Neurotoxicology



Neurotoxicology


Laura M. Tormoehlen

Daniel E. Rusyniak



Neurotoxins are compounds that are toxic, or potentially toxic, to the central and/or peripheral nervous system. Capable of mimicking neurologic disorders, neurotoxins can be classified into one of three categories: (1) drugs (prescription and illicit), (2) chemicals (industrial, household, and abused agents), and (3) environmental (biologic agents and naturally occurring chemicals).

Establishing causation is paramount to the correct diagnosis and the treatment for any patient with a suspected neurotoxic syndrome. The steps involved in determining if a neurotoxin is the causative agent are those established by Sir Austin Bradford Hill in differentiating association from causation in epidemiologic studies.


1. Exposure.

Did an exposure occur? Requires quantifying the level of a toxin in biologic specimens (blood, urine, and hair) or in the environment (air and water). In some cases, historical features alone may be adequate.


2. Temporality.

Did symptoms begin concurrent with or after the exposure? A few toxins have long latent periods before symptoms develop but most cause symptoms that begin shortly after exposure.


3. Dose-response.

Do persons with higher doses and longer exposures have more severe symptoms?


4. Similarity to reported cases.

Are the symptoms similar to those previously reported?


5. Improvement as exposure is eliminated.

Do symptoms improve when the toxin exposure is eliminated or reduced? Most toxin-induced symptoms improve after cessation of exposure; although a period of worsening symptoms, or even chronic symptoms, can occur after exposure to a few toxins.


6. Existence of animal model.

Do animal studies establish biologic feasibility? Animal studies can be helpful to predict toxicity in the absence of human studies; although some toxins do not have animal models and some toxins affect animals differently than humans.


7. Other causes eliminated.

Are nontoxicologic causes excluded?

This overview is intended as a quick reference of those toxins clinicians are most likely to encounter. For more detailed work on the topic, see the recommended readings.


I. PERIPHERAL NERVOUS SYSTEM


A. Peripheral neuropathy.

Toxic peripheral neuropathies typically present as acute or subacute, symmetric axonopathies, affecting the distal axons of the lower extremities.


1. Heavy metals.



  • Arsenic.



    • Sources. Ground and well water, seafood (organic arsenic, nontoxic), paints, fungicides, insecticides, pesticides, herbicides, wood preservatives, cotton desiccants, and homicidal agents.


    • Route of exposure. Ingestion is the most common, but absorption through skin and inhalation can occur.


    • Acute toxicity.



      • Systemic signs. Gastrointestinal (GI; nausea, vomiting, abdominal pain, and bloody diarrhea) symptoms occur within 24 hours of exposure; if severe, can be followed by hypovolemic shock, pancytopenia, and ventricular arrhythmias.


      • Neurologic manifestations. Within 2 weeks, patients may develop a distal symmetric peripheral neuropathy presenting with burning and numbness in the feet. May present as ascending weakness similar to Guillain-Barre’s syndrome. Encephalopathy can develop in severe poisoning.



    • Chronic toxicity.



      • Systemic signs. Hypertension, peripheral vascular disease, renal failure, hepatitis, and keratoses of the palms and soles; associated with cancers of the skin, lung, liver, bladder, kidney, and colon.


      • Neurologic manifestations. Peripheral neuropathy, stocking-glove distribution, and sensory > motor.


    • Physical examination findings. Hyperpigmentation and keratosis develop on the palms and soles. Mees lines (transverse semilunar white bands across the nails) may be present in a minority of cases and may take as long as 40 days to develop.


    • Mechanism of toxicity. Trivalent arsenite binds sulfhydryl groups on critical enzymes inhibiting the Krebs cycle and oxidative phosphorylation. Pentavalent arsenate uncouples oxidative phosphorylation.


    • Diagnosis.



      • Laboratory. The 24-hour urine arsenic concentration is the gold reference standard for confirming recent exposures (<30 days): normal results <50 µg per L or <100 µg per 24 hours. False-positive results are common after seafood ingestion (from nontoxic organic arsenic) and necessitate repeating after abstaining from seafood. Blood testing (normal result <7 µg per dl) is less reliable owing to short half-life of arsenic. Hair testing (normal <1 mg per kg) may be useful for chronic or remote exposures.


      • Radiographs. May show radiopacities in the GI tract.


      • Nerve conduction studies (NCS). Severe acute exposure may cause conduction slowing characteristic of proximal demyelination (similar to acute inflammatory demyelinating polyradiculopathy), and distal, motor, and sensory axonopathy. In less severe, or chronic, exposures patients develop a distal, sensory greater than motor axonopathy.


      • ECG can show a prolonged QT interval with risk for torsades de pointes.


    • Treatment.



      • Removal of exposure.


      • If material is retained in the GI tract, consider either whole-bowel irrigation or use of cathartics.


      • If clinical presentation is highly suggestive, then begin chelation therapy before laboratory confirmation.



        • Dimercaptosuccinic acid (DMSA) is useful in the treatment of subacutely or chronically poisoned patients (10 mg per kg by mouth three times a day for 5 days then twice a day until the urinary arsenic level is <50 µg per L per 24 hours). Complications include transient increases in liver function tests.


        • British anti-Lewisite (BAL) is useful in severe exposures when oral therapy cannot be given or the patient has an ileus (3 to 5 mg per kg intramuscularly [IM] every 4 to 6 hours until urinary arsenic level is <50 µg per kg per 24 hours). Complications include pain over the injection site, hypertension, febrile reactions, and agitation.


        • Dimercaptoproprane-1-sulfonate is not approved in the United States but used in other countries (loading dose of 1,200 to 2,400 mg per day in equal divided doses [100 to 200 mg 12 times daily] followed by maintenance of 100 mg orally two to four times a day).


      • RBC and plasma exchange may be useful to remove components of RBC lysis and to further reduce arsenic levels in cases of intravascular hemolysis from arsine gas poisoning.


  • Lead.



    • Sources. Lead-based paint (houses painted before 1978), soil, ceramic glaze, gun ranges, battery manufacturing, retained foreign bodies, and ethnic folk remedies.


    • Route of exposure. Ingestion or inhalation.


    • Systemic signs. Abdominal pain, anorexia, constipation, anemia, nephropathy (Fanconi’s syndrome), hypertension, and rarely gout.


    • Neurologic manifestations.




      • CNS signs are more common in children: encephalopathy, coma, visual perceptual defects, seizures, and signs of increased intracranial pressure (bulging fontanel or papilledema).


      • PNS signs are more common in adults: peripheral neuropathy manifesting as a motor axonopathy (arms > legs and extensors > flexors [causes foot or wrist drop]). It can be symmetric or asymmetric.


    • Physical examination findings. Bluish black lines around gums (Burton’s lines) are rarely noted.


    • Mechanism of toxicity. In children, lead affects many neurotransmitters by increasing the release of dopamine, acetylcholine, and γ-amino butyric acid, and by blocking N-methyl-D-aspartate glutamate receptors. Disruption of intercellular junctions interferes with the blood-brain barrier causing capillary leakage and increasing pressure. In adults, lead causes Schwann cell destruction followed by demyelination and axonal destruction.


    • Diagnosis.



      • Laboratory. The gold standard for testing is blood lead levels. Normal result is <10 µg per dl. In children levels >10 µg per dl necessitate investigation and environmental lead reduction. Levels >45 µg per dl necessitate chelation. In adults, levels >40 µg per dl necessitate removal from work site. Levels >70 µg per dl necessitate chelation. CBC may show microcytic anemia with basophilic stippling.


      • Radiographs may show lead lines (increased metaphyseal densities) in growth plates and retained radiopaque material in GI tract.


      • NCS may show normal or decreased conduction velocity.


    • Treatment.



      • Remove from exposure.


      • If material is retained in GI tract, consider either whole bowel irrigation or cathartics.


      • Chelation therapy.



        • DMSA may be used as the sole agent if patients are able to take oral medications (10 mg per kg by mouth three times a day for 5 days and then three times a day for 14 days, after 1-week remeasure the lead level). Start for levels >45 µg per dl in children, or for symptomatic adults with levels >70 µg per dl. Continue until levels are <25 µg per dl in children or <30 µg per dl in adults.


        • BAL (3 to 5 mg per kg IM four times a day if unable to take orals).


        • Ethylenediaminetetraacetic acid (35 to 50 mg per kg every day by continuous intravenous [IV] infusion in combination with BAL). Start 4 hours after initiation of BAL.


  • Thallium.



    • Sources. Homicidal agent, rodenticides (no longer in United States), and manufacturing of optic lenses and semiconductors.


    • Route of exposure. Ingestion and dermal.


    • Systemic signs. Constipation, myalgias and arthralgias, alopecia beginning approximately within 2 weeks of exposure.


    • Neurologic manifestations. Within 1 week of exposure, patients develop a rapidly progressive ascending, predominantly sensory, peripheral neuropathy (symptoms are dysesthesias and paresthesias of the feet, and less commonly the hands). Can see encephalopathy, insomnia, and cranial neuropathies.


    • Physical examination findings. Blackened hair roots (under low-power light microscopic) and Mees’ lines on fingernails (rarely).


    • Mechanism of toxicity. Interferes with K+-dependent processes resulting in a decrease in catabolism of carbohydrates and impaired ATP generation through oxidative phosphorylation, inhibits sulfhydryl-containing enzymes.


    • Diagnosis. Twenty-four hour urine thallium concentration (normal <10 µg per specimen), hair thallium concentration (normal <20 ng per g), examination of darkened hair roots under light microscopy, and NCS show sensorimotor axonopathies with severity of abnormalities correlating with the severity of symptoms.



    • Treatment. Prussian blue (3 g orally three times a day). If Prussian blue cannot be obtained, multidose activated charcoal should be given until available.


  • Mercury.



    • Sources. There are three forms that differ in characteristic and toxicity.



      • Elemental mercury. Used in thermometers, barometers, thermostats, electronics, batteries, and dental amalgams.


      • Inorganic mercury salts. Found naturally as mercury (II) sulfide, mercuric chloride, mercuric oxide, mercuric sulfide, mercurous chloride, mercuric iodide, ammoniated mercury, and phenylmercuric salts. These compounds have been used in cosmetics and skin treatments. Most exposures come from old skin products and exposure to germicides, pesticides, and antiseptics.


      • Organic mercury. Used as preservatives and antiseptics, and previously common for industrial and medicinal purposes in the early 20th century. Ethyl mercury (thimerosal) was used in multidose vaccine vials, although it has been recently removed. Methyl mercury exposure occurs through the consumption of predatory fish.


    • Route of exposure. Elemental mercury exposure occurs by inhalation of the vapor, ingestion of the liquid, or cutaneous exposure. Ingestion and cutaneous exposure are of little clinical consequence as mercury is poorly absorbed via these routes. Ingestion of inorganic mercury salts results in the greatest absorption, but it may also be inhaled and dermally absorbed. Organic mercury exposure occurs primarily by ingestion and dermal absorption.


    • Systemic signs.



      • Elemental mercury. Acute toxicity presents within hours of a large inhalational exposure with GI upset, chills, weakness, cough, and dyspnea. Patients may progress to adult respiratory distress syndrome and renal failure. Chronic toxicity develops over weeks to months, depending on the level of exposure and presents with constipation, abdominal pain, poor appetite, dry mouth, headache, and muscle pains.


      • Inorganic mercury salts are corrosive to the GI mucosa causing oral pain, burning, nausea, vomiting, diarrhea, hematemesis, bloody stools, or abdominal discomfort with ingestions. Patients may develop acute tubular necrosis within 2 weeks exposure and membranous glomerulonephritis and nephrotic syndrome with chronic exposures.


      • Organic mercury. Patients may develop renal failure.


    • Neurologic manifestations.



      • Elemental mercury. Chronic exposure can produce proximal weakness involving the pelvic and pectoral girdle. Patients can develop erethism (memory loss, drowsiness, lethargy, depression, and irritability). Patients can also suffer from incoordination, fine motor tremor of the hands, and a sensorimotor neuropathy without conduction slowing.


      • Inorganic mercury salts. Patients can develop erethism as above.


      • Organic mercury.



        • PNS. Paresthesias of mouth and extremities occur as result of a predominantly sensory neuropathy.


        • CNS. Damage occurs to gray matter of cerebral and cerebellar cortex, mainly affecting the temporal and occipital lobes. Patients present with concentric constriction of bilateral visual fields, ataxia, incoordination, tremor, dysarthria, and auditory impairment. In utero exposure may cause a cerebral palsy-like condition known as Minamata disease.


    • Physical examination findings.



      • Elemental mercury. Oral findings include reddened, swollen gums, mucosal ulcerations, and tooth loss. Patients may display characteristics of acrodynia (sweating, hypertension, tachycardia, weakness, poor muscle tone, and an erythematous desquamating rash to the palms and soles). Symptoms associated with acrodynia may mimic the presentation of pheochromocytoma (mercury also may elevate catecholamine levels).



      • Inorganic mercury salts. Prolonged use can cause skin changes including hyperpigmentation most pronounced in skin folds of face and neck, swelling, and a vesicular or scaling rash. Patients can develop symptoms associated with acrodynia as described above.


      • Organic mercury. Mainly display abnormal neurologic exams as described above in I.A.1.d.(4).(c).


    • Mechanism of toxicity. All three forms combine with sulfhydryl groups on cell membranes and interfere with cellular processes.


    • Diagnosis.



      • Elemental mercury. Clinical presentation, history of exposure, and elevated body burden of mercury. Because of a short half-life, blood levels have limited usefulness (concentrations are typically <10 µg per L). Twenty-four-hour urine levels are normally <50 µg of mercury.


      • Inorganic mercury salts. Twenty-four-hour urine levels are the gold standard.


      • Organic mercury. Best identified in blood or hair as 90% of methylmercury is bound to hemoglobin within the RBCs. Urinary mercury levels are unreliable because methylmercury is eliminated in bile. Normal whole blood values are <0.006 mg per L. Diets rich in fish can increase levels to 0.200 mg per L or higher.


    • Treatment.



      • Elemental mercury. Remove the patient from the source. As there is minimal toxicity from ingestion, there is no role for GI decontamination. The usefulness of chelation therapy remains unclear. Suggested agents include DMSA, dimercaprol, and D-penicillamine (doses I.A.1.a.(8).(c).).


      • Inorganic mercury salts. Volume resuscitation and prompt chelation are critical to prevent renal injury. BAL is effective within 4 hours of ingestion, but DMSA may be substituted if oral intake is tolerated. Hemodialysis is indicated in renal failure for the elimination of dimercaprol-Hg complexes. See I.A.1.a.(8).(c). for doses.


      • Organic mercury. Remove from the source. Chelation may be attempted although studies have not demonstrated appreciable improvement. BAL is not recommended because of increased CNS concentrations of mercury post treatment.


  • Other metals.



    • Cisplatin. Used in chemotherapy, toxicity manifests as distal symmetric paresthesia that may not occur for months after treatment. NCS show sensory neuronopathy.


    • Gold salts. Used in rheumatoid arthritis, rarely associated with seizures and encephalopathy. Toxicity manifests as distal symmetric sensorimotor polyneuropathy.


    • Zinc. Sources include denture creams and vitamin supplements. Zinc toxicity results in copper deficiency by inhibiting dietary copper absorption. Copper deficiency is associated with anemia, neutropenia, and myeloneuropathy. Diagnosis is made by history and a CBC combined with serum and 24-hour urine copper and zinc levels. Treatment is removal of the zinc-containing product and copper supplementation.


2. Solvents.



  • N–hexane, methyl–n–butyl ketone, 2,5-hexandione.



    • Sources. Exist in industrial and household glues, varnish, cement, and ink.


    • Route of exposure. Inhalational and abused (huffing or bagging).


    • Systemic signs. Anorexia, weight loss, and renal tubular acidosis (mixtures containing toluene).


    • Neurologic manifestations. Distal weakness, paresthesias, sensory loss, and areflexia. Progression of neuropathy may occur for weeks after exposure ends (coasting). NCS show motor > sensory polyneuropathy with reduced sensory and motor amplitudes and prolonged motor conduction velocity.


    • Physical examination findings. Solvent odor on breath and absent Achilles’ reflexes.



    • Mechanism of toxicity. Impairs neurofilamentous transport.


    • Diagnosis.



      • Clinical history and physical examination findings.


      • Sural nerve biopsy (axonal degeneration, demyelination, and paranodal axonal swelling with neurofilament accumulation).


      • Electromyography (denervation and decreased recruitment).


    • Treatment. Removal from the source results in improvement, although symptoms may progress for a time after exposure (coasting).


  • Other solvents.



    • Acrylamide. Sensorimotor neuropathy.


    • Carbon disulfide. Distal axonal neuropathy with axonal swellings, extrapyramidal signs, and psychosis.


    • Ethyl alcohol (chronic). Sensorimotor neuropathy effecting distal lower extremities first.


    • Ethylene oxide. Distal axonopathy.


    • Methyl-ethyl-ketone. Nontoxic alone, but synergistically promotes peripheral neuropathy from other solvents.


    • Methyl bromide. Both peripheral and pyramidal effects.


    • Styrene. Sensorimotor, demyelinating neuropathy.


    • Trichloroethylene. Cranial mononeuropathies.


3. Organophosphates or carbamates.

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Aug 18, 2016 | Posted by in NEUROLOGY | Comments Off on Neurotoxicology

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