24: Neurologic Principles

The central nervous system (CNS) coordinates responses to the fluctuating metabolic requirements of the body and modulates behavior, memory, and higher levels of thinking. These functions require a diversity of cells: astrocytes, neurons, ependymal cells, and vascular endothelial cells. Disruption or death of any one cell type can cause critical changes in the function or viability of another. This cellular interdependence, along with the high metabolic demands of the CNS, makes neurons especially vulnerable to injury from both endogenous neurotoxins and xenobiotics. Endogenous neurotoxins, such as the metals iron, copper, and manganese, are substances that may be critical to CNS function but are harmful when their penetration into the CNS is poorly controlled.

The understanding of the normal chemical and molecular functions of the CNS is limited at best. Interestingly, cellular mechanisms have sometimes been revealed by investigating xenobiotic-induced neuronal injuries.^38,68 For example, the pathophysiology of Parkinson disease, which affects movement and motor tone, was elucidated by the inadvertent exposure of individuals to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The mechanisms of axonal transport were elucidated by investigations of the effects of acrylamide exposures in human and animal models.⁵⁸ The neurodegenerative changes of amyotrophic lateral sclerosis have a promising xenobiotic model in β-methylamino-l-alanine (BMAA), a neurotoxin found in the cyanobacteria associated with cycad plants ingested by the Chamorro people of Guam (Chap. 14).

There are few minimally invasive methods available to investigate xenobiotic-induced CNS injury. Biomarkers are usually nonspecific and not readily available. Xenobiotic concentrations of blood and urine rarely reflect tissue concentrations of the CNS.⁶⁰ Cerebrospinal fluid (CSF) may be useful in excluding CNS injury from infection, hemorrhage and inflammatory processes, but is, with few exceptions, poorly reflective of the etiology of neuronal injuries.⁹⁰ Similarly, electroencephalograms and electromyelograms are useful in only a few types of xenobiotic exposures, and neuroimaging, while progressively evolving,⁵⁴ is a poor substitute for neuroanatomical evaluations that are usually available only on autopsy. Much of the current study to elucidate the mechanisms of CNS injury uses animal models, cultured astrocytes, and other tissue, or postmortem investigations. Less commonly, occupational evaluations, such as the enzyme activity of cholinesterases in pesticide exposed workers, are used.

This chapter reviews some basic anatomic and physiologic principles of the nervous system and the common mechanisms by which xenobiotics exploit the functional and protective components of the CNS with a few relevant examples. The multiple factors determining the clinical expression of neurotoxicity are reviewed.

Neurons

Neurons are the major pathway of cellular communication in the CNS. Having one of the highest metabolic rates in the body, these cells are especially sensitive to changes in the microenvironment and are dependent on astrocytes, choroidal epithelium, and capillary endothelium to confer protection and deliver glucose and other sources of energy.

Although each neuron is capable of receiving information through different neurotransmitters and receptor subtypes at the dendrite, neurons typically produce and release a single type of neurotransmitter at the axonal terminal. This specificity allows for cellular classification of neurons based on the neurotransmitter released, for example, serotonergic, cholinergic, and dopaminergic neurons (Chap. 14). Other substances such as adenosine may be produced and released that are less specific to the neuron type.

The anatomic structure of neurons facilitates their function. Dendrites located on the cell body are lined with receptors that bind neurotransmitters and affect cellular changes via several mechanisms. The soma, or cell body, is responsible for coordination and production of multiple proteins required to carry out normal physiological functions. This synthesis occurs at a rate several times greater than the liver or kidney. These proteins, organelles, and substrates must then be transported across long distances to the terminal axon. This energy-dependent function is supported by a cytoskeleton comprised of neurofilaments, microfilaments, microtubules, and complex transport proteins. Fast anterograde transport of membrane-bound organelles occurs through kinesin, a transport protein, at a rate of 200 to 400 mm/d. Channel proteins, synaptic vesicles, mitochondria, Na⁺-K⁺-ATPase, glycolipids, and other substances are transported by kinesin. Slow anterograde transport also occurs at a substantially slower rate (0.5–4 mm/d). The retrograde transport protein, dynein, is produced in the soma and delivered to the nerve terminal for the movement of larger vesicles and reusable proteins back to the cell body.

In the CNS, groups of neurons are organized into complex functional pathways, with a single class of neuron regulating different functions and clinical effects depending on the brain region. As an example, dopaminergic neurons regulate cravings, movement, and resting muscle tone, each of which is determined not only by dopaminergic neurons and receptor subtype, but the location in the cortex or basal ganglia (Chap. 14).

Neurons must be able to respond to changes in the local environment and alter the expression of different receptors in response to signaling from neurotrophic factors, variations in metabolic requirements, and xenobiotic interactions. This “neuroplasticity” accounts for the diversity of clinical responses to xenobiotics that induce tolerance such as ethanol (Chap. 15).

Glial Cells

Glial cells are comprised of astrocytes, oligodendrocytes, Schwann cells, and microglia. These cells serve to support the neurons both structurally and functionally.

Astrocytes comprise between 25% and 50% of the brain volume.^{1, 3, 4, 11} In addition to the anatomic contribution to the blood–brain barrier (BBB), astrocytes play a critical role in maintaining neuronal function.^1,2,93 They contribute to three major areas: homeostasis of the extraneuronal environment, provision of energy substrates, and limitation of oxidative stress. In addition, astrocytes contribute to the “plasticity” of cells and receptor expression in the CNS (see later discussion).

In order for cells of all types to function in the CNS, membrane potentials must be adequately maintained. Astrocytes contribute to this by closely regulating the extracellular pH, water, and, like brain capillaries, the extracellular potassium concentration. Metallothioneins, which control the entry of metals necessary for CNS function, are produced by astrocytes.^28,93 Astrocytes also release energy substrates such as lactate, citrate, alanine, glutathione, and α-ketoglutarate for utilization by neurons.¹¹

Astrocytes metabolize glutamate, the main excitatory amino acid (EAA) neurotransmitter in the CNS, as well as ammonia. These cells also produce superoxide dismutase and glutathione peroxidase to reduce free radical propagation. Glutathione, the major antioxidant for the brain, is predominantly located in the astrocytes. It can be released into the extracellular space or cleaved for neuronal uptake and intracellular reformulation.¹¹

Through the release of complex trophic factors, astrocytes control the expression of endothelial transporters of the BBB and the production of tight junctions in both the blood–CSF barrier and BBB. Angiogenesis is similarly astrocyte regulated, as is detection of neuronal injury, immune mediation, and neurotransmitter production. The growth of neurites, the branches of neuronal cell bodies that eventually become dendrites or axons, is similarly modulated by astrocytes.

Oligodendrocytes are a type of glial cell that provide anatomical support, protective insulation, and facilitate rapid neuronal depolarization by the production of myelin. Myelin is the primary constituent of white matter in the CNS. The production of myelin in the peripheral nervous system (PNS) is performed by the Schwann cells. Although oligodendrocytes support several axons, each Schwann cell is anatomically dedicated to a single axon.

Finally, microglial cells modulate immune response, inflammation, and tissue repair from a variety of CNS injuries. Like neurons, microglia are dependent on signaling from astrocytes.

The nervous system has multiple protective mechanisms. Xenobiotics are prevented from accessing the CNS by the blood–brain and blood–CSF barriers. For xenobiotics that enter the CNS, there are multiple cellular specializations to limit oxidant stress as reviewed below.

Blood–Brain Barrier

The BBB confers an anatomic and enzymatic barrier to xenobiotic entry into the CNS. Brain capillaries are surrounded by the foot processes of adjacent astrocytes. The potential spaces between endothelial cells are limited by tight junctions, or zonulae occludentes, which are between 50 and 100 times tighter than those found on peripheral capillaries.^{1, 2, 4, 52,63} This anatomic barrier prevents movement of substances between cells, also known as the paracellular aqueous pathway, due to osmotic and oncotic forces.^1,2,4,52,63

Transendothelial movement of critical substrates and, potentially, xenobiotics occurs through three major mechanisms: diffusion, transport proteins, and endocytosis.^1,4 These routes allow carefully controlled entry of critical substrates and cofactors while limiting the potential for injury from either endogenous or exogenous neurotoxins.

Lipophilic substances may move directly across the luminal and abluminal endothelial membranes abutting the CNS. Other substances may enter the endothelium through bidirectional transport proteins on the luminal surface. These proteins may be specific, such as the glucose transporter 1 (GLUT1) protein for uptake of glucose, or less specific large neutral amino acid transporters that move amino acids and xenobiotics, such as baclofen, intracellularly. These transporters also line the abluminal surface of the endothelial cell for movement of substrates and xenobiotics into the CNS. The third line of entry for larger proteins is via endocytosis. This can be adsorptive, or mediated through specific receptors such as those for insulin or transferrin.^{1, 3, 4, 52,63,93}

Endothelial cells have other protective properties, including intracellular enzymes, to metabolize xenobiotics and efflux proteins to transport certain xenobiotics back into the capillary lumen. These efflux proteins include energy-dependent P-glycoproteins that are ATP-binding cassette transporters and are sometimes referred to as multidrug-resistant (MDR) proteins (Chap. 9). Several hydrophobic xenobiotics are prevented from accumulating in the CNS through these transporters, including vinca alkaloids, digoxin, cyclo­sporine A, and protease inhibitors. Nonsedating antihistamines may have limited sedative properties due, in part, to efflux through P-glycoproteins.²⁵ Another type of saturable transporter, known as organic acid transport (OAT) protein, facilitates the efflux of hydrophilic xenobiotics such as valproic acid or baclofen. The expression of each of these transporters may be upregulated under certain conditions such as intermittent disruptions in the BBB from seizures. This expression upregulation is theorized to account for the resistance of anticonvulsant medications in patients with epilepsy. Comprehensive lists of xenobiotics that are substrates for these transporters are available elsewhere.^2,52,53

Blood–Cerebrospinal Fluid Barrier

The ventricles of the brain are lined by the epithelial cells of the choroid. These cells also have tight junctions but not as extensive as those of the BBB. They are, however, rich in glutathione peroxidase and other xenobiotic-metabolizing enzymes in concentrations approximating those of the liver. Similar to brain capillary cells, the choroid contains efflux transporters for organic anions and cations, as well as MDR efflux proteins (P-glycoproteins) to limit entry of xenobiotics into the CSF.^{1, 4, 52, 93}

Excitotoxicity

Neuronal function is strictly dependent on aerobic metabolism. When energy expenditure exceeds production, cellular dysfunction and ultimately cell death, or apoptosis, results. The specific cascade of molecular events relating to this process is termed excitoxicity.^10,73

The initial event is traced to an oxidant stress and excessive stimulation of N-methyl-d-aspartate (NMDA) receptors by glutamate, an EAA neurotransmitter. An influx of intracellular calcium changes membrane potentials across the cellular and mitochondrial membranes. The mitochondria become progressively more inefficient at ATP production and handling the resulting reactive oxygen species. As membrane damage is propagated, calcium further depolarizes the mitochondria, activating a permeability transition pore across the mitochondrial membrane. Gradients are further disrupted, precipitating more injury, energy failure, and ultimately cell death.

Excitotoxicity is considered a common mechanism of cell death due to xenobiotic, ischemic, traumatic, infectious, neoplastic, or neurodegenerative injury. It is the subject of study for many therapeutic interventions in CNS injury.

Determinants of Neurotoxicity

The clinical expression of neurotoxicity is related to many factors. These include the chemical properties of the xenobiotic, the dose and route of administration, xenobiotic interactions, and underlying patient characteristics including age, gender, and comorbid conditions.

Chemical Properties of Xenobiotics

One of the most important determinants of neurotoxicity is the ability of a xenobiotic to penetrate the BBB. Water-soluble molecules larger than M_r200 to 400 (molecular weight ratio, or mass of a molecule relative to the mass of an atom) are unable to bypass the tight junctions.⁴ Xenobiotics with a high octanol/water partition coefficient are more likely to passively penetrate the capillary endothelium, and potentially the BBB, whereas those with a low partition coefficient may require energy-dependent facilitated transport.⁶³ Xenobiotics that are substrates for capillary endothelial efflux mechanisms will have limited penetration regardless of the coefficient.^{1, 4, 52, 63}

Route of Administration

The route of xenobiotic administration may also be consequential. Although most xenobiotics gain access to the nervous system through the circulatory system, aerosolized solvent and heavy metals in industrial and occupational exposures gain CNS access through inhalation, traveling via olfactory and circulatory routes. Alternatively, some substances may move from the PNS via retrograde axonal transport to the CNS. Naturally occurring proteins such as tetanospasmin, as well as rabies, polio, and herpes virus may use this mechanism to access the PNS and CNS.^13,16,47 The toxalbumins ricin and abrin as well as bismuth salts may also use this mechanism to a limited extent.^85,91 This understanding may prove beneficial from a therapeutic perspective. For example, in one small experimental series of patients experiencing severe pain, doxorubicin was injected into the involved peripheral nerves. Therapeutically, a chemical ganglionectomy occurred through retrograde “suicide” transport of doxorubicin, which provided substantial relief for these patients.⁵⁰

Some xenobiotics may be delivered directly into the CSF (intrathecally), the consequences of which are variable (Special Considerations: SC3).

Xenobiotic Interactions

Coadministration of xenobiotics may precipitate neurotoxicity by several mechanisms.⁴⁵ Extraaxially (outside of the CNS), xenobiotic interactions that result in an increase of the blood concentration of one or both may overwhelm the protective mechanisms of the BBB.²⁰ Similar effects may occur in the PNS where elevated blood concentrations may enhance clinical effects resulting in peripheral neuropathies.⁹³

Xenobiotic interactions can be synergistic, acting on the same neuroreceptor. Benzodiazepines and ethanol, for example, both stimulate the γ-aminobutyric acid type A (GABA_A) receptor. The excessive neuroinhibition can result in deep coma and even respiratory depression when these xenobiotics are administered simultaneously.

In some circumstances, xenobiotic interactions result in excessive neurotransmitter availability.⁹ This neurotransmitter excess is demonstrated in patients with the serotonin toxicity, which results from the coadministration of a monoamine oxidase inhibitor and a serotonin reuptake inhibitor or other serotonergics as an example (Chap. 75).

Access to the CNS may be altered by one of the xenobiotics, allowing the other to bypass the BBB. For example, mannitol causes transient opening of the BBB; as a result, therapeutic use of mannitol is under investigation for the delivery of chemotherapeutics that might otherwise be unable to access the nervous system.⁵³ Similarly, some xenobiotics, such as verapamil, cyclosporine, and probenecid, are blockers of capillary endothelium efflux.^4,93 These theoretically limit efflux of other substrates of P-glycoprotein or OAT. The clinical utility of employing such efflux blockers is under investigation as was done in a study in which primates received intrathecal methotrexate. The CSF clearance of methotrexate was reduced in animals administered intrathecal probenecid.^12,76

Patient Characteristics

Patient-specific variables may affect the ability of a xenobiotic to penetrate the BBB and/or the clinical effects of a given exposure. For example, age of the patient at the time of exposure is critical, especially in the fetus and neonates.⁷⁸ The structural and enzymatic development of the BBB is incomplete, and synaptogenesis, or formation of intercellular relationships, is especially sensitive to impaired protein synthesis or other excitotoxic events. This is demonstrated classically by maternal exposure to methylmercury. The mother may be minimally affected, but the developing fetus suffers profound neurological and developmental consequences (Chaps. 31 and 98).

In neonates, immature liver function may lead to the accumulation of circulating bilirubin. Due to incomplete formation of the BBB, the bilirubin may access the CNS and produce a form of encephalopathy known as kernicterus.

Elderly patients may also have increased susceptibility to neurotoxins as a result of relatively impaired circulation or age-related changes in mitochondrial function that predispose to excitotoxicity.⁸¹ Xenobiotic-induced parkinsonism, or the unmasking of subclinical idiopathic Parkinson disease, may occur more readily than in younger patients. Animal models also suggest age-related sensitivity with one study noting increased manganese toxicity with advanced age.³⁶

Gender may be contributory to the expression of xenobiotic-induced neurological injury. In animal models, the presence of estrogen-related and progesterone-related compounds may be neuroprotective for some xenobiotic injuries.^64,71 In humans, women are more susceptible to some movement disorders such as xenobiotic-induced parkinsonism and tardive dyskinesia, whereas dystonias and bruxism are more prevalent in young men.⁷⁴ The etiologies of these gender-related differences are incompletely understood.

Neurologic Comorbidities

Conditions affecting the integrity of the BBB can affect CNS penetration of xenobiotics and endogenous neurotoxins. For example, glutamate concentrations are normally higher in the circulatory system than the CNS.⁵⁷ Patients with trauma, ischemia, or lupus vasculitis³ may experience neuropsychiatric disorders as a result of increased penetration of glutamate or sensitivity to additional xenobiotics. Similarly, inflammation associated with meningitis and encephalitis causes openings in the BBB, which may be exploited therapeutically. Intravenous penicillin achieves a higher CSF concentration in animals with meningitis than in those without meningitis.⁷⁷

In some patients, previously undiagnosed diseases become evident on exposure to xenobiotics. This is especially true in patients with peripheral neuropathies. For example, patients being treated with therapeutic doses of vincristine suffered a severe polyneuropathy due to unmasking of a previously undiagnosed Charcot-Marie-Tooth disease.^9,22 Similarly, patients with diabetes mellitus, the commonest cause of peripheral neuropathy, or human immunodeficiency virus disease may have exacerbation of symptoms in the presence of antiretrovirals.^24,72 Patients with myasthenia gravis may have exacerbation of weakness with aminoglycoside administration, which can affect transmission at the neuromuscular junction (NMJ).⁹²

Chronic exposures to some neuroinhibitory xenobiotics such as ethanol may alter neuronal receptor expression and upregulate or increase the amount of receptors for EAAs. In addition to receptor augmentation, neurotransmitter concentrations of the excitatory neurotransmitters glutamate and aspartate are increased, as is homocysteine. These changes induce a tolerance to neuroinhibitory xenobiotics acting on the same receptor, and patients require escalating doses to achieve the same clinical effect. In such patients, cessation of ethanol intake results in a relative deficiency of exogenous inhibitory tone. The patient experiences neuroexcitability and the clinical syndrome of withdrawal^17,18 (Chap. 15).

Adequate nutritional status is important for the maintenance of normal neurological function. The BBB may not be adequately maintained in patients with malnutrition. Deficiencies of metal cofactors such as manganese, copper, zinc, and iron can affect neurological function. In some cases, the deficiencies enhance absorption of other xenobiotics. For example, iron deficiency enhances lead and manganese absorption in the gastrointestinal tract, which can ultimately overwhelm neuroprotective mechanisms. Vitamins serve as enzymatic cofactors in modulating the production of glutamate, homocysteine, and other amino acids. Specific vitamin deficiencies can precipitate neurological syndromes such as Wernicke encephalopathy in thiamine-depleted patients (Antidotes in Depth: A24 and Chap. 47). The toxicity of xenobiotics may also be enhanced. For example, a relative pyridoxine deficiency in patients with acute isoniazid overdose may result in seizures as a result of a relative excess of EAAs (Antidotes in Depth: A14 and Chap. 58). Glucose is a critical energy substrate that can cause profound neurological impairment when delivery is inadequate (Antidotes in Depth: A12 and Chap. 53).

Interestingly, certain conditions such as temperature may affect the toxicity of xenobiotics. For example, cooling may limit the impedance of acetylcholine neurotransmission caused by botulinum toxin.⁴¹

Extraaxial Organ Dysfunction

Kidney failure may impair metabolism or elimination of xenobiotics or endogenous neurotoxins such as urea, rendering it more available to the CNS. Hyperglycemia in patients with diabetes mellitus may also increase formation of CNS reactive oxygen species. Similarly, patients with liver failure may have elevations in CNS manganese resulting in Parkinsonism.^51,79

Hepatic encephalopathy illustrates the concept of excitotoxicity from endogenous neurotoxins. Hyperammonemia increases oxidative stress and free radical formation in astrocytes. Ammonia potentially decreases critical metabolic enzymes such as catalases, superoxide dismutase, and glutathione peroxidase. Nitric oxide (NO) production is increased due to elevations in NO synthetase. Under these conditions, astrocytes upregulate the expression of the peripheral benzodiazepine receptor (PBR) on the outer mitochondrial membrane. The PBR modulates the production of neurosteroids and, in turn, the GABA_A receptor. Continued CNS exposure to ammonia and other endogenous solutes propagates this oxidative and nitrosative stress to the mitochondrial membrane, potentially opening the mitochondrial permeability transition pore. Osmotic swelling of the mitochondrial membrane followed by excitotoxicity results in cerebral edema and hepatic encephalopathy.^{64, 65, and 66}

Alteration of Endogenous Neurotransmission

Xenobiotics can induce neurotoxicity by triggering changes in neurotransmission in either the CNS or PNS. In some cases xenobiotics enhance neurotransmission through a specific receptor subtype. This enhanced transmission can occur through inhibition of presynaptic metabolism (monoamine oxidase inhibitors), stimulation of neurotransmitter release (amphetamines), impairment of neurotransmitter reuptake (cocaine), or inhibition of synaptic degradation (acetylcholinesterase inhibitors).

Alternatively, synaptic neurotransmission may be impaired.⁸⁰ Xenobiotics may inhibit the presynaptic release of neurotransmitters (botulinum toxin), block receptors (antimuscarinics), or alter membrane potentials at the postsynaptic membrane (tetrodotoxin).^32,33 Patients may present with a clinical syndrome of toxicity associated with altered neurotransmission of the specific receptor (Chap. 3).

Direct Receptor Interaction

Some xenobiotics are able to directly stimulate receptors. Both kainate and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) aresubclasses of the glutamate receptor, which are targeted by some naturally occurring xenobiotics.⁴² An example is β-N-oxalylamino-l-alanine (BOAA) found in the grass pea, Lathyrus sativus. BOAA stimulates the AMPA receptor and inhibits specific mitochondrial enzymes resulting in the spastic paraparesis of lathyrism.⁶⁹ Domoic acid stimulates the kainate receptor and causes the neuroexcitation associated with neurotoxic shellfish poisoning (Chap. 44).

Direct inhibition is also possible, as exemplified by phencyclidine, an NMDA receptor antagonist.

Enzyme and Transporter Exploitation

The classic example of xenobiotics that exploit endogenous enzymes and or transporters is MPTP.³⁸ Once MPTP crosses the BBB, it is converted by monoamine oxidase to the neurotoxic compound 1-methyl-4-phenylpyridine (MPP⁺) in astrocytes. MPP⁺ is taken up by dopamine transporters into the neurons of the substantia nigra pars compacta. MPP⁺ inhibits complex I of the mitochondrial electron transport chain resulting in dopaminergic excitotoxicity and the clinical syndrome similar to Parkinson disease (Disorders of Movement and Tone, below, and Chap. 38).

Altered Conduction along Membranes:Demyelinating Neurotoxins

Aside from xenobiotics that affect neurotransmission at the postsynaptic membrane, some affect the production or maintenance of myelin by oligodendrocytes and Schwann cells.^{23, 34, 37, 48} In the CNS these are often associated with white matter abnormalities and a leukoencephalopathy.³⁴ Xenobiotics such as hexachlorophene, arsenic, inhibitors of tumor necrosis factor α, neural tissue–derived rabies vaccine, and the act of “chasing the dragon” or inhaling volatilized heroin are associated with a demyelinating neurotoxicity.²³ In the PNS, nitrous oxide, suramin, and tacrolimus are associated with peripheral demyelination.⁴⁶

Inhibition of Intracellular Functions

Some xenobiotics are nonspecific inhibitors of cellular function.²⁹ For example, the neurotoxicity of carbon monoxide (CO) or cyanide that may appear as a diffuse impairment of neuropsychiatric dysfunction or, depending on the dose and specific vulnerabilities of an exposed patient, be more focal. Patients surviving acute CO exposure may experience delayed neurological sequelae that may include a diffuse impairment of neuropsychiatric function, or more focally, present with a xenobiotic-induced Parkinson syndrome (see later and Chap. 125).

Antineoplastics can affect the production of critical proteins required for cellular maintenance. These can be very specific such as the ability of vincristine to impair cytoskeletal transport in the peripheral nervous system (Chap. 36).

Alterations in Consciousness

The toxicological differential diagnosis of xenobiotics that induce alterations in mental status or consciousness is expansive. These xenobiotics can be broadly divided into those that produce some form of neuroexcitation and those that produce neuroinhibition. Although some xenobiotics such as phencyclidine have elements of both depending on dose, this categorization facilitates a general clinical understanding of neurotoxic alterations in mental status.

Xenobiotics resulting in neuroexcitation enhance neurotransmission of EAAs, or diminish inhibitory input from GABAergic neurons. The clinical presentation of the patient may vary; some patients may be alert and confused, or suffering from an agitated delirium, hallucinations, or a seizure.

Neuroinhibitory xenobiotics typically enhance GABA-mediated neurotransmission. These patients may be somnolent or in deep coma. Benzodiazepines hyperpolarize cells by increasing inward movement of Cl^– ions through the chloride channel of the GABA_A receptor. This hyperpolarization limits subsequent neurotransmission (Chap. 14). Less commonly, neuroinhibition is a result of diminution of EAA. Patients presenting the day after binging on cocaine may be sleepy but arousable and oriented in what is termed cocaine “washout,” theoretically related to depletion of EAA and dopamine. Xenobiotics that cause diffuse cortical dysfunction through impairment in the delivery or utilization of oxygen or glucose can also present with depressed or altered consciousness.

Clinical evaluation of patients with altered consciousness includes obtaining complete history, including medications, comorbid conditions, occupation, and suicidal intent when relevant or available. Patients should have a complete physical examination, with particular attention paid to vital sign abnormalities or findings that may indicate a toxic syndrome. Assessment and correction of hypoxia or hypoglycemia should be performed. An electrocardiogram may be useful in some circumstances (Chap. 16).

Xenobiotic-Induced Seizures

Seizures are the most extreme form of neuroexcitation. As with alterations of consciousness, this may be due to enhanced EAA neurotransmission(domoic acid, sympathomimetics) or inhibition of GABAergic tone (isoniazid). Unlike in traumatic or idiopathic seizure disorders with an identifiable seizure focus, the initiation and propagation of xenobiotic-induced seizures is diffuse. It is for this reason that most non–sedative–hypnotic anticonvulsants such as phenytoin are unlikely to be effective in terminating xenobiotic-induced seizures.

Seizures may be idiopathic as described with tramadol and bupropion, or they may be concentration-dependent events as described with theophylline and isoniazid toxicity. Alternatively, seizures may be a result of withdrawal from GABAergic substances.

Status epilepticus is variably defined but involves two or more seizures without a lucid interval, or continuous seizure activity for greater than 5 minutes.⁵⁹ True xenobiotic-induced status epilepticus is rare. Cicutoxin, the toxin in water hemlock, Cicuta maculata, is a potent inhibitor of GABA_A neurotransmission and may cause status epilepticus.

Theophylline toxicity precipitates seizures and status epilepticus through a different mechanism. Normally, endogenous termination of seizures is mediated through presynaptic release of adenosine during the release of the primary neurotransmitter at the terminal axon. Adenosine functions as a feedback inhibitor of the presynaptic neuron, disrupting propagation of excitatory neurotransmission. Theophylline is an adenosine antagonist. Adenosine administration is not a useful therapy for theophylline-induced seizures as adenosine is unable to cross the BBB. Generally high-dose sedative–hypnotics, affecting GABA_A receptors, are required for seizure control.

Some clinical conditions appear to be centrally mediated tonic–clonic movements but are due to glycine inhibition in the spinal cord. Glycine is the major inhibitory neurotransmitter of motor neurons of the spinal cord. Under normal conditions, glycine contributes to termination of reflex arcs. Glycine inhibition results in myoclonus, hyperreflexia, and opisthotonos, often without alteration in consciousness. Presynaptic glycine release inhibition is caused by tetanospasmin, the major neurotoxin from Clostridium tetani. Postsynaptic glycine inhibition is caused by strychnine, the toxin in Strychnos nux-vomica. Patients with exposures to tetanospasmin or strychnine are often treated in quiet environments where the stimuli to initiate hyperreflexia are minimized (Chap. 117 and Table 24–1).

Xenobiotic-Induced Mood Disorders

Certain xenobiotics are inconsistently associated with alterations in mood.^5,19 What predisposes individuals to xenobiotic-induced mood alterations is unclear. In some circumstances, patients with previously undiagnosed bipolar disorder are given a xenobiotic that unmasks their disease. Interestingly antibiotic-induced mania is found in some patients without a previous psychiatric history. The symptoms of mania are usually evident within the first week of therapy and, unlike the mania of purely psychiatric origin, readily abate within 48 to 72 hours of the last antibiotic dose. Some patients with clarithromycin-induced mania have documented recurrence on rechallenge.⁵ In general, xenobiotic-induced manias are idiopathic and very rare. More common are either psychosis from chronic CNS stimulant use or depression from ethanol or the xenobiotics listed in Table 24–2.

Disorders of Movement and Tone

Central Nervous System–Mediated Disorders.

Most movement disorders, including akathisia, bradykinesia, tics, chorea, and dystonias, are mediated by the complex dopaminergic pathways of the basal ganglia. Different dopamine receptor subtypes are modulated by serotonergic, GABAergic, glutaminergic, and cholinergic neurons (Chap. 14).

Chorea occurs in some cases of carbamazepine overdose, therapeutic oral contraceptive use,³¹ and after cocaine use when the stimulant effects have subsided.⁷⁴

Dopamine receptor antagonists can precipitate acute dystonic reactions. The D₂ receptor antagonists, in conjunction with alterations in muscarinic cholinergic tone, are usually implicated. Animal models suggest possible mediation through σ receptors, the craniofacial distribution of which corresponds to the common clinical manifestations of acute dystonias.⁴⁹

Diffusely increased motor tone may occur with glycine antagonists such as tetanospasmin and strychnine, and in adrenergic states such as acute toxicity with CNS stimulants, or withdrawal from sedative-hypnotics. The rare complication of bone fractures associated with severe muscle spasm and myoclonus is reported with chronic bismuth toxicity and inadvertent intrathecal administration of hyperosmolar contrast dye (Chap. 90 and Special Considerations: SC3).

Other centrally mediated disorders of tone include serotonin toxicity and neuroleptic malignant syndrome (NMS). Both of these potentially life-threatening disorders consist of altered consciousness, hyperthermia, rigidity, and autonomic instability. NMS may occur in patients taking dopamine receptor antagonists such as antipsychotics or in those with idiopathic Parkinson disease who abruptly stop their dopamine agonist therapy. Dopamine receptor agonists such as bromocriptine or restoration of antiparkinson medications are used therapeutically in these circumstances (Chap. 70). The diagnosis and management of serotonin toxicity is reviewed in Chap. 75.

Parkinsonism.

Xenobiotic-induced parkinsonism is a syndrome of unstable posture, rigidity, gait disturbance, loss of facial expression, hypokinesis, and variable presence of tremor.⁷ The common neuroanatomic target involves the dopaminergic neurons of the basal ganglia, specifically the substantia nigra.^26,86 In some circumstances, the toxicity is transient and the mechanism inadequately understood.

Some xenobiotics such as carbon monoxide and heroin produce tissue hypoxia and ischemia in the basal ganglia that occasionally results in xenobiotic-induced Parkinson syndrome.

Other xenobiotics such as MPTP, carbon disulfide, manganese, and the endogenous neurotoxin copper in patients with Wilson disease produce predictable mitochondrial impairment of the basal ganglia neurons. Viscose rayon workers exposed to carbon disulfide may present with a Parkinson syndrome refractory to l-dopa administration^43,44 (see Enzyme and Transporter Exploitation earlier).

Manganese is a critical substrate for production and metabolism of several neurotransmitters including glutamate. Excessive manganese interferes with normal uptake of glutamate and is critical to the function of superoxide dismutase and glutamine synthetase.^30,35 In patients with liver failure who accumulate manganese from occupational exposure, reversal or treatment of liver disease may result in resolution of parkinsonism.^36,79

A recent review of patients who intravenously injected the illicit methcathinone described a Parkinson syndrome thought to be secondary to contamination with manganese from a precursor, potassium permanganate, which is used in methcathinone production. Unlike patients with idiopathic parkinsonism, these patients did not suffer from a resting tremor, and they had a specific gait abnormality in which they walked on the balls of their feet.⁸⁴ Like those with occupational manganese exposures and normal liver function, these patients did not respond to l-dopa(Table 24–3).

Tremors.

Tremors may be observed with adrenergic excess, with specific xenobiotics such as lithium, or as a result of sedative–hypnotic withdrawal. These are well reviewed elsewhere.⁶²

The Neuromuscular Junction.

Flaccid paralysis usually occurs as a result of impaired transmission at the NMJ^14,15,80 or from xenobiotics causing demyelination.⁵⁵ Mechanisms of NMJ transmission impairment include impeded propagation of the action potential on the terminal neuron, impaired release of acetylcholine, depression of motor end-plate potential with failure of depolarization, and impedance of myofibril excitation^55,80 (Chap. 69).

Rarely xenobiotics can enhance transmission at the NMJ. Latrotoxin, the toxic compound in the black widow spider (Latrodectus spp) venom causes enhanced release of acetylcholine at the NMJ with severe, painful muscle contractions. Some types of scorpion venom act similarly (Chap. 118).

Cranial Nerves

Xenobiotics are a relatively rare cause of cranial nerve impairment. Some neuropathies are a result of direct delivery of the xenobiotic to the affected cranial nerve. For example, some patients may have optic nerve impairment from intraorbital installation of silicone oil⁶ or inadvertent deep space injection of a local anesthetic during dental anesthesia with a resultant abducens palsy.⁶¹ In some cases, a xenobiotic, methanol is converted into a toxic substance such as formic acid in the retina.

The neuromuscular junction of the cranial nerves is sensitive to disruptions in neurotransmission. When xenobiotics affect the occulomotor nerves (cranial nerves (CN) III, IV, VI), patients may describe diplopia or have gaze palsies on examination. Botulinum toxin, diethylene glycol toxicity, elapid snake venom, and the cranial neuropathy associated with the organic phosphorus insecticide-induced intermediate syndrome are some examples.

Absence of critical substrates such as glucose or thiamine can resultin ophthalmoplegia. In most cases, however, the mechanisms underlying the cranial neuropathy are poorly understood, such as is the casewith antineoplastics. Similarly, some patients who survive ethylene glycol poisoning experience transient ophthalmoplegia days after the initial exposure^56,83 (Table 24–4 and Chap. 25).

Peripheral Nerves

Complaints of pain, paresthesias, numbness, or weakness of extremities are clinically termed neuropathies. The mechanisms of evolution are variable. Common to most xenobiotic-induced neuropathies is early symmetrical involvement of the lower extremities. This may be due in part to the patient’s rapid recognition of impairment during an attempt to ambulate. Additionally, the axons serving the lower extremities are longer. Maintenance and transportation of substrates is more energy dependent and sensitive to xenobiotic-induced disruptions.

In some cases, the anatomic structure of the nerve is maintained, but the xenobiotic affects neurotransmission. This may be due to direct impairment of specific enzymes at the NMJ, such as cholinesterase inhibitors.²⁷ Tri-ortho-cresyl phosphate (TOCP) is an inhibitor of neuropathic target esterase. Contamination of food and the beverage Ginger Jake with TOCP resulted in irreversible lower extremity paralysis in several epidemic exposures.^70,88 Indirectly, the extracellular environment may be altered as in the case of hypermagnesemia, or hypokalemia which can be induced by multiple xenobiotics (Chap. 19). Ciguatoxin, a sodium channel opener, affects neurotransmission, causing paresthesias and the unusual symptom of temperature reversal in which the perception of temperature is opposite to the stimulus.

Xenobiotics such as amiodarone and tacrolimus induce peripheral demyelination. Patients present with weakness and flaccidity. Nitrous oxide impairs the production of S-adenosyl methionine essential to the production of myelin and is additive to the nitrous oxide disruptions of vitamin B₁₂, which further impair axonal function.⁸⁹

Other xenobiotics affect the structure or intracellular function of the peripheral nerves. Those that induce death of the cell body are termed neuronopathies, and they may be clinically indistinguishable from those that affect the axon, or axonopathies.

Peripheral nerve cell death is usually linked to injury at the spinal cord as was described above by the doxorubicin injection of the peripheral nerves.⁵⁰ Pyridoxine overdose is another cause of neuronopathy. However, neuronopathies are an unusual mechanism of peripheral nerve toxicity.

Unlike neuronopathies, axonopathies are potentially reversible and are the most common mechanism of xenobiotic-induced peripheral neuropathy. Xenobiotic-induced axonal injuries to the peripheral nerves are usually diffuse and bilateral, with preservation of the proximal cell body. These often target the cytoskeleton and impair the capacity for the microtubule system to deliver functional substrates.^21,40 Patients with occupational exposure to 2,5-hexanedione, a diketone metabolite of n-hexane present in certain glues, suffer from a sensorimotor axonopathy due to cross-linking of neurofilaments and impaired substrate transport.⁶⁷ Progressive neuropathy may occur long after the initial exposure. Vincristine similarly affects axonal transport. Acrylamide impairs fast anterograde and retrograde transport in animal models, suggesting effects on both kinesin and dynein.

Nucleoside reverse transcriptase inhibitors cause peripheral neuropathy by decreasing the production of mitochondrial DNA.

Myopathies

Some patients experience local muscle damage as a result of direct injury from extravasation of tissue toxic substances or enzymatic degradation associated with crotalid snake envenomations.

Most xenobiotic-induced muscle injuries or myopathies are morediffuse.^{39, 75, 82, 87}3-Hydroxy-3-methylglutaryl–coenzyme A (HMG Co-A)reductase inhibitors can cause myalgias, cramping, myositis, or rhabdomyolysis. The incidence appears to be higher in patients taking other medications that share the same liver metabolic enzymes. The mechanism underlying the myopathy may be related to impaired cholesterol synthesis in myocytes or diminished production of regulatory proteins such as ubiquinone and GTP-binding proteins required for mitochondrial function.

Another myopathy that presents predominantly with weakness is the acute quadriplegic myopathy of intensive care patients. This syndrome was originally described in ventilated patients with asthma who received glucocorticoids and nondepolarizing neuromuscular blockers, but is also reported in other critically ill patients⁸ (Chap. 69). The mechanisms underlying quadriplegic myopathy, eosinophilia myalgia syndrome, and toxic oil syndrome are poorly described. Xenobiotics associated with muscle injury can be found in Table 24–5.

• With improved understanding of these neurotoxic principles, therapeutic medications can be better delivered to the CNS while limiting the entry of potentially toxic xenobiotics.

• Toxicological models for the investigation of neurodegenerative disorders can be further developed as can new and creative therapies for mood disorders, hepatic encephalopathy, and injuries from infections, trauma, and ischemia.

• Elucidation of neurotoxicologic principles shows promise for the treatment of many nervous system disorders.

• The chemical properties of the xenobiotic and the characteristics of the patient exposed are critical to the clinical expression of neurotoxicity.

Acknowledgment

E. John Gallagher, MD, contributed to this chapter in previous editions.

References