Heavy Metal Poisoning
Heavy metal poisoning often enters the neurologic differential diagnosis when a patient presents with a constellation of abdominal pain, polyneuropathy, encephalopathy or coma. Because the constellation of symptoms is so widespread, and often the neurologic manifestations so quickly discounted, the neurologist may not be consulted until later in the disease course or even after the diagnosis is reached. So when you encounter a myriad of symptoms with multi-organ dysfunction of unclear etiology, this should raise your suspicion for metabolic and nutritional deficiencies, such as thiamine or B12 deficiency, substance intoxication, and lastly heavy metal toxicity. It is imperative that when possible, a thorough social, occupational, and exposure history be taken, as that may become the only reason serum or urine studies are sent for heavy metals.
From an epidemiologic perspective, the incidence of heavy metal poisoning has fallen out in the US due to raised awareness of lead in commercial paints and gasoline, and other forms of heavy metal acquisition, but it’s something you shouldn’t forget. So in this BrainWaves brief, we will be reviewing some of the major neurologic presentations of heavy metal poisoning. In alphabetical order.
A is for Arsenic. Unlike other heavy metals, high concentrations of arsenic are difficult to ingest by natural means, so poisoning is often intentional. Once ingested, it is stored in the kidneys and slowly excreted in the urine and stool, but it can build up in hair, the nervous system, and other organs (like the nail beds where it appears as white lines called Mee’s lines 2-3 weeks after exposure). Arsenic is one of the metals that causes multi-system dysfunction—with acute intoxication affecting the GI tract with abdominal pain and vomiting, bone marrow with resultant pancytopenia, liver failure, skin manifestations with alopecia, and neurologically it produces a painful sensory polyneuropathy, vertigo, encephalopathy, and rarely seizures or coma. Death occurs following malignant cerebral edema. More chronically, persistent exposure to arsenic can cause any of these symptoms to be milder, and can also cause a length-dependent axonal polyneuropathy with occasional optic nerve involvement. Each of these clinical manifestations are practically indistinguishable from lead toxicity, so you might consider testing for both metals in a patient with any of these symptoms or exposure history. 24-hour urine arsenic levels are checked at most centers. Treatment is also similar to that of lead poisoning, and involves chelation with DMSA or penicillamine.
Lead. Like most metal toxicities, you should distinguish the symptoms of acute and chronic exposure. Acute intoxication from lead results in abdominal cramping, nausea/vomiting or diarrhea, along with encephalopathy, seizures or even coma secondary to cerebral edema. Chronic exposure of low levels of lead, as in the case of accidental exposure to lead-based paints, can cause lethargy, behavioral changes, sleep disturbances, and ataxia, usually related to a peripheral neuropathy. On the medical student shelf exam, you’ll read a question about an otherwise healthy kid who develops subacute wrist drop. And although lead toxicity characteristically results in a motor-predominant neuropathy (often with radial nerve involvement), it can also produce microcytic anemia, autonomic neuropathy (manifesting as constipation), and even result in encephalopathy.1 Testing involves blood and urine lead levels, and the treatment of choice involves chelation with 2,3-dimercaptosuccinic acid (DMSA), 2,3-dimercaptopropanesulphonate (DMPS),2 or penicillamine.
Manganese. In the community setting, your usual patient works in an underground mine. In the hospital
setting, you usually see this in patients dependent on parenteral nutrition, with greater risk in patients with underlying liver dysfunction or biliary atresia—since manganese is almost entirely excreted in the bile. Early symptoms are recalled by the mnemonic “manganese madness”: headaches, irritability, hallucinations, and personality changes, along with parkinsonian features due to basal ganglia involvement. On MRI, you even see a classic high T1 signal in the globus pallidus. EDTA can be effective in some cases, but the underlying cause should be corrected—i.e., reducing manganese in the TPN, correcting biliary atresia, etc.
Mercury. Lucky element no. 80, and abbreviated Hg—from the Latin, hydrargyrum. Mercury poisoning is incredibly rare now that kids have stopped playing with broken 20th century thermometers. Acute intoxication is similar to that of lead poisoning with abdominal pain and encephalopathy. Chronic intoxication affects the dorsal root ganglion, purkinje cells, and large sensory nerve fibers resulting in a progressive sensory plus cerebellar ataxia and nystagmus. Serum and urine levels of mercury levels are not perfectly sensitive, so some experts recommend empiric treatment, again with penicillamine or DMSA.
Thallium. This metal exerts its effects on the human body by disrupting the sodium-potassium ATPase and disabling glutathione metabolism in the liver. Now, thallium has historically been used in some pesticides and rodent poisons, whose symptoms may also mimic cholinergic toxicity (remember, your characteristic SLUDGE symptoms—salivation, urination, defecation, GI discomfort and emesis). But unlike the procholinergic effects of some pesticides, thallium can also cause weakness and encephalopathy. Thallium is worth noting here that it produces an excruciatingly painful peripheral neuropathy, characterized by profound allodynia. The softest breeze going across a patient’s foot is enough to cause an eruption of sharp discomfort, and such sensitivity may be an initial manifestation of acute exposure. This is much like that of arsenic poisoning, both of which can also manifest visually with the characteristically white “Mee’s lines” in the nailbeds of patients 2-3 weeks after exposure. Alopecia may be a delayed symptom in thallium toxicity, which follows the same time course as Mee’s lines. Thallium is an extremely rare cause of neurotoxicity, with only a handful of case reports in the US in the past several decades. Urine thallium levels are diagnostic and treatment involves the use of Prussian blue and/or hemodialysis.3
Lastly, Z is for zinc. And by zinc toxicity, I really mean copper deficiency, which is clinically indistinguishable from B12 deficiency. Like B12 deficiency, zinc toxicity with copper deficiency results in anemia as well as a nearly irreversible myelopathy.1 Now, I used to think that zinc and copper compete for absorption in the GI tract, but it’s a little more complicated. Zinc absorption in enterocytes facilitates transcription of a protein called metallothionein, which essentially chelates the copper and prevents copper transport into the circulatory system. And due to the high turnover rate of these gastric enterocytes, the copper bound to methionine is excreted along with all of these sloughed enterocytes. Clinically, zinc toxicity (slash copper deficiency) presents as a sensorimotor axonal myeloneuropathy, like B12 deficiency, with features of ataxia, absent or diminished proprioception and vibratory sensation, and weakness. Treatment involves the elimination of excess zinc in the diet (i.e., replacement of outdated denture cream), or supplementing the diet with copper.
So that was a pretty quick review of metal toxicities in the nervous system. In general, heavy metal poisoning should be considered in the differential for patients with a known exposure history, such as TPN-dependent patients or miners (for manganese toxicity), and pesticide exposure for thallium toxicity. Symptoms are similar across many of the metals: abdominal cramping, peripheral neuropathy, and a spectrum of encephalopathy. But some manifestations are more particular to each element and may increase your suspicion for a specific toxicity: arsenic with alopecia, manganese with parkinsonism. And if you’ve ever got metal on your mind, you better hope your patient doesn’t have it on theirs.
The content in this episode was vetted and approved by Francis DeRoos.
Staff NP and Windebank AJ. Peripheral neuropathy due to vitamin deficiency, toxins, and medications. Continuum (Minneap Minn). 2014;20:1293-306.
Cao Y, Skaug MA, Andersen O and Aaseth J. Chelation therapy in intoxications with mercury, lead and copper. J Trace Elem Med Biol. 2015;31:188-92.
Sun TW, Xu QY, Zhang XJ, Wu Q, Liu ZS, Kan QC, Sun CY and Wang L. Management of thallium poisoning in patients with delayed hospital admission. Clin Toxicol (Phila). 2012;50:65-9.