Tuesday, 24 March 2015

Length-dependent hypothesis: sensory vs. motor attacks

Why are sensory attacks different to motor attacks? #MSBlog #MSResearch

“When we profile MSers, initial symptoms and the nature of early relapses have prognostic significance. It is generally accepted that sensory and visual symptoms are associated with a better outcome than motor attacks. Why? Recently when I was in Australia I presented my theory of MS being a length-dependent central axonopathy (disease of axons), which as you know is based on my observations of therapeutic lag and my asynchronous progressive MS hypothesis. Although I got a lot of nodding heads in the audience, not all agreed with my hypotheses. The work of Tomas Kalincik and others at MSBase (see below) was quoted as a possible exception to the rule. How does the length-dependent hypothesis explain the differential presentation of early and late attacks and their differential prognosis? Sensory relapses were more frequent in early or non-progressive disease. In comparison motor, sphincter (bladder and bowel) and cerebellar (incoordination) relapses were more common in older MSers and in progressive disease. Sensory, visual and brainstem relapses also showed better recovery than other relapses."

"Since my presentation in Melbourne I have been thinking about little else. It is well known that dirty little facts slay beautiful hypotheses. I may have a preliminary explanation based on the architecture and design of the nervous system to explain some of these observations. I have broken up the problem into several components:

1. Why are sensory attacks more common early on in the course of the disease?

The sensory system is synonymous with cutaneous sensation (light touch, pain, temperature, deep pressure, tickle, etc.). However, sensory should refer to all senses and hence should include vision, hearing, joint & head position, taste and smell. Physiologists call these the afferent systems; afferent simply means a neuronal input into the nervous system. In comparison, motor or output systems are called efferent systems. Afferent systems are designed for sensitivity; they need to pick-up and sense our environment so as to warn of us danger so that we can respond to them. From an evolutionary perspective our afferent/sensory systems are optimised for detection. A very large part of our cortex is devoted to perceiving the senses. In fact most of the parietal, occipital and temporal lobes are devoted to perceiving, integrating and interpreting sensory inputs. In comparison, the efferent/motor system is optimised for action and much less of our cerebral cortex is dedicated to motor activity. As a result of its size (cortical area) and optimised sensitivity a small lesion in the sensory pathways may be more likely to cause symptoms than a similar sized lesion in a motor pathway. This may explain why motor attacks have a worse outcome; larger lesions may be associated with greater damage. 

In my length-dependent model I propose that MS lesions may affect the nervous system randomly. Therefore, random MS lesions are more likely to hit sensory or afferent pathways, than motor pathways. We also have to get away from the dogma that MS is a white matter disease that only affects the so called subcortical white matter pathways. Recent pathological studies indicate that at least half the MS disease burden is found in cortical and subcortical gray matter. A small gray matter lesion in the sensory cortex could be a very common cause of early attacks. In comparison, a small lesion in the motor cortex may be less likely to cause symptoms. Please remember the sensory cortex is designed for perception that triggers awareness of our environment. In comparison the motor system is activated in via reflex, or through conscious volition. The motor system triggers a percept via a sensory feedback loops; for example we only perceive weakness because the sensory receptors in the joints and muscles tell our brains that there is mismatch between what is meant to be happening and what is happening. The feedback loop may result in the motor system having a much higher threshold; hence small or relatively minor lesions in the motor system may go unnoticed. 

The sensory fibre tracts

2. Could length-dependency explain the different prognostic significance of sensory and motor attacks?

The sensory system has shorter axons, compared to the motor system, and according to the length-dependent axonopathy hypothesis this may protect it. In comparison, motor neurones are much longer than sensory neurones and hence more likely to acquire multiple hits that lead to more rapid or earlier neurodegeneration. The architecture of the sensory system is such that afferent inputs go via first, second and third order neurones that communicate via synapses before reaching the cortex. Each relay axon is relatively short and hence this architecture may provide the sensory system relative protection from MS-associated neurodegeneration. In fact, the first-order sensory neurones are actually bipolar cells with their cell bodies residing outside the central nervous system in the dorsal, or posterior, root ganglia (DRG). A demyelinating plaque affecting the central axonal process is therefore unlikely to kill the neuron residing in the DRG by retrograde neurodegeneration. We know this because sensory radiculopathies that destroy the central neuronal processes before they enter the spinal cord are characterised by preservation of sensory nerve action potentials (SNAPs), which indicates that the neuronal cell bodies and peripheral axons are intact. The compartmentalisation of 1st-order sensory neuronal cell bodies, outside the CNS, away from the MS pathology, may provide the sensory pathway with a better chance of recovery, via axonal sprouting or axonal regrowth.

In comparison the axons from the pyramidal, or motor, neurons extend from the primary motor cortex to synapse on the anterior horn cells, or their equivalents, in the lateral columns of the spinal cord or brain stem respectively. Importantly, there are no motor interneurons, which is why the motor neurones are the longest neurones in the central nervous system. The cell bodies also reside within the CNS, in layer V of the cortex, and hence are not protected from being directly involved by focal MS pathology. 

The motor fibre tracts
3. Could reserve capacity explain the different prognostic significance of sensory and motor attacks?

Extending the arguments above that the sensory system may be more sensitive to small lesions due the reporting of percepts, in particular positive phenomena, that as it degenerates, loses neurones and axons, the likelihood of new lesions causing symptoms, in particular positive symptoms, diminishes. In comparison, as the motor system degenerates and compensatory mechanism fail new lesions are more likely to become clinically apparent. If reserve capacity in a particular pathway determines its sensitivity to cause relapses then one could hypothesise that proportion of positive sensory attacks (positive sensory symptoms) will diminish, in comparison to negative sensory attacks (loss of sensation). The latter hypothesis is testable and could be explored in existing databases or prospectively in clinical cohorts." 

"Apologies for this post being so technical; I simply want to get the idea into the open to stimulate discussion and debate."

Kalincik et al. Risk of relapse phenotype recurrence in multiple sclerosis. Mult Scler. 2014 Oct;20(11):1511-22.

Objectives: The aim was to analyse risk of relapse phenotype recurrence in multiple sclerosis and to characterise the effect of demographic and clinical features on this phenotype.

Methods: Information about relapses was collected using MSBase, an international observational registry. Associations between relapse phenotypes and history of similar relapses or patient characteristics were tested with multivariable logistic regression models. Tendency of relapse phenotypes to recur sequentially was assessed with principal component analysis.

Results: Among 14,969 eligible patients (89,949 patient-years), 49,279 phenotypically characterised relapses were recorded. Visual and brainstem relapses occurred more frequently in early disease and in younger patients. Sensory relapses were more frequent in early or non-progressive disease. Pyramidal, sphincter and cerebellar relapses were more common in older patients and in progressive disease. Women presented more often with sensory or visual symptoms. Men were more prone to pyramidal, brainstem and cerebellar relapses. Importantly, relapse phenotype was predicted by the phenotypes of previous relapses. (OR = 1.8–5, p = 10-14). Sensory, visual and brainstem relapses showed better recovery than other relapse phenotypes. Relapse severity increased and the ability to recover decreased with age or more advanced disease.

Conclusion: Relapse phenotype was associated with demographic and clinical characteristics, with phenotypic recurrence significantly more common than expected by chance.


  1. I thought you were on a sabbatical? When you get back can you give some thought to repairing the damage done to the spinal cord by this disease. Thanks.

    1. There seems to be a misunderstanding what a sabbatical is; in academia a sabbatical is giving you time off from admin, teaching and clinical work so that you can travel, think, write and work. I have done loads of all and feel refreshed with lots of new ideas. The length-dependent axonopathy hypothesis is just one of the ideas I have finessed over the last 6 months.

  2. Yes - very technical for the ordinary mug punter.........
    Re "Sensory relapses were more frequent in early or non-progressive disease. In comparison motor, sphincter (bladder and bowel) and cerebellar (incoordination) relapses were more common in older MSers and in progressive disease".
    Where does age at onset/diagnosis fit into this? I understand that the older the person is at onset/diagnosis the worse the prognosis generally is, but what about older people who have never had clearly identifiable acute relapses or sensory attacks, but only incredibly mild ones that are only recognisable as such in hindsight after the diagnosis is made?

    Are you saying that spinal lesions have more impact on motor skills/coordination because they affect some of the long neurones and that they have less reserves to be able to re-myelinate successfully? Also that deterioration in motor function is less noticeable because it is less dramatic as it occurs?

    Should General Practitioners (and neurologists) be paying more attention to leg weakness/coordination/balance/bowel/bladder problems as a "collection" of symptoms, even if not severe, to try and ensure that people who don't have clear relapses are diagnosed earlier and the damage and disability can hopefully be minimised before it is too late? Losing your sight or going numb down one side certainly gets a person into the Dr's office and consequently investigations into causes are done, but gradual deterioration of function just seems to get ignored, or you are told it's just part of getting older. I reported leg weakness, balance, coordination, and bladder problems (didn't have any sensory symptoms) to my family doctors numerous times, but it was not suggested that I see a neurologist until things had become quite bad. Thus my EDSS (useless thing that it is) was >3 at diagnosis, and is higher now.

  3. How does length dependency explain the high frequency of optic nerve involvement in MS?

    1. The optic nerve is an afferent system and is therefore liable to report out on small lesions, which explains why it is commonly involved. However, it short length explains why it is rare to see progressive visual failure; i.e. it is protected from early involvement in the non-relapsing progressive phase of the disease. We do see progressive visual failure, but it is rare.

  4. Very interesting post.

    So in summary you are suggesting that sensory attacks present earlier and are more likely to be noticed due to the proportionally greater area and sensitivity of the sensory systems versus the motor systems. Motor attacks may be worse as the lesions need to be bigger in size to be consciously recognised and their length also exposes them to the risk of multiple hits/damage. I do not really get the third point about reserve capacity.

    However, this still does not explain why older patients/progressive patients tend to present with motor symptoms. On the above rationale a good proportion should have had sensory symptoms initially ...

  5. My MS started at 21 with double vision and all the sensory problems. I went to the optician and ended up at the eye hospital. I didn't dream of going to my GP however foolish with my numbness and pins and needles in my arm and from the waist down my legs. After six months a relative saw me fall over and told me to go to the doctor. I went downhill very quickly and ended up guessing my diagnosis in hospital. I refused ACTH because I wasn't convinced this was for me I was slightly improving. Decades later I have SPMS, but the notion that the recovery from sensory relapses is better could also be due to age, no co-morbidities and pre-menopause. I find this post very useful as other MSers have mentioned they never had the violent attacks that I had, even though I seemed to be coping quite well and I was diagnosed at a much younger age.


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