Clinical manifestations

Presentation and course

Children most commonly display CNS dysfunction from lead intoxication. This may present as chronic cognitive dysfunction (developmental delay or loss of milestones) or as an acute encephalopathy (32). Encephalopathy is also seen with acute, high-level exposure in adults and, in both age groups, can progress to seizures, coma, or death (33; 43). Acute high-level exposure has been associated with marked tremulousness, gait dysfunction, and choreiform movements. Behavioral abnormalities, including hallucinations, may occur with high-level intoxication, and the severity of the aforementioned CNS disturbances correlates with blood lead levels (26). There may be some cognitive and behavioral dysfunction in adults with chronic, low-level lead exposure.

Peripheral neuropathy resulting from chronic lead exposure is most commonly seen in adults but can also occur in children. The neuropathy is typically accompanied by other systemic features of lead toxicity that include anemia (microcytic, hypochromic), gastrointestinal disturbance (constipation, abdominal pain), renal dysfunction, fatigue, weight loss, and occasionally gout. The neuropathy associated with lead toxicity develops insidiously with chronic exposure. The classic clinical manifestations are unusual in that motor dysfunction predominates, and there are few, if any, sensory symptoms or signs. The typical pattern is distal, symmetric weakness with atrophy, reflex loss, and occasionally fasciculations that may involve the arms relatively early. A report that analyzed a group of workers with elevated blood or urine lead levels raised some doubt about the pattern of clinical manifestations (35). In this series, 46 out of 151 workers with elevated lead levels had “neuropathic features." These patients had long exposure (mean duration 21 years) but relatively mild lead elevations. The clinical findings were exclusively sensory and autonomic (35). A report from Iran involving workers in a tile factory found sensory and CNS complaints as the primary symptoms in those with elevated lead levels (20). The literature contains reports of focal neurologic deficits such as wrist drop (18; 03; 14), but manifestations such as these are rare (05) and may be due to secondary compression neuropathies. Although some lower motor neuron damage is associated with lead exposure, there is no causal relationship to the development of idiopathic motor neuron syndromes such as amyotrophic lateral sclerosis (07). A report of lead intoxication causing a predominately motor neuropathy is clouded by the fact that the patient had concomitant vitamin B12 deficiency (17). This patient was exposed through a lip ointment.

Prognosis and complications

Complete recovery from neuropathy is usual except in severe cases. Mild cases may recover spontaneously if the source of exposure is discovered and eliminated (13). The improvement typically begins 2 weeks after the initiation of chelation therapy. With severe neuropathy, residual weakness may remain. Lead toxicity in children has been found to have adverse effects on subsequent cognitive functioning. This includes developmental delay and lower IQ (30). Those presenting with severe encephalopathy and seizures have a high mortality rate.

Biological basis

Etiology and pathogenesis

Lead gains access to the tissues via ingestion, inhalation, or dermal contact. The route of exposure is determined by whether the lead is organic versus inorganic as well as by the size of particles and the compound in which it is contained. Workers at risk for inorganic lead exposure include lead miners, plumbers, solderers, cable makers, automobile factory workers, tile factory workers (20), lead glass blowers, and pottery glazers. Construction, demolition, and foundry workers may be exposed to inhalation of lead oxides during the process of cutting metal with oxyacetylene torches. Exposure to organic lead is less common and is primarily through leaded gasoline. The ingestion of ayurvedic medications that contain animal products, herbal products, minerals, and metals has been reported to cause lead toxicity (40). Although blood lead levels are higher in dialysis patients, the presence of neuropathy was not correlated with the blood lead level in a study (21). A single case of lead toxicity in a dialysis facility, manifesting as peripheral neuropathy and abdominal pain, prompted an analysis of all their dialysis patients. Many were found to have elevated blood lead levels, but the authors did not discuss possible neuropathy in this cohort (12). Retained bullet fragments have been reported to cause lead toxicity that occurs shortly after the gunshot wound or many years later (25; 06). There has been a case report of a mild reversible neuropathy related to the use of a hair dye containing lead acetate (13). There are multiple reports of lead poisoning related to opium abuse, with some of the cases presenting with symptoms or signs of neuropathy (02; 29).

Nerve excitability studies carried out in a patient with acute lead neuropathy showed that there was altered nerve excitability related to impaired energy metabolism (worse with limb ischemia) that improved with treatment and recovery (22). More recently, a study of lead-exposed workers compared to controls showed that the resting membrane potential was hyperpolarized because of interference with potassium channel function that correlated with blood lead levels (09). Lead interacts with carboxyl, sulfhydryl, amino, and phosphate groups (16). Disruption of the heme biosynthetic pathway occurs via its interaction with the sulfhydryl groups of enzymes, thereby contributing to anemia. Reduced heme synthesis also results in deficient activity of cytochromes that are important for detoxification of harmful free radicals. A high level of inorganic lead displaces calcium ions, disrupts ion transport through calcium channels, inhibits calcium adenosine triphosphatase activity, and results in the accumulation of intracellular calcium, which may facilitate cell death. These factors may play an important role in neurologic toxicity (39; 27). A case of lead neuropathy in a dialysis patient lead to speculation that uremia may alter iron distribution between plasma and red blood cells (03).

In a model of lead toxicity on the nervous system, lead has been shown to cause reduced intracellular glutathione levels and increased caspase-3 activity, possibly leading to apoptosis (08).

Epidemiology

Despite the efforts to eradicate lead paint, its presence in older buildings leaves children at risk for ingestion. The prevalence of children with elevated blood levels has, however, dramatically declined due to lead paint elimination efforts. However, from 2007 to 2010, approximately 2.6% of school-aged children had lead concentrations above 5 ug/dL (11). Lead intoxication in adults is predominately an occupational hazard, although ingestion of "moonshine" or the burning of batteries may account for a small number of cases.

Prevention

Continued efforts to reduce the exposure to lead in the environment and workplace are necessary to decrease the potential for lead intoxication. These efforts include: enforcement of regulations regarding industrial lead emissions and occupational exposure levels; education of those at high risk regarding the potential long-term negative effects of lead exposure and how to prevent them (eg, good hygiene); regular monitoring of exposure levels; and protective clothing and respirators. Measurement of urinary lead levels may indicate excessive exposure before the development of clinical symptoms. Performance of nerve conduction studies may uncover a subclinical neuropathy (37) before it becomes severe.

There is evidence of an interaction between diet, calcium, and lead toxicity (10). To assess the effects of drinking milk on lead toxicity, Chuang and colleagues measured current perception thresholds and serum lead levels. They found that drinking milk had a protective effect on hand current perception thresholds but did not significantly effect foot current perception thresholds or blood lead levels (10).

A species of Lactobacillus bacteria with a high lead binding capacity has been shown in an animal model to reduce acute lead toxicity (24). This organism could be considered as a treatment to help eliminate lead after acute exposure.

Differential diagnosis

Due to the presence of gastrointestinal manifestations and anemia with peripheral neuropathy and central nervous system effects, lead toxicity needs to be differentiated from porphyria (15).

Diagnostic workup

Laboratory evaluation reveals a microcytic, hypochromic anemia with basophilic stippling of erythrocytes (42). Lead can be detected in the urine, and urinary levels may be increased by chelating agents that draw lead from the soft tissues and facilitate its excretion. This is helpful both therapeutically and diagnostically. Lead levels greater than 1 mg in a 24-hour specimen after chelation therapy (usually with calcium ethylenediamine tetraacetic acid) or a ratio greater than 0.6 mµ of lead excreted to mg of calcium ethylenediamine tetraacetic acid administered are considered abnormal (28). Blood lead levels are elevated following recent exposure, but this does not reflect the total body lead burden. Blood lead levels should not exceed 40 µg/100 mL of whole blood.

Lead interferes in the biosynthesis of heme by inhibiting the enzyme delta-ALA dehydratase (41). This results in an elevation of serum levels of the substrate delta-ALA. It has been suggested that lead-induced motor neuropathy cannot develop in the setting of normal delta-ALA levels, but the distal sensorimotor neuropathy may (41). In fact, this argument was used as evidence against a lead-induced mechanism of motor neuropathy in a reported case (34).

The electrophysiologic findings are controversial, being both axonal and demyelinating in different case reports. Despite the relative absence of sensory symptoms or signs, nerve conduction studies clearly show evidence of sensory axon loss. Abnormal nerve conductions may be seen in those without symptoms or in those exposed to "safe" levels (37). A study evaluating nearly 200 lead-exposed workers (mean bold level 41 mcg/ml) and 90 controls (mean blood level 1.5 mcg/ml) showed statistically significant differences in conduction velocity and distal latency in some sensory and motor nerves but no differences in amplitudes (01). The severity of nerve conduction abnormalities correlates with the amount of lead in the body (37). Nerve conduction studies can be used to document the presence of a suspected lead neuropathy as well as subclinical involvement (36), particularly in those with elevated blood levels. A report confirmed the mild sensory nerve conduction abnormalities in patients with chronic lead exposure (35). Electromyographic evidence of active denervation and chronic motor unit reinnervation reflect the presence of axonal degeneration. Somatosensory evoked potential amplitudes can correlate with blood lead levels in exposed workers. Latencies in both peripheral and central nerve segments have been reported to be prolonged. Sympathetic skin responses may be abnormal more frequently in those chronically exposed to lead (31). Neuropsychological testing reveals abnormalities in memory, attention, and visuospatial functioning.

Management

Supportive measures are discussed in Peripheral neuropathies: supportive measures and rehabilitation.

Removal of the affected individual from further exposure is the initial step. Treatment of lead intoxication is based on chelation. The effective agents include penicillamine, British anti-Lewisite, succimer, and calcium ethylenediamine tetra-acetic acid. Typically, these are administered in short courses. In the setting of encephalopathy, combination therapy with both ethylenediaminetetraacetic acid and British anti-Lewisite is recommended. In milder cases, succimer and penicillamine are usually adequate. The seizures caused by lead intoxication are often refractory but may respond to therapy with diazepam. Measures to lower intracranial pressure via mannitol, hyperventilation, and fluid restriction should be instituted in those cases with brain edema.

Outcomes

The improvement typically begins 2 weeks after the initiation of chelation therapy. With severe neuropathy, residual weakness may remain.

Special considerations

Pregnancy

The fetus is at risk of lead exposure if the mother has excessively high blood lead levels. The level of lead in the blood should not exceed 10 µg/100 mL at any time during the pregnancy. Exposure in utero has been associated with chronic cognitive dysfunction (33).