Drug-Induced Neurologic Conditions

Abstract and Introduction

Abstract

Pharmacists are trained to recognize the most common adverse effects of drugs; however, any member of the medical team can easily overlook side effects that appear to be new medical conditions. Drug-induced neurologic conditions may result from single-agent drug regimens, but they are more likely to occur when multiple agents that confer risk are administered concomitantly. Educating patients about these risks and remaining vigilant in clinical investigations of unusual adverse effects are key elements to increasing the safety of drug management.

Introduction

Along with awareness of the improved health outcomes resulting from drug therapy comes the recognition that drug therapy may also contribute to the emergence of new disorders. Mindful consideration of the possibility of drug-induced neurologic symptoms must be part of any ongoing evaluation of the evolving body of evidence obtained through clinical case reports. The emergence of new neurologic side effects of drugs heightens the challenges prescribers face when considering drug therapy. These side effects can result in potential misdiagnoses, including false psychiatric diagnoses, in the case of some drugs. Unexpected and unpredictable drug interactions can result in a confusing range of symptoms that may be identified as a new medical condition.

The term neurologic side effect is commonly used to describe a new drug-induced neurologic syndrome and/or disorder. Pharmacists may not routinely anticipate or recognize these new conditions caused by common drug agents. Changes in the central nervous system (brain, spinal cord) or peripheral nerves can cause a wide variety of symptoms, including loss of coordination and muscle strength, numbness, loss of consciousness, seizures, and paralysis (Table 1).^[1–3] In July 2013, the FDA added a black box warning to the antimalarial drug mefloquine about serious neurologic side effects, including dizziness, loss of balance, and tinnitus.^[4]

Often, it is difficult to determine whether a neurologic condition is caused by a drug. A key factor to consider when reviewing clinical case reports and/or reporting through MedWatch is clear and consistent identification of the suspect drug, as well as a detailed report of the proposed drug-induced disorder. One of the more difficult aspects of such an investigation is ensuring the specificity of the event related to the drug by ruling out other potential causes of the disorder. Limits in premarketing data make postmarketing surveillance essential to identifying new neurologic side effects of drugs.

Table 1. Neurologic Complications of Commonly Prescribed Drugs
Drug-Induced Disorder	Related Syndromes/Disorders	Adverse Effects
Cerebrovascular disease	Stroke, cerebellar syndrome	Ataxia; dysarthria; nystagmus
Cognitive impairment	Dementia	Confusion; memory loss; decreased ability to concentrate, think, and reason
Delirium	NA	Disturbance in consciousness; impaired cognition
Headache	Medication-overuse headache, intracranial hypertension	Headaches ranging in symptom type (cluster, migraine, generalized)
Nerve and muscle disorders	PN, GBS, neuromuscular blockade, myopathy, demyelination	Muscular weakness, loss of coordination, possible paralysis
Neuroleptic malignant syndrome	NA	Fluctuating heart rate, respiration levels, and level of consciousness
Movement disorders	Akathisia, dystonia, TD, parkinsonism	Tremor; muscular spasms; facial grimacing; tongue protrusion
Optic neuritis, visual disturbances	NA	Loss of visual acuity; color blindness
Seizure disorders	Withdrawal seizures, iatrogenic seizure threshold reduction	Possible loss of consciousness
Serotonin syndrome	NA	Cognitive behavioral changes; autonomic instability; neuromuscular excitability
Sleep disorders	Drug-induced insomnia	Excessive daytime sleepiness; decreased ability to concentrate, think, and reason

GBS: Guillain-Barré syndrome; NA: not applicable; PN: peripheral neuropathy; TD: tardive dyskinesia. Source: References 1–3.

Table 2. Drugs Included in Beers Criteria That Cause Cognitive Impairment
Drug	Rationale for Inclusion
1st-generation antihistamines (e.g., diphenhydramine, hydroxyzine)	Highly anticholinergic; reduced clearance with advanced age; tolerance develops when used at hypnotic doses; greater risk of toxicity
Antiparkinsonian agents (e.g., benztropine [Cogentin], trihexyphenidyl [Artane])	More effective agents available; anticholinergic AEs
Skeletal muscle relaxants	Anticholinergic AEs; sedation; risk of fracture; questionable effectiveness at doses tolerated by older adults (lower)
Tertiary TCAs	Highly anticholinergic; sedating; cause OH
Antipsychotics (FGA and SGA)	Increased risk of stroke and mortality in dementia
Benzodiazepines (short- and long-acting)	Increased sensitivity to class; increased risk of cognitive impairment, delirium, falls, fractures, motor vehicle accidents
AE: adverse effect; FGA: first-generation antipsychotic; OH: orthostatic hypotension; SGA: second-generation antipsychotic; TCA: tricyclic antidepressant.
Source: Reference 5.

Table 3. Drugs Within Classes That Have Seizure Risk
Class	Drugs Within Class^a
Antiarrhythmics	Lidocaine; verapamil; diltiazem
Antibiotics	Cephalosporins; carbapenems (imipenem)
Antidepressants	Bupropion; TCAs (e.g., clomipramine)
Antineoplastics	Alkylating agents (chlorambucil); antimetabolites (methotrexate)
Antipsychotics	Chlorpromazine; clozapine
Mood stabilizers	Lithium
Pain drugs	Fentanyl; Demerol (meperidine); Tramadol
Drug action–specific	Those that cause abnormal serum sodium or glucose levels; illicit drug use (e.g., angel dust [PCP], cocaine, amphetamines); those that cause extreme BP increases (malignant hypertension)—MAOIs, especially in combination with high-tyramine foods, and other antidepressants/sympathomimetics (see Antidepressants); withdrawal from alcohol, opioids (Demerol, Fentanyl), benzodiazepines (e.g., Valium)