____________________________________________________________ File Ch Table Of Contents Page (17-00) Introduction xi - xiii (17-01) 1 A Legacy Of Fats And Oils 3 - 5 4 MS: General Information 22 - 29 5 The Clinical Picture 30 - 34 6 Diagnosis 35 - 37 (17-02) 10 About Nutrition - Practical Points 97 - 98 10 Proteins 98 - 108 (17-03) 9 Genesis Of Multiple Sclerosis 80 - 93 9 Saturated-Fatty-Acid Hypothesis 90 - 91 9 Second MicroEmbolism Method 91 - 93
The random distribution of the symptoms, the accompaning Neurological Signs, and the frequent location of the pathological lesions, plaques or areas of DeMyelination in the Brain and Spinal Cord surrounding small Venous channels.
Suggest that the small Blood Vessels (MicroCirculation), which include the Arterioles, Capillaries, and Venules, play a role in the genesis of this disease.
This contention has been supported by the observations that small Arterioles and Venules of the CNS are thickened, often tortuous, nodular, and alternately constricted and dilated.
And by the occasional accumulations of Platelets (Thrombocytes) and small blood clots in small central Venules inside the DeMyelinated lesions.
It should be added that a substantial number of MS relapses develop abruptly, in a manner similar to Strokes. An early observation that has recently recieved added recognition concerns the Blood-Brain Barrier.
Tore Broman first demonstrated that many MicroVascular Blood Vessels in the Brains of MSers were permeable to the dye trypan blue. This phenomenon is known as a breakdown of the Blood-Brain Barrier. It does not occur in normal subjects.
Although this phenomenon was confirmed by another method using Bromide, it aroused little interest until it was repeatedly demonstated by Computerized Tomography (CT) technique after IntraVenous injection of radio-opaque Iodine solutions.
Because of its importance, we shall give the Blood-Brain Barrier further attention. The Vascular System which nourishes the Brain, has for some time been recognized as possessing properties that differ from those in other organs.
The classical observation of Felix Ehrlich that the Brain was not stained when Aniline dyes were injected IntraVenously, and the knowledge that certain toxins and bacteria did not penetrate the Blood Vessels to the Brain; led to the concept that the Brain vessels possessed a high degree of selective permeability.
While disagreement exists as to the anatomical representation of the barrier, there is increasing common agreement that the permeability of the Brain Capillaries is selective.
And that many substances of physiological significance penetrate Brain tissue from the bloodstream very slowly.
Louis Bakay pointed out that the permeability of the Capillary network is abnormally increased after a variety of Cerebral injuries including those caused by Heat, Chemical Agents, Ultrasound, Embolization, Thrombosis, Hemmorrhage, and Infection.
As mild an alteration of status as exposure of the Brain, especially if Dura were removed, produced reversible permeability of the Barrier. The permeability is also increased in Tumor tissue.
It has been stated that Anoxia, Ischemia, and passive congestion, the result of ligation of Veins draining the Brain, do not alter the Blood-Brain Barrier, unless they are associated with Necrosis of tissues or physical damage to the Brain or its Blood Vessels.
Anoxia is a condition in which there is not enough Oxygen for tissue Oxygenation.
Ischemia is an insufficient blood supply to an organ/tissue.
Hypoxia indicates a severe Oxygen shortage in tissue.Emboli are small particles that Occlude the circulation of smaller Blood Vessels.
Glial scars are produced by enlargement of the fibrils of Astrocytes (a type of Glia) that normally support the Nerve cells and their Nerve fibers.
When a portion of the Nervous System is damaged, these fibers enlarge and replace the damaged area. This process is referred to as Gliosis.
Necrosis is the death or decay of tissue in a part of the body which is the result of loss of blood supply, burning, and other severe injuries.
Of particular interest is the disturbance of permeability after after Embolization. Broman observed changes near solid particles (Emboli) after five to eight hours.
Roy Swank and Raymond Hain found that paraffin Emboli (particles) marked with carbon black of a size up to 17 microns in diameter produced lesions primarily in the White Matter where most MS lesions are found.
Many of these lesions eventually were converted to Glial scars, resembling the lesions seen in postmortems of MSers.
Larger Emboli from 35 to 60 microns produced lesions principally in the Gray Matter, most of which had a central core of Necrosis, similar to those frequently seen in postmortoms of cerebroVascular disease (Stroke).
Increased permeability of the Blood Vessels appeared within thirty minutes of Embolization, at first more marked on the Arteriolar and later more marked on the Venular side of the Capillary circulation.
The permeability was maximal at about three hours. The permeability in and near the Arterioles returned to normal in twenty-four to thirty hours, but around the Venules it returned in forty-eight hours to as long as two weeks.
After air and fat Embolization, a disturbance of Vascular permeability occured in ten to thirty minutes.
In other studies, Revis Lewis and Roy Swank observed PeriVascular Gliosis around the Embolized Capillaries, Arteroles, and Venules several days after Embolization.
One hundred days later, the PeriVascular Gliosis enveloped the vessels completely and was quite dense.
Jan CammermEyer and Roy Swank noted thickening of Vascular walls due to Hyperplasia of the cells as early as four days after experimental fat Embolization of the Brain.
It is of interest to recall that James Dawson and Giorgio Macchi observed PeriVascular Gliosis and thickening of Vascular walls in their HistoPathological studies of early as well as late lesions in the Brains of MSers.
It is not clear why Emboli have a more profound effect on the permeability than Anoxia and Ischemia. Normally the red blood cells flow near the center of the column of blood flowing in Blood Vessels and are surrounded by and separated from the Endothelium by a layer of Plasma.
This relationship is probably not altered by Ischemia and Anoxia. Emboli, however, when larger, become wedged into a blood vessel, dilate the vessel and stretch its walls, mechanicaly tramatizing the Endothelium.
At the same time, severe localized Anoxia occurs and tissue metabolites accumulate. It would thus appear that trauma to the Endothelium is a significant factor in the erosion of the Blood-Brain Barrier.
It seems likely that recovery of the Blood-Brain Barrier at the Venous end of the Capillary is delayed by the relatively low Oxygen tension of Venous blood.
Chester Cullen and Roy Swank observed striking and patchy increases in the permeability (breakdown) of the Blood-Brain Barrier, after injections of large-molecular-weight Dextran.
Which caused marked aggregation of the blood cells and in turn, Occluded many of the smaller Blood Vessels for minutes at a time.
The aggregates also greatly reduced the speed of the Cerebral circulation. It is felt that this effect on the Blood-Brain Barrier was due to Embolization of the Cerebral Arterioles and Capillaries by the aggregates of blood cells.
It is important in our hypothesis that Embolization has a more profound effect on the Blood-Brain Barrier than does Ischemia or Anoxia.
Embolization by aggregated blood cells or small solid paraffin Emboli slows, but does not permanently stop, the blood flow.
The flow was shown to be markedly retarded by paraffin Emboli to the extent that most small Emboli took from a few to thirty or more minutes to pass through the Cerebral Capillary bed.
A similar slowing of circulation occurred in a hamster's cheek pouch, when the Embolization was caused by aggregated blood cells, the result of large saturated meals or IntraVenous injections of large molecular weight Dextran or gelatin.
It is felt that this patchy breakdown of the Blood-Brain Barrier is an important link in the genesis of the lesions and symptoms of Multiple Sclerosis.
Recent study of Cerebral Blood-Brain flow (CBF) by Swank and his collaborators, revealed significant reduction of the flow in MSers.
In seventy-seven normal women and fifty-three normal men of different ages as controls, and twenty-six men and forty-five women with Multiple Sclerosis, using the inhalation radioactive Xe133 method.
In both normal and MS subjects, the CBF was high in teenagers but fell at first rapidly and then slowly in adult life.
In normals, the CBF was higher in women than in men, but when the differences in the red cell concentration (Hematocrit) in men and women were adjusted, the folw of red cells to the Brain was the same in the two sexes.
In MSers there was a progressive, generalized decrease in CBF in both men and women before and after adjustment for Hematocrit.
The rates of decrease were significantly greater than in normals, and they correlated directly with the speed of progress of the disease. Outside the CNS, PathoPhysiologic changes have been observed in the general circulation of MSers.
Marked tortuosity, irregularities, and spasms of the small Arterioles were described at the base of the nail bed. PeriVenular changes were seen around veins in the Retina of the Eye.
Coldness of one or more extremities, weak pulsation of the arteries of the legs and feet, and subnormal skin temperatures of one or more extremities also were reported.
These observations indicate a reduction of the general circulation as well as that seen in the Brain of MSers.
Increased fragility of the subcutaneous (skin) Capillaries and small spontaneous Hemorrhages in the subcutaneous tissues of the extremities, primarily of the legs, are frequently seen, particularly in women.
Physical changes in the circulating blood itself have been reported. Aggregation (or clumping) of blood cells in the circulating blood of smaller Arterioles of the Conjunctiva and Retina of the Eyes and at the base of the nail beds have been observed.
The blood Platelets, the smallest of the blood cells that control bleeding from damaged small Blood Vessels, have been closely linked to the disease. As early as 1951, Platelet counts were reported to vary considerably in MSers.
A search for a mechanism that could cause both an interference with, and slowing down of, the Cerebral and general body blood flow, and a breakdown of the Blood-Brain Barrier in the CNS.
Leads to consideration of Circulatory changes that have been observed in a number of species, including humans, following large saturated-fat meals.
Swank and his associates observed that large saturated-fat meals, caused marked aggregation of blood cells both in vitro and in vivo in dogs, humans, and hamsters; and also increases in the viscosity of Venous blood in dogs and hamsters.
In hamsters, dogs, and rabbits, fat meals caused slowing of circulation and decreased Oxygen availability in the Brain, and they also caused Convulsions, and marked increases in Potassium and decreases in Sodium excretion.
Oil meals either produced no such changes or much lesser changes. In dogs IntraVenous injections of lipemic chyle also caused paralysis.
Other investigators reported aggregation of blood cells in the vessels on the surface of the Cerebrum in cats and aggrigation of blood cells in the conjunctival MicroCirculation of humans after fat meals.
Swank suggested that the aggregation of blood cells (breakdown) of the suspension stability of the blood, after fat meals was due to competition of all blood elements.
Including the massive entry of Chylomicrons (small fat globules) into the Bloodstream, for emulsifying factors, that consequently become temporarily deficits.
In still other studies, Swank demonstrated a breakdown in the Blood-Brain Barrier (increase in permeability) in hamsters by MicroEmbolism due to marked aggregation of blood cells caused by high-molecular weight Dextran infusions.
And similar increases in permeability, the result of paraffin MicroEmbolism of the Brain in dogs.
Aside from alterations already described, these aggregates in the circulation could cause severe focal areas of Ischemia and Hypoxia and shift the acid-base balance to the acid side, in the surrounding tissues.
This in turn could activate the digestive enzymes contained in the Lysosomes of the Embolizing cells and surrounding nerve tissues.
Erosion (digestion) of the surrounding tissues would result in DeMyelination, destruction, and finally Gliosis, similar to the lesions seen in postmortems on the Brains of MSers.
In addition the "door" would be open to passage of subtances, in the blood that are toxic to nerve tissues in the CNS, as first suggested by Swank and his associates and later by Frederick Seil. Either or both mechanisms could cause the lesions of MS, as envisioned in this hypothesis.
A toxic substance that destroyed Spinal Cord Myelin, the fatty sheath surrounding nerve fibers, was demonstrated by Arthur Weil in the urine of 115 of 165 MSers (70%) in the 1930's.
The Urine from 28 of 43 patients (65%) with a different destructive Neurological Disease, PostEncephalic Parkinsonism, also contained a similar Myelin destroying substance. Nearly thirty years later, these findings for MS were confirmed.
In other studies, it was found that blood Serum from MSers caused reversible DeMyelination of cultured nerve fibers and also blocked the passage of nerve impulses through these fibers.
Cortical electrical Evoked Response were also reversibly blocked or attenuated, by application of both normal and MSers Sera to the rat Cortex.
The possible that normal Plasma contains NeuroToxins that can alter the function of the human Brain in MSers was indicated, by the development of varying degrees of Necrosis.
And occasionally by a temporary increase in the Neurological deficit soon after infusions of normal Plasma into MSers in exacerbation.
It was postulated that these symptoms were due to penetration of the Blood-Brain Barrier by toxic components of the Plasma. Recovery occurred in three to four days.
After the second infusion of two units of normal Plasma, no untoward effects occurred, and the patients rapidly improved and remained stable for several months to a year or more.
The absence of Necrosis after the second infusion suggests that normal Plasma also contains substances essential to an intact Blood-Brain Barrier, as well as substances toxic to nervous tissues.
In addition to the toxic compounds of Plasma described in the preceding paragraphs, an abnormality in Plasma, probably due to a deficiency, has been disclosed in Multiple Sclerosis Plasma.
Swank, Franklin, and Quastel, using a two-dimensional paper chromatography technique, found that normal and MS Plasma differed. In a few cases, these differences disappeared after transfusions of normal blood.
Abnormalities were not observed in normal people (controls). It is of interest that, after butterfat meals, similar protein patterns were seen in the blood of dogs.
This observation was subsequently elaborated, using the Field's Red-Cell Mobility Test, which demonstrates a reduced red-cell mobility in MSers' blood.
In a collaboration of Swank with Seaman and his laboratory, it was shown that the reduced mobility of MSers' red blood cells in an electrical field was due to an abnormality in the Plasma.
Rather than in the red cell membrane, since placing MS red cells in normal Plasma returned the mobility to normal, and placing normal red cells in MS Plasma reduced the mobility of the normal red cells.
Further confirmation that MS Plasma differed from normal Plasma was demonstrated, when plastic beads immersed in MS Plasma were found to be less mobile in an electric field, than were the same beads immersed in normal Plasma.
Subsequently, Swank and his associates showed that infusions of normal Plasma into MSers in exacerbation, resulted in rapid recovery of the patient. Especially in the early phases of the disease, and return of the mobility of the patient's red cells to normal.
On the basis of these experiments it was concluded that blood Plasma of MS patients is abnormal and that this abnormality is probably a deficiency.
This hypothetical deficient substance(s) will be referred to as factor X in the ensuing discussion. It is possibly the genetic component throught to be missing in MSers.
With so many clinical and biochemical factors related to the circulating blood in a disease that seems to be related to a high fat intake, it is reasonable to explore the possible ways in which these "facts and near facts" can be linked to explain the genesis of MS.
One of these, the saturated-fatty-acid hypothesis, developed by the senior author of this book, is as follows:
In the meantime Robert Thompson found reduced levels of Serum Linoleate in MSers.
Other investigators with Thompson found similar reductions in Linoleate in Platelets and red cells, and also a tendency for the concentration of Linoleate to be lower, and that of Oleate to be higher, in Sera from MSers than in controls during supplemental feedings of Linoleate.
These results suggest that Linoleate is metabolized somewhat differently in patients than in controls. Earlier we showed that a reciprocal relationship of fat and Oil consumption existed in our MSers on the low fat diet.
Patients did best when the intake of fat was very low and Oil relatively high, and poorest when the fat intake was high and Oil low. We feel that the high Oil intake in patients doing very well was increased by them to improve the taste of their food.
These considerations lead one to no definite conclusion regarding the importance of the Oil intake for MSers on the Swank low-fat diet. Sinclair's hypothesis still remains alive despite what seemed earlier to be a serious setback.