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Nerve Fiber Fatigue In Multiple Sclerosis

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It is important to be aware that several different causes and types of Fatigue may co-exist, and usually do.

Nerve Fiber Fatigue

Nerve Fiber Fatigue in MS is a distinct problem not usually thought of as *Fatigue* and is rarely covered in discussions of MS Fatigue. However, it is a central feature that affects function and significantly contributes to clinical Disability.

Nerve Fiber Fatigue has distinct characteristics and a diurnal variation, similar to disease related Fatigue. It usually predates the first clinical MS symptoms, is experienced by most MSers, and worsens as the disease progresses.

Nerve Fiber Fatigue is an activity and/or temperature related failure, of DeMyelinated or ReMyelinated Axons to conduct Nerve Impulses (Action Potentials). Even Dr. Charcot, who wrote the classic description of MS in 1868, knew DeMyelinated Axons could conduct.

He stated: "MS very rarely issues in complete blindness. This is especially worthy of notice if you remember. Patches of Sclerosis have been found after death, occupying the whole thickness of Nerve trunks in the Optic Nerves in cases, where during life, an enfeeblement of sight simply had been noted." {1}

This apparent discrepancy between symptoms and Lesions, constitutes one of the most powerful arguments that the functional continuity of the Axon is not always permanently interrupted.


Scientific literature regarding Conduction failure in DeMyelinated Axons is old and quite extensive. During an exacerbation, Saltatory Conduction fails along Axons, as they are DeMyelinated; however over time, conduction in most of the surviving Axons is restored.

The causes of conduction failure during DeMyelination are incompletely understood but include:

The role if any, of alterations in the ExtraCellular fluid composition, in the inflamed area is unclear. There is evidence the Nodal Axon is damaged by LysoLecithin and other detergent LysoLipids generated, by enzymes present in Inflammation.

Various enzymes are released by Inflammatory Cells, including Nitric Oxide, a variety of Proteases, Lipases, NeurAminidase, Phosphatases, and Glycosidases. Of these, Phospholipase appears to produce the most rapid and extensive Myelin damage.

Phospholipase also specifically destroys Sodium Channels as measured by SaxiToxin binding {2,3}. Once the acute Inflammatory Response is over, repair processes take over and Nerve conduction resumes.


The Axon's InterNodes (Area beneath Myelin) normally contain, very few Sodium channels.

Indeed, if Sodium channels on a Myelinated Axon were evenly distributed over its entire length, their density would be much less than half that in most UnMyelinated Axons and would be too few to support conduction {6,7,8}.

In order for continuous conduction to develop in a DeMyelinated Axon, the Axon must form additional Sodium channels.

This is prerequisite for the restoration of continuous conduction, along a DeMyelinated Axon; but, this alone will not ensure that conduction will occur.

Because a DeMyelinated Axon has a giant Capacitance Charge. This increased capacitance results in, a huge increase in the amount of current required, to depolarize its membrane to Threshold.

So the current passing down the Axon, from the last Myelinated region is normally insufficient, to discharge a DeMyelinated membrane's capacitance to Threshold.

This is more easily understood if you regard the Axolemma and Myelin, as the Di-Electric of a tubular Capacitor. It separates the charged plates (the positive ExtraCellular Fluid from the Axon's negative interior).

By definition: Capacitance is inversely proportional to the distance between two plates of a Capacitor (Fig 1). Therefore, the capacitance of a DeMyelinated Axon is many times that of a Myelinated Axon.

Whose numerous Myelin layers, electrically insulate the negatively charged Axon's interior, from the positively charged ExtraCellular Fluid.


Fig 1. Diagram of the Capacitance charge on a cross section, (1A) of a Myelinated Axon and (1B) of a DeMyelinated Axon.

Capacitance Charge

In 1A, Myelin separates the negatively charged Axon from the positively charged ExtraCellular Fluid.

So the capacitance charge on the Axolemma (Axon's membrane) is very small and little current is required to DePolarize it.

In 1B, there is no Myelin separating the charges; thus, the capacitance charge is exceedingly large.

It is so large, current coming down the Axon from the Myelinated segments cannot discharge it - this Conduction Block is due to Impedance Mismatch.


Current passing along the last Myelinated segment to a DeMyelinated segment is mainly from the last Node.

On a large Axon, this distance can be 2 mm away (Fig 2); so the generated current is insufficient to DePolarize the DeMyelinated membrane (Axolemma) to Threshold.

Thus, conduction fails at the junction of the Myelinated and DeMyelinated segments; because the number of Sodium channels in the DeMyelinated Axolemma are insufficient, for NonSaltatory Conduction (Fig 2C).

In ElectroPhysiological literature, this conduction problem is termed Impedance Mismatch.


Fig 2.  Conduction Restoration Following DeMyelination

  1. A DePolarization wave reaches Node on left.

    Conduction Restoration

     

  2. Sodium channels open initiating an inward Sodium current, which DePolarizes the next Node.

  3. The DePolarizing current is diffused, by the large capacitance on the DeMyelinated Axon and is therefore inexcitable; since there are not enough Sodium channels, in the newly bared InterNodes, to support conduction.

  4. ReMyelination has occurred with thin Myelin and short InterNodes. These Nodes DePolarize, almost simultaneously.

  5. The additive effect (Summation) of the current from several adjacent Nodes, DePolarizes the DeMyelinated Axolemma enabling conduction.

    Because, as part of the recovery process, enough Sodium channels have been added to the DeMyelinated Axolemma enabling NonSaltatory Conduction.

Note that a great deal more Sodium enters the Axon, with each Impulse in D and E, resulting in a marked increase in energy requirement per Impulse - one cause of Fiber Fatigue with Conduction failures.


Conduction Block is overcome by ReMyelination at the Plaque margins (Figure 2D and 2E) and an increase in the number of Sodium channels in the DeMyelinated Axon {9}. (Also See: Conduction Block)

New Myelin (ReMyelination) has very short InterNodes, which allows Summation of the current from several Nodes.

This results in an increase of the Sodium current, overcoming the Impedance mismatch and initiates continuous conduction in the DeMyelinated Axon.

    This Has Several Consequences:
  1. The amount of Sodium entering the Axon, with each Impulse, is greatly increased. The Sodium Pump cannot keep up with the high rates of Sodium entry, when Nerves are very active. Resulting in:
    • Flooding of the Axon with Sodium
    • Exhaustion of ATP supplies
    • Conduction Failure

  2. Recovery time between Impulses is prolonged and many Impulses drop out, during fast trains of Impulses.

  3. Axons become Temperature Sensitive:
    • From the low safety margin for conduction, due to the Sodium channel's response to higher temperature {11}

When a Nerve Impulse triggers a Node, essentially all Sodium channels sequentially open and Sodium pours in, DePolarizing the Axon. But, the rate Sodium channels close is much more temperature dependent.

Such that with an increase in temperature, they close faster. Decreasing the time in which current can flow, which decreases total current producion, and is another cause of conduction failure.

Cooling has the opposite effect, increasing the time that channels are open, which improves efficient current production and prolongs continuous conduction.

Studies of experimentally DeMyelinated Axons show Temperature Sensitivity, such that a rise in temperature of as little as 0.5癈 above normal, will cause conduction failure in some DeMyelinated Axons {11}.

It is this Fiber Fatigue that accounts for the problem many MSers have, in walking more than short distances, or performing extended physical activity, and is know to us as heat sensitivity.

When Fiber Fatigue occurs and Axons stop conducting, the legs simply will not move, until the Axons are rested enough and begin conducting again {13}.

This lack of stamina is more pronounced, during the early stages of recovery from an exacerbation.

You may only be able to make a particular movement once or twice initially; but over the next few months, you will be able to increase the number of repetitions and be near your former functioning level.


Fiber Fatigue is often physically limiting and is markedly influenced by body core temperature; a cool environment may help, particularly during physical activity.

Studies show that individuals can exercise longer with appropriate cooling, most find a cool swim enables better functioning for hours.

It lowers the core temperature and causes cooling and VasoConstriction in the extremities, which serve as heat sinks, keeping your body temperature lower for some time.



References

  1. Charcot JM
    Lectures On Diseases Of The Nervous System. First series lectures 6, 7, and 8 delivered in 1868
    Sigerson G, trans. London
    The New Sydenham Society; 1877:157

  2. Kasckow J, Abood LG, Hoss W, Herndon RM
    Mechanism Of Phospholipase A2 Induced Conduction Block In Bullfrog Sciatic Nerve I ElectroPhysiology and Morphology
    Brain Res 1986a;373:384391

  3. Kasckow J, Abood LG, Hoss W, Herndon RM
    Mechanism Of Phospholipase A2 Induced Conduction Block In Bullfrog Sciatic Nerve II BioChemistry
    Brain Res 1986b;373:392398

  4. Ritchie JM, Rogart RB
    Density Of Sodium Channels In Mammalian Myelinated Nerve Fibers And Nature Of The Axonal Membrane Under The Myelin Sheath
    Proc Natl Acad Sci 1977;74:211215

  5. Waxman SG, Kocsis JD, Black JA
    Pathophysiology Of DeMyelinated Axons
    In: Waxman SG, Kocsis JD, Stys PK, eds.
    The Axon. New York: Oxford; 1995:438461

  6. Hirano A, LLena JF
    Morphology Of Central Nervous System Axons
    In: Waxman SG, Kocsis JD, Stys PK, eds.
    The Axon. New York: Oxford; 1995:4967

  7. Ritchie M.
    Physiology Of Axons
    In: Waxman SG, Kocsis JD, Stys PK, eds.
    The Axon. New York: Oxford; 1995:6896

  8. Querfurth HW, Armstrong R, Herndon RM
    Sodium Channels In Normal And Regenerated Feline Ventral Spinal Roots
    J NeuroSci 1987;7:17051716

  9. Sears TA, Bostock H
    Conduction Failure In DeMyelination: Is It Inevitable?
    Adv Neurol 1981;31:357375

  10. Rasminsky M
    The Effects Of Temperature On Conduction In DeMyelinated Single Nerve Fibers
    Arch Neurol 1972;28:287292

  11. Franssen H, Wieneke GH, Wokke JH
    The Influence Of Temperature On Conduction Block
    Muscle Nerve 1999 Feb;22(2):166173

  12. Guthrie TC, Nelson DA
    Influence Of Temperature Changes On Multiple Sclerosis: Critical review of mechanisms and research potential
    J Neurol Sci 1995 Mar;129(1):18

  13. Brenneis M, Harrer G, Selzer H
    On Temperature Sensitivity In Multiple Sclerosis
    Fortschr Neurol Psychiatr Grenzgeb 1979 Jun;47(6):320325



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