radically different conditions: "[post-infectious] diffuse peri-axonal encephalomyelitis" and "[hereditary] diffuse cerebral sclerosis" (74, 77, 78, 79).

Ferraro's Even Less Discriminative Lesion Conception
In 1937, Armando Ferraro wrote that the pathological category of the "primary demyelinating central nervous affections" into which Carswell's "peculiar diseased state" had meanwhile become integrated could be differentiated only as to whether the individual processes possessed "patchy", or "diffuse", modes of spread. The results of his microscopical studies on correspondingly categorized cerebrospinal damages led Ferraro to formulate a virtually all-comprehensive multiple sclerosis conception, based on the following premises:
  1. "No fundamental objections exist as to the unification [histological identification] of multiple [patchy] and diffuse sclerosis".
  2. "[As to patchy sclerosis, there are] no...histopathological observations [which would permit us to] establish a distinction between multiple sclerosis and disseminated sclerosis".
  3. "Knowledge of histology does not allow ... [us] to make a differential diagnosis in the various forms of demyelinating processes." (46)
Although Ferraro's observations simply testified to the non-specificity of his histological findings, his statements were commonly taken to mean that all the indicated forms of sclerosis were caused by the same, or at least closely related, disease processes.

Multiple Sclerosis: Macropathological Misrepresentations
More recently, the ways in which lesion patterns of multiple sclerosis have come to be illustrated stand in stark contrast to Carswell’s and Charcot's real-life pictorial lesion specifications. As for the spinal cord, a 1939 schematic drawing by Wohlwill, republished by Hallervorden in 1955, appears to show that it is peculiar to multiple sclerosis to involve the spinal cord not from its sides but in its antero-medial sector (53). And according to a 1969 sketch by Werner, the same condition is simply marked by a haphazard scattering of large, rather compact lesion foci into the interior of the spinal cord's white matter (157). As for the brain, on the other hand, an often reproduced 1930 illustration by Spatz evokes the impression that also cerebral multiple sclerosis is characterized by a random disposition of a number of lesion foci – apparently with a certain spatial concentration close to the outer angles of the lateral ventricles and immediately underneath the cerebral cortex (131).
A quick browse through the more recent literature on multiple sclerosis shows that the confusion still persists about what is actually multiple slerosis-specific. Anybody who has access to depictions of lesions of “multiple sclerosis” on magnetic resonance imaging scans can pass his own judgments on this central point by comparing the MRI findings with the classic evidence concerning
  1. the specific damages to the spinal cord (Plate I; Plate II, fig. 1, 1'; Plate III; Plate IV, figg. 3, 4; Plate V, figg. B, C, D; Plate VIII, fig. B; Plate IX, figg. A, B; Plate X ), as well as
  2. the specific damages to the brain-stem (Plate I; Plate II, figg. 1, 1'; Plate III; Plate IV, fig. 3; Plate V , figg. B, C, D), and
  3. the specific damages to the cerebrum (Plate IV, fig. 1; Plate V, fig. A;  ; Plate VII; Plate VIII , fig. A).
(II-3-c) The Root of All Evil: Demyelination
Since no really distinctive pathological traits have ever been posited for multiple sclerosis, the speculations as to the lesion's cause(s) have always been mainly conformable to the dominant research interests of their times. The currently established working hypotheses underlying multiple sclerosis research evolved in the following ways.

From Toxin to Virus
Marburg expected that multiple sclerosis would ultimately be explained as being a result of the spread of some myelin-dissolving toxin(s) (75,76,79).
The search for a demyelinating agent was then continued over several decades by Heinrich Pette, the main promoter of some fictitious "myelin aggressor". Assuming that the term "multiple sclerosis" stood for nothing but the randomly scattered foci of demyelination, Pette inferred the existence of a somewhat more compact agent possessing a similarly specific myelin affinity. Because of the lack of any evidence for such an agent, Pette at first proposed that, since it was obviously extremely small, it had to be some sort of virus (95, 96, 97).

Modern Dogma: "If not a viral agent, then an auto-immune process"
Since no proper evidence for a virus was forthcoming, Pette felt urged to postulate that multiple sclerosis could only be caused by some cell capable of launching a myelin-specific attack, the kind of behavior which only definite strains of immunocytes could be imagined to be capable of. Thus multiple sclerosis came to be ascribed to an auto-allergy, i.e. an excessive auto-sensitizing towards particular constituent(s) of the myelin sheath (97, 101). The specifically patterned marks of Carswell's "remarkable spinal cord lesion", "Dawson's fingers" and "Steiner's splashes" thus were seen as the result of accordingly delimited tissue invasions by certain strain(s) of myelin-autoallergic immunocytes.
In this context it seems worth mentioning that Babinsky, in a 1885 paper, had already incriminated "lymphatic cells" as the cause of a certain variety of gross multifocal cerebrospinal damages, which he referred to as instances of multiple sclerosis. But in the same paper, he paradoxically also provided evidence on two facts militating against this assumption: He showed that (1) demyelinated axons are not peculiar to multiple sclerosis, and that (2) the "lymphatic cell" activities posited as causing multiple sclerosis also regularly evolved in the proximal stump of a sectioned peripheral nerve (6).
Remarkably, Prineas rationally re-established Babinsky's hypothesis in 1994, by conceiving of multiple sclerosis lesions as areas in which not only the myelin sheaths, but also their generative cells, the oligodendrocytes, were (auto-) immunologically affected (104, 106). This in spite of the fact that he himself had stated in 1985: "In the classical lesions of multiple sclerosis there is remarkably little cellular reaction, even during the acute phases of plaque development. It is upon this undisputed fact that the balance of opinion has always favored the view that the disease is a ... degenerative process" (103).

(II-3-d) Lymphocytic Infiltrations: Active, Or Re-active?
A sober analysis of Pette's writings reveals that, however eloquent and tenacious his teachings on the myelin-autoallergic nature of multiple sclerosis was, they were never founded on specific facts.

Immunocytes and "Myelophages": Rare, or Late to Appear
The basic facts: In the documentation on his first observation of a specific instance of multiple sclerosis, Charcot stressed the scarcity of "fat granules" in the damages to the spinal cord's sides -- which implied a negligible local prevalence of myelin debris-filled scavenger cells. In keeping with this, both Frommann's and Lauenstein's lateral cord lesions impressed observers by their lack of not only fat granule cells but also round cell infiltrates -- the latter finding implying that the lesion areas did not harbor a significant population of immunocytes. Dawson noticed fat granule cells, not in the spinal cord's lateral scars, but in posterior spinal and in cerebral lesions. However, even in the latter locations the fat granule cells appeared only to occur in more advanced stages of lesion development. Whenever perivascular infitrations of small round cells, which might have been immunocytes, were found, they appeared slight and secondary to, i.e. provoked by, local accumulations of debris-laden fat granule cells. All this can be taken to show that no special local concentrations of immunocytes and myelophages, that is of cells usually suspected of causing damage, are necessary for a multiple sclerosis-specific lesion's emergence. Accordingly, the affection of a lesion's myelin sheaths has often been observed to constitute not a dissolution or decomposition on the part of adjacent immunologically competent cells, but as a protracted dwindling or abrupt physical breakdown of entire sheaths, not seldom attended by the axon's fragmentation. The most reliable documentations on the specific lesions' histology thus clearly contradict the assumption of a primary autoimmune attack.

Autoimmunity: Not Solving Problems But Raising Questions
It is difficult to imagine how immunocytes, or also viruses or toxins, could become (and remain) localized, or how particular myelin constituents could be altered in such a way that the resulting damage might show the characteristic lesion pattern of a specific instance of multiple sclerosis. There is, accordingly, no indication of a primary existence of any conformable concentration-gradient, be it in particular agents or myelin compounds, between those areas which the process of multiple sclerosis specifically affects and those which it spares.
There is a long history of incriminating any scavenger cell found in the domain of a myelinated nerve fiber as an auto-aggressive grazer off of the particular sheath. However, an equally long history of contrary findings exists. Both Charcot, in the 1880 edition of his lectures, and Gledhill in 1973, demonstrated that, in compressive spinal cord lesions, a number of axons were encompassed by scavenging phagocytes instead of by their myelin sheaths (30, 52). Also in 1916, in concussive spinal cord lesions, direct invasions of myelin sheaths by myelophages (“myelin-eaters”) were observed (88). Thus even massive local concentrations of myelophages glutted with sheaths-debris in, say, a multiple sclerosis-specific lesion, need not be causal to the injury.
"Perivenous cuffings", i.e. accumulations of immunocytes about venules, on the other hand, have been registered as a constant, normal finding in plain mechanical traumatization of the spinal cord (5). The so-called autoimmune, i.e lymphocyte reactions in multiple sclerosis have never been shown to differ, either qualitatively or quantitatively, from those which naturally ensue from comparable tissue destructions of mechanical or vascular origin (60, 73, 153, 164).
In fact there are many immunological observations which aptly show that the immune reactions of multiple sclerosis are nothing more than secondary reactions to some preceding injury. But in none of these observations was the necessity of demonstrating the presence of specific lesions ever taken into account (except for possibly one magnetic resonance imaging study which indicated that any pertinent immune activation strictly followed, instead of preceded, the lesions' eruptions (90). For obvious reasons, this immunological evidence will not be discussed.
It may thus be concluded that, in genuine multiple sclerosis, neither immunocyte nor scavenger cell activities have ever been shown
  1. to qualitatively differ from those in comparable brain and spinal cord lesions such as, in particular, purely vascular and mechanical cerebrospinal damages;
  2. to exceed in severity what normally follows comparable damages; and,
  3. to actually precede the specific destructions.
The interesting question arises as to why there has been so little explicit resistance to the explanations of the multiple sclerosis-specific pathological changes in terms of the work of particular strain(s) of auto-allergic immunocytes.

(II-3-e) Primary Inflammation: Adding to the Confusion
The still fashionable interpretation of multiple sclerosis as an "inflammatory process" has further hindered the recognition of multiple sclerosis-specific pathological findings. The term "inflammation", taken by itself, simply refers to the highly complex, either passively consequential or reactive changes which tend to evolve in the wake of any kind of tissue damage, excepting extremely delayed structural degenerations.
But the expression "inflammatory damage" has also come to imply damages apparently attributable to the process of inflammation itself or, in more recent times, to some immunological event forming part of it. The interpretation of multiple sclerosis as a kind of "inflammatory injury" has accordingly mainly been wielded against the lesion's original understanding as an essentially degenerative or sclerosing pathological process (87, 75, 95, 96, 97). Being such an extremely complex and multi-facetted process, "inflammation" has proved to be a magical black box suited for conjuring up ever new explanations for the indicated conditions.
In this connection, the inflammatory processes’ ways of dissemination are still up for discussion. The important question of whether circulating agents would even be capable of producing part or all of the multiple sclerosis-specific lesion formations will find its answer in the fourth chapter of this book.

(II-3-f) Histology: Not the Key to Understanding Multiple Sclerosis
The categorizations of multiple sclerosis according to its tissue changes, culminating in the condition's re-specification as primary demyelination, have not contributed towards clarifying the nature of this condition. Conceiving of multiple sclerosis in non-specific histological terms has instead put research at the mercy of momentarily prevailing medical interest or fads. Instead of clearly differentiating which features of the condition are truly distinctive and evaluating their meaning, investigations into the disease's cause have, up to the present day, predominantly proceeded on pure speculations whose impacts have simply depended, to a considerable degree, on the respective proponents' professional authority and leverage. It is no wonder that all conventional attempts at elucidating the lesion's cause have not succeeded. The goal of the following chapters is to point the way out of the blind alley which multiple sclerosis research is presently proceeding down.

To chapter: Go!

© Dr. F. Alfons Schelling, M.D.