Therefore simply put, we need your help to be part of our team.
One vital part of this is that you are our ears and eyes and if you find something that interests you or don’t understand, it is likley to interest someone else or likely that someone will not understand either.
You can simply come to the blog and write a comment.
We will not comment on personal circumstance as this is not a consultation vehicle, so keep it general if you are asking health related questions. Likewise we are here to discuss science.
Frankly it rather saddens me if people think that we need to be adversorial. However, I can see some people will believe this, just as I sometimes (currently as I write think) think that there is a “them” (dumb-assed neurologists) and “us” (enlightened scientists. Sorry can’t say more as the air would be blue:-).
Bruce D Trapp, Megan Vignos, Jessica Dudman, Ansi Chang, Elizabeth Fisher, Susan M Staugaitis, Harsha Battapady, Sverre Mork, Daniel Ontaneda, Stephen E Jones, Robert J Fox, Jacqueline Chen, Kunio Nakamura, Richard A RudickCortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study. Lancet Neurol 2018.
Background: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination.
Methods:Brains and spinal cords were removed at autopsy from patients, who had died with multiple sclerosis, at the Cleveland Clinic in Cleveland, OH, USA. Visual examination of centimetre-thick slices of cerebral hemispheres was done to identify brains without areas of cerebral white-matter discoloration that were indicative of demyelinated lesions (referred to as myelocortical multiple sclerosis) and brains that had cerebral white-matter discolorations or demyelinated lesions (referred to as typical multiple sclerosis). These individuals with myelocortical multiple sclerosis were matched by age, sex, MRI protocol, multiple sclerosis disease subtype, disease duration, and Expanded Disability Status Scale, with individuals with typical multiple sclerosis. Demyelinated lesion area in tissue sections of cerebral white matter, spinal cord, and cerebral cortex from individuals classed as having myelocortical and typical multiple sclerosis were compared using myelin protein immunocytochemistry. Neuronal densities in cortical layers III, V, and VI from five cortical regions not directly connected to spinal cord (cingulate gyrus and inferior frontal cortex, superior temporal cortex, and superior insular cortex and inferior insular cortex) were also compared between the two groups and with aged-matched post-mortem brains from individuals without evidence of neurological disease.
Findings: Brains and spinal cords were collected from 100 deceased patients between May, 1998, and November, 2012, and this retrospective study was done between Sept 6, 2011, and Feb 2, 2018. 12 individuals were identified as having myelocortical multiple sclerosis and were compared with 12 individuals identified as having typical multiple sclerosis. Demyelinated lesions were detected in spinal cord and cerebral cortex, but not in cerebral white matter, of people with myelocortical multiple sclerosis. Cortical demyelinated lesion area was similar between myelocortical and typical multiple sclerosis (median 4·45% [IQR 2·54–10·81] in myelocortical vs 9·74% [1·35–19·50] in typical multiple sclerosis; p=0·5512). Spinal cord demyelinated area was significantly greater in typical than in myelocortical multiple sclerosis (median 3·81% [IQR 1·72–7·42] in myelocortical vs 13·81% [6·51–29·01] in typical multiple sclerosis; p=0·0083). Despite the lack of cerebral white-matter demyelination in myelocortical multiple sclerosis, mean cortical neuronal densities were significantly decreased compared with control brains (349·8 neurons per mm 2 [SD 51·9] in myelocortical multiple sclerosis vs419·0 [43·6] in controls in layer III [p=0·0104]; 355·6 [46·5] vs 454·2 [48·3] in layer V [p=0·0006]; 366·6 [50·9] vs 458·3 [48·4] in layer VI [p=0·0049]). By contrast, mean cortical neuronal densities were decreased in typical multiple sclerosis brains compared with those from controls in layer V (392·5 [59·0] vs 454·2 [48·3]; p=0·0182) but not layers III and VI.
Interpretation: We propose that myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and can be an independent pathological event in myelocortical multiple sclerosis. Compared with control brains, cortical neuronal loss was greater in myelocortical multiple sclerosis cortex than in typical multiple sclerosis cortex. The molecular mechanisms of primary neuronal degeneration and axonal pathology in myelocortical multiple sclerosis should be investigated in future studies.
This is distinct from primary demyelination which is where there is the relative sparing of axons, but loss of the oligodendrocyte. This new lesion type is found in about 10% of cases. However, they have demyelinating lesions typical of MS in the spinal cord and deeper layers of the brain, although the level of demyelination in the spinal cord was less than in “normal” MS.
The authors suggest that “myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter.”
First MS was a demyelinating disease, now it’s a neurogenerative disease (after they rediscover in the 1990s that there is nerve loss in MS). All they had to do was read and remember the work done over a hundred years before.
Next, it was a white matter disease, now its a grey (& white) matter condition. This was found once the pathologists changed their staining technique, so they could see myelin in the grey matter. The MRIers still struggle with this (i.e. seeing lesions in grey matter with conventional MRI).
Now there are 10% of people with this neurodegenerative brain lesions and it’s an MS subtype.
It has taken hundreds of years to find them.
This is a pretty shocking state of affairs, if these observations are found to be reproducible. It is likewise shocking that pathologists can often not agree with each other on what is going on.
OK now I have got this off my chest.
Well first thing first. This is simples. Should we be surprised that you can find lesions that are neurodegenerative without real evidence of demyelination?
Not really, you have to look no further than EAE.
What is suprising to me is that one can think that the idea that you can have neurodegeneration without apparent demyelination is new.
Mouse EAE is a neurodegenerative disease without much evidence or no evidence of primary demyelination (axon present with no myelin). It has the same root of trigger as marmoset or guinea pig EAE, which can have lots of primary demyelination, but has different genetics and biology that means that the nerves go rather than the oligodendrocytes.
Is this a different disease?
Not really. It is a variant of the same disease.
Therefore, they did the study to show something that even the MRIers said was going on.Indeed, there already been a number of pathology studies showing that neurodegenerative brain lesions that occur, not correlate with demyelination
Carassiti D, Altmann DR, Petrova N, Pakkenberg B, Scaravilli F, Schmierer K.Neuronal loss, demyelination and volume change in the multiple sclerosis neocortex. Neuropathol Appl Neurobiol. 2018 Jun;44(4):377-390.
Next thing to think about is neuroanatomy and MS.
This is because even if demyelination was the cause of the nerve loss. Would it have to occur in the same area being examined? I think the answer is no.
Some nerves have to grow to stretch over a long distance. The spinal cord is about 45cm long so that would be
450mm and 450,000 micrometre, so about 90,000 five micrometer pathological tissue section. So you fail to find demyelination in section X when the damage occurred maybe 50,000 sections away. They only looked a centimeter (2000 sections) away Likewise the survival of nerves depends on imput from the nerves that innovate them.So the damage does not even need to be in the nerve (e.g. you have your leg cut off and you will loose nerves that control you leg in the brain).
In these individuals there was demyelination in the spinal cord for example and this could and probably would affect the inputs into the nerves in the brain
Will it need a different treatment. Well maybe?
There is little point using remyelination therapy, if the nerves are gone. It does not take a rocket scienctist to realise that you can’t raise the dead.
The sad thing would be however, if neuros who would plan pointless trials to do this.
Therefore, we really do need better imaging tools to detect remylination verses nerve loss.
Again we know that brain atrophy MRI measures does not directly measure nerve loss, as such in the spinal cord we have shown that you can loose significant numbers of nerves without apparent tissue shrinkage.
Maybe DrK will have something to say on this.
Is this an MS subtype? Maybe,
Many years ago we used to call neuromyelitis optica, Devics MS. Now it is considered to be a different entity, with different treatment requirements.
Should we surprisied if we cannot find different pathologies within MS?
Not really. We have found different subsets with the NMO spectrum disorders, with some giving response to aquaporin 4 and others to myelin oligodendrocyte glycoprotein for example. MS will be no different.
He is suggesting that MS is one disease and that primary and secondary MS are not distinct diseases.
Obviously we know that secondary progressive MS follows relapsing remitting MS but this is part of spectrum that encompassess PPMS.
Whilst speaking of heterogeneity in MS, we know it exists. Here’ another new example.
Behrens JR, Wanner J, Kuchling J, Ostendorf L, Harms L, Ruprecht K, Niendorf T, Jarius S, Wildemann B, Gieß RM, Scheel M, Bellmann-Strobl J, Wuerfel J, Paul F, Sinnecker T.. 7 Tesla MRI of Balo’s concentric sclerosis versus multiple sclerosis lesions. Ann Clin Transl Neurol. 2018 Jun 29;5(8):900-912.
Baló’s concentric sclerosis (BCS) is a rare condition characterized by concentrically layered white matter lesions. While its pathogenesis is unknown, hypoxia-induced tissue injury and chemotactic stimuli have been proposed as potential causes of BCS lesion formation. BCS has been suggested to be a variant of multiple sclerosis (MS). Here, we aimed to elucidate similarities and differences between BCS and MS by describing lesion morphology and localization in high-resolution 7 Tesla (7 T) magnetic resonance imaging (MRI) scans.
METHODS: Ten patients with Baló-type lesions underwent 7 T MRI, and 10 relapsing remitting MS patients served as controls. The 7 T MR imaging protocol included 3D T1-weighted (T1w) magnetization-prepared rapid gradient echo, 2D high spatial resolution T2*-weighted (T2*w) fast low-angle shot and susceptibility-weighted imaging.
RESULTS: Intralesional veins were visible in the center of all but one Baló-type lesion. Four Baló-type lesions displayed inhomogeneous intralesional T2*w signal intensities, which are suggestive of microhemorrhages or small ectatic venules. Eight of 10 BCS patients presented with 97 additional lesions, 36 of which (37%) had a central vein. Lesions involving the cortical gray matter and the U-fibers were not detected in BCS patients.
CONCLUSION:Our findings support the hypothesis that BCS and MS share common pathogenetic mechanisms but patients present with different lesion phenotypes.