Optic Neuritis Trial should we be worried?

Liu S, Zwinger P, Black JA, Waxman SG. Tapered withdrawal of phenytoin removes protective effect in EAE without inflammatory rebound and mortality. J Neurol Sci. 2014 Mar 19. pii: S0022-510X(14)00173-7. doi: 10.1016/j.jns.2014.03.029. [Epub ahead of print]

Axon degeneration has been identified as a major contributor to non-remitting neurological deficits in patients with multiple sclerosis (MS), which has elicited substantial interest in the development of neuroprotective therapies. Sodium channel blockers, including phenytoin, carbamazepine, flecainide and lamotrigine, have been shown to protect axons from degeneration, attenuate immune cell infiltrates and slow the acquisition of neurological deficits in mice with experimental autoimmune encephalomyelitis (EAE), a model of MS. However, the sudden withdrawal of sodium channel blockers, phenytoin and carbamazepine, is associated with severe exacerbation of EAE characterized by massive inflammatory infiltrates and high mortality. In the present study, we asked whether a slow, tapered withdrawal of phenytoin treatment from mice with EAE produced sudden worsening similar to that of sudden withdrawal. Our results demonstrate that gradual withdrawal of phenytoin treatment from mice with EAE is associated with worsening of clinical scores which approach non-treated levels, but was not associated with increased immune cell infiltrates or deaths as have been observed with abrupt withdrawal. These observations support sodium channel blockers as a potential therapeutic agent in the treatment of MS, but indicate caution if treatment is ceased.

Phenytoin is an anti- epileptic that is being tested as neuroprotective drug in optic neuritis as we speak. it was also planned to be tested in primary progressive MS by the Waxman group and they had done a few EAE experiments and had found that it was immunosuppressive and stopped disease developing, but when they stopped the dug, disease returned all at the same time an looked like the disease was rebounding, panic ensued and the Primary progressive trial was cancelled and the ongoing trial  of lamotrigine had to be extended to follow up the people on drug to see if disease rebounded when drug was stopped…Thankfully it did not. When you stop any drug in a decent EAE model, unless there is tolerance, disease invariably comes back this may take a few days to a few weeks, so an apparent rebound could be just the natural return of disease, but as it is was synchronised it may appear worse and in this case death in animals occurred. In this new study they tapered the drug withdrawal and the rebound did not occur but disease came back as expected. Will the Primary progressive Trial, planned many years ago be revived? if this experiment had been one many years ago would the trial have been canned.

Did we see this rebound effect in Animals….well not really, but we would not expect it because in our hands carbamazepine & phenytonin were not immunosuppressive (see with six different compounds) to prevent disease from occurring. maybe putting drugs inside food, as opposed to direct delivery so you know they are getting drugs that we used, is some how stress full and this is why they are good immunosuppressives. Should we test it?

At present Dr Kapoor and ProfG have a trial with phenytonin and ProfG is about to start the PROXIMUS trial with Oxcabazepine. 

Will this new animal data mean that their trials have to be modified to incorporate the drug tapering, if it is not there already. Maybe it will be too late for the phenytonin trial as most people have been recruited and a number of MSers will have finished,. I don’t know if there was a tapering or if there is a worsening….It is blinded but surely alarm bells would be ringing it this were a problem.

Hopefully prof G will tell you more about PROXIMUS after all the hurdles to the delayed start have been met. I have seen the approval letter from the MHRA, but is this a spanner in the works? Hard to ignore. 

Does this return of disease occur in MS? yes is can because we have heard of relapses post-tysabri treatment, so unless immune tolerance is induced this re-ignition of disease after cessation of treatment.  

In the lamotrigine trial the anti-inflammatoy effect associated with loss of swelling reversed after the drug trial ceased

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  • Reading between the lines, it looks like we are being set up for another failure/s. I am a betting man, and would be happy to wager quite a bit of money that the various progressive MS trials underway will deliver the same results as the earlier lamotrigine and cannaboid trials. No doubt the blame will be placed on the trial design or the dosing regime. In reality, the failure will reflect the poor science – EAE and a lack of understanding of what this disease is.

    • Reading between the lines the lamotrigine and cannabinoids were both positive and with a different design you may not be moaning today.Your assertion that is all the fault of EAE, is off the mark. If 50% of the active arm are not taking their drugs, it sort of makes it very hard to get any positive results or are you blaming the animals for the lack of compliance.

      How many drugs failed in relapsing remitting MS before the interferons…a lot.

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