-
Journal of Neurology, Neurosurgery, and Psychiatry
1988;51:28-34
Quantitative objective assessment of peripheralnociceptive C
fibre functionN PARKHOUSE, PAMELA M LE QUESNE
From the Departments ofSurgical Studies and Neurological
Studies, The Middlesex Hospital Medical School,London andMRC
Toxicology Unit, Carshalton, Surrey, UK
SUMMARY A technique is described for the quantitative assessment
of peripheral nociceptive Cfibre function by measurement of the
axon reflex flare. Acetylcholine, introduced by electrophoresis,is
used to stimulate a ring of nociceptive C fibre endings at the
centre of which the increase in bloodflow is measured with a laser
Doppler flowmeter. This flare (neurogenic vasodilatation) has
beencompared with mechanically or chemically stimulated
non-neurogenic cutaneous vasodilation. Theflare is abolished by
local anaesthetic and is absent in denervated skin. The flare has
been measuredon the sole of the foot of 96 healthy subjects; its
size decreases with age in males, but not in females.
In recent years quantitative measurement of variousmodalities of
peripheral sensation has come to beincreasingly important in both
diagnosis and manage-ment of peripheral neuropathy.' 2 Although
sensitivemethods are available for measuring mechano-receptor and
thermal function, techniques suitable forclinical measurement of
nociceptor function are lesssatisfactory. In early classical work
on pain, Hardyet al3 used radiant heat as a stimulus amd
morerecently heat-pain threshold has been measured usingthe more
precisely controlled stimulus produced by aPeltier thermode.' A
device for measuring mechani-cally induced pain was produced by
Lynn and Perlsand used in the measurement of pain threshold
indiabetics by Le Quesne and Fowler.6 The value of allthese
techniques is limited by the particular problemsof subjective pain
assessment.
During a study of sweating in diabetics using thetechnique
developed by Low et al7 whereby axonreflex sweating was induced by
electrophoresis ofacetylcholine, Ahmed and Le Quesne8 noted that
incontrol and some diabetic subjects a spreading flaredeveloped,
whereas in others the flare was absent.Lewis9 demonstrated that the
spreading vaso-dilatation of the triple response was an axon
reflexdepending on the integrity of nociceptor afferentnerves.
Recently there has been a resurgence of inter-
Address for reprint requests: Dr Pamela M Le Quesne,
MiddlesexHospital Medical School London WIN 8AA.
Received 27 March 1987. Accepted 8 June 1987
est in neurogenic inflammation and the vasoactivepeptides,
particularly substance P, responsible for theaxon reflex flare.'0
Lembeck" has re-emphasised thedual role of the small C fibres
forming Lewis's noci-fensor system, whereby stimulation of
cutaneousnociceptor endings produces impulses which travelboth to
the CNS to produce the sensation of pain andto axon collaterals to
initiate neurogenic inflam-mation. By means of a technique for
quantifying theflare response,'2 we have used the linking of the
twofunctions in one fibre to provide an objectivemeasurement of
peripheral pain pathways. Inaddition, we can measure neurogenic
inflammation,whose impairment may be important in somediseases.The
flare depends on a cutaneous vascular reaction.
This assumes that the vasculature is capable ofresponding to the
vasodilator peptides released by theaxon reflex. To assess the
capacity of the vessels todilate, use has been made of another
component ofLewis's9 triple response, the direct local red
reaction,which is independent of nerves. This reaction, whichcan be
produced in a variety of ways and is confinedto the area
stimulated, will reveal any intrinsic vascu-lar abnormality due for
example to microangiopathyor occlusive vascular disease.
Methods
Apparatus and techniqueCapsule Stimulation and measurement were
performedconcurrently using a small capsule applied to the skin
(fig 1).This capsule is a modification of the one described by
Low
28
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Quantitative objective assessment ofperipheral nociceptive
C.fibre function
Fig I (a) Photograph ofcapsule; (b) diagram ofcapsuleshowing
spread offlare both outwards and inwardsfrom thering
ofstimulation.
et al7 to measure axon reflex sweating. It has two
concentricchambers, each fitted with an inlet and outlet vent, and
witha platinum wire electrode, which is used as the anode
forelectrophoresis. The walls of the chambers are thick and thebase
smooth so that double sided adhesive rings (3M) pro-duce a water
tight seal with the skin, which was prepared bygentle cleansing.
The probe of the laser Doppler flowmeterused for measuring blood
flow is mounted vertically at thecentre of the capsule with the
probe inserted to a distance of1 mm from the skin. The cathode for
electrophoresis is a leadplate, 4 x 6cm, wrapped in saline soaked
gauze andattached to the skin, previously cleansed with spirit,
withmicropore tape. A constant current generator designed andbuilt
at The Mayo Clinic was used to provide a 1 mA stimu-lus.
The laser Doppler flowmeter A PF2 laser Dopplerflowmeter linked
to a BBC chart recorder was used to mea-sure the changes in
superficial cutaneous blood flow. A nar-row laser light beam is
transmitted through a fibre opticcable to the probe head and
penetrates the skin to a depth of1-5 mm. The coherent light is
scattered in the tissues; the raysscattered by moving red blood
cells undergo a frequencyshift according to the Doppler principle.
The backscatteredlight travels back through a separate fibre optic
channel to aphotodetector which produces an output linearly related
tothe flux of red cells i.e. the number of cells times their
veloc-ity. This output signal is fed to the pen recorder. The
signal,expressed in mV rather than conventional flow units, is
anindirect measure of blood flow but a close correlation hasbeen
obtained between laser Doppler flux and red cell veloc-ity
determined by direct capillary microscopy.13The laser Doppler
signal is sensitive to small changes in
flow; sympathetic arousal stimuli cause clearly
detectablechanges. Movement of the subject or the probe causes
anabrupt artefact which is easily distinguishable from
physio-logically induced changes. Measurements have generallybeen
made on the 12 kHz scale with a gain of x 3 and a timeconstant of 1
5 s.
Procedure Measurements were made after 30 minutesacclimatisation
in a warm room maintained at 26°C in orderto reduce sympathetic
vasoconstrictor tone and to enablecomparison with data from
neuropathic patients in whomlimb temperature is often higher than
in healthy subjects.The skin temperature was 34-35 C° throughout
the test.To produce the axon reflex flare, the outer ring was
filled
with 10% acetylcholine (ACh) and, when the Doppler signalwas
stable, a current of 1 mA was passed for 5 min throughthe outer
chamber. The flare produced spreads both out-wards, where it is
visible, and inwards where it is measuredby the probe (fig lb).For
the direct, chemically induced non-neurogenic reac-
tion, the central well was filled with either 10% ACh or
1%pilocarpine, and a stimulus of 1 mA applied for 5 minthrough the
central chamber.A direct, mechanically induced red reaction was
produced
by making a firm stoke with a spring loaded dermograph,which
produces a pressure of 2 5 N. The flux was measuredwith the probe
at the same site before and after stimulation.
Results
Characteristics of the vascular reactionsTypical findings in a
control subject are shown infig 2. The increasing laser Doppler
flux recorded fromthe centre of the capsule during electrophoresis
ofACh from the outer ring is shown in fig 2a. This is theaxon
reflex flare. Pilocarpine was then electro-phoresed from the
central wall under the laserDoppler probe and the further rise in
flux duringdevelopment of the non-neurogenic direct reaction
isseen. This non-neurogenic reaction is the same fol-lowing
electrophoresis of either pilocarpine or AChfrom the central well,
although pilocarpine, unlikeACh, does not in addition produce a
flare. The direct
29
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30
20r 0
> 15E
x
0.lo-
0o
o,) 5
0 L
Firr
IACh 1mA) Pilo(1mA)*Outer ring .Centre,.. . . . . . . . .0 2 4 6
8 10 12
Time (min)Fig 2 Laser Dopplerflux (mV): (a) and (b)sole offoot
ofJ.H. (F, aged 44). (a) during eleofacetylcholine (ACh) from outer
ring, followepilocarpinefrom central well; (b) afirm strokemade
with a dermograph at an adjacent site andplaced over the area of
visible vasodilatation.
red reaction following a firm strokemograph is shown for the
same patient irdirect mechanically induced red reactiosmaller than
the pilocarpine reaction, incmaximal vasodilatation is not
producedcedure.The classical stimulus for the flare is
histamine. The flux recorded from ainduced flare is shown in fig
3b. It is simnitude to the ACh-induced flare recordadjacent site of
the forearm of the sz(fig 3a).The specificity of ACh as a
stimulus
was demonstrated by comparing it withlack of reaction to
electrophoresis of salinwith the rapid increase in flux during
eleiof ACh can be seen in fig4a.The neurogenic origin of the axon
refli
demonstrated by examining locally aiskin. Five ml 1% lignocaine
were injectedthe subcutaneous tissue to minimise lo(which would
itself produce a flare. The tried out after an area of approx 4 sq
cm Iinsensitive. The results are shown in fig 4bno increase in flux
when ACh was electfrom the outer ring, but non-neurogenicinduced
vasodilatation occurred whenwas electrophoresed from the central
well.
Further confirmation of the neurogeni
Parkhouse, Le Quesnethe axon reflex flare was obtained by
examiningtotally denervated skin. Surgically transferred freeflaps,
consisting of skin and subcutaneous tissue on avascular pedicle,
were examined at a time when com-plete nerve degeneration must have
occurred. Theaxon reflex flare to ACh was absent in the skin of
suchflaps, along with all other sensory modalities. Thedirect red
reaction to mechanical stimulation wasunaffected. There was,
however, some slight reduc-
f tion in the non-neurogenic direct pilocarpineI ~~response.
n stroke Passage of I mA current produces, in most sub-jects,
a-prickling sensation. Increasing the current to apainful intensity
(usually 2 mA) did not increase themagnitude of the vasodilatation
(fig 4c).
In order to investigate the influence of chronic, , ischaemia on
the vascular reactions on the sole of the0 2 4 foot, five subjects
with clinical evidence of severe
major arterial disease in the lower limbs were studied.The flare
was absent in two and reduced in three. The
recordedfrom non-neurogenic reaction to both pilocarpine and
actrophorests firm stoke were also reduced. All reactions wered by
absent in the patient with the most severely ischaemicwas then
legthe probe
Control dataData have been obtained on the two types of
vascular
with a der- reaction, the flare and the direct response, by
exam-a fig 2b. The ining 45 male and 54 female healthy subjects,
aged,n is usually 20-72 years. The sole of the foot was examined
since.icating that this site is most commonly affected in patients
withby this pro- peripheral neuropathy. In each case the probe was
sit-
uated on the supple skin immediately posterior to theintradermal
first metatarsal head.histamine- The size of the flare can be
expressed either as the
tilar in mae- absolute magnitude of the flux recorded or as
anled from aname subject
for the flareXsaline. Theie comparedctrophoresis
ex flare wasnaesthetiseddeeply intocal trauma,est was car-had
become'. There wastrophoresedchemically-pilocarpineic nature of
Ir
E
4 ,
L-o
a
a
10 v
5
OL ACh(lmA)0 . .
0Hist.
4t-
0 2 4 6 8 10 120 2Time (min)
4 6 8 10
Fig 3 Laser Dopplerflux (m V): (a) and (b) recordedfromforearm
ofP.L. (a) during electrophoresis of (ACh) fromouter ring; (b)
intradermal histamine was then injected at anadjacent site and the
probe placed over theflare whichdeveloped.
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Quantitative objective assessment ofperipheral nociceptive
Cfibre function
20r o151-
10
ACh (1mA)
01 I I I I 110 112 11L 16 18 20 22%A15
Prior s.c.10 - 1% Lignocaine
5 -
_ACh(1mA) Pilo.1mA) lmA 2mAOuter ring Centre
O 2 4 6 8 10 12 14 0 2 41 6 8 10Time (min)
Fig 4 Laser Dopplerflux (m V): (a) recordedfrom the soleoffoot
ofP.L. during electrophoresis ofsalinefollowed byacetylcholine
(ACh), bothfrom outer ring; (b) and (c) fromforearm ofP.L. (b)
during electrophoresis ofAChfromouter ringfollowed by pilocarpine
from central well 5 minafter sc. injection of1% lignocaine; (c)
duringelectrophoresis ofAChfrom outer ring with I mA
currentfollowed by 2mA current.
increase from the resting value. It was shown that thehigher the
resting flux, the higher the figure afterinduction of the flare (R
= 0-225, p < 0 02), but the
Males
Table Flux values for various vascular reactions recordedfrom
the sole of thefoot of90 healthy subjects
Resting Flare Stroke Pilocarpine Index
Mean 32 117 159 219 705%SD 1-8 3-7 41 66 28-6%p NS
-
32index was 70 5% and like the absolute size of theflare, it
decreased significantly with age (p < 0 001)(table). The direct
red reaction, although not maximalvasodilatation, has been used for
this index, becauseof the slight reduction in pilocarpine or
ACh-vasodilatation in totally denervated skin.
Discussion
We have used the electrophoresis of ACh as a stan-dard,
reproducible, atraumatic stimulus which willproduce a maximal flare
within a few minutes.Douglas and Ritchie"4 demonstrated that ACh
has adirect excitatory action on non-myelinated C fibres inthe
saphenous nerve of the cat, this being abolishedby hexamethonium
but not by atropine. Pilocarpineproduces direct vasodilation
identical to that pro-duced by ACh but no flare; these two
observationsboth suggest that stimulation of the flare depends
onthe nicotinic action of ACh. Other substances whichproduce a
flare are less convenient for clinical use andfor producing a
quantifiable response. Histaminemust be injected intracutaneously.
A singleapplication of capsaicin produces a flare, but it
isabolished by repeated applications probably due todepletion of
substance P.'5 The flare produced bymustard oil is so variable that
it is only possible todetermine whether a flare is present or
absent. 16
Previous attempts at quantification of the flarehave depended on
measurement of the area of visiblevasodilatation. This can be
difficult, not only becauseof variability due to lack of
standardisation of thestimulus, but also because the flare has an
irregularoutline and crenated edge9 due to anatomical vari-ations
in the distribution of the responsible nerves.We have overcome
these problems by measuring thechange in superficial cutaneous
blood flow at onefixed point at the centre of a ring stimulus.
LaserDoppler measurement has the additional advantagethat an
objective measurement may be made whenerythema is not visible to
the naked eye, such as wherethe skin is thickened, as on the sole
of the foot, and onpigmented skin.
Electrophoresis of ACh over the area of the ring ofthe capsule
produces, in most people, a "prickling"sensation, which is not
actually painful. Prickling hasin the past been ascribed to the
small cutaneous nervefibres responsible for pain sensation.'7 Pain
is pro-duced by the simultaneous stimulation of many neu-rons, the
pattern of impulse discharge probably beingof importance.
Microneurographic studies haveshown that low frequency firing of
nociceptive fibresdoes not produce pain, whereas pain does occur at
ahigher firing frequency of the same fibres.'8 It istherefore quite
understandable that maximum reflexvasodilation is evoked by a
stimulus which is not per-
Parkhouse, Le Quesneceived as painful. We have shown that
increasing thestrength of the electrophoresis current to a level
whichproduces pain does not increase the vasodilatation.Chronic
ischaemia impairs non-neurogenic vaso-
dilatation, so that little significance can be attached toan
absent flare in an ischaemic limb. It is thereforeimportant that
the flare should always be comparedwith directly stimulated
vasodilatation. Intradermalnitroprusside is probably the best agent
for producingmaximal vasodilatation. '" We did not use this
stimu-lus because we sought to make the whole
techniquenon-invasive. It was hoped that pilocarpine or AChwould
provide an adequate direct stimulus but it wasfound that in totally
denervated skin this reaction wasslightly reduced. In keeping with
this finding, recentexperimental observations have suggested that
ACh-vasodilatation is less in totally denervated vessels inthe
rabbit's ear.20 For these reasons we have useddirect mechanical
stimulation with the dermograph asa stimulus totally independent of
neural influence,even though this dilatation is not maximal.Many
neurological functions decrease with age.
For example, in the lower limb threshold forvibration
perception21 - 23 and for cooling andwarming24 25 have been found
to increase with age.Sensory nerve action potential amplitude26 and
thedensity of nerve fibres in peripheral nerve trunks27both
decrease with age in the lower limb. In a pre-vious study of the
flare produced by topical capsaicinthe area of the flare over the
trapezoid ridge wasfound to decrease with age, as was the substance
Pcontent of skin from the cubital fossae and ankle.28When sensory
thresholds have been estimated sepa-rately for males and females
the decrease in age hasbeen more marked in males, for example
forvibration29 30 and for temperature.3' Thus, thepresent findings
of an age decrease in the flare, whichis more marked in males, is
similar to the findings forother peripheral nerve functions. To be
able to detectthis effect gives an indication of the
quantitativesensitivity of the technique.
This technique provides an indirect method ofmeasuring the
integrity of peripheral pain pathways,providing an objective,
atraumatic alternativeto psychophysical techniques for measuring
pain.Quantification of pain pathways will be valuable inassessment
of peripheral neuropathies; for example,in analysing the multiple
defects contributing to theformation of diabetic neuropathic foot
compli-cations. The presence or absence of an axon reflex hasbeen
diagnostically useful in the past, but a quan-titative test is more
valuable. The flare may be absentin diabetics,32 - 3 and we have
now been able to studyit quantitatively in diabetics with
neuropathic ulcer-ation and Charcot arthropathy.35 Following
tractioninjuries to the brachial plexus, the presence of a
flare
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Quantitative objective assessment ofperipheral nociceptive
Cfibre functionin an area of sensory loss indicates a
pre-ganglioniclesion.3637 We have found its quantification to
beuseful in the diagnosis of mixed pre- and post-ganglionic
lesions. A histamine flare test is valuable inthe diagnosis of
familial dysautonomia (theRiley-Day syndrome),38 since
non-myelinated noci-ceptive fibres are lost as well as autonomic
nerves. It ispossible that a quantitative deficit might be found
inobligate heterozygotes which would permit accurategenetic
counselling in affected families.
It is increasingly apparent that neurogenicinflammation plays an
essential part in the body'sdefence mechanisms. The quantitative
test nowdescribed allows us to explore the importance of adeficit
in this mechanism. In diseases such as con-genital insensitivity to
pain, where the flare isabsent,39 and in diabetes, loss of the
neurogenicinflammatory response may be as important as loss ofpain
sensation in the manifestations of the disease.
In conclusion, the dual role of the nociceptive sys-tem allows
the flare to be used to study deficits both ofpain and of
neurogenic inflammation. It has beenadded to our battery of other
quantitative tests toproduce a profile of abnormalities of the
differenttypes of fibre making up a peripheral nerve.
NP was supported by the William Scholl Foundationadministered
through the London Foot Hospital towhom he is most grateful. We are
also grateful toMr Tarlock Gajree for assistance, to Dr Bruce
Lynn,Dr J C Foreman and Mr J H Scurr for their adviceand to Mr N M
Breach, Mr M D Brough, Mr D MEvans and Mr R Sanders for allowing us
to studytheir patients with free flaps.
References
I Dyck PJ, Karnes J, O'Brien PC, Zimmerman IR.
Detectionthreshold of cutaneous sensation in humans. In: Dyck
PJ,Thomas PK, Lambert EH, Bunge R, eds. Peripheral Neuro-pathy 2nd
ed, Philadelphia: Saunders 1984:1103-38.
2 Lindbolm U. Quantitative testing of sensibility including
pain. In:Stalberg E, Young RR, eds. Clinical Neurphysiology.
Butter-* orths Int Medical Reviews, London:
Butterworths1981:168-90.
3 Hardy JD, Wolff HG, Goodell H. Pain Sensations and
Reactions.Baltimore: Williams and Wilkins 1952.
4 Fruhstorfer H, Lindblom U, Schmidt WG. Method for
quan-titative estimation of thermal thresholds in patients. J
NeurolNeurosurg P.s(chiatr 1976;39: 1071-5.
5 Lynn B, Perl ER. A comparison of four tests for assessing
thepain sensitivity of different subjects and test areas. Pain1
977;3:353-65.
6 Le Quesne PM, Fowler CJ. A study of pain threshold in
diabeticswith neuropathic foot lesions. J Neurol Neurosurg
Psychiatry1986;49:1 191-4.
7 Low PA. Caskey PE, Tuck RR, Fealey RD. Dyck PJ. Quan-titative
sudomotor axon reflex test (Q = SART). Ann Neural1983;
14:573-80.
8 Ahmed ME, Le Quesne PM. Quantitative sweat test in
diabeticswith neuropathic foot lesions. J Neurol Neurosurg
Psychiatry1986;49:J059-62.
9 Lewis T. The Blood Vessels of the Human Skin and
theirResponses. London: Shaw and Sons, 1927.
10 Foreman JC. Peptides and neurogenic inflammation. Br Med
Bull1987;43:386-400.
11 Lembeck F. Sir Thomas Lewis's nocifensor system, histamineand
substance P-containing primary afferent nerves. Trends
inNeuroscience 1983;6:106-8.
12 Le Quesne PM, Parkhouse N. Laser Doppler measurement
ofacetylcholine-induced axon reflex flare to assess human
noci-ceptive C-fibre function. J Physiol (Lond.) 1987;384:3P.
13 Tooke JE, Ostergren J, Fagrell B. Synchronous assessment
ofhuman skin microcirculation by laser Doppler flowmetry anddynamic
capillaroscopy. Int J Microcirc Clin Exp1983;2:277-84.
14 Douglas WW, Ritchie JM. The excitatory action of
acetylcholineon cutaneous non-myelinated fibres. J Physiol
(Lond.)1960;150:501-14.
15 Carp_nter SE, Lynn B. Vascular and sensory responses of
humanskin to mild injury after topical treatment with capsaicin. Br
JPharmacol 1981 ;73:755-8.
16 Jancso N, Husz S, Simon N. Impairment of axon
reflexvasodilatation after herpes zoster. Clin Exp
Dermatol1983;8:27-3 1.
17 Zotterman Y. Touch, pain and tickling: an
electrophysiologicalinvestigation on cutaneous sensory nerves. J
Physiol (Lond.)1939;95:1-28.
18 Torebjork HE, Hallin RG. Identification of afferent C units
inintact human skin nerves. Brain Res 1974;67:387-403.
19 Duncan HJ, Faris IB, DeYoung NJ. The effectiveness of
localinjections of vasodilating agents to produce vasodilatation
insubcutaneous tissue in rabbits. Clin Physiol 1985;5:71-80.
20 Mangiarua El, Bevan RD. Effect of denervation on the
relaxationresponse in growing rabbit ear arteries. Blood
Vessels1986;23:88(A).
21 Goldberg JM, Lindblom U. Standardised method of
determiningvibratory perception thresholds for diagnosis and
screening inneurological investigation. J Neurol Neurosurg
Psychiatry1 979;42:793-803.
22 Bloom S, Till S, Sonksen P, Smith S. Use of a biothesiometer
tomeasure individual vibration thresholds and their variation in519
non-diabetic subjects. Br Med J 1984;288:1793-5.
23 Le Quesne PM, Fowler CJ. Quantitative evaluation of
toxicneuropathies in man. In: Ellingson RJ, Murray NMF,Halliday AM,
eds. The London Symposium. EEG J Suppl.I 987;39:347-54.
24 Bertelsmann FW, Heimans JJ, Weber EJM, van der Veen
EA.Thermal discrimination thresholds in normal subjects and
inpatients with diabetic neuropathy. J Neurol NeurosurgPsychiatrvy
1985;48:686-90.
25 Jamal GA, Hansen S, Weir Al, Ballantyne JP. An improved
auto-mated method for the measurement of thermal thresholds.1.
normal subjects. J Neurol Neurosurg Psychiatry 1985;48:354-60.
26 Buchthal F, Rosenfalck A. Evoked action potentials and
conduc-tion velocity in human sensory nerves. Brain Res
1966;3:1-122.
27 O'Sullivan DJ, Swallow M. The fibre size and content of
theradial and sural nerves. J Neurol Neurosurg Psychiatry1 968;31
:464-70.
28 Helme RD, McKernan S. Flare responses in man followingtopical
applications of capsaicin. In: Chahl LA, Szolcsanyi J,Lembeck F,
eds. 29th IUPS Satellite SYmp. Budapest:Akademiai Kiado.
1984;303-12.
29 Steiness IB. Vibratory perception in normal subjects. A
bio-thesiometric study. Acta Med Scand 1957;158:315-25.
30 Halonen P. Quantitative vibration perception thresholds
inhealthy subjects of working age. Eur J Appl Physiol1
986;54:647-55.
33
Protected by copyright.
on June 26, 2021 by guest.http://jnnp.bm
j.com/
J Neurol N
eurosurg Psychiatry: first published as 10.1136/jnnp.51.1.28 on
1 January 1988. D
ownloaded from
http://jnnp.bmj.com/
-
3431 Fowler CJ, Carroll MC, Burns D, Howe N, Robinson KA. A
portable system for measuring cutanieous thresholds forwarmth
and cold. J Neurol Neurosurg Psychiatry1987;50:121 1-5.
32 Moore JM, Frew ID. Peripheral vascular lesion in diabetes
mel-litus. Br Med J 1965;2:19-23.
33 Hutchison KJ, Johnson BW, Williams HTG, Brown GD.
Thehistamine flare response in diabetes mellitus. Surg
GynaecolObstet 1974;139:566-8.
34 Clements RS, Aronin N, Leeman S. Abnormal neuronal
metabo-lism of substance P in diabetic neuropathy.
Diabetologia1984;27:264(A).
35 Parkhouse N, Le Quesne PM, Scurr J. Reduced axon reflex
flare
Parkhouse, Le Quesnein diabetics with neuropathic foot lesions.
Br J Surg1987;74:534.
36 Bonney G. The value of axon responses in determining the site
oflesion in traction injuries of the brachial plexus.
Brain1954;77:588-609.
37 Bonney G, Gilliat RW. Sensory nerve conduction after
tractionlesion of the brachial plexus. Proc R Soc Med
1958;51:365-7.
38 Smith AA, Dancis J. Response to intradermal histamine in
famil-ial dysautonomia-diagnostic test. J Paediatr
1963;63:889-94.
39 Toth-Kasa I, Katona M, Obal F, Husz S, Jansco G.
Pathologicalreactions of human skin: involvement of sensory nerves.
In:Chahl LA, Szolcsanyi J, Lembeck F, eds. 29th IUPS SatelliteSymp,
Budapest: Akademiai Kiado 1984:317-28.
Protected by copyright.
on June 26, 2021 by guest.http://jnnp.bm
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eurosurg Psychiatry: first published as 10.1136/jnnp.51.1.28 on
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