Chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis: a reasonable approach.

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

Continue reading

Progressive multifocal leukoencephalopahy and Rituximab

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.

Continue reading

Fingolimod, two years view

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.

Continue reading

The shameful story of Rituximab in Multiple Sclerosis

Two weeks ago a few collegues from Spain and  I attended the 3rd Preceptorship Program in MS at Steven Hauser’s department in UCSF. The scientific program and the overall quality of the course were outstanding. We had the opportunity to hear and ask those that have been ahead of MS research in the last years (Oksenberg, Goodin, Cree, Baranzini and, of course, Hauser). We heard beautiful stories of genetics, Vitamin D, EB virus, in vivo imaging and, what matters most at last, new treatments. It really was an extraordinary experience. But this is not the topic i wanted to  talk about… One of the treatment stories was one we heard before in 2010 ISNI meeting in Sitges (SPAIN), the one about Rituximab and MS.  Apart from the commercial history of Idec, Biogen, Genentech and so on, the important thing is that it all ended up in an phase II clinical trial. A revolutionary clinical trial. It was revolutionary because it challenged the “MS-is-(for-sure)-a-T-cell-mediated-disease” dogma showing that a B cell therapy was able to achieve unbelivable results in MS. But most importantly it was revolutionary because it got a striking 91% reduction in new enhancing lessions compared to placebo and, despite being a phase II trial, achieved a 50% reduction in relapse rates compared to placebo in less than a year. These are Natalizumab-level results, but with a quite safer profile than Natalizumab. At least, the experience with other diseases yields a progressive multifocal leukoencephalopathy (PML) rate much lower to that of Natalizumab. Just 6 reumathoid arthritis (in which Rituximab is used routinely) patients have suffered PML over more than 120000 patients treated despite RA patients having used much more frequently concomitant immunessuppresants than MS patients do usually. The results achieved in the study deserved a NEJM paper and, for sure, a

Continue reading

Fingolimod approved!

First, the good news, a week ago the EMEA informed positively for Gilenya (Fingolimod) approval. This will expand the spectrum of therapeutic options for patients with multiple sclerosis and will fulfill the long desired availability of oral drugs for that chronic disease. The bad news are that only selected patients will have access to this new drug and will not need to inject anything. Candidate pantients will be those that do not respond to a complete “a full and adequate” course of Interferon beta or those with high activity at the begining of the disease. This indication copies that of the Tysabri and restricts quite a bit the number of candidate patients. It is quite surprising that EMEA had not reserved a third indication for those that have cutaneous or systemic side effects wih current treatments, mostly when the great advantages that fingolimod pills add are comfort in administration and tolerance, and not efficacy that only slightly overtakes that of interferons. On one hand we may have an alternative for those patients with increased activity in which we think natalizumab may be too much but in the other hand this can delay natalizumab start in those patients who really deserve it. Anyway, Gilenya approval is good news for the Neuroimmunology community and hope we can have it available the sooner to treat MS. For details, find attached the EMEA report.

Continue reading

Plasmapheresis guidelines for NeuroImmune disorders

AAN evidence based reviews don’t add anything new to what we probably know (or should know) or suspect about a treatment or intervention, but it’s always useful to have all data summarized to avoid the whole process of revision by oneself. In the last issue of Neurology journal we’ll find an evidence-based review about the use of plasmapheresis in neurological disorders. Not any surprise in GBS and CIDP being the diseases with a better level of evidence in plasmapheresis efficacy. Not anything to question, but just highlight a (small) paradox… One of the main mechanisms of action of plasmapheresis is pathogenic antibody removal, then, how can a well known antibody mediated disease like myasthenia have less evidence than those diseases in which cellular immunity is considered more important, such as MS or CIDP?  

Continue reading

The exorcist girl explained…

Though its first description was published in Annals of Neurology in 2005, we started to pay atention to NMDA receptor autoimmune encephalitis in 2007, when several more cases and the pathogenic antibodies were described. It was difficult to believe that it could be possible to discover a new disease well into the twenty first century. It was not that a diagostic marker, a rare onset of a known disease or a particular clinical feature were described. It was the description of a disease, like in the Charcot days, but adding the diagnostic test, the pathogenic mechanism and the (almost) miraculous treatment. This happened just three years ago… After three years of intense publishing, meetings and deserved attention to Dr Dalmau (and co-workers)  it turned out that this disease was not that uncommon. Hundreds of cases arose when nobody had been aware of these patients. Most of them may still have an “idiopathic” adjective at their diagnosis field in the discharge report or may have died while their doctors still wonder what could that be. Some may think that chance always plays a role when such discoveries are made, but in this case an entire life devoted to the study of immunlogic mechanisms of paraneoplastic diseases was the key to success. It’s not just a discovery, it’s a great amount of lab and clinic work. It could have been just another interesting case report but it was the description, not only of a syndrome, but of the basic immunopathology of it as well. More, it was the stablisment of a consistent model of approach to the study of neuro-immune diseases, starting with patients sera to follow with murine models and not the other way. A model that has in anti-NMDAR encephalitis its best example but that has contributed to the description of

Continue reading

Here we go!

Taking a look around the internet, trying to find a blog/podcast/newsfeed/whatever, to discuss, learn and update about neuroimmunology i found almost nothing and decided to create this blog with that purpose. There may not be many neuroimmunologists out there but i think it’ll be enough if a few gather round this blog and comment what will come in the science and clinical practice of our field. So, anybody interested is welcome to provide information or even write posts, and every one out there is invited to join the discussion (if any).

Continue reading