A test for MS...Are we there yet?

Wow you said a new study that shows a simple test that can detect MS,

Hailing from “Gods own Country”,  I thought I would Investigate

The local Huddersfield rag (Newspaper) says

 “They have worked out how it can be detected using a simple blood test - up to now the only way to diagnose the disease has been through an invasive and often painful process of collecting fluid from the brain and spine”.

So already you know the newspaper is already talking rubbish and giving you visions of needles in the head. 

A lumbar puncture is not the typical diagnostic test these days and it is certainly not diagnostic as many conditions have oligoclonal bands. Importantly let’s not forget the good old magnetic resonance imaging machine for spotting those lesions. This is far more diagnostic.

Michael I. Page MI, McHugh P, Powles NT. Sphingosine and dihydrosphingosine as biomarkers for multiple sclerosis identified by metabolomic profiling using coupled UPLC-MS. Analytical Methods 2017.

The project aim was to identify differences in the metabolomic profiles in the serum of patients with multiple sclerosis (MS), those with neuropathic pain (NP) and those with both MS and NP compared with controls and to identify potential biomarkers of each disease state. Metabolomic profiling was performed using ultra-high-performance liquid chromatography coupled to mass spectrometry and the data analysis involved parametric methods, principal component analysis, and discriminating filter analysis to determine the differences between disease and control serum samples. Sphingosine and dihydrosphingosine were identified as significant biomarkers.

Apparently they found that "Sphingosine"  a lipid that makes spingosine-1 phosphate and "dihydrosphingosine" involved in ceramide production, which are Sphingolipids, are reduced in the blood. 

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In comparing Bloods from 30 people with MS verses 60 controls showed that Sphingosine levels were significantly lower in the multiple sclerosis groups compared with the control group giving p =  6.06 x 10*10. The control group had a mean peak area of 18, 990

±   6,286 (12,704-25,276). The multiple sclerosis groups had mean peak areas of 9, 535 ± 3,032 (6,503-12,567)for multiple sclerosis and 11 254 ± 3,863 (8,791-16, 117) for multiple sclerosis with neuropathic pain.

Similarly, the dihydrosphingosine levels were signicantly lower in the multiple sclerosis groups compared with the control group with p = 4.89 x  10*6 . The control group had a mean peak area of 7,723 ± 2,345, whereas the multiple sclerosis groups had mean peak areas of 4,936 ± 1, 389  for MS and 5,904 ± 1,581, respectively. Further studies will also need to be done with other controls.

It is therefore evident that there is not 100% specificity and 100% sensitivity to detect every one with MS and exclude people who don't have MS. Therefore, it will not be absolutely diagnostic. 

However, I would ask what are the biological processes that account for this? It is hard to think of anything that would be specific for multiple sclerosis as many of the pathological processes can occur in other conditions.

The Work is published in a local Newspaper on work from a Local University...So I doubt the breakthrough is really a breakthrough as it would be picked up by more media.

Does MS affect peripheral nerves?

There are few things that all MSologists agree on. 

Perhaps one of the least controversial statements you can make about MS is that it is a disease of the Central Nervous System - i.e. the brain, brainstem, cerebellum, and spinal cord - and that it does not affect the peripheral nerves.

Plus ca change.


A new study from Heidelberg has questioned the dogma that MS does not affect peripheral nerves. Although this idea has been floated in the past, hard proof for it has been lacking. Kollmer and co. recruited 36 pwMS and 35 healthy controls with a similar age and gender distribution. After some careful questioning to exclude other causes of peripheral nerve damage, they assessed the function of the participants' peripheral nerves in two ways: Nerve conduction studies (NCS), and MRI. 

Using these two techniques, they asked whether there is any evidence that pwMS accrue demyelinating lesions of peripheral nerves akin to CNS lesions.

They found no strong evidence of demyelination on NCS in either pwMS or controls. 

However, they found that pwMS had significant more hyperintense lesions on T2-MRI in their peripheral nerves than controls. These changes are not readily explained by compression of the spinal nerve roots, the presence of spinal cord lesions, or disease-modifying therapy as there was no clear relationship with any of these factors. Interestingly, nerve width was also increased in pwMS for large nerves compared to controls, but there was no such difference in smaller, terminal branches. 

These findings are incredibly interesting.

It is worth noting that the healthy controls had quite a few lesions, implying that using MRI may pick up very subtle disturbances of peripheral nerve myelin which don't have any functional importance. Importantly, the peripheral nerve lesions were not associated with abnormalities of nerve conduction. This means that the functional significance of these lesions is unclear at this stage. It would be useful to know how these people fare in the long-term to see whether these subtle MRI changes pre-empt frank disturbances of peripheral nerve conduction. 

It is also unclear what causes these abnormalities. Some possibilities are...
- Inflammatory demyelination of the peripheral nerves is part and parcel of the same process that affects the CNS in MS;
- CNS damage (lesions/atrophy/both) leads to demyelination of peripheral nerves;
- An unknown genetic/enviromental factor predisposes to MS and demyelinating peripheral nerve damage.

Regardless of the cause, I think the lack of concordant MRI and NCS suggests that the lesions picked up here are very subtle and may be epiphenomenon. That said, if this result can be followed-up with more definitive evidence of demyelination - such as biopsy evidence - it will require us to radically rethink our view of MS biology. If MS really does affect peripheral nerves this will not only have far-reaching implications for our understanding of the disease but will open up lots of new avenues for diagnosing and predicting MS. 

***

Abstract:

Objective:To detect and quantify peripheral nerve lesions in multiple sclerosis (MS) by magnetic resonance neurography (MRN).

Methods: 36 patients diagnosed with MS based on the 2010 McDonald criteria (34 with the relapsing-remitting form, 2 with clinically isolated syndrome) with and without disease modifying treatment were compared to 35 healthy age/sex-matched volunteers. All patients underwent detailed neurological and electrophysiological examinations. 3T MRN with large anatomical coverage of both legs and the lumbosacral plexus was performed by using 2D fat-saturated, T2-weighted and dual echo turbo-spin-echo sequences as well as a 3D T2-weighted, fat-saturated SPACE sequence. Besides qualitative visual nerve assessment, a T2w-signal quantification was performed by calculation of proton-spin-density and T2-relaxation time. Nerve diameter was measured as a morphometric criterion.

Results:T2w-hyperintense nerve lesions were detectable in all MS patients with a mean lesion number at thigh level of 151.5±5.7 vs. 19.1±2.4 in controls (p<0.0001). Nerve proton-spin-density was higher in MS (tibial/peroneal: 371.8±7.7/368.9±8.2) vs. controls (tibial/peroneal: 266.0±11.0/276.8±9.7;p<0.0001). In contrast, T2-relaxation time was significantly higher in controls (tibial/peroneal:82.0±2.1/78.3±1.7) vs. MS (tibial/peroneal:64.3±1.0/61.2±0.9; p<0.0001). Proximal tibial and peroneal nerve caliber was higher in MS (tibial:52.4±2.1mm2; peroneal:25.4±1.3mm2) vs. controls (tibial:45.2±1.4mm2; p<0.0015; peroneal:21.3±0.7mm2; p=0.0049).

Interpretation:Peripheral nerve lesions could be visualized and quantified in MS in vivo by high resolution MRN. Lesions are defined by an increase of proton-spin-density and a decrease of T2-relaxation time, indicating changes in the microstructural organization of the extracellular matrix in peripheral nerve tissue in MS. By showing involvement of the peripheral nervous system in MS, this proof-of-concept study may offer new insights into the pathophysiology and treatment of MS. This article is protected by copyright. All rights reserved.