Tuesday, 2 September 2014

CCSVI, results from the first double-blind, sham-controlled study

Prospective randomized trial of venous angioplasty in MS (PREMiSe).
Siddiqui AH, Zivadinov R, Benedict RH, Karmon Y, Yu J, Hartney ML, Marr KL, Valnarov V, Kennedy CL, Ramanathan M, Ramasamy DP, Dolic K, Hojnacki DW, Carl E, Levy EI, Hopkins LN, Weinstock-Guttman B.
Neurology. 2014 Jul 29;83(5):441-9. doi: 10.1212/WNL.0000000000000638. Epub 2014 Jun 27.

We report the results of the investigation of safety and efficacy of venous angioplasty in patients with multiple sclerosis (MS) with findings of extracranial venous anomalies, considered hallmarks of chronic cerebrospinal venous insufficiency (CCSVI), in a 2-phase study (ClinicalTrials.gov NCT01450072).
Phase 1 was an open-label safety study (10 patients); phase 2 was sham-controlled, randomized, and double-blind (10 sham procedure, 9 treated). All study patients fulfilled venous hemodynamic screening criteria indicative of CCSVI. Assessment was at 1, 3, and 6 months postprocedure with MRI, clinical, and hemodynamic outcomes. Primary endpoints were safety at 24 hours and 1 month, venous outflow restoration >75% at 1 month, and effect of angioplasty on new lesion activity and relapse rate over 6 months. Secondary endpoints included changes in disability, brain volume, cognitive tests, and quality of life.
No perioperative complications were noted; however, one patient with history of syncope was diagnosed with episodic bradycardia requiring placement of a pacemaker before discharge. Doppler evidence-based venous hemodynamic insufficiency severity score (VHISS) was reduced >75% compared to baseline in phase 1 (at 1 month) but not phase 2. In phase 2, higher MRI activity (cumulative number of new contrast-enhancing lesions [19 vs 3, p = 0.062] and new T2 lesions [17 vs 3, p = 0.066]) and relapse activity (4 vs 1, p = 0.389) were identified as nonsignificant trends in the treated vs sham arm over 6 months. Using analysis of covariance, significant cumulative new T2 lesions were related to larger VHISS decrease (p = 0.028) and angioplasty (p = 0.01) over the follow-up. No differences in other endpoints were detected.
Venous angioplasty is not an effective treatment for MS over the short term and may exacerbate underlying disease activity.

Image: Jean-Marie Charcot's treatment for Parkinson's disease, the "fauteuil trepidant" (translation; shaking chair) or its portable version the shaking helmut. He devised this after observing that Parkinson's patients exhibited reduced symptoms after long carriage rides...lets just say the idea didn't take off. Which goes to show you that not everything you see is what it appears to be.

In short, this study found that there was no clinical improvement in those who participated.

Conversely they found that it may even worsen the disease. There were 20 patients in total in the phase 2 portion of the study: 4 relapses were in the treatment arm and 1 in the placebo/sham-arm, whilst 5 out of 9 patients in the treated arm showed new contrast-enhancing MRI lesions compared to 2 in the placebo/sham-arm. 

It is not the first time that worsening disease activity has been noted, and has been reported in 4 other studies. It is thought that re-opening the veins may increase the perfusion of the micro-circulation of the brain, but inadvertently bring in more immune cells worsening the disease activity.

Was this study needed to be done? YES...

A double-blind placebo-controlled clinical trial needed to be done as their was uncertainty about the efficacy of venous angioplasty in CCSVI in MS. 

But in order to do such a trial, "clinical equipoise requires that uncertainty exists about the efficacy of an intervention being studied in a clinical trial" - editorial comment. 

But as the findings are negative, there is no longer this equipoise.....and further studies of this ilk cannot be justified on ethical grounds alone.

The numbers were small, but for a phase 1/2a interventional study this sample size is adequate. The placebo/sham arm patients still underwent the procedure, wherein an angioplasty balloon was inserted, but not inflated to achieve the dilatation as in the treatment arm. Therefore the risk of complication ~ 4% (4 in every 100) associated with cerebral angiograms still applies to the placebo/sham arm as well. 

Infact, the argument works both ways, the authors assertion that angioplasty was performed safely in MS patients is also diminished by the small sample size.

How to get involved in Burning Debates at ACTRIMS-ECTRIMS

It doesn't matter if your an MSer, a MSologist, a nurse or if your just interested. Anyone can get involved in our social media sessions at ACTRIMS-ECTRIMS this year. We will be running two different types of events throughout the conference, Burning Debates and Question Time Hangouts everyday! Even the President of ACTRIMS is excited about it.

How to get involved in the Burning Debates:

The three debated topics will be:
  1. The Only Way is Pharma: Academic trials go nowhere 
  2. Repair from within or outside in...is transplanting stem cells the best way forward?
  3. Early affective therapy is the only way.
If your not attending the conference, you can watch the debates on the conference website. The live streaming link will appear when the debate starts.  If you have any comments or questions then please tweet them to us using #burningdebate as the chair of the debate will be keeping track of the twitter activity. 

If you are attending the conference, come along to a Burning Debate where two experts in the field will debate a hot topic each day. Be warned - you can only vote for or against the motion via twitter (so people watching at home have a fair vote). So, if your a Neuro and not on twitter sign up now!

After each speaker has argued their side and questions have been taken, the Barts MS Blog Twitter account will tweet two tweets: one FOR the motion, one AGAINST. The tweet that has the most retweets will WIN the debate.

Schedule for Burning Debates (Boston Time):
  • Wednesday 10th September 15:00-16:00 
  • Thursday 11th September 15:30-16:30 
  • Friday 12th September 15:00-16:00
Schedule for Burning Debates (BST):
  • Wednesday 10th September 20:00-21:00 
  • Thursday 11th September 20:30-21:30 
  • Friday 12th September 20:00-21:30

Saving nerves

Lee J, Taghian K, Petratos S. Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?Acta Neuropathol Commun. 2014 ;2(1):97. [Epub ahead of print]

Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages. While the aetiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS. Specialized imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS). A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies. The clinical translation of a combined Na+ and Ca2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS. We highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.

This is a review and goes to show that there are loads of ideas for treatments.

ClinicSpeak: pregnancy outcomes with natalizumab exposure

Is pregnancy the great DMT differentiator? #ClinicSpeak #MSBlog #MSResearch

"I predict that pregnancy will be the next marketing battleground for the DMTs. Which is the safest drug to take during pregnancy? The answer is none. None of the current DMTs have a license to be used during pregnancy. The following study, albeit small, looks at pregnancy outcome in babies with first-trimester exposure to natalizumab and concludes that foetal exposure to natalizumab in early pregnancy does not appear to increase the risk of adverse pregnancy outcomes. This study is only powered to detect common adverse outcomes and won't detect rare events. It is however important as it is provides some reassurance to women with highly active MS that they can fall pregnant on natalizumab before stopping it. This is important as it hopefully will prevent rebound disease activity as pregnancy in itself is disease-modifying. The other option open to women with highly-active MS is to opt for alemtuzumab treatment and to try and fall pregnant about 4 months after the second course of treatment. This is hopefully in the window before the peak incidence of thyroid autoimmunity develops, but after treatment when MS is hopefully under control. Thyroid autoantibodies, and presumably other autoantibodies, that can develop post-alemtuzumab could cross the placenta and cause disease in the unborn child."

"Other treatment options available include glatiramer acetate (GA) that appears to have a very good safety profile in pregnancy and a large number of neurologists are prescribing GA as their drug of choice in women wanting to have children. Dimethyl fumarate (DMF), as a normal metabolite, has the potential to be used in pregnancy. But until the there is more real-life pregnancy safety data I would be reluctant to prescribe in pregnancy based on this lone. What about emerging therapies? Ocrelizumab, a potent B-cell depleting antibody, may work as an induction agent, but there are reports of B cell depletion in babies born to patients treated with rituximab. Clearly, these anti-CD20 antibodies hang around longer in the body than alemtuzumab." 

"What would I do? If had highly active MS and was on natalizumab and was at high-risk of rebound on withdrawal of natalizumab I would probably follow the strategy below. If was deciding on which treatment to start and was planning to have children in the future, I would consider alemtuzumab. Clearly, pregnancy will not be the only factor differentiating the available therapies, but an important one nevertheless."

"What is clear is that we need more data!"

BACKGROUND: Safety data on first-trimester natalizumab exposure are scarce, as natalizumab is usually withdrawn three months before pregnancy.

OBJECTIVE: The objective of this paper is to investigate the foetal safety of exposure to natalizumab during the first trimester of pregnancy using disease-matched (DM) and healthy control (HC) comparison groups.

METHODS: total of 101 German women with RRMS exposed to natalizumab during the first trimester of pregnancy were identified. Birth outcomes in the exposed group were compared to a DM group (N = 78) with or without exposure to other disease-modifying drugs, and an HC group (N = 97).

RESULTS: A total of 77, 69 and 92 live births occurred in the Exposed, DM and HC groups, respectively. The rates of major malformations (p = 0.67), low birth weight (<2500 grams) (p = 1.0) and premature birth (p = 0.37) did not differ among groups. Higher miscarriage rates (p = 0.002) and lower birth weights (p = 0.001) occurred among the Exposed and DM groups, as compared to the HC; however, there was no significant difference between the Exposed and DM groups.

CONCLUSION: Exposure to natalizumab in early pregnancy does not appear to increase the risk of adverse pregnancy outcomes in comparison to a DM group not exposed to natalizumab.

"The following is a table comparing the attributes of natalizumab and alemtuzumab treatment in MS; pregnancy is an important differentiator." 

CoI: multiple