Neurotoxicology
Most neurotoxic agents cause dysfunction or destruction of subcellular structures, specific group of cells, axonal tracts, and diffuse neuronal or myelin dysfunction.
Neurotoxic Agents Affecting Specific Subcellular Structures of the PNS
|
Neurotoxic Agents Affecting Specific Subcellular Structures of the CNS
| |||||||||||||||||||||
Neurotoxic Agents Used as Models of Human Diseases
|
Manganese Toxicity
Manganese typically enters the body by ingestion or inhalation. As manganese uses the same transporter than iron for absorption in the gastrointestinal tract, iron deficiency increases its absorption. Manganese is eliminated almost exclusively via biliary excretion. Hence, hepatic excretion mechanisms are crucial in preventing excess blood manganese from crossing into the blood-brain barrier and selectively concentrating in the striatum. Manganese toxicity arises from mining, welding, ferromanganese smelting, industrial and agricultural work, liver failure (acquired hepatolenticular degeneration), total parenteral nutrition, and ingestion of Chinese herbal pills.
Ephedronic encephalopathy can develop in those addicted to methcathinone (also known as ephedrone), which can be synthesized by combining pseudoephedrine (Sudafed), a common over-the-counter cold remedy, with potassium permanganate. The phenotype is reminiscent of PSP.
Manganese transporter mutation due to homozygous mutations in the SLC30A10 gene (1q) leads to dystonia-parkinsonism, hypermanganesemia, cirrhosis, and polycythemia. Paraparesis may also be part of the phenotype.
Manganese toxicity causes a parkinsonism with marked axial deficits in the form of early dysarthria, dysphagia, and postural impairment. Unlike Parkinson disease (PD), deficits are symmetric, tremor is postural, and response to levodopa nil. A characteristic “cock walk” gait (walking on toes with arms flexed and erect posture) develops, with freezing and tendency to lean backward. Brain MRI shows pallidal T1W hyperintensity with normal T2W signal. Normal fluorodopa-PET scans suggest an intact nigrostriatal system. On pathology, there are no Lewy bodies or direct involvement of the substantia nigra pars compacta; instead, the internal segment of the globus pallidus is predominantly affected. Epidemiologic studies have failed to establish a cause-effect relationship between manganese exposure and PD or that such exposure accelerates the development of PD.
Abnormal T1- and T2-weighted signal in the globus pallidum moves the differential diagnosis away from manganese toxicity (T1W-only hyperintensity) to Wilson disease, neurodegeneration with brain iron accumulation 1, melanoma, neurofibromatosis type 1, calcification, hyperglycemia, blood products, and fat.
Management of manganese toxicity is dependent on the source of exposure. Welders are advised to have adequate ventilation and personal respiratory protection during welding. N-acetylcysteine may be used in cases of potassium permanganate poisoning. Manganese supplementation should be kept below 0.018 µmol/kg/d in total parenteral nutrition to prevent toxicity. Liver transplantation may be necessary in cases of liver cirrhosis-induced acquired hepatolenticular degeneration. Iron deficiency increases the gastric absorption of manganese and needs to be corrected. Chelation with ethylene-diamine-tetra-acetic acid (EDTA) may result in modest improvements. Permanent sequelae are likely.
Botulism
Botulism is a paralyzing disease caused by a powerful toxin, lethal at the small dose of 0.05 µg, produced by an anaerobic, spore-forming, soil-dwelling gram-positive bacteria Clostridium botulinum. The bacteria can generate heat-resistant and eight immunologically distinct heat-labile (A, B, C1, C2, D, E, F, and G) exotoxins. When ingested, heat-resistant spores are responsible for infant botulism. Recovery time from type A poisoning is longer than from type E. The toxin blocks the release of acetylcholine (ACh) by binding to the presynaptic terminal and entering into the cell by endocytosis. The two main protein enzymatic cleavages needed for prevention of exocytosis of ACh depends on the specific toxin: A, C, and E cleave the protein synaptosome-associated protein (SNAP-25); B, D, and G cleave the synaptobrevin vesicle-associated membrane protein (VAMP-2).
Classical Botulism
Botulinum toxin types A, B, and E are the most common cause of food-borne or classical botulism. The most common source is contaminated fish and seafood (type E). It leads to symmetric cranial nerve dysfunction, especially ptosis, diplopia, dysarthria, and dysphagia, within 12 to 48 hours from the ingestion of contaminated food, and is followed by “descending paralysis,” including respiratory weakness. There are no sensory abnormalities, no preceding fever, and no mental status changes but prominent gastrointestinal (cramping, early nausea, and diarrhea) and autonomic (dry mouth, urinary retention, constipation, hypotension, and bradycardia) symptoms. Fixed dilated pupils and normal reflexes in a pattern of descending weakness are most suggestive. Besides seafood, other important historical clues are “skin popping,” heroin use, and unsterile wound. Repetitive stimulation studies show decrement of the CMAP amplitude in at least two muscles with postexercise or tetanic facilitation (>20%) for at least 2 minutes, with no postactivation exhaustion. The only other condition with similar electrophysiology is hypermagnesemia. When high-frequency repetitive stimulation (50 Hz) causes facilitation >100%, the differential diagnosis should include Lambert-Eaton myasthenic syndrome (LEMS). Other neuromuscular disorders must be in the differential diagnosis such as MG, Miller-Fisher variant of GBS (areflexia, descending weakness, GQ1b autoantibodies), tick paralysis, and diphtheritic neuropathy (tonsillar exudate). Antitoxin, catharsis, FVC monitoring, and symptomatic support are recommended.
Infant Botulism
Spores (rather than preformed toxin), which are found in soil or honey products, are ingested and germinate in the intestinal tract of an infant, which lacks protective bile acids and bacterial flora. The toxins generated cause early constipation, weak cry, difficulty feeding, and bulbar and limb weakness. Over 1 to 3 days, there is loss of head control, hypotonia, tachycardia, hypotension, and dry mouth. Most infants recover within weeks or months with supportive care. Botulism immune globulin (BIG) appears to shorten the duration of respirator dependence but its use is not widely accepted yet.
Nonbotulism Causes of Toxic Weakness
Diphtheria is rare due to widespread immunization.
Tetanus Poisoning
The anaerobic spore-forming rod Clostridium tetani forms tetanospasmin, one of the most potent toxins, which is retrogradely transported from the neuromuscular junction, adjacent to seemingly insignificant wounds, to the upper motor neurons and by transcytosis to the inhibitory Renshaw cells. The termolabile tetanospasmin then cleaves the vesicle-associated membrane protein (VAMP), blocking the presynaptic release of glycine and GABA from spinal and brainstem inhibitory interneurons. Early manifestations include rigidity of the masseter muscles (trismus or lockjaw), neck or face (risus sardonicus), and painful abdominal wall rigidity and opisthotonus with relative sparing of distal muscles and preservation of consciousness. Painful reflex spasms and autonomic dysfunction (sweating, hypersalivation, tachycardia, labile hypertension) are common. The severity of symptom reaches a peak in 2 weeks and begins to recede at 4 weeks. Neonatal tetanus results in muscular spasms and is caused by contamination of the umbilical cord. Tetanus toxoid as a prophylaxis is part of the five doses of DPT given during childhood immunization up to the age of 6 years. Tetanus-diphtheria toxoid boosters are recommended every 10 years.
Strychnine Poisoning
Available from rodenticides and pesticides, strychnine poisoning can mimic tetanus except by its faster onset (within 1 hour from ingestion), less abdominal rigidity, and lack of trismus. Strychnine competitively blocks the postsynaptic glycine receptors by modulating Cl− permeability in the spinal cord and motor neurons.
Curare is a plant-derived toxin of the Strychnos species, like strychnine, used traditionally as arrow poisons in the South American rain forest. Curare introduced directly into the bloodstream competes with acetylcholine for the receptor and thus blocks neuromuscular transmission and causes progressive flaccid paralysis of striated muscle and eventual respiratory failure.
Lathyrism refers to the development of a purely motor spastic paraparesis, resulting from the consumption of a variety of toxic chickpea named Lathyrus sativus. The chickpea poison responsible for the paraparesis is the excitatory glutamate analogue β-N-oxalyl-amino-L-alanine (L-BOAA), a powerful agonist of the AMPA glutamate receptors. The clinical picture is similar to HTLV-related tropical spastic paraparesis.
Lytico-Bodig (Parkinsonism-dementia complex of Guam) applies to the combination of motor neuron disease and parkinsonism present in the Chamorro people in Guam, one of the Mariana Islands in the Pacific Ocean, presumed to be caused by the excitotoxin β-methylamino-L-alanine (BMAA). The mode of poisoning occurs via the ingestion, for food and medicine, of the cycad seed plant, which contains BMAA and cycasin, as well as the fruit bat, which feeds on cycad seed.
Envenomations
Spider envenomation occurs after the bite of the female back widow spider, Latrodectus mactans, which injects the potent latrotoxins. Latrotoxins activate presynaptic calcium channels allowing massive influx of calcium, rapid release of acetylcholine at the NMJ, and excessive muscle depolarization. Latrodectism manifests as muscle spasm with irritability, hypertension, diaphoresis, and increased salivation, evolving into seizures and, rarely, death. Calcium gluconate with or without methocarbamol or dantrolene are used as first-line treatments for muscle spasms. Latrodectus antivenin is reserved for severe envenomation.
Tick paralysis results from the inoculation of toxin contained in the saliva of a fertile female tick at the time of a blood meal. The neurotoxin is produced by the Rocky Mountain wood tick (Dermacentor andersoni), American dog tick (Dermacentor variabilis), and Australian marsupial tick (Ixodes holocyclus). Like botulinum toxin, these neurotoxins block presynaptic acetylcholine release. Patients exhibit an acute ascending paralysis with few sensory symptoms, reminiscent of the Guillain-Barré syndrome. Disengagement or active removal of Dermacentor ticks ends neurological toxicity within 24 hours.
Scorpion stings occur when accidentally touching or stepping on these arthropods. The Mexican Durango scorpion (Centruroides suffuses) causes 200,000 envenomations and almost 1,000 deaths annually. Only one scorpion species in the United States is medically relevant, the Arizona bark scorpion (Centruroides sculpturatus). Regional paresthesias at the sting side give way to a hyperparasympathetic syndrome (salivation, lacrimation, urinary incontinence, defecation, gastroenteritis, and emesis [SLUDGE syndrome]). Scorpion stings cause abnormal eye movements (ptosis, nystagmus) and neuromuscular hyperactivity (“restless child with roving eyes”), particularly fasciculations. Ataxia, myoclonus, dystonia, rigidity, clonus, opisthotonus have been reported.
Toxic mushroom poisoning occurs when toadstools (Amanita phalloides, gyromitrin, muscarine, and psilocybin) are confused with truffles (edible mushrooms). Amanita consumption causes toxicity directly from its heat-stable α-amatoxin or indirectly as brain edema from liver failure. Muscarine mushroom toxin causes the SLUDGE syndrome without any CNS symptoms, as it does not cross the blood-brain barrier. Gyromitrin mushroom poisoning may cause nystagmus, ataxia, tremor, and rarely seizures in the setting of liver failure.
Buckthorn (aka, Tullidora, wild cherry, Capulin tullidor, coyotillo) is an invasive poisonous plant from Mexico, Southern United States, Central America, and the Caribbean whose ingestion causes a Guillain-Barré-like disorder with GI symptoms.
Snake envenomation by Mohave rattlesnake (Crotalus scutulatus; Southwest United States and central Mexico) may cause myokymia, cranial nerve palsies, weakness, rhabdomyolysis, myoglobinuria, renal failure, and respiratory paralysis.
Lead Poisoning
Plumbism (from the Latin plumbum [Pb]) results from exposure to inorganic lead. The common ways of absorption are transdermal, inhalation, or ingestion. Ingested lead is only 10% but is the commonest mechanism of toxicity in children with compulsive lead-based paint chewing (pica). Inhaled lead gets into the bloodstream at a 40% rate and represents the usual mechanism for occupational exposure in adults, especially those involved in painting, printing, pottery, glazing, lead smelting, and battery manufacturing. Inhalation of gasoline fumes in workers of gasoline storage tanks causes organic lead intoxication with tetraethyl and tetramethyl lead. Calcium and iron deficiency increase absorption and the risk of lead poisoning. Long-term storage occurs in the skeletal system and recirculation of bone-bound lead may be increased during enhanced bone resorption (e.g., pregnancy, lactation, menopause, osteoporosis).
Children have predominantly CNS symptoms. Brief but intense exposures (lead levels, 50-70 µg/dL) are reminiscent of acute intermittent porphyria, with an encephalopathy and acute abdomen. Anorexia is followed by vomiting and irritability, tremor, fatigue, hallucinations, and headache with depressed sensorium. Wrist drop from radial and other focal palsies may occur. The degree of neuropathy does not correlate with lead level or length of exposure.
Symptoms and Signs of Chronic Low-Level Lead Exposure
|
Adults show predominantly PNS symptoms. Encephalopathy is rare but colic, anemia, and peripheral neuropathy are common. A gingival lead line may develop. In these cases, insomnia, irritability, delusions, and hallucinations, associated with a maniacal state define the clinical picture. No hematological abnormalities are found and chelating agents are of no value.
Basophilic stippling of red cells with microcytic hypochromic anemia, leukopenia, hemolysis, and renal insufficiency are serologic markers. Lead lines at the bone metaphyses suggest the diagnosis. High excretion of urinary coproporphyrin (UCP) and of δ-aminolevulinic acid (ALA) confirms it.
Chelation therapy is recommended when blood lead levels are >45 µg/dL: 2,3-dimercaptosuccinic acid (DMSA) or parenteral calcium disodium ethylene-diamine-tetra-acetic acid (CaNa2EDTA). When levels are >70 µg/dL, British anti-Lewisite (BAL) should be administered before CaNa2EDTA to prevent the latter from increasing the distribution of lead into the brain. Mannitol can be used in cases of cerebral edema. Intravenous diazepam is preferred for control of seizures. Renal function should be monitored because a nephrotoxic reaction may develop.
Mercury Intoxication
The three major current sources of exposure are fish consumption, dental amalgams, and vaccines, each causing a distinctive syndrome of intoxication.
| ||||||||||||||||||||||||||||
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
