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(I-1) Pioneering Spinal Cord Findings

The illustrations of the first instances of multiple sclerosis, which showed a specific damaging of the spinal cord, were done seventeen decades ago, and yet their relevance for the proper identification and understanding of the disease's pathology has still not been fully appreciated. By means of these distinctive naked-eye findings alone multiple sclerosis was substantiated as a distinct disease entity, and they thus constitute the standard of reference by which every statement regarding the condition should be evaluated. Because of their crucial conceptual significance, the classic multiple sclerosis-specific spinal cord observations will be the focal point of the following chapter.

(I-1-a) Bilateral Spinal Cord Flank Lesions

Carswell's Testimony
In 1830, Robert Carswell, a young Scottish doctor, was confronted twice with one and the same unknown kind of lesion. This discovery, however, became public only after a number of years, when Carswell had taken over the chair of pathological anatomy in London.
Indicated by Carswell simply as "a peculiar diseased state", imposing itself as a special form of atrophic scarring, the lesion was specifically characterized by an illustration of its brownish, remarkably firm "spots", or, more concretely, their distinctive mode of arrangement. What stirred Carswell's interest in the first place were, even more than the "points" punched into the pons of one of the specimens, what he presented as the "patches" of a "remarkable lesion of the spinal cord" (24).
Carswell did his best to accurately document these findings: In plain drawings - see Plate I – he pictorially defined the pathological changes so clearly that they could hardly be mistaken for a lesion of a different kind. But he did not verbally refer to the lesion's distinctive characteristics, i.e. he did not concretely explain its true peculiarities. His classic illustration gave evidence of the following (for its non-specificity, the softening of the lower cervical cord will be ignored):
There are four pairs of lesions extending specifically along and, in roughly pointed ways, into the spinal cord's flanks. The damage appears thus characterized primarily by its unmistakable pattern of arrangement. In the individual lesion domains two kinds of tissue changes are spread from the spinal cord’s lateral contour to different depths. On two spinal cord cross-sections the coherent flank lesions are seen to broadly insert themselves, alternatively on the cord’s two sides, into the flanges of the H-shaped girder of its central grey matter.
This entire picture is unique, and of and by itself it holds the key to the understanding of the process of spinal multiple sclerosis.

Cruveilhier's Duplication of Carswell's Findings
Two spinal cord specimens depicted by the leading Parisian pathologist, Jean Cruveilhier, in 1839 and 1841, were marked by scars unmistakably identical to the patches of Carswell's "remarkable spinal cord lesion".
In Cruveilhier's first specimen, taken from an inmate of Paris' vast "Salpétrière" asylum, the cervical cord was now shown not only anteriorly, but also posteriorly. The uneven extension of the patches exclusively from the spinal cord's flanks was particularly evident, and the tissue lying closer to the lesion's lateral line of origin -- compare Plate II, figg. 1, 1 and Plate I -- was again shown to have undergone more intense changes.
And yet Cruveilhier spoke of the singular marks merely as "reddish grey islets", and referred to their entire appearance simply as "a grey degeneration of the [white matter] columns of the spinal cord" (34).
Cruveilhier's second illustration of multiple sclerosis, once more only vaguely indicated as an instance of "grey degeneration or transformation of the spinal cord" (34), is unique not only in displaying the spinal cord affection in its entirety, but also for its depiction of another typical feature of spinal multiple sclerosis unknown until then: The additional lining up of more circumscribed lesion zones, preferentially along the spinal cord's posterior midline.
As illustrated in Plate II , Cruveilhier's second specimen also paralleled Carswell's previous exemplar in some of the peculiarities of its cross-sectional lesion pattern: The slim, laterally based patch, ending in an apex which deviates markedly towards the spinal cord's posterior midline, together with the broader, also peripherally based posterior lesion wedge (34), distinctly reflect the manner of lesion spread: A consistent alignment preferentially with the spinal cord's lateral contour and a continuous, unusually oriented encroachment upon the neighboring tissues. In connection with their peculiar positioning, the patches' manner of extension thus appears different from that of any other lesion.

Charcot's Report on Spinal Multiple Sclerosis
In 1865 a specimen exhibiting the maximum possible longitudinal extension of direct damage to the spinal cord's flanks was detected by Jean-Martin Charcot while working as a pathologist at the "Salpétrière". Even more remarkable than his personal post mortem observation, however, was his synoptic summary of the then available illustrations of corresponding affections of the spinal cord's flanks. This original, anatomically substantiated understanding of spinal multiple sclerosis (which he later, unfortunately, speculatively modified) has hardly ever been taken note of, since it was merely expressed in the form of a footnote to this specific case report.
This footnote deserves special attention as it seems to constitute the sole historical advance towards a consistent specification of spinal multiple sclerosis - originating simply by Charcot's intuitive equation of his specific observations with Carswell's and Cruveilhier's identical findings (shown on Plates I and III ).
In the specimen which Charcot himself described, both flanks of the spinal cord were affected in their entire lengths, yet to varying depths: In the spinal cord's thoracic section, the quite symmetrical lateral lesion wedges extended deepest by far, only to lose substantially in depth, both upwards from the spinal cord's cervical, and downwards from its lumbar enlargements, vanishing completely at the cord's upper end -- cf. fig. 3 of Plate IV , and figg. B and C of Plate V -- and lower end (26).

(I-1-b) Primary Multiple Sclerosis Specification
Since Charcot's 1865 paper, no substantial advances in the gross characterization of the spinal patches of multiple sclerosis have been made, provided the condition be understood as a specific form of pathology directly identifiable with Carswell's "remarkable spinal cord lesion". As regards the lesion's tissue changes, however, neither the apparent discolorations nor the related hardenings are of and by themselves in any way distinctive. The abnormal tissue, with its singular patterns, merely puts the specific changes into relief.

(I-2) Detection of Distinctive Brain Lesions

One of Carswell's and both of Cruveilhier's archetypal multiple sclerosis specimens were also marked by pontine lesion spots. But -- as Plate I , figg.1, 1' and Plates II and III clearly demonstrate -- the pattern of all these damages to the pons' front differed essentially from that of the specific patches of the spinal cord, both as to lesion configuration and grouping. Remarkably, both Carswell, who discriminated the spinal scars as "patches" and the pontine marks as "points", and Cruveilhier, who initially depicted spinal and pontine "islands" in different colors, considered the pontine and spinal lesions as damages pertaining to one and the same pathology.
The question arises: What motivated these two pathologists to present the separate injuries to pons and spinal cord as lesions of the same nature, despite their different configurations and arrangements? Formally, the pontine "points" and specific spinal "patches" could hardly be regarded as identical. What, therefore, justifies Carswell's and Cruveilhier's assumptions as to the two lesion types' specific relationships?

(I-2-a) Ventricle-Based Knuckles, Fingers, and Fists
It was probably not only the lesions' similar discoloration and firmness which made Carswell and Cruveilhier suppose that the concurrent brain and spinal cord lesions represented the same pathology. Also the comparable size and compactness of the spinal "patches" and pontine "points" might have encouraged them to make this inference. However, the idea that the not yet absolutely distinctively specified multicentric rounded brainstem damages and the specifically patterned flank lesions of the spinal cord were related pathologies, was soon to be supported by other post mortem observations.

Unexploited Discoveries by Charcot
A somewhat more instructive cerebral lesion picture was presented in 1867, in a 35 year old victim of multiple sclerosis, who had died in the "Salpétrière". There were written indications that the spinal cord's flanks had throughout been primarily and, in their lumbar section exclusively, injured. The illustrations of these findings -- see Plate IV , figg. 3, 4 -- further provided clear evidence of the presence of a spinal lesion identical to those referred to above (93).
Truly revolutionary, however, was Charcot's masterly depiction of a lesion quite simply described as "a sclerotic plaque affecting the wall of the lateral ventricle [of a cerebral hemisphere]", elsewhere characterized as "grey sclerotic plaques, like scars, in the walls of the ventricles, up to a thickness of one centimeter" (93). The particular figure 1 of Plate IV actually shows the massive, undulating expansion of a quite homogenous lesion into the otherwise undamaged tissues of the roof of the brain's lateral ventricle. The lesion embeds prominent veins, coursing within often distinct, eccentrically widened perivascular spaces.
This plate of Charcot's is of inestimable evidential value: In it we find illustrated for the first time the entire spectrum of multiple sclerosis-specific changes, i.e. both the cerebral plaques' vein-related expansion in the ventricular wall and the spinal patches' extension along and into the spinal cord's flanks. Charcot, the renowned "Father of Clinical Neurology", has never been duly acknowledged for this, his potentially most momentous achievement. This lack of recognition may, in part, have been due to the incorporation of Charcot's masterpiece into a thesis by a little-known pupil of his, Leopold Ordenstein, focusing mainly on the in vivo manifestations of the disease.
In 1884, other valuable pictorial documents of Charcot's on the subject of multiple sclerosis appeared. Although presented merely as "sclerotic plaques affecting the corpus callosum on its ventricular side", the illustrated lesions (cf. figure A of Plate V) for the first time revealed another peculiarity of the condition's brain pathology: In the corpus callosum, the main connection between the cerebral hemispheres, a series of smooth, interconnected lesion spikes and waves arises perpendicularly off of the corpus callosum's underside, into the substance of its bulky bow. Against the healthy surroundings the damage appears sharply delineated throughout. As regards the lesion figures B, C, and D (Plate V), particular interest is due not so much to the illustrations of typical pons plaques as to the depiction of the related lateral spinal patches' upper terminations (31).
Charcot's "Lectures", however, referred to these truly unique brain and spinal cord lesion pictures simply as "unpublished [multiple sclerosis] observations".

Siemerling and Raecke: Serial Sections of Specific Cerebral Changes
In 1914, Ernst Siemerling and Julius Raecke, physicians at the Hospital for Nervous Diseases in Kiel, Germany, again demonstrated cerebral findings identical to those by which cerebral multiple sclerosis had first been pictorially specified. Plate VI discloses their illustration of this particular kind of brain lesion in a series of sections drawn parallel to the brain's median plane: In the cerebral hemispheres, there emerge ventricle-based plaques, expanding straight out in the direction of the cortex. The corpus callosum lesions evolve in a comparable way. The cerebral damage's mode of spread -- compare Plate IV, fig. 1, Plate V, fig. A , and Plate VI -- is here obviously the same as that in Charcot's cases, although the lesion pattern appears more diversified.
Siemerling and Raecke also seem not to have been aware of their observation's unique nature and implications. They merely indicated a "sclerosis of the ventricular linings", "extensive plaques and numerous smaller foci in cerebral cortex and white matter", a penetration of the corpus callosum by "large lesions", and the presence of "additional foci" in spinal cord, optic nerve, and brainstem (127).

Dawson's Conceptual Switch
In 1916, the unique naked-eye appearance of multiple sclerosis of the brain was correctly defined, curiously enough, in a work devoted to elucidating the condition's tissue changes, histologist James Walker Dawson's "The Histology of Disseminated Sclerosis". Regarding the naked-eye findings in the spinal cord of Dawson's standard specimen, there was mere mention that "the [spinal cord] sclerosis frequently mapped out the triangular portion between the anterior and posterior root entry zones and extended inward to involve the grey matter", and that posterior lesions appeared centered by the median or paramedian septum of the spinal cord (5).

Dawson's Description of Cerebral Damages
The dense sclerosis encompassing the brain's lateral ventricles originates in separate, roughly finger-, dome- or cone-shaped lesions arising immediately upon the ventricular lining and surging, or digitating as it were, outwards off of this lining. Peripherally, the otherwise smoothly rounded or crested lesion elevations tend to flatten against the bordering cerebral cortex. Ventricle-based and separate more peripheral plaques can fuse into ampulla-shaped lesions, whose neck tissue is often only slightly affected. Other ventricle-based lesion-projections appear outwardly prolonged into a co-axial series of peripheral plaques (35).
The peculiar lesion-expansions off of the ventricles, now commonly referred to as "Dawson's fingers", were observed to force their way more easily into the brain's white matter, such as that of the corpus callosum, than into the central nuclei's and cerebral cortex' grey matter. In places the “fingers” were yet found to invade both of them. Comparable lesion formations appeared to sit, like hoods, on the lateral ventricles' three "horns" (their three extensions’ ends) or to rise into apices or rounded offshoots of varying lengths. Other plaques directly silhouetted part of the ventricles' edges by an outwardly wavy or spiky front line, occasionally rising into peaks broadened and flattened at their contacts with the cortical border.
In focusing primarily on multiple sclerosis of the brain, Dawson's famed account marked a definite switch in researchers' attention from spinal to cerebral multiple sclerosis, thus virtually adopting the lesion's cerebral form as a pathological entity in its own right. Subsequently, accounts on multiple sclerosis of the spinal cord comparable to Carswell's "remarkable spinal cord lesion" ceased to appear.

Steiner's Lesion Sketches
In 1931 Gabriel Steiner, at the University of Heidelberg, drew vivid pictures of the spread of multiple sclerosis into the cerebral hemispheres. Apart from presenting schematic drawings of process-typical intrusions into the cerebral cortex from its outer side, he illustrated impressively the specific plaques' bumpy, stalked or splashy projections off the ventricular borders. Because the lesion formations preferentially burst forth at the lateral cerebral ventricles' outer angles, this site was referred to by the telling German name "Wetterwinkel", denoting a source of thunderstorms and deluges. This site has also come to be known as "Steiner's Wetterwinkel". All in all, Steiner's pictures lucidly highlighted what Dawson's description of cerebral multiple sclerosis had disclosed fifteen years before (134).
In 1962 Steiner, then at Wayne State University, demonstrated again that cerebral multiple sclerosis is primarily characterized by smooth, rounded or peaked lesions rising off of the ventricular border. Besides showing that ventricle-based lesion “tongues” can also connect with more peripheral plaques, Steiner now observed that isolated, ovoid or spherical lesion "splashes" also arise from blood-vessels far away from the ventricles (135). Such separate plaques are here referred to as "Steiner's splashes".
As regards the specific patches of the spinal cord, Steiner never mentioned anything of their essentially different image as compared with that of the brain plaques. His 1962 publication nevertheless revealed some interesting details: Its three sections of a piece of lower thoracic spinal cord showed, as can be seen in Plate VIII , B, that the lesions to the spinal cord's sides are formally quite different from the injuries surging up off of the cerebral ventricular border (135).

(I-2-b) Cerebral Multiple Sclerosis: A Pathological Entity in Its Own Right?
Steiner's publications are clear examples of just how, from Dawson onwards, the specific image of spinal multiple sclerosis ceased to be taken note of. In fact, the lesion extension along, and into, the spinal cord's flanks directly identifiable with that of Carswell's "remarkable spinal cord lesion" has never again, since Dawson's time, been demonstrated.
Neither Charles E. Lumsden, who pointed to the "knuckles" by which multiple sclerosis first may poke into the brain (69), nor Colin W.M. Adams, who depicted a corresponding "fist" (2), ever referred to the multiple sclerosis-specific spinal lesion's radically different mode of development.
It must be emphasized that such terms as "knuckle", "finger" or "fist" are absolutely adequate, in fact unsurpassed in illustrating the multiple sclerosis-specific brain injuries' massive, directed punches -- but that these terms are entirely inappropriate for characterizing the related, bizarrely angulated lesion encroachments upon the spinal cord's flanks. Yet before delving more deeply into this problem, another distinctive trait of cerebral multiple sclerosis, equally perceptible to the unaided eye, must be focused upon.

(I-2-c) The Specific Vein-Relationship of Cerebral Multiple Sclerosis
Whereas Carswell's lateral spinal patches, according to the condition's classical illustrations of Plate I, Plate II, figg. 1, 1, Plate III, Plate IV, figg. 3, 4, and Plate V, figg. B, C, D, did not seem to be pervaded by any special structures, Charcot's specific brain plaque was, as fig. 1 of Plate IV immediately discloses, plowed through with conspicuous vascular channels. Knowledge of cerebral vascular anatomy enables us to identify these ramifying structures as relatively large veins draining the central parts of the cerebral hemispheres. This relationship appears unusual enough to merit a concrete, careful scrutiny.

Charcot: First Indication of a Plaque-Vein Relationship
A closer look at figure 1 of Plate IV , Charcot's first illustration of cerebral multiple sclerosis, reveals the following: The lesion is spread about the periventricular veins’ central course, i.e. the injurious process primarily involves the stronger vein segments. In addition, the peripheral lesion projections show a certain dependence on the course of major venous branches. The involved vein lengths themselves appear partly contoured by distinct, generally one-sided or at least eccentrical widenings of their perivascular spaces. As to the actual wall of the lesion veins, however, the illustration does not reveal anything unusual.
Curiously, it is not Charcot but Otto Buss of Göttingen who is generally credited with the discovery of a vein-relationship of the lesions of multiple sclerosis in general. What is thereby consistently referred to is a case report of Buss', presented in 1889 (22), whose macroscopical lesion description seems at least compatible with a multiple sclerosis-specific affection of certain lateral and posterior sectors of the spinal cord. The observation that only the brain lesions preferentially harbor one larger or several medium-sized veins is also of interest. Yet neither as to the spinal cord nor to the brain did Buss provide a lesion specification which proves really distinctive of multiple sclerosis. In the given context, his report therefore deserves not to be paid further attention to.

Dawson's Detailed Evidence
The first written indication of an involvement of periventricular veins in the process of cerebral multiple sclerosis, as related by Dawson, revealed the following: In the extensive areas of sclerosis immediately contiguous with the brain's ventricles, some large collecting veins running immediately underneath the ventricular lining, so-called subependymal veins, are directly outlined by zones of gelatinous tissue. The involved vein walls appear partly homogenized, lacking their normal structural differentiation, and are encompassed by distinctly widened perivenous spaces in which residues of minor hemorrhages are to be found (35). Nothing was mentioned as regards the significance of all these peculiar changes.

Putnam: Remodeling Brain Lesions and their Veins
Tracy J. Putnam and Alexandra Adler illustrated for the first time, in 1937, that cerebral plaques characteristically spread in a rather odd, specific relationship to large epiventricular veins and, further, to bizarrely altered affluents of these vessels. These researchers' most relevant observations are comprehensively summarized in Plate VII . Their three-dimensional reconstruction model of one particularly interesting, serially sectioned brain specimen demonstrated especially well the curious distensions and distortions of the involved veins.
Plate VII shows their observations made on a section of cerebral white matter, thirteen millimeters by nine, which contained some veins arising nearly perpendicularly off the ventricular border. The specimen stemmed from a patient whose nervous affection was said to have run for twelve years a course typical of multiple sclerosis and whose post mortem was simply noted to have demonstrated "spread throughout brain and brainstem, numerous old and fresh plaques" (109).
The small brain specimen illustrated in Plate VII is of inestimable informative value. It shows a ventricle-based lesion cone, a typical "Dawson's finger", projecting along an oddly distended affluent of the major venous conduit running within the epiventricular sclerosed area. Additional isolated plaques ("Steiner's splashes") have also emerged, farther out, from the main branch of the distended vein of the “Dawson’s finger”, along its grotesquely distorted peripheral course, and from the trifurcation of a small affluent of another epiventricular vein. The specific epi- and paraventricular cerebral lesions were thus, for the first time, demonstrated to rise along and expand from definite segments of usually fairly large periventricular veins.

Fog on the Vein-Conditioned Plaque Development
In 1965 Torben Fog, directly investigating the multiple sclerosis-specific cerebral lesions' relationship to the course of their veins, found the distinctive plaques to consistently develop in a peculiar dependence upon definite vein segments.
Not only any lesion spread along and any digitation ("dragging") of damages off of the ventricular border, but also any projection of isolated plaques beyond the reach of the ventricle-based "Dawson-fingers'" stood in direct relationship to definite stretches of the lesions' "central" or "parent veins". The lesion advance from these vein segments proved regularly, and often strikingly, eccentric: Fog showed impressive images of veins somehow clinging to their lesions, and of plaques expanding extensively to only one side of a large vein, or also a bulky conglomerate of such veins.
Both the lesions' first emergence at, and their expansion off of, the cerebral ventricular walls thus proved to be determined by great venous trunks collecting the blood from inside the cerebrum, respectively by some of these veins' affluents. Especially the isolated peripheral lesions were found to preferentially emerge from their plaque-veins' bends, branchings or terminal ramifications. The veins involved again exhibited unusual tortuosities, twistings and distensions.
Although the largest lesions were commonly found to have emerged from large veins, the range of a lesion's expansion from the vessel wall could not be said to have stood in any definite proportion to the involved vein’s caliber. Another curious finding concerned abrupt peripheral endings of large, cylindric, perivenous lesions without any discernible modification in their plaque-veins' walls (48).

Lumsden and Adam's Confirmatory Observations
In once more providing unmistakable pictorial evidence on the venous conditioning of cerebral multiple sclerosis, Charles E. Lumsden, in 1970, observed that in the brainstem as well multiple sclerosis-specific plaques consistently originate on veins. Specific pons lesions were accordingly shown to equally evolve as vein-dependent "Dawson-fingers" (71).
The results of Colin W. Adams' researches into the development of cerebral multiple sclerosis, on the other hand, led to a fresh realization of the fact that "the early stage of the periventricular plaque is the formation of a lesion around a subependymal vein" (1). Besides thus confirming that the changes definitively set out from veins running underneath the cerebral ventricular lining, Adams again found the lesion spread into the periphery of the cerebral hemispheres to be consistently related to the course of particular veins. The fluid inside the cerebral ventricles was accordingly not felt to play a part in the specific lesion developments (2).

(I-3) Macropathology: Unexploited Key Evidence
The initial identification of multiple sclerosis as a distinct kind of pathological process was founded on specific post mortem findings of a spontaneously arising spinal cord lesion, which was to be recognized with the naked eye alone (24,34,26). The peculiar spinal cord pathology was then found to be frequently correlated to a different, again simply macroscopically discernible brain pathology (93,31).
Charcot, who for the first time put together evidence on the specific involvement of the spinal cord's sides, and first clearly documented the spread of related and no less distinctive damages in and off of the cerebral ventricular border, seems also to have been the earliest observer to point out that multiple sclerosis is essentially defined by its unique and uniform gross pathology (17,29). And it has since been confirmed again and again that, in typical cases of multiple sclerosis, the specific lesions can confidently be identified with the naked eye alone (44).
However, in those medical communities presently involved in multiple sclerosis research and treatment there seems as yet to be no full agreement on which traits ultimately distinguish multiple sclerosis. On the one hand, it has been explicitly stated that the diagnosis of multiple sclerosis can be made definitively at post mortem alone (84). On the other hand, it seems to be widely presumed that there are no morphological findings peculiar to the disease. The unique macroscopical lesion characteristics have gained little attention and the condition's dual character, i.e. the fact that cerebral and spinal multiple sclerosis, though commonly emerging side by side, present essentially different pathological pictures, has as yet not been properly realized. If, in keeping with current thinking on the theme, the condition's histological and clinical conceptions are considered first, it should not be forgotten: For the purpose of elucidating the condition’s nature and cause, no more reliable information can be found than that provided by naked eye pathological findings.

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© Dr. F. Alfons Schelling, M.D.