eMedicine Specialties > Neurology > Neurotoxicology

Lead Encephalopathy

Adam K Rowden, DO, Assistant Professor of Emergency Medicine, Thomas Jefferson University; Director, Division of Toxicology, Department of Emergency Medicine, Albert Einstein Medical Center; Consulting Toxicologist, Children's Hospital of Philadelphia
Christopher P Holstege, MD, Associate Professor of Emergency Medicine and Pediatrics, University of Virginia; Director, Division of Medical Toxicology, Center of Clinical Toxicology; Medical Director, Blue Ridge Poison Ctr, Associate Medical Toxicology Fellowship Director, VA Dept of Health; J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center; Rika Nagakuni O'Malley, MD, Fellow, Division of Toxicology, Department of Emergency Medicine, Albert Einstein Medical Center

Updated: Oct 26, 2009

Introduction

Background

For centuries, lead poisoning has been one of the most significant preventable causes of neurological morbidity from an environmental toxin. A heavy metal, lead is ubiquitous in our environment but has no physiologic role in biological systems. Its effects are pervasive yet often subtle, with consequences ranging from cognitive impairment in children to peripheral neuropathy in adults. While occupational exposure among workers at smelters or battery recycling plants remains an occasional problem, the greatest public health problem at the present time is exposure of young children to decaying fragments of leaded paint.

Pathophysiology

The pharmacokinetics of lead in humans is complex. Humans are in a state of positive lead balance from birth. In the United States, the average blood lead concentration has been reported at 0.03 mg/L in children aged 1 year and 0.11 mg/L in children aged 5 years.

• Gastrointestinal absorption
  • The percentage of lead absorption through the gastrointestinal tract is variable. Children are more at risk than adults for lead absorption. Lead absorption is dependent on several factors including the physical form of lead, the particle size ingested, the gastrointestinal transit time, and the nutritional status of the person ingesting.
  • Lead absorption is inversely proportional to the particle size; the smaller the particle, the more completely the lead is absorbed. Lead absorption is augmented in the presence of iron, zinc, and calcium deficiency. Lead absorption is also augmented by malnutrition, with lead absorption decreased if phosphorus, riboflavin, vitamin C, and vitamin E are in the diet. Lead absorption is inversely proportional to chronological age. In general, approximately 30-50% of lead ingested by children is absorbed compared with approximately 10% in adults.
• Inhalational absorption
  • If inhaled in a fine particulate state, lead may be absorbed directly through the lungs or it may be carried by the mucociliary tree to the throat, where it is swallowed and absorbed via the gastrointestinal system. The amount of absorption of particulate lead that occurs through the respiratory system depends on the particle size, the patient's respiratory volume, the amount of deposition, and the mucociliary clearance of the lead inhaled. The majority (nearly 100%) of lead inhaled as vapor or fumes is absorbed directly through the lungs.
• Dermal absorption
  • The cutaneous absorption of lead is limited (typically far less than 1%). The amount absorbed through the skin depends on the physical characteristics of the lead (ie, organic vs inorganic) and the integrity of the skin. Although inorganic lead is not absorbed through intact skin, organic lead compounds (ie, tetraethyl lead) are absorbed.
• Distribution
  • Absorbed lead that is not excreted is exchanged primarily among 3 compartments: blood, soft tissue (liver, kidneys, lungs, brain, spleen, muscles, and heart), and mineralizing tissues (bones and teeth). Following absorption, lead enters the blood compartment. Lead in the blood is primarily found within red blood cells. Although the blood generally carries only a small fraction of the total lead body burden, it serves as the initial receptacle of absorbed lead and distributes lead throughout the body, making it available to other tissues or for excretion. The elimination half-life of lead in adult human blood has been estimated to be 1 month, whereas in children it may be as high as 10 months.
  • Approximately 99% of the lead in blood is associated with red blood cells; the remaining 1% resides in blood plasma, which transfers lead between the different compartments. Blood lead is also important because the blood lead level (BLL) is the most widely used measure of lead exposure. The less-sensitive erythrocyte protoporphyrin (EP) assay is also used as a measure of blood lead. These tests, however, do not measure total body burden, rather they are more reflective of recent or ongoing exposures.
  • Lead moves quickly in and out of soft tissues. The blood distributes lead to various organs and tissues. Animal studies indicate that the liver, lungs, and kidneys have the greatest soft-tissue lead concentrations immediately after acute exposure. The brain is a site of distribution as well. Children retain more lead in soft tissue than do adults. Selective brain accumulation may occur in the hippocampus. Lead in soft tissues has an approximate half-life of 40 days.
  • Most retained lead in the human body is ultimately deposited in bones. The bones and teeth of adults contain more than 90% of their total lead body burden and in children approximately 75%. Lead in mineralizing tissues is not uniformly distributed with accumulation in bone regions undergoing the most active calcification at the time of exposure.
  • Bone is viewed as a double compartment, with a relatively shallow labile compartment (trabecular bone) where the elimination half-life is 90 days and a deep inert compartment (cortical bone) where the elimination half-life may be 10-30 years. Teeth also are considered part of the terminal compartment. The labile component readily exchanges bone lead with the blood, whereas lead in the inert component may be stored for decades. In times of physiologic stress, the body can mobilize lead stores in bone, thereby increasing the level of lead in the blood. Bone-to-blood lead mobilization increases during periods of pregnancy, lactation, menopause, physiologic stress, chronic disease, hyperthyroidism, kidney disease, fractures, and advanced age, and is exacerbated by calcium deficiency. Consequently, the normally inert pool poses a special risk because it is a potential endogenous source of lead that can maintain BLLs long after exposure has ended.
• Excretion
  • The majority of lead that is absorbed into the body is excreted either by the kidney or through biliary clearance in the feces. The percentage of lead excreted and the timing of excretion depend on a number of factors. Significant drops in a person's BLL may take several months, or sometimes years, even after complete removal from the exposure sources. It is important that clinicians, as they evaluate a patient with potential lead poisoning, examine potential current and past lead exposures and look for other factors that affect the biokinetics of lead (eg, poor nutrition).
• Maternal-fetal kinetics
  • Lead readily crosses the placenta with the fetus retaining lead cumulatively throughout gestation. Specific health problems, such as malnutrition and iron deficiency, may result in higher lead absorption in the mother. Elevated maternal lead levels subsequently result in higher lead distribution to the fetus.

Lead exerts numerous adverse mechanisms of toxicity. Lead has a high affinity for sulfhydryl groups. It is therefore particularly toxic to multiple enzyme systems. Many of lead's toxic effects also result from its inhibition of cellular function requiring calcium. Lead binds to calcium-activated proteins with much higher (105 times) affinity than calcium.

The interaction of lead and calcium with cellular sites depends upon the concentration of free ions present (Pb²⁺, Ca²⁺). Pb²⁺ and Ca²⁺ compete at the plasma membrane for transport systems, which affect their entry or exit (ie, Ca²⁺ channels and the Ca²⁺ pump.) Intracellular Ca²⁺ is buffered by proteins, endoplasmic reticulum, and mitochondria; Pb²⁺ disturbs this intracellular Ca²⁺ homeostasis. A (Ca²⁺)-(Pb²⁺) interaction at the mitochondria have been described. Pb²⁺ interacts with a number of Ca²⁺ -dependent effector mechanisms, such as calmodulin (a Ca²⁺ receptor protein, which couples to several enzymes, eg, phosphodiesterase, protein kinases), protein kinase C, Ca²⁺ -dependent K⁺ channels in the plasma membrane and neurotransmitter release.

The development of encephalopathy is considered the most detrimental lead health hazard. The microvasculature of a child's developing brain is uniquely susceptible to high-level lead toxicity and is characterized by cerebellar hemorrhage, increased blood-brain barrier permeability, and vasogenic edema. Previous studies on the toxic effects of lead on the brains of young animals have shown damage to the blood-brain barrier, which in severe forms appears as a hemorrhagic encephalopathy.

The cellular, intracellular, and molecular mechanisms of lead neurotoxicity are numerous, as lead impacts many biological activities at different levels of control: at the voltage-gated channels and on the first, second, and third messenger systems. Lead impacts postnatal reorganization of brain through a number of recognized mechanisms: decreased oligodendrite density; myelin deposition; cortical synaptogenesis; induces precocious glial cell differentiation; blocks voltage-sensitive calcium channels; interferes with neurotransmitters; disorganized synaptic pruning; interferes with protein kinases.

Chronic occupational exposure led to atrophy and increased white matter lesions years after termination of the exposure in a cohort of workers. Total brain volume, frontal and total gray matter volume, and parietal white matter volume were found to be decreased. Higher measured bone levels were also associated with regionally diminished volumes in the cingulate gyrus and insula.¹

Lead also impacts the auditory nervous system. Lead exposure affects conduction in the distal auditory nerve and the auditory pathway in the lower brainstem. Subtle impairments of auditory processing could have profound effects on learning. Traditionally, the neuromuscular disorder associated with lead poisoning has been purely motor. However, patients may also note sensory and autonomic neuropathic features. It has been proposed that the traditional motor syndrome associated with subacute lead poisoning is more likely to be a form of lead-induced porphyria rather than a direct neurotoxic effect of lead. Toxic neuropathy caused by lead was a frequent phenomenon before 1925. In modern times, it is a distinct rarity.

Lead has an effect on heme biosynthesis, causing anemia at high blood levels; however, at low levels, Pb²⁺ causes microcytosis (ie, decreased mean corpuscular volume [MCV] and mean corpuscular hemoglobin [MCH]) and a compensatory increase in number of red blood cells. Lead irreversibly binds to the sulfhydryl group of proteins, causing impaired function without any discernible threshold. The enzymes delta-aminolevulinic acid dehydratase, which catalyzes the formation of the porphobilinogen ring, and ferrochelatase, which inserts iron into the protoporphyrin ring, both are compromised by lead.

The inhibition of these enzymes may begin with lead levels as low as 5 mcg/dL. Ferrochelatase is the enzyme that catalyzes the incorporation of iron into the porphyrin ring. If the enzyme is inhibited (ie, lead toxicity) or inadequate iron is present, zinc is substituted for iron and zinc protoporphyrin concentrations increase. The major consequence of this effect is the reduction of circulating levels of hemoglobin. Basophilic stippling of erythrocytes may be present.

Lead poisoning inhibits the proximal tubular lining cells. Abnormalities that may be seen with lead toxicity include aminoaciduria, phosphaturia, and glycosuria (Fanconi syndrome). These effects are reversible. This acute from of nephropathy is more frequently reported in children. Gout secondary to lead-induced nephropathy is typically a long-term complication of occupational lead exposure. Chronic lead nephropathy, a chronic tubulointerstitial nephritis on biopsy, occurs in the setting of long-term lead exposure and is often associated with hypertension and gout. Diagnosis of chronic lead nephropathy is more difficult since the laboratory abnormalities seen with acute lead intoxication are not present with chronic lead exposure.

Nawrot et al published a meta-analysis focusing on the epidemiological reappraisal of the association between blood pressure and blood lead.² Previous studies have reached divergent conclusions. In this meta-analysis, the association between blood pressure and blood lead was similar in both men and women. In the combined studies, a 2-fold increase in blood lead concentration was associated with a 1 mm Hg rise in the systolic pressure and with a 0.6 mm Hg increase in the diastolic pressure. This study suggests that there is a weak association between blood pressure and blood lead.

Lead toxicity has been associated with decreased fertility. Males with elevated lead levels have been found to have reduced sperm counts and impaired sperm motility. In females, increased infertility, stillbirths, and miscarriages have been reported in association with lead toxicity as well as reduced birth weight. Lead poisoning has also been associated with menstrual irregularity.

The accumulation of lead in bone cells may have toxic consequences for bone status itself. Skeletal development and the regulation of skeletal mass are ultimately determined by the 4 different types of cells: osteoblasts, lining cells, osteoclasts, and osteocytes. These cells, which line and penetrate the mineralized matrix, are responsible for matrix formation, mineralization, and bone resorption, under the control of both systemic and local factors. Systemic components of regulation include parathyroid hormone, 1,25-dihydroxyvitamin D-3, and calcitonin. Local regulators include numerous cytokines and growth factors. Lead intoxication directly and indirectly alters many aspects of bone cell function.

First, lead may indirectly alter bone cell function through changes in the circulating levels of those hormones, particularly 1,25-dihydroxyvitamin D-3, which modulate bone cell function. Second, lead may directly alter bone cell function by inhibiting the ability of bone cells to respond to hormonal regulation. For example, the 1,25-dihydroxyvitamin D-3–stimulated synthesis of osteocalcin, a calcium-binding protein synthesized by osteoblastic bone cells, is inhibited by low levels of lead. Impaired osteocalcin production may inhibit new bone formation as well as the functional coupling of osteoblasts and osteoclasts. Third, lead may impair the ability of cells to synthesize or secrete other components of the bone matrix, such as collagen. Finally, lead may directly effect or substitute for calcium in the active sites of the calcium messenger system, resulting in loss of physiological regulation.

Compartmental analysis indicates that the kinetic distribution and behavior of intracellular lead in osteoblasts and osteoclasts occurs by perturbation of the calcium and cAMP messenger systems in these cells. A lead line refers to the metaphyseal line of increased radiodensity that occurs in lead poisoning. The histologic lesion consists of impaired resorption of calcified metaphyseal cartilage, depressed bone deposition on cartilaginous surfaces, and the accumulation of numerous multinucleate giant cells, some containing lead inclusions. The lead line is the result of a lead-induced inability of cartilage-resorbing cells to degrade mineralized matrix, with a resultant impairment of metaphyseal cartilage resorption. The radiodensity of the lead line is due to persistent mineralized metaphyseal cartilage and not to a primary osseous change or lead itself.

Lead may also cause other signs and symptoms. Lead colic is a symptom of chronic lead poisoning and is associated with obstinate constipation. The Burton line or gingival lead line is a dark blue line along the gums, signifying lead poisoning. It occurs typically when lead poisoning is associated with poor oral hygiene. Lead causes activation of protein kinase C³ (PKC) and binds to PKC more avidly than Ca²⁺, its physiologic activator. This further compounds the problem with neurotransmitter release described above. Alteration of PKC function also compromises second-messenger systems within the cell, leading to further changes in gene expression and protein synthesis.

At higher blood levels, Pb²⁺ disrupts the function of endothelial cells in the blood-brain barrier. This may lead to hemorrhagic encephalopathy, characterized by seizures and coma.

Frequency

United States

Although no blood level of lead is considered safe, Centers for Disease Control and Prevention (CDC) have established 10 mcg/dL as the level of concern. Approximately 9% of children aged 1-5 years have blood levels higher than 10 mcg/dL; children in inner cities are at highest risk. In some rural areas of the United States, 20% of children have been reported to have levels higher than 10 mcg/dL.⁴

Mortality/Morbidity

Essentially, 2 syndromes of lead poisoning exist, depending upon exposure: one syndrome is associated with acute or subacute high-level lead exposure and another syndrome is associated with chronic low-level lead exposure.

• With exposure to high levels of lead, patients develop lethargy, progressing to coma and seizures. Death is uncommon with appropriate medical management. Long-term sequelae depend on the duration, as well as the amount, of exposure.
• With chronic exposure to low or moderate levels of lead, subacute symptoms develop. These are discussed later under Prognosis.

Race

• Although no compelling evidence exists that one race is predisposed biologically to lead toxicity, covariant conditions such as poor nutrition and lower socioeconomic status clearly are associated with chronic lead poisoning.
• Certain populations, such as African American children and new immigrants living in homes with decaying lead-based paint in low-income urban centers, are at increased risk of lead poisoning.

Age

• Young children who are independently mobile are at greatest neurological risk from chronic exposure to low or moderate levels of lead.
• From the time children are able to crawl until they enter school, they are at risk of ingesting lead-containing dust. While this sometimes is associated with pica and intentional ingestion of paint chips, lead poisoning often occurs without such behavior.
• The long-term effect of lead exposure is maximal during the first 2 or 3 years of life, when the developing brain is in a critical formative stage.

Clinical

History

The clinical presentation varies widely, depending upon the age at exposure, the amount of exposure, and the duration of exposure. Younger patients tend to be affected more than older children and adults, because lead is absorbed from the gastrointestinal tract of children more effectively than from that of adults.

• Most children with elevated blood lead levels demonstrate few, if any, symptoms that immediately suggest lead poisoning. For this reason, the Centers for Disease Control and Prevention (CDC) advocate obtaining blood lead levels in children at ages 1 and 2 if they meet ANY one of the criteria noted below. In addition, children aged 3-5 years who have not previously been tested and meet ANY one of the criteria below should also be tested.
  • Eligible for or receiving Medicaid, or WIC benefits
  • Living in a ZIP code determined to be high risk based on age of housing and other factors
  • Living in or regularly visiting a house or daycare center built before 1950
  • Living in or regularly visiting a house built before 1978 with peeling or chipping paint or recent (within the last 6 mo), ongoing, or planned renovation
  • Living with or regularly visiting a sibling, housemate, or playmate with lead poisoning
  • Living with an adult whose job or hobby involves exposure to lead
  • Living near an active lead smelter, battery recycling plant, or other industry likely to release lead
• Furthermore, when the symptoms do occur, they are typically nonspecific. The symptoms are as follows:
  • Temperamental lability, irritability, behavioral changes
  • Hyperactivity or decreased activity
  • Loss of developmental milestones, language delay
• More significant exposure to lead may cause symptoms in children that are more likely to lead to a medical evaluation. They are as follows:
  • Abdominal pain, loss of appetite, vomiting, constipation
  • Headache, ataxia, somnolence
  • Lethargy, seizures, stupor, coma
• In adults, similar symptoms may develop, although cognitive changes may be discerned more easily, especially since exposures are more typically acute. In addition, adults with chronic exposure may develop other symptoms, such as the following:
  • Weakness of extensor muscles (eg, foot drop, wrist drop)
  • Delirium, hallucinations
• A meticulous environmental history is necessary in patients with suspected lead exposure. Depending on whether it is tailored to children or adults, it should include the following information:
  • Present and recent residences - Including location, age and condition of building, renovations, inspections, deleading programs; analysis of indoor and outdoor surfaces, water, and soil (if available)
  • Other potential sources of lead - Other homes where the child stays; parent working as painter or renovator or in a battery factory, shooting range, or other industry that uses lead; lead-based kitchen utensils, pottery, imported toys; lead-based folk remedies
  • Past medical history - Developmental milestones or delays; hygiene; pica; prior lead exposure
  • Occupations or hobbies - Activities of all adults in the home; practices concerning changing of clothes; work areas in the home
  • Siblings - Ages; developmental history and school performance; blood lead levels

Physical

• Subtle changes in cognitive performance are not identified easily on physical examination.
• Careful mental status examination may detect changes in more severe cases, while formal neuropsychological testing may be needed to detect changes in other cases.
• Impaired fine-motor coordination⁵ or subtle visual-spatial impairment may be seen.
• In adults, chronic distal motor neuropathy may be seen with decreased reflexes and weakness of extensor muscles. Sensory function is relatively spared.
• Cranial nerve involvement, particularly the optic nerve, is possible. Chronic lead exposure has been shown to cause optic neuritis and blindness.⁶

Causes

All causes of lead poisoning are environmental; however, the source of lead is quite varied. Lead-based paint remains the single most significant source of lead exposure to children in the United States. Although lead in paint has been recognized as a source of neurotoxic effects for a century, not until 1977 did the Consumer Product Safety Committee mandate that lead would no longer be added to residential paint. However, this did not address problems of deteriorating paint in older homes and use of leaded paint for exterior surfaces. Flaking, dusting, and peeling lead paint is by far the number one source of lead exposure in children. However, other sources of lead in a child's environment may result in acute lead poisoning or contribute to an already elevated blood lead level.

• Work environment: Adults may become exposed or bring lead dust home from their job on clothes, hands, hair, and shoes. Occupations with exposure to lead include house painting or wallpapering; home renovation; furniture refinishing; lead smelting or mining; firearms instruction; automotive repair; battery manufacturing or recycling; or bridge/tunnel/elevated highway construction.
• Hobbies: Certain hobbies may contaminate the home with lead dust or fumes, or contaminate the parent's clothes, hands, hair, or shoes. Examples include melting lead for homemade musket balls or fishing tackle; target shooting; making stained glass (artists may use lead solder and solid lead came, which wraps around pieces of glass and frames the artwork); and ceramics.
• Soil: Though lead was completely phased out of gasoline by 1995, lead particles emitted in engine exhaust still persist in some soil near major roadways. In addition, deteriorating exterior lead paint may contaminate the soil around old homes. Children who play in bare soil risk exposure to lead, and family members may track contaminated soil into the home on their shoes.
• Ceramics: Lead is used in some ceramic glazes because it produces certain colors and helps prevent cracking. Improperly fired glazes and deteriorating glazes may leach lead into food and beverages, especially following prolonged contact or if the food is hot or acidic. The Food and Drug Administration (FDA) has established leaching limits on commercially made or imported products, but handmade items are not regulated. Ceramics bought in foreign countries and items not intended for food use may also leach high levels of lead.
• Folk remedies: Some Hispanic, Indian, Asian, and Middle Eastern folk medicine practices consider heavy metals to be therapeutic. Certain folk remedies for digestive ailments have been found to contain very high levels of lead. Names include Azarcon, Alarcon, Coral, Pay-loo-ah, and Greta. The product is likely a capsule, or an orange or yellow powder, which is ingested.
• Lead solder: Solders with varying concentrations of lead are used in the electronics industry and in making stained glass. Though illegal, some people may use them to make fishing tackle or in home plumbing projects. Homemade moonshine stills may be soldered with lead, which can result in lead leaching into the drink.⁷ In 1995, the FDA banned lead-soldered food cans, but some may still occasionally be imported illegally into the United States, especially to ethnic grocery stores. Soldering is messy and creates tiny fragments and dust-sized particles of lead, as well as lead fumes.
• Drinking water: Most public water sources are routinely tested and do not exceed the Environmental Protection Agency (EPA) lead limits of less than 15 ppb (for bottled water: <5 ppb). However, water may become contaminated if it encounters old lead-soldered pipes or lead-containing faucets inside old buildings. Lead levels are highest in water left standing in pipes for more than a few hours and in hot or acidic water. Lead levels in Washington DCs drinking water were recently found to be above EPA standards.^8,9 The cause was uncertain but may have been due to a change in water purification techniques.
• Fishing tackle: Lead weights and sinkers are small and smooth and easily swallowed by curious children; especially when imitating adults who use their teeth to manipulate the tackle.
• Costume/toy jewelry: Cheap jewelry marketed to children, often sold in vending machines, has been the source of several documented cases of acute lead poisoning. Children readily chew or suck on the items or unintentionally swallow them. Toy jewelry containing lead is a banned hazardous substance; however, such items may be on the market. Imported jewelry is especially suspect.
• Curtain weights: Some are made of lead and are of swallowable size. They are sewn into the hem of curtains or drapes.
• Artist oil paint: One color of fine art oil paint, "flake white," contains lead carbonate. Many artists feel there is no substitute for this product, which enhances a painting's durability. They lobbied successfully for its exemption from the US Consumer Product Safety Commission's 1977 ban on lead paint.
• Vinyl mini-blinds: Vinyl mini-blinds made before 1997 may contain lead. Over time, exposure to heat and sunlight deteriorates the vinyl and lead dust forms on the surface. Blinds made with lead were recalled and banned by the Consumer Product Safety Commission in 1997, but prior to then millions of them were sold and are likely still in many US homes.
• Pool cue chalk: The use of lead as a coloring agent in pool cue chalk is often denied by the industry. Nevertheless, one study in 1996 did conclude that 3 of 23 brands of pool cue chalk tested contained lead; one as much as 7000 ppm.
• Antique toys: The Consumer Product Safety Commission continually screens newly produced toys for hazardous substances including lead or lead paint. Antique toys, however, may contain lead, especially toy cars, planes, or trucks; painted toys; and toy soldiers or other figurines.
• Glassware (leaded crystal): Like ceramics, leaded crystal can leach lead into food or beverages, especially following prolonged contact or if the beverage is acidic. Experts advise against storing beverages in a lead crystal container or drinking from crystal routinely. Leaded crystal baby bottles should never be used.
• Kohl: Kohl is an ancient black cosmetic still used by some women in the Middle East, Asia, and Africa. It often contains ground galena, a metallic mineral and source of lead. Some cultures also put kohl on the umbilical stump of newborns, or decorate the eyes and faces of children. Kohl is illegal in the United States, yet it may be found in some ethnic shops or available for purchase online. Travelers may bring kohl home to the United States unaware of its dangers.
• Mexican candies: Studies have found high levels of lead in many Mexican candies, especially those with tamarind or chili powder as an ingredient. Ink used to print the wrappers has also been shown to contain dangerous amounts of lead.
• Projectiles (eg, bullets): Lead has been used to make projectiles since the mid 15th century. Its widespread availability, malleability, and high density continue to make it ideal for this purpose. Today, most bullets for shotguns, handguns, and rifles are made of a lead core surrounded by a copper or steel jacket to protect the lead from changing shape at high speeds. Economical solid lead bullets are also available, as are traditional lead musket balls. Curious young children will readily swallow projectiles. Buckshot (small balls of lead used by hunters) may remain in cooked game and be unintentionally eaten. Also, lead from projectiles that remain lodged in the acidic synovial fluid of joints can be absorbed into the blood.

Differential Diagnoses

Confusional States and Acute Memory Disorders
Diabetic Neuropathy
Epileptic and Epileptiform Encephalopathies
Frontal Lobe Syndromes
Organic Solvents
Radial Mononeuropathy

Other Problems to Be Considered

Attention deficit hyperactivity disorder
Learning disorder
Developmental delay
Language disorder
Peripheral neuropathy
Autism/pervasive developmental disorder

Workup

Laboratory Studies

• Venous blood lead level: Although not an accurate measure of the whole-body burden of lead, the blood lead level is a reasonable approximation of lead exposure¹⁰ , as levels decline in a predictable manner after removal from the source of lead. Capillary (ie, finger-stick) blood levels do provide a reliable measurement if performed correctly, though samples improperly collected may be contaminated by lead dust on the skin or from the collecting equipment.
  • Levels above 70 mcg/dL (ie, class V) are considered medical emergencies, regardless of whether neurological symptoms are present. Risk of encephalopathy is high and treatment is required. However, lead levels should be reviewed in the context of the clinical exam and history.
  • For example, a child can swallow a lead foreign body and have a documented level above 70 mcg/dL within 2 days, but the total body burden would be low (the lead would be predominantly within the blood compartment in this scenario). Encephalopathy would not be expected in this scenario. However, a child with chronic ingestion of lead paint dust may have a lower lead level, but with a much higher body burden and subsequent neurological findings (the lead has had time to redistribute amongst all the compartments).
  • Levels ranging from 45-69 mcg/dL (ie, class IV) warrant chelation therapy, according to CDC criteria, and a medical evaluation including further blood testing and possibly abdominal radiograph looking for lead paint chips. Removal from the source of lead exposure is paramount.
  • Levels ranging from 20-44 mcg/dL (ie, class III) require medical evaluation including further lab testing and possible abdominal radiographs. Removal of the source of lead and an environmental evaluation are also required. There is no good evidence that treatment with chelation agents for lead levels below 45 mcg/dL is of benefit (in fact, the evidence tends to point to potential harm by chelating at lower levels).¹¹
  • Levels ranging from 15-19 mcg/dL (ie, class II) require repeat blood lead level screening and lead prevention education. If elevated levels persists in this range or rise over a 3-month period, treat patient as above (levels 20-44 mcg/dL).
  • Levels ranging from 10-14 mcg/dL (ie, class I) require no further treatment other than lead prevention education, but periodic screening in young children should continue.
• Free erythrocyte protoporphyrin (FEP): This provides a good estimate of the acuity of exposure. If FEP in normal in the context of high blood lead levels, the exposure is more likely acute; if both are elevated, the exposure is more likely chronic. FEP elevation lags behind the blood lead elevation that causes it.
• Hemogram: Significantly elevated blood lead levels are associated with a microcytic anemia. Iron deficiency, also associated with anemia, may produce an elevation of FEP, confounding the significance of FEP measurement.
• These work-up guidelines are based on the recommendations from the CDC Advisory Committee on Childhood Lead Poisoning Preventions, the National Center of Environmental Health/Agency for Toxic Substances and Disease Registry, and the American Academy of Pediatrics Committee on Environmental Health.¹²

Imaging Studies

• Neuroimaging (eg, MRI, CT) does not play an important role in the diagnosis of lead poisoning. However, cerebral edema and microhemorrhages may be seen in patients presenting with acute encephalopathy on both CT and MRI. With chronic exposure to lead, patchy calcifications may be seen. Atrophy and white matter changes may be present with chronic exposures. Atre et al reported a case of lead encephalopathy with MRI findings of symmetric occipital lobe lesions that were bright on T2-weighted and fluid-attenuated inversion recovery images and hypointense on T1-weighted images.¹³ These lesions disappeared after chelation therapy with clinical laboratory improvement.
• Classic findings of lead lines on radiographs of long bones are seen rarely, as most cases of lead poisoning in children are due to exposures to low or moderate amounts of lead. Obtaining radiographs in search of lead lines is not recommended by the CDC.
• In selected cases, abdominal radiographs may demonstrate lead-containing paint chips or other lead-containing objects. Retained lead objects within the gastrointestinal tract are an acute emergency and should prompt referral for potential removal.
• EEG findings can be normal or show nonspecific findings and are generally not helpful in the diagnosis.

Other Tests

Formal neuropsychological testing provides the best measure of a patient's cognitive impairment. This is effective in tracking improvement in attention, visual-spatial abnormalities, and memory as a result of treatment and in establishing the extent and nature of long-term impairment.

Staging

The CDC has established 5 stages of lead toxicity, based upon blood lead levels. These are discussed under Lab Studies.

Treatment

Medical Care

Medical treatment is but one element of a comprehensive treatment plan for exposure to lead; removal of the source of lead exposure is more important. Interventions described below relate to chelation therapy for the most severe cases of lead poisoning. Chelation is of only transient benefit in the patient whose source of lead exposure has not been identified and removed. Further information about each of the agents mentioned below is available in the Medication section.

• Succimer (Chemet) is a water-soluble, oral chelating agent that is appropriate for use with blood lead levels above 45 mcg/dL.¹⁴
• D-penicillamine (Cuprimine) is a second-line oral chelating agent, although it is not approved by the US Food and Drug Administration (FDA) for use in lead poisoning.
• Calcium disodium ethylenediamine tetra-acetate (CaNa₂ EDTA [calcium disodium versenate]) is a parenteral chelating agent. It should never be used as the sole agent in patients manifesting with lead encephalopathy because this agent does not cross the blood-brain barrier and can potentially lead to exacerbation of lead encephalopathy. Dimercaprol, which does cross the blood-brain barrier, should be administered first. Life-threatening hypocalcemia has been reported when disodium EDTA was inadvertently substituted for calcium disodium EDTA.
• Dimercaprol (British antilewisite [BAL]) is another parenteral chelating agent recommended as an agent of first choice for patients with lead encephalopathy. With high blood lead levels (ie, >100 mcg/dL), it is used in conjunction with CaNa₂ EDTA.

Consultations

Local or county health departments, responsible for monitoring children with lead toxicity, should be informed about patients with elevated lead levels or those undergoing medical treatment. Medical toxicology services should also be considered in consultation and can be typically located by contacting the local poison center.

Medication

Several drugs are available to treat lead poisoning. All are capable of binding or chelating lead and reducing body stores of lead. Reducing blood lead levels also may mobilize skeletal stores of lead. Therefore, caution must be exercised in using the medications, both because of their adverse effects and because of their ability to mobilize lead.

Antidotes

These agents are used to prevent intoxication resulting from poisoning.

Succimer (Chemet)

Meso 2,3-dimercaptosuccinic acid (DMSA) has high sensitivity for lead, while its ability to chelate essential trace metals is low. Excellent oral chelating agent approved for use in children in 1991. Available as capsules of 100 mg.

Dosing

Adult

10 mg/kg PO q8h for 5 d initially, followed by 10 mg/kg q12h for an additional 14 d

Pediatric

Administer as in adults

Interactions

Do not administer concomitantly with edetate calcium disodium or penicillamine

Contraindications

G-6-PD deficiency; allergy to sulfa drugs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment; to prevent toxicity, patient should be well hydrated

Edetate disodium calcium (Calcium disodium versenate)

Chemical name calcium disodium ethylenediamine tetra-acetate (CaNa₂ EDTA). Limitation is that it removes lead from extracellular spaces only. Because painful when administered IM, should be given IV, diluted to concentration of <0.5% in D5W or isotonic saline. In patient with acute lead encephalopathy and increased intracranial pressure, dilution to concentration of <3.0% may be necessary, or IM route may be preferred to limit fluids. Ideally, first dose of dimercaprol should be given at least 4 h before CaNa₂ EDTA. Note that CaNa₂ EDTA initially may aggravate symptoms of lead toxicity because of its mobilization of stored lead.

Dosing

Adult

IV protocol as described below for children also may be used for adults
Alternative dose: 60-80 mg/kg IV bid for up to 5 d
If given IM rather than IV, same total daily dose used; however, it is administered as 20% solution and given in 2-4 divided doses, with preservative-free procaine added to make final procaine concentration of 0.5-1%

Pediatric

Symptomatic patients: 750 mg/m² IV infusion over several hours bid for 5 d; treatment may be repeated after an interval of at least 2 d, with a third course at least 7 d following second
May be given IM as noted above; however, because this is painful, it should be mixed with procaine (for final procaine concentration of 0.5-1%)

Interactions

Enhances hypoglycemic effects of insulin in diabetic patients

Contraindications

Documented hypersensitivity; renal failure

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Note that calcium disodium EDTA should be used; if disodium EDTA used in children, may cause tetany and possibly fatal hypocalcemia
CaNa₂ EDTA may cause renal damage, and requires adequate urinary flow for excretion; monitor urine output throughout therapy and discontinue therapy if patient becomes anuric
Do not confuse with the similarly named product edetate disodium (Endrate), which is indicated for hypercalcemia and ventricular arrhythmia secondary to digitalis toxicity; each of these 2 products are commonly referred to as EDTA and as a result, the 2 products are easily mistaken for each other when prescribing, dispensing, and administering; deaths in patients when mistakenly given edetate disodium instead of edetate calcium disodium or when edetate disodium was used for chelation therapy; for more information, see the FDA MedWatch Safety Information

Dimercaprol (BAL in Oil)

BAL, or 2,3-dimercapto-1-propanol, is chelating agent that diffuses into RBCs. Is excreted primarily in bile, making it an agent that can be used in patients with renal failure. Used with CaNa₂ EDTA in patients with blood lead levels >100 mcg/dL. At present, available only in peanut oil; therefore, should not be used in patients allergic to peanuts.

Dosing

Adult

Initial dose: 4 mg/kg IM, followed q4h by injections of 3-4 mg/kg; can be continued for 2-7 d
When given concurrently with CaNa₂ EDTA, give at separate sites

Pediatric

75 mg/m² by deep IM injection q4h for up to 5 d; often combined with CaNa₂ EDTA, which should be administered at separate site

Interactions

Selenium, uranium, iron, or cadmium may increase toxicity

Contraindications

Allergy to peanuts or peanut oil; G-6-PD deficiency (may cause hemolysis); concurrent supplemental iron

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

If iron deficiency anemia exists and requires treatment, iron supplementation should follow treatment with BAL; may be nephrotoxic and may cause hypertension; caution when administering to patients with oliguria or G-6-PD deficiency; may induce hemolysis in G-6-PD-deficient patients

D-penicillamine (Cuprimine)

D-penicillamine, or 3-mercapto-D-valine, is second-line oral chelating agent. Can be administered over extended period of time (weeks to months) for children with lead levels <45 mcg/dL. Available as capsules of 125 mg and 250 mg. Pyridoxine supplementation required. Adjust dose for patients with compromised renal function.

Dosing

Adult

1000-1500 mg/d PO to be administered 2 h before or 3 h after meals; treatment typically continues for 1-2 mo

Pediatric

Target dose: 25-35 mg/kg/d PO in divided doses; some authorities recommend doses of 30-40 mg/kg/d; adverse effects may be minimized by giving one fourth of target dose during first week, half of target dose during second week, then full dose thereafter; duration of therapy may be 1-6 mo

Interactions

Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; zinc salts, antacids, and iron may decrease effects

Contraindications

Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Thrombocytopenia, agranulocytosis, and aplastic anemia may occur

Follow-up

Further Outpatient Care

• After chelation, the blood lead level should be rechecked in 7-21 days to determine whether repeat chelation therapy is required.
• Do not discharge patients from the hospital until they can go to a lead-free environment.

Transfer

Chelation therapy, especially in the setting of encephalopathy, can be complicated. Consider transfer to an institution that is capable of managing an encephalopathic patient and also has a provider experienced in lead poisoning and chelation therapy.

Deterrence/Prevention

• In cooperation with local health departments, the physician should educate families about the following:
  • Causes and effects of lead poisoning
  • Relationship between blood lead level and anticipated medical or neuropsychological problems
  • Importance of follow-up or serial blood lead level determinations to monitor effects of treatment and environmental lead abatement
  • Identifying and eliminating possible sources of lead exposure
  • Increased lead absorption in patients with iron-deficiency anemia
  • Local resources about lead exposure and treatment
• Each patient requiring treatment for lead toxicity should be reported to local health authorities, so that they may initiate appropriate environmental evaluation and lead abatement.

Prognosis

• Lead poisoning in children has been associated with lower intelligence quotient (IQ) scores. Prospective cohort studies have demonstrated effects with blood lead levels as low as 10 mcg/dL. Cohort studies demonstrate an effect regardless of socioeconomic group and indicate a loss of 3 IQ points for every 10 mcg/dL blood lead level above 10 mcg/dL.^15,16,17,18
• Impairment of attention also may result from lead poisoning, creating a clinical syndrome difficult to distinguish from attention deficit hyperactivity disorder.
• Fine motor coordination may be impaired, with one cohort study suggesting a dose-effect relationship between incoordination and lifetime postnatal lead exposure.⁵
• Both receptive and expressive language may be impaired with lead poisoning. Verbal comprehension and auditory processing have been reported in affected children.
• With occupational exposure, progressive cognitive decline years after the exposure has terminated has been documented.

Patient Education

See Deterrence/Prevention.

Miscellaneous

Medicolegal Pitfalls

• The primary medical legal pitfall is not considering lead as a potential cause of encephalopathy in a child or adult. Lead toxicity is a tremendous mimicker of other diseases.
• Another pitfall is failure to assess the source of lead. Children in particular should not be allowed to return to a lead-contaminated environment. Involvement of the local Health Department can assist in assessment of the source of lead.

Special Concerns

Lead can cross the placenta. Blood lead levels tend to remain constant throughout pregnancy in women who were exposed to lead previously, even if no additional exposure to lead is present. Further occupational exposure or ingestion of lead may result in harm to the fetus. This may range from delay in later cognitive development to stillbirth, depending on the extent of exposure.

References

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Keywords

lead encephalopathy, lead poisoning, lead toxicity, plumbism, lead-based paint, lead absorption, effects of lead poisoning, lead exposure

Contributor Information and Disclosures

Author

Adam K Rowden, DO, Assistant Professor of Emergency Medicine, Thomas Jefferson University; Director, Division of Toxicology, Department of Emergency Medicine, Albert Einstein Medical Center; Consulting Toxicologist, Children's Hospital of Philadelphia
Adam K Rowden, DO is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, American College of Osteopathic Emergency Physicians, American Osteopathic Association, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Christopher P Holstege, MD, Associate Professor of Emergency Medicine and Pediatrics, University of Virginia; Director, Division of Medical Toxicology, Center of Clinical Toxicology; Medical Director, Blue Ridge Poison Ctr, Associate Medical Toxicology Fellowship Director, VA Dept of Health
Christopher P Holstege, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American Association for the Advancement of Science, American College of Emergency Physicians, American College of Medical Toxicology, American Medical Association, Medical Society of Virginia, Society for Academic Emergency Medicine, Society of Toxicology, and Wilderness Medical Society
Disclosure: Nothing to disclose.

J Stephen Huff, MD, Associate Professor, Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia Health Sciences Center
J Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Rika Nagakuni O'Malley, MD, Fellow, Division of Toxicology, Department of Emergency Medicine, Albert Einstein Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Jonathan S Rutchik, MD, MPH, Assistant Professor, Department of Occupational and Environmental Medicine, University of California at San Francisco
Jonathan S Rutchik, MD, MPH is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Occupational and Environmental Medicine, and Society of Toxicology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine
Disclosure: Abbott Labs  Honoraria Consulting; Teva Marion Honoraria Consulting; Boeringer-Ingelheim Honoraria Speaking and teaching

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author David A Griesemer, MD to the development and writing of this article.

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