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 multi-compartmental model with lead distributed to blood, then to soft tissues, then to the bone. This process of redistribution may occur over months and results in a final volume of distribution of approximately 7L/kg.[8]

The half-life of lead in the fast compartments (blood and soft tissue) is 1 to 2 months but might be decades in the slow compartment (bone). Clearance rates are also dependent on whole blood lead levels. Lead is primarily excreted renally, with about 70% being 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 the setting of 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]

Lead encephalopathy can present as an acute critical illness, and the most important initial consideration in managing these patients is the stabilization of 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] Particularly in sub-acute cases, 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 will primarily reveal CNS derangement. Generally speaking, patients afflicted with lead encephalopathy will appear to be globally altered. They may also exhibit signs of peripheral neuropathy on the exam, 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 of lead encephalopathy is primarily clinical, with supporting evidence obtained through both laboratory and imaging studies. If there is a clinical suspicion of lead encephalopathy, a careful history of potential lead exposure(s) is important. A thorough neurologic examination should be performed both to assess for the degree of dysfunction and to establish a baseline on presentation.[12]

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

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 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 has been shown to be 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, imbedded 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.

Lead encephalopathy is a serious illness and requires ICU level of care. The main goals of care include mitigating the rise in ICP, optimization of 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] 

A urine output of 1 to 2 mL/kg/hr should be achieved if possible. This often requires IV fluid resuscitation as these patients will frequently be volume depleted due to vomiting and decreased oral intake, though care should be taken to avoid hypervolemia and worsening of 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 will generally require renal replacement therapy.[14]

The goal of chelation therapy is 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 CaNaEDTA intravenously and British anti-lewisite (BAL) intramuscularly, if possible. Of note, BAL should be administered at least 4 hours prior to 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]

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 will generally be associated with fever. Alcohol or benzodiazepine withdrawal will often present with delirium, seizures, or abdominal pain. However, there will also be other associated signs of increased sympathetic tone, not common in lead encephalopathy.  Ischemic stroke, intracranial hemorrhage, or mass may also present with cerebral edema and/or lateralizing deficits, which may be found in acute lead encephalopathy. In any case, under the appropriate conditions, a whole blood lead level will help make the diagnosis of lead encephalopathy, while other appropriate diagnostic adjuncts will help to rule in or rule out other diseases.

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 will 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 of lead encephalopathy are due primarily to the effect of increased intracranial pressure. If not promptly identified and treated, this can and will 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.

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

Lead encephalopathy is a critical illness that requires the coordination of an interprofessional healthcare team to optimize patient outcomes. Lead encephalopathy will often first be recognized by primary clinicians or emergency medicine providers. 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 long-term morbidity of this condition. Finally, interprofessional communication between health care workers and the CDC, environmental, or occupational health organizations is a critical component to identify sources of lead exposure and prevent further exposure or outbreaks of lead intoxication.