Wednesday, 25 May 2011

Why repeated lumbar punctures to assess neuroprotective trials?

In response to one of the comments from my posting in relation to disease outcomes.
In MS damage to nerve processes called axons releases proteins into the spinal fluid. One class of these proteins are neurofilaments, which  supports the structure of the axon. I think of neurofilaments as the scaffolding or supporting structures of axons. What is important is that if neurofilament levels are raised in the spinal fluid it indicates that axons are being damaged at that point in time and is predictive of a worse prognosis. Effective disease-modifying and neuroprotective therapies should reduce or even normalise the levels of spinal fluid neurofilament levels. This is the basis of our proposal to test neuroprotective therapies. The study design is to take PwMS in the progressive phase of the disease and do a lumbar puncture to measure the level of spinal neurofilament levels. Patients are then randomised to a putative neuroprotective therapy or placebo. After 6 months another lumbar puncture is done and the spinal fluid neurofilament levels measured. If the neuroprotective therapy works it should reduce the level of neurofilament levels in the spinal fluid compared to baseline and this shoudl not occur in PwMS on placebo. This sort of trial means an answer can be done very quickly within 6-12 months on only 30 subjects. At the moment clinical trials in progressive MS involve hundreds of patients and last 3 or more years. 
What do you think? Would you have two lumbar punctures? I must remind you that we have gotten much better at doing lumbar punctures; we now use atraumatic needles and sonar or x-ray guidance that limit the potential complications. 

7 comments:

  1. I really like this idea for measuring axonal damage and the impact of treatments. I've never really understood how MRI imaging and other imaging could measure this damage - unless it was over several years so it could measure volume loss.

    If this works, it would be possible to test lots of potential therapies quickly i.e. in different groups of patients. Are there plans to use this technique?

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  2. We have a grant under consideration at the moment to test a neuroprotective drug using this trial design. However, I am worried that the MS community are not ready for serial LPs. Any ideas how get this idea adopted? Your help would be much appreciated.

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  3. (i) some honesty about what progressive MS does. I'm not suggesting scaremongering, but I'm always surprised how few MS patients have looked at the EDSS or believe that they have a 'benign' disease course (even when they are in the progressive phase).
    (ii) I'm sure you could flag up the trial on the MS Society or MS Trust websites. Cost / benefit needs to be highighted. Cost = some discomfort with LP (although much improved now). Benefit = finding an effective treatment to slow progression.
    (iii) A friend was in the Lamotrigine trial. Negative result, but she would happily have a couple of LPs a year if there was the chance of finding a treatment to slow progression.
    (iv) If a treatment is found to be effective, patients on the intiial trial should be offered the treatment (if it's an existing therapy) without having to wait until more trials have concluded.

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  4. In another post you said 'Please don't give up hope; your hope is what motivates us to work so hard'

    As parent of a teen with MS, hope is what I offer as an antidote to realism and statistics. But realism / scaremongering might be needed for patients to consent to serial LPs.

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  5. Related question: Do normal lumbar punctures check these neurofilament levels?
    Our doctor said that when the diagnosis is clear there is no need to do a lumbar puncture. Should I ask for one in order to get some sort of baseline?

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  6. I have just had the 2nd LP for the ASCEND trial. I did not enjoy the first one but the second was painless and went very smoothly. No longer frightened of having more LP's
    If this process of assessing the effectiveness of drugs is proven then every trial for MS drugs needs to be done this way. It it going to happen?

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