British3Journal ofOphthalmology 1993; 77: 284-288

Manchineel keratoconjunctivitis

John F Pitts, Nigel H Barker, D Clive Gibbons, Jeffrey L Jay

Tennent Institute ofOphthalmology, GlasgowGIl 6NT, ScotlandJ F PittsN H BarkerJ L Jay

Queen ElizabethHospital, St Michael,Barbados, West IndiesD C GibbonsCorrespondence to:Dr Nigel Barker, TennentInstitute of Ophthalmology,38 Church Street, GlasgowGIl 6NT, Scotland.Accepted for publication12 January 1993

AbstractThe Manchineel tree is an evergreen widelydistributed in tropical regions. The toxicnature of Manchineel has been known sincethe early sixteenth century. Contact with itsmilky sap (latex) produces bulious dermatitisand acute keratoconjunctivitis. We identified19 patients who had ocular injuries caused byManchineel between 1985 and 1990 and wereable to review 12. AU ofthese patients had beentreated by lavage, cycloplegia, and topicalantibiotics. Of 20 episodes of exposure 14affected both eyes. The cornea was damagedin 16 episodes, the extent varying from largecorneal epithelial defects to superficialpunctate keratitis. The epithelial changes hadresolved in a mean period of 3*75 days (range 1to 14 days). Two episodes caused stromalinfiltration to appear and in one of these astromal opacity remained 5 years later. The

Figure I A typicalManchineel tree.

final visual acuity was 6/9 or better in all eyesexcept in one patient who had visual impair-ment because ofglaucoma. Our results suggestthat despite the severity of the acute reaction,the long term visual prognosis is excellent inManchineel keratoconjunctivitis. The histori-cal and toxicological literature on Manchineelis reviewed.(BrJ Ophthalmol 1993; 77: 284-288)

The Manchineel tree is found in the West Indies,Central America, the Bahamas, South America,and the west coast of Africa. ' It has beendescribed as the most toxic tree on the NorthAmerican continent2 and so in the United Statesit is allowed to grow only in the Everglades ofFlorida and the Virgin Islands National Park.The tree is capable of flourishing in a highlysaline enrivonment and is therefore usuallyfound in coastal regions.3 It has an extensive rootsystem which has led to planting in an effort toprevent coastal erosion.

This round-topped tree with dense foliage(Fig 1) grows to 20-40 feet in height and has atrunk 1-2 feet in diameter, covered by a smoothgrey bark. The shiny, dark green leaves arebroadly ovate in shape, finely serrated and 2-4inches long. The green, inconspicuous flowersare arranged in stiff spikes. The fruit resemblesthe common green apple, being rounded,greenish-yellow, and 1-2 inches in diameter. Thetree commonly forms dense thickets alongbeaches (Fig 2), but it can also exist in a stuntedform on windward cliffs, where it may be nomore than a few inches in height. When cut orbroken, all parts of the plant exude a milky sap,or latex (Figs 3 and 4), which is strongly irritantto the skin and mucous membranes. It is alsoknown that rainwater dropping through thecanopy of the tree contains enough dissolvedirritant to produce irritation45 and for this reasonnotices are often displayed on the tree in touristareas warning against taking shelter under it in arain shower.

Figure 2 A thicket ofManchineel trees growing in their typical habitat above the high-water Figure 3 Latex exudingfrom the broken end ofa branch.mark along the coast.

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Figure 4 Latex exudingfrom thefruit and stem.

The toxic properties of the Manchineel treehave been known for centuries to the nativepopulations of the countries where it occurs. Thewarlike Caribs, who replaced the peacefulArawaks as the aboriginal population of theCaribbean islands, apparently used the sap as an

arrow poison, and it seems also to have had a

medicinal role and one in 'trial by ordeal'.6 Thescientific name, Hippomane mancinella, isderived from hippoman (horse poison) andmancinella (little apple) (Fig 4). Fatalities havebeen reported in humans and livestock eating thefruit and leaves.36 The main symptoms noted insystemic poisoning are lacrimation, salivation,vomiting, diarrhoea, and CNS depression lead-ing to coma and death. It seems likely that thesesystemic effects are caused by physostigmine(see below). Another form of 'systemic' toxicityoccurs when the fruit or leaves are eaten, produc-ing pharyngeal oedema which has necessitatedtracheostomy. The widespread, non-specificeffects ofManchineel as an irritant are illustratedby the disastrous effects on the genitalia andperianal region by the unsuspecting use of the

leaves as toilet paper, or by children carrying thefruit in their swimming trunks.3 7Although the acute toxic effects ofManchineel

on the human eye have been known for centuriesin the countries where the tree grows,3 and havebeen described before, there have been no

studies to determine the prognosis followingexposure. We have therefore reviewed a series ofpatients to determine the long term sequelae.

Patients and methodsPatients with chemical burns caused byManchineel were identified using the wardadmissions record in the Department ofOphthalmology of the Queen Elizabeth Hospital(the only public hospital in Barbados) between1985 and 1990. Details of patient age, sex, eyeinvolved, visual acuity on presentation, extent ofcorneal involvement, treatment, and length ofhospital stay were extracted. The patients werethen invited to attend the clinic for further study.A more detailed history was then obtained todetermine the reason for exposure and the part ofthe tree acting as the source of irritant. Anophthalmic examination was carried out torecord the final visual acuity and look for abnor-malities by slit-lamp biomicroscopy, endothelialspecular reflection, and fluorescein staining.

ResultsNineteen patients were identified. Twelve ofthose were able to attend for review and for theremainder the only clinical details available werethose extracted from the case records. Table 1gives the details of the 19 patients. The mean agewas 39-2 years (range 2-73). There was a strongmale preponderance, with only one woman

patient. One of the patients was a visitor to theisland and had been ignorant of the tree, whereasthe 18 Barbadian patients were aware of itsdangers before exposure (in the youngest

Table I Clinical details ofthe 19 cases ofManchineel exposure

Visual acuity Visual acuity(Snellen) Time in Time to on review

Age Mode of Source of Eye Corneal hospital reviewPatient (years) Sex exposure toxin involved involvement R L (days) (months) R L

1 32 M OCC Wood Both None 6/9 6/9 2 31 6/4 6/42 73 M Gar Wood Right Epi Def 6/60 6/9 5 16 HM 6/123 19 M OCC Wood Left Epi Def 6/6 6/4 1 2 6/4 6/44 27 F OCC Wood Left SPK 6/4 6/4 1 2 6/4 6/45 16 M Shelter Rain Left Epi Def 6/5 HM* 5 . 60 6/6 6/6

Sup stromal scar6 22 M Shelter Rain Right Epi Def CF 6/5 5 18 6/4 6/47 2 M ACC Unknown Both Epi Defs t t 14 178 28 M Gar Wood Both SPK 6/6 6/69 44 M OCC Wood Both Epi Defs 6/24 6/24 4 7 6/4 6/4

Sup stromal opacityRE resolving with time10 20 M ACC Leaf Left Epi Def 6/5 6/5 1 7 6/4 6/411 28 M OCC Wood Both Epi Defs 6/18 6/18 3 36 6/4 6/412 19 M ACC Wood Both Epi Defs 6/18 6/18 3 36 6/4 6/413 46 M Unknown Unknown Both Epi Defs 6/24 6/36 2 DNA DNA DNA14a 36 M Gar Wood Both Epi Defs CF CF 5 DNA DNA DNA14b Unknown Unknown Both Epi Defs CF CF 4 0 6/9 6/915 25 M Gar Wood Both Epi Defs 6/9 6/6 4 7 6/5 6/616 24 M Unknown Unknown Both None 6/6 6/6 1 2 6/6 6/617 51 M Unknown Unknown Both None 6/9 6/9 Unknown DNA DNA DNA18 13 M Unknown Unknown Both SPK 6/9 6/12 Unknown DNA DNA DNA19 30 M ACC Leaf Both None 6/4 6/4 1 DNA DNA DNA

M=male; F=female; OCC=occupational; ACC=accidental; DNA=did not attend follow up; SPK=superficial punctate keratitis;Gar=gardening; Epi Def(s)=epithelial defect(s).*VA reduced by advanced glaucoma.tFormal assessment of acuity unsuccessful.

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patient, the parents, who were supervising thechild at the time of exposure, were aware ofthese). In all but one case, the patients had asingle episode of exposure; case 14 had twoepisodes, recorded separately in the table. Wewere able to determine the circumstances ofexposure in 15 of the 20 episodes. Nine episodesoccurred while cutting the plant (five in thecourse of the patient's employment, and fourduring home maintenance). Four were caused byinadvertent contact with the tree and two bytaking shelter beneath it in a rain shower. Thepart of the plant responsible for injury wasascertained in 14 episodes: the wood in 10 andthe leaves in four (direct contact in two andfiltering rain in two).Of 20 episodes, 14 were bilateral. All eyes

showed severe conjunctivitis and the cornea was

involved in 16 episodes. Thirteen of thoseshowed large corneal epithelial defects (Fig 5)and three showed superficial punctate epithelialkeratitis. All patients had been treated byprompt lavage, cycloplegia to relieve pain, andinstillation of antibiotic to prevent secondaryinfection while the cornea re-epithelialised.Steroids were not used in any case. The mean

period to complete resolution of epithelialdamage was 3-75 days (range 1-14). Two of ourpatients had stromal involvement: in one

(patient 9), there was superficial stromal infil-trate in the acute phase (Fig 6) which disap-peared in 3 weeks with return of visual acuity to6/4. In another (patient 5), we noted a stromalscar persisting 5 years following the injury. (Thispatient had visual acuity of HM in the affected

Figure 6 Superficialstromal opacification, seen inthe left eye ofthe paxtient inFigure S, following healingofthe epithelial defect (14daysfollowing contact). Intime this opaciy wasobseved to diminish in size.

eye, but also had an afferent pupil defect, denseoptic atrophy, and raised intraocular pressuredue to previously undiagnosed glaucoma). Wedid not encounter limbal ischaemia, cornealthinning, or detectable intraocular inflammation.

DiscussionThe historical literature dealing with Manchineelwas reviewed by Lauter et al in 1952.6 Referencesto the poisonous effects are found in the writingsof Peter Martyr, court geographer to QueenIsabella, the patroness of Columbus, who wrotein De Orbe Novo in 1509 that 'even the shade ofthis fruit-tree affects the head and hurts theeyes'. The early settlers clearly regarded the treeas a deadly one, and frequently commented on itstoxic effects to the eyes. Seeman, in his accountofthe voyage ofHMS Herald, states that some ofthe ship's carpenters were temporarily blindedby the sap getting into their eyes while felling thetrees.7 In 1673, Richard Ligon, a Barbadosphysician, wrote, 'the fellers as they cut themdown are very careful of their eyes, and thosethat have cipers (handkerchiefs) put them overtheir faces, for if any of the sap fly into theireye they become blind for a month'.8 AdmiralHoratio Nelson, while commanding a Britishexpedition into Spanish Nicaragua, waspoisoned by hostile Indians who had saturatedspring water with Manchineel leaves.9 In 1943,Satulsky and Wirts' reported 60 cases of facialdermatitis due to Manchineel exposure in troopson night manoeuvres in Panama, despite priorwarning of the dangers of the plant by the USmilitary in the Manual ofJ7ungle Warfare. At least50% of the soldiers were effectively blinded andrequired morphine analgesia before evacuation.It is of interest that many of those troops had nothad direct contact with the tree; there had been aparticularly heavy dew on the night in question,and the distribution of the skin lesions suggestedthat this had been the source ofirritant. All ofthemen returned to active duty in 8 days, withoutsequelae. Harley'" reported four cases of acutekeratoconjunctivitis among 18 cases of derma-titis venenata caused by Manchineel occurring in1 year in Panama. Like Satulsky's cases, thedermatological lesions occurred mainly on theface, arms, trunk, and penis (contaminatedduring micturition).These authors5 10 emphasised how rapidly the

symptoms develop following exposure, withmild burning in a few minutes, progressing tosevere burning, lacrimation, and blepharospasmwithin an hour. All of their patients recoverednormal vision within 8 days, but Earle3 com-ments on persistent corneal ulceration inneglected cases. Harley'0 also conducted limitedexperimental work on human skin and threerabbit eyes. He found, essentially, that irrigationof the rabbit eye 5 minutes after exposurereduced the healing time by one half, whereasirrigation at 15 minutes had no effect.Manchineel is a member of the Euphorbiciae

(spurges), an extremely diverse family which islarge enough, in the opinion of some botanists,"to merit reclassification as an order (theEuphorbiales). The family contains some 300genera and 5000 species of trees, shrubs, and

FigureS Skin ulcers andbilateral corneal epithelialdefects 18 hoursfollowingcontact with Manchineel sap(patient 9).

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herbs. Superficially these may bear little resem-blance to one another but have in common theovary, unisexual flowers, and fruit, which gener-ally ripens 1 month after flowering; many have amilky sap.'2The Euphorbiciae are widely distributed

around the globe,'3 although the majority aretropical. There are 18 species which occur in theBritish countryside,'2 all of which are ratherinconspicuous herbs such as dog's mercury(Mercuralis spp) found on shady mountain rocks,and Euphorbia portlandica, which grows oncoastal dunes in the south east of England.The non-botanical reader may well be moreacquainted with the ornamental varieties grownin cultivation in this country, such as Euphorbiapulcherrima (poinsettia) and the Codiaeumspecies (croton), or with the common productsof the Euphorbiciae such as rubber (Heveabrasiliensis), castor oil (Ricinus communis), ortapioca (Marihot spp).The topical Euphorbiciae include other

poisonous plants' "6 such as Hura crepitans(javille, sandbox) the sap of which causes severedermatitis, the Sapium species (one of thosebeing used as a source of rubber in SouthAmerica) and the common weed Euphorbia lata(Jamaican milkweed) which causes skin ulcera-tion. Other poisonous Euphorbiciae includeAfrican sandalwood (tombiti), yokes of whichhad to be discarded as they caused inflammationof necks of oxen, geor ('blind-your-eye'),and musine, which has been used in Englandfor flooring and which some workmen findextremely irritant. Dermatitis, blepharitis, andkeratoconjunctivitis have been described asoccupational hazards in lumber workers andcarpenters working with these woods, and muchresearch has gone into the identification of theirritant chemicals. The main class responsibleseems to be the terpenes, such as euphorbol."6Duke-Elder also points out that some Euphor-biciae are responsible for a violent iridocyclitiswith hypopyon (Tithymalus cyparissias andEuphorbia antiguorum), but Manchineel had notbeen reported to do so.'5

Schaeffer et al'7 described the isolation of2-hydro-4, 6-dimethoxy-acetophenone and acarotenoid substance from Manchineel leaves.Lauter and Foote'8 suggested the presence ofphysostigmine. Neither study, however, investi-gated the toxicity of these substances. Rao"carried out systemic fractionation of Manchineellatex based on toxicity to mice on intraperitonealinjection. He obtained a water soluble and anether soluble fraction, both of which were toxic.He found eight fractions within the water solubleelement, including the acetophenone describedby Schaeffer, and a variety of the methyl deriva-tives ofellagic acid. The bulk ofthe water solublefraction, however, consisted of substances whichhe named hippomanin A and B. Hippomanin Awas later shown by the same author to be a'crystalline tannin' which hydrolysed to glucose,gallic acid, and ellagic acid. The ether solublefraction, meanwhile proved more toxic thanthe aqueous but was unstable and difficult toidentify.

In 1984, Adolf and Hecker' reviewed thetoxicological literature on the Euphorbiciae

before investigation of Manchineel latex, andconcluded from a chemotaxonomic point ofviewthat physostigmine and hippomanin A would beunlikely candidates for skin irritants. Theybased this hypothesis on work on other toxicspecies of Euphorbiciae, in which the irritantprincipals were found to be oxygenated diterpeneesters of the tigliane, ingenane, or daphnanetype (some of which had also been noted tobe carcinogenic in mice). They separatedManchineel latex into a highly irritant hydro-philic fraction containing a large proportion ofesters of 513-hydroxyresiniferonol-6a, 7a-oxidewith 9, 11, and 14C chain fatty acids. Thestructure of one of these esters was found to beidentical to huratoxin, the toxic principal ofHura crepitans. The non-irritants in the hydro-phobic fraction could, however, be chemicallyactivated to form irritant substances and werelabelled 'cryptic irritants'. These were inactivetriterpenes, a complex mixture of esters oftigliane and daphnane type (that is, the parentalcohols 12-deoxyphorbol and resiniferonalesterified with the even-numbered, unbranchedfatty acids from C16 to C26). The authorsconclude that owing to the presence of tumourpromoting activity by these substances in mice,chronic contact with Manchineel productsshould be avoided.

It would seem, therefore, that Manchineellatex is a highly complex mixture of toxins. Themost likely candidates for the production ofkeratoconjunctivitis would appear to be amixtureof oxygenated diterpene esters. These small,non-protein organic molecules are soluble inwater, which explains why rainwater or dew cancause the syndrome of Manchineel-inducedkeratoconjunctivitis without direct contact withthe tree. The precise mechanism of toxicity isunknown but seems likely to be a direct effect onthe cells. Further in vitro studies on cornea usingfractioned components of Manchineel sap wouldbe needed to elucidate this.

Despite the complexity of the chemical toxi-cology and the severity of the acute reaction,our study suggests that the long term effectsof Manchineel keratitis are not as drastic ashistorically believed. Unlike previous casereports, our patients consisted mainly of localpeople and in episodes of occupational exposure,the problem was not lack of awareness of thedangers of the plant, but inadequate eye protec-tion.We would like to thank Suzanne Small for typing the manuscript.

1 Adolf W, Hecker E. On the active principles of the spurgefamily. Skin irritants, cocarcinogens and cryptic cocarcino-gens from the latex of the Manchineel tree. J NaturalProducts 1984; 47: 482-96.

2 West E, Arnold LE. The native trees ofFlorida. Gainsville, FL:University of Florida Press, 1946: 110.

3 Earle KV. Toxic effects of Hippomane mancinella. Trans RoySoc Trop Med Hyg 1938; 32: 363-70.

4 Satulsky EM. Dermatitis venenata caused by the manzanillotree. Arch Dermatol Syph 1943; 47: 36-9.

5 Satulsky EM, Wirts CA. Dermatitis venenata caused by themanzanillo tree. Arch Dernatol Syph 1943; 47: 797-8.

6 Lauter WM, Fox LE, Ariail WT. Investigation of the toxicprinciples of Hippomane mancinella. J Am Pharm Assoc1952; 41: 199-201.

7 Snow JS, Harley RD. Dermatitis venenata and keratoconjun-ctivitis caused by the manzaniilo tree. Arch Dermatol Syph1944; 49:236-9.

8 Ligon R. A true and exact history of the island of Barbadoes.London: Peter Parker and Thomas Guy, 1673: 68.

9 Southey R. The life of Admiral Horatio Nelson. New York:Perkins Book Co, 1902: 23.

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10 Harley RD. Keratoconjunctivitis caused by the manzanillotree. AmJ Ophthalmol 1944; 87: 628-31.

11 Hutchinson J. Thefamilies offlowering plants. 3rd ed. Oxford:Oxford University Press, 1973: 329-31.

12 Clapham AR, Tutin TG, Moore DM. Flora oftheBritish Isles.3rd ed. London: Cambridge University Press, 1987: 296-300.

13 Rendle AB. The classification offlowering plants. Volume II.London: Cambridge University Press, 1925: 256-65.

14 Kingsbury JM. Poisonous plants of the United States andCanada. New Jersey: Prentice Hall, 1964: 185-90.

15 Duke-Elder S. System of ophthalmology. Voume 8, Diseases ofthe outer eye. London: Henry Kimpton, 1965: 1185.

16 Woods B, Calnan CD. Toxic woods. BrJ Dermnatol 1976; 95(suppl 13): 1-97.

17 Schaeffer HJ, Lauter WM, Foote PA. A preliminary phyto-chemical study ofHippomane mancinella. Am Pharm Assoc1954; 43:43-5.

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19 Rao KV. Toxic principles of Hippomane mancinella. Plantamedica 1974; 25: 166-71.

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