Endoneurial Fluid Dynamics

The Peripheral Neuropathy Solution

Dr. Labrum Peripheral Neuropathy Program

Get Instant Access

4.1. Continuity Between CSF and Endoneurial Fluid

4.2. Proximodistal Gradient

The extracellular space within a nerve fascicle is about 20-25% of the total intrafascicular volume. The endoneurial hydrostatic pressure (EHP) exerted by this fluid is about 2-3 mmHg. In terms of fluid dynamics, the endoneurial contents consist of a noncom-pressible aqueous solution, and a somewhat compressible cellular content constrained by an elastic sheath, the perineurium. Hence, the EHP will be determined by the volume of the endoneurial contents and the compliance of the perineurial sheath. Fluid enters and leaves a given segment of the endoneurial space across the walls of the endoneurial microvessels, and by convective proximodistal EFF. Given the slight positive tissue hydrostatic pressure of the endoneurial space, fluid does not normally enter this space across the perineurium. Thus, endoneurial extracellular fluid exchanges material with blood directly across the endoneur-ial vascular endothelium, indirectly across the multilayered perineurium, and is turned over by convective EFF.

The meninges of the CNS are continuous with sheaths of peripheral nerve (4). The epineurial connective tissue layers are continuous with the dura mater at the subarachnoid angle (Fig. 1), while the relationship between the other meninges (pia mater and arachnoid layer) and perineurium is more complex. At the root attachment zone (Fig. 1), there appears to be continuity of the subarachnoid and endoneurial spaces and thus continuity between CSF and endoneurial fluid, providing a conduit through which material passes from CSF to the endoneurial fluid (55). The embryological aspects of this continuity do not appear to have been investigated.

In addition to the blood-nerve exchange discussed above, another putative source of input to and output from the endoneurium is convective EFF. In an elegant series of experiments, the presence of a proximodistal flow of fluid was demonstrated in rat and guinea pig sciatic nerve (56). As indices of fluid movement, endoneurial injections of dyes, crystals, and radioactive mineral salts were used, with conclusions based on comparisons of proximodistal spread of the indicators in dead and living tissue. The two major limitations of this study are (1) the use of injection volumes no smaller than 100 mL and (2) the use of small hydro-philic tracers that could have migrated down the nerve by entering the vascular compartment and later reentering the endoneurial space. Therefore, they were unable to calculate a precise rate of convective fluid flow from their data but suggested an approximate rate of 3 mm per hour, similar to results by others studying traumatized chicken sciatic nerves (57). Low (58), injecting 10 ml of tetrodotoxin into the endoneurium and monitoring the rate and spread of inactivation, concluded that convective fluid flow is about 4-8 mm per hour. Morphological studies demonstrating continuity between the spinal subarachnoid space and the endoneurial space at the root attachment zone suggest (4, 59) that CSF contributes to endoneurial fluid. Earlier, it was suggested that the diphtheric toxin enters the CNS through peripheral nerves (60), probably exploiting the continuity between subarachnoid and endoneurial space.

Experiments with radiotracers have clearly demonstrated a proximodistal convective flow of endoneurial fluid (Fig. 2). Here, the pattern of 22Na distribution along the length of the nerve at the three different survival times clearly demonstrates a progressive asymmetrical proximodistal movement of the isotope.

4.3. Driving Force There does not appear to have been any mechanistic studies of Proximodistal addressing the driving force of proximodistal fluid flow. The

Fluid Flow descriptive studies on EHP (61) are consistent with the CSF pres sure in the spinal cord being the pressure head for the proxim-odistal flow of endoneurial fluid. The hydrostatic pressure in the cord is about 10 mmHg, in the dorsal root ganglia it is about 3-5 mmHg, and in the peripheral nerves it is about 2-3 mmHg (62). The presence of this pressure gradient from the interstitial spaces of the spinal cord to the endoneurial interstitium of peripheral nerves supports the contention that the CSF pressure is the main propulsive force of the endoneurial fluid. Unfortunately, this postulate is not without theoretical limitations. For example, what would be the fate of this CSF pressure driven endoneurial fluid when it reaches the distal ends of sensory nerves that do not have open perineurial sleeves is not clear (63). One possibility is that the perineurium in such nerves is more permeable distally than proximally to allow for a transperineurial dissipation of endoneurial fluid. Alternatively, one has to postulate a slower turnover of endoneurial fluid at the distal end of a sensory nerve, which would account for the greater vulnerability of sensory nerves to pyridoxine toxicity.

Distance along nerve (mm)

Fig. 2. The rate of endoneurial convective fluid flow of 22Na as a function of time is shown. In all three experiments, 70 nL of saline with 22Na were microinjected into a rat sciatic nerve. The nerves were harvested either 1, 2 or 4 h later, cut into 3 mm segments, counted for 22Na activity, dried and weighed. Negative numbers indicate distances proximal to the site of injection and positive numbers represent distances distal to the site of injection. The data in this figure are consistent with a convective flow of endoneurial fluid. The shift of the curve to the right (proximal to distal) from the first to the second hour is clear-cut, while that from the second to the fourth hour is somewhat more subtle, but nevertheless evident upon closer inspection of the two curves. While both curves seem to peak at the 5 mm, the 2-h curve has a bigger shoulder at lengths less than 5 mm, and the 4-h curve has a shoulder at lengths greater than 5 mm (Weerasuriya, unpublished data).

Distance along nerve (mm)

Fig. 2. The rate of endoneurial convective fluid flow of 22Na as a function of time is shown. In all three experiments, 70 nL of saline with 22Na were microinjected into a rat sciatic nerve. The nerves were harvested either 1, 2 or 4 h later, cut into 3 mm segments, counted for 22Na activity, dried and weighed. Negative numbers indicate distances proximal to the site of injection and positive numbers represent distances distal to the site of injection. The data in this figure are consistent with a convective flow of endoneurial fluid. The shift of the curve to the right (proximal to distal) from the first to the second hour is clear-cut, while that from the second to the fourth hour is somewhat more subtle, but nevertheless evident upon closer inspection of the two curves. While both curves seem to peak at the 5 mm, the 2-h curve has a bigger shoulder at lengths less than 5 mm, and the 4-h curve has a shoulder at lengths greater than 5 mm (Weerasuriya, unpublished data).

4.4. Endoneurial Fluid The albumin content of desheathed human sural nerve was reported Turnover to be 8.7 mg/mg of dry weight (64). If it is assumed that endoneur ial wet/dry weight ratio is 3.0, endoneurial albumin is extracellular and free, and endoneurial extracellular space is about 25%, then the above value can be converted to an albumin concentration of 11.6 mg/mL in the endoneurial fluid. Plasma albumin concentration is 33.1 mg/mL (64). From these two concentration terms and the PS to albumin (65), the calculated rate of blood-nerve albumin transfer is about 1.2 mg.g-1.day-1. At this rate of transfer, and assuming relatively constant albumin concentrations in endoneurium and plasma, about 30% of the endoneurial albumin is turned over each day. By comparison, CSF and its constituents are turned over about four times each day (66).

The rate of removal of albumin from the endoneurium is also about 1.2 mg.g-1.day-1. In nonneural tissues, lymphatic drainage plays a role in clearing interstitial albumin, and, in the CNS, CSF, and perivascular drainage are the sinks for extracellular albumin (27). In peripheral nerve, in the absence of both lymphatics and an active CSF circulation, the route of removal for albumin and other macromolecules remains to be identified. The metabolic breakdown of albumin to supply amino acids to axons and glia is one possibility; another is the long suspected proximodistal convective flow of endoneurial fluid.

4.5. Endoneurial Protein Concentration

From the equation proposed by Landis and Pappenheimer (67), endoneurial albumin can be expected to exert an interstitial oncotic pressure of about 3 mmHg. The recorded EHP of 2-3 mmHg will oppose the endoneurial oncotic pressure and thus minimize net fluid filtration from the endoneurial vasculature. However, this balance of forces can be disturbed if the capillary permeability to albumin increases slightly allowing the endoneurial albumin concentration to rise and thus draw in more fluid from the vascular compartment into the endoneurial inter-stitium. The resulting endoneurial edema together with the low compliance and hydraulic conductivity of the perineurium will elevate EHP. The net fluid gain by the endoneurial space will cease when a new equilibrium is established among the hydrostatic and oncotic pressures of the endoneurial and intravascular compartments. It is quite likely that this is the mechanism for edema formation observed in experimental diabetic and lead neuropathy, as well as in early Wallerian degeneration. On the other hand, the edema present in galactose-induced neuropathy is likely to be due to the presence of an excess of nonvascularly derived osmolytes in the endoneurium, corroborated by the absence of change in the PS of BNB to mannitol in galactose-intoxicated rats (68).

4.6. Perineurial Compliance Decreases with Age

The developmental increase of EHP has two plateaus (69). The first one is from about 3 to 13 weeks of age, and the second one is from 6 months onward. Elevations of EHP can be produced either by increased EFF or by reduced perineurial compliance. These observations (69) demonstrated that reduced perineurial compliance with aging contributes to the second increase in EHP.

4.7. Implications for Entrapment Neuropathies

Extrafascicular mechanical compression and the resultant ischemia certainly contribute to the symptomatology of entrapment neuropathies. But, it is quite likely that there are other factors more closely tied to the endoneurial microenvironment that affect the susceptibility and evolution of the nerve injury. For example, it is hypothesized that the initial event in the evolution of an entrapment neuropathy is the limitation and reduction of EFF due to externally applied mechanical forces. Secondly, elevation of EHP due to obstruction of EFF and continued application of these external forces leads to endoneurial ischemia and its attendant pathology. Additionally, the reduced compliance of the aged nerve (69) makes it more susceptible to externally applied mechanical pressures causing an elevation of EHP. This hypothesis is consistent with the paucity of carpal tunnel syndrome (CTS) in arcade game-playing teenagers, higher incidence of CTS in conditions with increased tissue water content or edema, such as pregnancy and diabetes, and the presence of symptoms quite proximal to the site of entrapment. However, this hypothesis does not explain the higher incidence of CTS in females or the varying patterns of recovery seen after resection of the flexor retinaculum.

Was this article helpful?

0 0
Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

This guide will help millions of people understand this condition so that they can take control of their lives and make informed decisions. The ebook covers information on a vast number of different types of neuropathy. In addition, it will be a useful resource for their families, caregivers, and health care providers.

Get My Free Ebook


Post a comment