and Amodiaquine as Used for Malaria

Robert Wittes, MD, CCFP

Adverse Reactions to Chioroquine

and Amodiaquine as Used for MalariaProphylaxis: A Review of the LiteratureSUMMARY RESUMEThis paper reviews the published material onadverse reactions to chloroquine (CQ) andamodiaquine (ADQ) as used for anti-malarialchemophrophylaxis. Dermatologic reactions,including pruritus and photosensitivity,appear to be rather common. Ophthalmologicreactions include difficulty in visualaccommodation, comeal deposits, andretinopathy, the last a serious condition that isreversible in its early stage by drugwithdrawal, and that generally will not occurwith less than four years of weekly CQ use.Neuromyopathy is a rare and serious reactionthat may develop idiosyncratically after asmall cumulative dose; it, too, is reversible bydrug withdrawal. Seizures, syndromes ofinvoluntary movements, psychosis, andototoxicity have been reported occasionally.Fatal toxic overdoses may occur, especiallyfollowing accidental ingestion by children.ADQ should not be used for anti-malarialprophylaxis because of associatedagranulocytosis. Rabies vaccine givenintradermally is less effective for pre-exposureprophylaxis while the patient is taking CQ.Care should be taken when prescribingprophylactic CQ to patients with heart block.In spite of its adverse effects, however, CQ isgenerally an extremely safe drug. CQprophylaxis is recommended for pregnantwomen in CQ-sensitive malarial areas. (CanFam Physician 1987; 33:2644-2649.)Key words: malaria, chloroquine, amodiaquine,

Cet article revise la litt6rature concernant les effetssecondaires de la chloroquine (cQ) et del'amodiaquine (ADQ) utilisees dans lachimioprophylaxie antimalarique. Certainesreactions dermatologiques telles le prurit et laphotosensibilite semblent plutot courantes. Lesreactions ophtalmologiques incluent la difficulted'accommodation visuelle, les depots corneens et laretinopathie. Cette derniere reaction constitue uneaffection serieuse mais reversible si l'on cesseprecocement le medicament et qui ne se manifestegeneralement qu'apres quatre ans d'usagehebdomadaire de chloroquine. La neuromyopathieest une reaction rare et serieuse qui peut sedevelopper de facon idiosyncrasique suite al'ingestion d'une faible dose cumulative; le retraitmedicamenteux en permet aussi la reversibilite.Convulsions, syndromes de mouvementsinvolontaires, psychose et ototoxicite ont eterapportes occasionnellement. Les intoxicationsfatales peuvent s'averer un probleme, surtout suite aune ingestion accidentelle par des enfants. L'ADQ nedevrait pas etre administree comme prophylaxieantimalarique 'a cause du risque d'agranulocytose.Chez le patient trait6 a la cQ, le vaccin contre la ragepar voie intradermique est moins efficace commeprophylaxie en pre-exposition, et ses effets sur lesreponses immunitaires aux autres vaccinsnecessitent une etude plus poussee. L'usageprophylactique de la CQ est contre-indique chez lespatients qui presentent un bloc cardiaque. Chez lesfemmes enceintes, toutefois, l'usage prophylactiquede la CQ est recommande contre le paludisme, dansles regions oiu la malaria est sensible 'a lachloroquine.

chemoprophylaxis, treatment

Dr. Robert Wittes did hismedical training andfamily-practice residency at McGillUniversity, where he is now aresident in Community Medicine.He is currently on leave from theMcGill University Centre forTropical Diseases to doschistosomiasis research as anInternational EpidemiologyResearch Fellow in the Division of

Parasitic Diseases, Centers forDisease Control, Atlanta, Ga.Requests for reprints to: Dr.Robert Wittes, Division of ParasiticDiseases, Chamblee 23, Centres forDisease Control, 1600 Clifton Rd.N.E., Atlanta, GA. 30333 U.S.A.

pHLOROQUINE (CQ) is the drugof first choice for the chemopro-

phylaxis of CQ-sensitive species of ma-

laria, and prophylactic CQ is recom-mended for use in all malarial areas ofthe world, including those areas whereCQ-resistant strains of Plasmodiumfalciparum exist.1-3 CQ is one of alarge series of 4-aminoquinolines thatwere investigated for use as anti-malarials and that have subsequentlybeen used in auto-immune disorders aswell. The only 4-aminoquinolineavailable in Canada for malaria che-

CAN. FAM. PHYSICIAN Vol. 33: NOVEMBER 1987

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moprophylaxis is CQ phosphate (Ara-len®), at a recommended adult dose of500mg of the salt (= 300mg of thebase) per week. CQ sulfate (Niva-quine®) is available and is often rec-ommended abroad. Amodiaquine(ADQ) (Flavoquine®, Camoquin®) isno longer recommended for malariachemoprophylaxis, but remains avail-able abroad. Hydroxychloroquine(HCQ) (Plaquenil®) is available in Can-ada but is used generally for rheuma-toid arthritis and other immunologicdisorders, and is not usually recom-mended for either the chemoprophy-laxis or the treatment of malaria.As used for the chemoprophylaxis

and treatment of malaria, CQ is a verysafe drug, and adverse or serious side-effects are only rarely reported. Suchreactions may occur, however, andwith the increase in foreign travel,physicians must be aware of them.Herein follows a review of the majorpublished adverse reactions to the 4-aminoquinolines as used for malariachemoprophylaxis. They are describedin terms of dermatologic reactions,ophthalmologic effects, neuromy-opathy, neuropsychiatric reactions,acute toxic overdose, hematologic re-actions, effect on concurrent vaccineadministration, miscellaneous reac-tions, and teratogenic effects. Unlessotherwise stated, all dosages men-tioned in this review are in terms of thesalt, not the base. The frequency rateof any of these side-effects is un-known, as there exist no denominatordata on the number of people whohave used 4-aminoquinolines for ma-laria chemoprophylaxis. It can be as-sumed, however, that serious adversereactions that have been reported onlyrarely do, in fact, occur only rarely.

Dermatologic ReactionsPreviously reported dermatologic

reactions to 4-aminoquinolines haveincluded pruritus, photosensitivity, li-chen-planus-like eruptions, and pig-mentation changes. Although urticariahas been noted anecdotally in the liter-ature,4 a review of the literature dis-closed no actual case reports.

Photosensitivity reactions haverarely been reported in individuals.5 Ina chloroquinized salt campaign inGuyana, however, where individualswere ingesting varying amounts of CQdaily for malaria prophylaxis, a photo-allergic dermatitis developed in about1% of the population. The lesions

ranged in severity from nummularerythematous eruptions to severe ex-foliative dermatitis; they were morecommon among lighter-skinned peo-ple.6 The racial distribution of CQ-in-duced pruritus is quite the reverse. Ithas been reported only once in a Cau-casian,7 but has been commonly foundamong Black Africans.8 In one sur-vey, 28% of Nigerians who had taken4-aminoquinolines reported pruritus.9However, pruritus is not considered acontraindication to the use of amino-quinolines.Among a group of 30 volunteers

taking CQ for one year in a weeklydose of 833mg, two persons developedcutaneous eruptions that began eightand 12 months after they commencedtaking CQ. These were scaly maculo-papular eruptions on the trunk andupper limbs of a lichen-planus-likegross and histologic appearance.'0, lAnother case of nummular erythema-tous scaly psoriatic lesions, not con-fined to sun-exposed areas, has beenreported.12 Finally, rare cases of CQ-induced pigmentation disorders haveoccurred. These have included bleach-ing of hair,13 as well as generalizedhyperpigmentation; 14 15 in the lattercases, biopsies of hyperpigmentedareas disclosed melanin-chloroquinecomplexes.14 Similar skin-hyperpig-mentation lesions have been inducedby phenothiazines. Any of these der-matologic reactions should dictate sub-stitution of an unrelated anti-malarialsuch as pyrimethamine or proguanil.

Ophthalmologic ReactionsOn beginning CQ or ADQ, many pa-

tients report a difficulty in changingfocus quickly between near and far ob-jects.4' 10, 16 This difficulty in accom-modation is thought to result from astabilization of the action potential ofthe membranes in the ciliary musclesby competing with calcium ions forbinding sites.4 Generally, this initialsymptom resolves after a few weeks,and it causes no permanent visual se-quelae.Comeal deposits may occur. Fifty

per cent of patients with these depositsare asymptomatic, while the others re-port the presence of halos around lightsources, flashing lights, and photopho-bia.16 Pathologic examination of thesecorneal deposits in one case of ADQtoxicity showed intracytoplasmic in-clusion bodies in the comeal epithe-lium, similar to those seen in a number


of drug-induced phospholipidoses.1 7The corneal deposits resolve com-pletely on discontinuance of thedrug. 16, 17

Retinopathy is the most seriousophthalmologic effect and the mostcommon of the serious adverse effectsof CQ and ADQ. The symptoms of thisretinopathy include difficulty reading(as though words or letters are miss-ing), blurred distance vision, blacked-out areas in the visual fields, lightflashes, and photophobia. The fundo-scopic findings consist initially of ma-cular hyperpigmentation surroundedby a clear zone of depigmentation.Later, there is constriction of retinalarterioles with pallor of the optic discand a corresponding loss of visualfields. Visual testing may show centralscotomata and later defects in periph-eral visual fields, impaired color vi-sion, and abnormal electrooculogramsand electroretinograms. 16' 17The pathophysiology of CQ reti-

nopathy has not been fully elucidated.It is known that CQ concentrates in me-lanin-containing tissues, where itsconcentration is higher than in anyother tissues and is approximately1,000 times the plasma concentra-tion. 18 19 Furthermore, while the tis-sue half-life of CQ on discontinuanceof the drug is about seven days, the ex-cretion of small amounts of CQ may bedetected in the urine for as long as fiveyears after the last known administra-tion.20 The high concentration of CQ inthe melanin-containing retinal pig-mented epithelium seems to be respon-sible for the retinopathy. It has beenpostulated that this occurs because CQinterferes with lysosomal function, in-terfering with the scavenging functionof the retinal pigmented epithelium tophagocytose photoreceptor discs thatare shed diurnally from rod and conecells.4' 16,17,19 Similar findings havebeen used to explain the comeal de-posits and the pigmentary retinopathycaused by phenothiazines.21CQ retinopathy has been linked to

high daily dosage over many years (asused in the treatment of rheumatoid ar-thritis and systemic lupus erythema-tosus). Few cases have been reportedin patients on a daily dose of less than250mg of CQ, or 4mg/kg body weight,and most cases have occurred in pa-tients on a daily dose exceeding500mg. Taken as a daily dose, an ac-cumulation of 100g salt of CQ (250mgper day for one year) may cause reti-

2645

nopathy, but the risk significantly in-creases only when the total accumu-lated dosage surpasses 300g.6 22, 23Although this is generally true, theremay also be occasional toxic phenom-ena at an idiosyncratically low totaldose. (See "Neuromyopathy" below.)In a similar vein, a case of pigmentaryretinopathy resulting from a low dailydose of the phenothiazine thioridazinewas recently reported.24

Retinal changes occur prior to theonset of abnormalities in visual testingor visual symptoms, and the reti-nopathy at this time is completely re-versible on discontinuance of the drug.Later the retinopathy becomes irre-versible and even progressive after dis-continuance of the drug. If ophthalmo-scopic examination is done on patientstaking a daily dose of CQ after a cumu-lative dose of lOOg salt, and at everylOOg thereafter, the risk of irreversibleCQ retinopathy approaches zero. 16

It is not clear what the implicationsof the above observations are for pa-tients taking CQ for malaria prophy-laxis. There have been few reportedcases of retinopathy among patientstaking weekly (as compared to daily)CQ, and it has been suggested that it isthe total daily dosage rate, and not thecumulative dose, that determines thedevelopment of retinopathy.22 None-theless, it seems prudent to advise thatpatients taking weekly CQ be assessedby an ophthalmologist after four yearsof taking CQ, 500mg per week (yield-ing a cumulative dose of lOOg salt).A final point to be made is that the

CQ congener hydroxychloroquine(HCQ) is two to three times less toxic inanimals than is CQ, and at identicalplasma concentrations, HCQ has only40% of the tissue concentrations ofCQ.18 HcQ is generally safer than CQ,and specifically safer as regards retino-pathy '16, 18, 19, 22, 23, 25 Although HCQwas developed as an alternative to CQas an anti-malarial,26 and although it isless toxic than CQ, it has nonethelessnot been widely used or recommendedas an anti-malarial. Therefore its use inthis context cannot be advocated, butclinical trials of HCQ for malaria pro-phylaxis could prove worthwhile.

NeuromyopathyTwenty cases have previously been

reported of neuromyopathy that devel-oped in patients who were taking CQ orADQ.27 36 The symptoms were weak-ness of the proximal muscles, initially

of the legs and then of the trunk, neck,and shoulders. Eighteen patients hadbeen taking CQ or ADQ on a daily basisfor non-malarial reasons includingrheumatoid arthritis and systemiclupus erythematosus, but in all casesthe neuromyopathy was almost defi-nitely secondary to the drug as com-pared to the underlying disease. Twopatients had been taking weekly CQ orADQ for malaria prophylaxis, at150% -300% of the recommendeddosage.33, 34

Discontinuance of the drug led toimprovement in symptoms within twoto four weeks, with complete recoveryfrom symptoms, abnormal physicalsigns, and abnormal electromyelo-grams (EMG's) in one to 15 months.The cumulative dose had been45- 1,000g taken over a period of sev-eral weeks to four years, but beginningafter a minimum of six months in 17 ofthe 20 patients. In a recent case reportof ADQ neuromyopathy, a patient hadbeen taking weekly ADQ at 50%greater than the recommended dose formalaria chemoprophylaxis for 10months, for a total cumulative dose of3 1g, prior to the onset of her symp-toms.34 Physical examination of all ofthese patients showed muscle weak-ness and diminished or absent deeptendon reflexes of the involved mus-cles. The only serum abnormality wasfrequently a slight elevation of theserum levels of glutamic oxaloacetictransaminase (SGOT) and creatininephosphokinase (CPK). EMG and nerveconduction studies showed abnormalmuscle fibrillations and irritability, di-minished motor-unit amplitude andduration, and loss in the number of re-cruited motor units. Motor-nerve con-duction was either normal or dimin-ished, and afferent sensory nerveconduction was always intact. The 20cases were generally considered torepresent a primary myopathy, al-though in some of the cases there alsoexisted the possibility of an indepen-dent lower motor neuron neuropathy.

Fifteen of the 20 patients underwentmuscle biopsy; two of these showednormal results, and five showed de-generative changes. The remainingeight biopsies showed a vacuolar myo-pathy;28-32 the vacuoles contained gly-cogen in the four cases where specifichistochemical tests were done.29' 32Along a similar line, experimentalstudies of chronic toxicity of oral CQgiven to rats disclosed some cases offocal necrosis and fibrosis of striated

2646

muscle.36' 37 These vacuoles may rep-resent a similar pathologic process tothe ocular toxicity, especially to the in-tracytoplasmic inclusions in cornealepithelium.17 Furthermore, among the11 of the above 20 patients who wereevaluated by an ophthalmologist, nineexhibited the typical corneal or retinalchanges associated with CQ and ADQ.Neuromyopathy seems to be a rare

but definite adverse reaction of CQ andADQ. While both the neuromyopathyand the keratopathy/retinopathyusually develop after prolonged dailydoses, it seems that both may idiosyn-cratically develop after a small cumu-lative dose.

Neuropsychiatic ReactionsFour cases were reported of grand

mal seizures on CQ therapy for Enta-moeba histolytica, only one of whichhad evidence for extra-intestinal amoe-biasis. Three of the four had no pre-vious or subsequent history of seizuresor of abnormal electroencephalograms(EEGs), but had taken a cumulativedose of 2g-4g over two to six days.38Where studied, CQ has had varying ef-fects on the EEG.39 Ten cases havebeen reported of CQ-induced psychosison cumulative doses of 2g-6g overtwo to four days. The symptoms wereagitation, hallucinations, disorienta-tion, and change in sensorium.39-41 Ithas been suggested that some cases offatal CQ overdoses were not voluntaryoverdoses per se, but rather occurred"involuntarily" as a result of drug au-tomatism.3Twenty cases of acute syndromes of

involuntary movements induced by CQor ADQ treatment of malaria have beenreported.42-44 These consisted of acutedystonic movements of the tongue,face, and neck, including buccofacialmovements with salivation, torticollis,and oculogyric crisis. These wereidentical to the dyskinesias sometimesinduced by phenothiazines, and the ap-propriate treatment for both are suchanti-cholinergic drugs as benztropine.Both 4-aminoquinolines and phenoth-iazines, in their avid attachment to me-lanin, may also block dopaminergicreceptors in the brain, since dopa is aprecursor of melanin.45

Acute Toxic OverdoseIn a review of published cases up to

1982, a total of 134 CQ overdoses withtoxic effects were found, of whichover 75% proved fatal.39 Many of


these followed accidental ingestion bychildren, and so parents must ensurethat these drugs are kept in child-proofcontainers. Lethal doses may occurwith as little as 2g- 4g in adults, and isalmost invariable with 8g- lOg. Thereis a two- to three-fold discrepancy be-tween this and toxicity studies in rats,where the LD5o is 330mg/kg.46 Acutetoxic overdoses cause weakness, dys-phagia, dyspnea, hypotension, tre-mours, convulsions, coma, cardiac ar-rythmias, cardiogenic shock, andrespiratory arrest. 47,48 Suggested treat-ment for toxic overdoses has beenacidifying the urine with ammoniumchloride and administering dimerca-prol to increase the urinary excretionof CQ.49 A recent experimental studyon rats suggested that administrationof diazepam may be effective.46

Hematologic ReactionsTwenty-five cases of agranulocy-

tosis have recently occurred in peopletaking ADQ (23 in the last two years),of whom 21 were taking the appro-priate dosage for malaria chemopro-phylaxis.50 Sl Seven of the cases werefatal. Fourteen of the patients wereknown to have been using anotheranti-malarial prophylactic drug con-currently (either pyrimethamine-sulfa-doxine or proguanil). In the previous30 years, there had been only threecases of agranulocytosis in people tak-ing ADQ for malaria chemoprophy-laxis. Whether the recent dramatic in-crease in cases of ADQ-agranulocytosiswas caused by increased use of ADQalone for chemoprophylaxis, increaseduse of other drugs along with ADQ forchemoprophylaxis, or some other fac-tors remains unknown. However,these cases prompted the Centers forDisease Control to cease recommend-ing the use of ADQ for anti-malarialchemoprophylaxis;5I nonetheless, thedrug remains available and may oftenbe used for this purpose in malaria-en-demic regions.CQ may cause an exacerbation of

symptoms in patients with porphyriahepatica of the mixed type or por-phyria cutanea tarda.52 In northernIndia, three male children with G-6-PD deficiency developed acute severeintravascular hemolysis on receivingthe standard CQ dosage for the treat-ment of malaria.53 As contrasted withprimaquine, which has often been im-plicated as the cause of hemolysis inG-6-PD-deficient patients, there have


been no other reports of CQ-inducedhemolysis. Some suggest that careshould perhaps be taken among G-6-PD-deficient persons from India andthe Mediterranean, who seem to bemore susceptible to drug-induced he-molysis than are G-6-PD-deficientBlacks.53 However, G-6-PD defi-ciency does not constitute a contra-in-dication to CQ.

Effects on ConcurrentVaccine AdministrationAn American woman in Kenya died

of rabies three months after being bit-ten by her pet dog. Although shereceived no post-exposure rabies pro-phylaxis, she had received the recom-mended intra-dermal dosage of humandiploid-cell rabies vaccine (HDCV) forpre-exposure prophylaxis six monthsbefore the dog bite, while taking CQanti-malarial prophylaxis.54 This eventled to a prospective trial of 51 veteri-nary-student volunteers, who receivedthe standard vaccination regime forrabies pre-exposure prophylaxis by theintra-dermal route of HDCV; 26 alsotook concurrent CQ, 500mg per week,while 25 did not.55 The post-vaccina-tion mean rabies-neutralizing antibodytitre for the CQ group was significantlylower than that for the control group,and there was an inverse relationshipbetween blood levels of CQ and anti-body titres to rabies. It was speculatedthat CQ interference with lysosomalfunction within macrophages had ledto diminished T-cell-dependent anti-body production to HDCV. Subse-quently, it was recommended thatHDCV pre-exposure prophylaxis couldbe given either by way of the intra-der-mal or by way of the intra-muscularroute if the person were not concur-rently taking CQ; it should be adminis-tered only by way of the intra-muscu-lar route and dosage if the person istaking CQ prophylaxis.56No significant reduction in vaccine-

induced antibody responses betweenpersons taking CQ as compared tothose not taking CQ were observed fol-lowing a tetanus-measles-meningococ-cal vaccine in Nigeria57 or followingthe injection of pneumococcal poly-saccharide vaccine in patients withsystemic lupus erythematosus.58 How-ever, it has been pointed out that theeffects of CQ on vaccine response aredifficult to evaluate in the presence ofother factors affecting the immune re-sponse (such as endemic malaria or

lupus), and that further controlledtrials are indicated.59

Miscellaneous ReactionsMinor electrocardiographic changes

(diminution of the height of T-waves)have been noted with chronic adminis-tration of CQ, but these resolved fol-lowing discontinuance of the drug.10However, syncope has been describedin three patients who had heartblock-complete in two cases andfatal in one-attributable to CQ,250mg weekly for two to three years.All three had CQ retinopathy.60 61 Ithas been suggested, too, that the CQneuromyopathy may also involve car-diac muscle, causing a vacuolar car-diomyopathy.32 62 It is recommendedthat patients with a known history ofheart disease who will be prescribedprophylactic CQ be given an electrocar-diogram, and that heart block be con-sidered a relative contra-indication tothe prophylactic use of CQ.

Tinnitus, vertigo, and a few cases ofnerve deafness have occurred on pro-longed daily doses of 4-aminoquino-lines.63 A total of 16 cases of acuteCQ-induced sensorineural deafnesshave also been reported, and this hasbeen attributed to the affinity of CQfor melanin-containing cells in thestria vascularis of the cochlea and inthe ampullae of the semi-circularcanals.64, 65 Ototoxicity in the fetuswill be discussed below.

Teratogenic EffectsOnly two cases have been docu-

mented of probable CQ teratogenicity.The first case involved a woman withdiscoid lupus erythematosus who wastaking CQ, 250mg-500mg daily, forvarious time periods during four of herseven pregnancies.66 The childrenborn of her three drug-free pregnancieswere perfectly normal. Of the otherfour pregnancies, one resulted in aspontaneous abortion, and three chil-dren were born with congenital abnor-malities. Two had severe cochleovesti-bular and dorsal column spinal cordabnormalities, while a third had unilat-eral limb abnormalities. All of thesechildren, as well as the mother, had re-tinal pigmentary changes typical of CQretinopathy. Although eighth-nerve in-jury and retinal pigment abnormalitiesmay occur together as a hereditarytrait, it was considered that CQ was avery likely cause of these congenitalabnormalities.'66 67

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The second case, recently reported,involved a woman who contractedPlasmodium falciparum malaria dur-ing the first trimester of her first preg-nancy while taking CQ, 500mgweekly. Her child was born with uni-lateral limb abnormalities, and a sub-sequent pregnancy resulted in a per-fectly normal child.68 The role of CQ inthe congenital anomalies in this case isfar from being certain.

It is generally agreed that in CQ-sen-sitive areas, the risk of malaria and itseffects on both the pregnant "non-im-mune" woman and the fetus faroutweigh the possible teratogenicity ofCQ. Therefore, pregnant women fromnon-endemic areas who go to reside ina CQ-sensitive malaria-endemic areaare advised to take CQ prophy-laxis.69-71

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5. van Weelden H, Bolling HH, de laFaille HB, et al. Photosensitivity caused bychloroquine. Arch Dermatol 1982; 118:290.

6. Giglioli G, Dyrting A, Rutten F, et al.Photo-allergic dermatitis during a chloro-quinized salt anti-malaria campaign inGuyana. Trans R Soc Trop Med Hyg 1967;61:313-30.

7. Spencer HC, Poulter NR, Lury JD, et al.Chloroquine-associated pruritus in a Euro-pean. BrMed J 1982; 285:1703-4.

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11. Craige B, Whorton CM, Jones R, et al.A lichen-planus-like eruption occurringduring the course of chloroquine adminis-tration. J Clin Invest 1948; 27 Suppl.:56-9.12. Kirschenbaum MB. Psoriasis follow-

ing administration of antimalarial drugs.JAMA 1963; 185:1044.13. Rees RB, Maibach HI. Chloroquine. Areview of reactions and dermatologic indi-cations. Arch Dermatol 1963; 88:280-9.14. Tuffanelli D, Abraham RK, Dubois El.Pigmentation from antimalarial therapy.Arch Dermatol 1963; 88:419- 26.15. Levy H. Chloroquine-induced pigmen-tation. S Afr Med J 1982; 62:735-7.16. Bernstein H. Opthalmologic consider-ations and testing in patients receivinglong-term antimalarial therapy. Am J Med1983; 75:25- 34.17. Hirst LW, Sanborn G, Green WR, etal. Amodiaquine ocular changes. ArchOphthalmol 1982; 100:1300-4.18. McChesney EW. Animal toxicity andpharmacokinetics of hydroxychlorqouinesulfate. Am J Med 1983; 75:11- 18.19. MacKenzie AH. Pharmacologic ac-tions of 4-aminoquinoline compounds. AmJ Med 1983; 75:5- 10.20. McChesney EW, Fasco, MJ, BanksWF. The metabolism of chloroquine inman during and after repeated oral dosage.J Pharmacol Exp Ther 1967; 158:323- 31.21. Potts A. Uveal pigment and phenothia-zine compounds. Trans Am OphthalmolSoc 1962; 60:517- 52.22. MacKenzie AH. Dose refinements inlong-term therapy of rheumatoid arthritiswith antimalarials. Am J Med 1983; 75:40-5.23. Rynes RI. Ophthalmic safety of long-term hydroxychloroquine sulfate treat-ment. Am J Med 1983; 75:35- 9.24. Lam R, Remick RA. Pigmentary reti-nopathy associated with low-dose thiorida-zine treatment. Can Med Assoc J 1985;132:737.25. Scherbel AL. Use of synthetic antima-larial drugs and other agents for rheuma-toid arthritis: historic and therapeutic per-spectives. AmJMed. 1983; 75:1-4.26. Surrey AR, Hammer HF. The prepara-tion of 7-chloro-4-(4-N-ethyl-N-B-hydrox-yethylamino)- 1-methylbutylamino)- quino-line and related compounds. J Am ChemSoc 1950; 72:1814-5.27. Loftus LR. Peripheral neuropathy fol-lowing chloroquine therapy. Can MedAssoc J 1963; 89:917-20.28. Whisnant J, Espinosa R, Kierland R, etal. Chloroquine neuromyopathy. MayoClin Proc 1963; 38:501- 13.29. Eadie MJ, Ferrier TM. Chloroquinemyopathy. J Neurol Neurosurg Psychiatry1966; 29:33 1-7.30. Ebringer A, Colville P. Chloroquineneuromyopathy associated with kera-topathy and retinopathy. Br Med J 1967;2:219-20.31. Hicklin JA. Chloroquine neuromy-opathy. Ann Phys Med 1968; 9:189-92.32. Itabashi HH, Kokmen E. Chloroquineneuromyopathy; a reversible granulova-

cuolar myopathy. Arch Pathol Lab Med1972; 93:209- 18.33. Karstorp A, Ferngren H, Lundbergh P,et al. Neuromyopathy during malaria sup-pression with chloroquine. Br Med J 1973;2:736.34. Wittes, R. Neuromyopathy associatedwith amodiaquine hydrochloride. Can MedAssoc J 1987; 137(7):635-6.35. Marks JS. Motor polyneuropathy andnystagmus associated with chloroquinephosphate. Postgrad Med 1979; 55:569.36. Fitzhugh OG, Nelson AA, HollandOL. The chronic oral toxicity of chloro-quine. J Pharmacol Exp Ther 1948;93:147-52.37. Schmalbruch H. The early changes inexperimental myopathy induced by chloro-quine and chlorphentermine. J Neuro-pathol Exp Neurol 1980; 39:65-81.38. Torrey EF. Chloroquine seizures.JAMA 1968; 204:115-8.39. Good MI, Shader RI. Lethality and be-havioral side effects of chloroquine. J ClinPsychopharmacol 1982; 2:40-7.40. Sapp OL. Toxic psychosis due to quin-acrine and chloroquine. JAMA 1964;187:373-5.41. Kabir SMA. Chloroquine psychosis.Trans R Soc Trop Med Hyg 1969; 63:549.42. Akindele MO, Odejide AO. Amodia-quine-induced involuntary movements. BrMed J 1976; 2:214- 5.43. Umez-Eronini EM, Eronini EA.Chloroquine-induced involuntary move-ments. BrMedJ 1977; 1:945-6.44. Singh S, Singh P, Singh M. Chloro-quine-induced involuntary movements. BrMed J 1977; 2:520.45. Majumdar SK. Mechanism of chloro-quine-induced involuntary movements. BrMedJ 1977; 1:1350.46. Crouzette J, Vicant E, Palombo S, etal. Experimental assessment of the protec-tive activity of diazepam on the acute toxi-city of chloroquine. J Toxicol Clin Toxicol1983; 20:271-9.47. Czajka PA, Flynn PJ. Nonfatal chloro-quine poisoning. Clin Toxicol 1978;13:361-9.48. Don Michael TA, Aiwazzadeh S. Theeffects of acute chloroquine poisoning withspecial reference to the heart. Am Heart J1970; 79:831-42.49. Rubin M, Bernstein HN, Zvaifler NJ.Studies on the pharmacology of chloro-quine. Arch Ophthalmol 1963; 70:474- 81.50. Hatton CSR, Peto TEA, Bunch C, etal. Frequency of severe neutropenia asso-ciated with amodiaquine prophylaxisagainst malaria. Lancet 1986; 1:411-4.51. Agranulocytosis associated with theuse of amodiaquine for malaria prophy-laxis. MMWR 1986; 35:165-6.52. Cripps DJ, Curtis AC. Toxic effect ofchloroquine on porphyria hepatica. ArchDermatol 1962; 86:575-81.

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53. Choudhry VP, Madan N, Sood SK etal. Chloroquine-induced haemolysis andacute renal failure in subjects with G-6-PDdeficiency. Trop Geogr Med 1978; 30:331-5.54. Human rabies-Kenya. MMWR 1983;32:494- 5.55. Pappaioanou M, Fishbein D, Dreesen,DW, et al. Antibody response to pre-expo-sure human diploid-cell rabies vaccinegiven concurrently with chloroquine. NewEng J Med 1986; 314:280- 4.

56. Rabies prevention: supplementarystatement on the pre-exposure use ofhuman diploid cell rabies vaccine by the in-tradermal route. MMWR 1986; 35:767-8.

57. Greenwood BM. Chloroquine prophy-laxis and antibody response to immunisa-tion. Lancet 1984; 2:402-3.58. Van Der Straeten C, Klippel JH. Anti-malarials and pneumococcal immuniza-tion. New Eng J Med 1986; 315:712.

59. Pappaioanou M, Fishbein D. Antima-larials and pneumococcal immunization.New Eng J Med 1986; 315:712.

60. Ewards AC, Meredith TJ, Sowton E.Complete heart block due to chronicchloroquine toxicity managed with perma-nent pacemaker. Br Med J 1978;1:1109- 10.61. Oli JM, Ihenacho HNC, Talwar RS.Chronic chloroquine toxicity and heartblock: a report of two cases. E Aft Med J1980; 57:505- 7.

62. Hughes JT, Esiri M, Oxbury JM.Chloroquine myopathy. Q J Med 1971;40:85- 93.63. Scherbel AL, Harrison JW, Atdjian M.Further observations on use of 4-amino-quinolone compounds in patients withrheumatoid arthritis or related diseases.Clin Quart 1958; 25:95- 111.

64. Dwivedi GS, Mehra YN. Ototoxicityof chloroquine phosphate: a case report. JLaryngol Otol 1978; 92:701-3.65. Mukherjee DLO. Chloroquine ototoxi-city-a reversible phenomenon? J Laryn-gol Otol 1979; 93:809- 15.

66. Hart CW, Naunton RF. The ototoxicityof chloroquine phosphate. Arch Otolaryng1964; 80:407- 12.67. Chloroquine (Aralen) and fetal injury.Med Lett Drugs Ther 1965; 7:9-10.

68. Drouin J, Rock G, Jolly EE. Plasmo-dium falciparum malaria mimicking au-toimmune hemolytic anemia during preg-nancy. Can Med Assoc J 1985; 132:265- 7.69. Lewis R, Lauersen NH, Birnbaum S.Malaria associated with pregnancy. ObstetGynecol 1973; 42:696- 700.

70. Malaria prevention in travellers fromthe United Kingdom. Br Med J 1981;283:214- 18.71. Flici 0, Tadjerouni A, Leroy F, et al.La paludisme chez la femme enceinte.Presentation de deux cas et revue de lalitterature. J Gynecol Obstet Biol Reprod1982; 11:981-90.

Answer to Dermacase (page 2468)4. Perioral dermatitis

This condition was first described byMihan and Ayres in 1964.1 It ischaracterized by red papules and, lessoften, by pustules on the face aboutthe mouth, naso-labial folds, andsometimes around the eyes. Thesurface of the affected skin may showa fine scaling. The condition isusually asymptomatic. The lesionscan come on rather suddenly, and willwax and wane over several weeks. Ifuntreated, the condition may last forseveral years. -

Perioral dermatitis appears to be acondition exclusive virtually tofemales between the ages of 16 and50 years, though it has been seen onrare occasions in young males. Thecause of this condition is unknown.Several causal factors have beenpromoted, such as ultra-violet light,candida and bacterial infections,contact agents, topical steroids, andhormonal factors.' The predominanceof the condition in women, thepre-menstrual flare-up, and theextensive involvement duringpregnancy tend to suggest some sortof hormonal association.Though biopsy for histologic

examination is not often taken, thechanges are generally non specific,with a mild sub-acute inflammationand accumulation of the inflammatorycells about the follicles and vessels.

In the typical case, the diagnosisgives little trouble. The conditionmay, however, be confused withrosacea, acne, or seborrheicdermatitis. Rosacea is more centrallylocated, and lesions are prominent on

the nose. In addition, theinflammatory papules are larger andoften pustular or cystic. Erythema andtelangiectasia are also prominent inrosacea. The use of strong topicalcorticosteroids will often confuse thepicture, since this treatment maycreate telangiectasia. Acne generallyshows comedones, largeinflammatory papules and pustules,and lesions on the periphery of theface. Very often women with perioraldermatitis are greatly distressed, sincethey have had little or no acneproblems.

Since its recognition in 1964, avariety of topical and systemicmedications have been tried to relieveperioral dermatitis. The treatment thatgives the greatest success is oraltetracycline.4 The medication is givenfor six weeks or more, using an initialdose of 750mg/day and reducing to250mg/daily after three weeks.Patients who do not respond totetracycline may be treated withminocycline (50mg b.i.d.). In mostcases the response to treatment isexcellent, and the incidence ofrecurrence is very low.

References1. Mihan R, Ayres S. Perioral dermatitis.Arch Derm 1964; 89:803.

2. Cotterill JA. Perioral dermatitis. Br JDermatol 1979; 101:259.3. Wilkinson DS, Kirton V, WilkinsonJD. Perioral dermatitis: a 12-year reviewBr J Dermatol 1979; 101:245.4. Ellis CN, Stawiski MA. The treatmentof perioral dermatitis, acne rosacea andseborrheic dermatitis. Med Clinic NA1982; 66:819.

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