Multiple Sclerosis

(IV-1) Lawless or Specific Pattern(s) of Spread?
Multiple sclerosis is usually supposed to be the result of some agent's chance scattering via the brain's and spinal cord's vascular supply lines. But the question of how the specific cerebral "Dawson's-fingers" and flank lesions of the cord actually arise, consistently expand, and even - according to serial magnetic resonance brain images - continually re-emerge has never been properly addressed. The physical events underlying the specific lesions' development thus need to be thoroughly reconsidered.
An insufficient arterial perfusion has only rarely been suggested as the cause of multiple sclerosis, as ischemic lesions are known to conspicuously conform to the involved arteries' zones of irrigation. In fact, beginning with Carswell's pioneering observations (23, 24) (cf. Plate XIII) and continuing right up to the present, more and more evidence has accrued to show that, although often occurring in similar sizes, outlines, and numbers, the ischemic lesions show an overall configuration which differs radically from the spread pattern of both Carswell's "remarkable spinal cord lesion" and Dawson's periventricular lesion projections.
Putnam asserted that multiple sclerosis plaques were due to vein thrombosis. Two peculiar findings were supposed to support this idea: the emergence, in a living dog's brain, of demyelinated plaques along affluent veins of a cerebral venous sinus which had been clogged by a countercurrent injection of inert lard oil (107); and the presence, in a victim of multiple sclerosis, of a thrombus obstructing a vein draining a number of well-defined cerebral plaques (Plate VII ) (108, 109). But Putnam's inference was rendered implausible by the fact that a cerebral venous obstruction typically becomes manifest by one diffuse zone of edema dotted with hemorrhages, which had already been demonstrated by Cruveilhier (34).
There apparently remained only one segment of the cerebral and spinal vascular trees from which multiple sclerosis could, and had to, originate: The tiny vascular ramifications forming the transitions from arteries to veins. In fact, of the entire vascular bed, these minute blood vessels represent that segment which has the largest total surface, is the most slowly perfused, and proves the most permeable - thus constituting a -borne agent's easiest way of escape into the substance of brain and spinal cord.
Current hypotheses about the causes of multiple sclerosis proceed on the common assumption that its lesions, however long or large, are simply the result of a coalescence of sufficient numbers of such small vessel involvements. The question thus arises: Can massed transitional vessel involvements really combine to form the different multiple sclerosis-specific lesion patterns?
In this chapter it will be shown how the archetypal depictions and descriptions of multiple sclerosis, i.e. both Carswell's "remarkable spinal cord lesion" and "Dawson's fingers", came to be integrated into the protean class of conditions caused by multifocal small vessel involvements.

(IV-1-a) Multiple Sclerosis by Blood-Borne Dissemination?
Also referred to as "disseminated sclerosis" and understood as an unexplained form of multifocal "(post-) inflammatory scarring", multiple sclerosis is conventionally attributed to some minute cryptic agent's systemic scattering. But on looking at the lesion illustrations on Plates I and IV , it is hard to believe that the massive plaque projections off of the lateral cerebral ventricles or the slender patches extending over considerable lengths of the spinal cord's flanks could be caused by the spread of blood-borne agents.
Taking on the role of advocatus diaboli, we ought to be able to prove that a blood-borne agent can actually be spread in such a way as to produce the specific lesion patterns of multiple sclerosis. We must explain how the necessary clusters of separate (micro-) vascular units can become simultaneously involved, why these aggregates' consistently become enlarged out in definite directions, and how new lesions emerge in the brain again and again.
To attempt to settle these points we will shortly focus upon the characteristics of those lesions which were observed to result from a definite blood-borne agents' systemic spread. We will clarify just why minute agents cannot be distributed in a manner which produces typical multiple sclerosis-specific lesion patterns. Finally, special attention will be paid to the peculiarities of those instances of "disseminated encephalomyelitis" which continue, up to the present day, to be likened to and confused with specific observations of multiple sclerosis.

Character of Disseminated Myelitis
Especially before the medical community had begun to become acquainted with infectious microbes and diverse mechanisms by which so-called "spontaneously arising" spinal cord lesions can be brought about, the term "myelitis" - inflammation of the spinal cord - was used to designate damages of the most varied kinds. It was not until well into the second half of the nineteenth century that decisive attempts to illustrate the origins of disseminated myelitis in different blood-borne agents' systemic spread were made.
In 1874 the multifocal spread pattern of two inflammatory spinal cord affections due to a local scattering of blood-borne agents was precisely defined in drawings by the Berlin specialist for nervous diseases, Carl F. O. Westphal. He depicted numerous spinal cord cross-sections obtained in both a case of smallpox and one of "phtisis pulmonum" (pulmonary tuberculosis) (159). The extremely varied patterns of inflammatory foci spread, obvious already from comparing closely neighboring cross-sections of one cord, so surprised Westphal that he decided that this form of pathology had to be characterized by "an absolutely irregular scattering of spot-shaped foci over most of the spinal cord". He further observed that this spinal cord affection had emerged in strict dependence upon tiny blood vessels (159).
Westphal's illustrations gave evidence of a certain predominance of radial lesion extensions in the cord periphery, many forming offshoots of central grey matter damages, fanning out and tapering off outwardly, or terminating abruptly, within the surrounding white matter.
Plate XII renders the pictorial characterization of the inflammatory cord lesions of a small-pox victim, made in 1913 by the Zurich pathologist Hermann Eichhorst. Eichhorst emphasized the following observations: The very numerous inflammatory foci -- a dozen of them discernible on a single cord cross-section -- were generally of poppy-seed size. Their numbers and distribution patterns varied extremely -- even on neighboring cord cross-sections the patterns of spread were rarely comparable. Based on his microscopic findings, Eichhorst was led to conclude that the specific pathological changes consistently originated in a primary affection of the tiny vessel coursing amidst each of the lesions (41).
In a victim of measles, Friedrich Wohlwill of Hamburg observed inflammatory foci, virtually free of cell infitrates, dispersed over the entire spinal cord, each evolving and extending into a close relationship to a small venule (162). Regarding the present-day opinions about multiple sclerosis this observation is of double significance: The abstract pathological notion of multiple sclerosis has, on the one hand, become closely associated with the idea of a perivenular lesion; on the other hand, the entity is supposed to be caused by certain strains of immunocytes (which, in Wohlwill's case, were conspicuous by their absence).

Spinal Multiple Sclerosis: Simply Cryptogenic Disseminated Myelitis?
In 1928 Pette presented a number of illustrations depicting what he felt sure was a special kind of spinal cord lesion (96). However, in contrast to Carswell's much earlier observations of a "remarkable spinal cord lesion" Pette's cord findings were marked by the following peculiarities:

A radiating out of lesion cones and streaks from the spinal cord's central grey matter (cf. Plate XII) -- a feature particularly evident in the second cord lesion.
A lesion circumvallation by closely packed interstitial cells, forming a fairly smooth contour line, occasionally (in larger lesions) appearing distorted by irregular crenations and tattered appendices (this point is highlighted in the first and third instances).
A lack of any lengthy involvement of the spinal cord's sides or back by inward-directed lesion wedges.
No evidence of lesion extensions following the spinal cord's fibrous septa, or of correspondingly advancing lesion fringes.

What Pette had presented were in fact three definite cases of disseminated myelitis, all having one particular characteristic in common: their causal agent had not been identified. In keeping with this, Pette consistently adhered to the opinion that multiple sclerosis was simply a multifocal central nervous inflammation, identified primarily by the lack of evidence for a definite cause (95,96,97,98,99).
Apparently unaware of any truly multiple sclerosis-specific findings, Pette strove hard and quite successfully towards convincing the medical community to embrace his conception of multiple sclerosis. It seems not to have been realized that what came thus to be spoken of was disease without a clearly defined identity.

Character of Disseminated Encephalitis
Up until the end of the nineteenth century the term "encephalitis" also appeared rather ill-defined, comprising different kinds of "inflammatory" brain lesions, many of which were ascribed to primary or idiopathic, i.e. essentially cryptogenic, inflammations. This situation began to change at the beginning of the twentieth century.
The preferential emergence of the foci of encephalitis from tiny blood vessels of the brain's subcortical white matter was expertly illustrated in 1907. In the two lithographs of Plate XIII Hermann Oppenheim and Richard Cassirer clearly demonstrated that also in the brain inflammatory foci typically spread from tiny blood vessels.
Even when appearing spread throughout the cerebral white matter, including the lateral ventricular angle and corpus callosum (62, 68, 130, 132), such multifocal cerebral inflammations never resembled the image of "Dawson's fingers".

Cryptic Disseminated Encephalitis Versus Cerebral Multiple Sclerosis
Pette's first example of "multiple sclerosis" also showed stray inflammatory lesions in the brain, lying directly underneath the temporal cortex. In his third case mention was made of findings of actual periventricular damages - but these appeared to have evolved - not as "Dawson's fingers" do - away from, but in the direction of the lateral cerebral ventricles (96). Pette's cryptogenic multifocal inflammatory "multiple sclerosis" thus also did not exhibit any multiple sclerosis-specific features in the brain.
Other researchers made considerable efforts toward providing a clearer distinction of cerebral multiple sclerosis plaques, but they were unable to discriminate them from large, homogenous and well-circumscribed inflammatory plaques, such as those found in chickenpox (133, 148). But even more extensive cirrocumulus-like sheets of multifocal inflammatory changes found in the brain of victims of measles appeared to present no problems for differential diagnosis (155). In all these attempts at characterizing cerebral multiple sclerosis, the observations on the truly unique features of "Dawson's fingers" were never taken into account.

Postvaccinal "Multiple Sclerosis"
In the second half of the twentieth century even observations of disseminated encephalomyelitis, attributed to a definite, albeit not fully understood cause, namely a series of vaccinations or supposedly therapeutic inoculations came to be referred to as instances of multiple sclerosis.
The first of two much-quoted papers attempting to explain multiple sclerosis in terms of a "demyelinating" encephalomyelitis of neuroallergic origin (the case histories indicating rabies vaccinations as causes) was presented by I. Uchimura and H. Shiraki at Tokyo University in 1957 (145). Large agglomerates of merged inflammatory foci adjoining the outer angle of the lateral cerebral ventricles were illustrated in their first, second, third, and seventh specimens, and in four of the five remaining specimens comparable damages were said to have embraced the occipital and temporal ventricular horns. While appearing, as to their location, comparable to "Dawson's fingers", the lesions yet showed tattered, partly blurred edges, manifold internal inhomogeneities, and small attendant foci spread at random over the entire brain. The cord lesions' conformity to the foci and striae of disseminated myelitis was even more blatantly evident (145). It is unclear why the two researchers specified these observations as instances of multiple sclerosis.
A more detailed account on corresponding pathological changes was presented in the following year by Franz Seitelberger at Vienna (126). The brain of a man who had died of unexplained neurological troubles after receiving several inoculations of calf brain extracts after a diagnosis of multiple sclerosis showed, especially in its central white matter, a diffuse edema and engorged blood vessels. The white matter was beset by small inflammatory foci, varying from pinhead to rice-grain size. The changes, all of which appeared to be of the same age, were related to a generalized vascular engorgement and effusion. The two major lesions capping the ventricular angle seemed to have evolved in the direction of the lateral ventricular angle and originated in a fusion of small inflammatory foci; their margins proved "moth-eaten" and presented many unevenly structured and bizarrely crenated lesion-tongues. The spinal cord lesions lined the anterior fissure or marked the course of deeper blood vessels (126). Categorizing this encephalomyelitis as a specific instance of multiple sclerosis is out of the question.

Unexplained Encephalomyelitis Is Not Specific Multiple Sclerosis
Clinically defined multiple sclerosis has come to be specified by subsuming, under one and the same (dysfunctional) term, all sorts of structural pathologies. Curiously, ever since the disease and its causes has been officially defined using trivial, enigmatic or ill-understood observations of multifocal cerebral and spinal inflammations. Identifying commonplace findings by offering unexplainables as proof apparently seems quite acceptable when dealing with multiple sclerosis.
And yet, the truth must out. There are only two forms of multiple sclerosis which are really specific and unique: That of the spinal cord, showing the peculiar flank lesions first documented by Carswell (24) and ultimately implied by Oppenheimer (92); and that of the brain, depicted as "Dawson's fingers" (and similarly, "Steiner's splashes") - defined pictorially first by Charcot (31) and later, rather abstractly, by Adams (1).

(IV-1-b) Inflammatory Versus Specific Plaques
A comparison of Carswell's and Charcot's pictorially specified examples of multiple sclerosis with "multiple sclerosis-like" cases of disseminated encephalomyelitis shows that there is no single specific parallel of either the spinal or the cerebral multifocal inflammations to the truly distinctive observations of multiple sclerosis. It is important to find out why these two radically different lesion forms are confused even today, and to suggest how such confusions might be avoided in future.
One significant factor is clear: Inflammatory affections may, in diverse non-specific respects, so-to-speak mimic multiple sclerosis-specific damages, though both conditions can definitely be differentiated. Having realized this, another false premise once and for all proves false - the multiple sclerosis-specific pathology can no longer be ascribed to a cryptic blood-borne agent's circulatory spread.

Large Idiopathic Plaques: Not Proof of Multiple Sclerosis
Both blood circulation and cerebrospinal fluid shifts (engendered by the brain's arterial pulsations, and often more so by fleeting expansions of the veins of definite cerebral or spinal drainage systems) present the most efficient means for any microscopic agent to be distributed swiftly and extensively throughout the entire craniovertebral space. In the blood stream any virus or immunocyte may quickly be carried to any surface point of the vascular bed and, after entering into the cerebrospinal fluid, to any point of the brain and spinal cord's inner and outer surfaces. Among all of these possibilities of "docking" on tissues only those equally easily accessible will actually be affected "at random". Cerebrospinal tissues then may appear evenly strewn over with inflammatory foci or perivenular sleeves of less than a millimeter's breadth. The question is, in which ways such tiny dots and streaks can become metamorphosed into large (pseudo-)plaques.

Inflammatory lesions, attributable to one and the same blood-borne agent, may exhibit widely differing patterns of spread. It is easy to conceive of the efficacy of some "inflammatory" occlusion of a smaller artery or vein. Also, it is not difficult to imagine that some agent's release in dense wisps, its primary deposition (or secondary settling around a previously affected site) in varying clusters may result in protean lesion formations. Thus very different forms of even larger inflammatory lesions may evolve, and their intermittent growth may be due to contiguous depositions of comparable damages. If the tissue between thick-set foci is swamped by edema, foci clusters may turn into large, more or less homogenous and rather smoothly contoured lesions resembling, at least superficially, an isolated specific plaque of multiple sclerosis. Streaky perivascular inflammations may merge into larger lesions more easily where their tracks converge, i.e. around the spinal cord's central grey matter and at the lateral cerebral ventricle's outer angle. In the spinal cord, corresponding lesion patterns were already illustrated by Westphal in 1874 (159), while at the lateral ventricles' outer angle they appear to have been observed only by Seitelberger (126) and Uchimura (145).
The fact is that in the brain, even more so than in the spinal cord, to properly differentiate specific multiple sclerosis lesions from similarly configurated inflammatory damages not only the lesion positions, as they present themselves on single pathological slices, need to be taken into account. In order to reliably identify, for example, a "Steiner's-splash" or a "Dawson's finger" as against a large, confluence of inflammatory foci or streaks localized at and beyond the lateral ventricular angle, it is necessary to consider not only the lesion's overall configuration, but also its inner organization and, above all, the kind of vascular or tissue structure(s) from which it has originated, as well as the overall direction(s) of lesion spread.

Viruses: Incapable of Causing Specific Multiple Sclerosis Lesions
Any virus, as a minute immotile particle, depends entirely on the flow of body fluids to reach distant structures which it has a special affinity to. The richer the local blood supply and the ampler the local effusion of fluid towards adequate substrata, the greater the chances viruses have to settle at a definite site.
As to how viruses might be capable of selectively colonizing cerebrospinal tissues in patterns peculiar to spinal and cerebral multiple sclerosis, no explanation has ever been offered. Neither any property of a virus itself nor any ordinary or inflammatory fluid dynamics can conceivably induce a viral lesion to spread in a multiple sclerosis-specific way. The patterns in which viruses are scattered and the patterns in which Carswell's "remarkable spinal lesion" and the cerebral "Dawson's fingers" evolve in no wise parallel each other - they are in fact fundamentally different.

Myelin Autoaggression: An Inapposite Postulate
Owing to their ongoing circulation in great numbers throughout the body, the distribution of immunocytes (lymphocytes, plasmocytes) on brain and spinal cord might a priori be expected to be fairly even. Whereas many extrinsic infectious agents may leave the vascular bed simply of their own accord or through tiny vascular leaks, the immunocytes' evasion from blood vessels is conditional on intricate mechanisms: Immunocytes will only come sufficiently close and adhere to the inside of a blood vessel if and when the local blood flow has been abnormally slowed down. For immunocytes actually to attach to a blood vessel's inner lining, it must have acquired a specific "stickiness", conditional on the presence of compounds to which a strain of immunocytes specifically reacts.
Even if these requirements were to be fulfilled, the immunocytes' tissue invasion would further depend on the speed of the local fluid exudation and the presence in the tissue of higher concentrations of definite compounds which steer, chemotactically, the reactive immunocyte's own extremely sluggish advance. Under these circumstances, white blood cells, such as immunocytes, have been observed to invade affected tissues first through thin-walled venules and then, possibly, also capillaries, but only exceptionally through other vascular branches (32, 139).
Regarding the ranges of the perivascular inflammatory streaks' extension, it is further important to be aware of the fact that, following any physical or other insult severe enough to provoke an inflammatory reaction, the point of transition between fluid-filtrating and fluid-absorbing blood vessels regularly shifts, for a variable distance, from postcapillary transitional vessels towards smaller and larger venules, possibly even to small veins (33).
In bluntly attributing multiple sclerosis to a cryptogenic autoimmune process, the following questions have never been answered:

What limits the immunocytes' vascular attachments exclusively to certain sharply punched out cerebral or frayed out spinal lesion domains?
What motivates and enables immunocytes to locally penetrate not only the vessel walls but also the close patchwork of astroglial "feet" encasing the brain and spinal cord's proper tissue elements?
What -- and this appears to be the decisive point -- prevents the immunocytes from exerting any injurious effects outside of the specifically patterned lesion domains?

The idea that the specific lesion patterns of multiple sclerosis are brought about by certain autosensitized strain(s) of immunocytes is thus at least as much out of place as the assumption of a conformable scattering of particular viruses. Both the kind of structures from which the distinctive changes emerge and the specific orientation and limitation of their growth principally contradict the assumption that multiple sclerosis - understood as a specific form of injury -- is caused by an agent carried about by blood circulation and interstitial fluid flow (139).

(IV-1-c) Injurious Inflammation: The Cart Before The Horse
In referring (with Charcot) to the specific spinal and cerebral multiple sclerosis observations as "disseminated sclerosis", the epithet "disseminated" can certainly not be understood as indicating some agent's spread via the organism's fluid circulation. And the notion of "inflammation" cannot soundly explain the specific changes. Not only is there no evidence for any inflammatory or immunological phenomena peculiar to multiple sclerosis. Quite to the contrary: Whenever properly identified instances of multiple sclerosis are spoken of, all inflammatory phenomena are either observed to be secondary in nature (as in the brain), or found not worth mentioning, or totally absent (as in the spinal cord's sides).
Precisely those lesion traits at variance with multiple sclerosis, on the one hand, and multifocal central nervous inflammations, on the other, are most revealing about the causes of specific multiple sclerosis lesions. Therefore, to arrive at a proper understanding of the condition, the basic misconceptions about the pathogenesis of multiple sclerosis need to be subjected to a clarifying critique.

Spinal Multiple Sclerosis - Not an Essentially Vascular Lesion
The multiple sclerosis-specific spinal patches' most characteristic feature is their extension primarily along the flanks, and from there directly into or even across the spinal cord. This distinctive mode of lesion spread is the most consistent trait in the lesion's genuine specification (Plates I through V, IX, X). Especially in its extreme expressions, this lesion characteristic (cf. Plate II , figg. 1, 1', left-sided scar), most clearly characterized in Charcot's 1865 case report (26) (lesion sketches at Paris' "Bibliothèque Charcot"), cannot be accounted for by any form of vascular affection.
The involvement of the spinal cord's sides with slender boat-shaped patches, constituting a particularly noteworthy diagnostic trait, was not seldom misinterpreted as bilateral nerve tract degeneration and referred to as "primary combined systemic degenerations of the spinal cord". And this regardless of the lesions' capricious changes in depth and their tapering off or even abrupt termination, both upwards and downwards, within the involved nerve tracts' course (). Both these lesion features clearly contradict a lesion interpretation in terms of an affection of nerve tracts.
From Dawson to Fog, specific patches involving shorter stretches of the spinal cord's flanks were preferably ascribed to some sort of correspondingly aligned vascular affections. But all studies on the spinal cord's vascular patterns, up to the latest, rich 1988 documentation by Thron (140), have shown that a vascular pattern corresponding to the specific spinal cord lesions' pattern of spread simply does not exist.
In multiple sclerosis-specific spinal patches, even the vessel-related changes do not support the thesis that the lesions are actually of a vascular origin. This is already apparent from the manner in which tissue clefts - such as those in figg. C and D of Plate IX , or those illustrated by Ballet (8) -- open up from the spinal cord's surface along major vessel stems entering the spinal cord's flanks. Both these peculiar clefts and the patches' wedge shapes await explanation, as do the reasons why concerned arteries and veins are only affected in their most peripheral parts.
The "inflammatory demyelination" theories are further disproved by the many lesion vessels which present themselves, up to their finest ramifications, here and there as zones of departure of sclerosed fiber strands, which may be lined by inconspicuous myelin sheaths and nerve fibers (35, 50).
A last peculiarity of spinal multiple sclerosis which contradicts the idea of a strictly vessel-related lesion concerns the manner in which the distinctive lateral patches first evolve (see Plate VIII, B) and then advance (illustration in Plate IX , figg. C and D). Microscopically, the patches' more or less sclerosed fabric everywhere inserts into spiky and bizarrely angulated fibrous projections, penetrating a priori into particularly strong fibrous strands which are affected lesionwards by a dense fibrillary hyperplasy. These strands' transition into healthy fibrous tracts occurs in the form of a plain fiber hypertrophy.
The tissue changes marking the lateral spinal patches' advance show no actual dependence on particular blood vessels. Accordingly, in evolving patches of the spinal cord's sides hardly any inflammatory cell infiltrates have ever been traced (35, 50, 64). One further feature of spinal multiple sclerosis which does not agree with the conception of a multifocal inflammation can be observed in the direct modification of fibrous structures in the lesions' entire extent -- degrading them, at its worst, to homogenous lumps located at, in particular, the spinal cord's circumference, or altering them just by way of the plain hypertropy marking the patches' terminal extensions.
In the lesions of "disseminated encephalomyelitis", by contrast, interstitial fibrosis has always been noted to form not the first but the last of the tissue changes -- and it has consistently been found to evolve, around each individual focus of inflammation, as a broadening circumferential sclerosis advancing in reverse order, i.e. towards the lesion center (35, 96).

Encephalitis-Foci and Specific Brain Plaques: Worlds Apart
The earliest illustrations of specific lesions of cerebral multiple sclerosis make it obvious that the massive plaques surging up in and off of definite areas of the ventricular border (Plate IV, fig. 1; Plate V, fig. A; Plate VI) and the damages "punched" into the pons (Plate IV, fig. 2) are distinct from the cerebral lesion patterns which blood-borne agents typically produce. The same applies to any evidence on the modes of expansion of "Dawson's fingers" and "Steiner's splashes" along and away from particular cerebral veins (Plate VII; Plate VIII , fig. A).
One unique feature of multiple sclerosis-specific brain lesions is their origin primarily from definite stretches of relatively large plaque-veins reaching to, and then coursing along, the border of cerebral ventricles and the surface of the brainstem. The same applies to the emergence of ovoid "Steiner's splashes" from venous segments, bendings and branchings, upstream along a "Dawson's fingers" parent vein (Plate VII )(109). No less remarkable are the observations on a leakage of blood primarily from the plaque veins' strongest-walled proximal lengths or stems (35,109,2).
As to the widespread confusion of the venous conditioning of the plaques of cerebral multiple sclerosis with the typically transitional vessel-related random spread of the foci of "disseminated encephalomyelitis", the terms "vein" and "venule" need to be more clearly differentiated. The lack of a consistent definition and separation of these two vascular units has substantially contributed to the confusion regarding the origins and nature of multiple sclerosis.
Venules connect capillaries and veins, normally resorbing fluid exuded from the capillary bed. The seepage out of the capillaries ordinarily turns into a flow back, beginning with venules having a diameter of about one hundredth of a millimeter (33). However, while the point at which capillaries turn into venules appears well defined, the diameters beyond which venules are said to become veins range considerably -- from less than a twentieth of a millimeter to more than half a millimeter.
According to much of the literature on multiple sclerosis, specific brain lesions are said to arise in venules, while "encephalitic foci" apparently stem from veins, although the specific multiple sclerosis plaques -- in all specific observations -- are said to originate from veins measuring from one tenth of a millimeter up to two millimeters in diameter, while the foci and streaks of "cerebral inflammatory foci", according to all available evidence, proceed from venules of less than a tenth of a millimeter diameter. And so a specific lesion vein of approximately half a millimeter diameter is referred to as a "venule", while a far smaller venule lying amidst a focus of inflammation is spoken of as a "vein". This mix-up may have contributed to the fact that investigators of specific multiple sclerosis lesions never seem to have been challenged or felt obliged to ask why and how the diverse supposed "MS-agents" become injurious specifically in the neighborhood of strong, scarcely penetrable venous channels (35,109,47,1).

Multiple Sclerosis: Notional Veil Covering Lesion Identity
There can be no doubt that Carswell's "remarkable spinal cord lesion", as well as Charcot's specific findings of cerebral multiple sclerosis, on the one hand, and "disseminated encephalomyelitis", on the other, are two entirely different kinds of pathological entities which could only become notionally integrated by characterizing them with, and subsuming them under, sufficiently broad histological and neurological terms. The designation "multiple sclerosis" has thus turned into a blanket label covering all sorts of unexplained pathological entities. As the specific multiple sclerosis pathology is not to be accounted for by a blood-borne agent's scattering, it must be of interest to find out why and how researchers trying to unravel the cause of multiple sclerosis became so fixated on a circulating agent's trail.

(IV-2) From Randomly Spread Foci to MS-Agent
Though not based on any specific evidence, the simplistic tenets that multiple sclerosis constitutes nothing but a definite kind of multilocular (grey) tissue degeneration, scarring, or demyelination, caused by some sort of cryptogenic, systemically disseminated inflammatory agent, have been fervently propagated. We will try to retrace the series of (mis-)conceptual propositions which have led to positing various (consistently mysterious, invisible and evasive) blood-borne agents as the cause of an all too vaguely defined disease entity.

Cruveilhier's Suppositions about the Lesion Cause
A relationship of Carswell's "peculiar diseased state" to metastases of malignant growths or infectious processes had been insinuated before microbes and malignant cells were properly identified. Despite the lack of evidence for any protuberant or infiltrating growth, Cruveilhier, in presenting his first specimen of multiple sclerosis (Plate II, figg. 1, 1'), already speculated that the apparent tissue degeneration might have resulted from a dissemination of cancerous masses. Cruveilhier also directly misidentified his specific observations with an unspecified condition marked by a spread of distinctly bulging lesions into the posterior columns of the spinal cord (Plate II, fig. 2), and he additionally subsumed under one and the same title of "grey degeneration", manifestations of two long-known infectious processes - syphilis and tuberculosis (Plate II , figg. 3, 4).

An Enticing Notion: "Lawless Lesion Spread"
As early as 1866, Edme F. A. Vulpian critically distorted the picture of spinal multiple sclerosis which Charcot's earliest synopsis of the specific observations had projected. In a threefold manner Vulpian's paper proved disastrous in confusing the issue:

Firstly, by directly identifying as "sclérose en plaques" -- the preferred French synonym for multiple sclerosis -- two specific (Plates I and III), one entirely different (Plate II, fig. 4) and several ill-defined post mortem findings.
Secondly, by misinterpreting Charcot's 1865 genuine instance of spinal multiple sclerosis as a case of systemic nerve tract degeneration.
Thirdly, and most counterproductively, by positing that the lesions of multiple sclerosis are spread, both individually and generally, without any perceivable order (152).

Vulpian's last dictum was readily embraced by all researchers in this field: Ordenstein subscribed to it, stating that the locations of multiple sclerosis lesions were absolutely indefinite (93); Ribbert noted that no two specimens resembled each other in their lesion localizations (112); and Marburg was convinced that the particular lesions were not specifically localized (76). In keeping with the quick establishment of this point of view the well-defined, identifying characteristics of the specific observations of multiple sclerosis consistently escaped notice.

Charcot Misread: Multilocular Affection Not Proof of Systemic Spread
Charcot paradoxically introduced his second, later widely adopted synonymous designation of cases of multiple sclerosis as "disseminated sclerosis" in his classical report on a specimen with a spindly scar involving both of the spinal cord's sides in almost their entire lengths and to varying depths -- the deepest in its thoracic section (26). The reasons for Charcot's choosing the epithet "disseminated" are unclear, as he subsequently pointed out that "the predominant role ascribed to the blood vessels in the evolution of the pathological process [of multiple sclerosis] has not by any means been demonstrated", and further explicitly noted that there was no proper explanation for the unique lesion disposition of multiple sclerosis (31).

Ordenstein's Referential Mix-Up
In his 1867 thesis, Ordenstein erroneously mismatched his specific observation of multiple sclerosis with diverse other nervous affections, in particular with a clear instance of disseminated encephalomyelitis, originally presented by Rindfleisch in 1863 as a cryptic case of "grey degeneration" of brain and spinal cord (93). Rindfleisch's account on this particular specimen relates that its cerebral and anterior spinal white matter were covered over with miliary inflammatory foci, each emerging from a massively engorged and infiltrated blood vessel. There was thus neither any distinctive parallel to Ordenstein's findings nor any evidence for lesion traits which would by themselves have proven indicative of a specific form of multiple sclerosis (113).
In his 1872 "Manual of Pathological Histology", Rindfleisch pointed out that, aside from the just described inflammatory form of grey degeneration, there also existed a plain, non-inflammatory form -- exemplified by Frommann's classic observation of multiple sclerosis of the spinal cord (Plate IX , figg. A, B, 114).

Leyden's Misequations
Ernst Leyden's publications on multiple sclerosis only made matters more confusing. On the one hand, Leyden referred to Frommann's case of genuine spinal multiple sclerosis as an instance of nervous tract degeneration (65); on the other, he indiscriminately presented three specific instances of spinal multiple sclerosis as well as two cases of a multifocal spinal scarring after smallpox as cases of myelitis (66). Eventually, Leyden even related a purely clinical account of a child's unexplained nervous troubles under the strictly anatomical pathological heading of "multiple focal sclerosis. (Encephalomyelitis disseminata, Leyden.)" (67). By now it was obvious that "encephalomyelitis disseminata" and multiple sclerosis had become inseparably merged, at least in a terminological sense.

Kahler and Pick: Emergence of the Multiple Sclerosis Agent
The existence of an infectious "MS-agent" was first postulated by Otto Kahler and Arnold Pick in 1879, three years after Robert Koch's earliest description of a pathogenic microbe's (anthrax) life cycle (56). The two physicians announced that the evolution of multiple sclerosis in the wake of infectious diseases had been demonstrated by certain well-known (and thus not quoted!) instances of multiple sclerosis following attacks of cholera and smallpox, as diagnosed by Charcot himself, and by the observation of a period of ataxia (!) in a typhus patient of Clement's and another typhus patient of their own (56).
The data presented could hardly be considered in any wise peculiar to a definite form of multiple sclerosis, which was "by nature infectious", but the cases were the ultimate source of the unshakable belief that multiple sclerosis is brought about by some (sub-) microscopic agent.

Marie's Infectious Multiple Sclerosis
The idea of an infectious origin of multiple sclerosis was propagated with much enthusiasm by Pierre Marie, a student of Charcot's and later a leading neurologist in Paris. Of the plethora of data which Marie marshaled to support his claims, only his two best-documented observations will here be focused on.
Marie referred to only one case of multiple sclerosis of his own, which was identified by certain neurological symptoms having evolved subsequent to typhoid fever. Marie's case history revealed the following:
In the first one or two years after the patient's recovery from typhoid fever, his speech turned into a drawling "marked by all of the characteristics observed in multiple sclerosis". During the next two years "other symptoms of multiple sclerosis" supervened, including difficulties in writing and walking. Apparently the only observation made by Marie himself half a year later, of intensified tendon reflexes, oculomotor troubles and tremor during exertion, affecting mainly the left hand, concluded the entire diagnostic evaluation (81).
To radically eliminate any doubts as to the infectious origin of "disseminated sclerosis", Marie then quoted abstracts of five comparable reports, stressing that these were by no means exhaustive: "To bring together all the corresponding cases would have the entire bibliography on multiple sclerosis pass revue" (81). Among the five select case-reports Marie referred to, one provided by Wilhelm Ebstein in 1872 is unique for its complementary post mortem study (40), which Marie considered absolutely confirmatory of his diagnosis of multiple sclerosis.
In his original paper, Ebstein had actually claimed that the particular findings had shown a most complete analogy to those observed in "multiple insular sclerosis of the central nervous system" (40). He reported: A patient with a persistent weakening of tongue, neck and limb motion, which had become manifest in the wake of typhus abdominalis, succumbed eight years later to "pulmonary phtisis" (tuberculosis). At post mortem, the white matter of spinal cord and spinal bulb, especially in its central and posterior areas, was strewn over everywhere with roundish grey foci, up to the size of millet seeds, shading off into normal white matter. Under the microscope, many foci presented themselves as nodular scars marked by a dwindling of nerve fibers and distended blood vessels (40).
Ebstein's findings were thus certainly not identical with Carswell's "peculiar diseased state", but reflected an apparent multifocal scarring process subsequent to typhus abdominalis. In view of this clear instance of multifocal myelitis, it was hard to argue with Marie's idea that "multiple sclerosis" was attributable to "fungal (micro-) embolisms" of different infections (81).
Marie's 1892 lectures on the diseases of the spinal cord blurred the conception of multiple sclerosis even more thoroughly: The renowned neurologist defined multiple sclerosis as the subject of certain unspecified illustrations by Carswell, Cruveilhier and Charcot, and as the topic of some vaguely indicated works by Rokitansky, Türck, Frerichs, Rindfleisch and Vulpian. There followed a lengthy discourse on the condition's neurology, and then Marie reiterated: "There is a plainly clear cause of the sclerotic cerebrospinal plaques. This quite effective cause is infection, or a series of infections. Regarding the multitude of observations of instances of postinfectious multiple sclerosis, this causal relationship can no longer be denied" (82).
Stressing once more, as the prime feature of this kind of pathology, the absolute irregularity of its multifocal spread, Marie further repeated Ribbert's assertion that it was impossible to find even two cases of multiple sclerosis -- compare Plate I to Plates VI, IX and XI -- which resembled each other (112), so fitful and bizarre, so independent of any anatomical system were the lesions' localization and progression. The non-distinctive patterns of the dozens of crude lesion illustrations which attended Marie's assertions on multiple sclerosis were made-to-order.
Ultimately, however, a definite mechanism determining the lesions' disposition was defined: The damages were noted to originate in blood clots adhering to the walls of certain blood vessels, the actual damages being correlated to perivascular infiltrations of lymphatic corpuscles (immunocytes). For Marie, the cause of "multiple sclerosis" by some infectious agent was beyond doubt (112).
Though lacking precise substantiation, Marie's lecture on multiple sclerosis proposed two types of multiple sclerosis, which were to be strictly distinguished: "Actual multiple sclerosis", marked by plaques appearing sharply punched out; and "multilocular diffuse sclerosis", whose lesions were characterized by "certain continuations, or at least prolongations [of the tissue affection], into the neighboring tissues". Marie thus gave a description of two kinds of changes remotely reminiscent of specific spinal patches and cerebral plaques. But as the lesion types were neither assigned particular sites nor concretely exemplified, Marie's multiple sclerosis conception remained throughout non-specific of the condition (82).
Marie's theses on the nature of multiple sclerosis reflected or were borne out by the medical "hot topics" and domineering scientific interests of his time. His monopolizing of the term "sclérose en plaques" (multiple sclerosis) for post-infectious cerebrospinal affections is understandable, but in referring to Carswell and other authors of illustrations specifically identifying multiple sclerosis he left doubts as to what kind of lesion he was ultimately talking about.

Marburg's Circulatory Toxin Spread
Marburg's numerous papers on multiple sclerosis -- none of which referred to any multiple sclerosis-specific pathological observation -- illustrate best the vague meaning which the term "multiple sclerosis" had taken on by the turn of the 20th century. Also entirely ignoring the necessity of providing some distinctive characteristics of multiple sclerosis, Marburg campaigned primarily against an understanding of (acute) multiple sclerosis as a primary fibrosis. Indicating that this sort of multilocular cerebrospinal inflammation was equally related to childhood infections and hereditary cerebral white matter diseases (74, 77), and emphasizing an absolutely irregular random lesion spread as token of its strictly uniform macroscopical pathology (75), he invited a large spectrum of speculations as to the condition's origin(s).
In the end, however, Marburg was convinced that multiple sclerosis resulted from a disseminated encephalomyelitis brought about by a circulating toxin (75, 76, 79). Without ever offering any concrete feature for identifying the condition itself or discriminating it from Kahler, Pick and Marie's infectious multiple sclerosis, Marburg finally proposed that the infectious type be terminologically distinguished from his toxic one as demyelinating and sclerosing par-encephalomyelitis (80).

Pette's Mediating Decision: Multiple Sclerosis Due to an Allergy
Again, without presenting any specific evidence, and detached from any findings relating to Carswell's "peculiar diseased state", Heinrich Pette, beginning in 1927, achieved the conceptual integration of Marie's infectious and Marburg's toxic multiple sclerosis under the common designation of, not disseminated encephalomyelitis, but rather multiple sclerosis. The term multiple sclerosis thus ultimately came to refer to diverse, non-distinctive and unexplained, cerebral and spinal inflammatory affections ascribed to certain (postulated) blood-borne agents.
Whether a corresponding cerebrospinal lesion was labeled multiple sclerosis or disseminated encephalomyelitis was, according to Pette, just a matter of the neurologist's personal preference, dependent simply upon whether he imagined the inflammatory process to have already been superseded by scarring, or not (95).
Pette conceived of multiple sclerosis as being the result of an exposure to different microbes or complex organic compounds, a welcome conciliatory proposition which he justified in attributing the condition to an allergic reaction (97,100). Under Pette's premise that the affection was actuated by way of some hypersensitivity reaction, postvaccinal encephalomyelitis came to be commonly accepted as the key to understanding multiple sclerosis (98). Unacquainted with any genuine multiple sclerosis specifications, Pette considered his allergy hypothesis in fact as the only possible explanation of the condition's cause (99, 100).
In presenting brain and cord specimens of three cases of a so-called "acute disseminated encephalomyelitis" of unknown origin, Pette actually claimed, without substantiation or questioning, that the lesions in these cases -- all emerging from small inflamed blood vessels or surfaces to the cerebrospinal fluid (96, 99) -- were identical with those in old and oldest cases of multiple sclerosis and corresponded to the classical pathological findings referred to under this term. There were not even any objections to Pette's pompous announcement that his third case, apparently because it had run a somewhat longer course than the others (four months as against five respectively two weeks) would provide a full explanation of the entire development of multiple sclerosis (96).

The Aftermath
With the adoption of Pette's allergy conception, the specific pathology of Carswell's "peculiar diseased state" appeared doomed to fall into oblivion. After having first been subjected to diverse trivial characterizations, inappropriate blanket definitions as well as misleading categorizations, then next to curious co-evaluations with essentially different or simply ill-defined pathological entities, the truly specific multiple sclerosis-findings seemed to have actually been rationalized out of existence.
In surveying their "multiple sclerosis-like" postvaccinal encephalomyelitis findings, two researchers treading in Pette's footsteps accordingly had to admit: "We have no definite clues as to the pathogenesis, or even consistently adequate criteria for the specific diagnosis of multiple sclerosis" (145).

(IV-3) LOOKING BACK IN FRUSTRATION
Neither by interpreting multiple sclerosis in terms of a cryptogenic multifocal inflammation nor by explaining it with some (sub-)microscopic blood-borne agents' systemic scattering have the classic - and clearly specific - multiple sclerosis observations ever been taken into account. Though still frequently represented in the form of a decorative frontispiece introducing some historical account on the discovery of multiple sclerosis, Carwell's "peculiar diseased state", unmistakably identified in his earliest pictorial documentation of what later came to be referred to as multiple sclerosis, has as yet never been the subject of a sober formal analysis. The special features of Carswell's "peculiar diseased state" and the kind of injury it represents have never actually been closely scrutinized and specified.
Instead, in dealing with a purely notional disease entity deprived of any relationship to concrete exemplary observations, current researchers apparently dare not venture beyond postulating a specifically demyelinating and yet clinically defined multiple sclerosis. It seems in fact that the present speculative approach to the subject matter, involving the futile quest for some figmentary, in particular immunological multiple sclerosis agent, can be abandoned without scruples. This should be done in all haste to avoid prolonging unnecessary human (and animal) suffering.
Chapter 5 is devoted to divulging and delineating the injurious events and causes behind multiple sclerosis.