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Observations on the brain vasculature in multiple sclerosis: A historical perspective
Multiple Sclerosis and Related Disorders
To review the literature on vascular aspects of multiple sclerosis (MS) specifically pathological observations of the perivenular distribution of MS lesions and venous pathology in MS.
Comprehensive literature search from 2012 back to 1839.
One hundred and thirty two papers from 1839 to 2012 were included in this study. Multiple authors observed central venules in MS lesions as a feature of MS with the first specific mention by Rindfleisch in 1863. Recent high field strength MRI has reintroduced the perivenular distribution of MS lesions to a new generation, and has suggested that there is disease specificity to this distribution. In addition Putnam and others in the 1930s hypothesized that venous disease was causative for MS. Treatments based on these observations have included anticoagulation, hyperbaric oxygen therapy, and recently endovascular venous procedures. The significance of these findings in terms of MS pathogenesis has been debated over the same period of time.
While the controversy over venous disease in MS is new, the observation of perivenular MS plaques and venous theories about MS pathogenesis are as old as the history of MS research.
- A historical review of pathological observations and venous pathology in MS.
- The perivenous distribution of MS lesions has been recognized since 1863.
- Putnam and colleagues proposed venous sinus disease as a cause for MS in the 1930s.
- Therapies have been developed based on these observations.
Keywords: Multiple sclerosis, Pathology, Venous, Vein, CCSVI, History.
It is common in medicine for observations to be made and then become lost or obscured by other events in a certain field. In the case of multiple sclerosis (MS), both the perivenular distribution of lesions and the hypothesis that larger veins may be involved in MS have been noted many times over the past 160 years, with varied interpretations regarding the potential role of blood vessels in MS pathogenesis. In this study we review the literature exploring the relationships between the venous system and the central nervous system in MS.
We performed a literature search focused on vascular observations relating to MS from 1946 to 2011 (OvidMEDLINE, OvidOLDMEDLINE), with hand searched references of articles earlier than Ovid databases dating back to 1839. The search included the following search terms: multiple sclerosis, vascular, pathophysiology, vein, jugular, azygous, and venous (multiple sclerosis and (vascular or vein or jugular or azygous or venous.mp.)). We performed a secondary search using the same terms in Google Scholar ( 〈http://scholar.google.com/〉 ). We also performed a text search using McAlpine's Multiple Sclerosis 1998 and 1955 editions, Churchill Livingstone, London; Multiple Sclerosis, Principles of Neurology, Adams et al., McGraw-Hill, 1997, USA; and Multiple Sclerosis, the History of a Disease, T. Jock Murray, 2005, Demos, New York. Studies were included in the final reviewed group of papers if they met the following criteria:
- (1) Primary papers referring to multiple sclerosis which discussed vein, venule, or venous sinus appearance or pathology in the multiple sclerosis population.
- (2) Languages limited to English, French, and German to provide for translation.
- (3) We excluded multiple studies from one group if they reviewed similar findings or populations.
- (4) We did not comprehensively review the literature after the observations by Zamboni et al. (Zamboni as they were not germaine to the historical record prior to his papers. However we did look at the frequency of publications over time prior to and after 2009.
- (5) We excluded articles on retinal venous changes in MS unless they were connected with studies looking at brain or systemic venous changes.
Our initial search yielded 1420 articles of which all abstracts were reviewed. Of the 1420, we excluded 1237 articles which did not meet all inclusion criteria. We excluded articles specifically dealing with the presence of retinal vessel abnormalities unless they referred to how this would relate to brain vascular change, as well as many articles which referred to vessels only in passing.
We reviewed the remaining 183 articles from the Medline search, a Google scholar search and the hand searched texts using the above criteria. Of these only the articles which were primary sources or which commented directly upon the sociology of vascular theories for MS were included in the final manuscript. A final 102 articles met inclusion criteria were utilized in this review, though not all were included in the final reference list.
4. Early history
Early observations of blood vessels in MS focused on descriptions of the anatomy and histology of the disease's plaques. In his classic pathological text, French anatomist Jean Cruveilhier ( Cruveilhier, 1928–1842 ) in a series of pathological manuscripts dated 1829–1842 provides some of the earliest descriptions of the MS plaque. Cruveilhier compared areas of sclerosis with the results of embolism, noting “curious irregular scars ‘almost like areas of embolism”. Thus Cruveilhier alluded to a vascular relationship without specifically documenting a perivenular distribution of lesions.
Georg Eduard von Rindfleisch was the Chair of Pathology at the University of Würzburg. In 1863 he described vessel changes in autopsied brains of MS patients and first noted that a blood vessel was often prominently positioned in the center of MS plaques ( Rindfleisch, 1863 ). He also noted that the vessels show changes typically found in chronic inflammatory processes, with thickened walls and the accumulation of cells in the adventitia. He observed that the vessels seemed dilated and the capillaries appeared double walled with ‘round cells’ between layers.
Hugo Ribbert, a German Professor of pathology at the University of Bonn, suggested in 1882 that the cause of MS lay in the blockage of capillaries by minute thrombi ( Ribbert, 1882 ). He noted the accumulation of small ‘nuclei’ (likely leukocytes) around vessels and described changes appearing within the course of the disease when leukocytes leave vessels to accumulate in the surrounding tissue similar to an inflammatory process. “We observed even with the naked eye in the center of each [plaque] a red dot or line”.
Jean-Martin Charcot, Professor of Neurology at the Université de Paris, lectured extensively on the clinical and pathological aspects of MS. In 1886 he described ‘voluminous fatty globules’ around blood vessels (“l'apparence des corps gras;ces globules se présentent sous deux aspects principaux:les uns figurent des masses relativement volumineuses”) ( Charcot, 1886 ), but questioned the vascular causation of MS. He ascribed the cause of MS to glial hypertrophy and degeneration of nerve tissues.
R.T. Williamson, a physician at the Manchester Royal Infirmary, in 1903 concluded that lesions of MS are produced by ‘some abnormality’ of blood vessels ( Williamson, 1903 ). Anton in 1912 argued that blood vessels are the carriers of disease-causing agents and that in small blood vessels with slower blood circulation the disease-causing agents are able to reach toxic concentrations ( Anton and Wohlwill, 1912 ). Borst in 1903, Simerling and Raecke in 1914, and Jacob in 1929 noted thrombi, engorgement of vessels, and perivascular hemorrhages in cases of MS, extending the observations of predecessors (Borst, 1897, Simmerling and Raecke, 1911, and Jacob, 1929). Jelliffe in 1904 hypothesized that vessel spasms in white matter might lead to sclerotic plaques ( Jelliffe, 1904 ).
James Walker Dawson, a pathologist at the University of Edinburgh, published a landmark monograph on the pathology of MS in 1915 ( Dawson, 1915 ). He reviewed the evidence for various vascular theories of MS causation, including ‘primary blood-vessel alterations,’ also crediting Dejerine, and Pierre Marie among others for their contributions on vascular relationships in MS lesions (Dejerine, 1884 and Marie, 1895). He noted that “the disposition of the areas in relation to the blood vessels has led to the supposition that these play an important role in the genesis of the areas”. He left open the question of causation, and reviewed other theories including inflammatory and toxic causations.
Falkiewicz in 1926 concluded that while vessel pathology may not initiate MS lesions, it may help to spread a virus with high affinity to myelin sheaths that later affects other elements of the central nervous system ( Falkiewicz, 1926 ).
Thus, early authors were aware of the relationship between plaques and vessels, and they had various hypotheses about the nature of this relationship. In these studies, vascular evaluation was limited to small intraparenchymal vessels, and we found no studies of larger veins during this time. There appeared to be no consensus on the role of the venocentric nature of plaques in MS during this time, nor recommendations for therapeutic interventions based on these observations.
“The ultimate etiological factor should probably be sought in a local vascular abnormality or in some alteration in coagulability of the blood”.Tracy J. Putnam, 1935
Tracy J. Putnam was a physician who trained in neurosurgery under Harvey Cushing and neurology under Stanley Cobb. He is best known for developing phenytoin with Dr. H. Houston Merritt. While at the Boston City Hospital he developed animal models of MS using a variety of techniques, including injecting cod liver oil into the carotid arteries of dogs and subsequently into their sagittal sinuses (see Fig. 1 ) ( Putnam, 1935 ). Putnam wrote prolifically on the topic in the 1930s and 1940s (Putnam, 1934, Putnam and Adler, 1937, and Putnam et al, 1947). He ascribed these occlusions to “abnormal coagulation of blood,” and in 1937 described acute thrombi and chronic fibrous changes in vessel lumina as well as dilation and extravasation of blood in human cases ( Putnam and Adler, 1937 ). On the basis of this work, Putnam introduced the notion of anticoagulant therapy for MS in 1940, and he began using dicoumarin in his MS patients and published his experience in 1947. For example, he stated that in 23 of 27 cases of relapsing MS, the disease was static while on treatment with dicoumarin ( Putnam et al., 1947 ). No comparison group or historical controls were available in his reports. Treatment of MS with anticoagulation fell into disuse by the early 1950s, possibly due to negative evaluations from others such as Derrick Denny-Brown ( Denny-Brown, 1952 ).
In 1942 Robert Dow and George Berglund carefully studied 5 pathological cases of MS and elegantly showed the vasculocentric orientation of lesions primarily related to capillaries (see Fig. 2 ) ( Dow and Berglund, 1942 ). They noted the presence of thrombi and perivascular inflammation in many vessels of the brains. They traced the central lesions to draining veins, showing that they were not arterial in character. In 9 lesions a venous thrombosis was found, although they noted that in a case of sagittal sinus thrombosis, no MS lesions were seen. They attributed the thrombi seen in their study to a “thromboplastic substance”. However, Zimmerman and Netsky in 1950 reviewed 50 pathological cases of MS and did not see a vascular orientation of their lesions, contradicting Dow's observation ( Zimmerman and Netsky, 1950 ).
Despite multiple studies, the central position of vessels in plaques, presence of thrombi in MS brains, and the overall role of vessels continued to be disputed through this period. It is interesting to note that there was a paucity of editorial comment during this time, despite the potentially revolutionary nature of Putnam's theories and related therapeutic interventions used in MS.
In 1963 Fog noted that “modern textbooks of neurology generally reject the ‘vascular’ hypothesis on account of the negative correlation between plaques and vessels”. ( Fog, 1963 ). Fog used a painstaking projection technique to magnify tissue sections for study and demonstrated that MS cerebral plaques, ventricle-based “Dawson's fingers”, and peripheral “Steiner's splashes”, originated from venous branches radiating off of cerebral ventricular border emptying into epiventricular collecting veins.
Fog's statement about textbooks of the time had some exceptions. For example, McAlpine et al. in their 1955 textbook reviewed this literature extensively and concluded that ‘while the veins and venules have some influence in determining the sites of origin of the plaques they do not determine the subsequent evolution or form of the plaque and that thombosis, when it occurs, is a secondary process due to absorption of thromboplastic substance from the plaque’ ( McAlpine et al., 1955 ).
During the 1970s various authors confirmed the observation of a perivascular distribution of inflammation, and noted that this was more typical of the acute rather than chronic phase of the plaque (Adams, 1975, Guseo and Jellinger, 1975, and Tanaka et al, 1975). Further work by Adams and colleagues documented perivenous iron deposition and other vascular damage in MS (Adams et al, 1985 and Adams, 1988). Adams concluded that ‘the cerebral vein wall in MS is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis’ ( Adams, 1988 ).
In the late 1970s and early 1980s, the potential vascular component of MS led some to hypothesize that hyperbaric oxygen may be beneficial on this basis ( Neubauer, 1978 ). Small clinical studies using hyperbaric oxygen as treatment for MS were published with encouraging results (Neubauer, 1978 and Nieman et al, 1985). Later studies using a randomized trial design showed disappointing results and in general this approach to treatment was then abandoned (Barnes et al, 1987 and Fischer et al, 1983).
In 1986 Schelling hypothesized that damaging venous reflux into the skull or spine may cause MS, but he did not follow this up with experimental studies ( Schelling, 1986 ). Soon after, Nicolson and McLaughlin framed the debate of vascular versus immune theories of MS from a sociological perspective ( Nicolson and McLaughlin, 1988 ). They noted that immunologists reviewed results from a framework built from their own background, while vascular proponents did the same from their perspective. They framed this as an either/or proposition, and did not evaluate the situation where both camps may be correctly observing components of a disease from different vantage points. In 1987 Lightman posited a primarily venous initiation of the cascade of events for pathogenesis of MS based on his observations of retinal venous sheathing in optic neuritis ( Lightman et al., 1987 ).
After the 1980s, vascular papers in the MS field became rare as the immune theory of MS became more prominent. An exception to this was a paper by Wakefield et al. (1994) . They reviewed three pathological cases of MS, noting ‘Early vascular endothelial cell activation which may progress to vasculitis and vascular occlusion…vascular endothelial cell activation may be an early and pivotal event in the evolution of multiple sclerosis, and that demyelination may have an ischaemic basis in this condition’.
A few additional reports noted the concurrence of MS and cortical vein thromboses, but generally attributed this to lumbar puncture and intravenous solumedrol therapy (Albucher et al, 1999, Vandenberghe et al, 2003, and Al Bunyan and Ogunniyi, 1997).
In 2000 Barkof and colleagues analyzed MR venography in MS and showed that the perivenous distribution of lesions could be visualized in vivo ( Leng Tan et al., 2000 ).
In 2006 Paoli Zamboni published a theoretical paper regarding iron-dependent inflammation in venous disease and possible parallels to multiple sclerosis ( Zamboni, 2006 ). He proposed that back pressure from venous structures caused iron deposition in neural tissues, and secondary inflammatory and demyelinative injury. A few years later, he and his colleagues asserted that venous disease in the internal jugular, azygous, and deep cerebral veins was present and causative of MS, coining the term chronic cerebrospinal venous insufficiency, or CCSVI ( Zamboni et al., 2009 ). The technology and techniques employed by Zamboni for assessing the venous structures were relatively new, making difficulty the replication of these sentinel studies. Some initial subsequent studies provided partial support for an increased incidence of the proposed entity CCSVI in MS, but more recent studies have not supported it. A metanalysis of the early studies by Laupacis et al. (2011) left the door open for a relationship between ‘CCSVI’ and MS, but noted the significant heterogeneity in study outcomes, suggesting variable methodology Laupacis et al. (2011) . Media attention and response to the CCSVI hypothesis began in 2009, possibly in part due to a widely publicized TV documentary in Canada chronicling anecdotal results of endovascular CCSVI interventions.
Subsequent to the seminal 2009 paper by Zamboni, an explosion of both primary research and commentaries was published (see Table 1 ). Prior to the 2009 paper there were no editorial comments on vascular observations in MS, and the number of publications on the topic was small. A total of 31 articles on vascular observations in MS were published between 1969 and 2009, of which 7 were authored by Zamboni. Between the JNNP article and August 2012 a total of 152 articles were published on the subject, of which 56 were editorials or letters, 30 were reviews, and 64 were primary research of various types. Thirty eight articles have been published by Zamboni and his colleagues since 2009.
Legend: Papers published since 1969 referring to vascular structures in multiple sclerosis.
Where Zamboni's observations differ from the historical record is that they were based on human large vessel rather than smaller vessel observations. Putnam's group remains the only group observing MS like changes in animal models of large vein disease, but they did not evaluate human pathological cases or radiological venous studies to support the presence of human large vein pathology in MS.
Why is the observation by Zamboni's group any more controversial than the previous vascular observations in MS? We feel that a number of factors have confluenced to render this so in the modern age. First, Zamboni's group made it clear that this is an entirely new framework for MS pathogenesis in which immunological activation is a downstream byproduct of venous stricture rather than a primary event ( Zamboni, 2006 ). This hypothesis stands directly against the current understanding of MS as a primary immune disease ( Zuvich et al., 2009 ). Second, the techniques were new and difficult to reproduce, requiring novel ultrasound equipment and specialized training. Third, the CCSVI ultrasound diagnostic criteria shifted over time, and proponents still debate whether the ultrasound criteria are a diagnostic or simply screening for subsequent catheter-based angiography. Fourth, the observation came from an ‘outsider’ to the field (a vascular surgeon), rather than from an established MS researcher. Fifth (and perhaps most importantly), the CCSVI hypothesis came at a time when social media and the internet ensured that the debate would not be restricted to medical meetings and scientific literature, but would engage the widespread public (Vera et al, 2012 and Brant-Zawadzki et al, 2012). The apparent ‘simplicity’ of the CCSVI hypothesis (a blocked vein) and a readily available intervention (catheter venoplasty) made CCSVI an immediately palatable answer to an incurable disease.
As the CCSVI debate continued, high field strength MRI scanning has reemphasized the central nature of venules in the MS lesion, recapitulating an observation in vivo which was previously madeex vivo(Leng Tan et al, 2000 and Tallantyre et al, 2008). Other white matter diseases do not appear to share this venocentric propensity, reinforcing the specificity of the perivenous characteristic of MS plaques ( Sinnecker et al., 2012 ). Whether this has a primary or secondary role in MS pathogenesis remains unclear.
The spatial relationship between vessels and lesions of MS has been well defined in the literature. Multiple generations have rediscovered this relationship and reframed it in terms of their basic understanding of MS and contemporary therapies. The recent CCSVI hypothesis arose from a rich tapestry of vascular observations, assertions, and hypotheses. Although the CCSVI hypothesis appears to be losing traction as the central explanation of MS, the curious perivenular distribution of MS lesions remains poorly understood and may provide some clues toward the eventual unraveling of this enigmatic disease.
- Rae-Grant: literature review and manuscript preparation.
- Wong: literature review and manuscript preparation.
- Bernatowicz: manuscript review & edition and translation of German language references.
- Fox: literature review and manuscript preparation.
Conflict of interest
Dr. Rae-Grant has given talks in the past year for Biogen IDEC, Novartis and Teva Neurosciences and has received research support from the National MS Society (RC 1004-A-5). He serves on the Editorial Board of Neurology.
- Wong has no financial disclosures and no conflicts.
- Bernatowicz has no financial disclosures and no conflicts.
- Dr. Fox has received consultant fees from Avanir, Biogen Idec, Novartis, and Questcor; served on Clinical Trial Advisory Committees for Biogen Idec; received/receives research support from the National Multiple Sclerosis Society (RG 4091A3/1; RG 4103A4/2; RC 1004-A-5); and serves on the Editorial Boards of Neurology®and Multiple Sclerosis Journal.
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a Mellen Center, Cleveland Clinic, United States
b Case Western Reserve University, School of Medicine, United States
c Lerner Research Institute, Cleveland Clinic, United States
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