Alterations in Consciousness
The toxicological differential of xenobiotics that induce alterations in mental status or consciousness is expansive. These xenobiotics can be broadly divided into those agents that produce some form of neuroexcitation, and those that produce neuroinhibition. While some agents 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 are agents that enhance neurotransmission of EAA, or diminish inhibitory input from GABAergic neurons. The clinical presentation of the patient can 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 GABAA receptor. This hyperpolarization limits subsequent neurotransmission (see Chap. 13). 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 (see Chaps. 22 and 23).
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 patients with traumatic or idiopathic seizure disorders who have 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 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 15 minutes. True xenobiotic-induced status epilepticus is rare. Cicutoxin, the toxin in water hemlock, Cicuta maculata, is a potent inhibitor of GABAA 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. However, 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 GABAA 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 these agents are often treated in quiet environments where the stimuli to initiate hyperreflexia are minimized (see Chap. 112 and Table 18–1.)
Table 18–1. Xenobiotics That Commonly Induce Seizures |Favorite Table|Download (.pdf)
Table 18–1. Xenobiotics That Commonly Induce Seizures
|Concentration-Related||Idiosyncratic||Withdrawal Related||Tonic-Clonic Seizure-like|
|Organic phosphorous compounds|
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 48–72 hours of the last antibiotic dose. Some patients with clarithomycin-induced mania have documented recurrence on rechallenge of the antibiotic.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 agents listed in Table 18–2.
Table 18–2. Xenobiotics Commonly Inducing Mood and Neuropsychiatric Disorders |Favorite Table|Download (.pdf)
Table 18–2. Xenobiotics Commonly Inducing Mood and Neuropsychiatric Disorders
|St. John's wort|
Disorders of Movement and Tone
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, modulated by GABAergic, glutaminergic, and cholinergic neurons are involved (see Chap. 13). Chorea occurs in some cases of carbamazepine overdose, therapeutic oral contraceptive use,31 and after cocaine use when the stimulant effects have subsided.72
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 be seen with glycine antagonists such as tetanospasmin and strychnine, and in adrenergic states such as acute intoxication with CNS stimulants, or withdrawal from sedative-hypnotics.
Other centrally mediated disorders of tone include serotonin syndrome and neuroleptic malignant syndrome (NMS). Both of these potentially life-threatening syndromes consist of altered consciousness, hyperthermia, rigidity, and autonomic insufficiency. NMS may occur in patients on dopamine receptor antagonists such as antipsychotic medications, or in patients with idiopathic Parkinson disease who abruptly stop their dopaminergic therapy. Dopamine receptor agonists such as bromocriptine or restoration of antiparkinson medications are used therapeutically in these circumstances (see Chaps. 15 and 69).
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.26,84 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 which 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 administration43,44 (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.36,77
A recent review of patients who intravenously injected the illicit agent metcathinone described a Parkinson syndrome thought to be secondary to contamination with manganese from a precursor, potassium permanganate, which is used in metcathinone production. Unlike patients with idiopathicparkinsonism, 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.82 Like those with occupational manganese exposures and normal liver function, these patients did not respond to L-dopa (see Table 18–3).
Table 18–3. Xenobiotics Commonly Inducing Parkinsonism |Favorite Table|Download (.pdf)
Table 18–3. Xenobiotics Commonly Inducing Parkinsonism
|Calcium channel blockers||Cyanide|
|Dopaminergic agents (withdrawal)||Heroin|
Tremors may be observed in adrenergic states, with specific xenobiotics such as lithium, or as a result of sedative-hypnotic withdrawal. These are well reviewed elsewhere.60
The Neuromuscular Junction
Flaccid paralysis usually occurs as a result of impaired transmission at the NMJ14,15,78 or from xenobiotics causing demyelination. 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 excitation78 (see also Chap. 68).
Rarely toxins can enhance transmission at the NMJ. Latrotoxin, the toxic compound in the black widow spider (Latrodectus spp), causes enhanced release of acetylcholine at the NMJ with severe, painful muscle contractions (see Chap. 119).