(Video 59.1).

d.  Treatment.

(1)  Activated charcoal. 1 g/kg by mouth if the patient is awake and is not at risk of aspiration and if ingestion is within 1 hour.

(2)  Benzodiazepines. Repeated IV doses for agitation, tachycardia, and hypertension.

(3)  Cyproheptadine, an antihistamine and 5-HT2a antagonist, can be given orally, 12 mg as first dose, then 8 mg every 6 hours. Some atypical antipsychotics (olanzapine) may also be beneficial secondary to 5-HT2a antagonism and parenteral administration. Avoid when possibility of neuroleptic malignant syndrome (NMS) exists.

(4)  Supportive care. IV hydration and serial measurement of CK for rhabdomyolysis.

4.  Hallucinogens.

a.  Sources. Anticholinergic agents: see Section A.1.a under Central Nervous System. Illicit drugs: lysergic acid diethylamide, mescaline, PCP, ketamine, synthetic cannabinoids, phenethylamines (e.g., 25-I-NBOMe). Plants: morning glory, nutmeg, salvia. Mushrooms: Amanita muscaria, psilocybin mushrooms. Animals: bufotoxin from Bufo family of toads.

b.  Systemic signs. Tachycardia, hypertension, diaphoresis, mydriasis.

c.  Neurologic manifestations. Visual hallucinations, increased motor activity, hyperreflexia.

d.  Treatment.

(1)  Activated charcoal. 1 g/kg by mouth if the patient is awake and is not at risk of aspiration and if ingestion is within 1 hour.

(2)  Benzodiazepines. Repeat IV doses as needed for agitation.

(3)  Butyrophenones (haloperidol or droperidol) in addition to benzodiazepines for patients with severe agitation and acute psychosis.

(4)  IV hydration and serial measurement of CK for rhabdomyolysis.

5.  GABA-agonist withdrawal syndromes result in a hyperadrenergic state with symptoms similar to those of sympathomimetic syndrome.

a.  Benzodiazepines, barbiturates, and ethanol can cause a life-threatening withdrawal syndrome characterized by a hyperadrenergic state (tachycardia, hypertension, diaphoresis, piloerection, fever), nausea, vomiting, diarrhea, altered mental status, hallucinations, and seizures. Management of acute symptoms involves repeated IV doses of benzodiazepines (high doses at times) followed by scheduled oral benzodiazepines for prevention.

b.  Baclofen can cause a life-threatening withdrawal syndrome characterized by disorientation, hallucinations, fever, rebound spasticity, seizures, and coma. Treatment involves reinstituting oral or intrathecal baclofen and benzodiazepines.

c.  f–Hydroxybutyrate (GHB). Abrupt discontinuance of chronically abused GHB compounds results in a withdrawal syndrome similar to benzodiazepine and ethanol withdrawal. Treatment is with IV or oral benzodiazepines and supportive care.

6.  Wernicke encephalopathy.

a.  At-risk populations are persons with chronic alcoholism or patients with other thiamine deficiency states (e.g., hyperemesis gravidarum, anorexia nervosa, malignant tumor of the GI tract, pyloric stenosis, inappropriate parenteral nutrition, and in patients with gastric bypass surgery as early as 4 to 12 weeks postoperatively).

b.  Symptoms. Characterized by altered mental status (global confusional state), ataxia, and ophthalmoplegia. Although classically diagnosed with the triad of mental confusion (66% of patients), staggering gait (51% of patients), and ocular abnormalities (40% of patients), Wernicke encephalopathy can occur in the absence of some or all of the symptoms.

c.  Diagnosis. By clinical features and improvement with treatment. Laboratory assessments of thiamine deficiency include erythrocyte thiamine transketolase, the blood thiamine concentration, or urinary thiamine excretion (with or without a 5-mg thiamine load). Abnormal MRI findings are hyperintense signals in the dorsal medial thalamic nuclei, periaqueductal gray area, and the third and fourth ventricle. Mammillary bodies enhance acutely and demonstrate atrophy chronically. MRI has a sensitivity of 53% and a specificity of 93% for the diagnosis of Wernicke encephalopathy. Treatment should be primarily based on clinical suspicion.

d.  Treatment. IV thiamine (100 mg) and magnesium (2 g) followed by daily thiamine and multivitamin supplementation. Daily thiamine doses should be 50 to 100 mg for 7 to 14 days, then 10 mg/day until full recovery is achieved, followed by at least 1 to 2 mg/day.

e.  Prognosis is favorable for most patients, but residual neurologic effects, including Korsakoff psychosis, memory loss, ataxia, nystagmus, and neuropathy, may persist.

B.  Subacute encephalopathy.

1.  Bismuth. Long-term use of bismuth salts for ostomy odor or in the management of peptic ulcer disease can manifest as subacute progressive encephalopathy.

a.  Symptoms. Patients have symptoms of progressive dementia and delirium, ataxia, severe myoclonus, and in rare instances, seizures. Symptoms may not occur until after weeks or years of continued use. Other symptoms include dark stools and dark staining of the gums. This syndrome can be mistaken for Creutzfeldt–Jakob disease, Alzheimer’s dementia, or other progressive forms of encephalopathy and can be fatal if not diagnosed.

b.  Diagnosis. In acute encephalopathy, the bismuth blood level is typically between 150 and 2,000 mg/100 mL instead of the normal 10 to 30 mg/100 mL. Head computed tomography (CT) may show increased attenuation in the basal ganglia and cerebral cortex.

c.  Treatment. Stop the drug and provide supportive care. The syndrome usually regresses in 3 to 12 weeks after cessation of bismuth.

2.  Lithium. Chronic use or acute overdose of lithium salts can manifest as progressive encephalopathy. Impaired excretion (e.g., dehydration-induced renal insufficiency) and excessive intake of lithium are the usual causes of lithium intoxication.

a.  Symptoms. Patients come to medical attention with tremor, altered mental status, ataxia, myoclonus, and in rare instances, seizures. Other symptoms include nausea, vomiting, diabetes insipidus, hypothyroidism, mutism, and renal failure.

b.  Diagnosis. An elevated serum lithium level supports the diagnosis. Therapeutic levels of lithium range from 0.6 to 1.2 mEq/L. Toxic effects of lithium are generally related to serum levels, with mild to moderate severity seen with levels of 1.5 to 2.5 mEq/L, serious toxicity with levels of 2.5 to 3.0 mEq/L, and life-threatening toxicity with levels 3.0 to 4.0 mEq/L.

c.  Treatment. Patients with severe symptoms require urgent hemodialysis (impaired kidney function and a level >4.0 mEq/L or if demonstrating impaired consciousness, seizure, or life-threatening dysrhythmia). Dialysis clears extracellular lithium but the intracellular lithium may cause a rebound in the serum lithium concentrations after dialysis. IV saline should be given to rehydrate and avoid hyponatremia (excretion of sodium and lithium are related).

3.  Carbon monoxide (CO). Patients with recent history of CO poisoning may have a syndrome known as delayed neurologic sequelae, occurring 2 to 40 days after exposure and recovery. The incidence of delayed neurologic sequelae increases with the duration of unconsciousness and age greater than 30.

a.  Symptoms. Manifested as altered mental status, personality changes, and memory loss. Patients may also have ataxia, seizures, urinary and fecal incontinence, parkinsonism, mutism, cortical blindness, and gait and motor disturbances. Physical examination findings may include hyperreflexia, frontal lobe release signs (glabellar reflex, palmar grasp), masked facies, and other parkinsonian features.

b.  Diagnosis. Neuropsychometric testing displays cognitive dysfunction. MRI findings may include bilateral globus pallidus infarcts (because of the acute hypoxia) and diffuse demyelination of subcortical white matter [because of delayed post-hypoxic leukoencephalopathy (DPHL)]. DPHL can also occur after exposure to other toxins that cause hypoxia (e.g., opioids).

c.  Treatment. Supportive care. It is unclear whether treatment of acute CO poisoning influences the risk of delayed neurologic sequelae. The majority of patients will show some recovery.

4.  Aluminum. Long-term use of aluminum phosphate binders, aluminum-contaminated dialysates, or medications containing aluminum (e.g., sucralfate) in the care of patients with renal failure can result in progressive encephalopathy. Patients come to medical attention with agitation, speech disorder, confusion, myoclonus, coma, and/or seizures. Aluminum exposure is also associated with osteomalacia and microcytic hypochromic anemia. Diagnosis is made by elevated aluminum level but if within normal limits and diagnosis is still suspected, bone biopsy may confirm the diagnosis. Treatment involves removal of sources of aluminum and for some patients chelation with deferoxamine.

5.  NMS. Subacute encephalopathy associated with hyperthermia, rigidity with elevated CK, and autonomic instability in the setting of neuroleptic administration. Treatment is supportive care with external cooling and benzodiazepines as necessary. Consideration can also be given to bromocriptine and/or dantrolene for antidotal therapy. Care must be taken to differentiate NMS from serotonin syndrome (see Section A.3 under Central Nervous System) as bromocriptine may worsen serotonin syndrome.

C.  Coma and CNS depression. Many toxins causing CNS depression and coma can mimic brain death, including loss of brainstem reflexes. Many of these toxins have long half-lives, so clinical criteria of brain death do not apply.

1.  Sedative hypnotics.

a.  Sources. Ethanol, benzodiazepines, barbiturates, central-acting muscle relaxants, chloral hydrate, buspirone, zolpidem, baclofen, clonidine, antihistamines, and numerous antidepressants and antipsychotics.

b.  Systemic signs. Pressure sores, arterial hypotension, bradycardia, hypothermia.

c.  Neurologic manifestations. Somnolence, coma, areflexia, nystagmus, amnesia. Coma from baclofen poisoning can be prolonged and profound with physical exam findings that can mimic brain death.

d.  Treatment. Supportive care, activated charcoal 1 g/kg by mouth if the patient is awake and is not at risk of aspiration and if ingestion is within 1 hour. The use of flumazenil, a benzodiazepine antagonist, is generally not recommended because of increased risk of seizures in habituated patients.

2.  Opioids, opiates.

a.  Sources. Pharmaceuticals: hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, meperidine, fentanyl, methadone. Illicit drugs: Heroin, designer opioids.

b.  Systemic signs. Hypotension, bradycardia, bradypnea, pulmonary edema, track marks on skin, skin abscesses, decreased bowel sounds, cyanosis.

c.  Neurologic manifestations. Coma, miosis, deafness, areflexia, and seizures (meperidine). Seizures from meperidine are the result of elevated levels of normeperidine (a major metabolite of meperidine). Risk factors for normeperidine seizures are renal failure and chronic dosing. Naloxone (Narcan; Endo Pharmaceuticals, Chadds Ford, PA, USA) does not reverse meperidine- or propoxyphene-related seizures.

d.  Treatment. Supportive care, Naloxone 0.04 to 0.4 mg IV push followed by 0.04 to 0.4 mg every minute until reversal of respiratory depression or to a maximum of 8 mg. In habituated patients in whom immediate reversal is not warranted (not in cardiac or respiratory arrest) it is recommended to start with lower concentrations to avoid precipitating acute opioid withdrawal.

3.  GHB.

a.  Sources. GHB (Xyrem), γ-butyrolactone, butanediol (used for mood enhancement, sleep induction, and by body builders for purported increased growth hormone release).

b.  Systemic signs. Bradycardia, hypotension, hypothermia, nystagmus, vomiting.

c.  Neurologic manifestations. Areflexic coma (typically short duration—less than 6 hours with rapid reversal), normal or miotic pupils, seizures.

d.  Treatment. Supportive care.

4.  Carbon monoxide.

a.  Sources. Automotive exhaust, smoke inhalation, faulty heaters, external heating sources, propane- and gas-powered tools and vehicles.

b.  Systemic signs. Tachycardia, hypotension, chest pain, dyspnea, myocardial infarction, cardiac arrhythmia, flushed skin, pressure sores, nausea, vomiting.

c.  Neurologic manifestations. Headache, confusion, cognitive deficits, coma, seizures, stroke, parkinsonism, delayed neurologic sequelae (see Section B.3 under Central Nervous System).

d.  Diagnosis. Carbon monoxide levels are indicative of exposure but are not reliable predictors of toxicity or symptoms. The normal result is <5% for nonsmokers and <10% for smokers.

e.  Treatment.

(1)  Removal from source of carbon monoxide

(2)  100% oxygen (via non-rebreather) for 6 to 12 hours for mild or moderate symptoms

(3)  Indications for hyperbaric oxygen therapy (although availability is limited):

(a)  Unconsciousness at the scene or hospital

(b)  Coma or persistent neurologic deficit or

(c)  Myocardial ischemia or ventricular dysrhythmia or

(d)  Hypotension or cardiovascular compromise or

(e)  Pregnancy with any of the above, levels >20%, or signs of fetal distress.

5.  Cocaine or stimulant washout syndrome occurs among abusers of cocaine or other stimulants, the increased use of which decreases the level of CNS catecholamines resulting in depressed mental status, confusion, or coma (unresponsive to stimuli, including intubation). Patients may have dysconjugate gaze. Other physical examination findings, vital signs, and laboratory findings are generally normal. Symptoms may last for 8 to 24 hours, and treatment is supportive. This should always be a diagnosis of exclusion.

D.  Cerebellar disorders.

1.  Toluene–solvent abuse syndrome.

a.  Sources. Toluene-containing paint thinner, paint stripper, and glue.

b.  Route of exposure. Inhalational: huffing (inhaling soaked rags) or bagging (inhaling from bags containing solvent).

c.  Systemic signs. Abdominal pain, anorexia, weight loss, gastritis, possible renal tubular acidosis (hypokalemia and acidosis), rhabdomyolysis, hepatitis, solvent odor on breath.

d.  Neurologic manifestations. Tremor of the head and extremities, ataxia, staggering gait, cognitive deficits, personality changes, optic nerve atrophy, hearing loss, loss of smell, spasticity, and hyperreflexia.

e.  Diagnosis.

(1)  Laboratory. Elevated serum toluene levels and urine hippuric acid levels confirm exposure, but are not always detected.

(2)  Imaging. MRI of the brain often shows cerebellar and cerebral atrophy. Evidence of white matter disease can be seen with increased signal intensity on T2-weighted images in the periventricular, internal capsular, and brainstem pyramidal regions.

(3)  Electrophysiologic studies. Brainstem auditory evoked response testing may show sparing of early components and loss or decrement of the late components (waves III and IV). Abnormal pattern visual evoked cortical potentials and prolonged P100 peak latency may occur in patients with toxic optic neuropathy caused by toluene abuse.

f.  Treatment. Supportive care and addiction rehabilitation.

2.  Mercury poisoning (see also Section A.1.d under Peripheral Nervous System). Poisoning with elemental mercury vapor or organic mercury (along with other symptoms described in Section A.1.d under Peripheral Nervous System) can result in cerebellar symptoms including ataxia and tremor with pathologic neuronal damage seen in visual cortex, cerebellar vermis and hemispheres, and postcentral cortex.

3.  Anticonvulsant drugs including phenobarbital, phenytoin, and carbamazepine, in elevated concentration or acute overdose, manifest toxicity with predominantly ataxia, nystagmus, and CNS depression. Chronic use of phenytoin may also result in cerebellar atrophy.

4.  Ethanol. Both acute intoxication and chronic abuse of ethanol can result in ataxia, tremor, and altered mental status. Wernicke encephalopathy should be considered when any patient with chronic alcoholism has changes in mental status and ataxia not related to acute intoxication.

E.  Parkinsonism.

1.  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a byproduct in the production of a synthetic analog of meperidine, can cause acute parkinsonism in drug users, scientists, and pharmaceutical workers. Although not itself neurotoxic, MPTP is metabolized by monoamine oxidase to a compound (MPP+) that inhibits electron transport in dopaminergic neurons. This syndrome was characterized by the rapid (24 to 72 hours) development of end-stage parkinsonism with tremor, rigidity, bradykinesia, postural instability, masked facies, and decreased blink rate. Investigation of the mechanism of toxicity has led to the development of an animal model for Parkinson’s disease.

2.  Manganese. A parkinsonian-like illness has been described among miners or workers exposed to manganese oxide and among those who have ingested potassium permanganate, associated with methcathinone abuse. This syndrome is the result of degradation of the globus pallidus and striatum rather than the substantia nigra. It begins with a prodrome of nonspecific symptoms (insomnia, irritability, muscle weakness) and progresses to psychiatric manifestations (hallucinations, emotional lability, delusions) and finally to classic parkinsonian features of gait disturbance, masked facies, bradykinesia, rigidity, and less commonly tremor, which tends to be more postural or kinetic rather than resting. Patients with manganese-induced parkinsonism also experience dystonia consisting of facial grimacing and/or plantar flexion of the foot. These patients have little or no response to levodopa. Diagnosis is made by clinical history of significant exposure with associated physical exam and MRI findings. Fluorodopa positron emission tomography (PET) can help distinguish manganism (normal fluorodopa PET imaging) from Parkinson’s disease.

3.  Neuroleptic drugs. The use of neuroleptic agents, both typical and atypical, has been associated with the acute development of extrapyramidal side effects, most commonly parkinsonism. Patient’s age and the duration and potency of neuroleptic treatment are risk factors for neuroleptic-induced parkinsonism. The presentation of neuroleptic-induced parkinsonism includes bradykinesia or akinesia, which may be associated with decreased arm swing, masked facies, drooling, decreased eye blinking, and soft, monotonous speech; tremor, that is most commonly a rhythmic, resting tremor; and rigidity of the extremities, neck, or trunk. Cessation of the neuroleptic typically results in resolution of symptoms within a few weeks. Patients can be treated with anticholinergics or dopaminergic agents although levodopa is not recommended because of insufficient efficacy and risk of exacerbating psychosis. Prolonged use of neuroleptics can result in tardive dyskinesia with choreiform movements of the face, tongue, and limbs. If recognized early, most symptoms of tardive dyskinesia resolve within 5 years.

4.  Mitochondrial toxins (carbon monoxide, cyanide, hydrogen sulfide). Agents that inhibit the mitochondrial respiratory chain can cause development of bilateral globus pallidus infarction and subsequently a parkinsonian syndrome. This typically results from a combination of arterial hypotension and hypoxia in severe poisoning and can have neuropsychiatric manifestations or more classic parkinsonism.

F.  Seizures. Toxins cause seizures by one of four mechanisms: (1) decrease in the seizure threshold of a patient with an underlying seizure disorder, (2) direct effects on the CNS, (3) withdrawal seizures, or (4) metabolic derangements. Most toxin-related seizures are generalized tonic–clonic. (If there is any suggestion of focal onset, then brain imaging is necessary.) Most patients with toxin-induced seizures can be treated with standard seizure algorithms, except that treatment is more often successful with benzodiazepines and barbiturates than with phenytoin.

1.  Stimulants (see also Section A.2 under Central Nervous System).

a.  Sources. Cocaine, amphetamines, methamphetamine, PCP.

b.  Mechanism of toxicity. Secondary to increased extracellular levels of CNS catecholamines with subsequent excitation of the sympathetic nervous system. Can cause vasculitis, vasospasm, accelerated atherosclerosis, and increased risk of both ischemic and hemorrhagic stroke.

c.  Treatment.

(1)  Diazepam 10 mg or lorazepam 2 mg IV, repeat doses as needed, or

(2)  Phenobarbital 20 mg/kg IV at rate of 25 to 50 mg/minute for refractory seizures.

2.  Cholinergics (see also Section A.3 under Peripheral Nervous System).

a.  Sources. Organophosphate and carbamate insecticides, chemical warfare agents.

b.  Mechanism of toxicity. Increased CNS concentration of acetylcholine with secondary release of glutamate.

c.  Treatment.

(1)  Diazepam 10 mg, lorazepam 2 mg IV, repeat doses as needed, or phenobarbital 20 mg/kg IV at rate of 25 to 50 mg/minute for refractory seizures.

(2)  Atropine 2 to 4 mg IV for signs of cholinergic excess.

(3)  Pralidoxime 1.5 g IV over 30 minutes for nicotinic symptoms.

3.  GABA antagonists.

a.  Sources. Tricyclic antidepressants, phenothiazines, flumazenil, chlorinated hydrocarbons, hydrazines, cephalosporins, ciprofloxacin, imipenem, penicillins, isoniazid, steroids, clozapine, olanzapine. Plants: cicutoxin (water hemlock), picrotoxin (fish berries), and wormwood (absinthe).

b.  Mechanism of action. Direct or indirect inhibition of GABA_A receptors or decreased synthesis of GABA through inhibition of either glutamic acid decarboxylase or pyridoxal kinase (e.g., isoniazid, hydrazines).

c.  Treatment.

(1)  Diazepam 10 mg, lorazepam 2 mg IV, repeat doses as needed, or phenobarbital 20 mg/kg IV at rate of 25 to 50 mg/minute for refractory seizures.

(2)  Pyridoxine. For isoniazid or hydrazine overdose. The amount of pyridoxine administered should be equivalent (gram for gram) to the estimated amount of isoniazid ingested. It can be given IV push to patients with severe symptoms or as an IV infusion. If an unknown amount of isoniazid has been ingested, 5 g IV can be given empirically.

4.  Glutamate agonists.

a.  Sources. Domoic acid (shellfish), ibotenic acid (A. muscaria mushrooms), β-N-oxalylamino-l-alanine (BOAA found in legumes of the genus Lathyrus).

b.  Mechanism of action. Direct agonists at glutamate receptors (NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid).

c.  Other clinical features. Patients with lathyrism from BOAA have spastic paraplegia.

d.  Treatment.

(1)  Diazepam 10 mg or lorazepam 2 mg IV for seizures, repeat doses as needed or phenobarbital 20 mg/kg IV at a rate of 25 to 50 mg/minute for refractory seizures.

5.  Antihistamines.

a.  Sources. First-generation (sedating) antihistamines (diphenhydramine, chlorpheniramine, brompheniramine).

b.  Mechanism of action. Central histamine-1 receptor antagonism.

c.  Other clinical features. See anticholinergic syndrome (Section A.1 under Central Nervous System).

d.  Treatment.

(1)  Diazepam 10 mg or lorazepam 2 mg IV for seizures, repeat doses as needed, or phenobarbital 20 mg/kg IV at rate of 25 to 50 mg/minute for refractory seizures.

6.  Adenosine antagonists.

a.  Sources. Theophylline, caffeine, theobromine, pentoxifylline, carbamazepine.

b.  Mechanism of action. Antagonism of presynaptic A1 receptors preventing inhibition of glutamatergic neurons, and A2 receptors causing cerebral vasoconstriction. Theophylline may decrease GABA levels by decreasing pyridoxal-5-phosphate levels.

c.  Other clinical features.

(1)  The manifestations of theophylline toxicity are similar to those of sympathomimetic syndrome (see Section A.2 under Central Nervous System).

(2)  The manifestations of carbamazepine toxicity are similar to those of anticholinergic syndrome (see Section A.1 under Central Nervous System).

d.  Treatment.

(1)  Phenobarbital 20 mg/kg IV at rate of 25 to 50 mg/minute for altered mental status, CNS agitation, theophylline levels greater than 100 mg/mL, or seizures additionally may use repeated doses of diazepam 10 mg or lorazepam 2 mg as needed. Avoid phenytoin and fosphenytoin.

(2)  Hemodialysis for theophylline or caffeine overdose with seizures.

7.  Withdrawal seizures.

a.  Sources. Ethanol, benzodiazepines, barbiturates, baclofen.

b.  Mechanism of action. Prolonged use of GABA agonists results in decreased activity at GABA receptors and increased activity at glutamate receptors.

c.  Other clinical features. Delirium, hallucinations, tachycardia, arterial hypertension, fever, autonomic instability, and hypertonicity because of emergency of underlying tone (baclofen).

d.  Treatment.

(1)  Diazepam 10 mg or lorazepam 2 mg IV for seizures, repeat doses as needed, or phenobarbital 20 mg/kg IV at a rate of 25 to 50 mg/minute for refractory seizures.

(2)  For baclofen withdrawal oral baclofen should be restarted at the previous rate, or the baclofen pump should be refilled.

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