# OAR Box 1126 Prepped by Ollie Stewart



# Document

Number: 

# 5)11-1-12 6 Docket Number: 

# A-83-2 2

Printed 4/18/20089:58:21 AM Sheet 5of 182 P. 1

### -EJ U 

# A-Z-i-XL -g-J Lea d Neuropath y an d Sickl e Cel l Diseas e Geral d Erenberg , M.D. , Steve n S . Rinsler , M.D. , and Bernar d G . Fish , M.D . l-'witt tin: Departments tif

Seitroliij'ij, Pediatric S : eurolu«ijSuction and Pediatrics, Moiitefinre Hospital and ^ j Mctlit til Critter tmtl Albert Einstein Cvlleire uf

Medicine, Hrtmx, Xeu: York

ABSTRACT . Fou r

case s o f lea dneuropath y i n childre n wit h hemoglobi n S- S o r

S- C diseas e ar e reported . Neuropath y i s a rar e manifestatio n o f

lea dpoisonin g i n children , an donl y te n othe r case s hav e hee n wel l documente di n th e pediatri c lit erature . Th e las t

previou s cas e repor t

o l lea dneuropath y wa s als o i n achil dwit hlteuinglohi n S- S disease . Th e neuropath y see n i n th e childre n wit hsickl e cel l diseas e wa s clinicall y simila r t o tha t see n i n th e previousl y reporte dcase s i n non sicklers , hu t

differe di n bot hgroup s fro mtha t usuall y see n i n adul t cases . I t

is , therefore , postulate dtha t childre n wit h sickl e cel l diseas e hav e a n increase dris k o l developin g neu ropath y wit hexposur e t o lead . Th e exac t mechanis mfo r

thi s associatio n remain s unknown , bu t i n childre n wit hsickl e cel l diseas e presentin g wit hsymptom s o r sign s o f

periphera l weakness , th e possibilit y o f lea dpoisonin g mus t

b e consid ered . I'etlitttrir.s. 54:438 , 1974 , I.K.A D .\I-:UI«>I>,\TIIY , SICKI.I- : (KM . DI.SKASK , I.KAI ) KM'OSlUll-: .



### Sickl e cel l diseas e an dlea dpoisonin g ar e bot h common'problem s o

f blac k childre n i n America . Althoug hth e possibilit y o f aspecia l relationshi p betwee n thes e tw o condition s ha s bee n suggested, 1 

### n o evidenc e for

thi s ha s previousl y bee n docu mented . O f

th e man y effect s o

f lea dpoisoning , symptomati c neuropath y i s considere darelative l y rar e manifestatio n o f plumbis mi n children. 1 

### Eve n thoug hchroni c lea dingestio n ha s recentl y bee n demonstrate dt o alte r periphera l nerv e con ductio n characteristic s i n alarg e percentag e o f ex pose dchildren, - onl y te n case s o f well-document e dlea dneuropath y hav e bee n reporte di n th e pe diatri c literature. 3 8 

### Th e author s hav e ha dth e op portunit y t o observ e fou r blac k childre n wit hbot h sickl e cel l diseas e an dlea dneuropathy . Thre e o f thes e childre n hav e hemoglobi n S-S diseas e an d on e ha s hemoglobi n S- C disease . Th e findin g o f lea dneuropath y an dsickl e cel l diseas e concur rentl y i n thi s numbe r

o f childre n suggest s aspecia l sensitivit y t o som e o

f th e toxi c effect s o

f lea din childre n wit hsickl e hemoglobinopathies . 43 8 PEDIATRIC S Vol . 5 4 No . 4 Octobe r197 4 CAS E REPORT S Cas e 1 P.C . wa s ablac k

bo y wit hknow n hemoglobi n S- C disease , li e ha dexhibite dpic awhil e livin g i n Virginia , an dpic acontinue dalte r

he'move dt o Ne w Yor k Cit y a t th e ag e o f

4 years . On e yea r

late r h e wa s admitte dt o aNe w Yor k Cit y hospita l io r headach e an dabdomina l pain , an dadiagnosi s o f hemo globi n S- C diseas e wa s made . Ove r th e nex t

severa l months h e develope dweaknes s i n hi s hand s an dfeet . H e wa s read mitte dt o th e hospita l an dadiagnosi s o f lea dpoisonin g wit

h3H5' : encephalopath y an dneuropath y wa s made . Afte r discharg e h e continue dt o exhibi t pic aan dwa s treate dwit hdimereap-' . ro l (MAL ) an dedeti c aci d(EDTA ) o n severa l occasions . Weaknes s o f

hi s hand s an dfee t

wa s note dt o advanc e be twee n treatment s an dregres s durin g treatment . Th e hema tocri t readin g remaine dbetwee n 17 % an d24% , an dh e did no t requir e bloo dtransfusions . H e firs t cam e t o th e attentio n ofth e author s i n 197 0 when h e wa s 7 year s old . Examinatio n reveale dmuscl e weaknes s i n al l extremities , greate r distall y tha n proximaily , wit hinabil it y t o exten dhi s wrists , fingers , ankles , o r toes . Dista l muscl e atroph y vva s presen t

a s wa s astockin g an dglov e distributio n o f hypesthesia . Reflexe s a t th e ankle s wer e absent . Th e bloo d lea dleve l wa s 3()/ig/10 0 m l bu t acours e o f

BA Lan dEDT A wa s decide dupon , an durin e lea dexcretio n increase d1,(XX) - fol ddurin g treatment . Fo r th e nex t yea r h e wa s treate da s a

n outpatien t

wit haregime n o f

penicillamin e an dfoli c acid . Durin g thi s tim e hi s strengt himprove dalthoug hincreasin g equinu s foo t

postur e wa s associate dwit hgai t deterioration . Mi s nex t hospitalizatio n wa s a t Montefior e Hospita l an d Medica l Cente r

(MHMC ) i n Jun e 1971 . A t tha t tim e h e wa s H'A year s old , an dh e wa s admitte dbecaus e o f abdomina l pain . Hi s bloo dlea dlevel , whic hdurin g th e previou s 1 8 month s ha dbee n belo w 40/ig/10 0 ml , wa s foun dt o b e 6 5 fig/10 0 nil . Hematocri t readin g wa s 24% . Th e sourc e for.thi s lea dwa s late r

foun dt o b e pain t

fro mth e playgroun do f hi s apartmen t

building . Lon g bon e x-ra y film s reveale dn o evi denc e o f heav y meta l poisoning . Examinatio n agai n reveale d dista l weaknes s an dwastin g wit hdepresse do r absen t reflex -
(Receive dDecembe r

12 , 1973 ; revisio n accepte dfo r publi catio n Marc h15 , 1974. ) ADDRES S FO RREPRINTS : (C.E. ) Pediatri c Neurology , Montefior e Hospita l an dMedica l Center , 11 1 Eas t 210th Street , Bronx , Ne w Yor k 10467 .P. 3

tmmmu»0m.nt. ir - i • n - « uiiiinH<"iiiii<MirmP^j|i C

es . I n addition , ther e wer e no w fixe dequinu s contracture s o f bot hfeet . Th e abdomina l pai n disappeare di n severa l day s wit hintravenou s Huidtherapy , an danothe r cours e o l chela tio n therap y wa s given . Hi s bloo dure anitroge n (RUN ) leve l wa s betwee n 3 0 an d4 0 mg/10 0 m l a s it ha dbee n sinc e hi s initia l hospitalizatio n at 5 year s o

f age . Follow-u p i

n Jun e 1973 . tw o year s afte r th e patient' s las t hospitalization , reveale dpersisten t moderat e weaknes s an d atroph y o f th e dista l portion s o

f th e arm s an dlegs . Ili s lee t remaine di

u afixe dequinu s position , an dhi s famil y ha s re fuse drehabilitativ e orthopedi c surgery . Ili s bloo dlea dleve l ha s remaine dbelo w 30/ig/10 0 nil . Repeate dattempt s a t electrica l studie s o

f nerv e an dmuscl e functio n hav e bee n unsuccessfu l becaus e o

f lac k o f patien t cooperation . Case 2 L . R . wa s a5-year-ol dblac k bo y wit hknow n hemoglobi n S- S diseas e wh o wa s admitte dt o an MHMC-alliliate dhospi ta l in Marc h197 2 becaus e o f letharg y an dpallor . H e ha d hee n hospitalize dpreviousl y for sickl e cel l crises , respirator y trac t infections , an deczema . O n thi s occasio n h e wa s trans ferre dt o M11M C becaus e o f increasin g respirator) ' distress . H e ha dahistor y o

f pic aan dha dbee n see n eatin g pain t chips . Hi s hospita l cours e was marke db y man y problem s in cludin g transien t

hypothermia , hyponatremia , hypertension , an drespirator y distress . Ches t x-ra y films reveale dalef

t lower-lob e infiltrate , bu t ther e was n o evidenc e o f sepsis . Ab domina l films reveale dcalcifi c densitie s in th e descendin g colon ; lon g bon e films showe dn o evidenc e o f chroni c heav y meta l poisoning . Initia l therap y include dintravenousl y administere dfluids , ampicillin , an dabloo dtransfusion . O n th e nint hhospita l day . treatmen t wit hBA Lan dEDT A wa s begu n becaus e o

f a n admissio n bloo dlea dleve l o f 13 6 ug/10 0 ml . O n th e 11thhospita l da y h e was first note dt o hav e tenderness , dysesthesias , an dweaknes s o f al l extremi ties . Th e weaknes s wa s greate r distall y tha n proximall y an d resulte di n complet e bilatera l wris t dro p an dfoo

t drop . Th e dee p tendo n rellexc s wer e absen t i n th e lowe r

extremities . Respirator y distres s an dbloo dpressur e wer e note dt o b e in creasing . Encephalopath y was no t though t t o b e presen t

o n th e basi s o

f norma l CS Ffinding s an dth e absenc e o f papil ledema . Th e diagnosi s o f lea dneuropath y withpossibl e di aphragmati c involvemen t was made . Treatmen t

wit hBALWa s discontinued , bu t EDT A was continue dfo

r atota l o f fiv e days . Th e respirator y difficultie s abate dove r

afour-da y period , bu t

variabl e degree s o

f hyper tensio n remaine dpresen t durin g hi s entir e 53-da y hospitali zation . An intravenou s pyelogra man drena l arteriogra m wer e normal , an drena l functio n wa s norma l excep t for a transien t elevatio n o

f BU N presen t

o n admission . Electrodi agnosti c studie s performe do n th e 25t hhospita l da y reveale d severel y reduce dmoto r

conductio n velocit y i n th e righ t me dia n nerve , an dlef

t commo n peronea l nerv e latencie s coul d no t b e elicited . All muscle s sample di n th e uppe r an dlowe r extremitie s showe dnumerou s fibrillations , consisten t wit ha periphera l neuropath y o f sever e degree . Muscl e strengt himprove dslowl y durin g th e hospitaliza tio n t o th e poin t

wher e som e extensio n at th e wrist s an d ankle s wa s possible . Repea t bloo dlea dlevel s followin g ther ap y wer e 4 0 an d29/tg/K) 0 ml . Whe n las t see n i n Octobe r 1972 . fiv e month s afte r

discharge , h e wa s mildl y hyperten siv e an dha donl y mil ddista l weakness .

Case 3 E.G . wa s a6-year-ol dblac k bo y wit hknow n hemoglobi n S-S diseas e wh o was admitte dt o aNe w Jerse y hospita l i n Septembe r

197 0 becaus e o

f asix-monthhistor y o

f intermit ten t abdomina l an dle g pains . Th e le g pain s ha drecentl y be com e continuous . A histor v o f pic awas obtained , an dth e pa- '

t • i \tt' tien t was transferre dt o aNe w York.'City " hospita l whe n ' opaqu e materia l was discovere do n x-ra y films o f th e abdo men . Examinatio n reveale dgeneralizcd»weakncss . greate r distall y tha n proxhnallv , wit hbilatera l f'viti'sUdici p .an d.loot. : , drop . Th e chil dwa s irritable , aii(l^fe*fflTOl^i^^11^'wf 1 ?f"* " 140/11 0 nu n Hg . Hemoglobi n leve l was 7. 7 gm/10 0 nil , bloo dJea dleve l wa s (i()/jg/10 0 nil , urinar y coproporphyri a wer e strongl y positive , an dlea dline s wer e foun do n x-ray films o l th e knees . Tw o five-da

y course s o

f chelatio n therap y wit hBA Lan d EDT A wer e given , an dth e pos t therap y bloo dlea dleve l was 30fig/10 0 ml . H e was the n transferre dt o achildren' s reha bilitatio n hospita l wher e h e wa s see n b y on e o f us . Upo n dis charg e on e yea r

followin g hi s therap y fo r plumbism , onl y minima l residua l foo t

weaknes s was present . Durin g hi-s^ro longe dsta y i n th e rehabilitatio n hospital , h e wa s transferre d bac k t o th e acut e car e hospita l o n four occasion s becaus e o

f sickl e sequestratio n crises . Durin g on e o f thes e crises , aBU

N leve l o f 4 5 mg/10 0 m

l wa s noted . Evaluatio n to r thi s in clude danorma l intravenou s pyelogram . A rena l biops y was performe dan dshowe dchange s interprete da s bein g consis ten t wit hsickl e cel l anemia . Cas e 4 DM. was a5-year-ol dblac k girl wit hknow n hemoglobi n S-S diseas e wh o was admitte dt o aNe w Yor k suburba n hospi ta l in Septembe r

197 1 becaus e o

f fever , abdomina l pain , an d weakness . O n admission , bilatera l foot dro p was noted . A di agnosi s o f lea dneuropath) ' wa s mad e o n th e basi s o f abloo d lea dleve l o

f 65/ig/10( ) nil , strongl y positiv e urinar y copro porphyria , lea dline s o n x-ray films o f th e knees , an dde crease dnerv e conductio n velocities . Ther e wer e n o sign s o f encephalopathy . Hematocri t readin g was 22% ; urinalysi s an dBU N leve l wer e normal . Th e chil dwa s give n acours e o f chelatio n therapy , an dhe r strengt hprogressivel y improved . Bloo dlea dleve l tw o month s alte r therap y was 5()jug/10 0 ml . Whe n see n b y on e o

f th e author s thre e month s afte r therapy , muscl e strengt hwa s norma l an dn o abnormalitie s vver e foun do n complet e neurologica l examination .

DISCUSSIO N 

### Lea dpoisonin g i s afairl y commo n occurrenc e i n muc ho

f th e industrialize dworld . I t occur s i n bot hadult s an dchildre n bu t wit hsevera l differ ence s i n th e symptomatology . I n adult s chroni c occupationa l exposur e t o lea do r intak e o f lead containin g moonshin e whiske y ar e th e usua l cause s o f intoxication , resultin g i n coli c o r neurop athy . Encephalopath y i s les s commonl y seen . I n children , pic alead s t o th e ingestio n o f hig hlea d conten t pain t an dplaster . Ingestio n o f sufficient amount s lead s t o intoxicatio n whic husuall y mani fest s itsel f

i n symptom s an dsign s o f incipien t

o r over t encephalopathy . Neuropath y i s rare. 1 

### Th e highe r incidenc e o

f encephalopath y i n childre n i s though t t o b e du e t o ingestio n o

f large r amount s o

f lea dove r ashort perio do

f time . Neuropath y i s though t t o occu r

i n adult s becaus e the y ar e ex pose dt o smalle r

amount s o

f lea dove r

alonge r perio do f time. 9 

### A revie w o

f th e reporte dcase s o

f lea dneuropa th y in children 1 

### ' 8 

### reveal s differen t clinica l mani ARTICLE S 

### 43 9P. 4



### festation s a s compare dt o thos e foun di n adults . Th e neuropath y i n adult s primaril y affect s moto r nerves , mos t

ofte n involvin g th e extensor s o f th e wris t an dfingers an dresultin g i n wris t drop.' " Sen sory disturbance s ar e rare, 1 1 

### an dinvolvemen t o f th e lowe r

extremitie s i s uncommon . Th e patho logica l lesion s consis t

o f segmenta l myeli n degen eratio n o f periphera l nerves . I n th e mos t affecte d fibers th e axon s disappea r o r onl y irregula r

rem nant s ar e seen. 1 

### ' - I n children , however , foo t dro p o r wris t dro p an dfoo t

dro p hav e bee n reporte dt o occu r mor e frequently . Te n case s o

f lea dneuropath y i n childre n hav e bee n describe di n detail . Th e las t suc hcas e wa s re porte di n 1964 b y Set o an dFreeman, 8 

### whos e pa tien t wa s a3V&-year-ol

dblac k bo y wh o als o ha dhe moglobi n S- S disease . N o commen t wa s mad e o n an y possibl e relationshi p betwee n th e lea dneu ropath y an dth e sickl e cel l anemia . I n addition , al thoug hcomplet e detail s wer e no t given , amor e recen t repor t als o mention s achild , a10-year-ol d blac k boy , wit hhemoglobi n S- S diseas e an dlea d neuropathy.'- ' Table. I compare s th e findings i n th e nin e case s o f lea dneuropath y reporte di n nonsickler s wit h th e finding s i n th e five childre n (cas e o f Set o an d Freema n plu s th e fou r

childre n i n th e curren t

re port ) wit hsickl e cel l disease . I n th e latte r group , mil dproxima l weaknes s wit hsever e dista l weak nes s manifestin g a s bilatera l wris t an dfoo t dro p wa s th e commones t

patter n an dwa s see n i n four o f th e five children . Ther e wer e n o fatalitie s amon g thes e five children , an donl y on e deat hi n th e nin e childre n wh o di dno t hav e sickl e cel l dis ease . Of th e survivors , al l o

f th e nonsickler s ha d complet e o r

almos t complet e recover y o

f muscl e functio n withi n si

x months . On e o

f th e childre n wit hsickl e cel l diseas e ha s bee n lef t wit hsignifi can t residua l weakness . Whethe r thi s i s du e t o re peate dingestio n o

f lea drathe r

tha n arelationshi p t o th e sickl e cel l diseas e i s no t known . Th e possibilit y tha t

th e neuropath y see n i n ou r case s wa s secondar y t o thei r hemoglobinopath y wa s considered . I n th e repor t b y Gree r an dSchot land , however , n o case s o f neuropath y wer e see n amon g 40 0 patient s wit hhemoglobinopathy. 1 3 

### I n ou r cases , th e episode s o f neuropath y di dno t occu r durin g period s o

f sickl e cel l crise s an dth e hematologi c pictur e di dno t differ fro mtha t whic hi s usuall y see n i n patient s wit hsickl e cel l disease . Th e finding s o

f five case s o

f lea dneuropath y i n childre n wit hhemoglobi n S-S o r S- C diseas e seem s t o indicat e a n increase dsusceptibilit y t o thi s man ifestatio n o

f intoxicatio n wit hlead . Lea dpoison in g i s i n genera l muc hmor e commo n i n blac k chil dre n tha n i n whit e children, 1 4 

### bu t withou t thi s in TABL EI LEA D NEUMOPATII Y I N CHILDRE N WIT H AN D WITHOU T

SICKL ECEL LDISEAS E(SCD ) Distribution Wris t dro p onl y Foo t dro p onl y Wris t dro p an dfoo t

dro p Generalize d

, Outcome Ful l recover y o r minima l residua l Moderat e t o sever e residua l defici t Die d Age at onset (yr) < 3 3- 4 4- 5 5- 6 > 6 SC D (5cases) 0 1 4 0 No SCD

(9cases) 1 3 ' 2 3



### crease dsusceptibilit y on e woul dexpec t ther e t o b e man y case s o

f neuropath y i n childre n wit h sickl e cel l trai t

(S-A ) for eac hchil dwit hhemoglo bi n S-S o r

S- C disease . I t

is , therefore , postulate d tha t patient s wit hsickl e cel l anemi ao r th e doubl e heterozygot e (S-C ) ar e a t increase dris k

o f devel opin g thi s complicatio n o f lea dpoisoning . Th e mechanis mfor

thi s associatio n i s unknown , bu t i n blac k childre n wit hsickl e cel l diseas e presentin g wit hsymptom s o r

sign s o f periphera l weakness , th e possibilit y o

f lea dpoisonin g mus t

b e consid ered . SPECULATIO N 

### Severa l differen t

mechanism s ma y b e involve d i n th e occurrenc e o

f lea dneuropath y i n childre n wit hsickl e cel l disease . Th e somewha t olde r ag e o f thes e children , a s compare dt o th e usua l ag e wher e encephalopath y i s seen , ma y indicat e tha t neuropath y occur s a s afunctio n o f th e maturit y o

f th e nervou s syste ma t

th e tim e o

f th e insult . Pic a ma y persis t

i n childre n wit hsickl e cel l disease beyon dth e ag e i t

i s usuall y seen , secondar y per hap s t o insidiou s brai n damag e fro mcerebra l anoxi c changes . Th e possibilit y tha t prolonge dex posur e t o lea dma y b e responsibl e fo r th e In crease dincidenc e o

f neuropath y i s i n keepin g wit hpattern s previousl y see n i n Australia . I n chil dre n o f Queensland , Australi a(189 0 t o 1930) , in toxicatio n wa s note din nailbiter s an dfinger sucker s wh o receive dthei r

lea dfro mth e sun-pow dere dpain t

o f thei r hous e verandas , resultin g i n chroni c intoxication. 151 7 

### Thi s grou p i s remarkabl e in th althi. . uate . T l over in t l Woo Init i ter a tan t mi n an d all ; ov e reg ; ma ; ic t 

### Le ; ch u sic l ar o haiin g ife . de i m t 

### le a p o p a si l t n b e fe . t w tr . l e a l

44 0 SICKL E CEL L DISEAS EP. 5



### i n tha t ahig hrat e o

f neuropath y wa s reported , althoug hi t

wa s i n insufficient

detai l t o fully eval uate . Th e chronicall y increase dre dbloo dcel l turn ove r i n sickl e cel l diseas e ma y lea dt o alteration s i n th e relationshi p o

f sof t tissue-boun dlead , re d bloo dcel l boun dlead , an dfre e lea di n th e plasma . Initia l studie s o

f thi s possibilit y indicat e tha t a n al teratio n i n th e plasm alea dleve l i s no t a n impor tan t factor. 1 8 

### Whe n plasm alea dlevel s wer e deter mine di n norma l an dleadrintoxicate dchildre n andchildre n wit hsickl e cel l disease , th e result s i n all group s wer e remarkabl y similar an dconstan t ove r awid e rang e o

f bloo dlea dconcentratio n an d regardles s o

f hematocrit . I n spit e o f this , ther e ma y ye t prov e t o b e a n abnormalit y i n th e dynam i c transpor t

syste mbetwee n re dcell s an dplasma. ' Leadexcretio n ma y b e impaire dbecaus e o f change s i n rena l functio n see n i n childre n wit h sickl e cel l disease . Yet

anothe r possibilit y revolve s aroun dabnormalitie s o

f porphyri n metabolism . I t ha s bee n previousl y speculate dtha t lea dpoison in g an dporphyri acaus e simila r neurologica l man ifestation s via* acommo n fina l pathway , whic hi s demyelinatio n o

f periphera l nerves. 1 9 

### Porphyri n metabolis mi s know n t o b e altere di n patient s wit h lea dintoxication , bu t

perhap s i s altere di n way s potentiatin g th e possibilit y o f demyelinatio n i n patient s als o havin g sickl e cel l disease . A final pos sibility involve s th e interactio n betwee n lea dan d trac e metals . Patient s wit hsickl e cel l diseas e hav e bee n show n t o b e zin c deficient.'- " Th e toxi c effect s o f lea dma y depen dupo n a n interactio n be twee n excessiv e lea dan dadeficien t amoun t o f a trac e meta l suc ha s zinc , rathe r tha n a n effec t

o f lea dalone . Suc hinteractio n betwee n heav y met als , includin g lead,- 1 

### ha s bee n suggested.- 2 REFERENCE S 1 . Lin-Fu , J.S. : Undu e absorptio n o f lea damon g children— A ne w loo k

at a n ol dproblem . Ne w Eng . ] . Med. , 286:702 , 1972 . 2 . Feldman , R . G. , Haddow , J. , Kopito , L. , an dSchwach man , H. : Altere dperiphera l nerv e conductio n ve locity : Chroni c lea dintoxicatio n i n children . Amer . J . Dis . Child. , 125:39 , 1973 . 3 . Friedberg , E. : Chroni c lea dpoisonin g i n childre n (ab stracted) . JAMA , 78:1172 , 1922 . 4 . Goodwin , T . C : Lea dpoisoning : Repor t o f acas e i n a chil dwit hextensiv e periphera l neuritis . Bull . John s Hopkin s Hosp. , 55:347 , 1934 . 5 . Brown , J . E. , an dSmith , E . E. : Periphera l neuriti s du e t o lead . J . Pediat. , 10:656 , 1937 . 6 . Byers , R . K. , an dLord , E . E. : Lat e effect s o f lea dpoison in g o n menta l development . Amer . J . Dis . Child. , 66:471 , 1943 . 7 . Millichap , J . C. , Llewellin , K. R. , an dRonburgh , R . C : Lea dpaint , hazar dt o children . Lancet , 11:360 , 1952 . 8 . Seto , D . S . Y. , an dFreeman , J . M. : Lea dneuropath y i n childhood . Amer . J . Dis . Child. , 103:337 , 1964 . ' 9 . Haley , T . J. : Saturnism , pediatri c an dadul t lea dpoison ing . Clin . Toxicol. , 4:11 , 1971 . 10 . Aub , J . C „ Fairhall , L . T „ Minot , A . S. , an dRc/nikoir , P. : Lea dpoisoning . Medicine , 4:1 , 1925 . 11 . Tanquere l de s Planches : Lea dDiseases , C . L . Dan a (trans.-ed.) . Lowell , Mass. : D . Bixb y & Cp. , 1848 . 12 . Blackwood , W. , McMenemey , W . H. , Meyer , A.,-Nor man , R . M. , an dRussell , D . S. : Greenfield's'Neuro- ' pajhology , ed . 2 . Baltimore : William s & Wilkin s Co. , 1963 . 13 . Greer , M. , an dSchotland , D. : Abnorma l hemoglobi n a s a caus e o f neurologi c disease . Neurology , 12:114 , 1962 . 14 . Jacob/iner , J. : Lea dpoisonin g i n childhood : Epidemiol ogy , manifestations , an dprevention . Clin . Pediat. , 5:277 , 1966 . 15 . Turner , A . J. : Lea dpoisonin g amon g Queenslan dchil dren . Aust . Med . Gaz. , 16:475 , 1897 . 16 . Breinl , A. , an dYoung , W . J. : Occurrenc e o f lea dpoison in g amongs t

Nort hQueenslan dchildren . Ann . Trop . Med . Parasit. , 8:575 , 1914 . 17 . Counci l o

f th e Queenslan dBranc ho f th e Britis hMedi ca l Association : Historica l accoun t o f lea dpoison in g amon g Queenslan dchildren . Med . J . Aust. , 1:148 , 1922 . 18 . Rosen , J . F. , Zarate-Salvador , C , an dTrinidad , B . S. : Plasm alea dlevel s i n norma l an dlea dintoxicate d children . J . Pediat. , 84:45 , 1974 . 19 . Dagg , J . H. , Goldberg , A. , Lockhead , A. , an dSmith , J . A. : Th e relationshi p o

f lea dpoisonin g t o acut e inter mitten t porphyria . Quart . J . Med. , 34:163 , 1965 . 20 . Schoomaker , E . B. , Prasad , A. , Oelshlegel , F . J. , Ortego , J. , an dBrewer , G . J. : Rol e o f zin c i n sickl e cel l dis ease : I . Zin c deficienc y throug hhemolysis . Clin . Res. , 21:834 , 1973 . 21 . Ferm , V . H. : Th e synteratogeni c effec t of lea dan dcad mium . Experientia , 25:56 , 1969 . 22 . Pfeiffer , C . C , an dIliev , V. : A stud y o f zin c deficienc y an dcoppe r

exces s in the'schizophrenias . In Pfeiffer , C . C . (ed.) : Neurobiolog y o f th e Trac e Metal s Zin c an dCopper : Ne w York : Academi c Press , 1972 , p . 141 . ACKNOWLEDGMEN T Th e author s wis ht o than k Josep hH . French , M.D. , Laurenc e Finberg , M.D. , Ellio t D . Weitzman , M.D. , an dal l th e other s wh o reviewe dth e manuscrip t an doffere dsugges tions . Eugen e Moskowitz , M.D . mad e th e initia l diagnosi s o f lea dneuropath y i n cas e 4 .

ARTICLE S 

### 44 1