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Endoneurial fluid pressure in wallerian degeneration.

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Endoneurial Fluid
Pressure in Wallerian Degeneration
H. C. Powell, MB, BCh, R. R. Myers, PhD,
M. L. Costello, MS, and P. W. Lampert, M D
Endoneurial fluid pressure (EFP) was recorded by an active, servo-null pressure system after a glass micropipette
was inserted into rat sciatic nerve undergoing wallerian degeneration. The lesions were produced by crushing the
left sciatic nerve of the anesthetized animal at its point of entry into the thigh. Eighty-four animals were employed
in this experiment, in which EFP was recorded from sham-operated rats and other controls as well as from rats with
wallerian degeneration. The experiment was designed so that EFP could be recorded from 2 or more experimental
animals at daily intervals starting at day 0 and concluding on day 28. Pressure progressively increased during the
first week, reaching a peak elevation four to five times normal. T h e subsequent decline in EFP was more gradual,
with values approaching normal during the third week after injury. Linear regression analysis showed the progressive increase in EFP to be statistically significant ( p s 0.01). To determine the time at which EFP was maximum, we
used the Marquardt computer algorithm for least-squares estimation of nonlinear variables. By this procedure the
peak value for EFP occurred at six days. These biophysical observations were correlated with subsequent microscopic examination of 1 p thick sections of Araldite-embedded sciatic nerve. Microscopy confirmed the presence of
wallerian degeneration associated with edema, which was observed in every instance of elevated EFP.
Powell HC, Myers RR, Costello ML,
et al:
Endoneurial fluid pressure in wallerian degeneration.
A n n Neurol 5:550-557, 1979
T h e ability to measure endoneurial fluid pressure
(EFP) in vivo in small laboratory animals has been
made possible by newly developed techniques and
promises to be a powerful tool for investigating the
pathophysiology of peripheral nervous system disorders. Micropressure recording systems employed in
measuring hydraulic pressure in the microcirculation
can be adapted to measure fluid pressure in the endoneurium, a specialized environment regulated by a
functional blood-nerve barrier. Access to this compartment for measurement of EFP is possible either
by implanting a polyethylene matrix capsule within
which endoneurial fluid gradually accumulates [8] or
by direct insertion of a pressure-recording micropipette [141.
Use of these methods has already led to recognition of different pathophysiological mechanisms by
which EFP can be elevated. The first mechanism for
increased EFP was recently described by Low and
Dyck [7] in lead neuropathy, in which a permeability
change of the blood-nerve barrier is believed to
occur associated with endoneurial edema, detectable
lead in endoneurial fluid, cytolysis of Schwann cells,
and demyelination. T h e second example is hexa-
chlorophene neuropathy, in which EFP is elevated
by accumulation of fluid within the myelin sheath
[22]. Intramyelinic edema due to hexachlorophene results from a permeability change in the
myelin sheath itself, occurring in spite of a morphologically intact blood-nerve barrier and intact
tight junctions between axolemma and the investing
myelin sheath at the nodes of Ranvier [21]. This report describes a third condition which results in altered EFP and documents the rise and decline in EFP
that occur in peripheral nerve undergoing wallerian
degeneration produced by a proximal crush injury.
During wallerian degeneration, edema fluid accumulates in association with breakdown of the axon
and myelin sheath. Separation of nerve fibers in the
distal parts of sectioned nerves is thought to be due
to the spread of protein-rich edema fluid through the
endoneurial interstitium [19, 281 and can be seen
within the first two hours after injury [3]. with subperineurial fluid accumulation within three days. This
last observation and the biochemically demonstrated
increase in nerve water content [ 5 ] suggested to us
that EFP might be elevated in wallerian degeneration.
Therefore, the purpose of this study was to measure
From the Departments of Pathology (Neuropathology),Neurosciences, and Anesthesiology, University o f California, San Diego,
School of Medicine, La Jolla, CA, and the Veterans Administration
Hospital, San Diego, CA.
Address reprint requests to Dr Powell, Department of Pathology.
M-012, University of California, San Diego, School of Medicine,
La Jolla, CA 92093.
Accepted for publication Nov 20, 1978.
550 0364-5134/79/060550-08$01.25 @ 1978 by H. C. Powell
the EFP at daily intervals from the time of injury and
to correlate the changes in EFP with microscopic
findings and the other known changes associated with
wallerian degeneration.
Endoneurial fluid pressure was recorded by an active,
servo-null pressure system after glass micropipettes were
inserted directly into rat sciatic nerves at specified times
following induction of wallerian degeneration by crush injury. Normal adult Sprague-Dawley rats weighing between
200 and 250 gm were used. Test animals were anesthetized
with sodium ethyl-(I-methylpropy1)-malonylthiourea(Inactin), 110 mg per kilogram of body weight. The right
sciatic nerve was exposed at its point of entry into the thigh
by a lateral incision of the thigh and dissection of muscles
and fascia. The nerve was crushed repeatedly as close as
possible to its origin with a fine-tipped jeweler’s forceps.
The muscles and overlying skin were then sutured and the
animals allowed to recover in their normal laboratory environment.
Eighty-four animals were employed in the experiment;
also, 14 unoperated control rats were used and 8 rats had
sham operations. The experiment was designed so that EFP
could be recorded from 2 or more animals at daily intervals
starting at day 0 and concluding on day 28. EFP was recorded by exposing the right sciatic nerve of an anesthetized animal, irrigating it with warm (37°C) buffered
Ringer’s solution, and inserting the micropipette tip into a
nerve fascicle approximately 2 cm distal to the point of
injury. The Ringer’s solution around the nerve formed a
bath in which “zero” reference pressure could be recorded
before and after each EFP measurement.
At least three measurements were taken from each animal and the mean value recorded in the Table and expressed in graph form (Fig 1). After the EFP was measured,
the sciatic nerve was removed and placed in 2.5%
Individual and Mean Values (by Day) of Endoneurial Fluid Pressure Recorded from Animah
betueen Day 0 and Day 28 Follouiing a Proximal Crush 1njut.r t o the Sciatic Nerve
Mean EFP
(cm H,O)
2.0 2 0.3
1.2, 2.6, 0.3, 1.1,
1.8, 2.7, 2.3, 1.6,
3.2, 3.9, 1.1, 3.2,
1.2, 2.4
Day Ob
Day 1
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Day 17
Day 18
Day 20
Day 21
Day 22
Day 24
Day 27
Day 28
4.1 2 0.2
6.2 2 1.6
6.1 2 0.7
8.3 2 0.4
8.5 2 1.3
4.8 2 0.4
9.3 2 0.7
9.0 2 2.2
7.1 2 0.4
9.8 2 1.2
6.8 2 0.3
4.5 2 1.1
5.2 2 1.3
7.1 2 1.4
7.0 2 2.9
4.0 2 0.8
3.2 2 1.9
1.4 2 0.2
2.4? ...
3.6 2 1.0
2.0 2 0.4
2.2 2 0.8
3.0 2 . . .
0.6 2 0.2
4.3, 3.9
4.5, 7.8
4.3, 7.3, 7.1, 5.6
7.9, 8.7
9.8, 7.2
4.5, 5.2
8.6, 10.0
6.9, 11.2
6.5, 7.9, 7.0
8.1, 9.0, 12.2
6.6, 7.3, 6.4
6.6, 4.2, 2.7
7.6, 4.9, 3.1
8.5, 5.8
8.8, 1.2, 10.9
3.2, 4.8
1.3, 5.1
1.6, 1.2
2.6, 4.5
1.6, 2.5
3.1, 1.4
3 .O
0.8, 0.5
Individual Values
(Compared to
p s 0.01
=The significance of these data was calculated with respect to control values using Student’s r test.
bDay 0 values were taken 90 minutes after injury.
NS = not significant (p > 0.05).
Powell et al: Endoneurial Fluid Pressure in Wallerian Degeneration
phosphate-buffered glutaraldehyde and processed for
electron microscopy when properly fixed.
Endoneurial fluid pressures were determined in 54
rats with crush injury. Within 90 minutes of the
nerve crush, increased EFP was recorded which was
significant at thep s 0.01 level (see the Table). Successively higher pressures were recorded during the
first week and declining pressures were recorded
thereafter, with values returning to normal ( p >
0.05) during the third week after injury. No
significant difference in EFP was recorded between
sham-operated rats and unoperated littermate controls. The mean pressure recorded in control animals
was 2.0 & 1.0 cm HzO. The highest recorded pressures in test animals were four to five times greater
than control values.
Various statistical methods were applied to analyze
the data. Using Student's unpaired, one-tailed I distribution, controls were compared to experimental
animals; the results are recorded in the Table. Linear
regression analysis was used to obtain a correlation
coefficient ( r = 0.72) which showed the progressive
increase in EFP to be statistically significant, with a
peak occurring between the fifth and seventh day.
Using this method, the significance of the progressive
decline in EFP was also confirmed. In order to ascertain the time at which EFP was maximum and to fit
the data to the best smooth curve for modeling purposes, we used the Marquardt computer algorithm
for least-squares estimation of nonlinear variables
[ll]. The equation was constrained to the inverse
of the hyperbolic cosine (an exponential function),
which takes the form:
cash [tl
exp [tl
+ exp [-tl
where exp refers to the base of the natural logarithm
and time (t) is measured in days. The following result,
in cm HzO,
was obtained:
552 Annals of Neurology Vol 5 No 6 June 1979
F i g 1. Progressive changes in endoneurialPuid pressure (EFP)
following proximal crush i n j u v to rat sciatic newe. EFP was
recorded in 54 experimental animals and the mean ualue plotted
as a solid circle for all animals recorded that day (see the
Table for individual measurements).To produce the continuous
solid cuwe, each mean ualue was weighted by the number of
animals contributing to it, and these data were analyzed by
computer using the Marquardt algorithm to determine the
coefjicients of the modeling equation (see text for details).
1.2 exp [0.075 ( t - 2)] + 0.9 exp [ - 0.5 (t - 2)1
and is plotted as the solid line in Figure 1. By this
procedure the peak value for EFP in this experiment
would be expected to occur at about seven days.
Microscopy confirmed the presence of edema in
affected nerves, characterized by wide separation of
myelinated fibers, as well as pericapillary and subperineurial fluid accumulation (Figs 2, 3). Changes in
myelinated fibers included axon swelling in the early
stages; subsequent degeneration was associated with
collapse of the myelin sheath and accumulation of
osmiophilic debris, giving rise to myelin ovoids.
Edema was observed at three days and was well established at four days (Fig 3A). Edema was also evident in sections taken at six (Fig 3B), eight, twelve,
and sixteen days. At sixteen days regenerating axon
sprouts were numerous (Fig 3C), and by twenty days
edema had subsided considerably (Fig 3D).
Waller described a sequence of degenerative events
in the distal segments of nerves in which the axons
were interrupted by transection of the nerve trunk
[26]. The same histological changes occur in nerve
fibers when the nerve is crushed with sufficient severity to interrupt the axons, although the endoneurial sheath of the Schwann cell basal lamina, which
encompasses the nerve fiber, remains intact. The
perineurium remains intact after crushing, though it is
permeable to albumin at the injury site [13, 181.
Mechanical injwy to capillaries at that site as well
as degranulation of mast cells, liberating biogenic
Fig 2. Transverse section of sciatic newe from a control rat.
( x 1,200 before 5 % reduction.)
amines, further contributes to the alteration of permeability [2, 191. In this study we chose to crush
rather than transect nerves so that the epineurium
and perineurium would be preserved. The injury was
made as close to the origin of the nerve as possible in
order to reduce the influence of purely local permeability changes. T h e micropipette was inserted at a
point approximately 2 cm distal to the injury. The
prompt increase in EFP measured after 90 minutes
could be due to proximal-distal movement of
albumin-rich fluid arising at the site of injury. However, the continued rise in EFP over the next several
days (confirmed by linear regression analysis) indicated that other factors contribute to increased EFP.
In the course of wallerian degeneration, changes
occur in the axon, the Schwann cell and myelin
sheath, the endoneurial interstitium, and the vasa
nervorum. These changes include axoplasmic swelling, Schwann cell proliferation, mast cell degranulation and proliferation, and neovascularization with
early and late permeability changes.
As well as being selectively permeable to blood,
the perineurium, in conjunction with the epineurium, provides a semirigid sheath that tends to limit
expansion of endoneurial contents. Thus far, pathological conditions resulting in increased EFP have
been related to endoneurial edema, but it is also
conceivable that increases in cytoplasmic volume associated with axoplasmic swelling or Schwann cell
proliferation could lead to increases in EFP. The
marked increases in axoplasmic volume that occur
after axon transection may contribute to some extent
to increased EFP. These changes, however, are
localized and transient, being most severe at the
proximal and distal nerve stumps and subsiding after
48 hours [ l , 151. A more important contribution to
the increased EFP may be due to Schwann cells surrounding transected axons which start proliferating
after axonal injury. A two- to three-fold increase in
Schwann cell population can occur after a single
crush injury [25]. Schwann cells undergo increases in
volume and heightened metabolic activity [4].Proliferation of endoneurial cells has been documented
between the third and twelfth day with the highest
specific growth rate occurring on the fifth day after
injury [23], as was determined by studies of the nucleic acid/polyamine ratio.
Major physical and chemical alterations affect the
myelin sheath in the distal segment of crushed or
transected nerves. T h e first demonstrable change is an
increase in prominence of the Schmidt-Lanterman
(SL) incisures [27]. In vivo microscopy of freshly
crushed nerve shows widening of the SL incisures
within two minutes of crushing [30]. Widening of the
nodal gap and paranodal retraction of myelin are
early changes. Viewed by microscopy with polarized
light, physical changes in the myelin sheath have
been identified within three hours of injury and continue until degeneration is complete by fifteen to
sixteen days [24]. These findings show the best temporal correlation with our data (see the Table). Electron microscopy has shown the myelin sheaths to
loosen during the first day after transection [6], and it
appears that myelin lamellae become physically separated by accumulating edema fluid. Intramyelinic
edema becomes more pronounced as interstitial
edema subsides [171.
Other changes likely to affect EFP occur in the
endoneurial interstitiurn and vasa nervorum. Biochemical studies of water content of peripheral nerve
undergoing wallerian degeneration reveal a steady
Powell et al: Endoneurial Fluid Pressure in Wallerian Degeneration
increase in wet weight in the days following transection [ 5 , 9, lo]. The wet weight increases rapidly
during the first eight days [lo], then levels off and
slowly declines later. The increase in water content is
associated with a significant reduction in lipids [9].
The possible cause of edema has been subject to differing interpretations. Weiss [28, 291, whose studies
with colored and radioactive fluids established the
proximal-distal convection of endoneurial fluid, also
noticed increased endoneurial fluid following nerve
crush. Olsson [18] studied the distribution of circulating fluorescent serum albumin in crushed rat
nerve and established that increased permeability to
serum proteins occurs in the vasa nervorum following crush injury and that this leads to accumulation
Annals of Neurology
Vol 5
No 6 June 1979
F i g 3 . (At Tramsiierse serfion ofa nert'efascicle from rat .sciatic
tierilefour days after crush. Degenerafing nerve fibers are
separated by endoneurial edema. EndoneurialJuid pressure =
7.9 cm H,O. (B)Rat sciatic tierise six days after c-rush. Note
u?de separation of tieme fibers by endoneurial edema and
marked su bperineu rial fluid accumulation. E ndntteurial j u i d
pressure = 5.2 c m H,O. ( C ) Rat sciatic netlie sixteen days
after crush. This stage is charactrrized by diminished edema
and regenerating neriie fibers. Etido,ieuriaIpuid pressure =
3.2 cm H,O. (Dt Rat sciatic nenle ru,enty days after crush.
Edema has subsided considerably. EndnneurialfEuid pressure =
2.4 cm H .O. (All x 1,200 befare 5 F reduction.)
of a protein-rich exudate in the endoneurial interstitium.
When a nerve is crushed, there are both early and
late permeability changes. Upon injury, fluid at the
injury site seeps from both damaged vessels and the
injured perineurium. When fl uoresceinated albumin
was used as a tracer, intense accumulation occurred
in the crush area ten minutes after injury and spread
to the distal endoneurial space during the next 24
hours, where it was present mainly in the extracellular space between nerve fibers. Some fluorescence
was observed in the cytoplasm of cells in the endoneurial interstitium. Four days after nerve crushing
the intensity of the diffuse extravascular fluorescence
had diminished, and many more endoneurial macro-
phages with fluorescent material were present. Abnormal permeability of the vessels continues for
months, however [ 121. T h e continuing permeability
alteration is d u e in part to formation of new blood
vessels at the site of injury and along the distal segment 128, 291, since newly formed vessels are generally more permeable than mature ones. In contrast to
the increased permeability of vessels in the distal
segment o f crushed nerve, the perineurium retains its
normal permeability characteristics after crush in jury
1201. W e must also consider the role of the mast cells
in altering permeability and causing endoneurial
edema. Mas[ cells degranulate at the injury site,
liberating biogenic amines such as histamine and
serotonin which can cause permeability changes [ 191.
Powell et al: Endoneurial Fluid Pressure in Wallerian Degeneration
A five-fold increase in the quantity of mast cells occurs in the distal segment of transected nerves [21,
accompanied by elevated serotonin levels [ 191.
Although endoneurial edema appears to continue
for months after injury [ 12,181, the EFP recorded in this
experiment returned to normal after seventeen days,
as confirmed by the correlation coefficients obtained
from linear regression analysis and Marquardt leastsquares fitting of the modeling equation. The modeling equation was restricted to a simple exponential
function with a single peak since our hypothesis and
linear regression analysis suggested that this family of
curves best fit the data. O u r observation that EFP was
elevated during the first sixteen days after crush (see
the Table) accords with measurements of transverse
fascicular area previously published by Nichols and
associates [ 161, who documented increases in fascicular area during the first fifteen days after acute
crush injury.
Two aspects of our study require clarification.
First, although there was a sharp upward trend in EFP
during the first seven days, lower than expected values were recorded on day 6. Because of this, we
measured EFP in an additional pair of rats with sixday lesions but found no significant difference in
pressure. It is noteworthy that Nichols et a1 [161, in
their study of fascicular area following nerve crush,
recorded a much smaller degree of enlargement at
day 6 than at earlier and later stages in their experiment. The possibility exists that a biphasic or multiphasic pattern of increase in EFP follows crush
injury. T h e second point concerns the correlation between edema, as seen in histological sections, and
EFP. Although we never observed increased EFP in
the absence of edema, we did notice edema at sixteen
days (see Fig 5 ) . when the pressure was only twice
that of controls. As previously discussed, there are
other variables in wallerian degeneration, such as the
numerical increase in endoneurial cells [23], changes
in fiber diameter and distribution [16], and chemical
alterations [9]. These factors may act independently
or in concert to either augment or diminish the role
of edema in determining EFP. The most profound
EFP changes appear to be associated with the period
of physical alteration, such as disruption and swelling
of the myelin sheath, rather than with the subsequent
period of chemical digestion of myelin debris.
We believe that an understanding of the hydrostatic changes in nerve during wallerian degeneration
may provide insights into the origin of other
neuropathies in which the injury is not mechanical.
Furthermore, the recognition and quantitation of increased EFP is of potential importance for the treatment of human neuropathies, since increased pressure in the endoneurial space can be harmful to nerve
fibers [7, 221, and fluid accumulation may be treat556 Annals of Neurology
Vol 5
No 6 J u n e 1979
able by methods similar to those used to control elevated intracranial pressure caused by edema.
Supported in part by Grants NS 14162 and NS 09053, the Medical Research Service of the Veterans Administration, and by funds
from the Academic Senate of the University of California, San
We thank Dr Harvey Shapiro for helpful discussion and advice,
Miss Margarida Teixeira for technical assistance, Dr Benjamin
Zweifach for making his laboratory facilities available to us, and
Ms Nancy Zamfirescu for performing the computer studies.
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