A History Lesson- from Dr. Mark Haacke

January 9, 2010 at 12:24pm

We've been discussing the importance of knowing the history of MS. As MS patients and caregivers, it is vital that we understand why certain medical paradigms are discarded in preference for others. 

Doctors around the globe are digging into medical vaults and finding more on the venous vascular connection to MS. We will not let this moment pass unnoticed.

From Dr. Haacke:

A Brief History of the Early Venous Vascular Observations in MS

This section will be developing over time as we review the past and sometimes almost ancient literature related to MS. According to Putnam (1) who discussed vascular abnormalities in MS in 1936, the first observations related to abnormal vasculature or effects related to the vasculature appeared in Cruveilhier (2) in 1839, more than 170 years ago who compared areas of sclerosis with the results of embolism. Rindfleisch (3) noted in 1863 an engorged vessel in the center of a plaque and in the same year Charcot (4) described vascular obstruction in MS. These observations would be noted again and again over the next 135 years. What was missing was the advent of imaging as a tool to investigate the vascular system in three dimensions, something that ultrasound takes a step toward as used by Zamboni and more recently the use of magnetic resonance imaging in the study of cerebro-spinal vascular insufficiency or CCSVI.

But Putnam didn't stop there. With an ingenious idea, he proceeded to study the effects of obstructed venous flow in the cerebral veins of dogs. These animals developed a number of abnormalities many of them similar to encephalitis or multiple sclerosis. His comment at the end of his paper was as follows (5): "The later stages (up to ten months) of the lesions consist of plaques of demyelinization with practically complete preservation of the axis-cylinders and with dense fibrous gliosis confined to the white matter. The similarity between such lesions and many of those seen in cases of multiple sclerosis in man is so striking that the conclusion appears almost inevitable that venular obstruction is the essential immediate antecedent fo the formation of typical sclerotic plaques." Despite the wonderful immunological advances in the last 75 years, how can we ignore the early work that so clearly demonstrates the role of the venous system in MS? The precocious work of these early researchers today finds its laurels in the current extracranial obstructions proposed by and seen by Zamboni (6) and now others.

There are more intriguing connections as one reads these old papers. Venous blood is more prone to clot. And these micro-thrombi may rapidly disappear and so become unobservable. An increase in capillary density also seems to develop and this may well describe the "capillary recruitment for venous drainage hypothesis proposed by Haacke". In this hypothesis, the obstructed flow leads to endothelial damage (7) and iron build up (8) and the need to increase the outflow capacity in the venous system. The brain then recruits capillaries to become veins and these in turn are also damaged leading to further iron deposition. If this is the case, then the iron build up should take place backward along the venous drainage system, which appears to be the case (9).

The story continues with a reference to Borst who founded a theory on the occurrence of vascular obstruction where he mentions the process of significant narrowing to the point of complete obliteration, hyaline transformation, etc. Perivacular hemorrhages were also frequently described by many authors. Borst (10) also mentions the presence of pigments. Others describe the combination of all three: congestion, perivascular hemorrhage and pigments (possibly hemosiderin or iron related) in encephalitis post measles (11). Many noticed venous engorgement and one study showed that thrombi were visualized in nine of seventeen MS cases and all three encephalomyelitis cases.

(1) Putnam (1939). Evidences of vascular occlusion in multiple sclerosis and encephalomyelitis.
(2) Cruveilhier (1839).
(3) Rindfleisch (1863). Histologisches detail zu der grauen degeneration von gehirn und rueckenmark. Arch. Path. Anat. Physiol. Klin. Med. 26: 474.
(4) Charcot (1863).
(5) Putnam (1935). Studies in multiple sclerosis: encephalitis and sclerotic plaques produced by venular obstruction. Archives of Neurology and Psychiatry. 33: 929-940.
(6) Zamboni (2009). Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 80:392-399.
(7) Adams 1987. Periventricular lesions in MS. Neuropathol Appl Neurobiol. 13: 141.
(8) Singh and Zamboni (2009). Anomalous venous blood flow and iron deposition in multiple sclerosis Anomalous venous blood flow and iron deposition. JCBF 1-12.
(9) Haacke et al. Evidence of an increase in basal ganglia and thalamic iron content in multiple sclerosis and its vascular implications: An initial analysis with susceptibility weighted imaging. Submitted to Intern. Angiology.
(10) Borst Anatomica 9, 67, 1903 Die multiple sklerose des zentranervovensystems.
(11) F. Wohlwill. Ueber encephalomyelitis. Neurol and Psychiat, 112: 20, 1928.

The venous connection to MS- a timeline

January 3, 2010 at 6:09pm

To those doctors who insist the venous connection to MS is an unproven theory, I offer a timeline of doctors who might beg to differ.

1863 Rindfleisch

Dr. E. Rindfleisch noticed that, consistently in all the autopsy specimens of MS brains he viewed with his microscope, a vein engorged with blood was present at the centre of each lesion.

Rindfleisch wrote:

"If one looks carefully at freshly altered parts of the white matter ... one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood ... All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation."

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

1930s Putnam

Dr. T. J. Putnam researched lesions and noted that thrombosis of small veins could be the underlying mechanism of plaque formation-  He later created MS-like lesions in dogs by blocking their dural sinuses.

Putnam, T.J. (1937) Evidence of vascular occlusion in multiple sclerosis

1940s Dow and Berglund

Dr. Robert Dow and Dr. George Berglund continue on with Dr. Putnam's research and finding venous connections to MS lesions.

VASCULAR PATTERN OF LESIONS OF MULTIPLE SCLEROSIS Arch Neurol Psychiatry. 1942;47(1):1-18.

1950s  Zimmermann and Netsky

Dr. Zimmerman and Netsky carry on with Dow and Berglund's research, and note that the lesions are indeed venous in nature, but not caused by small thrombosis as Putnam surmised.

Zimmerman, H. M., Netsky, M. G.: The pathology of multiple sclerosis. Res. Publ. Ass. Nerv. Ment. Dis. New York 28, 271--312 (1950)

1960s Fog

Dr. Torben Fog, a Danish professor – noted that MS lesions are predominantly around the small veins. His subsequent study of 51 plaques from two cases of typical MS, making thin sections of the plaques and following their shape and course with direct drawings of each section, showed that most were prolongations of periventricular plaques, and that the plaques did follow the course of the venous system.

Fog Torben, The topography of plaques in multiple sclerosis, with special reference to cerebral plaques. Acta Neurol Scand, 41,Suppl. 15:1, 1965)

Fog T. On the vessel-plaque relations in the brain in multiple sclerosis. Acta Psychiat Neurol Scand. 1963; 39, suppl. 4:258

1980s Schelling

The story began in 1973, at the University of Innsbruck, when F. Alfons Schelling, M.D. began investigations into the causes and consequences of the enormous individual differences in the widths of the venous outlets of the human skull. The results of this study appeared, in 1978, in the official organ of the German-speaking Anatomical Societies, the "Anatomischer Anzeiger".

F.A. Schelling's 1981 discovery, at the Hospital for Nervous Diseases in Salzburg, of a striking widening of the main venous passageways through the skulls in victims of multiple sclerosis were to occupy the author's thoughts through the following decades of his quite diversified medical career. And in putting together, bit by bit, all the observations on the venous involvement in the emergence of the specific, and, in particular, cerebral lesions of multiple sclerosis, he was able to recognize their causes.

"Unequal propagation of central venous excess pressure into the different cerebral and spinal venous drainage systems is the rule rather than the exception. The intensity of the forces thus to be exerted on vulnerable cerebrospinal structures by the resulting pressure-gradients in the craniovertebral space is unknown. There is a need to consider the various conditions which may cause individual proneness to heavier reflux into particular cerebral as well as epi- and subdural spinal venous compartments. An attempt is made to indicate eventual consequences of excessive retrograde dilatation especially of internal cerebral veins. The importance of elucidating the neuropathological and clinical implications of undue reflux into the skull or spine is deduced from the probability of relations between localized backflow into the craniovertebral space and unexplicated cerebrospinal diseases. In this regard the features of multiple sclerosis are discussed."

Damaging venous reflux into the skull or spine: relevance to multiple sclerosis, Schelling F.

Here is Dr. Schelling's website for more information. His book (available for free on his site) outlines the history of the connection of MS to the venous system. Dr. Schelling is a brilliant, kind and generous man. When he came public with his research, he was dismissed, ridiculed and mocked. I am so happy that he is able to now witness Dr. Zamboni's technological corroboration of his findings. It was my pleasure and honor to meet him in Bologna, and to share his research with you.

link to Dr. Schelling's site