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P.1 
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A-Z-i-XL -g-JLead Neuropathy and Sickle Cell Disease 

Gerald Erenberg, M.D., Steven S. Rinsler, M.D., and Bernard G. Fish, M.D. 

l-'witt tin: Departments tif Seitroliij'ij, Pediatric S:eurolu«ij Suction and Pediatrics, Moiitefinre Hospital and ^j 

Mctlit til Critter tmtl Albert Einstein Cvlleire uf Medicine, Hrtmx, Xeu: York 

ABSTRACT. Four cases of lead neuropathy in children with 

hemoglobin S-S or S-C disease are reported. Neuropathy is a 

rare manifestation of lead poisoning in children, and only ten 

other cases have heen well documented in the pediatric literature. The last previous case report ol lead neuropathy was 

also in a child with lteuinglohin S-S disease. The neuropathy 

seen in the children with sickle cell disease was clinically 

similar to that seen in the previously reported cases in nonsicklers, hut differed in both groups from that usually seen in 

adult cases. It is, therefore, postulated that children with 

sickle cell disease have an increased risk ol developing neuropathy with exposure to lead. The exact mechanism for this 

association remains unknown, but in children with sickle cell 

disease presenting with symptoms or signs of peripheral 

weakness, the possibility of lead poisoning must be considered. I'etlitttrir.s. 54:438, 1974, I.K.AD .\I-:UI«>I>,\TIIY, SICKI.I-: 

(KM . DI.SKASK, I.KAI) KM'OSlUll-:. 

Sickle cell disease and lead poisoning are both 

common'problems of black children in America. 

Although the possibility of a special relationship 

between these two conditions has been suggested,1 

no evidence for this has previously been documented. Of the many effects of lead poisoning, 

symptomatic neuropathy is considered a relatively rare manifestation of plumbism in children.1 

Even though chronic lead ingestion has recently 

been demonstrated to alter peripheral nerve conduction characteristics in a large percentage of exposed children,- only ten cases of well-documented lead neuropathy have been reported in the pediatric literature.38

 The authors have had the opportunity to observe four black children with both 

sickle cell disease and lead neuropathy. Three of 

these children have hemoglobin S-S disease and 

one has hemoglobin S-C disease. The finding of 

lead neuropathy and sickle cell disease concurrently in this number of children suggests a special 

sensitivity to some of the toxic effects of lead in 

children with sickle hemoglobinopathies. 

438 PEDIATRICS Vol. 54 No. 4 October 1974 

CASE REPORTS 

Case 1 

P.C. was a black boy with known hemoglobin S-C disease, 

lie had exhibited pica while living in Virginia, and pica continued alter he'moved to New York City at the age of 4 years. 

One year later he was admitted to a New York City hospital 

ior headache and abdominal pain, and a diagnosis of hemoglobin S-C disease was made. Over the next several months 

he developed weakness in his hands and feet. He was readmitted to the hospital and a diagnosis of lead poisoning with 3H5': 

encephalopathy and neuropathy was made. After discharge 

he continued to exhibit pica and was treated with dimereap-'. 

rol (MAL) and edetic acid (EDTA) on several occasions. 

Weakness of his hands and feet was noted to advance between treatments and regress during treatment. The hematocrit reading remained between 17% and 24%, and he did 

not require blood transfusions. 

He first came to the attention ofthe authors in 1970 when 

he was 7 years old. Examination revealed muscle weakness in 

all extremities, greater distally than proximaily, with inability to extend his wrists, fingers, ankles, or toes. Distal muscle 

atrophy vvas present as was a stocking and glove distribution 

of hypesthesia. Reflexes at the ankles were absent. The blood 

lead level was 3()/ig/100 ml but a course of BAL and EDTA 

was decided upon, and urine lead excretion increased 1,(XX)-

fold during treatment. For the next year he was treated as an 

outpatient with a regimen of penicillamine and folic acid. 

During this time his strength improved although increasing 

equinus foot posture was associated with gait deterioration. 

Mis next hospitalization was at Montefiore Hospital and 

Medical Center (MHMC) in June 1971. At that time he was 

H'A years old, and he was admitted because of abdominal 

pain. His blood lead level, which during the previous 18 

months had been below 40/ig/100 ml, was found to be 65 

fig/100 nil. Hematocrit reading was 24%. The source for.this 

lead was later found to be paint from the playground of his 

apartment building. Long bone x-ray films revealed no evidence of heavy metal poisoning. Examination again revealed 

distal weakness and wasting with depressed or absent reflex-

(Received December 12, 1973; revision accepted for publication March 15, 1974.) 

ADDRESS FOR REPRINTS: (C.E.) Pediatric Neurology, 

Montefiore Hospital and Medical Center, 111 East 210th 

Street, Bronx, New York 10467. 
P.3 

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

es. In addition, there were now fixed equinus contractures of 

both feet. The abdominal pain disappeared in several days 

with intravenous Huid therapy, and another course ol chelation therapy was given. His blood urea nitrogen (RUN) level 

was between 30 and 40 mg/100 ml as it had been since his 

initial hospitalization at 5 years of age. 

Follow-up in June 1973. two years after the patient's last 

hospitalization, revealed persistent moderate weakness and 

atrophy of the distal portions of the arms and legs. Ilis leet 

remained iu a fixed equinus position, and his family has refused rehabilitative orthopedic surgery. Ilis blood lead level 

has remained below 30/ig/100 nil. Repeated attempts at 

electrical studies of nerve and muscle function have been 

unsuccessful because of lack of patient cooperation. 

Case 2 

L. R. was a 5-year-old black boy with known hemoglobin 

S-S disease who was admitted to an MHMC-alliliated hospital in March 1972 because of lethargy and pallor. He had 

heen hospitalized previously for sickle cell crises, respiratory 

tract infections, and eczema. On this occasion he was transferred to M11MC because of increasing respirator)' distress. 

He had a history of pica and had been seen eating paint 

chips. His hospital course was marked by many problems including transient hypothermia, hyponatremia, hypertension, 

and respiratory distress. Chest x-ray films revealed a left 

lower-lobe infiltrate, but there was no evidence of sepsis. Abdominal films revealed calcific densities in the descending 

colon; long bone films showed no evidence of chronic heavy 

metal poisoning. Initial therapy included intravenously 

administered fluids, ampicillin, and a blood transfusion. 

On the ninth hospital day. treatment with BAL and EDTA 

was begun because of an admission blood lead level of 136 

ug/100 ml. On the 11th hospital day he was first noted to 

have tenderness, dysesthesias, and weakness of all extremities. The weakness was greater distally than proximally and 

resulted in complete bilateral wrist drop and foot drop. The 

deep tendon rellexcs were absent in the lower extremities. 

Respiratory distress and blood pressure were noted to be increasing. Encephalopathy was not thought to be present on 

the basis of normal CSF findings and the absence of papilledema. The diagnosis of lead neuropathy with possible diaphragmatic involvement was made. 

Treatment with BAL Was discontinued, but EDTA was 

continued for a total of five days. The respiratory difficulties 

abated over a four-day period, but variable degrees of hypertension remained present during his entire 53-day hospitalization. An intravenous pyelogram and renal arteriogram 

were normal, and renal function was normal except for a 

transient elevation of BUN present on admission. Electrodiagnostic studies performed on the 25th hospital day revealed 

severely reduced motor conduction velocity in the right median nerve, and left common peroneal nerve latencies could 

not be elicited. All muscles sampled in the upper and lower 

extremities showed numerous fibrillations, consistent with a 

peripheral neuropathy of severe degree. 

Muscle strength improved slowly during the hospitalization to the point where some extension at the wrists and 

ankles was possible. Repeat blood lead levels following therapy were 40 and 29/tg/K)0 ml. When last seen in October 

1972. five months after discharge, he was mildly hypertensive and had only mild distal weakness. 

Case 3 

E.G. was a 6-year-old black boy with known hemoglobin 

S-S disease who was admitted to a New Jersey hospital in 

September 1970 because of a six-month history of intermittent abdominal and leg pains. The leg pains had recently become continuous. A historv of pica was obtained, and the pa-' 

t • i \tt' 

tient was transferred to a New York.'City" hospital when ' 

opaque material was discovered on x-ray films of the abdomen. Examination revealed generalizcd»weakncss. greater 

distally than proxhnallv, with bilateral f'viti'sUdicip .and .loot.: , 

drop. The child was irritable, aii(l^fe*fflTOl^i^^11^'wf1?f"*" 

140/110 nun Hg. Hemoglobin level was 7.7 gm/100 nil, 

blood Jead level was (i()/jg/100 nil, urinary coproporphyria 

were strongly positive, and lead lines were found on x-ray 

films ol the knees. 

Two five-day courses of chelation therapy with BAL and 

EDTA were given, and the post therapy blood lead level was 

30fig/100 ml. He was then transferred to a children's rehabilitation hospital where he was seen by one of us. Upon discharge one year following his therapy for plumbism, only 

minimal residual foot weakness was present. During hi-s^rolonged stay in the rehabilitation hospital, he was transferred 

back to the acute care hospital on four occasions because of 

sickle sequestration crises. During one of these crises, a BUN 

level of 45 mg/100 ml was noted. Evaluation tor this included a normal intravenous pyelogram. A renal biopsy was 

performed and showed changes interpreted as being consistent with sickle cell anemia. 

Case 4 

DM. was a 5-year-old black girl with known hemoglobin 

S-S disease who was admitted to a New York suburban hospital in September 1971 because of fever, abdominal pain, and 

weakness. On admission, bilateral foot drop was noted. A diagnosis of lead neuropath)' was made on the basis of a blood 

lead level of 65/ig/10() nil, strongly positive urinary coproporphyria, lead lines on x-ray films of the knees, and decreased nerve conduction velocities. There were no signs of 

encephalopathy. Hematocrit reading was 22%; urinalysis 

and BUN level were normal. The child was given a course of 

chelation therapy, and her strength progressively improved. 

Blood lead level two months alter therapy was 5()jug/100 ml. 

When seen by one of the authors three months after therapy, 

muscle strength was normal and no abnormalities vvere 

found on complete neurological examination. 

DISCUSSION 

Lead poisoning is a fairly common occurrence 

in much of the industrialized world. It occurs in 

both adults and children but with several differences in the symptomatology. In adults chronic 

occupational exposure to lead or intake of leadcontaining moonshine whiskey are the usual 

causes of intoxication, resulting in colic or neuropathy. Encephalopathy is less commonly seen. In 

children, pica leads to the ingestion of high lead 

content paint and plaster. Ingestion of sufficient 

amounts leads to intoxication which usually manifests itself in symptoms and signs of incipient or 

overt encephalopathy. Neuropathy is rare.1 The 

higher incidence of encephalopathy in children is 

thought to be due to ingestion of larger amounts of 

lead over a short period of time. Neuropathy is 

thought to occur in adults because they are exposed to smaller amounts of lead over a longer 

period of time.9 

A review of the reported cases of lead neuropathy in children1

'

8

 reveals different clinical maniARTICLES 439 
P.4 

festations as compared to those found in adults. 

The neuropathy in adults primarily affects motor 

nerves, most often involving the extensors of the 

wrist and fingers and resulting in wrist drop.'" Sensory disturbances are rare,11

 and involvement of 

the lower extremities is uncommon. The pathological lesions consist of segmental myelin degeneration of peripheral nerves. In the most affected 

fibers the axons disappear or only irregular remnants are seen.1

'- In children, however, foot drop or 

wrist drop and foot drop have been reported to 

occur more frequently. 

Ten cases of lead neuropathy in children have 

been described in detail. The last such case was reported in 1964 by Seto and Freeman,8

 whose patient was a 3V&-year-old black boy who also had hemoglobin S-S disease. No comment was made on 

any possible relationship between the lead neuropathy and the sickle cell anemia. In addition, although complete details were not given, a more 

recent report also mentions a child, a 10-year-old 

black boy, with hemoglobin S-S disease and lead 

neuropathy.'-' 

Table.I compares the findings in the nine cases 

of lead neuropathy reported in nonsicklers with 

the findings in the five children (case of Seto and 

Freeman plus the four children in the current report) with sickle cell disease. In the latter group, 

mild proximal weakness with severe distal weakness manifesting as bilateral wrist and foot drop 

was the commonest pattern and was seen in four 

of the five children. There were no fatalities 

among these five children, and only one death in 

the nine children who did not have sickle cell disease. Of the survivors, all of the nonsicklers had 

complete or almost complete recovery of muscle 

function within six months. One of the children 

with sickle cell disease has been left with significant residual weakness. Whether this is due to repeated ingestion of lead rather than a relationship 

to the sickle cell disease is not known. 

The possibility that the neuropathy seen in our 

cases was secondary to their hemoglobinopathy 

was considered. In the report by Greer and Schotland, however, no cases of neuropathy were seen 

among 400 patients with hemoglobinopathy.13 In 

our cases, the episodes of neuropathy did not 

occur during periods of sickle cell crises and the 

hematologic picture did not differ from that 

which is usually seen in patients with sickle cell 

disease. 

The findings of five cases of lead neuropathy in 

children with hemoglobin S-S or S-C disease seems 

to indicate an increased susceptibility to this manifestation of intoxication with lead. Lead poisoning is in general much more common in black children than in white children,14

 but without this inTABLE I 

LEAD NEUMOPATIIY IN CHILDREN WIT H AND WITHOUT 

SICKLE CEL L DISEASE (SCD) 

Distribution 

Wrist drop only 

Foot drop only 

Wrist drop and foot drop 

Generalized 

, Outcome 

Full recovery or 

minimal residual 

Moderate to severe 

residual deficit 

Died 

Age at onset (yr) 

< 3 

3-4 

4-5 

5-6 

> 6 

SCD 

(5 cases) 

0 

1 

4 

0 

No SCD 

(9 cases) 

1 

3 

'2 

3 

creased susceptibility one would expect there to 

be many cases of neuropathy in children with 

sickle cell trait (S-A) for each child with hemoglobin S-S or S-C disease. It is, therefore, postulated 

that patients with sickle cell anemia or the double 

heterozygote (S-C) are at increased risk of developing this complication of lead poisoning. The 

mechanism for this association is unknown, but in 

black children with sickle cell disease presenting 

with symptoms or signs of peripheral weakness, 

the possibility of lead poisoning must be considered. 

SPECULATION 

Several different mechanisms may be involved 

in the occurrence of lead neuropathy in children 

with sickle cell disease. The somewhat older age 

of these children, as compared to the usual age 

where encephalopathy is seen, may indicate that 

neuropathy occurs as a function of the maturity of 

the nervous system at the time of the insult. Pica 

may persist in children with sickle cell diseasebeyond the age it is usually seen, secondary perhaps to insidious brain damage from cerebral 

anoxic changes. The possibility that prolonged exposure to lead may be responsible for the Increased incidence of neuropathy is in keeping 

with patterns previously seen in Australia. In children of Queensland, Australia (1890 to 1930), intoxication was noted in nailbiters and finger suckers who received their lead from the sun-powdered paint of their house verandas, resulting in 

chronic intoxication.1517 This group is remarkable 

in th 

althi.. 

uate. 

Tl 

over 

in tl 

Woo 

Initi 

tera 

tant 

min 

and 

all; 

ove 

reg; 

ma; 

ict 

Le; 

chu 

sicl 

aro 

haiing 

ife. 

dei 

mt 

lea 

po 

pa 

sil 

tn 

be 

fe. 

tw 

tr. 

le 

al 

440 SICKLE CELL DISEASE 
P.5 

in that a high rate of neuropathy was reported, 

although it was in insufficient detail to fully evaluate. 

The chronically increased red blood cell turnover in sickle cell disease may lead to alterations 

in the relationship of soft tissue-bound lead, red 

blood cell bound lead, and free lead in the plasma. 

Initial studies of this possibility indicate that an alteration in the plasma lead level is not an important factor.18

 When plasma lead levels were determined in normal and leadrintoxicated children 

and children with sickle cell disease, the results in 

all groups were remarkably similar and constant 

over a wide range of blood lead concentration and 

regardless of hematocrit. In spite of this, there 

may yet prove to be an abnormality in the dynamic transport system between red cells and plasma.' 

Lead excretion may be impaired because of 

changes in renal function seen in children with 

sickle cell disease. Yet another possibility revolves 

around abnormalities of porphyrin metabolism. It 

has been previously speculated that lead poisoning and porphyria cause similar neurological manifestations via* a common final pathway, which is 

demyelination of peripheral nerves.19 Porphyrin 

metabolism is known to be altered in patients with 

lead intoxication, but perhaps is altered in ways 

potentiating the possibility of demyelination in 

patients also having sickle cell disease. A final possibility involves the interaction between lead and 

trace metals. Patients with sickle cell disease have 

been shown to be zinc deficient.'-" The toxic effects of lead may depend upon an interaction between excessive lead and a deficient amount of a 

trace metal such as zinc, rather than an effect of 

lead alone. Such interaction between heavy metals, including lead,-1

 has been suggested.-2 

REFERENCES 

1. Lin-Fu, J.S.: Undue absorption of lead among children— 

A new look at an old problem. New Eng. ]. Med., 

286:702, 1972. 

2. Feldman, R. G., Haddow, J., Kopito, L., and Schwachman, H.: Altered peripheral nerve conduction velocity: Chronic lead intoxication in children. 

Amer. J. Dis. Child., 125:39, 1973. 

3. Friedberg, E.: Chronic lead poisoning in children (abstracted). JAMA, 78:1172, 1922. 

4. Goodwin, T. C: Lead poisoning: Report of a case in a 

child with extensive peripheral neuritis. Bull. 

Johns Hopkins Hosp., 55:347, 1934. 

5. Brown, J. E., and Smith, E. E.: Peripheral neuritis due to 

lead. J. Pediat., 10:656, 1937. 

6. Byers, R. K., and Lord, E. E.: Late effects of lead poisoning on mental development. Amer. J. Dis. Child., 

66:471, 1943. 

7. Millichap, J. C., Llewellin, K. R., and Ronburgh, R. C: 

Lead paint, hazard to children. Lancet, 11:360, 

1952. 

8. Seto, D. S. Y., and Freeman, J. M.: Lead neuropathy in 

childhood. Amer. J. Dis. Child., 103:337, 1964. ' 

9. Haley, T. J.: Saturnism, pediatric and adult lead poisoning. Clin. Toxicol., 4:11, 1971. 

10. Aub, J. C„ Fairhall, L. T„ Minot, A. S., and Rc/nikoir, P.: 

Lead poisoning. Medicine, 4:1, 1925. 

11. Tanquerel des Planches: Lead Diseases, C. L. Dana 

(trans.-ed.). Lowell, Mass.: D. Bixby & Cp., 1848. 

12. Blackwood, W., McMenemey, W. H., Meyer, A.,-Norman, R. M., and Russell, D. S.: Greenfield's'Neuro-' 

pajhology, ed. 2. Baltimore: Williams & Wilkins 

Co., 1963. 

13. Greer, M., and Schotland, D.: Abnormal hemoglobin as a 

cause of neurologic disease. Neurology, 12:114, 

1962. 

14. Jacob/iner, J.: Lead poisoning in childhood: Epidemiology, manifestations, and prevention. Clin. Pediat., 

5:277, 1966. 

15. Turner, A. J.: Lead poisoning among Queensland children. Aust. Med. Gaz., 16:475, 1897. 

16. Breinl, A., and Young, W. J.: Occurrence of lead poisoning amongst North Queensland children. Ann. 

Trop. Med. Parasit., 8:575, 1914. 

17. Council of the Queensland Branch of the British Medical Association: Historical account of lead poisoning among Queensland children. Med. J. Aust., 

1:148, 1922. 

18. Rosen, J. F., Zarate-Salvador, C, and Trinidad, B. S.: 

Plasma lead levels in normal and lead intoxicated 

children. J. Pediat., 84:45, 1974. 

19. Dagg, J. H., Goldberg, A., Lockhead, A., and Smith, J. A.: 

The relationship of lead poisoning to acute intermittent porphyria. Quart. J. Med., 34:163, 1965. 

20. Schoomaker, E. B., Prasad, A., Oelshlegel, F. J., Ortego, 

J., and Brewer, G. J.: Role of zinc in sickle cell disease: I. Zinc deficiency through hemolysis. Clin. 

Res., 21:834, 1973. 

21. Ferm, V. H.: The synteratogenic effect of lead and cadmium. Experientia, 25:56, 1969. 

22. Pfeiffer, C. C, and Iliev, V.: A study of zinc deficiency 

and copper excess in the'schizophrenias. In Pfeiffer, C. C. (ed.): Neurobiology of the Trace Metals 

Zinc and Copper: New York: Academic Press, 

1972, p. 141. 

ACKNOWLEDGMENT 

The authors wish to thank Joseph H. French, M.D., 

Laurence Finberg, M.D., Elliot D. Weitzman, M.D., and all 

the others who reviewed the manuscript and offered suggestions. Eugene Moskowitz, M.D. made the initial diagnosis of 

lead neuropathy in case 4. 

ARTICLES 441