Chelation Therapy and Cognitive Outcome in Children Exposed to Lead

Abstract & Commentary

Source: Rogan WJ, et al. N Engl J Med. 2001;344:1421-1426.

Many children in the united states are exposed to lead levels that appear to be associated with impaired cognitive performance. Several studies (eg, Pediatrics. 1991;87:219-227; Pediatrics. 1992;90: 855-861) suggest that exposure to lead levels as low as 20 mcg/dL before 2 years of age are associated with impaired performance on developmental tests performed some 2-8 years after exposure. It is not known if these cognitive impairments are lifelong.

The medical treatment of lead neurotoxicity in children has focused upon chelation therapy. Chelating agents such as succimer (dimercaptosuccinic acid) bind lead ion and form a complex that is much more readily excreted from the body. The Centers for Disease Control (CDC) has set guidelines, based on blood lead levels, for appropriateness of initiation of chelation therapy. Such therapy is recommended for children whose blood lead levels are > 44 mcg/dL, a level associated with other symptoms of lead poisoning besides cognitive impairment. The CDC has made no definite recommendations for children whose blood lead levels fall in the 20-45 mcg/dL range; these children might be expected to have cognitive impairment as their only symptom, and clearly there are far greater numbers of children with these levels of exposure than those with overt (> 44 mcg/dL) lead toxicity.

Rogan and colleagues performed a randomized, double-blind, placebo-controlled trial of orally-administered succimer to children aged 12-33 months, whose blood lead levels were within the range 20-44 mcg/dL. Cognitive, motor, behavioral, and neuropsychological performance in these children was then monitored over the next 3 years. The study was statistically designed to detect as little as a 3-point difference in mean IQ at a 3-year follow-up. As might be expected, the study population was largely comprised of inner-city poor, with approximately 75% of the study patients African-American and approximately 35% with an annual family income of < $10,000. A total of 780 were randomized to receive from 1 to 3 26-day oral courses of either succimer or placebo. The mean blood levels in both treatment groups were approximately 26 mcg/dL, and succimer therapy led to a mean reduction of blood lead levels lower than 20 mcg/dL sustained for 1 year. Thus, patients in the succimer-treated group had their blood lead level reduced below the presumed "neurotoxicity threshold" of 20 mcg/L whereas placebo-treated patients had mean blood levels well above the "neurotoxicity threshold" for the next year.

Rogan et al then examined multiple neuropsychological measures 36 months after treatment. They found no statistically significant differences between either group with respect to performance, verbal or full-scale IQ, as determined using a modified Wechsler Scale. Assessment of attention, language, sensorimotor, visuospatial, and memory function in the 2 groups was performed using the Developmental Neuropsychological Assessment subscales (NEPSY). Also, a revised version of the widely used Conner’s parental rating scale found no differences in the incident of measures of hyperactive or oppositional behavior in the 2 groups.

Commentary

This study demonstrated that a reduction of blood lead levels below the CDC-accepted threshold of 20 mcg/dL during the third year of life in children with "moderate" lead exposure did not result in a significant difference in cognitive outcome, as assessed 3 years later. This suggests that, if there is significant neurotoxicity caused by lead levels between 20-44 mcg/dL (and much evidence suggests that there is), such toxicity must be essentially irreversible after 2 years of age, and perhaps sooner. This study is a potential death-blow to aggressive chelation of children with lead levels of 20-44 mcg/dL. Instead, efforts should be made to reduce the number of children exposed to lead levels > 20 mcg/dL. Thus, significant progress in this area is more likely to occur by means of social science and public policy than by postexposure medical treatment. —Rosario R. Trifiletti