Electrotonic conduction, myelin, and multiple sclerosis

Wednesday, 11 November 2020 4:30 PM

• Electrotonic conduction:
- It is a passive spread of charges from the
site of stimulus.
- The potential decays exponentially with
distance. Electrotonically conducted
signal dies away over a distance of a few
mm.

- Length constant: The distance over

which the potential change decreases to
1/e (37%) of its maximal value is called
the length constant or the space
constant. (e is the base of natural
logarithms and is equal to 2.7182.) For
mammalian axons, the length constant is
about 1-3 mm.
- Since length constant is about 1-3 mm
(and the potential decreases
exponentially over the distance), it will
be completely dissipated by 10 mm
length of the axon.

- Importance of the myelin:

Myelin increases the membrane
resistance (decreases the membrane
capacitance). Hence, it prevents the
leakage of charges, thereby increasing
the length constant.
- Considering that the average internodal
distance to be about 1 to 3 mm (if we
take 3 mm as the internodal distance),
demyelination involving more than 3
nodes will result in appearance of
conduction blocks. [However, it will be
temporary. As the Na+ channels will get
redistributed, the conduction will begin
again.]

• Multiple sclerosis:
- Most common demyelinating disease of
the CNS
- Autoimmune disease directed against
the myelin or oligodendrocytes
- S/s ~ decreased visual acuity due to optic
neuritis; diplopia (double vision) due to
degeneration of neurons that innervate
extraocular muscles; Lhermitte sign -
Electrical sensation that shoots down the
back and into the legs when the neck is
flexed.

- MS is defined clinically as a disease that

involves demyelination of CNS with
episodes separated in both time and
space - i.e., at least two episodes of
demyelination involving at least two
separated regions of the CNS.
- Exacerbation of symptoms - when there
is active inflammation of a white matter
tract in the CNS.

- Molecular changes - Replacement of NaV

1.6 channels by NaV 1.2 channels in the
demyelinated axons.
NaV 1.6 is the primary voltage-gated Na+
channel at the nodes of Ranvier. This
channel is able to sustain repetitive
excitation and firing.
NaV 1.2 is found at the distal end of the
axon hillock.
In early stages of myelination, immature
NaV 1.2 channels are greater in number
(as compared to NaV 1.6). However, NaV
1.6 channels gradually replace the other
Na+ channels.
In MS, NaV 1.6 is replaced by NaV 1.2.

- Conduction in demyelinated fibers is just

about adequate under normal
circumstances; it becomes inadequate
under stressful conditions.

• Uhthoff’s symptom:- HEAT SENSITIVITY

When the body temperature of an MS
patient is elevated (due to fever or hot
water bath), conduction is compromised
and symptoms of neurological deficit will
appear. There may be transient visual
blurring or such symptoms.
Low temperatures improve the
symptoms. Reason:- At low
temperatures, the gating kinetics of Na+
channels are slowed; also, the
conduction velocity is slowed.

• Physiology:-

[In myelinated axons, AP travels as

saltatory conduction with much faster
velocities (~ 70 m/sec). In unmyelinated
axons, there is a continuous propagation
(velocity ~ 1 m/sec).]
• In MS, a segment of an axon may get
demyelinated. This would result in a
conduction block (the nerve impulse will
be unable to traverse the demyelinated
segment).
• The conduction failure may be because
of the following two reasons:- (1)
Leakage of currents as they travel
through the demyelinated segment.
(Na+ ions fail to reach the next node of
Ranvier in substantial amounts. Hence,
AP can not be generated at the next
node.) (2) With demyelination, K+
channels (normally burried underneath
the myelin sheath) are exposed. K+
leakage —> hyperpolarization.
• The conduction block is temporary.
Eventually, the Na+ channels (which are
originally concentrated at the nodes) will
be redistributed along the naked axon.
Now, continuous propagation (non-
saltatory, as in unmyelinated axons) will
start. However, it is slower.
• Variable conduction block can occur with
raised body temperature or metabolic
alterations; this explains clinical
fluctuations (typical of MS) that vary
from hour to hour, or in association with
fever or exercise.
Diagnostic tests for MS:
1. MRI
2. Evoked potentials:-
- Repetitive stimulation of some selected
peripheral nerves (or of the brain) will
evoke specific electric potentials in the
CNS; such potentials are measured as
“evoked potentials”.
- These tests will be most useful when the
pathways studied are NOT clinically
involved. E.g., in a patient with a spinal
cord syndrome with sensory deficits in
the legs, an abnormal somatosensory EP
after posterior tibial nerve stimulation
will not provide NEW information. But,
in this patient, an abnormal VISUAL EP
(related to the optic nerve) would permit
a diagnosis of clinically definite MS.
(Remember:- two or more lesions
needed to disgnose MS.)
3. There is also the scoring system for MS:-
Kurtzke expanded disability status score
(EDSS).
The score has a scale of 0.0 to 10.0
(E.g., 0.0 = 0 Normal neurologic exam;
10.0 = 10 death due to MS)

Treatment strategy:-
The augmented currents of the broader
spike make it more likely that the
threshold for continued conduction will
be reached.
Certain drugs can prolong the duration
of AP and facilitate conduction through
demyelinated axons. Mechanism:
Demyelination exposes the voltage-
gated K+ channels underneath the
myelin. Activation of outwardly
rectifying K+ channels can further impair
spike production in demyelinated axons.
However, these K+ channels can be
acted upon (now that they are accessible
due to demyelination) by the class of
drugs - the K+ channel blockers called
AMINOPYRIDINES.
Blocking the K+ channels can prolong the
spike; propagation through the
demyelinated region may be facilitated.

• The most common demyelinating

disease of the PNS is Landry-Guillain-
Barre syndrome.
It is caused by autoimmunity to myelin
sheath formed by Schwann cells in the
PNS. These patients recover fully
because the PNS has the ability to
remyelinate itself. (Axons of CNS do not
remyelinate; hence, recovery is not
common in MS.)