Sunday, 21 August 2016

Measuring Neurofilament is a marker of nerve damage

Bergman J, Dring A, Zetterberg H, Blennow K, Norgren N, Gilthorpe J, Bergenheim T, Svenningsson A. Neurofilament light in CSF and serum is a sensitive marker for axonal white matter injury in MS. Neurol Neuroimmunol Neuroinflamm. 2016 Aug 2;3(5):e271. doi: 10.1212/NXI.0000000000000271. eCollection 2016 Oct.
OBJECTIVE:In an ongoing, open-label, phase 1b study on the intrathecal administration of rituximab for progressive multiple sclerosis, an intraventricular catheter was inserted for drug delivery. The objective of this study was to characterize the limited white matter axonal injury evoked by catheter insertion by analyzing a panel of markers for tissue damage in CSF and serum.
METHODS:Lumbar CSF and serum were collected before catheter insertion and at regular intervals during the follow-up period of 1 year. Levels of neurofilament light polypeptide (NF-L), glial fibrillary acidic protein, microtubule-associated protein tau, and S100 calcium binding protein B were measured in the CSF, and NF-L was also quantified in serum at each time point.
RESULTS:One month after neurosurgical trauma, there was a distinct peak in NF-L concentration in both CSF and serum. In contrast, the biomarkers S100 calcium binding protein B, glial fibrillary acidic protein, and microtubule-associated protein tau did not show any significant changes. NF-L levels in both CSF and serum peaked at 1 month post surgery, returning to baseline after 6 to 9 months. A strong correlation was observed between the concentrations of NF-L in CSF and serum.
CONCLUSIONS:The NF-L level, in CSF and serum, appears to be both a sensitive and specific marker for white matter axonal injury. This makes NF-L a valuable tool with which to evaluate acute white matter axonal damage in a clinical setting. Serum analysis of NF-L may become a convenient way to follow white matter axonal damage longitudinally.
What causes progressive MS?

Some neuros have convinced themselves that it is B cells  in follicles in the CNS. So what do you do about it?

You inject an anti-B cell treatment into the CNS!

So they inject rituximab intrathecally and what do they find?

Nothing... because the flow of the cerebral spinal fluid is downwards!

So by doing this they do nothing about the B cells and antibody in the CNS but they deplete B cells in the blood as the intrathecal antibody delivered to the lower spine simply leaks out into the blood. 

This isn't enough for progressive MS, unless its ocrelizumab:-)

However, I think we will find that the success of ocrelizumab in progressive MS was really because it was inhibiting "active" (gadolinium positive at some time in the 2 year trial) relapsing progressive MS. (the alternative way to think about this is that rituximab works in active MS because in these people there is blood brain barrier dysfunction and so in this case the antibody gets in the brain...so the solution is to get antibody into the brain) I wonder what the regulators will think? 

Will the regulators be "WOWed" by the clinical trials data? or Not? 

ProfG will be glass half-full and say yes..WOWed, but the cynic in me..wonders if the "robotic-referee mentality" will come in 
to play and spoil the party. 

Anyway undeterred by their failures, neuros are now drilling holes into the brain and delivering the rituximab into the ventricles of the brain. So delivering antibody at the bottom of the fountain rather than the top of the fountain as done with intrathecal antibody.

This still won't kill plasma cells that produce antibody, because rituximab does not kill those B cells

However what happens when you put a catheter into the brain?

If you look at neurofilament ( a structuraly protein of nerves) levels in the spinal fluid and the blood. Initially it appears that there is an increase indicative of some nerve damage due to the surgery, and then this returns to baseline after one year.

There was a strong correlation between CSF and blood levels, however if the levels are back to normal after surgery could neurofilament levels be used to measure progression?

Yes they can and ProfG and NeurDocG will tell you this.

2 comments:

  1. So could this be used as an alternative for someone who is allergic to gadolinium to detect active damage?

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  2. So from what I understand MD, conversely, the little that drugs such as Rituximab and Ocrelizumabe can do in MS is due to the fact that they do not reach and stay current directly into the cerebrospinal fluid?

    As the Cladribine realemente penetrates the CNS which is its action on the levels of Neurofilament?

    Since Cladribine is the only drug that really Pentre CNS (just to fingolimod), do not know why not think of similar molecules with the same power of action ...

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