INTERNATIONAL JOURNAL OF LEPROSY^ Volume 54, Number 2

Printed in the U.S.A.(ISSN 0148-916X)

INTERNATIONALJOURNAL OF LEPROSY

And Other Mycobacterial Diseases

VOLUME 54, NUMBER 2^ JUNE 1986

Episodic Edema in Type 2 Lepra ReactionCan Be Caused by Transient Lymphatic

Obstruction in the Lymph Node'John N. A. Stanley, John M. H. Pearson, and Dennis B. Ridley 2

Edema is caused by the accumulation ofexcessive interstitial fluid. It is a neglectedsubject in leprosy; it has not, for instance,appeared in the subject index of theINTERNATIONAL JOURNAL OF LEPROSY for thepast decade. Nevertheless, it is not uncom-monly seen in patients with lepra reactions,both type 1 and type 2 ('). Moreover, it canbe damaging. Ulcers of edematous feet andlegs are notoriously hard to heal, and thebizarre contractural deformities of the handsand feet seen in "burnt-out cases" indicatethe damage that can be caused by fibrosisfollowing chronic edema.

In a normal limb there is rapid turnoverof the interstitial fluid, and the absence ofedema is the result of balanced flows of fluid

' Received for publication on 13 August 1985; ac-cepted for publication in revised form on 17 January1986.

2 J. N. A. Stanley, M.B.B.S., Research Officer,Dhoolpet Leprosy Research Centre, Hyderabad 500006,India (present address: Department of PostgraduateMedicine, North Staffordshire Medical Institute, Stokeon Trent, England). J. M. H. Pearson, D.M., F.R.C.P.,Physician, Dhoolpet Leprosy Research Centre, Hy-derabad 500006, India. D. S. Ridley, M.D., F.R.C.Path.,Consultant Pathologist, Hospital for Tropical Diseases,London NW1 OPE, England (present address: TheBland-Sutton Institute of Pathology, Middlesex Hos-pital Medical School, London W1P 7PN, England).

Reprint requests to Dr. Pearson.

in and out of the interstitial space. The fac-tors controlling these movements (Starling'sforces) are intracapillary pressure, tissuepressure, and colloid osmotic pressure. Atthe arterial (high pressure) end of the cap-illary bed, the balance favors movement outof the capillary; at the venous end, the lowerintravascular pressure and the serum os-motic pressure cause interstitial fluid to en-ter the capillary. Any fluid tending to ac-cumulate in the interstitial space travels viathe lymphatic capillaries and regional lymphnodes to re-enter the circulation via the tho-racic duct. The lymphatics are particularlyconcerned with transport of protein-con-taining interstitial fluid formed as the resultof inflammatory or immune injury to bloodvessels back into the general circulation.

The lymphatics of the normal limb ap-pear adequate to carry large flows of pro-tein-containing fluid. A patient with severetype 2 lepra reaction, for instance, may haveextensive skin lesions; inflammatory exu-date will enter the interstitial space as a re-sult of increased capillary permeability dueto the immune response that follows theformation of immune complexes at the site.Nevertheless, it is unusual to see anythingmore than trivial edema of the hands andfeet in such cases. On the other hand, edema

231

232^ International Journal of Leprosy^ 1986

in type 2 lepra reaction can also occur inthe absence of severe skin manifestations.

This paper presents evidence that attacksof edema in type 2 lepra reaction can becaused by transient lymphatic obstructionat the level of the regional lymph nodes.

PATIENTS AND METHODSThe patients included in this study were

all receiving outpatient treatment for lepro-matous leprosy with type 2 lepra reaction(erythema nodosum leprosum, ENL) atDhoolpet Leprosy Research Centre in Hy-derabad, India. They were entered into thestudy at the time they were observed to havedeveloped edema of the hands and/or feet.At this time almost all showed active ENLlesions of the skin.

On entry a detailed history was taken,particularly of any previous episodes of ede-ma and their association with reaction andenlarged or tender lymph nodes. The pa-tients were examined with particular ref-erence to the possible presence of such lymphnodes. Skin smears were taken if they hadnot been done in the previous year.

Enlarged supratrochlear lymph nodeswere excised from five patients, four ofwhom had swollen hands at the time. Thefifth had swollen feet and developed edemaof the hands with lymphadenopathy inanother attack soon after the biopsy. ,In fourmore patients, biopsies were taken fromedematous skin areas in such a way as toinclude an underlying subcutaneous vein.No patient was receiving corticosteroids atthe time of biopsy. Biopsies were fixed informaldehyde (40%, 10% v/v), mercuricchloride (2% w/v), and glacial acetic acid(3% v/v) (FMA), and processed for routinehistology.

When investigations were completed, thepatients were, in most cases, treated with ashort course (2-3 weeks) of prednisolone ( 2 );the edema usually resolved in a week or less,although attacks often recurred for somemonths and the patients needed furthercourses of steroids. None of the patients,however, developed chronic edema duringa follow-up period of 6-12 months.

RESULTSFourteen patients were included in the

study, classified clinically as LL (13) and BL

(1); there was biopsy confirmation in tencases. They were aged 14-70 years (averageage = 34) and had been treated for 1-10years (average = 4). The bacterial index (BI)at the time of study ranged from 0 to 4.3+(average = 3.3 +). All of the patients werereceiving repeated short courses of prednis-olone for type 2 reaction, and five were alsoreceiving clofazimine.

The edema was mild in all but one case,and it was nearly always bilateral and sym-metrical. ENL lesions were present in al-most all of the cases at the time of exami-nation, and were seen on edematous limbsin most cases. However, they were not oftensevere or extensive. The regional lymphnodes (inguinal for feet, axillary for hands)were enlarged and often tender, even in thosepatients without ENL lesions on the edem-atous limbs. The supratrochlear nodes wereoften enlarged and tender. In three episodesof edema, the state of the lymph nodes wasnot recorded.

From questioning and follow up, it be-came clear that lymph nodes could be en-larged and tender in the absence of edema.Indeed, most of the patients in this seriesdeveloped episodes of lymphadenopathywithout edema (24 such episodes were re-corded in 52 episodes of lymphadenopa-thy).

The four biopsies of edematous skin weretaken from sites overlying subcutaneousveins, and ENL lesions were avoided. Thebiopsies showed, in three instances, the fea-tures of regressing LL leprosy with no signof reaction; the fourth was reported as oldhealed leprosy. All biopsies showed markeddilatation of the lymphatic channels in theupper dermis. Of the four veins, one lookednormal apart from the presence of acid-fastbacilli (AFB) in the smooth muscle layer.The other three were edematous, with AFBin the muscle and, in two cases, also in theendothelium. One of the veins was also in-filtrated with neutrophils, suggesting thepossibility of ENL in the vein wall.

Five lymph nodes were biopsied. Theywere much enlarged, being usually aboutfive times the normal diameter. Histologi-cally, all of the nodes showed capsular thick-ening, which was severe in 4 of the 5 biopsycases. Sometimes the fibrosis extended intothe node itself and destroyed the normal

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54, 2^Stanley, et al.: Edema in Type 2 Reactions^233

FIG. 1. Thickened fibrosed capsule of lymph nodeand destruction of the subcapsular sinus by foamy mac-rophages, cellular infiltration and, probably, previousreaction (H&E x 150).

demarcation of capsule and node (Fig. 1).In one case the capsule showed a hyalineappearance. The capsular sinuses, by con-trast, were narrow and in part obliterated.In one case, a dilated afferent lymphaticchannel was seen just outside the capsule.

The nodes themselves had the appear-ance of lepromatous leprosy, with accu-mulations of foamy macrophages in thesubcapsular sinuses, the paracortical areas,and the medulla. One biopsy showed a focusof classical ENL in the cortex (Fig. 2). Oneother node showed an area of severe edemaand exudate near the subcapsular sinus, andan increase of mast cells in this region (Fig.3). These changes were reactional but notquite typical of ENL. Two other casesshowed some increase of mast cells in thesubcapsular area. The patient who did notdevelop edema of the hands until after thetaking of the biopsy showed no reactionalchanges in the lymph node.

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DISCUSSIONEnlarged supratrochlear lymph nodes are

commonly present in active lepromatousleprosy. They are not tender, and shrinkduring treatment so they are seldom foundwhen skin smears become negative.

The supratrochlear and other nodes of thepatients in this study were enlarged, andthey underwent episodes of pain, tender-ness, and further increase in size. A specificlocalized ENL lesion was observed in onecase, and reactional edema in another.However, the constant finding was markedfibrosis and thickening of the capsule,brought about by chronic inflammation inthe nodes (as is also the case in other chronicinfective conditions). The subcapsular si-nuses tended to be compressed against thefibrous capsule by the increased mass of thenode which was brought about by the infil-tration of foamy macrophages together withsome degree of nonspecific reactive changeand enhanced by episodes of acute reaction.Lymphatics are low pressure channels, and

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234^ International Journal of Leprosy^ 1986

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Flo. 3. A reaction in the subcapsular region of alymph node, characterized by edema, exudate and (notvisible in the figure) mast cells. Not so typical of ENL.Note the thickened capsule (H&E x 150).

it would only require a small increase inintranodal pressure to obstruct the flow inthe subcapsular sinus. An increase in lymphflow to the node due to ENL in the limbwould further increase the likelihood of ede-ma developing.

The nature of the intranodal inflamma-tory process is not exactly clear. LocalizedENL was demonstrated in one case, andcould have been present in unsectioned partsof this or other nodes. However, the acuteedema, extravasation of red cells, and in-crease in mast cells in one case were sugges-tive in some respects of exacerbation reac-tion ( 4 ). They were not exacerbationreactions because the AFB were scanty andnot solid staining, but possibly the ENL ismodified somewhat by the periodic arrivalin the node of large amounts of antigendraining from ENL lesions in the limb.

There was good correlation between ede-ma and lymphadenopathy. In every casewhere the state of the lymph nodes was re-

corded, they were enlarged when edema waspresent. However, almost half the attacksof lymphadenopathy were not accompaniedby edema. This is to be expected, since it ishardly possible that all of the regional nodescould be equally severely affected in everyattack. Moreover, the flow of lymph is likelyto vary according to the extent of ENL le-sions in the limbs.

This study gives no information on thecause of the chronic edema that can developduring or after a type 2 lepra reaction, al-though one can speculate that extensivepostinflammatory fibrosis in the regionallymph nodes could cause persistent edema.However, this study clearly indicates thatwhen patients with type 2 lepra reaction de-velop lymphadenopathy, the reaction in-creases the bulk of the nodes. Thus, internalexpansion compresses the subcapsular sinusagainst the unyielding fibrotic capsule of thenode, obstructs the flow of lymph into andthrough the node, and so can and often doescause peripheral edema.

SUMMARYFourteen patients with lepromatous lep-

rosy developed attacks of edema of the handsand/or feet associated with attacks of type2 lepra reaction (erythema nodosum lepro-sum). The regional lymph nodes were en-larged and often tender when edema waspresent. Lymph node biopsies in five casesshowed compression of the subcapsular si-nus against the thickened fibrotic capsule ofthe inflamed node. It is suggested that thisobstructs the inflow of lymph into the re-gional nodes, thereby causing the edema.

RESUMENCatorce pacientes con lepra lepromatosa desarrolla-

ron ataques de edema en los pies y/o manos, asociadoscon cuadros reaccionales del tipo 2 (eritema nodosoleproso). Cuando hubo edema, los ganglios linfaticosregionales estuvieron agrandados y a menudo reblan-decidos. Las biopsias de los ganglios linfaticos de 5pacientes mostraron compresiOn del seno subcapsularcontra la capsula fibreltica engrosada de los gangliosinflamados. Se sugiere que esto obstruye el influjo delinfa a los ganglios linfaticos regionales originando eledema.

RESUME

Quatorze malades atteints de lepre lepromateuse ontdeveloppe des episodes d'oedeme aux mains, aux pieds,

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54, 2^Stanley, et al.: Edema itz Type 2 Reactions^235

aux quatre extremites, lors d'attaque de reaction le-

preuse de type 2 (erytheme noueux lepreux). Les gan-

glions lymphatiques regionaux etaient augmentês devolume, et souvent plus sensibles au toucher lorsqu'il

y avait de l'oederne. Les biopsies de ganglions lym-

phatiques preleves chez cinq malades ont montre quele sinus sous-capsulaire etait comprime contre la cap-

sule fibreuse epaissie du ganglion enflamme. On sug-gere que ce mecanisme entraine une obstruction de Ia

circulation de Ia lymphe dans les ganglions regionaux,ce qui des lors produit l'oedeme.

Acknowledgments. We thank Dr. Marian Ridley for

helpful comments. Dhoolpet Leprosy Research Centreis administered by Victoria Hospital Dichpalli in col-laboration with the Medical Research Council (of Great

Britain), and is also supported by the British LeprosyRelief Association (LEPRA).

REFERENCES1. JOPLING, W. H. Reactions in leprosy. (Letter) Lepr.

Rev. 41 (1970) 62.2. PEARSON, J. M. H. The use of corticosteroids in

leprosy. Lepr. Rev. 52 (1981) 293-297.

3. RIDLEY, D. S. and JOPLING, W. H. Classification of

leprosy according to immunity. A five-group sys-tem. Int. J. Lepr. 34 (1966) 255-273.

4. RIDLEY, D. S. and RIDLEY, M. J. Exacerbation re-

actions in hyperactive lepromatous leprosy. Int. J.

Lepr. 52 (1984) 384-394.