History and Timeline
The hypothesis that MS has a fundamental vascular component is not a new idea. Rather, it is supported by multiple scientific observers dating back 170 years. While autoimmune theories of MS have dominated recent MS research, the first scientific inquiries into MS strongly suggested a vascular correlation, if not a vascular cause. Subsequently, a small but important body of research undertaken during the 20th and 21st centuries – including Dr. Paolo Zamboni’s work – has both corroborated and extended those early observations.
Provided below is an abridged timeline of research documenting the vascular connection with MS. For those looking for a more detailed history with discussion of how these early findings are being corroborated by emerging MS research and theory, we recommend you also review Dr. E. Mark Haacke’s History of vascular observations in MS.
According to Putnam1, who pioneered experiments linking vascular abnormalities to MS in 1936, the first observations related to abnormal vasculature were documented by French anatomist Cruveilhier2 in 1839. Cruveilhier compared areas of sclerosis with the results of embolism.
1863, Rindfleisch and Charcot
In 1863, Rindfleisch3 microscopically observed autopsy specimens of MS brains and noted an engorged blood vessel in the center of each plaque. In the same year Charcot4 described vascular obstruction in MS.
Putnam studied the effects of obstructed venous flow in the cerebral veins of dogs. These animals developed a number of abnormalities similar to encephalitis or multiple sclerosis. His comment was as follows5:
"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 to the formation of typical sclerotic plaques."
Putnam and his colleagues in the neurology department at Boston City Hospital, Harvard University, and Columbia University continued to investigate damage caused to the brain and central nervous system resulting from disruption of blood flow well into the 1950's.
1942, Dow and Berglund
Dr. Robert Dow and Dr. George Berglund continued Dr. Putnam's research, finding further venous connections to MS lesions. The authors note that Ribbert6 earlier maintained that the demyelinated areas were related to a primary disseminated thrombosis. He described a congested central vessel in all the sclerotic patches.
1950, Zimmermann and Netsky
Drs. Zimmerman and Netsky furthered Dow and Berglund's research. They noted that the lesions were indeed venous in nature, but not caused by small thrombosis as Putnam had surmised7.
Dr. Torben Fog, a Danish professor, noted that MS lesions were predominantly found around the small veins. Fog summarized his results from a series of cadaver brain studies8 stating "30 plaques showed that they definitely followed the course of the veins, so that course and dimensions of the veins determine the shape, course and dimension of the plaques."
In 1973, at the University of Innsbruck, F. Alfons Schelling, M.D. began investigations into the enormous individual differences in the widths of the venous outlets of the human skull. The results of this study appeared in 1978 in "Anatomischer Anzeiger"9, from the German-speaking Anatomical Societies.
Schelling's 1981 discovery, at the Hospital for Nervous Diseases in Salzburg, of a striking anomolies 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 career. A crucial observation was the venous involvement in MS7 and lesion genesis. Predating Dr. Zamboni’s similar (but more detailed) CCSVI hypothesis, Dr. Schelling suggested that MS may be at least partially a result of venous ‘back-jets’ (reflux) into the CNS. While Dr. Schelling’s early hypothesis now appears strikingly relevant, when Schelling went public with his research at the time, he was ridiculed, dismissed, or simply ignored.
1981 Allen et al.
Further evidence of the vascular mechanical effect comes from the observations of I.V. Allen, who noticed the wide vascular beds around veins and the central widening of the venous tree indicative of intermittent increases in cerebral pressure10.
1987, Adams et al.
C. W. M. Adams, who specialized in microscopic tissue studies of MS plaque development (“histopathology”), lead a series of experiments in the 1980s which confirmed the fundamental vascular nature of MS plaque development 11.
1990, Kermode et al.
In a seminal publication, “Breakdown of the Blood Brain Barrier Precedes Symptoms and Other MRI Signs of New Lesions in Multiple Sclerosis,”12 Kermode et al. demonstrated via four meticulously documented cases studies that breach of the BBB (Blood Brain Barrier) occurred before MS symptom onset. Kermode concludes that “This supports the view that a defect in the blood brain barrier, and therefore inflammation, is an early and possibly crucial event in the pathogenesis of the new lesion in MS.” Kermode also notes that “Such perivascular inflammation [inflammation around veins] has also been seen in the normally appearing white matter… leading to the conclusion that perivascular inflammation in MS can occur in the absence of myelin breakdown, and the suggestion that a vascular event is a necessary preliminary to the development of structural damage.”
1994, Kwon & Prineas
Validating Kermode’s findings, Kwon and Prineas’ histological studies corroborated that BBB permeability appears prior to demyelination13.
In a hypothetical presentation14, B.H.J. Juurlink of the Cameco MS & Neuroscience Research Center in Saskatoon, Canada, tied together a wide body of research linking MS with white blood cell infiltration of the CNS via abnormal vascular permeability. Juurlink’s work, which stressed the role of hypoperfusion (decreased blood flow), built a compelling case for endothelial breakdown as a key component of BBB breach that is often considered a hallmark of MS.
Zamboni; Zamboni et al., 2006; 2009
In 200615, prior to proposing CCSVI, Dr. Zamboni presented a paper noting the remarkable similarity between Chronic Venous Disease (CVD), and MS, including similar liaisons and iron/fibrinogen deposition. In 200916, Dr. Zamboni used duplex ultrasonography to demonstrate a strong correlation between CCSVI and MS.
2008, Ge et al. 2008
Ge, Zohrabian, and Grossman used state-of-the-art ultra-high resolution imaging techniques available to “describe the perivenous relationship of MS lesions”17. Producing images with detail never before seen, Ge et al. note that of the 80 lesions studied in RRMS patients, “all lesions showed a strict perivascular distribution, following the form, orientation, and course of the vessels". They note that “these findings, which have never been shown on conventional field of MRI, not only allow for direct evidence of vascular pathogenesis in MS in vivo, but have important implications for monitoring lesion activity and therapeutic response.”
McQuaid, Kirk, et al. in Ireland have spent a decade researching MS plaque development and MS pathogenesis. Summarizing their work, McQuad et al. (2009)18 confirms that “Dysfunction of the BBB is a major hallmark of MS.” Additionally, they note that abnormal fibrinogen leakage (as hypothesized by Zamboni, 2006, above) is “one of the earliest events associated with MS lesion formation,” noting finally that “fibrinogen could function to mediate the initial activation of resting microglia leading to increased phagocytosis” (in other words, fibrinogen that has migrated across the BBB due to endothelial dysfunction can effect (regulate) native CNS cells and accompanying immune activity).
From the very first observations of MS lesions over 150 years ago up to the most current state-of-the-art histological and Magnetic Resonance Imaging and studies, the clear link between MS and the vascular system has been apparent. Recent findings that vascular dysfunction, whatever its cause, may precede both T-cell and B-Cell activation and demyelination advances our understanding of the complex interplay between the immune and vascular components of MS. It is hoped that the groundbreaking research summarized above, research conducted across four continents and over 150 years, will contribute to creative new approaches for managing, ameliorating, and avoiding MS onset and progression.
- Putnam (1939). Evidences of vascular occlusion in multiple sclerosis and encephalomyelitis. Arch. Neurol. Psychiatry 6: 1298-1321.
- Cruveilhier (1835-1842) Anatomie pathologique du corps humain. Paris, Bailliere, Vol 2.
- Rindfleisch (1863). Histologisches detail zu der grauen degeneration von gehirn und rueckenmark. Arch. Path. Anat. Physiol. Klin. Med. 26: 474.
- Charcot (1868) Histologie de la sclerose en plaques.Gaz Hopit Civils Milit. 41: 554-566.
- Putnam (1935). Studies in multiple sclerosis: encephalitis and sclerotic plaques produced by venular obstruction. Archives of Neurology and Psychiatry. 33: 929-940.
- Dow, Berglund (1942). Vascular Pattern of Lesions of Multiple Sclerosis. Arch Neurol Psychiatry. 1942;47(1):1-18.
- Zimmerman, H. M., Netsky, M. G.: The pathology of multiple sclerosis. Res. Publ. Ass. Nerv. Ment. Dis. New York 28,
- Fog (1963). On the vessel-plaque relations in the brain in multiple sclerosis. Acta Psychiat Neurol Scand. 1963; 39, suppl. 4:258.
- Schelling (1986). Damaging venous reflux into the skull or spine: relevance to multiple sclerosis. Med Hypotheses. 1986 Oct;21(2):141-8.
- Allen et al. (1981). Demyelinating diseases. The pathology of multiple sclerosis: fact, fiction and hypothesis. Neuropath and Applied Neurobiology. 1981; 7: 169.
- Adams, et al. Periventricular Lesions on Mlutiple Sclerosis: Their Perivenous Origin and Relationship to Granular Ependymitis. Neuropathology and Applied Neurobiology. 1987; 13:41-152.
- Kermode, et al. Breakdown of the Blood-Brain Barrier Precedes Symptoms and Other MRI Signs of New Lesions in Multiple Sclerosis. Brain. 1990; 113: 1477-1489
- Kwon, Prineas. Blood-brain barrier abnormalities in longstanding multiple sclerosis lesions. An immunohistochemical study. Journal of Neuropathol Exp Neurol. 1994; 53(6):625-36
- Juurlink. The multiple sclerosis lesion: initiated by a localized hypoperfusion on a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated? Medical Hypotheses. 1998; 51:299-303
- Zamboni. The Big Idea: Iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. Journal of the Royal Society of Medicine. 2006; 6:589-593
- Zamboni et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009; 80:392-399.
- Ge et al. 7T MRI: New Vision of Microvascular Abnormalities in Multiple Sclerosis. Archives of Neurology. 2008; 65(6): 812-816
- McQuaid, et al. The effects of blood-brain barrier disruption on glial cell function in multiple sclerosis. 2 Neuroscience Ireland Conference. 2009; 37: 329-331