Neurotoxicology



Neurotoxicology


Christopher Zammit



INTRODUCTION

Xenobiotics are substances within an organism that are not normally found in or produced by that organism. Neurotoxicology refers to the adverse effects of xenobiotics, or poisons, on the nervous system. This is a massive field with well over 350 documented neurotoxic xenobiotics. To facilitate digestibility and clinical use of the topic, this chapter will focus on acute neurotoxicology. Chronic neurotoxic associations and syndromes will be listed and briefly described. Neurotoxicology with reference to neurodevelopment, withdrawal syndromes, and psychiatric disorders, such as psychosis and mood disorders, will be minimally discussed.

Xenobiotics can include medications; industrial chemicals such as heavy metals, air pollution, solvents, and vapors; substances produced by other organisms (e.g., marine toxins, snake venom); food additives; herbal products and botanicals; recreational drugs; and insecticides, herbicides, rodenticides, and other household products. Acute neurotoxic events have been better described and causational links are more convincing. Neurotoxic effects from chronic exposures are more challenging to prove, as the clinical symptoms may be temporally distant from the exposure or the concentration of the xenobiotic in the organism is so low that it may be difficult to detect.


EPIDEMIOLOGY

The specific incidence, prevalence, and demographics of specific neurotoxins, where available, will be mentioned individually in the following sections. Age, gender, and certain comorbidities have been associated with the occurrence and severity of various toxicity syndromes.

Clinical toxicity is more commonly seen in older patients for several reasons. Age-related decrements in renal and hepatic function impair the ability to clear and eliminate xenobiotics. Reductions in neuronal quantity increase the sensitivity to the presence of xenobiotics. Finally, changes in mitochondrial function are known to occur with advanced age, increasing the possibility of excitotoxicity.

Gender has been associated with certain clinical manifestations in the setting of xenobiotics. Bruxism and dystonia are more prevalent in males, whereas tardive dyskinesia and parkinsonism are more frequently observed in females.

Comorbidities can increase the risk of neurotoxicity if they impair elimination of the xenobiotic (e.g., renal insufficiency or cirrhosis) or facilitate its entry into the central nervous system (CNS) via disturbance of the blood-brain barrier (e.g., meningitis, encephalitis). The presence of or prior exposure to other nonneurotoxic xenobiotics (e.g., prescription medications) can influence the relative neurotoxicity of a xenobiotic by impairing its metabolism or elimination; hastening its conversion to a neurotoxic metabolite; and altering gene expression, neurotransmitter production, release, breakdown, and neurotransmitter receptor density or function. Efflux transporters on the blood-brain barrier, such as P-glycoproteins and organic acid transport proteins, are typically responsible for shuttling xenobiotics out of the CNS. Some medications and conditions are known to inhibit the function of P-glycoproteins (Table 128.1), increasing the concentration of the neurotoxic xenobiotics in the CNS. Some nutrition inadequacies, such as heavy metal deficiencies, can enhance the uptake of neurotoxic xenobiotics. Lastly, some neurologic disorders can be unmasked with the introduction of a xenobiotic (Table 128.2).


PATHOBIOLOGY

For neurotoxicity to occur, a xenobiotic must come into contact with the nervous system. CNS toxicity occurs when certain xenobiotics cross the blood-brain barrier via endocytosis, transport proteins, or diffusion. Lipophilic xenobiotics gain entry via diffusion, whereas hydrophilic ones must engage with one of the two other mechanisms.

Neurotoxicity occurs through a variety of mechanisms that are summarized in Table 128.3. The most elusive mechanism to associate with a xenobiotic are those that alter gene expression, as the appearance of clinical toxicity may not occur until the xenobiotic has been eliminated from the system. Excitotoxicity is a common end point for several of the neurotoxic xenobiotics whether it is through activation of excitatory pathways or via retarded energy production, which leads to metabolic failure in the setting of neuroexcitation.

Neurotoxicity can manifest pathophysiologically as central or peripheral demyelination, neuronal death, clinical syndromes
related to the activation or inhibition of neurotransmitter pathways, or impaired function due to disrupted neuronal or glial processes.








TABLE 128.1 Selected P-glycoprotein Inhibitors and Inducers












































Inhibitors


Inducers




  • Amiodarone




  • Avasimibe




  • Ceftriaxone




  • Carbamazepine




  • Clarithromycin, erythromycin




  • Clotrimazole




  • Cyclosporine




  • Phenytoin




  • Diltiazem




  • Phenobarbital




  • Hydrocortisone




  • Rifampin




  • Ketoconazole, itraconazole




  • St. John’s wort




  • Nicardipine




  • Tipranavir/ritonavir




  • Propranolol




  • Prazosin




  • Ritonavir, saquinavir, nelfinavir




  • Progesterone




  • Tamoxifen





  • Tacrolimus





  • Verapamil









TABLE 128.2 Neurologic Disorders Unmasked by Xenobiotics















Xenobiotic


Neurologic Disorder


Aminoglycosides


Myasthenia gravis


Vincristine


Charcot-Marie-tooth


Antiretrovirals


HIV-related peripheral neuropathy



CLINICAL FEATURES

Neurotoxic presentations are protean and may include seizures or status epilepticus, ataxia, tremor, encephalopathy, movement disorders, peripheral neuropathies, lethargy, stupor, coma, cognitive impairment, neuropsychiatric behavioral disturbances, or diffuse weakness. Lateralization of neurologic deficits is uncommon unless the toxicity is unmasking a prior neurologic insult.

Seizures are a not uncommon neurotoxic presentation. Table 128.4 lists some xenobiotics known to cause seizures. A variety of movement disorders have been reported to be caused by xenobiotics, including dyskinesias, akathisia, chorea, parkinsonism, dystonias, myoclonus, and asterixis (Table 128.5). Tremors associated with xenobiotics, which can be resting, sustention, or kinetic, are summarized in Table 128.6. Medications and toxins known to cause ataxia are listed in Table 128.7. Cranial and/or peripheral neuropathies can be the result of demyelination, axonal injury, or failed transmission at the neuromuscular junction (NMJ) or of the action potential and present with diffuse weakness, autonomic dysfunction, and/or sensory disturbances. Tables 128.8 and 128.9 summarize xenobiotics associated with each of these mechanisms. Lastly, Table 128.10 lists xenobiotics associated with myopathies, which present with diffuse myalgias and weakness.








TABLE 128.3 Mechanisms off Neurotoxicity





















Cellular


Membrane


Cellular Signaling




  • Oxidative injury/neuroexcitation




  • Disrupted ion homeostasis




  • Altered neurotransmitter production, release, metabolism, or uptake




  • Disturbed energy production




  • Antagonism/agonism of ion channels




  • Blunted or exaggerated neurotransmitter receptor activation




  • Altered gene expression or transcription





  • Mimics neurotransmitter, stimulating receptor




  • Altered protein function or structure









COMMON NEUROTOXIDROMES

Neurotoxins with similar mechanisms of action typically produce distinct syndromes that allow for their clinical recognition and commonalities in their treatment. This section will summarize several syndromes, provide lists of known culprit neurotoxins, outline treatment options, and describe their expected clinical outcomes.


ANTICHOLINERGIC TOXICITY

Approximately 20,000 patients are exposed to anticholinergic xenobiotics per year. This is likely an underestimate, as this only accounts for the recognized and reported cases. To be specific, these substances have antimuscarinic properties that produce their characteristic clinical symptoms. Xenobiotics with antinicotinic actions are separate and distinct from those mentioned here. Hundreds of medications have anticholinergic properties, which
places many patients at risk for subtle toxicities that may manifest in mild behavioral or cognitive disturbances.








TABLE 128.5 Movement Disorders Associated with Xenobiotics























































































































Chorea


Dystonia


Reversible Parkinsonism


Irreversible Parkinsonism




  • Anticholinergics




  • Anticholinergics




  • Carbon disulfide




  • Calcium channel blockers




  • Antiepileptics




  • Dopamine antagonists




  • Carbon monoxide




  • Chemotherapeutics (several)




  • Levodopa




  • Levodopa




  • Copper




  • Cyclosporine




  • Amantadine





  • Cyanide




  • Antipsychotics




  • Bromocriptine





  • Heroin




  • Antiemetics




  • Carbon monoxide





  • Manganese




  • Sertraline




  • Corticosteroids





  • MPTP




  • Valproate




  • Dopamine antagonists






  • Trazodone




  • Toluene






  • Progesterone




  • Sympathomimetics






  • Kava-kava




  • Oral contraceptives







  • Lithium





Dyskinesia


Akathisia


Myoclonus





  • Antidopaminergics




  • Antidepressants




  • Anticholinergics





  • Calcium channel blockers




  • Antidopaminergics




  • Antiepileptics






  • Calcium channel blockers




  • Sedatives/hypnotics






  • Tetrabenazine




  • Bismuth






  • AMPT




  • Ethanol







  • Lead







  • Levodopa







  • Mercury







  • Tricyclic antidepressants


MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; AMPT, alpha-methyl-p-tyrosine.



Clinical Features

Clinical symptoms of anticholinergic toxicity are summarized in Table 128.14 and are secondary to antimuscarinic actions. Patients rarely have all of the associated symptoms; tachycardia and dry mucous membranes are the most commonly seen. The most severe exposures produce hyperthermia, coma, and/or seizures. Xenobiotics with antimuscarinic activity are summarized in Table 128.15. Note that ophthalmic drops are absorbed systemically and therefore can produce anticholinergic symptoms in the setting of liberal administration. Additionally, recreational drugs have been contaminated with anticholinergic adulterants on more than one occasion (e.g., heroin tainted with scopolamine).



SYMPATHOMIMETIC TOXICITY AND ACUTE EXCITED STATE

The clinical presentation of patients with a toxin-induced excited delirium and those with sympathomimetic toxicity is largely indistinguishable. The risk factors, patient characteristics, and management are largely the same as well, so they will be discussed together. Some pertinent idiosyncrasies of some of the xenobiotics will be mentioned. Table 128.16 summarizes the various agents known to cause excited delirium.









TABLE 128.6 Xenobiotics Associated witth Tremors
















































































Resting Tremor


Sustention Tremor


Kinetic Tremor




  • Hypoglycemics




  • Amiodarone




  • Amiodarone




  • Calcium channel blockers




  • Hypoglycemics




  • Hypoglycemics




  • Antidopaminergics




  • Methylxanthines




  • Sedative/hypnotics




  • Carbon disulfide




  • Carbon disulfide




  • Carbamazepine




  • Carbon monoxide




  • Carbon monoxide




  • Colistin




  • Captopril




  • Antidopaminergics




  • Lithium




  • Lithium




  • Sympathomimetics




  • Phenytoin




  • Manganese




  • MAOIs




  • Valproic acid




  • Methanol




  • TCAs





  • MPTP




  • Ethanol





  • Phenytoin




  • Sedative/hypnotics





  • Tetrabenazine




  • Phenytoin






  • Valproic acid






  • Phencyclidine






  • Corticosteroids






  • Arsenic, lead






  • Lithium






  • Levodopa


MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.


Widespread use of prescription, botanical, and recreational stimulants and hallucinogens has brought the neurotoxic effects of these substances into daily clinical conversation. There are well over 100,000 presentations to emergency departments each year in the United States related to these xenobiotics. Their neurotoxic effects are exerted through manipulation of the mechanisms carried out by the central monoamine neurotransmitters (serotonin, norepinephrine, and dopamine). This includes increased neurotransmitter release, exaggerated effects at its postsynaptic receptor, decreased neurotransmitter breakdown, and receptor agonism or antagonism, among other mechanisms. In several cases, the culprit xenobiotic’s effects are not isolated to one neurotransmitter or receptor, making their clinical manifestations less predictable and reliable.








TABLE 128.7 Medications and Toxins Associated with Ataxia































  • Antiepileptics: phenytoin, carbamazepine, oxcarbazepine, gabapentin, levetiracetam, lamotrigine, valproate sodium




  • Antineoplastic agents: cytarabine, methotrexate, 5-fluorouracil, asparaginase




  • Heavy metals: methylmercury, arsenic, lead, thallium, manganese




  • Lithium




  • Hydrocarbons: toluene, benzene, n-hexane, carbon tetrachloride




  • Sedatives/hypnotics: benzodiazepines, barbiturates, ethanol




  • Amiodarone




  • Carbon disulfide




  • Cyclosporine




  • Tacrolimus




  • Metronidazole




  • Bismuth




  • High-dose corticosteroids



Clinical Features

Clinically, these patients will present with hypervigilance, agitation, paranoia, hallucinations, stereotyping, dyskinesias, choreoathetoid movements, tachycardia, hypertension, mydriasis, and/or diaphoresis. More severe toxicity can cause delirium, combativeness, severe hyperthermia (>40°C), and seizures. Wide complex tachycardia can be seen in the setting of cocaine- (due to its sodium channel blockade) or rhabdomyolysis-induced hyperkalemia. The patient may have a depressed level of consciousness due to other co-ingested intoxicants. Diaphoresis is absent in anticholinergic toxicity, making this finding suggestive of excited delirium. However, it can be absent in sympathomimetic toxicity if the patient is volume depleted.

Jul 27, 2016 | Posted by in NEUROLOGY | Comments Off on Neurotoxicology

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