Research:Another sclerosis may teach us about MS

R

Kanai K et a. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012 May 7 [Epub].


OBJECTIVE: The aim of this study was to investigate whether axonal
excitability indices are associated with survival in patients with
amyotrophic lateral sclerosis
(ALS=Motor neuron disease in UK and Lou Gerhig’s disease in USA). Previous nerve excitability studies suggested increased
persistent sodium currents in motor axons of patients with ALS, which
lead to axonal hyperexcitability (Overactivation of nerve) and potentially enhance neuronal
death.
METHODS: 112 patients with sporadic ALS were followed up until
endpoint (death or tracheostomy). Multivariate analyses were performed
using the Cox proportional hazard model. Threshold tracking was used to
measure
multiple
axonal excitability indices in median motor axons, such as
strength-duration time constant (SDTC; a measure of nodal persistent
sodium current). Latent addition was also used to estimate the magnitude
of persistent sodium currents.
RESULTS:The overall median
tracheostomy-free survival from onset was 37 months. Prolonged SDTC was
strongly associated with shorter survival (adjusted HR 4.07; 95% CI 1.7
to 9.8; p=0.0018) compared with older onset age (>60 years; HR=1.80)
and bulbar onset (HR=1.80). Estimated median survival was 34 months in
the longer SDTC group and 51 months in the shorter SDTC group. This
index was highly statistically significant even after
multiple
testing adjustments with age and site of onset (bulbar or limb). Latent
addition study results were consistent with these
findings.
CONCLUSIONS. Axonal persistent sodium currents, estimated by SDTC
and latent addition, are strong and independent predictors for shorter
survival in patients with ALS. Membrane hyperexcitability is possibly
associated with motor neuronal death, and modulation of excessive sodium
currents could be a novel therapeutic option for ALS.
It is thought the demyelination in MS can be associated with problems of sodium channels and sodium loading. Furthermore over stimulation of the nerve is thought to lead to excitotoxicity. Although ALS and MS, have different causation, excititoxicity is thought to be a problem in both MS and ALS. ALS is a more aggressive disease than MS so things are more easy to detect. However, there is, but there is one drug (Riluzole) that is licenced for ALS. Could it have any benefit in progressive MS there is an indication that it could do..

In
addition to demyelination and damage to oligodendrocytes, axonal injury
and neuronal cell death are dominating histopathological
characteristics of
multiple sclerosis
(MS). Still little is known about the cause of the damage.
Extracellular accumulation of glutamate contributes to excitotoxic
injury of neurons and glial cells, suggesting that the maintenance of
subtoxic extracellular glutamate levels may be crucial.
Riluzole
is a neuroprotective agent that inhibits the release of glutamate from
nerve terminals and modulates glutamate, i.e., kainate and NMDA
receptors. It inhibits excitotoxic injury in several experimental models
of neurodegenerative disease. We performed a small run-in versus
treatment MR-monitored pilot study in 16 primary progressive MS
patients. The results suggest that
riluzole
reduces the rate of cervical cord atrophy and the development of T1
hypointense lesions on magnetic resonance imaging in primary progressive
MS. The rate of brain atrophy was only slightly decreased. The results
indicate an effect on mechanisms involving lesion evolution and axonal
loss, but no clear effect on new lesion formation. However, the data
suffer from several limitations and must be confirmed in future trials.



Hopefully these studies will get done soon, it is only ten years since these initial investigator led studies….All I can say is “Shame on You Pharma” as this could have been looked at many, many years ago. It probably is not great but perhaps it could do something positive and slow down progressive MS.

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MouseDoctor

3 comments

  • MND may be more aggressive than PPMS but are they not essentially the same thing? It's the death of nerves. Is there any difference in terms of what you'd see on a scan or in a lumber puncture test?

  • MND is as different to MS as Alzheimer's disease ofr Parkinson's is. You're right in that they all show nerve death but the location, mechanism and types of nerves lost are very different. However, there are only so many ways you can kill a nerve and so if something shows promise in a disease like MND, the likelihood of it doing something useful in progressive MS is high.
    This is the main focus of my research.

  • Re: "MND may be more aggressive than PPMS but are they not essentially the same thing? It's the death of nerves. Is there any difference in terms of what you'd see on a scan or in a lumber puncture test?"

    MND and MS are different diseases; i.e. the have different pathologies, age of onset, epidemiology, MRI scans, spinal fluid findings, etc.

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