Neurologic Toxidromes

Questions

1. Twenty-four hours after an alcoholic binge lasting more than a week, a 42-year-old man develops coarse tremor of his arms, and 2 days later, he becomes abruptly agitated with fluctuating delirium. Pulse is 130/min, blood pressure is 160/120, and temperature is 38 °C. There is profuse sweating alternating with chills, and he seems to be experiencing visual hallucinations. Which of the following is the most appropriate first line pharmacological treatment?

A. An antipsychotic agent (dopamine receptor antagonist)

B. Benzodiazepine

C. Carbamazepine

D. Clonidine

E. Ethyl alcohol

View Answer

1. Answer B. (MN-131) Benzodiazepines have cross-tolerance with ethanol and so directly address ethanol withdrawal. Treatment of alcohol withdrawal consists of administration of benzodiazepines and thiamine supplementation (Table 18.1.1). Ethyl alcohol is a tissue toxin, including the peripheral and central nervous systems, and given parenterally, it has a narrow range of dosage safety. Carbamazepine, clonidine, or neuroleptic agents have no cross-tolerance with ethanol. Neuroleptics lower the seizure threshold, cause hypotension, prolong the QT interval, and impair thermoregulation.

TABLE 18.1.1 Treatment of Ethanol Withdrawal

Prevention or Reduction of Early Symptoms

Lorazepam 1-4 mg orally or IV; diazepam 5-20 mg; or chlordiazepoxide 25-100 mg repeated hourly until sedation or mild intoxication; successive daily doses tapered with resumption of higher dose if withdrawal symptoms recur
Thiamine 100 mg and multivitamins IM or IV
Magnesium, potassium, and calcium replacement as needed

Delirium Tremens

Lorazepam 2-4 mg IV or IM or diazepam 10 mg IV, repeated every 5-15 min until calming; maintenance dose every 1-4 h as needed
If refractory to benzodiazepines, phenobarbital 260 mg IV repeated in 30 min as needed
If refractory to phenobarbital, propofol 25-100 mg/kg/min, with endotracheal intubation and repeated doses to produce general anesthesia
Careful attention to fluid and electrolyte balance; several liters of saline per day, or even pressors, may be needed.
Cooling blanket for high fever
Prevent or correct hypoglycemia.
Thiamine and multivitamin replacement
Consider coexisting illness (e.g., liver failure, pancreatitis, meningitis, subdural hematoma).

IM, intramuscularly; IV, intravenously.

Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

2. A 55-year-old man who drinks more than a pint of vodka daily becomes increasingly withdrawn and inattentive. Responses to questions are delayed and when forthcoming reveal impairment of recent memory, including disorientation to month and year. There is bi-directional limitation of horizontal gaze, nystagmus, and he needs assistance to maintain balance standing or walking. Which of the following is the most likely cause of his symptoms?

A. Cerebellar hemorrhage

B. Ethanol intoxication

C. Hepatic encephalopathy

D. Thiamine deficiency

E. Vitamin B₁₂ deficiency

View Answer

2. Answer D. (MN-131) The patient has the symptomatic triad of Wernicke encephalopathy: altered mental status that includes abulia (apathy) and inattentiveness in addition to memory impairment; horizontal limitation of eye movements; and gait ataxia (Table 18.2.1). None of the other diagnostic considerations would be likely to cause this particular syndrome.

TABLE 18.2.1 Major Nutritional Disturbances in Alcoholics

Disorder	Clinical Disorder	Deficiency
Wernicke syndrome	Dementia with lethargy, inattentiveness, apathy, and amnesia Ophthalmoparesis Gait ataxia	Thiamine
Korsakoff syndrome	Dementia, mainly amnesia, with or without confabulation	Thiamine
Cerebellar degeneration	Gait ataxia; limb coordination relatively preserved	Probably thiamine plus other vitamins plus ethanol neurotoxicity
Polyneuropathy	Distal limb sensory loss and weakness; less often autonomic dysfunction	Probably thiamine plus other vitamins plus ethanol neurotoxicity
Amblyopia	Optic atrophy, decreased visual acuity, central scotomas; total blindness rare	Probably thiamine plus other vitamins plus ethanol neurotoxicity
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

3. A 47-year-old man who is a chronically heavy drinker develops unsteady gait that progresses over a few weeks to inability to stand. On examination, mental status, including recent memory, is normal. Eye movements are full without nystagmus. There is no dysarthria, and there is neither tremor nor dysmetria on finger-to-nose testing. Heel-to-shin testing is mildly ataxic, but his gait is broad-based, and he cannot stand with feet together without falling. Which of the following is the most likely cause of his symptoms?

A. Acute alcoholic intoxication

B. Alcoholic cerebellar degeneration

C. Alcoholic hypoglycemia

D. Alcoholic sensory polyneuropathy

E. Hepatic encephalopathy

View Answer

3. Answer B. (MN-131) Alcoholic cerebellar degeneration, which is probably both toxic and nutritional in origin, preferentially affects the cerebellar vermis, resulting in truncal ataxia and relative sparing of eye movements, speech, and limb movements. Alcoholic intoxication would not be progressive over weeks and would produce characteristic altered mental status. Hepatic encephalopathy would also be expected to cause progressive altered mental status. Alcoholic sensory polyneuropathy causes distal limb sensory loss, but impaired proprioception is not usually prominent; in such patients, cerebellar degeneration is a more likely explanation for gait ataxia. Alcoholic hypoglycemia tends to occur during a binge and to cause seizures or coma, not gait ataxia.

4. Which of the following is the most vulnerable period for fetal alcohol spectrum disorder?

A. Equal vulnerability among all three trimesters

B. First trimester

C. Second trimester

D. Third trimester

View Answer

4. Answer B. (MN-131) Fetal harm secondary to maternal alcohol use can occur before a woman is aware she is pregnant. Although the fetus is most vulnerable in the first trimester, women are counseled to avoid alcohol throughout pregnancy.

5. A chronically heavy drinker notes impaired visual acuity. Examination reveals bilateral central scotomas. Mental status is normal. Which of the following is the most likely funduscopic abnormality?

A. Bilateral macular degeneration

B. Bilateral nasal optic disc pallor

C. Bilateral papilledema

D. Bilateral retinal hemorrhages and exudates

E. Bilateral temporal optic disc pallor

View Answer

5. Answer E. (MN-131) Alcoholic/nutritional amblyopia, like many neurological complications of alcohol use disorder, is probably both nutritional and toxic in origin. Damage consists of optic nerve atrophy, especially affecting the maculopapular bundle; hence, optic disc atrophy tends to be maximal in the temporal rim, and visual loss is maximal centrally. Vision usually improves with abstinence.

6. A 35-year-old man is found unconscious; he responds only to noxious stimuli with appropriate limb withdrawal, his pupils are 1 mm and reactive to light, his eyes move conjugately in both horizontal directions, and his respirations are 5/min and shallow. Which of the following is an appropriate pharmacological intervention for this patient?

A. Cannabidiol

B. Dextroamphetamine

C. Flumazenil

D. Methadone

E. Naloxone

View Answer

6. Answer E. (MN-132) The patient’s examination is characteristic for opioid overdose (miosis, depressed mental status, reduced respiratory rate), and naloxone is a specific mu opioid receptor antagonist used in opioid overdose (Table 18.6.1). Flumazenil is a benzodiazepine receptor partial agonist and might temporarily reverse benzodiazepine overdose. Methadone, an opioid mu receptor agonist, would worsen the patient’s symptoms. Cannabidiol, a non-psychoactive cannabinoid compound present in marijuana, has anticonvulsant properties but is of no use in opioid overdose.

TABLE 18.6.1 Commonly Used Opioids

Agonist

Camphorated tincture of opium (paregoric)
Morphine
Meperidine
Methadone
Fentanyl
Hydromorphone
Oxycodone
Hydrocodone
Propoxyphene
Heroin

Antagonist

Naloxone
Naltrexone

Mixed Agonist-Antagonist

Pentazocine
Butorphanol
Buprenorphine

Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

7. Which of the following is most characteristic of cocaine withdrawal?

A. Choreiform movements

B. Convulsive seizure

C. Delirium

D. Hypertensive crisis

E. Sleepiness and depression

View Answer

7. Answer E. (MN-132) Depression, hunger, and sleepiness are characteristic of cocaine withdrawal. The other symptoms listed are features of cocaine intoxication.

8. A 15-year-old boy in a rural community is found delirious with hallucinations. Temperature is 39 °C, pulse is 125/min, and pupils are fully dilated and unreactive to light. A friend reports that he had consumed a flowering weed that they discovered on their farm. Which of the following is the most appropriate pharmacological treatment for this patient?

A. Carbamazepine

B. Lorazepam

C. Naloxone

D. Phenobarbital

E. Physostigmine

View Answer

8. Answer E. (MN-132) The symptoms are characteristic of anticholinergic poisoning; in this case, probably following recreational use of Datura stramonium, or Jimson Weed, a plant that contains atropine and scopolamine. Ingestion or overdose of prescription medications with anti-cholinergic properties would cause a similar syndrome. Physostigmine, a reversible acetylcholinesterase inhibitor, would be the drug of choice. Naloxone is useful in reversing opioid overdose but not overdose from other classes of recreational drugs. Barbiturates and benzodiazepines have sedative properties but no specificity for anticholinergic poisoning. Carbamazepine is an anticonvulsant, but the patient is not having seizures, and if he were, carbamazepine would not get to the crux of the problem.

9. A 40-year-old polydrug user develops sweating, yawning, mydriasis, lacrimation, rhinorrhea, myalgia, muscle spasm, nausea, vomiting, hot flashes, fever, and tachycardia. Except for irritability and distress, mental status is normal. Which of the following drugs is most likely to be responsible for his symptoms?

A. Gamma-hydroxybutyric acid

B. Lysergic acid diethylamide (LSD)

C. Methamphetamine

D. Opioids

E. Phencyclidine

View Answer

9. Answer D. (MN-132) Symptoms are characteristic for opioid withdrawal. Notable is the preserved mental status except for irritability and distress. Methamphetamine and phencyclidine in overdose would likely cause delirium or psychosis without the flu-like symptoms associated with opioid withdrawal. Methamphetamine withdrawal resembles cocaine withdrawal. Phencyclidine withdrawal is usually mild with tremor and nervousness. LSD intoxication causes illusions and hallucinations, and in high doses, obtundation and seizures; withdrawal symptoms do not occur. Gamma-hydroxybutyric acid is a sedative with intoxication and withdrawal symptoms similar to those produced by ethyl alcohol.

10. In the context of substance abuse, the term “bath salts” refers to which of the following?

A. Designer analogs of cathinone

B. Methamphetamine

C. Phencyclidine

D. Smokable alkaloidal cocaine

E. Synthetic cannabinoid compounds (K2, spice)

View Answer

10. Answer A. (MN-132) “Bath salts” refers to designer analogs of cathinone, an amphetamine-like psychostimulant derived from the African shrub khat. Like other psychostimulants, bath salts cause euphoria, increased motor activity, tachycardia, and hypertension. Inhalable alkaloidal cocaine is called “crack.” Methamphetamine is called “speed” or “ice.” Phencyclidine is called “angel dust” or “PCP.” Psychostimulant withdrawal classically produces fatigue, depression, and hunger.

11. A 50-year-old man presents with diaphoresis, restlessness, and seizures. According to his wife, he removed several cans of old insecticide from a barn the day before. Examination reveals bronchorrhea, fasciculations, and miosis. What medication should be considered in treating this patient?

A. Chelation therapy

B. Dantrolene

C. Lorazepam

D. Physostigmine

E. Pralidoxime

View Answer

11. Answer E. (MN-133) The patient suffers from organophosphate poisoning. Organophosphates are acetylcholinesterase inhibitors, causing symptoms consistent with increased acetylcholine transmission, such as miotic pupils, bradycardia, bronchorrhea, salivation, and lacrimation (Table 18.11.1). Symptom onset ranges from minutes to hours. The high lipophilicity of organophosphates allows them to be absorbed in adipose tissues, although delayed effects can be seen when they diffuse into the circulation. Treatment involves high-dose atropine (1-2 mg doubled every 5 minutes until respiratory secretions improve), followed by pralidoxime. Physostigmine is an acetylcholinesterase inhibitor and is used in anti-cholinergic toxicity, which results from anti-muscarinic medications. Clinical manifestations of anti-cholinergic toxicity include mydriasis, tachycardia, dry mucous membranes, flushed skin, hyperthermia, and seizures. Dantrolene is used to treat neuroleptic malignant syndrome, which results in fever, muscle rigidity, and elevated creatinine kinase after exposure to dopaminergic blocking antipsychotic agents. Chelation therapy can be used in severe heavy metal poisoning, such as lead toxicity. Lead toxicity causes delayed-onset peripheral neuropathy and neurocognitive changes, although acute lead intoxication can result in cerebral edema.

TABLE 18.11.1 Clinical Findings of Neurotoxic Syndromes

Anticholinergics	Flushed skin Anhidrosis Dry mucus membranes Urinary retention Constipation/ileus/decreased bowel sounds Hyperthermia Mydriasis Blurred vision (impaired accommodation) Agitation, confusion, delirium, psychosis Visual hallucinations Myoclonus, choreoathetosis, picking behavior Stupor/coma (higher doses) Seizures (very rarely status epilepticus)	Organophosphate and carbamate toxicity (continued)	Diaphoresis Muscle fasciculations Seizures/convulsions Confusion to stupor/coma Blurred vision/miosis^a Bronchospasm^a Bradycardia^a Hypotension^a
Sympathomimetic	Diaphoretic Hypertensive Tachycardic Hyperthermia Agitation, combativeness, psychosis Hallucinations Mydriasis Seizures	Neuroleptic malignant syndrome	Confusion/delirium Catatonia/mutism Stupor/coma Lead pipe rigidity Hyperthermia Tachycardia Hypertension Tachypnea
Organophosphate and carbamate toxicity	Restlessness Diarrhoea Lacrimation Salivation Urination Bronchorrhea	Serotonin syndrome	Agitation, hypervigilance Confusion, delirium Hyperthermia Tachycardia Hypertension Diaphoresis Diarrhoea Ocular clonus Mydriasis Akathisia Tremor Rigidity Hyperreflexia^b Clonus^b
^aCholinergic activity at the preganglionic sympathetic fibers leads to increased release of norepinephrine at the postganglionic nerve terminals in the target organs. Clinically, this results in activation of the sympathetic and parasympathetic pathways, which may lead to normocardia, tachycardia, normotension, bronchodilation, or mydriasis.
^bMore pronounced in the lower extremities.
Reprinted with permission from Louis ED, Mayer SA, Noble JM, eds. Merritt’s Neurology. 14th ed. Wolters Kluwer; 2022.

12. Which of the following is the preferred first line treatment or toxin-induced seizures?

A. Benzodiazepines

B. Emergency hemodialysis

C. Phenobarbital

D. Phenytoin

E. Physostigmine

View Answer

12. Answer A. (MN-133) Benzodiazepines have broad effectiveness for seizures of all types. The best choice of agent would be intravenous lorazepam, which is also the first-line agent of choice for status epilepticus.

13. A 23-year-old woman presents with encephalopathy, lower-extremity hyperreflexia, axial clonus, fever, and rigidity after recently starting citalopram for depression and sumatriptan for migraine. What is the most likely diagnosis?

A. Malignant hyperthermia

B. Neuroleptic malignant syndrome

C. Organophosphorus poisoning

D. Serotonin syndrome

E. Strychnine poisoning

View Answer

13. Answer D. (MN-133) Serotonin syndrome can be precipitated when two or more serotonergic medications are co-administered, although it can also occur with monotherapy. Serotonin receptors are primarily found in the central nervous system in the brain stem (midline raphe nuclei) and peripherally in the gastrointestinal tract, vasculature, and platelets. Rapid increases in serotonin concentration at these sites produce the symptoms of serotonin syndrome. Mild symptoms include tremor, diarrhea, and restlessness or hypervigilance. More severe symptoms result in further autonomic dysfunction, hyperthermia (>40 °C), and more significant deficits in mental status. Clonus (ocular, spontaneous, and induced) and hyperreflexia are specific for serotonin syndrome and is most pronounced in the lower extremities. The onset is typically within minutes to hours of exposure to the serotonergic agent.

14. Which agent can be used as a treatment option for severe serotonin syndrome refractory to benzodiazepines and supportive measures?

A. Cyproheptadine

B. Flumazenil

C. N-acetyl-cysteine (NAC)

D. Pralidoxime

E. Valproic acid

View Answer

14. Answer A. (MN-133) Mild serotonin syndrome can often be managed with fluids, benzodiazepines, and removal of the offending agent. However, if agitation, clonus, fever, or autonomic dysfunction persists despite with conservative measures, then cyproheptadine, a histamine and serotonin antagonist, maybe given. It is only available for oral administration. The initial dose is 12 mg, followed by 2 mg every 2 hours. NAC is an antidote for acetaminophen toxicity. Valproic acid actually has been reported as a cause or contributing factor to serotonin syndrome and should be avoided. Flumazenil, a benzodiazepine antagonist, increases seizure risk and would be similarly contraindicated in this patient. Pralidoxime is an anticholinergic agent used as an antidote for organophosphorus poisoning.

15. A 68-year-old man with glioblastoma treated with resection, radiosurgery, and concomitant temozolomide 6 months ago presents for worsening headache. His examination is notable for worsening of his baseline deficits from his tumor. Follow-up magnetic resonance imaging (MRI) shows a ring enhancing lesion that is relatively hypoperfused on perfusion sequences, with an elevated lactate and no choline peak on MR spectroscopy. What is the best next step in this patient’s treatment?

A. Edaravone

B. Glucocorticoids and bevacizumab

C. Neurosurgical consultation for consideration of repeat tumor debulking

D. Radiation oncology consideration for consideration of further radiation treatment

E. Switch from temozolomide- to a nitrosourea-based chemotherapy regimen

View Answer

15. Answer B. (MN-134) This patient’s presentation is most consistent with radiation necrosis, a side effect of radiotherapy. Radiation necrosis classically occurs between 6 months and 7.5 years after radiotherapy and presents as new focal symptoms that localize to the site of the tumor bed (Table 18.15.1). MRI may show ring enhancement, new mass lesion, and edema mimicking the initial neoplasm. Lower apparent diffusion coefficient values on MRI, hypo-metabolism on positron emission tomography, hypo-perfusion on MR perfusion, and a reduction in choline levels in MR spectroscopy are all suggestive of radiation necrosis versus tumor recurrence. Treatment for radiation necrosis involves glucocorticoids and possibly bevacizumab, in addition to serial imaging to monitor the difference between radiation necrosis and disease progression.

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