Leading Article

Medical Toxicology 2: 1-9 (1987)0112-5966/87/0001-0001/$04.50/0© ADIS Press LimitedAll rights reserved

Treatment of Human Amatoxin Mushroom PoisoningMyths and Advances in Therapy

G.L. FloersheimDepartments of Surgery and Research, Zentrum fur Lehre und Forschung,Kantonsspital, Basel

The purpose of this article is to review the cur­rently available literature on poisoning with ama­toxin-containing mushrooms, and to provideguidelines for treatment.

Every autumn, doctors may be faced with oneof the most dramatic situations known in humantoxicology, namely the poisoning with the mush­room Amanita phal/oides (death cap) or the similarspecies Amanita verna and Amanita virosa. An in­clination towards the merits of natural products ,combined with an inadequate knowledge of mush­room morphology, may lead to the preparation ofa fatal dish. When the victims complain after acharacteristic latent period of many hours of severegastrointestinal symptoms, the diagnostic skills ofthe physician are not too seriously taxed. However,when the physician starts to search the literaturefor effective therapeutic measures, he will rapidlyrealise that firm advice and guidance is hard tofind. This situation is apt to engender a frantic po­lypragmasia, with more and more treatments beinginstituted until the risk of treatment interactionsbecomes quite considerable.

Consulting more recent literature does not assistin the selection of proper treatment (Hanrahan1984). Even textbooks of high repute are noncom­mital or lay a smoke screen over the field insteadof providing hard data and clear recommenda­tions. Statements such as 'treatment is largely sup­portive; thioctic acid may be an effective antidote. ..; but the evidence for this is largely based on

anecdotal studies' (Taylor 1980) or 'only suppor­tive measures are of any avail' (Volle 1971) offerthe medical team in the emergency room or in theintensive care unit little more than earlier, purelymythical nostrums, such as the peroral adminis­tration of ground rabbit brain or stomach , or theinjection of 'serum antiphalloidien' raised in horsesor other animals with a more natural aversion topoisonous mushroom than homo sapiens.

This rather resigned attitude to therapy is com­pensated by a multitude of reports based on smallseries of patients with high survival rates ascribedto the respective treatment. However, these seriesare probably too small to allow statistically validconclusions to be drawn as to the value, or other­wise, of any particular measure. The aim of thisarticle is to steer a course between the distressingand unjustified resignation and the reports of somecase histories, where survival is surmised but notproven to be related to the variety of treatmentemployed. With an attempt to evaluate criticallythe current concepts of how the intoxication shouldbe treated , real advances may be identified asmeasures which are supported by facts.

1. Clinical Course, Lethality andPrognostic Factors

The clinical course of Amanita intoxication iswell known. Symptoms commence after a char­acteristic latent period of approximately 8 to 12

Treatment of Human Amatoxin Mushroom Poisoning

hours. After this symptom-free interval, nausea,vomiting, abdominal cramps and severe diarrhoeadevelop. After 2 to 3 days, the gastrointestinal phaseof the intoxication, which is amenable to treatmentby fluid and electrolyte substitution, is largely re­solved, but 1 or 2 days later, severe hepatic diseasewith extensive necrosis of liver cells leads to anaggravation of the patient's condition. This phaseis characterised by a marked increase in plasmaconcentrations of hepatic enzymes including al­kaline phosphatase, ALT (SGOT), AST (SGPT) andof bilirubin, causing jaundice. Concomitantly, bloodcoagulation deficiency as a consequence of im­paired synthesis of clotting factors appears , whichis closely linked to the prognosis. The most reliableindicator for the severity of the poisoning is throm­boplastin time (Quick). Values below 10%were as­sociated with a fatal outcome in 84% of poisonedpatients, but no patient with values above 40%died(Floersheim et al. 1982). Since serum creatinineconcentrations showed no correlation with the out­come, it seems unlikely that nephrotoxic effects ofthe mushroom contribute significantly to the fa­talities. If remission does not occur, hepatic comawith central nervous symptomatology ensues.

It is generally accepted that the amatoxins(mainly o-amanitin), and not phallotoxins, are thecyclopeptide toxins which are responsible for thelethality of Amanita species (Faulstich & Fauser1980). However, some experimental data contra­dict this hypothesis (Floersheim 1978, 1983).

In particular, why do mice poisoned with mush­room extract die after 8 to 10 hours , while withamatoxins death occurs after 3 to 5 days? Why canthe toxicity of the extract be antagonised by 'pure'phallotoxin antagonists such as rifampicin and an­tamanide? Finally, why does cytochrome c displaysignificant curative effects against o-amanitin andnot against the extract?

1.1 Influence of Age

The mortality rate in 288 cases of clinical deathcap intoxication recorded in Switzerland from 1919to 1958 was 30% (Alder 1961). No great improve­ment was revealed when 205 cases of intoxications

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recorded throughout Europe from 1971 to 1980were analysed (Floersheim et al. 1982).The overallmortality was 22.4%, but a significant differencebetween adults and children was observed. While51.3% of children below 10 years of age died, themortality in patients older than 10 years was only16.5%. The higher lethality observed in children ispossibly due to the fact that they often eat similarquantities of mushrooms as adults , but by virtueof their lower bodyweight, absorb a larger dose ofthe toxins per kg bodyweight. Thus, it seems clearthatthe prognosis of the intoxication is determinedto a major extent by the quantity of mushroomeaten.

1.2 Influence of the Latent Period

As well as age, the latent period between theingestion and the appearance of the symptoms isa prognostic factor (Floersheim et al. 1982). Fatalcases of death cap poisoning displayed an averagelatent period of 10.3 hours, while the interval insurviving patients averaged 12.6 hours.

1.3 Size of Population in Patient Studies

The fact that the overall survival rate is 75 to80% (or even 83.5% if no children below 10 yearsof age are included) should be considered whensmall patient series are evaluated and recommen­dations on new 'effective' therapies are derived.Small series of 10 to 20 cases will lack predictivevalue as to the usefulness of the involved therapy.This may be illustrated by an example drawn fromour 205 cases with 46 fatalities (Floersheim et al.1982), where all of the 16 patients treated with sil­ibinin survived. When the statistical comparisonof 0/16 fatalities versus 46/189 fatalities was per­formed , the therapeutic efficacy of this treatmentwas not statistically significant. If age and latentperiod are taken into account, even larger seriesmay fail to reach statistical significance if they con­sist predominantly of adults and intoxications oflow or moderate severity (as expressed by rela­tively long latent periods). This makes it quite dif­ficult to establish the efficacy of new treatments,

Treatment of Human Amatoxin Mushroom Poisoning

particularly if additional measures whose delete­rious effects cannot be excluded are taken into ac­count, as will be inevitable with any retrospectiveanal ysis of cases. Small groups of patients, con­sisting mainly of adults , may provide valuable data,but will not permit evaluation of the efficacy of atherapy. A relatively small number of cases may'allow an answer, however, if it consists of childrenbelow age 10 or of patients with Quick values below10%.

Unfortunately, this proviso precludes a clear-cutassessment of therapies applied in the great ma­jority of clinical studies. Since controlled prospec­tive studies are unlikely to be performed, the in­stitution of therapies which have been shown to beeffective experimentally, particularly in the dogmodel , seem a more realistic approach. In this pa­per, the current concepts in the therapy ofAmanitapoisoning are examined.

1.4 Influence of Ethanol

An assessment of the therapeutic efficacy of aparticular treatment must consider the importantprognostic variables of age and the latent periodbetween ingestion of the mushrooms and the onsetof symptoms. However, another variable has re­cently been identified, linked with the beverage in­gested with the mushrooms.

The possible relevance of the drink taken withthe mushroom meal derives from the puzzling ob­servation that acute , but not long term pretreat­ment of mice with ethanol diminished the toxicityof subsequent doses of a lyophilisate from Amanitapha//oides (Floersheim & Bianchi 1984). Ethanolboth increased the survival rate of the mice andlargely prevented hepatic confluent necrosis, whichwas a feature of the histopathological damagecaused by the mushroom. This finding may be inaccord with occasional clinical impressions thatAmanita pha//oides intoxication had a less severecourse if the patient had consumed an alcoholicbeverage together with the meal. These observa­tions suggest that ethanol ingestion with the mealmay be a prognostic variable which could influencefavourably the outcome ofAmanita pha//oides poi-

3

soning. It should be taken into account when ther­apeutic measures in Amanita pha//oides intoxica­tion are evaluated. This finding may also partiallyexplain the higher mortality rates in children whoprobably do not consume alcohol with the mush­room meal.

2. Concepts In Therapy

2.1 Benzylpenicillin (Penicillin G)

The introduction of penicillin for the treatmentof Amanita poisoning was based upon the experi­mental finding that various antibacterial agents suchas benzylpenicillin, sulphamethoxazole, chloram­phenicol and rifampicin protected mice and ratsagainst lethal doses of extracts of Amanita phal­/oides or of o-amanitin (Floersheim 1971, 1972a;Floersheim et al. 1971). Corroborative evidence forthis effect came from a follow-up study in whichbenzylpenicillin was administered curatively, i.e.at 5 and 24 hours after dogs had ingested a sub­lethal preparation of Amanita pha//oides (Floer­sheim et al. 1978). In this study, indicators ofliverdamage and clotting disorders showed a significantprotection by penicillin (fig. 1). Similar effects ofbenzylpenicillin were observed on the liver en­zymes AST (SGOT), ALT (SGPT) and 'Y-glutamyltransferase and on coagulation factors includingFactors II, V, X, fibrinogen and the thromboplas­tin time (Floersheim et al. 1978; Floersheim 1978),and when silibinin was administered (Vogel 1980)in dogs. Moreover, in our retrospective clinicalstudy involving 205 patients, multiple regressionanalysis of the cases revealed that the administra­tion of benzylpenicillin was significantly more oftenassociated with survival (Floersheim et al. 1982).Doses of 300,000 to 1,000,000 U/kgjday wereclearly more effective than doses below 300,000 U/kg/day. Of course, the potential risks of high-dosepenicillin must be considered (Hruby et al. 1983).Among the theories which have been advanced toexplain the effect of penicillin, the hypothesis whichlinks penicillin to 'Y-aminobutyric acid (GABA)seems attractive. In liver failure due to Amanitapha//oides, this principal inhibitory neurotransmit-

Treatment of Human Amatoxin Mushroom Poisoning 4

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Fig. 1. Percentage changes (mean) of alkaline phosphatase (vs initial values) in the serum of groups of 6-10 dogs given a Iyophilisateof boiled Amanita phalloldes by the oral route (hour 0) and treated intravenously with various drugs administered 5 and 24 hourslater. Treatments: Controls (0--0); benzylpenicillin (penicillin G) 1000 mg/kg at 5 hr (0'" '0); silymarin, 50 mg/kg at 5 hr and 30mg/kg at 24 hr (0- - -0); cytochrome c. 50 mg/kg at 5 and 24 hr (0- - -0); prednisolone, 30 mg/kg at 5 and 24 hr (0- -0)[Floersheim et at 19781.

ter which is derived from enteric bacteria may beinsufficiently metabolised: raised plasma concen­trations of GABA may thus explain the symptom­atology of neural inhibition. Accordingly, orallyadministered penicillin, by sterilising and reducingthe GABA-producing intestinal flora, may preventthe severe encephalopathy likely to be the finalcause of death in Amanita poisoning. The fact thatvery high intravenous doses of benzylpenicillin are,in contrast to orally administered antibacterials,clinically associated with increased survival maybe due to the greater impact of intravenous and ,bile-excreted penicillin on the intestinal flora. Inaddition, penicillin has been shown to inhibit theuptake of amanitin into liver cells(Jahn et al. 1980).

If, despite consistent experimental and statisti­cal evidence, the overall survival of the patientstreated with penicillin was not impressively higherthan in the total patient population (Floersheim etal. 1982), this may be due to the fact that the pos­sible beneficial effect to penicillin was often coun­terbalanced by concomitant treatments includingthioctic acid, haemodialysis and exchange trans­fusion which on their own seemed to impair theprognosis.

A recent case history of 2 young tourists trav­elling through Switzerland in September 1985 mayillustrate this point. They ate a meal comprisingperhaps 300 to 500gof self-collectedAmanita phal­loides in the evening. Seven hours later, they awoke

Treatment of Human Amatoxin Mushroom Poisoning

with severe abdominal cramps, vomiting and diar­rhoea. When they were brought to the hospital 17hours after the meal, Amanita intoxication was di­agnosed. Treatment consisted of intravenous ben­zylpenicillin (1,000,000 U/kg/day) and silibinin (50rug/kg/day) and, in addition, haemoperfusion,dexamethasone and forced diuresis, etc. were in­stituted. Both patients died after 5 days. As in ourstudies, haemoperfusion was not associated withincreased survival, and glucocorticosteroids wereassociated with impaired liver function, the pos­sibility that these additional measures compro­mised the chances of survival cannot be excluded.It must, however, be stressed that probably notherapy whatsoever available at present is effectiveagainst mushroom doses above a certain threshold.

2.2 Silibinin

Silibinin is a water-soluble preparation of thechief constituent of silymarin, the active principleof the milk thistle Si/ibum marianum, whose he­patoprotective and antagonistic effect againstAmanita toxins (Trost & Lang 1984; Vogel 1980)and extracts (Floersheim et al. 1978) [fig. I] wasimpressive and confirmed in each tested experi­mental model. Silibinin is thought to inhibit thepenetration of the amatoxins into liver cells (Jahnet al. 1980). In our clinical series of 205 patientswith 46 fatalities, all 16 patients receiving silibininsurvived (Floersheim et al. 1982). Unfortunately,as pointed out before, the relatively small numberof cases did not allow to ascribe a statistically sig­nificant therapeutic efficacy to this treatment. Apositive impression was also obtained from aclinical series of 18 cases of Amanita poisoning(Hruby et al. 1983), in which the severity of theintoxication was correlated with the time elapsedbefore commencement of silibinin therapy: the ear­lier silibinin was administered, the more benign wasthe clinical course. It was concluded that early,(within 48 hours) administration of 20 to 50 mg/kg/day of silibinin was an effective prophylacticmeasure against severe liver damage. The combin­ation of clear-cut experimental efficacy and pre­dominantly positive impressions from clinical

5

administration seems to support the recommen­dation of this agent as a clinical antidote.

2.3 Hyperbaric Oxygenation

Hyperbaric oxygenation in the treatment ofAmanita intoxication has been used almost exclu­sively by French authors (Larcan et al. 1981). Withmultivariate regression analysis, taking into ac­count age and the latent period as well as the effectof all other applied measures, oxygenation andpenicillin contributed independently to a highersurvival rate (Floersheim et al. 1982). However,while penicillin provided undeniable experimentalefficacy (Floersheim et al. 1978), oxygenation in asmall scale experiment against Amanita extract wasonly marginally effective in conjunction with zincpretreatment (Floersheim et al. 1984) but was in­effective in mice not pretreated with zinc.

2.4 Thioctic Acid

Reports from Czechoslovakia (Dudova et al.1980), Hungary (Zulik & Kassay 1980) and USA(Bartter et al. 1980) advocating the use of thiocticacid (a-lipoic acid) began to appear from the 1960sto the I970s. Although favourable impressions wereobtained, no rigorous evaluation with adequate si­multaneous controls was provided. Accordingly, theconsequence of the administration of thioctic acidin the presented clinical cases could not be ascer­tained . Again, high survival rates in small groupsof patients were mistakenly taken as proof for drugefficacy(Berkson 1980). In our study involving theretrospective analysis of 205 cases of Amanita in­toxication (Floersheim et al. 1982), the adminis­tration of thioctic acid was more often associatedwith a fatal outcome than when no thioctic acidwas administered. In another recent report (Olsonet al. 1982), the efficacy of this agent was not shown.Experimentally, thioctic acid was totally ineffectiveas an antidote against an extract of Amanita phal­loides in mice and dogs (Alleva et al. 1975) or inmice poisoned with a-am anitin and phalloidin(Trost & Lang 1984). There is thus no reason tocontinue the use of thioctic acid in the therapy ofAmanita intoxication.

Treatmentof Human Amatoxin Mushroom Poisoning

2.5 Steroids And Cytochrome c

Some early experimental studies suggested a fa­vourable effect of glucocorticosteroids against ex­tracts of Amanita phalloides (Floersheim 1975,1976) and of cytochrome c against a-amanitin inmice (Floersheim I972b,c). Cytochrome c dis­played significant curative activity even if admin­istered 2 hours after the toxin . However, in themore exacting model where dogs were given an oralsublethal dose of mushroom extract and treated 5and 24 hours later with various 'antidotal' agents(Floersheim et al. 1978), prednisolone and cyto­chrome c not only failed to influence favourablythe intoxication but actually worsened the symp­tomatology (fig. I). Also in our clinical study(Floersheim et al. 1982), prednisone and cyto­chrome c seemed rather to compromise survivalthan to enhance it.

3. Elimination Procedures

Since the advent of radioimmunological meth­ods to detect amatoxins in the plasma of poisonedpatients, active elimination measures like haemo­perfusion , haemodialysis, exchange transfusion,forced diuresis , etc. have been applied extensively.However, their value has not been ascertained incontrolled studies. In our clinical series, eliminat­ion procedures such as exchange transfusion andhaemodialysis were associated with a lower sur­vival rate, while beneficial effects offorced diuresisand charcoal haemoperfusion were not substanti­ated (Floersheim et al. 1982). In Amanita phal­loides intoxication, the absence of a correlation be­tween plasma concentration of amatoxins and theclinical outcome (Langer et al. 1980a) and the lackof evidence that toxicologically significant quan­tities of toxins are removed, would militate in myview against elimination procedures which are in­vasive and, in the context of frequently astoundingpolypragmasia (up to 20 measures in I patient havebeen recorded), potentially hazardous. Although theenhancement of toxin elimination seems to be alogical principle on which the treatment of poison­ing should be based, the value of drug removalmeasures has also been questioned more generally

6

(Todd 1984) since no proof of its value in drugpoisoning, e.g, with salicylates or barbiturates, isavailable. In Amanita poisoning, the series men­tioned above indicates that drug removal proce­dures may actually worsen the prospect of recov­ery, perhaps by influencing unfavourably thealready compromised coagulation pattern. A highdistribution volume of the toxins may preclude ef­fective removal from the blood. However, if a clin­ician elects to perform such procedures, they shouldbe carried out within the first 48 hours after themeal and continued as long as traces of amatoxinscan be detected in serum (Langer et al. I980a), andwith forced diuresis within 10 hours at the most(Langer et al. 1980b). Hyperinfusion, particularlywith dextran, has also been shown to have a det­rimental effect in mice poisoned with Amanita ex­tract (Floersheim I972c). Simpler measures to pre­vent further toxin uptake, such as gastric lavageand oral charcoal administration, are indicated,even if vomiting and diarrhoea have occurred priorto hospital admiss ion.

Two important aspects of Amanita intoxicationwhich are relevant to therapy are the early bindingof toxins to liver cells and enterohepatic circula­tion of the amatoxins (Faulstich & Fauser 1980;Fauser & Faulstich 1973). With regard to the firstpoint, it should be mentioned that silibinin andpenicillin inhibit the uptake of o-amanitin in theliver (Jahn et al. 1980). With regard to the secondpoint , a sound theoretical principle would be tointervene with the cycle from bile excretion toreabsorption and reuptake of toxins in liver cells.Installation of a bile fistula allowed dogs to survivean otherwise lethal dose of amanitin (Fauser &Faulstich 1973). The practical value of removingAmanita toxins from the gastrointestinal fluid (Busiet al. 1979) by duodenal drainage in patients hasnot yet been assessed.

The radioimmunoassay for amatoxins remainsof value for confirming the diagnosis of Amanitapoisoning, but not to indicate the severity of theintoxication. The latter is likely to be determinedby the amount of toxin bound to liver cells, whichdoes not seem to be correlated with the plasmaconcentration of amatoxins.

Treatment of Human Amatoxin Mushroom Poisoning

At present, no incontrovertible evidence isavailable as to the therapeutic value of toxin elim­ination procedures. It is unlikely that a controlledprospective clinical evaluation will ever be under­taken. However, a controlled study in dogs poi­soned with Amanita, and subjected to eliminationmeasures , may indicate whether elimination pro­cedures are of any value in ameliorating the courseof Amanita intoxication.

4. New Strategies in AmanitaIntoxication

4.1 Bile Salts

The observation that the hepatic uptake systemfor phalloidin, the phalloidin antagonist antaman­ide (Wieland & Faulstich 1983), and bile salts isidentical (Wieland et al. 1984), may open newpathways for determining the mechanism ofAmanita intoxication. Additional data indicate thatthe sinusoidal bile salt transport system involvedin the uptake of phalloidin and antamanide alsomediates the uptake of amatoxins into hepatic cells(Kroncke et al. 1986). The uptake of amatoxins wasinhibited by antamanide, phalloidin, taurocholate,prednisolone and silibinin , but not by benzylpen­icillin and thioctic acid, although adequate plasmaconcentrations of benzylpenicillin may not havebeen reached. The concept of identical transportsystems for hepatocellular uptake of bile salts andamatoxins suggests that non-toxic bile salt deriv­atives with similar kinetic properties to taurocho­late could be of clinical use for the therapy ofAmanita poisoning. However, preliminary in vivoexperiments have failed to demonstrate that cho­late or taurocholate protect rats from death byphalloidin (Wieland & Faulstich 1983), or that ur­sodeoxycholate saves mice from death by Amanitaextract (Floersheim, unpublished data) . The ques­tion of whether the inhibition of the uptake ofAmanita toxins into liver cells reflects the capacityof a substance to protect against Amanita pha/­/oides also remains unanswered when one consid­ers that the natural antidote for phalloidin, anta­manide, which inhibits the uptake of phalloidin and

7

o-amarunn into liver cells, protects specificallyagainst phalloidin and not against o-amanitin(Wieland & Faulstich 1983).

4.2 Zinc and Other Metals

Another interesting and potentially useful ob­servation was that pretreatment with zinc aspartateincreased the survival of mice poisoned withAmanita phalloides Iyophilisate (Floersheim et al.1984), and that liver injury (confluent necrosis)cleared earlier in zinc-treated mice. Preliminary ex­periments also indicate that salts of other metalssuch as zirconium, yttrium, lanthanum and cobalthave protective potency (Floersheim, unpublisheddata).

4.3 Thiol Compounds

A further therapeutic option was suggested bythe finding that d-penicillamine improved the sur­vival of mice poisoned with the extract of Amanitaphalloides (Floersheim et al. 1984). This result in­dicates the necessity for a more systematic evalu­ation of other thiols. Preliminary studies indicatethat diethyldithiocarbamate in mice has not onlyprotective, but also curative activity against themushroom extract (Floersheim, unpublished data) .

5. Conclusions and TherapeuticRecommendations

In conclusion, in Amanita phalloides poisoningwe would recommend measures to avoid furthertoxin absorption, such as gastric lavages and duo­denal drainage combined with charcoal adminis­tration. Full supportive measures with fluid andelectrolyte substitution are also mandatory. As tomore specific antidotal therapy , one ought to optfor a treatment which has shown both experimen­tally and clinically statistically significant efficacy.So far, this is only the case for benzylpenicillin(Floersheim et al. 1978, 1982). Silibinin comes asa close second with clear-cut experimental activity(Floersheim et al. 1978; Trost & Lang 1984; Vogel1980) and an impressive clinical record (Floer-

Treatment of Human Amatoxin Mushroom Poisoning

sheim et al. 1982; Hruby et al. 1983) whose statis­tical significance remains, however, to be corrob­orated. The statistically significant association ofhyperbaric oxygenation with clinical survival(Floersheim et al. 1982) has not yet been supple­mented by experimental evidence of antagonisticactivity. Neither statistically significant experimen­tal nor clinical evidence of benefit is available formeasures such as thioctic acid or elimination pro­cedures. If the possible benefit of penicillin and sil­ibinin is not to be compromised, it is imperativeto avoid combining them with detrimental meas­ures. Finally, it is safe to keep in mind that at pre­sent, even the best treatment is apt to change thecourse of the intoxication from death to survivalonly within a relatively small range of toxin dose.The outcome of the intoxication seems to a largeextent to be determ ined by the amount of mush­room ingested. If the toxin dose is small enough,patients will in general survive with any therapy.If the toxin dose is large enough, the victims willsuccumb in spite of even the best currently avail­able treatment.

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Author's address: G.L. Floersheim, Kantonsspital Basel, Univ­

ersitatkliniken, Departement Forschung, Hebelstrasse 20, CH-4031

Basel (Switzerland).

CND17th World Congress for Dermatology

Date: 24-29 May 1987Venue: Berlin, West Germany

For further info rmation, please contact:Prof. Dr C.E. Orfanos,General Secretary,

Un tversltats-Hautklinik und Poliklinik,

Klinikum Steglitz der Freien Unlversttat Berlin,Hindenburgdam 3D,0 -1000 Berlin 45,West Germany.