nerve compressioninjury and endoneurial fluid miniature ...lundborg, myers, powell impairment of the...

Journal of Neurology, Neurosurgery, and Psychiatry 1983;46:1119-1124

Nerve compression injury and increased endoneurialfluid pressure: a "miniature compartment syndrome"GORAN LUNDBORG, ROBERT MYERS, HENRY POWELL

From the Division for Hand Surgery, Department of Orthopedics, University of Lund, Departments ofOrthopedics and Rehabilitation and ofNeurosciences, Anesthesiology and Pathology (Neuropathology),University of California, San Diego, School ofMedicine, La Jolla, CA., and the Veterans AdministrationMedical Center, San Diego, CA, USA

SUMMARY An inflatable miniature cuff was used to apply local compression of 80 mm Hg or30 mm Hg to a segment of rat sciatic nerve for time periods varying from two to eight hours. Theendoneurial fluid pressure was measured by direct micropipette measurement techniques at oneor 24 hours after removal of the cuff, and the nerves were subjected to histological analysis.Endoneurial oedema, associated with a four-fold increase in endoneurial fluid pressure, wasobserved after compression at 80 mm Hg for four hours, and a three-fold increase was foundafter compression at 30 or 80 mm Hg for eight hours. Such an increase in endoneurial fluidpressure may interfere with intrafascicular capillary flow, and thereby constitute an importantpathophysiological mechanism in nerve compression injuries.

The pathophysiological mechanisms of acute andchronic nerve compression injuries are not com-pletely understood, although considerable know-ledge has accumulated during recent years. In acutecompression lesions, for example tourniquet palsyand other conditions where pressure of high mag-nitude has been directly applied to a nerve trunk,the resulting disturbances in nerve function arebased mainly upon local myelin changes under theedge of the cuff. The redistribution of tissue fromcompressed to non-compressed levels of the nerve isassociated with invagination of the myelin sheaths atthe nodes of Ranvier.' 2 The resulting myelin dam-age is associated with partial or complete local con-duction block, usually reversible within weeks ormonths. Also a possible microvascular factor hasbeen considered as irrelevant by Williams et al3 andwe have demonstrated the occurrence of endo-neurial oedema in the transitional zones of a nervesegment, subjected to higher pressure.4 Duringcertain circumstances this oedema maybe associated with a no-reflow phenomenon in theaffected nerve segment.5

Address for reprint requests: Goran Lundborg, MD. Div for HandSurgery, Lunds University Hospital, S-221 85 Lund, Sweden.

Received 1 February 1983 and in revised form 7 May 1983.Accepted 28 June 1983.

Chronic nerve compressions may be more compli-cated in their general pathophysiology, since thelocal anatomy at different common entrapmentlevels of the extremities may vary with respect tosize and shape of extraneural tissue compartments,muscles and fascia edges, as well as the force appliedto the nerve (stretch-bending-compression). It hasalso been suggested that in these cases the symptomspresented are based exclusively on local myelinchanges in the affected nerve segment.6 However, itis a common clinical experience, that even chronicentrapments with longstanding muscle weaknessand sensory disturbances sometimes show a veryrapid reversibility of some or all of the symptomsafter surgical decompression of the nerve. Thesefindings suggest the existence of a local metabolicblock in the compressed segment of the nerve. Therapid reversibility indicates that such a disturbancemay be based upon temporary microvascular disor-der in the compressed part of the nerve in additionto local myelin changes.79

In recent investigations we have studied theeffects of compression on intraneural microvascularflow.5 The present study was concerned with themicrovascular factors in experimental nerve com-pression injuries, this time with special reference tothe occurrence of an intrafascicular oedema with cor-responding increase in endoneurial fluid pressure atthe site of injury. The study was- made possible by

1119

Protected by copyright.

on May 25, 2021 by guest.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.46.12.1119 on 1 Decem

ber 1983. Dow

nloaded from

http://jnnp.bmj.com/

1120

the use of micropipette techniques for direct meas-urements of the endoneurial fluid pressure.'"Material and methods

Adult Sprague-Dawley rats weighing 250-300 grams wereanaesthetised by intraperitoneal injection of a solutioncomposed of Nembutal (50 mg/ml), saline and diazepam(5 mg/ml) in volume proportions of 1:1:2.

Compression procedureThe sciatic nerve of the left midthigh was exposed by alateral incision. The nerve was compressed by a specialcompression chamber constituting a smaller modificationof the chamber described in detail by Rydevik and Lund-borg.4 This compression device consists of two symmetricalhalves of plexi-glass into which thin rubber membranes areglued. The two halves were placed around the nerve trunkand joined by four small screws. The chamber was con-nected to a servo pressure system (AB Stille-Werner,Stockholm) allowing inflation of the rubber cuffs in thechamber to a desired pressure. The system automaticallycompensated for any leakage of air, thus maintaining thepressure of the system at a constant level. The length of thecompressed nerve segment was approximately 3 mm.After the compression chamber was secure, the skin wassutured, thereby allowing only the connecting tubes topenetrate the skin into the wound.

Animal experimentsIn one series of animals (n = 4), a pressure of 30 mm Hgwas applied to the nerves for 2, 4, 6 and 8 hours. Inanother series (n = 4), a pressure of 80 mm Hg wasapplied for the same time periods. In four animals, shamexperiments were performed so that only the chamber wasapplied around the nerve for 2, 4, 6 and 8 hours withoutbeing inflated. The pressure levels of 30 and 80 mm Hgwere chosen because it is known from previous experi-ments- that these pressures will interfere with intraneuralvenular flow (30 mm Hg) or cause a circulatory arrest inthe nerve (80 mm Hg).

After the compression periods, the skin was opened andthe compression device removed. One hour or 24 hourslater a direct measurement of the endoneurial fluid pres-sure was performed as described below. The animal wasthen killed by an overdose of Nembutal, and the nerve wasremoved for histological analysis.

Measurement of endoneurial fluid pressureEndoneurial fluid pressure was measured directly with aservo-null micropipette system by inserting the tip of aglass micropipette (4 microns diameter) through theperineurial membrane into the endoneurium, a methodwhich has been described in detail elsewhere by Myers etal.'0 The measurements were made in the transitional zonebetween compressed and non-compressed parts of thenerve, under the edge of the cuff, since we know fromprevious experiments4 '° that the maximal structural andfunctional injury is induced in the nerve at this level. Foreach animal, three or more recordings were taken andaveraged together. The nerve was surrounded and irri-gated with a physiological salt solution which was

Lundborg, Myers, Powell

bicarbonate-buffered and temperature controlled. Allendoneurial fluid pressure measurements were referencedto atmospheric pressure by establishing a baseline pressurefrom the fluid bath surrounding the nerve.

Histological analysisAfter measurement of endoneurial fluid pressure, the scia-tic nerve was removed and processed for light microscopyby fixation in 2-5% phosphate-buffered glutaraldehyde,post-fixation in osmium tetroxide, dehydration in serialalcohols and embedded in araldite. One-micron-thick sec-tions were stained with paraphenylenediamine for lightmicroscopic analysis.

Results

Endoneurial fluid pressureThe results from the pressure measurements arepresented in fig 1.

80 mm HgAfter compression periods up to 4 hours there was acontinuous increase in endoneurial fluid pressure asrevealed by measurements one hour as well as 24hours after release of the compression. The maximalendoneurial fluid pressure was recorded 24 hoursafter compression for 4 hours when the endoneurialfluid pressure was 8-5 cm H2O, that is more thanfour times the normal pressure. Extending theperiod of compression more than 4 hours did notincrease the endoneurial fluid pressure; on the con-Vary, there was a tendency to decrease endoneurialfluid pressure with longer periods of compression.Following 8 hours compression, endoneurial fluidpressure was 5*8 cm H2O, at one-hour as well as 24hours after release of the compression cuff.

10-

I

E

c_ 6ILw

80mmHg- 30 mmHgO 1 h atteroperation* 24 h after operation

0--

a*..-...........

Normal EFP

..

2 4. 6Duration of compression ( hours)

8

Fig 1 Graphical results ofchanges in endoneurial fluidpressure associated with nerve compression at differentpressure levels for various periods of time. Normalendoneurial fluid pressure is 2-0 + 1 0 cm H,O; elevation ofendoneurial fluid pressure beyond normal levels is plotted.



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1983. Dow

nloaded from


Nerve compression injury and increased endoneurial fluid pressure

30 mm HgTwo hours of compression was not followed by adetectable increase in endoneurial fluid pressure,while longer periods of compression induced a con-tinuous increase in endoneurial fluid pressure lastingat least 24 hours. The maximal increase ofendoneurial fluid pressure was observed following 8hours compression. Endoneurial fluid pressure wasfound to be approximately 6-0 cm H2O, that isnearly the same as after compression at 80 mm Hgfor 8 hours.

Sham experimentsApplication of the chamber around the nerve for2-8 hours without inflating it did not result in anyincrease of endoneurial fluid pressure above normalvalues (2.0 + 1-0 cm H20).

HistologyNo histologic changes were observed in sham-operated rat nerves (fig 2). There was a strong corre-lation between the recorded endoneurial fluid pres-sure and the histological appearance of the corres-ponding nerve segment. Endoneurial oedema wasmost prominent in nerves compressed for 4 hours ata pressure of 80 mm Hg. The sections showedwidely separated nerve fibres with extensive oedemamost prominent in the subperineurial space (fig 3).This was observed in nerves subjected to a pressure

*.;;:._..

*.0 ZF<i0i. 9

Fig 2 Light micrograph ofmajor fascicle from sciaticnerve ofSprague-Dawley rat after sham experiment inwhich the pressure cuff was placed around the nerve but notinflated. Fascicle appears normal with tightly packed axonsin close association with perineurium. (x 500)

Fig 3 Light micrograph ofmajor fascicle from sciaticnerve of rat which was compressed at a pressure of80 mmHg for 4 hours. Note extensive oedema in sub-perineurialand perivascular spaces. Oedema also separates nerve

fibres. (x 500)

Fig 4 Higher power light micrograph of degeneratingnerve fibres 24 hours after compression at 80 mm Hg for 4

hours. Note extensive endoneuial oedema. (x 1000)

of 80 mm Hg for 2 and 6 hours, while the oedemawas less advanced following 8 hours compression.Severe nerve damage was observed in some nerves(fig 4). The nerves compressed at 30 mm Hg

1121



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1983. Dow

nloaded from


1122

showed moderate oedema only after 8 hours com-pression while shorter compression periods did notinduce any visible oedema.

Discussion

The peripheral nerve trunk is a well vascularised andcomposite structure with numerous tissue compo-nents, each of which could suffer individually from acompression lesion. The nerve fibres and theintraneural microvessels should be considered sepa-rately in this respect. As in other tissues of the body,trauma may alter vascular permeability, andendoneurial oedema may occur.4 "'-,s In theepineurium, the vessels are comparatively vulner-able to compression trauma, and respond with per-meability changes. The endoneurial vessels, how-ever, are more resistant to change. Due to theblood-nerve-barrier located in the endothelium ofthese vessels'6 17 and the protective function of theperineurium,'8 19 oedema is not induced as easilyintrafascicularly as extrafascicularly.

However, certain neurological disorders areknown to be associated with an endoneurial oedemaand an increase in the endoneurial fluid pressure.20Normally, the pressure inside fascicles is2-0 cm H20 as revealed in experimental animals bydirect measurement techniques'0 or techniquesinvolving implantation of small polyethylene matrixcapsules intrafascicularly.2' An increase in this pres-sure has been observed in association with toxicinjuries (hexachlorophene and lead neuropathy),metabolic disorders (galactosaemia andstreptozotocin-induced diabetes), nerve trauma(crush with associated Wallerian degeneration) andcryogenic lesions.'5 20 Endoneurial oedema may notbe drained easily since the endoneurial space lackslymphatic channels, and the selective diffusion bar-rier, formed by the perineurium, makes it impossibleto drain the oedema through the perineurialmembrane.From animal experiments and clinical experience

it is clear that even moderately increased pressuremay significantly affect a peripheral nerve. Theimpulse transmission is dependent on a local energysupply as well as preserved functional and structuralintegrity of the axoplasma membrane. Thus, itwould seem that any disturbance of the intraneuralmicrocirculation or the axoplasmic flow would havesecondary effects on the impulse transmission. Thedata available on "critical pressure levels" in thiscontext are important for our understanding of thepathophysiology of compression neuropathies. Inanimal experiments it has already been demon-strated that a pressure of 30 mm Hg will cause


impairment of the intraneural venular flow.5 Thesame magnitude of local pressure blocks the fastaxoplasmic flow, as observed in the vagus nerve ofrabbits.22 Clinically, measurements have been per-formed on the extraneurial tissue pressure in thecarpal tunnel in patients with carpal tunnel syn-drome.23 The mean pressure was found to be32 mm Hg. Also, in experiments where externalpressure was applied to the carpal tunnel of volun-teers, the first neurophysiological and clinical signsof nerve dysfunction, including paraesthesia of thehand, occurred at a tissue pressure of 30 mm Hg inthe carpal canal.24 The same pressure level, experi-mentally induced to create compartment syndromesin dogs, was found to induce the first signs of nervedysfunction.25

In the present study a pressure of 30 mm Hg,applied for eight hours, was followed by a three-foldincrease in endoneurial fluid pressure. This increasein endoneurial fluid pressure has to be consideredwhen discussing the pathophysiology of nerveentrapment, for example, the carpal tunnel syn-drome. The early phase of this condition is charac-terised by intermittent paraesthesiae of the hand,most prominent during night time and often com-pletely reversible during day time. The horizontalposition of the body in combination with muscleinactivity during sleep may normally result in anincrease of tissue pressure in the carpal canal. Thecarpal tunnel patient has a poor tolerance for anyincrease in carpal tunnel pressure. When such apatient wakes up early in the morning, the paraes-thesiae may well be based upon an impaired mic-rocirculation in the median nerve in combinationwith an increase in endoneurial fluid pressure. Reliefof the symptoms may parallel restoration of normalintraneurial microvascular flow, disappearance ofthe endoneurial oedema and normalisation ofendoneurial fluid pressure.The maximal increase in endoneurial fluid pressure

in our series of experiments was seen followingcompression at 80 mm Hg for 4 hours. This mag-nitude of pressure is known to induce completeischaemia in the nerve,5 and the subsequentendoneurial oedema might be considered a result ofincreased vascular permeability based upon directinjury to the capillary walls. The diffusion barrier ofthe perineurium is known to be comparatively resis-tant to ischaemia.26 Thus, the oedema cannot bedrained through the perineurial membrane but isaccumulated inside the fascicles; a "compartmentsyndrome in miniature" is constituted. An unex-pected finding was a decrease in endoneurial fluidpressure when the compression was applied for timeperiods exceeding 4 hours. This may be due to ananoxic injury to the perineurium which increases



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1983. Dow

nloaded from


Nerve compression injury and increased endoneurial fluid pressure

with duration of ischaemia, resulting in deteriora-tion of barrier function. One should also considerthe possibility of a no-reflow phenomenon in thecompressed nerve segment as described by Rydeviket al,5 probably based upon severe vascular injury atthe edges of the compressed nerve.

Endoneurial oedema may affect nerve function invarious ways. A sustained increase in endoneurialfluid pressure may injure nerve fibres.2' 27 A changein the electrolyte composition of the endoneurialfluid in association with oedema may impair nervefunction.28 29 Another important factor is possibleinterference with capillary flow induced by increasedtissue pressure. Such a reduction in nerve blood flowin association with increased endoneurial fluid pres-sure has recently been demonstrated by Myers etal.30 In these experiments, isotope-tracer techniqueswere used to measure the blood flow in the sciaticnerve of rats suffering from experimental hexach-lorophene neuropathy. It was demonstrated thatincrease of endoneurial fluid pressure from controlvalues around 20 + 1-0 cm H20 to over ap-proximately 6-0 cm H20 was associated with asignificant reduction in nerve blood flow to about50% of control values. Such a reduction of intrafas-cicular blood flow may be explained by the specialmicrovascular architecture of peripheral nerves. Inanimal-as well as in human-nerves, anastomosingvessels between the epineurium and endoneuriumpass obliquely through openings in the perineurialmembrane,'2 4, thereby constituting a "valvemechanism." An increase in endoneurial fluid pres-sure may occlude these openings in the perineurium.

It is apparent that the pathophysiology of nervecompression lesions should not be over-simplifiedand expressed only in terms of mechanical injurywith structural changes of myelin and axons. On thecontrary, there are reasons to believe that there areimportant haemodynamic factors involved, and thata local disturbance in the nerve may be based uponmicrovascular dysfunction and endoneurial oedemawith an increase in endoneurial fluid pressure. It isa common surgical experience that rapid decom-pression of an entrapped nerve sometimes may re-sult in an almost immediate relief of symptoms, anobservation which is consistent with neurophysiolog-ical measurements performed intraoperatively.3' 32This immediate relief is probably based upon a rapidimprovement of intraneural microvascular flow.Slower resolution of symptoms over days or weeksmay be related to gradual disappearance of endo-neurial oedema with corresponding reduction inendoneurial fluid pressure, while functional recov-ery over longer time intervals should be explained interms of local myelin repair within the compressedsegment and/or outgrowth of regenerating nerve

fibres.

Supported by grants from the Swedish MedicalResearch Council No. 5188, The Swedish WorkEnvironment Fund, The Swedish Society for Medi-cal Sciences, The Veterans Administration, TheAmerican Heart Association 82-650, NIH GrantNS 14162.

References

'Ochoa J, Fowler J, Gilliat RW. Anatomical changes inthe peripheral nerves compressed by a pneumatictourniquet. J Anat 1972;113:433-55.

2 Gilliat RW. Acute compression block. In: Sumner AJ,ed. The Physiology ofPeripheral Nerve Disease. Lon-don: Saunders Co, 1980:287-315.

Williams JR, Jefferson D, Gilliat RW. Acute nerve com-pression during limb ischemia. J Neurol Sci1980;46: 199-207.

Rydevik B, Lundborg G. Permeability of intraneuralmicrovessels and perineurium following acute, gradedexperimental nerve compression. Scand J Plast Recon-str Surg 1977;11:205-12.

Rydevik B, Lundborg G, Bagge U. Effects of gradedcompression on intraneural bloodflow. J Hand Surg1981 ;6:3-12.

6 Ochoa J. Histopathology of common mononeuropathies.In:Jewett DL, McCarroll Jr Hr eds. Nerve Repair andRegeneration: Its clinical and Experimental Basis. StLouis, Toronto, London: Mosby Co, 1980: 36-52.

Gilliat RW. Chronic nerve compression and entrapment.In: Sumner AJ, ed. The Physiology of PeripheralNerve Disease. London: WB Saunders Co, 1980:316-39.

8 Fullerton PM. The effect of ischaemia on nerve conduc-tion in the carpal tunnel syndrome. J NeurolNeurosurg Psychiatry 1963;26:385-97.

Sunderland S. The nerve lesion in the carpal tunnel syn-drome. J Neurol Neurosurg Psychiatry.1976;39:615-26.

10 Myers RR, Powell HC, Costello MC, Lampert PW,Zweifach BW. Endoneurial fluid pressure: directmeasurement with micropipettes. Brain Res 1978:148:510-5.

"Rydevik B, Nordborg C. Changes in nerve fibre struc-ture induced by acute, graded compression. J NeurolNeurosurg Psychiatry 1980;43:1070-82.

12 Lundborg G. Ischemic nerve injury. Experimentalstudies on intraneural microvascular pathophysiologyand nerve function in a limb subjected to temporarycirculatory arrest. Scand J Plast Surg 1970;Suppl 6:1-113.

3 Lundborg G. Structure and function of the intraneuralmicrovessels as related to trauma, edema formationand nerve function. J Bone Joint Surg1975;57A:938-48.

4 Lundborg G. The intrinsic vascularization of humanperipheral nerves - structural and functional aspects. JHand Surg 1979;4:35-41.

1123



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1983. Dow

nloaded from


1124

'5 Myers RR, Powell HC, Heckman HM, Costello ML,Katz J. Biophysical and pathological effects ofcryogenic nerve lesion. Ann Neurol 1981:10:478-85.

6 Olsson Y. Studies on vascular permeability in peripheralnerves. I. Distribution of circulating fluorescent serumalbumin in normal, crushed and sectioned peripheralnerve. Acta Neuropathol (Berlin) 1966;7: 1-15.

Olsson Y, Kristensson K, Klatzo I. Permeability of bloodvessels and connective tissue sheaths in the peripheralnervous system to endogenous proteins. ActaNeuropath (Berlin) 1971 ;Suppl 5:61-9.

18 Olsson Y, Kristensson K. The perineurium as a diffusionbarrier to protein tracers following trauma to nerves.Acta Neuropath (Berlin) 1973;23: 105-11.

'9 Rydevik B, Lundborg G. Nordborg C. Intraneural tissuereactions induced by internal neurolysis. Scand J PlastReconstr Surg 1976;10:3-8.

20 Myers RR, Powell HC. Endoneurial fluid pressure inperipheral neuropathies. In: Hargens A, ed. Tissuefluid pressure and composition. Baltimore; Williams &Wilkins Co, 1980:193-214.

21 Low RA, Dyck PJ. Increased endoneurial fluid pressurein experimental lead neuropathy. Nature 1977;269:427-8.

22 Dahlin LB, Danielsen N, McLean WG, Rydevik B,Sjostrand J. Critical pressure levels for impairment offast axoplasmic transport during experimental com-pression of rabbit vagus nerve. J Physiol (Lond)1982;325:84 P.

23 Gelberman R, Hergenroeder P, Hargens A, LundborgG, Akeson W. The carpal tunnel syndrome. A studyof carpal tunnel pressures. J Bone Joint Surg 1981;61-A:380-3.

24 Lundborg G, Gelberman R, Minteer-Convery M, LeeVF, Hargens A. Median nerve compression in the


carpal tunnel: the functional response to experimen-tally induced controlled pressure. J Hand Surg1982;7:252-59.

25 Hargens A, Romine J, Sipe J, Evans K, Mubarak S,Akeson W. Peripheral nerve conduction block by highmuscle compartment pressure. J Bone Joint Surg1979;61-A: 192-200.

26 Lundborg G, Nordborg C, Rydevik B, Olsson Y. Theeffect of ischemia on the permeability of theperineurium to protein tracers in rabbit tibial nerve.Acta Neurol Scand 1973;49:287-94.

27 Powell HC, Myers RR, Zweifach BW, Lampert PW.Endoneurial fluid pressure in hexachloropheneneuropathy. Acta Neuropathol (Berlin)1978;41:139-44.

28 Jacobsen J. Peripheral nerves in early experimental dia-betes: expansion of the endoneurial space as a causeof increased water content. Diabetologica 1978;14:113-9.

29 Myers RR, Heckman HM, Powell HC. Endoneurial fluidis hypertonic. Results of microanalysis and itssignificance in neuropathy. J Neuropathol Exp Neurol1983;42:217-24.

30 Myers RR, Mizisin AP, Powell HC, Lampert PW.Reduced nerve blood flow in hexachloropheneneuropathy. Relationship to elevated endoneurialfluid pressure. J Neuropathol Exp Neurol 1982;41:391-9.

31 Hongell A, Mattsson HS. Neurographic studies before,after and during operation for median nerve compres-sion in the carpal tunnel. Scand J Plast Reconstr Surg1971 ;5:103-9.

32 Eversman W, Ritsick J. Intraoperative changes in motornerve conduction latency in carpal tunnel syndrome. JHand Surg 1978;3:77-81.



http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1983. Dow

nloaded from


nerve compressioninjury and endoneurial fluid miniature ...lundborg, myers, powell impairment of the...

Documents