Acute Lead Encephalopathy Research Articles

The Conquest of Lead Poisoning: A Pyrrhic Victory

The Conquest of Lead Poisoning: A Pyrrhic Victory

The Current State of Knowledge About the Effects, Risks, and Science of Children’s Environmental Exposures

In the preface1 to this supplement, we pointed out that pediatricians and other clinicians have made major contributions to the discovery of environmental toxicants. Many acute illnesses that are caused by high exposures to some toxicants are clinically diagnosable or at least are commonly in the differential diagnosis, eg, organophosphate poisoning, infant botulism, acute lead encephalopathy, carbon monoxide poisoning, acrodynia, hypervitaminosis A and some cases of aplastic anemia, convulsions, asthma, respiratory distress, methemoglobinemia, Reyes syndrome, kernicterus, and many of the recognizable syndromes that result from exposures to teratogenic drugs and chemicals. In contrast to the obvious effects of high exposures to environmental toxicants, there is less information and less certainty concerning the magnitude of the contribution of many low exposures of environmental toxicants to morbidity, mortality, and subtle alterations in children as well as adults or how the effects of these exposures vary with age or chronicity of exposure. We also informed the readership that we were going to address the issue of environmental toxicology from both a clinical and a toxicologic viewpoint. Very low exposures to environmental toxicants may lead to diseases that resemble many common illnesses that have other causes, or they may lead to decrements in functioning that are subtle or nonspecific. It is an almost insurmountable task for individual practitioners to conclude a cause-and-effect relationship from low exposures to environmental toxicants among patients in the physician’s patient population. Only well-planned, sophisticated epidemiologic and animal studies can answer the questions that pertain to the toxicity of low-level exposures to environmental toxicants, given that not all individuals will be affected equally, if at all, at any particular level of exposure. Many of the previous multi-authored compendia that have been published by groups of scientists have been unified in their conclusions that environmental toxicants are a very serious … Reprint requests to (R.L.B.) Rm 308, R/A, Alfred I. duPont Hospital for Children, Box 269, Wilmington, DE 19899. E-mail rbrent{at}nemours.org

The road to primary prevention of lead toxicity in children.

The clinical recognition of lead toxicity in children in the United States has changed drastically over the past 50 years. Accordingly, both medical management and public policy in such cases needs to be modernized in keeping with these changes. Fifty years ago lead poisoning in children was often only recognized in the severe acute phase (acute lead encephalopathy). Today this condition is rare, and children are detected in screening programs most often in the asymptomatic phase. The removal of lead additives from gasoline and the removal of lead solder from food and beverage cans has greatly reduced the background level of lead absorption during the past decade.1 The changes in exposure to lead and its clinical presentation mandate that we change the approach to the management of childhood lead toxicity. We must place reduced emphasis on chelation therapy and major emphasis on the environmental history to identify the source(s) of lead in the child's environment and steps to separate the child from these sources. The primary source of lead in childhood lead toxicity 50 years ago was deteriorating lead paint in old housing: it remains the primary source in the United States today. Reduction of exposure is the single most important modality of long-term management, as it has been for >50 years. When chelating agents first appeared—2,3-dimercapto-1-propanol (BAL)2 in 1946 and calcium disodium ethylenediaminetetraacetate (CaNa2EDTA)3 in 1950—childhood lead poisoning was recognized clinically only in the severe acute phase. These agents alone reduced the mortality of severe acute lead encephalopathy from 66% to approximately 25% to 30%.4Subsequently, it was found that these agents given in combination5 reduced mortality to about 1% to 2%. They were not effective in reducing the neurologic sequelae.6Ongoing prospective studies conducted now to at least 10½ years …

Treatment of Acute Lead Encephalopathy

Treatment of Acute Lead Encephalopathy

Acute lead encephalopathy in early infancy--clinical presentation and outcome.

We studied 19 infants with a mean age of 3.8 months who presented with features consistent with acute lead encephalopathy following the use of traditional medicines. All presented with convulsions; CT scans of the brain on admission showed brain oedema in four, atrophy in four and normal findings in 11. Cerebrospinal fluid analysis in nine patients showed pleocytosis in six and a high protein content in eight. The median lead level in these 19 infants which encephalopathy was 3.6 mumol/l (74.5 micrograms/dl). Seven had a mean lead level of only 2.7 mumol/l (56.9 micrograms/dl) which is much below 70 micrograms/dl, the level usually proposed as the threshold for encephalopathy. Thirteen infants developed brain damage during follow-up; statistical analysis correlated the lead level at 2 months post chelation with an abnormal neurological outcome. Our findings indicate that in very young infants acute lead encephalopathy may occur at lead level lower than previously reported.

Acute lead encephalopathy in neonates and children

Acute lead encephalopathy in neonates and children

Childhood lead poisoning and its treatment.

The 30-year federal war on childhood lead poisoning began in the activist days of the 1960s and was codified in the Lead Paint Poison Prevention Program of 1970 (1) introduced by Senator Edward Kennedy. Since that time the mean blood lead of US children has decreased from above 1 j.l.mollL (20.7 j.l.g/dL) to below .25 j.l.mollL (5.2 j.l.g/dL). With only two reported deaths in children from acute lead encephalopathy in the past 20 years (2), the politically attuned could call it a preordained triumph. The clinically oriented will credit early screening and diagnosis with the infrequency of life-threatening symp­ toms. The environmentalist can relate the elimination of leaded gasoline to the decline in mean blood lead. The skeptic might question the validity of current evidence for the neurobehavioral risk of low-level lead. The pharma­ cologist might express astonishment at the limited evidence for the therapeutic efficacy of chelation therapy acquired over all these years. To address the latter two concerns, this is a review of the current status of childhood lead poisoning and its treatment. To facilitate comparisons of data relating to blood lead, all subsequent values of blood lead are cited as the traditional j.l.gldL rather than as the molar concentration (1 j.l.g/dL = .0483 j.l.mollL)

Aetiology of Acute Lead Encephalopathy in Omani Infants

Twenty-five Omani infants were admitted with acute lead encephalopathy. They ranged in age from 1 to 8 months with the majority less than 4 months old. The source of poisoning in 20 infants (80 per cent) proved to be a local medication called bint al dahab. In a further three infants (12 per cent) there was a strong recent history of administration of a local medication, but the agent could not be identified with certainty. As with older children acute lead encephalopathy has serious consequences and in this series only 44 per cent of infants were thought to be neurologically normal at the time of discharge. The administration of lead containing medications to young infants in Oman is a significant preventable cause of morbidity and mortality having implications, in particular, for physicians involved in the care of Arabic communities. In any infant presenting with an unexplained encephalopathy the diagnosis of lead poisoning should be considered.

Lead Lines in Young Infants with Acute Lead Encephalopathy: a Reliable Diagnostic Test

Fifteen Omani infants, ranging between 2 and 4 months of age, with acute lead encephalopathy underwent plain skeletal radiology. X-rays in all 15 infants revealed dense metaphyseal bands in long bones. These were best seen around the knee joint. Six infants had evidence of multiple lead lines indicating previous episodes of exposure to lead while four infants also had lead lines in the axial skeleton. We suggest that any young infant presenting with an unexplained encephalopathy should undergo an X-ray of the knee and that the presence of dense metaphyseal bands strongly supports the diagnosis of lead poisoning. A plain X-ray of the knee is a cheap, widely available investigation which can be rapidly obtained.

Transient hydrocephalus and acute lead encephalopathy in neonates and infants. Report of two cases

In the Sultanate of Oman acute lead encephalopathy in neonates is common. Brain oedema in acute lead encephalopathy occurs predominantly in the cerebellar vermis and may act as a midline posterior fossa mass, occluding the fourth ventricle. The resultant transient obstructive hydrocephalus may need emergency drainage of cerebro-spinal fluid. The hydrocephalus is transient as vermis oedema subsides with medical treatment. Two such cases are reported and discussed.

Pediatric Lead Poisoning in 1987: The Silent Epidemic Continues

Great gains in the understanding and control of childhood lead poisoning have been made since this disease was first diagnosed in the early years of this century. Efforts of pediatricians, public health officials, and enlightened regulators have brought about substantial reductions in the lead content of paint, food, milk, water, air, and, most recently, gasoline. Significant decreases in children's blood lead levels and in the incidence of lead poisoning have resulted. Few American pediatricians trained in the past decade have ever seen a child with the coma, papilledema, and convulsions of acute lead encephalopathy. Despite these advances, the silent epidemic of childhood lead poisoning is not yet over. It is particularly well now that we function in this manner because some of the important issues that we are dealing with at this time are items that cannot be completed by this date. We will depend upon the new Executive Committee and new Executive Board to carry these issues to completion. Last year, I spoke to you with a great deal of concern about our problems in medical liability. I expressed a conviction that an independent research on this subject could contribute to a real resolution of the problem. We have pursued this plan during the year and I can tell you now that, at the instigation of the Academy, the Institute of Medicine of the National Academy of Sciences has held a feasibility study and a planning meeting during this year. This has lead to the formation of a proposal for the research that is now waiting only for the funding to proceed.

Lead poisoning in infancy—unusual causes in the U.A.E.

Six infants, three of them neonates, were diagnosed as having acute lead poisoning; four of them had acute encephalopathy. All had been given an indigenous preparation, 'Bint Al Zahab' (Daughter of Gold), for abdominal colic and early passage of meconium after birth. Chemical analysis of this powder revealed a lead content of 82.5%. The index case had anaemia with punctate basophilia, dense metaphysial lines on X-ray and markedly raised blood lead levels, arousing a strong index of suspicion for the early diagnosis of subsequent cases. Computerized axial tomography (CAT) scan in three cases showed signs of early cerebral cortical atrophy. The picture of cerebral oedema was absent in the four cases of acute lead encephalopathy. The importance of prevention and the ideal management is discussed.

Blood-Brain Barrier Dysfunction in Acute Lead Encephalopathy: A Reappraisal

Acute lead encephalopathy was induced in adult guinea pigs by administering daily oral doses of lead carbonate. During the development of the encephalopathy, the structural and functional integrity of the blood-brain barrier was evaluated with electron microscopy and tracer probes. Blood, cerebral gray matter, liver, and kidney were analyzed for lead, calcium, and magnesium content. The animals regularly developed an encephalopathy after four doses of lead. There were no discernible pathomorphologic alterations in the cerebral capillaries or perivascular glial sheaths. Furthermore, no evidence of blood-brain barrier dysfunction was demonstrated with Evans blue-albumin complex or horseradish peroxidase. Blood-brain barrier permeability to radiolead was not increased in the intoxicated animals. During the development of the encephalopathy there was a progressive rise in the lead concentration in all tissues. Concurrently, there was a significant rise in brain calcium. These results suggest that the encephalopathic effects of lead may be mediated directly at the neuronal level.

Blood-brain barrier dysfunction in acute lead encephalopathy: a reappraisal.

Acute lead encephalopathy was induced in adult guinea pigs by administering daily oral doses of lead carbonate. During the development of the encephalopathy, the structural and functional integrity of the blood-brain barrier was evaluated with electron microscopy and tracer probes. Blood, cerebral gray matter, liver, and kidney were analyzed for lead, calcium, and magnesium content. The animals regularly developed an encephalopathy after four doses of lead. There were no discernible pathomorphologic alterations in the cerebral capillaries or perivascular glial sheaths. Furthermore, no evidence of blood-brain barrier dysfunction was demonstrated with Evans blue-albumin complex or horseradish peroxidase. Blood-brain barrier permeability to radiolead was not increased in the intoxicated animals. During the development of the encephalopathy there was a progressive rise in the lead concentration in all tissues. Concurrently, there was a significant rise in brain calcium. These results suggest that the encephalopathic effects of lead may be mediated directly at the neuronal level.

Acute lead encephalopathy in the guinea pig.

Acute lead encephalopathy was induced in adult guinea pigs with daily oral doses of lead carbonate. Cerebral capillaries were examined by electron microscopy, and the blood-brain barrier (B-BB) evaluated with Evans blue and horseradish peroxidase. Brain lead levels were also determined during the developing encephalopathy. There was no cerebral capillary alteration or demonstrable B-BB dysfunction. Brain lead concentrations increased over the 5-day period. The encephalopathy in the absence of any vascular alteration suggests that lead can produce a primary toxic effect at the neuronal level.

Development of behavioral tests for the assessment of neurologic effects of lead in sheep.

Reports of neurologic impairment of children following recovery from acute lead encephalopathy have raised questions concerning the effects of chronic low-level lead exposure on the central nervous system. Behavioral toxicologic techniques have been employed to assess the effects of lead on the central nervous system in sheep. Mature sheep receiving daily doses of 100 mg lead/kg showed a significant decrease in performance on an auditory signal detection task. Daily oral doses of 120 and 230 mg lead/sheep for 27 weeks did not alter the performance of mature sheep on a fixed-interval schedule of reinforcement behavioral task. Prenatal exposure to maternal blood lead levels of 16 or 34 mug/100 ml during gestation and postnatal daily ingestion of 16, 8, 4, or 2 mg lead/kg did not alter performance of lambs on a closed-field maze task. Slowed learning was demonstrated in lambs prenatally exposed to maternal blood lead levels of 34 mug/100 ml during gestation when tested on nonspatial, two-choice visual discrimination problems at 10-15 months of age.

Experimental acute lead encephalopathy in the juvenile rhesus monkey.

Lead subacetate (0.5g) and 1000 units of vitamin D were given three times a week to four newly-weaned rhesus monkeys. In addition, two animals received only the vitamin D. The poisoned animals had an increase in the urinary excretion of delta-aminolevulinic acid, an elevated content of lead in the blood, and a fall in hemoglobin concentration. Between 6 and 18 weeks the animals suddenly developed ataxia, nystagmus, generalized weakness, and convulsions. At this time the animals were killed by perfusion of fixative and the brain prepared for light and electron microscopic studies. Definite morphological evidence of disease was confined to the central nervous system, except for one animal which showed the characteristic renal inclusions of lead poisoning. All animals showed PAS-positive globules associated with blood vessels and an exudative edema involving the white matter of the cerebral hemispheres and cerebellum. Ultra-structurally, this appeared as a granular precipitate within an expanded extracellular space. Alterations of nerve fibers were not seen in the white matter but axonal swelling was observed in the cerebral cortex. The perikaryon and neuropil appeared normal. The control animals showed no significant cerebral changes.

Experimental Acute Lead Encephalopathy in the Juvenile Rhesus Monkey

Experimental Acute Lead Encephalopathy in the Juvenile Rhesus Monkey

Management of increased lead absorption and lead poisoning in children.

THE primary aim of treatment for plumbism in children is the prevention of injury to the nervous system. In the long run, societal steps to minimize adventitious lead absorption will be needed to obtain this goal. In practice today, therapeutic intervention at the subclinical stage of lead poisoning and close follow-up observation during the preschool years can do much to prevent the severe forms of residual nervous-system injury. At least 25 per cent of young children with acute lead encephalopathy or recurrent but less severe clinical bouts of plumbism sustain permanent injury to the nervous system.1 2 3 Current chelation therapy started . . .

ACUTE AND CHRONIC CHILDHOOD LEAD POISONING

Lead poisoning in childhood is a preventable disease. Virtually all cases occur in children who live in old, deteriorated houses which were built and painted years ago when the use of lead-based paints on housing surfaces was widespread. Eighty-five percent of recognized cases occur in children in the 1- to 3-year age range in which pica (the habit of eating non-food substances) is prevalent. Consequently, the disease results from the interaction between hazardous housing and the child with pica. Early diagnosis of plumbism on clinical grounds alone is exceedingly difficult, and often impossible. Furthermore, by the time the clinical diagnosis is obvious, permanent brain damage which cannot be modified by therapy may already have taken place. Although the true incidence of plumbism is not known, careful surveys have revealed that 10 to 25% of young children who live in deteriorated urban slum housing show evidence of increased absorption of lead and that 2 to 5% show evidence of poisoning. While recent therapeutic advances have reduced the mortality of acute lead encephalopathy, it is now apparent that at least one-third of the survivors of encephalopathy sustain permanent irreversible damage to the brain. Significant reduction in the risk of permanent brain damage, therefore, requires identification of the child with increased body lead burden prior to the onset of poisoning. Fundamentally, both the prevention of adverse health effects due to lead and the treatment of identified cases depend upon the elimination of the housing hazard which lies at the root of the problem.