Lead Encephalopathy

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 with lead encephalopathy may present with a wide variety of central nervous system 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, 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 gastrointestinal 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 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 that 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] Lead 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 gastrointestinal 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

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 for management is stabilizing 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 centtral nervous system derangement. Generally speaking, patients 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 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 or magnetic resonance imaging 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 gastrointestinal 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 intensive care unit level of care. The main goals of care include mitigating the rise in intracranial pressure (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] (B3)

If possible, a urine output of 1 to 2 mL/kg/hr should be achieved. This often requires intravenous 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](B3)

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 central nervous system absorption otherwise. Patients may later be transitioned to dimercaptosuccinic acid 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](B3)

Differential Diagnosis

Lead encephalopathy typically presents as primary central nervous system 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. Older patients or those 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.