Knowing is not enough we must apply.
Willing is not enough we must do.”
Chronic cerebrospinal venous insufficiency is a novel hypothesis, proposed for the first time by Dr Paolo Zamboni, to try to explain the elusive cause of multiple sclerosis (MS). Briefly, this hypothesis proposes that the autoimmune attack against oligodendrocytes and the demyelination process, hallmarks of MS pathology, are caused by an excessive deposition of iron around small veins in the brain. This hypothesis is proposed after having found that venous blood flow may be altered in MS patients and, attending to Dr Zamboni’s studies, that yugular and azigos veins show an increased frequency of stenosis compared to normal controls. This hypothesis has never been accepted for a number of reasons but what matters most to me are the consequences of the disregard with which the neurological community has received this hypothesis.
Nature Journal has recently published a paper about the power of social networks to movilize patients and its potential to divert funding to studies or procedures demanded by patients. The example to illustrate the power of social networks is Zamboni’s CCSVI. In Canada, the attention paid by the mainstream media to this condition and to Dr Zamboni has turned into many patients claiming for the treatment of their vein stenoses, a procedure called, not randomly, “the liberation procedure”. But not always new healers deserve and receive attention by the media. But the context with this story is perfect…for both mainstream media and patients.
Dr Zamboni’s wife suffers MS. He is a vascular surgeon, attending to his Pubmed profile, a reputed one in the field of varicose veins surgery, but he has now focused on trying to help his wife (and others) studying MS from his vascular surgeon perspective. That means he is an outsider. Someone not familiar for the “MS stablishment”. He proposes a radically different approach in a pretty frequent and severe disease with huge pharma and national funding agencies investments, a growing number of neurologists, radiologists, biologists, immunologists, etc dedicated to it and an exponential increase in its research. And proposes a “liberation procedure” to something that nowadays has no cure… The perfect context for swindlers, mainstream media misunderstood headings, pharmaconspiracy theories, personal heroisms and the perfect environment for politicians. And that’s what we have… patients rallying for something not properly studied under the certainty that all the people involved in MS care, funding, research or market have something to hide in order to keep their positions and privileges.
Zamboni proposes an etiologic pathway that presents many unsolved questions with current evidences: it does not clarify the role of HLA genetics, the Epstein-Barr virus issues, the distance-to-the-equator gradient, the early involvement in many patients of the optic nerve, the oligoclonal bands at the beginning of the disease, the selective attack to oligodendrocytes (and not to astrocytes, neurons, microglia…) and many more. But we may assume that it’s a valid hypothesis. Then Zamboni should clarify in large epidemiologic studies what he sees in small ones, he should also answer scientifically to those who have published against his theory , he would have to integrate his findings to those that already have been accepted in MS pathogenesis theories, his findings would need to be validated in a different cohort and, after that, design one or more trials clearly showing the benefits of his procedure. That is the only approach possible. Until then, being so sorry for patients, what he does should be considered iatrogenesis.
Alternative hypotheses, those that challenge a paradigm, a stablished way of thinking and doing things in any science field usually are either believed or mocked. Believed is the appropriate word because when an hypothesis leaves the field of speculation to become a truth, an absolute, peer-reviewed, well-stablished, replicated truth is neither mocked nor believed anymore. Is just a fact. Something to include in guidelines and textbooks.
Science history is full of left aside hypothesis, dead-end streets and beautiful, logic, coherent explanations never demonstrated. And that’s why science is so often unbearably slow. The process, to be fair and, at last, useful, needs to be that slow. That’s something science journalists with big sounding headings and patients with big problems don’t understand sometimes.
Before the internet era it was quite easy to condemn to oblivion those ideas that did not fit the stablished standards. Those ideas wrongly left aside because they challenged the stablished ones were always able to arise and finally prevail. The misleading, wrong or even malicious ideas were properly forgotten. But now anyone with a favorable context (such as Zamboni’s) can spread challenging ideas, regardless of being true, untrue, good or fatal. Before, we had leaders in opinion, academic hierarchies. Now we have trends and impact factors. Now,unvalidated (but revolutionary and “liberative”) proposals are available to anyone. More, they may be, though incorrect or insufficient, published in good science journals because they increase their impact factors (remember the chronic fatigue syndrome issue in Science). Experts and academy have several problems when spreading ideas, mostly with the revolutionary ones or those that challenge the ideas of the stablished experts. They are not well organized, are not fully open and don’t communicate with their patient communities properly. That means that general public, people, patients, etc, without any filter, are scientifically abandoned in the internet to the will of those with powerful and attractive (but false) ideas or to those with personal or monetary interests but bold and shameless enough to mobilize patients’ organizations and appear on TV selling their own thing.
So, in my opinion, we need to get two conclusions from the CCSVI experience (an others, the most important the mumps-measles-rubella vaccine controversy, that lead to disease outbreaks). First, that we, doctors, need to communicate better not only in private but also in those places where people go to gather information by themselves (internet, media, etc). If not, others will and that’s not desirable for neither us nor patients. And second, the only way to get treatments approved is the (unfortunately damn slow) way of science and more science. An example: check how long took to natalizumab to get approved… So, Zamboni, keep working that hard and shut our mouths up.
Como parte del #15m me declaro una persona pacífica y condeno radicalmente todo tipo de violencia: la de los violentos infiltrados en nuestras manifestaciones, y la del Estado, que ha causado más dolor y heridos. Además, condeno la manipulación mediática que enfatiza la información sesgada, parcial o errónea con el propósito de demonizar a los ciudadanos.
Si me manifiesto en la calle es porque:
Mi participación como ciudadano se ha reducido a votar a listas cerradas cada cuatro años para ver cómo los representantes de los ciudadanos no respetan lo prometido en su programa.
Se hacen leyes a favor de grupos de interés en vez de hacerlas a favor del conjunto de la sociedad.
Se invierten recursos públicos para ayudar a minorías poderosas, y no a quienes están pasando situaciones desesperadas ocasionadas por la especulación financiera.
Los grandes partidos están más preocupados por mantener su poder que por ofrecer soluciones para superar esta crisis histórica.
Está a punto de firmarse un “Pacto del Euro” que consiste fundamentalmente en medidas para reducir la inversión pública en servicios esenciales.
Desde diferentes órganos del estado se ha insultado a los ciudadanos, e incluso se ha justificado el recurso a la violencia contra manifestantes pacíficos.
Como parte del #15m, acepto y respeto la diversidad ideológica del movimiento. Cuando participo en una manifestación no reclamo un régimen o una ideología en concreto, ni un modelo social no democrático, ni la eliminación de los partidos o los parlamentos. Lo que reclamo es una democracia mejor y más humana que, entre otras medidas, necesita urgentemente:
– Cambios en la Ley Electoral para permitir una mejor y más directa representación de los ciudadanos en los parlamentos y una mayor participación ciudadana en las decisiones importantes.
– Aprobación de una Ley de Transparencia y Acceso a la Información Pública para obligar a la publicación en formatos adecuados y reutilizables de todos los gastos, decisiones y reuniones con grupos de presión por parte de funcionarios y cargos públicos.
– Tolerancia cero a la corrupción de candidatos y cargos públicos, y controles ciudadanos para la exigencia de responsabilidad política.
– Separación clara, real y efectiva de los poderes del estado.
– Control fiscal efectivo de grandes fortunas y operaciones financieras; eliminación de privilegios fiscales a cargos electos.
– Políticas encaminadas a solucionar de forma efectiva los problemas hipotecarios y de vivienda.
– Servicios públicos de calidad, fundamentalmente salud, justicia y educación.
– Eliminación de las leyes que permiten el control administrativo de Internet. La red ha demostrado ser esencial para la libertad de expresión y para responder al peligro de manipulación mediática.
Por todas estas razones volveré a salir pacíficamente a la calle el 19 de junio, #19j.
Si estás de acuerdo, aprópiate del texto y divúlgalo.
In a previous post we discussed the shameful oblivion in which Rituximab has been left apart because of its patent expiry date. Just this week a new paper on Archives of Neurology deepens our disappointment. Besides the great efficacy of Rituximab, maybe comparable to that of Natalizumab (or even better as seen in their phase II trials), now we know that the most scaring side effect of multiple sclerosis new drugs, the progressive multifocal leukoencephalopathy (PML), occurs much less frequently (in a similar disease, rheumatoid arthritis) than in Natalizumab.
Despite this new paper is a case series, with several limitations, i think the neuroimmunological community should think about leaving aside a powerful drug which, moreover, will be soon free of patent. A shameful story, re-visited.
El diario Público hace hoy un reportaje espléndido sobre algunas cuestiones clave que ayudarían a mejorar nuestra democracia, con sus pros y contras. Básicamente son ideas que coinciden con las cuatro propuestas para mejorar la democracia de Nacho Escolar y el consenso de mínimos planteado por los propios acampados y en las que, en pleno momento álgido, yo mismo me planteé (debe ser porque, de lógicas y necesarias, es inevitable pensarlas). Sin embargo, en las propuestas de Público (igual que en las de Escolar), para mí faltan las relativas a la separación de poderes, especialmente la mejora de la Justicia, tanto en su independencia (clave para luchar contra la corrupción) como en su agilidad (imprescindible para que sea verdadera Justicia).
Siempre se tiende a pensar en democracia como todo aquello relativo a la representación y participación, pero falta el otro pilar fundamental, muy desarreglado también, que es la resolución efectiva de los conflictos en base a las leyes emanadas del pueblo, ya que sin esa ejecución efectiva de nada vale todo el cambio en el sistema representativo. Que, como publica El Pais hoy (y ayer el Periodico de Cataluña), haya una comunión casi masiva de la población con las reivindicaciones de los acampados, indica que las propuestas son factibles, probablemente inevitables. Ya que ese otro poder está muy mermado en su independencia y efectividad, al menos no lo olvidemos.
The last issue of the Lancet Neurology journal, has published the extension phase study of the TRANSFORMS trial. Briefly, the TRANSFORMS trial was a randomized controlled trial comparing i.m. interferon beta 1a versus two different doses of fingolimod (0.5mg and 1.25mg). Its results were published on New England Journal of Medicine on February 2010, together with FREEDOMS, a Fingolimod versus placebo trial and CLARITY, a cladribine versus placebo trial. It showed a better perfomance than interferon in annualized relapse rate, with a concerning profile of side effects and some red flags, such as the risk of developing skin neoplasms or herpetic infections. Despite that, the overall performance in that study led to its approval by the FDA and EMEA but, while its being commercialized already in the US, it’s still on its way to the pharmacy in Europe.
In the controlled phase of the trial relapse rate with fingolimod was about a 50% lower than with interferon, and 80% o f patients remained free of relapse with fingolimod while only 63% of them were free of relapse with interferon in the first year of the study. Those were quite good results. There were also good results in MRI parameters. However there were no differences in disability outcomes, in one hand probably because the EDSS is not that a precise measure and in the other hand because overall relapse rates were pretty low. Significant side effects were present in the fingolimod arm, mostly on the high those arm, being the most concerning ones two deaths of herpes virus infections (one varicella zoster and one herpes simplex encephalitis). Another intriguing fact was the higher incidence of skin neoplasms (basal cell carcinomas and in-situ melanomas) in the fingolimod arms. Also heart conduction blocks and macular oedema were more frequent on patients taking fingolimod.
With this background, an extension phase of the trial was started, switching all patients previoulsy on interferon to one of the two doses of fingolimod. It must be said that, the extension phase of the study was not blinded anymore. This extension phase does not add very much to the initial findings but confirms the good efficacy results shown on the first year and clearly demonstrates a reduction on relapse rate in the group of patients treated with fingolimod compared to their first year on the study, when they were on interferon. The reduction on relapse rate was abut 30% compared to that on the first year when patients were on interferon.
Side effects looked pretty similar to those on the first year, also more frequent on the high dose arm, but probably with a slight decrease in the percentage of patients suffering severe adverse events, including death and skin neoplasms.
The data on this extension study, though not new and probably biased by the unblinded uncontrolled nature of the study, provide additional support for Fingolimod as a strong, more effective and, most importantly, oral alternative to current conventional treatments. However, its safety issues make us wonder if it could be better, and even more tolerable, having a monthly iv treatment far more powerful, specific and, attending to the trials (and not post-commercialization surveillance studies, still lacking in fingolimod) almost as safe, called Natalizumab.