impairment vasomotor - bmj

Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:965-971

Impairment of vasomotor reflexes in thefingertips of leprosy patients

J Swanson Beck, N C Abbot, P D Samson, C R Butlin, J M Grange, I A Cree, A Forster,F Khan

AbstractA method is described for eliciting finger-tip vasomotor reflexes by inspiratorygasp and contralateral hand coldchallenge. The results of the two tests arereproducible on replicate testing and,when taken together, have proved reliablefor detection ofimpairment ofautonomicreflexes in 10 newly registered leprosypatients who did not have any obviousdeformity. Similar, but less severe,impairment of vasomotor reflexes wasnoted in a group of 10 fully treated,apparently cured ex-leprosy patients,none of whom showed clinically obviousneuropathy. Both the new patients andthe ex-patients were significantlydifferent from healthy contacts and fromhealthy Europeans, who were indistingui-shable by this test. Evidence is presentedsuggesting that impairment of thesevasomotor reflexes is mainly due todamage to the efferent pathway in theperipheral nerves. The method mightprove valuable for investigation of earlynerve damage in new patients or duringreversal reactions in leprosy at a stagebefore irreversible damage is done.

Department ofPathology, UniversityofDundee, DundeeJ Swanson BeckN C AbbotI A CreeRichardson LeprosyHospital, Miraj,Maharashtra, IndiaP D SamsonC R ButlinDepartment ofMicrobiology,National Heart andLung Institute,LondonJM GrangeDepartment ofNeurology, DundeeRoyal Infirmary,DundeeA ForsterVascular Laboratory,Ninewells Hospitaland Medical School,Dundee, UKF KhanCorrespondence to:Professor J Swanson Beck,Department of Pathology,Ninewells Hospital andMedical School, DundeeDD1 9SY, UK.Received 17 July 1990and in revised form 26March 1991.Accepted 5 April 1991

Much of the long term disability of leprosystems from the neuropathy which may cause

permanent damage to the peripheral nerves,leading to serious sensory loss with the dangerof trophic ulceration, or paralysis of motorfunction and secondary deformity. Thedevelopment of this neuropathy is sometimesclinically apparent with swollen painfulnerves,' but often .the onset is insidious andmuch permanent damage can occur' beforethere are clinical indications to start anti-inflammatory treatment.' Diagnosis by nerve

biopsy is practicable, but this expensiveapproach is not commonly used for ethicalreasons and the practical problems of usinginvasive techniques away from a referral hosp-ital. In the field, clinical examination is used tosearch for impairment of somatic sensation or

motor power, but the methods are relativelyinsensitive and not very objective. Nerve con-

duction studies can provide reliable informa-tion in impairment of conduction in the largermyelinated fibres in the peripheral nerves inclinical leprosy,45 but the techniques are

intricate and highly skilled operators are

required if reproducible results are to beobtained.There is good evidence that leprosy patients

may develop abnormalities of autonomic func-tion, such as localised loss of sweating inapparently uninvolved skin distant from theskin plaques.36 The efferent pathway responsi-ble for these autonomic functions is carried insmall non-myelinated or poorly myelinatedfibres in the peripheral nerves7 and these areparticularly vulnerable to damage from theinflammatory infiltrate of leprosy neuropathy.Autonomic neuropathy has been extensivelystudied in diabetes89 and a range of tests hasbeen developed for detection of several types ofvisceral autonomic impairment in this dis-ease.'1-2 Methods, such as the Valsalva man-oeuvre and the cold pressor test, have beenused to demonstrate visceral autonomicimpairment in patients with long-establishedleprosy,"" but these methods are unlikely tobe sensitive indicators of early peripheral nervedisorders of autonomic function in leprosy, adisease where the neuropathy is focal andconcentrated distally in the limb nerves. Accor-dingly, we have been interested in developing amethod for the detection of the focal abnor-malities that are commonly encountered inleprosy neuropathy.Low et al 16 proposed a new approach to the

detection of neuropathic autonomic abnor-malities by measuring the transient fall infingertip blood flow after inspiratory gasp, onstanding, during the Valsalva manoeuvre andfollowing cold stimulation. They showed thatthese reflexes are lost in patients who have hadavulsion of the corresponding spinal nerveroots. The clinical method they described had arather high variability, but the approach hasthe important advantage of localising the defectto small skin regions. The methods ofmeasurement of these reflexes has since beenmodified in Dundee to be sufficientlyreproducible for use in clinical investigationand the reflexes have been shown to beimpaired in Type I diabetics with clinicalevidence of peripheral neuropathy'7 and insome elderly people, perhaps as a consequenceof ischaemic neuropathy (unpublishedobservations). The vasomotor reflexes can betemporarily inhibited by administration ofprazosin (an al adrenoceptor antagonist), adrug which would be expected to paralyse theefferent process."8 This paper describes the useof a test of vasomotor reflexes based on laser-Doppler measurements for identification ofautonomic neuropathy in leprosy patients andassess its reproducibility. In our experience,the apparatus has been sufficiently robust foruse in outlying clinics and the method couldreadily be adapted for use in field studies.

965

on Novem

ber 19, 2021 by guest. Protected by copyright.

http://jnnp.bmj.com

/J N

eurol Neurosurg P

sychiatry: first published as 10.1136/jnnp.54.11.965 on 1 Novem

ber 1991. Dow

nloaded from

http://jnnp.bmj.com/

Beck, Abbot, Samson, Butlin, Grange, Cree, Forster, Khan

Patients and methodsThe methods were developed in studies on 10healthy subjects in Dundee (aged (SD) 33-0(8-18)) and then assessed at the RichardsonLeprosy Hospital, Miraj, Maharashtra, Indiaon 10 healthy subjects, 10 "contacts" frequen-tly exposed to patients with leprosy, aged (SD)35 1 (13-3), 10 newly diagnosed leprosypatients, aged 38-4 (14-3) and 10 subjects, aged

skin surface. The output signal was recordedcontinuously during the period of observationon a chart recorder (SE120, BBC GoetzMetrawatt, Austria) calibrated to a full scaledeflection of 10 V. The pulp of the finger wasselected for investigation because its abundantarteriovenous anastomoses are under strictautonomic control.2223

31-9 (6 26) who had received curative treat- MEASUREMENT OF AUTONOMIC REFLEXESment for leprosy many years previously. The All subjects were seated with the forearm andnewly registered patients were recruited for hand at heart level in an ambient temperaturethis method evaluation study because their of 26-29'C, since near maximal vasodilatationabnormalities covered the wide range ofclinical of the microcirculation in the fingertips isappearances seen in the disease: the diagnosis induced in healthy subjects stabilised underwas confirmed histologically by biopsy ofa skin these conditions.'8 Heating of the contralateralplaque and classified as LL in three, BL in limb was not used lest this induced a sweatthree, BT in three and indeterminate in one response which would complicate the inter-patient. No attempt was made to select a pretation of the tests. Each subject was seatedstatistically representative sample of any par- quietly at the ambient temperature for at leastticular category ofleprosy patients. All subjects 15 minutes before measurements were started.gave informed consent without coercion and In healthy subjects, the fingertip blood flowthe studies had been approved by the local is not constant: there are two forms ofEthics Committee. All subjects were tested periodicity, a rapid minor fluctuation in timetwice at an interval of one week. with the arterial pulse (approximately 70/min-

ute) and a slower rhythm of greater amplitude,CLINICAL ASSESSMENT OF PERIPHERAL NERVE termed vasomotion,24 of 5-10 waves/minute,FUNCTION thought to be due to changes in vascular tone.In the course of physical examination of the When the normal subject is fully vasodilated,patients and,controls, sensation in the upper vasomotion becomes small relative to thelimb was examined for integrity of touch (with arterial pulse effect. The "resting" fingertipvon Frey hairs) and by pinprick: the median blood flow was taken as the mean RBCfluxand ulnar nerves were palpated for enlarge- value during a 3 minute observation period onment. The physiotherapist assessed the an equilibrated subject.strength of the various voluntary muscle The autonomic control of fingertip bloodgroups in the upper limb. From this non- flow can be assessed by attempting to inducespecialist examination, the subjects were clas- two simple vasomotor reflexes. The inspiratorysified as having "severe" peripheral gasp reflex is induced by the subject taking aneuropathy if there was widespread abnor- sudden deep full inspiration, held for 10mality in the various groups of tests, and as seconds or until a minimum blood flow was"partial" if there was either a) focal partial loss recorded. In the normal subject there is a shortof sensation in the arm, forearm or hand, or b) a lag period (2 to 3 seconds), a sharp rapid fall inpalpably swollen nerve, or c) convincing blood flow velocity and then a quick return toevidence of muscle weakness in some muscle the original level. This response is controlledgroups. On this basis, the Dundee and Miraj by a spinal cord reflex with an unknowncontrols did not show any abnormality of afferent (?baroreceptor) and a sympatheticperipheral nerve function. Of the newly- efferent pathway;2526 it has been usedregistered leprosy patients, five had "severe" previously to test autonomic function.'627 Aand three had "partial" neuropathy. deep inspiratory "gasp" is required to trigger

this reflex: accordingly we took care to ensureMEASUREMENT OF FINGERTIP SKIN BLOOD FLOW that all subjects-especially non English speak-Blood flow over the pulp of the distal phalynx ing Indian subjects-understood fully whatnear the fingertip was measured with a laser- was required ofthem before starting a test. TheDoppler flowmeter (Model PF2, Perimed, cold challenge reflex is provoked by quicklyStockholm, Sweden) with machine settings of cooling the contralateral hand. The patterns of"gain, 3; band width, 12 KHz; time constant, blood flow changes were similar to those seen in02s; artefact filter, off'. The laser-Doppler the gasp reflex. This spinal reflex depends uponflowmeter measures movement oferythrocytes afferent conduction of the impulses in thein the most superficial 1 mm of skin from "cold" sensory fibres of the peripheral nerveschanges in the wavelength in coherent light and a sympathetic efferent pathway27l and itreflected out of the tissue. The instrument is has also been used to test for disorders ofinternally standardised and gives an integrated autonomic function.'6 In our experiments, themeasurement of microvascular blood flow cold stimulation was invoked by plunging the(RBCflux, expressed in Volts), which is related contralateral hand into a bath of cold water (atdirectly to the product ofthe number ofmoving or just below 15°C): the water was stirred quiteerythrocytes and their mean velocity at the vigorously by the attendant to ensure a rapidmeasurement site. 1921 The fibre-optic sensor fall in skin temperature on the subject's hand.was attached to the fingertip by a probe holder At each clinical examination, attempts werefixed with double-sided adhesive tape, ensur- made to elicit both reflexes on each of the fouring optimal alignment between sensor head and fingers on one hand, usually the right: the same

966

on Novem


http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1991. Dow

nloaded from


Impairment ofvasomotor reflexes in thefingertips of leprosy patients

Figure I Diagramshowing how the variousindices are calculatedfromtracing of a vasomotorreflex.

x

VmaxI Vf

2 -

0

O 20 40 6o 80Time (s)

hand was used in replicate testing. To minimisevariability in the gasp reflex due to misunder-standing from language difficulties, up to threedeep gasps were elicted for the test on eachfinger and the largest response was used forsubsequent analysis. During the cold challengetests, the contralateral hand was dried andallowed to reheat before testing the response onanother finger: this did not entail much delay inthe tropical conditions at Miraj (20-29'C).

MEASUREMENT OF RESPONSE TO VASOMOTORREFLEXES FROM TRACESFigure 1 shows the phases of the response andindicates how the measurements were madefrom the trace recording made at eachexperiment. Vmax indicates the prestimulationfingertip blood flow, Vf the extent of fall insignal during the reflex, Tf the time taken forthe blood flow to fall to its lowest level and Trthe total response time ("duration") of thereflex. From these measurements, Vf/VMaxindicates the proportionate fall in signal("amplitude"), Vf/Tf the rate of fall("velocity") and (Vf.Tr)/2 gives an estimate ofthe "magnitude" of response.

STATISTICAL ANALYSIS

The variation in measurements between fingerswas assessed by the Student t test and thereproducibility of replicate measurements onthe same finger at one week's interval was

analysed by the Bland and Altman method.29Discriminant analysis was used to evaluate therelative separation between leprosy patientsand healthy contacts, obtained by combiningthe results of the two vasomotor reflexes, toassess the potential clinical value of the variousmeasurements that can be made from thetracings. The position ofthe optimal separatingline is calculated and its Eigen value indicatesthe extent of separation achieved: the predic-tion table then indicates the number (%) ofcases that have been classified correctly by thediscriminant function. The calculations were

performed on a microcomputer with the Stat-graphics package (Release 3 0, STSC Rock-ville, MD, USA).

REPRODUCIBILITY OF VASOMOTOR REFLEXMEASUREMENTSThe differences between the measurements ofvarious features of the vasomotor reflexes madeat one week's interval on the healthy Dundeesubjects, the healthy subjects in India who hadhad considerable exposure to leprosy and thefully treated leprosy patients are summarised intable 1. Analysis by the Bland and Altmantechnique29 showed that the differences bet-ween replicates on the two groups of healthypeople was relatively small and not significantlydifferent from zero: for any parameter therewas no association between the size of themeasured character (mean of replicates) andthat of the differences between replicates. Stat-istically significant differences (after correctionfor multiple testing) were seen between thereplicates of abnormally low amplitude gasp

responses and of abnormally slow velocitymeasurements in treated ex-patients, but theextent of this variability was small relative tothe reduction in signal associated with thedisease (table 1). Moreover, discriminantanalysis of the clustering of the amplitude (Vf/Vmax) of the gasp and cold reflexes in eachgroup at one week's interval showed extensiveoverlap without statistical significance. It wasconcluded that the methods were sufficiently

Table I Means and differences (observation 2 - observation 1) between replicate measurements of vasomotor reflexes, one week apart on healthyEuropeans and people exposed to leprosy and treated ex-patients. Thefindings on new patients at first contact are shownfor comparison

Vf (V) Amplitude % Tf (sec) Tr (sec) Velocity Magnitude

Group Flux (V) G C G C G C G C G C G C

Healthy mean 6-59 5-34 4-77 79-8 73-4 7 13 6-03 18 73 17 95 0 81 0-88 48-76 40 95European SD 1-46 1 71 1-43 13-7 10-8 2 21 1-94 7-82 6-96 0 34 0-37 24-41 15 9

mean difference -0 06 0-56 0 31 3 1 1 55* -0-68 1-27 -2-35 -0-01 0-01 6 47 -4-61SD 1-96 1-88 1-67 14.1 15 8 2 85 3-55 10-58 16 8 003 0-04 33-01 29-95

Healthy mean 5-37 4 61 3-92 84-9 73-1 7-23 6-53 27-08 21-67 0-72 0 74 61 49 41-06exposed SD 1-44 1 51 1-45 9-3 14 7 2-87 4-3 20-15 12 68 0-34 0 43 41 6 23-87

mean difference 0-37 -0-22 -0 39 4-5 2-2 -0-77 -2-63 3 03 -0-97 -0-01 0-02 2-9 -8-33SD 2 34 2 06 2-11 18-1 22-6 4-42 6-66 25-1 21 9 0-05 0 05 47-65 45-93

Treated mean 4-46 2 46 1-18 52 25-5 9 14 7 81 30 31 26-2 0-44 0 31 39 95 19 72ex-patients SD 1 43 1 7 1-5 30-6 30 2 6-77 6-59 14-57 13 22 0-34 0-26 27 51 25-34

mean difference -0 21 0.73* 0 47 18.9* 9-7 0-31 -2-89 -4 03 -3 06 0.02* 0.02* -5-52 1-64SD 1-66 1 56 1 82 29-3 30 3 11-23 10 06 31-09 25 02 0 037 0-03 50-88 32 09

New patients mean 4-36 211 0-66 46 13 5 4-8 5-18 26-43 20 75 0-66 0 47 4014 20 87SD 1-72 2 14 2-01 36-8 4-7 2-12 1-78 19-24 8-6 0-41 0 35 32-7 12-45

*Significantly different from zero (p < 0-05).

967

on Novem


http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1991. Dow

nloaded from



reproducible and reliable for clinical use onleprosy patients. Reproducibility assessmentswere not made on newly diagnosed leprosypatients, since they were started at their firstvisit on standard potent antimycobacterialtherapy (Multidrug Therapy) which would beexpected to modify the disease.

ResultsFINGERTIP BLOOD FLOW CHANGES DURINGVASOMOTOR REFLEXES IN HEALTHY SUBJECTSThe responses of healthy Dundee volunteerswho have not had any known exposure toleprosy patients and the healthy contacts inMiraj were remarkably uniform. Figure 2 illus-trates the record obtained from a normal Indiansubject: shortly after provocation of either thegasp reflex or the cold challenge, there is asharp fall in blood flow to a very low levelfollowed by a rapid recovery to the prestimula-tion resting level.

UNUSUAL PATTERNS OF BLOOD FLOW CHANGESDURING VASOMOTOR REFLEXES IN LEPROSYPATIENTSSome of the leprosy patients respondedsimilarly to the healthy subjects, but mostshowed patterns not previously encountered innormal subjects. The patterns of abnormalityencountered were: 1) Reduction in Vmaxrelative to that of clinically-normal fingertipskin (fig 3A); 2) Reduction in Vf after attemp-ted elicitation of vasomotor reflex (fig 3A)-occasionally there is a complete absence of falland rarely an inversion of response with rise ofRBCflux after stimulation of either inspiratorygasp or cold challenge reflexes; 3) Slowing ofvelocity ofonset ofvasomotor reflex (fig 3A); 4)

O

=.il I.

~~~~~* I t r

I - min--I

A -A--4-IG cc IG

Figure 3 a) Vasomotor reflex test on newly diagnosed leprosy patient. The response toinspiratory gasp is reduced in amplitude, more gradual in onset and slower in recoverythan that seen in a healthy subject. This patient failed to respond to the cold challenge.b) Treated ex-patient. The inspiratory gasp reflex is intact with rapid onset of almostcomplete cessation of bloodflow, but recovery is delayed: the asterisk indicates atemporary hesitation in the slowed return of normal bloodflow. Cold challenge isdisproportionately affected.

Normal induction of reflex, but slowedrecovery (fig 3B); 5) Impairment ofresponse tocold challenge, with or without impairment ofgasp reflexes (fig 3B)-no patient was seen withan intact cold reflex when the gasp reflex wasseverely impaired or absent.There were no statistically significant

differences between individual fingers in thehands ofhealthy subjects in Dundee or India atthe first testing or subsequent testing.Many newly diagnosed or previously treated

leprosy patients showed marked differencesbetween individual fingers within the hand inthe extent of abnormality of vasomotorreflexes: it was not uncommon for the respon-

ses to be near normal in one finger and severelyimpaired or even absent in other fingers in thesame hand. The more severely affected patientsshowed marked impairment of the responses inall fingers. There was no evidence of selectiveinvolvement of particular fingers nor were theabnormalities segregated in the territories ofthe major nerves (median or ulnar). There wasno evidence of disturbance of somatic peri-pheral nerve function in either the Dundee orMiraj controls. The newly-registered leprosypatients with "severe" or "partial" somaticneuropathy showed more extensive distur-bance of vasomotor reflexes than those with noabnormality of peripheral nerves on physicalexamination, but the numbers were too smallfor statistical analysis. The curatively-treatedleprosy patients were reluctant to submit to anextended physical examination, so no compar-ison is available between autonomic andsomatic peripheral nerve function in thisgroup.

ASSESSMENT OF THE VALUE OF MEASUREMENTSOF VASOMOTOR REFLEX RESPONSES IN DETECTINGDISTURBANCE OF AUTONOMIC FUNCTION IN THEPERIPHERAL NERVES OF LEPROSY PATIENTS

Figure 4 shows the relationship betweenmeasurements of the amplitude of responses togasp and cold reflexes determined at the firstvisit in the four clinical groups. There was littledifference between the healthy non-exposedsubjects in Dundee (fig 4A) and healthy con-tacts in India (fig 4B), and both groups showeda large response in both reflexes. The newlydiagnosed (fig 4C) and previously treated ex-

patients (fig 4D) showed much diversity inresponse with the response to cold challengeoften being more severely affected than that togasp. Many patients showed a poor response inboth tests: in the newly-registered patients, 22/40 fingers showed the absence of either or bothgasp or cold reflexes, while the correspondingfigure for the ex-patients was 14/40, but thisdifference was not significant.Table 2 summarises the results of discrimin-

ant analysis on the four major measurementsfrom the traces using the mean value for eachpatient's hand (based on the observations onfour fingers) in the various clinical groups. It isclear that amplitude (Vf/Vmax) gives very goodseparation of healthy people from newly-diag-nosed or ex-leprosy patients. The calculateddiscriminant function for optimal separationbetween groups of healthy exposed people and

3x

m

Figure 2 RBCfluxmeasurement on R middlefinger of a healthy Indiansubject showing normalbrisk response to coldchallenge (CC) andinspiratory gasp (IG).

6

4

2

oL

6

4

2

tt I I'

1 W~~~~ffV

C IG IG IG

1-lmin_-

.~~~~~~~~~

-1

968

on Novem


http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1991. Dow

nloaded from


Impairment of vasomotor reflexes in the fingertips of leprosy patients

100'

75.

50-

25-

- O-m

~0100

75

50

25-

o-

. I

. .* l-.

* *-I*0

* * I I

O 25 50 75

II100

Inspirator

Figure 4 Scatter diagrams to show the relationshiAinspiratory gasp and cold challenge vasomotor refleia) healthy volunteers in Dundee, b) contacts of leprregistered leprosy patients and d) treated, apparentline on panels b) and c) indicates the discriminantfiof contactsfrom newly-registered patients using theThe zero points in panels c) and d) represent 13 anishowed absent responses to both gasp and cold challe

newly-diagnosecappropriate panAlthough the

some distinctionand the healthysiderable and theuseful in diag

*e* -

individual patients. Discriminant functionanalysis did not show any appreciable separa-tion between healthy non-exposed Dundeesubjects and healthy contacts in India for thefour parameters measured.

Discussion\*. * The technique developed by Low et al"6 for

*ID detection of peripheral nerve autonomic dys-function from abnormalities of fingertipvasomotor reflexes utilised direct heating ofthehands to 34-35°C to induce local hyperaemia.Under these conditions the median propor-tionate fall in laser-Doppler signal was 45%after inspiratory gasp and 51% after coldchallenge. For truly maximal vasodilatation,however, a sufficiently high core temperature isrequired to release central vasoconstriction

*8 , tone with subsequent opening of arterio-ven-ous anastomoses at the fingertips23" and thewarm blood entering the hand has an additionaldirect heating effect on the nutritionalmicrocirculation. The resting blood flow

*. achieved under these conditions is stable andhas fewer spontaneous or vasomotive fluctua-

. tions. In practice, a small elevation ofcore body. . temperature can be achieved by contralateral

* warming when the ambient temperature is* . * low,7 or by stabilising subjects at high ambient*-. temperature. In this study, healthy subjects at*. *. an ambient temperature of 26-29°C showed a

*. mean (SD) reduction in blood flow of 84-9* (9 3)% with inspiratory gasp and of 73-1

(14-7)% with cold challenge. These resultscompare well with those obtained with con-tralateral warming'7 and are more consistentthan those reported by Low et al. 16 Ourtechnique had poorer reproducibility in

o2550 75 100 patients than in healthy people, but the meth-

y gasp odological variability is small relative to themagnitude of the changes seen in disease.

p between amplitude of responses in From this study it is clear that leprosyxes in allfour fingers in one hand of patients may show several types of defects inrosy patients in Miraj, c) newly- finger tip vasomotor responses to inspiratoryly healthy ex-leprosy patients. The gasp or cold challenge. The commoner types of'unction for best separation of resultsmean value for each patient's hand. abnormality have been illustrated in this paper.d nine values respectively that It has been established that the defects in an!nge. individual finger are reproducible in repeated

testing and that the overall pattern of responsei patients is shown in the in the hands of the ex-patients did not changeels of fig 4. over the short period of observation in thisother measurements make study (up to one week). Certain abnormalbetween the diseased groups responses can be readily measured (for exam-subjects, the overlap is con- ple, the extent of fall in blood flow velocity, the

,se features do not appear to be rates of fall and recovery and the duration of;nosing abnormality in the slowed blood flow), but others such as the

Table 2 Summary of results of discriminant analysis to evaluate separation of mean valuesfor each person's handbetween healthy exposed subjects ("contacts") and either newly diagnosed leprosy patients or fully treated patients

Groups compared

Exposed healthy v new patients Exposed healthy v ex-patients

Number {,% correctly Number %a correctlyclassified as classified as

Eigen EigenMeasurement value P value Healthy Abnormal value P value Healthy Abnormal

Amplitude 2-83 0 00001 10 (100) 9 (90) 2-69 0 00002 10 (100) 9 (90)Velocity 0-137 0-382 7 (70) 5 (62-5) 1 10 0-0026 9 (90) 9 (90)Duration 0 010 0-929 3 (30) 5 (62-5) 0-054 0-656 7 (70) 5 (55 6)Magnitude 0-566 0-035 7 (70) 6 (75) 0-737 0-012 8 (80) 6 (66-7)

0~~~~~~~3..| | |

I

969

: :

on Novem


http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1991. Dow

nloaded from



biphasic recovery are essentially qualitative. Ithas not been possible to measure accurately thelag period between the stimulation of the reflexand the onset of an effective response, becauseof our inability to define the nature of theevoking stimulus: we do not yet know theprecise extent of thoracic expansion necessaryto trigger the inspiratory gasp reflex nor is itclear how far the temperature of the dermisaround the cold receptors must fall for the coldchallenge to be effective.

Disturbance of vasomotor reflexes was morecommon in newly-registered leprosy patientswith evidence of somatic peripheralneuropathy than in those with apparently nor-mal peripheral nerve function, but thedifference observed in the relatively smallnumbers (10) of newly-registered patientsrecruited for validation of the clinical methodwas not statistically significant: in subsequentstudies on 33 newly-registered patients we haveshown that the vasomotor reflex abnormalitywas greatest in those with "severe"neuropathy, and least in those without clinicalevidence of neuropathy (p < 0 05, unpubli-shed observations). It is clear that there can beconsiderable differences between responses inindividual digits of the hands of a leprosypatient when a constant evoking stimulation isapplied to the contralateral hand (coldchallenge) or to the thoracic cage (inspiratorygasp). Since there is no evidence, even inadvanced leprosy, of damage to the spinal cord(where the vasomotor reflexes are coordinated),it must be concluded that the major defect mustoccur in the efferent pathway. It is well knownthat peripheral nerves are a common site ofdamage throughout the whole spectrum ofleprosy.2 It is not possible to localise the site ofdamage from the anatomical distribution of theloss of function because of the complicatedintraneural topology in the peripheral nerveswith branching and fusion of fascicles in themedian, ulnar and radial nerves.3" Neverthe-less, the well established frequent occurrenceof swelling in the peripheral nerves (for exam-ple, the ulnar nerve) in leprosy suggests thatthis will be the commonest site of involvementof the autonomic efferent fibres, but presentevidence does not exclude the alternative pos-sibility of involvement of the smaller branches(for example, digital nerves) or even damage inthe dermal bundles of non-medullated fibreswhich may be abnormal in leprosy.32 It is evenpossible that the damage could lie in thesympathetic ganglia since there are olderreports of their involvement in leprosy,33 butthis has not been confirmed. Disorders of theafferent pathways probably contribute to alesser extent to the disturbance of vasomotorreflexes. The greater reduction of the reflexeselicited by the cold challenge than by ins-piratory gasp clearly demonstrated in thisstudy suggests concurrent damage to the coldafferents in the peripheral nerves.The demonstration of impairment of the

vasomotor reflexes need not necessarily be thewhole explanation for the disturbance of con-trol of the finger tip circulation. In advancedleprosy, there is pathological evidence of

damage to the dermal blood vessels54" andarteriographic evidence of narrowing of themedium-sized and smaller limb arteries.3638None ofthe patients reported in this paper werein the advanced stages of the disease or hadclinically abnormal fingers: the mean restingfinger tip blood flows were high and well withinthe normal range established in healthyEuropeans with the same apparatus.39 Thevasoconstrictive response to cold challenge wasfrequently more severely impaired than that toinspiratory gasp (fig 4) in both newly-regis-tered and curatively-treated leprosy patients:the disparity between the responses to alter-native methods for eliciting the reflex could nothave arisen if the lesions were restricted to thevessel walls. We concluded that leprosyarteriopathy did not make any substantial con-tribution to the impairment of vasomotorreflexes in the patients reported in this paper.

It is hoped that the method described in thispaper will provide a useful approach for serialstudies in monitoring the individual patient forearly subclinical evidence of neuropathy inreversal reactions, thereby making it possible toinstitute anti-inflammatory treatment whilenerve damage is still potentially reversible. Itshould also be useful for monitoring nervedamage during clinical trials ofnew regimes forthe treatment of leprosy.

We are grateful to LEPRA for generous financial suport and toDr Waters ofThe Leprosy Mission who enabled NCA and JSBto visit Maharashtra. We wish to acknowledge the help andsupport we received from Dr D Jadhav and the many staffmembers at the Richardson Leprosy Hospital in Miraj whomade the study possible. Dr R A Brown of the Department ofMathematical Sciences gave us valuable advice on the statisticalanalysis of the results. The study would not have been possiblebut for the active cooperation of the many patients whoparticipated in the study.

1 PfaltzgraffREP, Bryceson A. Clinical Leprosy. In: HastingsRC, ed. Leprosy: Edinburgh: Churchill Livingstone,1985:255-73.

2 Job CK. Nerve damage in leprosy. Int J Lep 1989;57:532-9.3 Jacobson RR. Treatment. In: Hastings RC, ed. Leprosy.

Edinburgh: Churchill Livingstone, 1985:53-87.4 Dash MS. A study of the conduction velocity of sensory

fibers of the ulnar nerve in leprosy. Int J Lep 1967;35:460-99.

5 Shetty VP, Mehta JN, Antia NH, Irani PF. Teased fibrestudy ofearly nerve lesions in leprosy and in contacts, withelectrophysiological correlates. J Neurol Neurosurg Psy-chiatry 1977;40:708-1 1.

6 Sehgal VN. Significance of the local sweat response in thediagnosis of leprosy. Dermatologica 1974;148:217-23.

7 McLeod JG. Autonomic dysfunction in peripheral nervedisease. In: Bannister R, ed. Autonomnic failure. Oxford:Oxford University Press, 1985:607-23.

8 Thomas PK, Eliasson SG. Diabetic neuropathy. In: DyckPJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheralneuropathy. Philadelphia: Saunders, 1984:210-30.

9 Ewing DJ, Clarke BF. Diabetic autonomic neuropathy:present insights and future prospects. Diabetes Care1986;9:648-65.

10 Levin AB. A simple test of cardiac function based upon theheart rate changes induced by the Valsalva maneuver. AmJ Cardiol 1966;18:90-9.

11 Wheeler T, Watkins PI. Cardiac denervation in diabetes.BMJ 1973;4:584-6.

12 Ewing DJ, Campbell IW, Murray A, Neilson JMM, ClarkeBF. Immediate heart-rate response to standing: simpletest of autonomic neuropathy in diabetes. BMJ1978;1:145-7.

13 Dabholkar VR, Gaitonde BB. A study of autonomic func-tions in leprosy. Lep Ind 1982;54:303-17.

14 Kyriakidis MK, Noutsis CG, Robinson-Kyriakidis CA, etal. Autonomic neuropathy in leprosy. Int J Lep 1983;51:331-5.

15 Ramachandran A, Neelan PN. Autonomic neuropathy inleprosy. Ind J Lep 1987;59:405-13.

16 Low PA, Neumann C, Dyck PJ, Fealey RD, Tuck RR.Evaluation of skin vasometer reflexes by using laserDoppler velocimetry. Mayo Clin Proc 1983;58:583-92.

17 Khan F, Spence VA, Wilson SB, Abbot NC. Quantificationofsympathetic vascular responses in skin by laser Doppler

970

on Novem


http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1991. Dow

nloaded from


Impairment of vasomotor reflexes in the fingertips of leprosy patients

flowmetry. Int J Microcirculation: Clin Exper 1991;10:145-53.

18 Khan F, Struthers AD, Spence VA. The effect ofprazosin onskin microcirculation as assessed by laser Doppler flow-metry. Brit J Clin Pharmacol 1988;26:267-72.

19 Nilsson GE, Tenland T, Oberg PA. A new instrument forcontinuous measurement of tissue blood flow by lightbeating spectroscopy. IEEE Trans Biomed Eng1980;27:12-19.

20 Nilsson GE, Tenland T, Oberg PA. Evaluation of a laserDoppler flowmeter for measurement of tissue blood flow.IEE Trans Biomed Eng 1980;27:597-604.

21 Holloway GA. Laser Doppler measurement of cutaneousblood flow. In: Rolfe P, ed. Non-invasive physiologicalmeasurement, vol 2. London: Academic Press, 1983:219-49.

22 Grant RT, Bland EF. Observation on arteriovenous anas-tomoses in human skin and in the bird foot with specialreference to cold. Heart 1931;15:385-406.

23 Hales JRS, Iriki M, Tsuchiya K, Kozama E. Thermallyinduced cutaneous sympathetic activity related to bloodflow through capillaries and arteriovenous anastomoses.Pflug Arch 1978;375:17-24.

24 Salerud EG, Tenland T, Nilsson GE, Oberg PA. Rhyth-mical variation in human skin blood flow. Int J Microcir-culation: Clin Exp 1983;2:91-102.

25 Bolton B, Carmichael EA, Sturup G. Vaso-constrictionfollowing deep inspiration. J Physiol 1936;86:83-94.

26 Gilliat RW. Vaso-constriction in the finger after deepinspiration. JPhysiol 1948;107:70-88.

27 Johnson RH, Spalding JMK. The nervous control of thecirculation and its investigation. Disorders ofthe autonomicnervous system. Oxford: Blackwell, 1974:33-58.

28 Sinclair D. Motor nerves and reflexes In: Jarrett A, ed. The

physiology andpathophysiology ofthe skin, vol 2. The nervesandblood vessels. London: Academic Press, 1973:475-508.

29 Bland JM, Altman DG. Statistical methods for assessingagreement between two methods ofclinical measurement.Lancet 1986;i:307-10.

30 Bini G, Hagbarth KE, Hynninen P, Wallin PG. Ther-moregulatory and rhythm generating mechanisms gover-ning the sudomotor and vasoconstrictoroutflow in humancutaneous nerves. J Physiol 1980;306:537-52.

31 Sunderland S. Intraneural topology of radial, median andulnar nerves. Brain 1945;68:243-99.

32 Karanth SS, Springall DR, Lucas S, Levy D, Ashby P,LeveneMM, Polak JM. Changes in nerves and neuropep-tides in skin from 100 leprosy patients investigation byimmunocytochemistry. J Pathol 1989;157:15-26.

33 Ermakova N. Studies in leprosy: the central sympathetic andperipheral nervous system. Int J Lep 1936;4:325-35.

34 Turkel SB, Van Hale HM, Rea TH. Ultrastructure of thedermal microvasculature in leprosy. Imt J Lep 1982;50:164-71.

35 Burchard G-D, Bierther M. An electron microscopic studyof the small cutaneous vessels in lepromatous leprosy. IntJLep 1985;53:70-4.

36 Yadav SS. Arteriographic evaluation of vascular changes inleprosy. Angiology 1978;29:17-21.

37 Chopra JS, Kaur S, Murthy JMK, Kumar B, Radhakrish-nan K, Suri S, Sawhney BB. Vascular changes in leprosyand its role in the pathogenesis of leprous neuritis. Lep Ind1981;53:443-53.

38 Agrawal BR, Agrawal RI. Arteriography in Leprosy. Int JLep 1981;57:138-45.

39 Khan F. The sympathetic control of skin blood flow and itssignificance in thermoregulation. (PhD Thesis), 1990.University of Dundee.

971

on Novem


http://jnnp.bmj.com

/J N

eurol Neurosurg P


ber 1991. Dow

nloaded from


impairment vasomotor - bmj

Documents