Lead is a known toxin and may affect the nervous, gastrointestinal, hematopoietic and other systems. Elevated blood lead (BPb) levels are also associated with lower intelligent quotient, neurodevelopmental abnormalities including attention deficit disorder, behavior disturbances, learning disabilities and deficits in fine and gross motor development(1). Toxic effects on the central nervous system and resultant long term neurobehavioral and cognitive deficits occur even with mildly elevated BPb levels (10-25 µg/dl)(1).

Despite growing concern regarding the detrimental effects of low to moderate levels of lead intoxication in children, pharmacological treatment of these children is controversial. The cornerstone of therapy is, however, prevention of exposure, which includes identification, and removal of lead sources and counseling of families to minimize exposure.

There are only a few reports from all over the world regarding the use of succimer in treatment of lead posoning(3-7). No study is, however, reported from India. The report indicates our experience with the use of succimer as a lead chelating agent in four children presenting with symptomatic lead poisoning.

Case 1: An 8-year-old male staying in an urban area in Delhi presented with increasing pallor for 6 months and recurrent episodes of abdominal colic with history of pica. There were no other gastrointestinal complaints. There was no history of drug intake, bleeding from any site, worm infestation, jaundice, blood transfusion, or petechiae. There was no history of exposure to paints or factories in neighborhood. Examination revealed moderate degree pallor without any other abnormality. There were no lead lines. The child was investigated for cause of anemia before he was referred here. His hemoglobin was 7.7 g/dL with peripheral smear showing hypochromic, microcytic picture with anisocytosis, poikilocytosis without any abnormal cells, basophilic stippling or evidence of hemolysis. The iron studies including serum iron, total iron binding capacity and percentage iron saturation were within normal range. Hemoglobin electrophoresis was also normal. Lead toxicity was suspected and BPb was estimated by Lead Care System (ESA, Inc., 22 Alpha Road, Chelmsford, MA United States). The BPb was 30.6 µg/dl. A repeat estimation done after 4 days also revealed a value of 29.2 µg/dl. Skeletal survey did not reveal any metaphyseal bands. The investigations are summarized in Table I.

Table I-Clinical Profile and Investigations

The BPb estimation was also performed for the whole family. The BPb values of parents were not elevated (father-6.1 µg/dl, mother-4.8 µg/dl) while the younger sister also had elevated BLL (22.6 µg/dl).

The index case was started on succimer in a dose of 30 mg/kg/day in three divided doses for 5 days followed by 20 mg/kg/day twice a day in two divided doses for 14 days. Along with succimer, the child was also started on iron (2 mg/kg), calcium (50 mg/kg), zinc (10 mg) and vitamin C (100 mg). Repeat estimation of BPb done immediately on finishing the course did not show any decline; however, it decreased to 12.6 µg/dl after one month. At the same time, hemoglobin also rose to 10.6 g/dL after one month. No side effects were reported. On follow up after 4 months, BPb was 13.8 µg/dL with hemoglobin increasing to 12.6 g/dL. The BPb values are shown in Fig. 1.

Case 2: A 7-year-old male child residing in a town 100 km from Delhi presented with pain in abdomen and decreased appetite for 9 months. There was no history of anemia, jaundice, vomiting, fever, or drug intake. Examination was noncontributory. The child had previously been investigated and there was no evidence of tuberculosis but he had empirically received antitubercular treatment without any improvement. Other investigations were also normal including ultrasound abdomen, hemogram and stool. Lead toxicity was suspected and BPb level was 46.9 µg/dL. Repeat estimation was also high (51.8 µg/dL). Skeletal survey was normal. The clinical profile and investigations are shown in Table I. The child was given succimer along with iron, zinc, calcium and vitamin C in the same schedule as Case I.

On follow up, the BPb level declined to 20.5 µg/dl. Clinical symptom of pain in abdomen also decreased along with improvement in appetite. Repeat BPb estimation after 3 weeks was in same range (22.6 µg/dL) and a course of succimer was repeated. The BPb declined after second course to 11.4 µg/dL. After 3 months of follow up, there was no rise in BPb. The serial BPb values are shown in Fig.1.

The BPb of the family members were also elevated (father-13.7 µg/dL, mother-14.2 µg/dl, and sister-22.3 µg/dL) but none of them were symptomatic. On follow up too, they remained symptom free without any rise in BPb.

Case 3: BPb estimation was done in an 8-year-old child with attention deficit hyperactivity disorder as a part of investigation protocol. He also had history of occasional abdominal pain. The examination was noncontributory except for hyperactivity. Regarding history of environmental exposure, their house is within 1 km of an industrial area.

On investigation, his hemoglobin was 12.6 g/dL with normocytic and normochromic picture on peripheral smear. BPb level was high (>65 µg/dL) twice. Exact value is not known as Lead Care System shows ‘High’ for values more than 65 µg/dL. He was started an succimer along with iron, zinc, calcium and vitamin C in same regimen as Case I and repeat blood lead estimation done after 5 days of therapy. The BPb declined to 24.6 µg/dL and succimer continued for full course when the BPb fell to 14.6 µg/dL. BPb after one month showed a slight rise to 17.3 µg/dl. Monthly BPb values showed a decline and BPb after 4 months was 7.7 µg/dl. BPb values and investigations are summarized in Fig. 1 and Table I, respectively.

On family screening, BPb of the mother was 12.5 ug/dL while rest of the family members had BPb less than 10 µg/dL.

Case 4: A 5-year-old male presented with right sided simple partial seizures for last 2 years in a fequency of one episode almost every 2 months and each episode lasting 1-5 minutes. There was also history of pica. There were no behavioral changes or problems in attention or symptoms of peripheral neuropathy. The patient was investigated for cause of seizures. Electroencephalogram showed asymmetry with attenuation of rhythm in left hemisphere without any epileptiform discharges. CT scan revealed focal white matter edema in left frontal region. Skeletal survey showed alternate lucent and dense metaphyseal bands. However, the child had no basophilic stippling on peripheral smear and had normal renal and liver functions. Due to X-ray findings, BPb was estimated which turned out to be 28 µg/dL and 30.9 µg/dL in two samples done at one week interval. A detailed history for suspected lead exposure was taken. There was a factory (fevicol) nearby within 1 km of their house. Father had also worked in a paint factory for 3 months 2 years back. The clinical profile and investigations are summarized in Table I. Father’s blood lead was also high (23.7 µg/dL) but he was asymptomatic. The BPb of the rest of the family members were normal.

The patient was started on succimer along with iron, zinc, calcium and vitamin C in the same regimen as Case I. BPb declined to 8.6 µg/dl after a week and to 6.7 µg/dL on finishing the course. Repeat BPb, however, after 2 weeks showed a rise to 32.6 µg/dL and the course of succimer was repeated. No significant source was identifiable. The BPb again declined to 12 µg/dL at the end of second course. Two weeks later, BPb again rose to 27.2 µg/dL. After 6 months of follow up, the blood lead remained in the same range (24.1 µg/dL). The BPb values are graphically shown in Fig. 1.

Elevated BPb is still a major problem in developing countries. As lead affects various systems, lead toxicity needs to be ruled out in a multitude of symptoms. The foremost principle of management of lead-poisoned children is identification and abatement of lead exposure. In Case 1 and 2, no source could be identified. In Cases 3 and 4, industrial exposure seemed likely source in the symptomatic children though it was difficult to withdraw the children from the environment due to social and financial reasons.

Chelation therapy is important to effectively lower lead as rapidly as possible. In the past, therapy was based on the ability of chelators to reverse the hematological effects of lead and halt the progression of lead encephalopathy. The necessity of chelation therapy without the hematologic or neurologic findings is not clear; a decrease in blood lead concentration is the only discernible goal for chelation therapy in this setting despite its limitation as an indication of the total lead burden.

Succimer is a water soluble analog of dimercaprol which is also known as 2,3-meso-dimercaptosuccinic acid or DMSA with the advantage of oral administration. In addition, it is relatively specific for heavy metals in vitro and only minimally enhances the excretion of iron, zinc and calcium in small series studied clinically(8).

Experience with succimer is relatively limited. Graziano et al. reported increased excretion of lead in the urine in a dose-dependent fashion(3). Few studies indicate that succimer does chelate well at levels below 45 µg/dL and above 70 µg/dL. Liebelt et al. compared the short-term efficacy of DMSA in lowering BPb in children with BPb of 25-45 µg/dL and with those >45 µg/dL. They reported a similar decrease in BPb in both groups(5). Besunder et al. reported 80% children with BPb between 25-49 µg/dl treated with DMSA had 20% reduction in BPb and/or zinc protoporphyrin(4). O’Connor et al(6) evaluated the effectiveness of DMSA and environmental remediation on children with BPb levels of 30-45 µg/dL. Nearly 20-35% decline was observed at 1 month (difference not significant). DMSA was not found to improve long-term blood lead levels(6). In a placebo controlled randomized trial on 780 children succimer treated children had an abrupt drop in blood lead level followed by rebound and up to three courses of succimer were administered in toddlers with BPb of 20-44 µg/dL. The mean BPb of the succimer treated children during the 7 months after initiation of treatment was 4.5 µg/dL (95% CI 3.7-5.3), lower than placebo-treated children)(7).

Succimer was helpful in our group of patients in lowering the blood lead except Case 4 where despite two courses of succimer, blood lead remained high. The reason for nonresponse could be ongoing exposure which seems likely.

Adverse reactions to succimer reported are mild and include general malaise, mild gastrointestinal symptoms, hypersenstivity reaction, reversible neutropenia, decrease in hemoglobin level, and transient elevation of liver enzymes(8). None of these or any other side effects were reported in our patients.

A limitation of this report is the small, heterogeneous population. Only BPb concentration was used as an index of efficacy, and we lacked urinary lead excretion data that would reflect succimer’s efficacy in chelating lead from soft tissues and bone. Ongoing exposure to lead during treatment could have affected the response to therapy.

To conclude, awareness and early diagnosis of lead toxicity is important. Succimer is an effective chelator in patients for lead toxicity. It can be administered orally and hospitalization eliminated. However, chelation therapy should never be used as a substitute for environmental assessment and lead abatement for lead poisoned children.