Continuing Education Activity

Lead intoxication is one of the most well described environmental intoxications worldwide and it continues to be a commonly encountered disease both in developing nations and in the first world. Lead encephalopathy results as a late-stage complication of lead intoxication. This activity reviews the presentation, evaluation, and treatment of lead encephalopathy and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiology of lead encephalopathy.
• Determine the appropriate evaluation steps for lead encephalopathy.
• Identify the treatment and management options available for lead encephalopathy.
• Determine interprofessional team strategies for improving care coordination and communication to advance lead encephalopathy care and improve outcomes.

Introduction

Lead intoxication is one of the most well-described environmental intoxications worldwide, and it continues to be a commonly encountered disease both in developing nations and in the first world. It was first described by the physician Galen of ancient Greece as early as 200 BC as a disease of the bowels after he observed the effects of drinking water from lead pipes on the gastrointestinal (GI) system.[1] Since then, lead intoxication has garnered the attention and study of clinicians and other healthcare professionals across the globe. Though it has been a known clinical entity for millennia, it has only been in the last century that public health efforts have significantly changed the global impact of this disease.[2]

In first-world nations, focusing on eliminating lead in gasoline and household paints has significantly decreased the incidence of high-dose lead exposures. However, low-dose chronic exposures, as well as higher-dose exposures in industrial settings and developing nations, continue to be an issue. One of the most deadly late-stage complications of lead intoxication is lead encephalopathy.[3] 

Mediated primarily by lead’s effects on cerebrovascular endothelium, lead encephalopathy often presents in vague or subtle ways that other effects of lead toxicity may also complicate. While uncommon, lead encephalopathy is a life-threatening illness that must be considered, diagnosed, and treated in the appropriate clinical settings.[3]

Etiology

Lead encephalopathy results as a late-stage complication of lead intoxication. Lead intoxication occurs via environmental exposure to lead, which may be absorbed through the skin or mucosal surfaces, ingestion, or inhalation of lead-containing fumes.[3] The effects of lead toxicity on the body are highly variable and are dependent on both the route and the magnitude of the exposure. Lead encephalopathy occurs in high whole-blood lead levels over 80 to 100 μg/dL. At such concentrations, lead crosses the blood-brain barrier and ultimately leads to the breakdown of cerebrovascular endothelium, causing increased capillary leak and edema. Patients suffering from lead encephalopathy may present with a wide variety of central nervous system (CNS) symptoms, including ataxia, altered mental status, lethargy, delirium, or seizures. As cerebral edema worsens, the condition progresses from increasing seizure activity to coma, increased intracranial pressure (ICP), and eventually death.

Encephalopathy generally occurs late in chronic exposures with escalating whole blood lead levels. A prodrome of other lead toxicity-related syndromes, such as neuropathy or GI distress, may precede it. A single large dose of lead exposure may also present with lead encephalopathy, although this is less common.

Epidemiology

Lead encephalopathy is a rare complication of lead intoxication, which has greatly decreased in incidence over recent years due to public health efforts to reduce the amount of lead in the environment. The Centers for Disease Control (CDC) estimates that about 535,000 children ages 1 to 5 years and approximately 1.2 million working adults in the United States have whole blood lead levels over 25 μg/dL.[4]

Common exposure sources in children are inhalation, ingestion, or absorption of lead paint dust and exposure to lead in imported toys, spices, or naturopathic remedies. Children may also be exposed to lead from their parent’s occupation. Adult occupational exposure may be encountered in the construction, smelting, firearm, battery, and automotive industries.[3][5]

Pathophysiology

Lead encephalopathy is primarily due to lead’s effects on cerebrovascular endothelium. These effects occur at high whole blood lead levels, generally greater than 80 to 100 μg/dL. At the cellular and molecular level, lead disrupts the functions of many calcium receptors.[6] It particularly affects the flow of calcium across cell membranes and the formation of microfilaments.[6] Tight junctions and other cell membrane structural components are damaged and ultimately break down, increasing the permeability of the blood-brain barrier and resulting in cerebral edema. As this process progresses, it manifests clinically as encephalopathy, seizures, coma, and ultimately death.[7]

Toxicokinetics

Lead is most commonly absorbed via contact with the skin and mucosal surfaces, by the GI tract after ingestion, and in the lungs after inhalation. Initially, absorbed lead has a high affinity for red blood cells (approximately 99% of lead is bound to erythrocytes) and, therefore, early on, has a relatively low volume of distribution.[7] Distribution follows a multicompartmental model with lead distributed to blood, then to soft tissues, and then to the bone. This redistribution process may occur over months and results in a final volume of distribution of approximately 7 L/kg.[8]

The half-life of lead in the fast compartments (blood and soft tissue) is 1 to 2 months, but it might be decades in the slow compartment (bone). Clearance rates are also dependent on whole-blood lead levels. Lead is excreted renally, with about 70% cleared in the urine.[7] The remainder is cleared mostly in the feces, with a small amount being excreted in hair, nails, and sweat. Renal clearance rates may be increased by chelating agents such as succimer or ethylenediaminetetraacetic acid (EDTA) and decreased in renal insufficiency or low flow state. There is no role for hemodialysis in patients with lead poisoning with normal renal function. However, those with lead poisoning and renal impairment may benefit from chelation combined with hemodialysis.[9]

History and Physical

Lead encephalopathy can present as an acute critical illness, and the most important initial consideration in managing these patients is the stabilization of the airway, breathing, and circulation. In the appropriate clinical setting, lead encephalopathy should be considered in patients presenting with delirium, altered mental status, or seizures.[10] As lead encephalopathy often presents with altered sensorium, obtaining a history directly from the patient can be challenging. Key features of the patient’s history that should raise the index of suspicion for lead encephalopathy may include associated abdominal pain, constipation, or anemia, which are other common findings of lead intoxication.[11] In subacute cases, an additional history of preceding ataxia, headache, sensory or motor deficits, agitation, or irritability may be present. Finally, obtaining a detailed environmental history is important in understanding the route and magnitude of potential lead intoxication.

A physical exam primarily reveals CNS derangement. Generally speaking, patients afflicted with lead encephalopathy appear to be globally altered. On the exam, they may also exhibit peripheral neuropathy, such as wrist drop and loss of 2-point discrimination. Patients also commonly exhibit ataxia on the exam. They may also present with generalized tonic-clonic seizures or, more rarely, focal seizures. In rare cases, patients with lead encephalopathy may present with focal neurologic deficits.[10]

Evaluation

Evaluation of lead encephalopathy is primarily clinical, with supporting evidence obtained through both laboratory and imaging studies. A careful history of potential lead exposure(s) is important if there is a clinical suspicion of lead encephalopathy. A thorough neurologic examination should assess the degree of dysfunction and establish a baseline for the presentation.[12]

Important laboratory studies to obtain include a whole blood lead level, which is markedly elevated, as well as a complete blood count (CBC). A CBC shows anemia, usually microcytic, but also possibly hemolytic in acute high-magnitude intoxication and may have basophilic stippling. A comprehensive metabolic panel (CMP) is also of benefit and may show mild prerenal azotemia or transaminitis in the setting of acute intoxication.[12] Brain imaging studies are used in lead encephalopathy, with either computed tomography (CT) or magnetic resonance imaging (MRI) being appropriate. These often demonstrate diffuse cerebral edema but may also demonstrate focal edema or collapse of the fourth ventricle and resultant hydrocephalus.

Treatment / Management

The treatment of lead intoxication in general, but particularly in lead encephalopathy, can be considered in 3 specific areas: Decontamination, supportive care, and chelation.

Decontamination

Decontamination methods depend on the type of exposure.[13] Ingestion is a common source of exposure, particularly in children, and gastric decontamination through whole-bowel irrigation is helpful. This should be considered particularly when large ingestion is suspected or when abdominal films demonstrate radiopaque lead particles in the GI system. Though rare, embedded lead projectiles such as bullet fragments or shotgun pellets have been shown to cause lead intoxication, particularly when adjacent to a fluid-filled space such as a cyst, synovial capsule, or bursa. In such cases, surgical removal of the retained object is recommended when feasible.

Supportive Care

Lead encephalopathy is a serious illness and requires ICU level of care. The main goals of care include mitigating the rise in ICP, optimizing urinary output and elimination of lead, and maintaining seizure prophylaxis and control. Measures to control ICP include treatment with mannitol or hyperosmolar saline as well as early hyperventilation. These patients generally require intubation and mechanical ventilation, given their depressed mental state. Benzodiazepines such as diazepam or lorazepam are the mainstay of seizure treatment.[14] 

If possible, a urine output of 1 to 2 mL/kg/hr should be achieved. This often requires IV fluid resuscitation as these patients are frequently volume-depleted due to vomiting and decreased oral intake. However, care should be taken to avoid hypervolemia and worsening cerebral edema. In patients that are euvolemic, loop diuretics may be used to increase urine output to goal as needed. Patients with lead encephalopathy in acute renal failure generally require renal replacement therapy.[14]

Chelation

Chelation therapy aims to bind lead in a soluble state, thus enhancing its excretion. To this end, multiple different chelation therapies have been recommended, many of which depend on the whole-blood lead level or clinical severity of intoxication. As lead encephalopathy represents the most severe form of lead intoxication, most experts recommend initial treatment with both edetate calcium disodium (CaNaEDTA) intravenously and British anti-lewisite (BAL) intramuscularly, if possible. BAL should be administered at least 4 hours before  CaNaEDTA, as the latter may be associated with increased CNS absorption otherwise. Patients may later be transitioned to dimercaptosuccinic acid (DMSA, succimer) orally.[14][15] 

Whole-blood lead levels should be obtained before and within 24 to 48 hours after chelation to help guide any further chelation doses that may be required. Finally, monitoring whole blood lead levels for 7 to 21 days after completion of chelation is suggested, as lead may redistribute in the tissues, causing re-exposure.[14]

Differential Diagnosis

Lead encephalopathy typically presents as primary CNS dysfunction. Therefore, an appropriate differential includes all critical diagnoses in encephalopathic patients. Encephalitis, meningitis, and sepsis may present similarly but are generally associated with fever. Alcohol or benzodiazepine withdrawal will often present with delirium, seizures, or abdominal pain. However, other associated signs of increased sympathetic tone are also uncommon in lead encephalopathy. Ischemic stroke, intracranial hemorrhage, or mass may also present with cerebral edema or lateralizing deficits, which may be found in acute lead encephalopathy. Under the appropriate conditions, a whole-blood lead level will help diagnose lead encephalopathy. In contrast, other appropriate diagnostic adjuncts will help to rule in or rule out other diseases.

Prognosis

There is limited formal data regarding the prognosis of lead encephalopathy. In children, the prognosis is guarded, as many have been shown to display permanent growth and neurocognitive deficits following severe intoxication.[16] Prognosis in the adult population is even less studied, though case reports suggest a more favorable outcome. Many adult patients regain close to baseline neurologic function after physical and neurocognitive rehabilitation, though the process may take months to years. Elderly patients or patients with chronic medical conditions may have persistent cognitive deficits.[17]

Complications

Complications of lead encephalopathy are due primarily to the effect of increased intracranial pressure. If not promptly identified and treated, this can lead to seizures, coma, and, eventually, death. There is also the threat of herniation and subsequent autonomic dysfunction. Apnea, aspiration, and other complications of a compromised airway are considerations due to the depressed mental state of patients with lead encephalopathy.

Deterrence and Patient Education

Lead encephalopathy is an entirely avoidable condition. Educating patients on proper avoidance techniques is key. For children, eliminating lead at home is critical. Proper education on personal protective equipment and reducing exposure is important for adults with occupational exposures. In all confirmed cases of lead intoxication, the CDC recommends an investigation as to the source of exposure, if possible, to limit further exposure.[17]

Enhancing Healthcare Team Outcomes

Lead encephalopathy is a critical illness that requires the coordination of an interprofessional healthcare team to optimize patient outcomes. Primary clinicians or emergency medicine providers often first recognize lead encephalopathy. Because of the gravity of the disease, early aggressive therapy and the involvement of a medical toxicologist is beneficial. Clinicians, nurses, and other ICU staff play an important role in the stabilization and acute management of lead encephalopathy.

In those patients who survive this serious illness, long-term outcomes are affected by behavioral, cognitive, physical, and occupational therapy. Therefore, coordination with the appropriate rehabilitative services is a key component to mitigating the long-term morbidity of this condition. Finally, interprofessional communication between healthcare workers and the CDC and environmental or occupational health organizations is critical to identifying sources of lead exposure and preventing further exposure or outbreaks of lead intoxication.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Eisinger J. Lead and wine. Eberhard Gockel and the colica Pictonum. Med Hist. 1982 Jul;26(3):279-302. [PMC free article: PMC1139187] [PubMed: 6750289]

2.

Needleman HL. The persistent threat of lead: medical and sociological issues. Curr Probl Pediatr. 1988 Dec;18(12):697-744. [PubMed: 3063440]

3.

de Souza A, Narvencar KP, Desai PK, D'Costa Z, Nilajkar G. Adult lead encephalopathy. Neurol Res. 2013 Jan;35(1):54-8. [PubMed: 23317799]

4.

COUNCIL ON ENVIRONMENTAL HEALTH. Prevention of Childhood Lead Toxicity. Pediatrics. 2016 Jul;138(1) [PubMed: 27325637]

5.

Egan KB, Tsai RJ, Chuke SO. Integrating Childhood and Adult Blood Lead Surveillance to Improve Identification and Intervention Efforts. J Public Health Manag Pract. 2019 Jan/Feb;25 Suppl 1, Lead Poisoning Prevention(Suppl 1 LEAD POISONING PREVENTION):S98-S104. [PMC free article: PMC6388394] [PubMed: 30507777]

6.

Stowe HD, Vandevelde M. Lead-induced encephalopathy in dogs fed high fat, low calcium diets. J Neuropathol Exp Neurol. 1979 Sep;38(5):463-74. [PubMed: 469567]

7.

Mitra P, Sharma S, Purohit P, Sharma P. Clinical and molecular aspects of lead toxicity: An update. Crit Rev Clin Lab Sci. 2017 Nov-Dec;54(7-8):506-528. [PubMed: 29214886]

8.

Mahaffey KR. Quantities of lead producing health effects in humans: sources and bioavailability. Environ Health Perspect. 1977 Aug;19:285-95. [PMC free article: PMC1637386] [PubMed: 908307]

9.

Wang H, Shi H, Chang L, Zhang X, Li J, Yang Y, Jiang Y. Association of blood lead with calcium, iron, zinc and hemoglobin in children aged 0-7 years: a large population-based study. Biol Trace Elem Res. 2012 Nov;149(2):143-7. [PubMed: 22528781]

10.

Lanphear BP, Hornung R, Khoury J, Yolton K, Baghurst P, Bellinger DC, Canfield RL, Dietrich KN, Bornschein R, Greene T, Rothenberg SJ, Needleman HL, Schnaas L, Wasserman G, Graziano J, Roberts R. Low-level environmental lead exposure and children's intellectual function: an international pooled analysis. Environ Health Perspect. 2005 Jul;113(7):894-9. [PMC free article: PMC1257652] [PubMed: 16002379]

11.

Needleman H. Lead poisoning. Annu Rev Med. 2004;55:209-22. [PubMed: 14746518]

12.

Wengrovitz AM, Brown MJ., Advisory Committee on Childhood Lead Poisoning, Division of Environmental and Emergency Health Services, National Center for Environmental Health. Centers for Disease Control and Prevention. Recommendations for blood lead screening of Medicaid-eligible children aged 1-5 years: an updated approach to targeting a group at high risk. MMWR Recomm Rep. 2009 Aug 07;58(RR-9):1-11. [PubMed: 19661858]

13.

Kim HC, Jang TW, Chae HJ, Choi WJ, Ha MN, Ye BJ, Kim BG, Jeon MJ, Kim SY, Hong YS. Evaluation and management of lead exposure. Ann Occup Environ Med. 2015;27:30. [PMC free article: PMC4681084] [PubMed: 26677413]

14.

Gordon RA, Roberts G, Amin Z, Williams RH, Paloucek FP. Aggressive approach in the treatment of acute lead encephalopathy with an extraordinarily high concentration of lead. Arch Pediatr Adolesc Med. 1998 Nov;152(11):1100-4. [PubMed: 9811288]

15.

ENNIS JM, HARRISON HE. Treatment of lead encephalopathy with PAL (2.3-dimercaptopropanol). Pediatrics. 1950 May;5(5):853-68. [PubMed: 15417286]

16.

Dietrich KN, Ware JH, Salganik M, Radcliffe J, Rogan WJ, Rhoads GG, Fay ME, Davoli CT, Denckla MB, Bornschein RL, Schwarz D, Dockery DW, Adubato S, Jones RL., Treatment of Lead-Exposed Children Clinical Trial Group. Effect of chelation therapy on the neuropsychological and behavioral development of lead-exposed children after school entry. Pediatrics. 2004 Jul;114(1):19-26. [PubMed: 15231903]

17.

Rao JV, Vengamma B, Naveen T, Naveen V. Lead encephalopathy in adults. J Neurosci Rural Pract. 2014 Apr;5(2):161-3. [PMC free article: PMC4064184] [PubMed: 24966557]

Disclosure: Kristina Eastman declares no relevant financial relationships with ineligible companies.

Disclosure: Laura Tortora declares no relevant financial relationships with ineligible companies.