Multiple Sclerosis

(V-1) The Dynamics of Lesion Formation
The development of the pattern of a lesion depends, in the final analysis, on plain mechanical principles. The first clues for determining the cause of a particular kind of injury are thus to be derived from its outer shape and inner organization. In multiple sclerosis, a sober consideration of the patterns of lesion “dissemination", i.e. of the "fibre-borne" extension of patches in the spinal cord's flanks, and the eccentric expansion of homogenous plaques from definite brain veins, will clarify several significant points:

Which forces are capable of bringing about the particular changes via the structures from which the lesions originate and in the observed directions and ranges of spread?
In which ways are the injurious forces transmitted onto the structures and zones from which the lesions arise?
From which sources do the injurious impulses arise?
Which forces control and check the lesion spread?

An explanation follows of the dynamics of lesion formation, as well as of the physical preconditions, i.e. the structural abnormalities required, for multiple sclerosis-specific changes to evolve. In light of the fundamental differences between cord patch extension and brain plaque expansion, the specific affections of spinal cord and brain will be discussed separately.

(V-1-a) The Spinal Patches' Peculiar Mode of Extension
We have already mentioned the unique naked-eye observations which serve as positive identification of spinal cord multiple sclerosis. Before focusing on the genesis of these changes, their most characteristic features will be reiterated.

Essential Gross Traits of Cord Affection
The specific observations of multiple sclerosis of the spinal cord all have one thing in common: the extension, within inconspicuous surroundings, of bizarrely shaped marks in both the spinal cord's sides, which are seen to encroach, via a more or less jagged front, on considerable lengths of mainly the lateral cord flanks (Plate I; Plate II, figg. 1, 1'; Plate III; Plate IV, figg. 3, 4; Plate V, figg. C, D; Plate VII, fig. B; Plate IX, figg. A, B, C; Plate X, Nerv. cerv. II-VII). Such lesions are occasionally seen to interconnect, inside the cord, up- and downwards, or also from flank to flank (Plate IV , fig. 4: B, B') (71).
Thus lateral patches may reach such a length as to be mistaken for a systemic affection of nerve tracts (Plate VIII , fig. B) (17,18,35). It is worth noting that a certain length of one side of the cord may show separate patches, whereas the same length on the opposite side proves fairly evenly altered to a definite depth (Plate II , figg. 1, 1').
Slight magnifications may also reveal a close array of small saw-toothed lesion spikes, or a series of crenelated rhomboid or bizarrely frayed-out patches encroaching upon the spinal cord's sides, as illustrated in a specimen in which also a tendency for posterior spinal patches to longitudinally interconnect is evident (Plate VIII, fig. B).
In considering all of these peculiar forms of lesion spread, the specific cord patches’ plain macroscopic appearance provides a number of clues on the injurious causes of lesion formation.

Subtle Peculiarities in Patch Development
Documenting the upper "speed limit" of cord lesion advance, Lauenstein's 1877 observations of homogenously softened patches in the cord flanks (Plate X), already discussed in more detail in the first chapter of this book, leave no doubt that the lesion domains can be abruptly affected within a very brief period of time.
A better understanding of the usual, more gradual mode of progression of spinal patches can be gained from Frommann's 1867 report: The local changes first manifested themselves in a plain thickening of prominent connective tissue tracts constituting the spinal cord’s interstitial framework, and then spread out to involve ever thinner fibrous structures. Along their farthest extensions, forming the patches' advancing fringe zones, the fibrous structures’ thickening fluidly tapered off into normal, prominent connective tissue structures surrounding lesions (Plate IX , figg. C, D) (35,42). Vascular segments showed a strengthening of their connections to neighboring tissues, developing rather irregularly in definite directions.
At a later stage, tiny fibrils had developed, first within and then out of certain sectors of thickened fibers, along the involved connective tissue tracts, and at definite sectors of blood vessels. From time to time, both thickened fibers and more or less recent fibril developments degenerated into hyaline lumps (Plate IX, figg.C, D).
Along blood vessels irradiating the periphery of not only the sclerosed but also otherwise inconspicuous adjoining sectors of the spinal cord, sooner or later, more severe changes had also occurred: The stems of many major blood vessels entering the lateral cord flanks were to certain depths marked by roughly delimited tissue clefts -- seamed by stumps of ruptured fibers and fibrils.
According to Dawson, the local changes primarily manifested themselves in an abnormal augmentation, i.e. reinforcement of a system of unusually prominent connective tissue structures inserting into the cord's sides. He asserted that these proliferative changes in the fibrous fabric of the spinal cord's sides must be directly due to the lesion cause.

Mechanical Determinants of the Specific Cord Changes
In considering the dynamics of these lesion developments, three points have not yet been properly considered: 1. the significance of the peculiar vascular involvements, 2. the meaning of the continuously progressive connective tissue changes, and 3. the reasons for the specific patterns of lesion spread.

The significance of the vascular involvements: The observations of torn fibrillary connections between lesion vessels and scarred surroundings led Frommann to assume that the tissue clefts irradiating the spinal cord sides along major vascular stems could only be mechanically caused. As to the cleft arrangements, such clefts could only have resulted from laterally directed tensile impacts. And regarding the blood vessel affections by specifically orientated scarring processes, all of these vessel-related changes must have been provoked by physical insults of the same nature.
Connective tissue changes: All in-depth microscopic studies on the patches’ gradual extension into the two sides of the spinal cord agree as to the primary nature of the local connective tissue affection, i.e. that the fiber thickening and fibril growth already start at the lesions’ earliest stage of development -- independently from any other kind of tissue changes. According to Frommann’s findings, this is also true of the hyaline degeneration affecting certain strands of thickened fibers and sprawling fibrils.

The striking parallels between the manner of spread of 1. the various connective tissue affections, and 2. the diverse vessel-related changes have, up until now, been given little attention. In fact, both vessel-related tissue clefts and scarring tissue wedges start at the lateral circumference of the spinal cord and proceed inwards from there. The idea that all fibrous tissue changes (plain fiber thickening, fibril development, degenerative hyalinization) are to be accounted for by outwards directed tensile impacts agrees with two principle considerations:

Both as to their course and strength, the developments of the fibers and fibrils of the connective tissue depend on the direction and intensity of locally effective tensile stresses;
A plain thickening and well-ordered replication of preformed fibrous structures is an adaptive reaction to the particular structures' exposure to unusual tensile strains.

Thus both the specifically oriented perivascular fibril developments and the corresponding strengthening of definite connective tissue tracts can be understood as adaptive processes to unusually intensified and chronically repeated tensile impacts exerted upon the spinal cord’s sides. The vessel clefts entering the spinal cord’s sides and the hyaline degeneration of equally flankbound fiber trains, on the other hand, can be accounted for as an overstraining of these parts by more vehement forces of the same type.
Steiner's illustrations of the changes at the spinal cord's outermost flanks (Plate VIII , fig. B) may serve to illustrate this point: The pictured lesion's saw-toothed and crenelated patterns must necessarily be the work of an energetic, peripherally directed pulling. The observations of strikingly strengthened connections between the specifically affected spinal cord's fibrous hull and the subjacent scarred tissue (18,87) are of particular interest in this respect.
The primary affection of the –- mechanically first and most strained – tough connective tissue structures irradiating the specific lesion-domains, and the progression of the changes by way of a "fiber-borne" spread (Plate IX , C, D) support the explanation of lesion formation by unduly intensified tensile impacts acting continually upon the spinal cord’s flanks.

The specific pattern of lesion spread: In 1978 David R. Oppenheimer pinpointed the anatomical element which alone accounts for the specific involvement of the spinal cord’s sides. Noting that some affected cord segments were drawn out from side to side, Oppenheimer was the first to realize that the lateral lesion wedges originated in the line of insertion of the right and left denticulate ligaments in the cord. He concluded that the observed changes might be attributable to an outward tug via the denticulate ligaments, the cord's main staying elements in the spinal subarachnoid space.
But there are also observations of additional patches affecting the cord especially along its posterior midline, for example by Cruveilhier (Plate III, figg. 1', 1''), or also at the front of the spinal bulb (Plate I; Plate V, fig. C) (23,31,42). In fact, the denticulate ligament, attached to the entire length of the spinal cord’s sides (55,165), forms the only constant outer fixation of the spinal cord. Further highly variable fibrous connections occur between especially the back of the spinal cord and the spinal subarachnoid space's outer walls (45,58,61), the most conspicuous anterior fixation reaching the spinal bulb (58). It seems as though any of these accessory fixations can also engender specific mechanical lesions, but there exists no equally impressive evidence of this.

Another principle consideration must be made concerning the pointed extensions marking all of these specific patches’ advancing fronts:

Explainable only as a mechanically induced phenomenon, these spinal patches are particularly characterized by the acute tapering off (down to a microscopic size) of the progressive fibrous tissue changes -- as evident from the sharply angulated or bizarrely angled terminal lesion extensions -- which no infiltrative organic process of diffusion or expansion can account for.

Having indicated the structures and forces via which the specific flank affections of the cord are brought about, the how and why of the injuriousness of the diverse outer fixations of the spinal cord will shortly be considered, as soon as the dynamics of the specific lesion developments of multiple sclerosis of the brain have been outlined.

(V-1-b) Dynamics of Brain Plaque Expansion
The basic differences between the peculiar flank affections of the spinal cord and the specifically related damages to the brain have never been thoroughly thought through or systematically investigated into. However, it is crucially important to appreciate the radical differences between the two types of lesion formations, in order to gain a proper understanding not only of the injuries to spinal cord or brain but also to comprehend the nature of the specific changes of multiple sclerosis in their entirety.

Gross Characteristics of Specific Brain Lesions
To describe cerebral multiple sclerosis, pathologists have developed a special vocabulary which distinctly reflects the condition’s massive and impetuous outbursts. Specific plaques found "punched out" of the periventricular tissue of the cerebral hemispheres and the front of the brainstem have been referred to as "fingers" (Dawson, Lumsden) or "fists" (Adams). And, as it is from here that the largest lesion imprints emerge, Steiner gave the lateral ventricular angle the ominous multiple sclerosis epithet “Wetterwinkel” (source of the thunderstorms).
The earliest clear and absolutely distinctive illustrations of multiple sclerosis of the brain gave evidence of a surging up of compact lesion waves in and off of the ventricular border, along the undersurface of the corpus callosum, sweeping also over wide inner expanses of the cerebrum. And Steiner, in his succinct overview of the specific spread patterns of cerebral multiple sclerosis, characterized the isolated plaque-projections into the periventricular tissue aptly as "splashes".
Although generally appearing -- in contrast to the frayed out cord patches -- very smoothly contoured, ventricle-based specific lesions may also appear projected out in the form of thin and pointed spikes or even a coherent series of spiky waves. But despite an occurrence of such pointed projections, the specific cerebral lesion formations are distinctly different from the spinal ones with respect to the striking evenness of the tissue affection, also over very large individual plaque domains.
Periventricular “Steiner’s splashes”, projected out so far as to appear cast onto the cerebral cortex, tend to become flattened upon touching this apparently less easily impressed border. And yet, according to Steiner’s lesion sketches, it seems that certain cortical surfaces of the brain can also become injured from the outside by fairly small, but otherwise typically shaped plaques. Lumsden, who was often confronted with comparable findings, actually asked himself what kinds of forces might bring about all these peculiar changes (69). There can yet be little doubt that, without a rather forceful mechanical impact, the cerebral plaques’ sweeping over at times enormously large tissue domains cannot be plausibly accounted for. One great enigma remains as to the nature and causes of these vigorous impulses.

Impacting Veins, the Real Agents of Brain Injury
Up until 1937, the issue of which structures determine the development of all the distinctive forms of cerebral plaque spread was not definitively resolved. And even today there is no more than a handful of solid documents on the where and how of the specific plaque spread in cerebral multiple sclerosis.
Putnam and Adler were the first researchers to provide clear evidence on the peculiar plaque-vein relationship characteristic of cerebral multiple sclerosis. The specific brain plaques were shown to originate along certain strangely distended and distorted vein stems (Plate VII) (109). Unfortunately, these two researchers did not realize the implications of their findings as to the condition’s genesis.
Scheinker, on presenting the most impressive cross-sectional image of a specific lesion's expansion (its "splattering out") to one side of its vein (Plate VIII , fig. A), spoke only of vascular distension, apart from indicating that this paravenous lesion development had perhaps originated in "local circulatory disturbances" (117,118).
Fog's systematic observations on the specific vein relationship of cerebral plaques provided the clearest proof of the vein's crucial role for lesion expansion and projection (47,48). And yet, once more there was no explanation of the significance of the particular findings in terms of lesion causation.
Fog definitively proved that the plaques of cerebral multiple sclerosis arise not from the ventricular lining but from definite segments of large epiventricular veins and that the lesions' digitating out into the cerebral hemispheres also consistently evolves in a corresponding vein relationship: Both ventricle-based "Dawson's fingers" and peripheral "Steiner's splashes" originate from venous branches radiating off of the cerebral ventricular border or (visualized in the opposite direction) emptying into epiventricular collecting veins.
Fog further found that isolated lesions preferentially arise from points where plaque veins begin to narrow down, where they turn, or arborize. His observations from a comprehensive study of two cerebral hemispheres also confirmed what Putnam and Scheinker's multiple sclerosis specimens had already illustrated, i.e. that lesion expansion proceeds in a generally highly eccentric manner with respect to its point of origin at some section of the particular plaque vein's walls. These findings made clear the reasons why previous investigators had commonly failed to trace the cerebral plaques' unique venous conditioning: Divergences between the longitudinal axes of the plaque veins, on the one hand, and the lesion axes, on the other, not only constitute the rule rather than the exception, they also capriciously change along the plaque veins’ courses -- whereby the veins’ eccentricities may be stunning. But the full meaning of all these observations for an understanding of multiple sclerosis has as yet not been properly appreciated.

Forces Behind Cerebral Plaque Expansion
Five features characterizing the spread of the specific brain lesions of multiple sclerosis prove useful for determining injurious impacts which cause the damages:

The common asymmetries of the plaque expansions away from their veins, especially in their bizarre extremes.
The plaques' emergence exclusively from certain segments or even sectors of the walls of their veins.
The consistent countercurrent spread of damage, i.e. its progression, without exception, in a direction diametrically opposite to the normal venous (and interstitial fluid) flow.
The origin of lesions -- and particularly of the largest lesion formations -- preferentially from strong, i.e. thick-walled and therefore scarcely penetrable vein segments.
The lesion spread only along a small, select system of cerebral veins.

Following is an evaluation of each of these five key aspects of lesion genesis, especially with regard to its significance for the understanding of the disease:

Asymmetries in the lesion expansion, and eccentric courses of the plaque veins: Compact lesion expansions or projections mainly or exclusively to one side of a length of plaque vein, such as are typical of cerebral multiple sclerosis, require a well-directed mechanical impact that no microscopic agent could conceivably provide, especially through such strong vein walls as have commonly been found in periventricular plaque expansions. Further explanations of the process responsible for the unique plaque projections are given below.
Peculiarities of the involved vein lengths: The central role of veins in the development of cerebral multiple sclerosis has mainly been obscured by the capricious eccentricities of plaque vein placement relative to lesions. The emergence of plaques only from certain sectors of the walls of their veins, which at first sight appears rather erratic, might also have contributed to the late realization of the role of veins. The expansion of brain plaques mainly from venous bends and narrowings, or from terminal venous arborizations, was in fact directly described only in 1964 by Fog (47,48). Of particular interest here is the occurrence of analogous findings in hypertensive encephalopathy, in which areas particularly exposed to the pressure of abutting arterial bends tend to become demyelinated, or even battered out to circumscribed hollows (reminiscent of the hollows surrounding Dawson's plaque veins) (117,146,163).
The lesion spread countercurrent to the normal venous flow direction: According to all available evidence, specific injuries to the brain consistently start out from strong proximal vein segments and then proceed for varying distances upstream. The process of cerebral multiple sclerosis thus advances in a direction diametrically opposed to that of normal venous flow. The extraordinary significance of this circumstance was already grasped by Carswell, long before the role of veins in cerebral multiple sclerosis was realized: "In inflammation the local congestion commences in the capillaries, afterwards extends to the small veins, but never to large branches; in mechanical congestion [by venous flow inversion] the blood accumulates first in the venous trunks, which are always conspicuous, and afterwards in the branches and capillaries" (24).
Carswell here indicated a relationship which actually constitutes the master key to the accurate understanding of multiple sclerosis. The advancement of the specific cerebral lesion formations of multiple sclerosis in the direction from wide vein stems upwards towards narrow venous roots shows the whole process to be essentially mechanical in nature.
Primary altering of strong-walled periventricular collecting veins. Putnam and Adler's first illustrations of the plaque veins' "gnarled" look, i.e. irregular distensions and distortions (Plate VII ) represent another finding awaiting its explanation in terms of mechanics. And there was one further significant finding: The maximal distension of plaque veins immediately downstream to their thrombotic obstructions and their maximal distortion downstream to other, more peripheral plaques. This included a stepwise increase in the thrombosed veins' proximal distension, in the direction of the obstruction, at each of three subsequent points of entrance of venous affluents. Comparable, though less detailed, observations made several years later underlined the necessity of providing a physical explanation for the plaque vein’s distention, not upstream, but downstream to its thrombotic occlusion (38).
In this connection a picture presented by Ingrid V. Allen in 1981 is especially relevant. On a cerebral hemisphere's medial aspect a number of vein-centered plaques are apparent, spread beneath the lateral ventricular wall and surging up off of the corpus callosum undersurface (3). On closer examination it can be discerned that the stem and first branches of a large ventricle vein have grooved for themselves wide beds whose breadth is nearly three times that of the involved vessels' diameters –- a detail reminiscent of Charcot’s first documentation on cerebral multiple sclerosis (Plate IV , fig. 1). Together with the findings of specific plaques rising up from strong, proximally strikingly distended veins, these observations again point to the effects of notably strong forces.
It seems obvious that the necessary physical impulses must have been exerted from inside the plaque veins, i.e. they can only have been exerted by venous blood. In considering the peripheral narrowing and central widening of the venous tree, as well as the excessive rises in pressure only in the central veins, the following conclusion appears self-evident:

The specific brain plaques of multiple sclerosis can only be caused by energetic venous back-jets set in motion by intermittent rises in the pressure in the large collecting veins of the neck, but especially of the chest.

Since the process of cerebral multiple sclerosis does not lead to an even distension of the proximal branches of a particular venous drainage system up to a definite length, since its plaques emerge preferentially from venous bends, narrowings and arborizations, and since the plaque expansions from veins show such striking eccentricities, the impacts of the regurgitant blood quite clearly tend to be very unevenly distributed (Plate VIII; Plate IX , fig. A). To be able to exert such effects the peripherally directed venous currents must at times attain remarkably high velocities and affect the brain in the course of very short periods of time.
As to the selective involvement of a definite venous drainage system in the brain: While injecting, under heavy pressure, carmine-gelatine into a human body's straight sinus in an attempt to render its tributary veins in the cerebral hemispheres more prominent, Benno Schlesinger, in 1939, came unawares very close to explaining the cerebral multiple sclerosis lesion's genesis. He realized that extravasations produced around the lateral ventricles' outer angles (Steiner's "Wetterwinkel") "closely simulate the distribution and even the shape of plaques in advanced cases of multiple sclerosis" (121). In this way, Schlesinger, an expert on cerebral vascular anatomy, clearly demonstrated that the most prominent plaque veins represented the main affluents of the straight sinus. The fact that other affluents of the straight sinus, i.e. veins of the brainstem, must equally be considered as classic plaque veins appears to have been noticed only by Lumsden, in 1970 (71).

Physical Containment of Cerebral Lesion Spread
The factors which limit the specific plaque spread everywhere within a sharply punched-out front have never been plausibly accounted for. And yet, we have now become acquainted with many revealing details. The following relationships appear of basic significance:

The compact massiveness of major “Dawson’s fingers” or “Steiner’s splashes” indicates that the thrust of the regurgitant blood is not simply exhausted by friction-induced vascular resistance.
Nevertheless, "plaque borders" forming a series of thin, outwardly pointing epiventricular lesion spikes -- as they would be expected to be brought about by a corresponding series of regurgitant blood columns’ deceleration tracks -- were found projecting into the corpus callosum (Plate VI, figure at bottom).
Farther off of the cerebral ventricles, the relative reluctancy of plaques to transgress the borders to the cortical grey matter is of particular interest: Rather than being conditioned by a local concentration gradient of some myelin constituent(s), the tendency of lesions to flatten out before impinging upon the relatively stronger pulsating cerebral cortex might testify to the greater effectivity of cortical arterial counterimpacts.

Because of the complexities of their dynamic interaction, the forces which are particularly effective in counterbalancing a local venous regurgitation's impact will be discussed in further detail below. But before embarking on this analysis of the dynamics of the venous back-jet into the brain, a brief interpretation follows of what the specific cerebral damages of multiple sclerosis imply with respect to local tissue changes.

Explanation of Microscopic Findings within Cerebral Lesion Domains
What merits comment first is the generally overestimated and overemphasized prominence of the damages to myelin sheaths over the damages to axons of nerve fibers. Upon its arrival in the brain, a venous back-jet acts upon the involved vein walls with a force directly dependent on their resistance to the retrograde venous shift. The vein walls which transmit the mechanical impacts directly to the embedding brain substance produce a sudden, centrifugally spreading tissue shearing or wave of tissue expansion. The concerned tissue layers' warping relative to their surroundings endangers the myelin sheaths and especially their delicate, vitally important connections to the oligodendrocytes, far more than the robuster axons of the nerve fibers. The more or less "selective" demyelination of the specific plaque domains can thus be expected to result primarily from destructions of the myelin sheaths' exceptionally frail supply lines. The lesion edges simply map out where local venous impacts have ceased being injurious.
The retrograde expansions of plaque veins -- and thus also of cerebral plaques -- must thereby be limited by pressure rises inside the involved vein, as well as inside the craniovertebral space as a whole, which suffice to cancel the thrust of the regurgitant blood. This explanation of lesion development admits solely of a very short timespan of brain plaque evolution, and it makes understandable why, as numerous pathologists -- from Dawson to Lumsden -- have noted again and again, brain lesions appear punched out "all in one piece".
The evolution of a diffuse halo of interstitial fibrosis silhouetting the edge of older cerebral plaques now appears equally explainable: The adaptive hypertrophy and hyperplasy of connective tissue can be regarded as a most sensitive indicator of repetitive, no longer destructive or demyelinating strains burdening the tissue beyond a certain distance from the impacting venous wall. However, in just diffusely shading off the cerebral plaque borders, this weak and even fibrosis (71) contrasts markedly with the isolated reinforcement of more prominent fibrous structures marking the spinal patches' fringe zones (50) –- a further detail pointing to a difference between the mechanisms injuring the brain and spinal cord respectively.
The plaque veins’ massive and bizarre wall distensions, hardly explainable by a single local impact (Plate VII ), and the diffuse hyperplasy of perivenous fibrous structures, most plausibly accounted for by a chronically repeated overstraining of the local tissue fabric, indicate that the venous regurgitations of cerebral multiple sclerosis intermittently recur in a persistent manner. In addition, the tendency of both the specifically affected brain and spinal cord areas to become gradually enlarged makes evident that the injurious events underlying the two forms of lesion development are capable of aggravating themselves and each other – a further peculiarity of multiple sclerosis which has, as yet, not been properly accounted for.
A sound, comprehensive explanation of the process of multiple sclerosis must therefore not only point out the factors effectuating (and delimiting) the distinctive ways and manners of spread of the different cerebral and spinal lesion formations, but also show why both lesion types continually enlarge their domains.

(V-2) Cause of the Injurious Impulses
As a result of his painstaking, well-documented investigations, Fog was led to postulate two revolutionary theses -- which unfortunately went almost unnoticed:

“The changes in the central nervous system may be the result of disturbances of circulation, especially in the venous drainage … these disturbances may be intermittent and of varying degree.”
The hypertrophy, i.e. excessive development of fibrous connective tissue, about the major plaque veins is somehow related to the pressure changes within the chest (47,48).

In 1955 Lumsden had stated that "… [from the available evidence] it does not follow that the agency [causing multiple sclerosis] is necessarily a living or even a chemical one". Instead, he suggested that vascular pressure was the condition's effective cause, since not only the way its lesions extended, but also their shapes, appeared determined by such mechanical factors as stress lines and pressure forces (69).
Later, after having realized the significance of Dawson's and Fog's (although, apparently, not of Schlesinger’s) observations on cerebral multiple sclerosis, Lumsden explicitly noted that its lesions were related to "the deep venous drainage of the white matter", i.e. to affluents of the straight sinus. Aware of the fact that the plaque-vein relationship actually constituted "a fundamental or even the dominant principle of the process of multiple sclerosis", Lumsden anticipated that the problems relating to its development would possibly be solved when "more is known about the relative venous pressures in these regions" (71).
Irrespective of these insights, since the 1970's no headway has been made towards a better understanding of the relationships between local venous pressures and specific plaque developments. But Lumsden's and Fog's notes may be taken to spotlight the legitimacy and urgency of the attempt at clarifying the injurious potential of venous back-jets selectively burdening, in particular, the deep system of venous drainage of the brain.

(V-2-a) Recurrence of Injurious Venous Back-Jets into the Brain
Although rises, inside the trunk, in central venous pressures of several hundred millimeters of mercury, i.e. meters of blood-column, can be considered physiologically normal, little is known regarding potential impacts of these pressures upon individual venous drainages of brain and spinal canal. While exploring the injurious effects of venous regurgitations into, in particular, straight sinus affluents, two principally interrelated questions must be answered:

How can venous regurgitations obtain the necessary thrust to produce the large lesion expansions projected into the cerebral hemispheres?
What limits retrograde central venous pressure propagations to exerting their effects only in the specific lesion domains?

Central Venous Pressure Dynamics and Distribution
Respiratory or other bodily efforts produce central venous pressure excesses which can increase at tremendous speeds to very high levels. During accidental mechanical impacts upon trunk and neck even more brutal central venous pressure rises can be anticipated, and these occurrences have never been properly investigated. As a result of these pressure rises the soft tissues surrounding the cerebral veins may become burdened by pressures which they cannot withstand, even under minor exposure. Whether the brain is thereby damaged or not depends mainly on three critical circumstances:

Speed, volume, and extent of the retrograde shifting of central venous blood;
Circumscription of the central venous excess pressures’ intracranial and, above all, intracerebral distribution;
Volume, in particular of venous blood, to be momentarily displaced out of separate compartments of the craniovertebral space.

Little reliable information exists on even the most fundamental structural and functional determinants of course and extent, let alone consequences, of more massive venous back-jets into the human brain. And due attention has not been paid to the critically enhanced risk of vehement repulsions of central venous blood into exclusively the one or the other cerebral venous drainage system.
Fog mistakenly assumed that the pressure in the cerebral veins simply fluctuates parallel to the pressure in the chest. Even more paradoxically, he explained the perivenous tissue stiffening along major plaque veins of cerebral multiple sclerosis as being a safeguard preventing these veins' inspiratory collapse (48). Thus no one has bothered ask the following questions:

Which quantities of blood can, with which force, be pushed up from central veins into the intracranial and, in particular, the intracerebral venous tributaries of either the right or the left internal jugular vein?
How is regurgitant blood volume distributed in dependence on individual venous valvular, anastomotic, and branching patterns?
To which extent can the spread of venous back-jets pushing up through only one internal jugular vein be confined to a particularly small cerebral venous territory?

Little reliable information exists already on such plain and fundamental facts as

individual prevalence, degrees, and bilateral relationships of the valvular incompetencies of the two internal jugular veins and of their extracranial venous tributaries and anastomoses;
the individual and temporal variability in the pre-filling, the maximal capacity, and the conductivity to flow, of the venous drainages capable of carrying regurgitant blood towards and into the brain; and
the individual and temporal variability in flow conductivity and pre-filling of the veins capable of venting the craniovertebral space for back-jets into a separate venous drainage system inside the cranial cavity or spinal canal.

Spread of Acute Rises in Central Venous Pressure into the Brain?
Any momentary excess central venous pressure tends to revert the flow in any venous drainage which is not guarded by competent valves. If a venous drainage system lacking competent valves is not vented by venous anastomoses (lacking opposing valves) and its pathways are nowhere compressed, regurgitant blood can most easily and rapidly be pushed back in any affluent vein as far as its outermost tributary vessels.
But so long as its circumvallation is intact and nowhere substantially yields to pressure, the craniovertebral space can accommodate regurgitant blood volumes only as long as a commensurate venting, i.e. evacuation of blood from separate venous drainages of cranial cavity and spinal canal, is possible. If back-jets into different cerebral or spinal venous drainage systems compete, length and flow resistance of the respective venous pathways will also influence the pressure load to which walls and neighborhood of the involved veins will be exposed.
Skull radiographs of supposed victims of multiple sclerosis, showing striking widenings of the main venous passageways out of (and into) the cranium first stirred the present author's particular interest in the diverse anatomical pathological specifications of multiple sclerosis (119). A closer scrutiny of the truly unique post-mortem observations of multiple sclerosis led him to the conclusion that the specific cerebral changes evolve under the following circumstances and in the following ways:
The first prerequisite for plaque veins' injurious activities appears to be a disproportionately severe valvular incompetence of that internal jugular vein by which these plaque veins are specifically drained (Plate XIV , figg. A, B). Via this vein regurgitant blood then must be conducted into a relatively minor intracranial catchment area – meaning, in a classic instance of cerebral multiple sclerosis, directly up into the straight sinus affluents. Provided there are no venous anastomoses strong enough to provide for the involved venous pathways' sufficient venting, venous regurgitations of injurious intensities into the straight sinus’ affluent veins must occasionally result (119,120).
The remarkable functional isolation of the straight sinus system of venous drainage has been consistently illustrated not only anatomically (9,120), but also – more dramatically -- in the literature on the disastrous effects of (especially thrombotic) straight sinus occlusions. The evidence presented demonstrates that, if the venous outflow through the straight sinus is blocked, the collateral venous drainage from the brain's central parts tends to decompensate under the mere perfusion load of blood circulation (). It becomes clear that the potentially far more massive overloading of the straight sinus affluents by intense venous back-jets can certainly not be expected always to be dissipated in a harmless fashion.
Apart from their typically being limited to affluents of the straight sinus, the brain plaques of multiple sclerosis expand from only certain small section(s) of a plaque vein's surface. The question arises as to what may limit and localize the particular venous regurgitation effects. A consideration of the acute, both absolute and relative rises in intra-abdominal and intra-thoracic pressure reveals the existence of a number of factors which can limit a spread of venous regurgitation into particular cerebral veins. The primary limiting factor against a strong retrograde venous invasion of a particular part of the brain lies in the rapidity with which the thrust of any correspondingly localized venous regurgitations is counterbalanced by separate competing venous regurgitant and ordinary arterial flows into the craniovertebral space. A regurgitation into particular cerebral veins may also end precipitously, due to an exhaustion of its own volume or, in cases involving a larger intracranial venous domain, because the veins providing for a venting of the craniovertebral space are emptied too quickly. Finally, the ordinary course of trans-diaphragmal pressure gradients makes it probable that venous regurgitations into the brain will often be stopped by competing venous back-jets from intra-abdominal collecting veins into the epidural vein plexus of the lower spinal canal.

The Development of Venous Back-Jets into the Brain
The conditions predisposing to injurious venous back-jets via one internal jugular vein into the brain are rather complex, and research must be initiated to directly determine when and how such potentially disastrous events take place. If the venous drainage of the straight sinus is critically isolated and the other venous tributaries of the large collecting veins of the trunk are guarded by competent valves, potentially disastrous back-jets of central venous blood will begin as soon as the valve of the straight sinus-related internal jugular vein has been burst through, become too distended, or if its valve-leaflets have critically shrunken.
However, this is only one requirement for the occurrence of potentially disastrous venous back-jets into the brain. The presence of opportunities for sufficiently massive venting effluxes out of the craniovertebral space is equally necessary. As soon as the venous back-jet has become established, it will always tend to become more severe -- simply because of its continual "washing out" of its own pathways into, and of the channels of concurrent venting effluxes out of, the craniovertebral space. Thus initially harmless venous regurgitations may, sooner or later, reach injurious intensities.
The physical impacts causing "Dawson's fingers" and "Steiner's splashes" thus appear comprehensively accounted for.

(V-2-b) Specific Spinal Scars: Also Venous in Origin?
The observations on Carswell’s remarkable spinal flank affection and its "fibre-borne" spread along the insertions of certain outer anchorages of the cord do not lend themselves to strictly the same lesion interpretation as the related damages to the brain. It shall therefore be explained under which circumstances certain stretches of the spinal cord’s sides, in particular, may become specifically injured.
Some researchers have supposed that the lesions of spinal multiple sclerosis also originate from veins, or that the lesions relate to definite venous territories. However, Oppenheimer, who first realized the denticulate ligament's pivotal role in specific spinal patch developments, stressed that only few of the lesions which he had studied had shown a relationship to veins, and that the only patches which had done so were found to irradiate the spinal cord's sides. Oppenheimer supposed that it was full flexions of the cervical spine, especially in the presence of rigid antero-lateral fixations of the spinal dural sac, which exerted the detrimental stresses upon the denticulate ligament's attachments to the spinal cord. But he failed to explain by which mechanisms and under which circumstances cervical flexion might stretch definite segments of, in particular, thoracic or still lower parts of the denticulate ligament in such a way and to such a degree as to result in a damaging of lower spinal cord sectors.
The spinal cord can be selectively injured in its sides either by being displaced posteriorly, relatively to unyielding lateral fixations, by a blunt impact upon its front (57), or also – in virtually any location – by an interference of particularly rigid outer spinal cord fixation(s) with the cord’s up or down movements relative to the dural sac (73,142). Violent impacts upon an individual's back effectuating sharp intradural displacements and, in particular, vehement subarachnoid fluid shifts, have been observed to actually lead to widely scattered, anchorage-related damages to the spinal cord’s flanks (12,88,122).
Regarding the mechanisms capable of producing bilateral cord lesions, even the most detailed accounts on classic instances of spinal multiple sclerosis consistently lack any indications of either some massive thrust upon the spinal cord’s front or of a heavy impact upon walls or surroundings of the vertebral canal. It is difficult to believe that in all these observations (series of) corresponding injurious processes or events were consistently overlooked. Therefore the search must begin for an endogenous source of comparably effective injurious impulses capable of continually injuring the spinal cord's specifically affected parts.
In view of the many striking parallels, both as to lesion patterns and tissue changes, between the remote effects of spinal concussion and spinal multiple sclerosis, vehement endogenous subarachnoid fluid shifts might be expected to play a preeminent role in disease genesis. If sufficiently intense, such fluid displacements could actually damage the spinal cord partially or in its entire length, conforming to the zones of insertion of the denticulate ligaments and of other particularly tough anchorages of the spinal cord to the dural sac. The question arises as to which mechanism actuates such intense endogenous shifts of spinal subarachnoid fluid -- shifts which are continually repeated and thereby tend to become intensified.
In comparing arterial as against venous conductivity, and the intensity of the pressure-dependent blood-displacements in the arteries as against the veins, the volume-displacements within the craniovertebral space, which are effected by local veins, can be expected to be far more effective than those of arterial vessels. This conclusion is corroborated by the results of studies on arterial and venous cerebrospinal fluid displacements, which show that far the most intense (endogenous) cerebrospinal fluid shifts are due to venous back-jets rushing back from veins inside the abdomen into veins encompassing the lowest part of the spinal dural sac (cf. Plate XIV, figg. C, D) (39,111). There are individuals who have shown subarachnoid fluid shifts so vehement as to be likened to "plunger strokes" (136).
Continually subjecting the spinal cord, in short-term repetitions, to this intrinsically self-aggravating mechanism, venous back-jet induced subarachnoid fluid displacements from the lower spinal canal may gradually become so intensified as to eventually be injurious. Dragging the spinal cord headwards, such intense subarachnoid fluid shifts may be capable of injuring the spinal cord by means of abrupt tensile impacts exerting their effects specifically along those fibrous structures which represent the spinal cord’s most stressed anchorages to the dural sac.
Both specific spinal cord patches and brain plaques, though differing essentially as to form and structure, thus become understandable in terms of one and the same causative mechanism, namely vehement, specifically localized venous regurgitation into the craniovertebral space.
Again, to cause the continual venous regurgitations into the lower spinal canal to individually attain injurious intensities, a mere progressive washing out, i.e. widening, of their own pathways and of those for the simultaneous venting effluxes may be sufficient. The strength of the individual retrograde flows will thereby tend to increase in proportion to the speed and ultimate height of the ascent of any infradiaphragmal, i.e. intraabdominal excess pressure -- dependent on the preceding emptying of the veins of the lower spinal canal. This emptying predisposes to more massive regurgitations, both directly and by a relatively stronger filling of separate veins providing the compensatory venting of the craniovertebral space. Spinal regurgitation, however, differs from cerebral as to the far greater number and complexity of the venous pathways connecting the intraabdominal collecting veins to the venous plexuses encompassing the lowermost part of the spinal dural sac.

(V-2-c) Co-Evolution of Specific Cerebral and Spinal Lesions
Given an individual anatomical predisposition to isolated venous back-jets into the brain's central veins, or to intensive venous regurgitations into the lower spinal canal, even trivial exertions or mechanical impacts from outside the body, producing an abrupt increase in intra-thoracic or intra-abdominal pressure, may cause multiple sclerosis-specific lesions to emerge. In these particular injurious events, the role played by blood-borne agents will never be anything but accessory (although a great number of bacteria may play a smaller or greater role in the selective destruction of an internal jugular vein valve or also the thrombotic obliteration of some functionally important venous connection).
Cerebral and spinal multiple sclerosis often co-evolve. And the central question remains as to why (and how) this is so.
Reduced cerebrospinal fluid volumes and pressures may a priori be considered as crucially important. They generally predispose to more intense venous back-jets both directly, by causing a weaker counterpressure to any retrograde venous flow into brain and spinal canal, and also indirectly, by implying a more abundant pre-filling of the venous vessels of brain and spinal canal, thus providing an opportunity for more massive displacements of venous blood from the craniovertebral space. The tendency towards intense back-jets into brain and spinal canal must thus be substantially enhanced.
Low cerebrospinal fluid volumes and pressures can result in various ways: Artificially, for example by lumbar punctures or operations opening the cranio-vertebral space; or constitutionally, in particular because of low arterial pressures, or a low venous outflow resistance from the brain. The latter of these factors is of particular interest: A low flow resistance in the venous pathways of the brain can, in the presence of an individual predisposition to venous regurgitations into a definite venous drainage system of both brain and spinal cord, critically "destabilize" the venous dynamics of the craniovertebral space, already by its predisposing to a lower cerebrospinal fluid pressure.
One common determinant factor for the development of intensified venous back-jets is again most relevant in this context: Any ongoing venous regurgitation into brain or spinal canal will progressively "wash out" its own pathways as well as those of the venting effluxes. Venous regurgitations into brain and spinal canal must thus, in the long run, mutually enhance each other -- because any substantial widening of venous passages draining a major compartment of the brain, whether it be due to local venous regurgitations or compensatory venting effluxes, lowers not only the flow resistance against the venous currents themselves but, in diminishing cerebrospinal fluid filtration pressure –- according to the dependence of this latter on the cranial venous outflow-resistance, also weakens the resistance against cerebrospinal fluid shifts in the cranio-vertebral space. The mutual enhancement of these pathomechanisms is a particularly relevant factor in the causation of specific cerebral and spinal lesions in multiple sclerosis.

(V-3) The Key to Decoding Multiple Sclerosis: Specific Data
What has been presented above are the results of the first thorough attempt to clarify which observations of multiple sclerosis can actually be considered specific, and to elucidate their meaning. These evaluations have unfortunately brought to light some serious problems in the understanding of the disease.

(V-3-a) Inadequate Disease Specifications
As it is presently understood, the term "multiple sclerosis" conceals, in a threefold manner, the nature of any disease process to which it is applied:

There is the misleading clinical multiple sclerosis conception, which reflects the setting apart of certain cryptic disease processes simply by means of two quantitative properties: number and time. No facts have ever been presented to prove that this manner of determining the presence or absence of multiple sclerosis by the timing of unexplained neurological episodes is actually justified.
No less confusion has been created in additionally specifying multiple sclerosis by two different, each sufficiently broad histological terms which are supposed to provide a morphological lesion specification coextensive with the neurological dysfunctional one. Here the early all-inclusive label “grey degeneration” became the forerunner of the expression “(multiple) sclerosis”, implying that the disease was due primarily to a scarring process. Since some researchers felt that the latter lesion definition (yet not the term itself) was too narrow, the vague notion “primary inflammatory demyelination” came to be used. Nowadays, in certain circles, multiple sclerosis is considered to be caused by some sort of unexplained inflammatory cellular infiltrate of auto-aggressive immunocytes causing a specific myelin destruction (less obtrusive damages to other tissue components being, without qualms, passed over in silence). But the distinctiveness of this disease entity has never been substantiated by any specific exemplary observations.
Even the most fundamental differences in the lesion patterns shown by individual instances of (clinical) multiple sclerosis were eventually simply glossed over in conceiving of multiple sclerosis as the result of some random form of lesion spread, effected by some essentially cryptogenic "disseminated encephalomyelitis". The epithet “disseminated” thereby complicates matters by
- supposing a form of lesion spread which is characterized by nothing but an absolute randomness -- which lesion-interpretation apparently justifies
- considering the specific patterns of, in particular, cerebral “Dawson’s fingers” and spinal cord flank affections just as coincidental, and eventually
- attributing any corresponding condition to a single, essentially cryptic, systemically scattered blood-borne agent.
This vagueness about multiple sclerosis is handy: It avoids the need to differentiate observed lesion patterns and to elucidate their meaning. Together with the speculative “inflammatory demyelination” conception, the idea of “disseminated sclerosis” has thus proved pivotal in establishing multiple sclerosis – including its specific forms -- as a “cryptogenic, autoimmune disease". However, regarding the indefiniteness of these clinical, histological and pathogenic disease characterizations, it is abundantly clear that no two victims of multiple sclerosis ever necessarily suffer from one and the same disease, in terms of a definite specific injurious process.

(V-3-b) Reappraising Specific Multiple Sclerosis Observations
Experts on the history of medicine and neurology have always acknowledged the genuine identification of the pathological entity of multiple sclerosis by Carswell in his illustration of “a peculiar diseased state” of pons and spinal cord. However, they have never made explicit in just which respects these observations proved to be "peculiar".
As a result, the insight has never dawned that the instances of multiple sclerosis showing lesion patterns essentially identical to either the cerebral or spinal lesions of Carswell’s “peculiar diseased state” in fact constitute a monolithic block of specific observations corresponding to one well-defined and absolutely distinct pathological entity. And so the specific pathological observations have never been definitively analyzed and traced back to their most plausible cause, i.e. the injuriously intensified effects of intermittent flow-reversals in definite venous drainages of the cranio-vertebral space.
Openly admitting, “We have no idea what the neurological episodes now being classified as `clinically definite multiple sclerosis´ are due to”, not only avoids the pretence of a false diagnostic security but will also prevent many, otherwise inevitable, (experimental) therapeutic blunders.
It was not possible, up until 1981, to identify Carswell’s “peculiar diseased state” in the living. Accordingly, it might then have been claimed that all these problems were merely of a theoretical interest. Since then, however, magnetic resonance imaging has shown ever more potential for tracing the peculiarities of the specific lesions of, first, cerebral and then, later, also spinal multiple sclerosis in vivo. And with respect to the most recent advances in magnetic resonance flow mapping it might become feasible to demonstrate the occurrence of injurious venous back-jets into the brain and of vehement subarachnoid spinal fluid shifts even before patients have succumbed to their first “bout(s)”, i.e. clinical manifestation(s) of multiple sclerosis.

(V-3-c) Practical Consequences of Specific Observations
The question of whether we decide to strive for a solid morphological multiple sclerosis specification is not only a matter of intellectual honesty. What is at stake is the development of the proper diagnostic and therapeutic procedures for patients falling prey to “Carswell’s peculiar diseased state”, i.e. to a potentially utterly serious and yet, in principle, fully curable central nervous affection.
Escaping from the ruts and sloughs which multiple sclerosis research has, over more than one and a half centuries, become entrenched in will be no easy endeavour. It is urgent to extricate ourselves from a confusing and misleading terminology, in which any research relating to multiple sclerosis has become hopelessly snarled. There are also countless private and corporate interests opposing any change in the present state of affairs –- and they work quite effectively perpetuating the belief that (clinical) multiple sclerosis can, in the near future, actually be cured pharmaceutically.
Having carefully weighed the available evidence, the impartial reader will yet realize that any promise of providing a cure for “clinically definite multiple sclerosis” cannot, either sooner or later, be fulfilled. Time is of the essence, if the suffering is to be stopped.
The two key-objectives for achieving real progress in multiple sclerosis-research must accordingly be the development of magnetic resonance techniques which are suitable to

identify multiple sclerosis-specific changes and
determine their cause(s).

Specific instances of multiple sclerosis could be definitively cured by employing two surgical procedures aimed at preventing a recurrence of injurious venous back-jets:

To prevent the development of “Dawson’s finger” projections, a ligature of the jugular vein carrying injurious venous back-jets into the center of the brain might form a simple method for curing an otherwise relentlessly progressing disease.
As to spinal cord flank lesions, the development of minimally traumatizing surgical procedures for interrupting the pathways of vehement venous regurgitations into the lowermost spinal canal appears – as challenging as this task may appear – equally promising.

Progress in the field of magnetic resonance imaging and flow mapping, which make it possible to trace, in living patients affected by “Dawson’s fingers” or also spinal cord flank lesions, the venous flow inversions and related subarachnoid fluid shifts responsible for the particular lesion-developments, will then open the way towards achieving a proper cure and even primary prevention of the corresponding diseases.