Historical note and nomenclature

The term "drug-induced neurologic disorders," a form of iatrogenic illness, specifically refers to unintended or undesirable effects on the nervous system that are either caused by drugs or associated with drug use. It includes neurologic disorders due to medications used for diagnostic procedures. The use of the word "induced" within the term "drug-induced neurologic disorders" does not necessarily imply a proven causal relationship of the drug to the disorder. The drug may affect the nervous system directly (primary neurotoxicity) or indirectly by other systemic disturbances caused by the drug (secondary neurotoxicity). Drug-induced neurologic disorders can include disorders caused by inappropriate use of a drug, overdose of a drug, or harmful drug interactions, but environmental and industrial toxins are excluded.

Terms that are commonly used to refer to adverse drug effects are defined by the World Health Organization as follows:

Adverse event or adverse experience. Any untoward medical occurrence that may present during treatment with a pharmaceutical product, but that does not necessarily have a causal relationship with this treatment.

Adverse drug reaction. An event that is related, or suspected to be related, to a medication. An adverse drug reaction is a response to a drug that is noxious, unintended, and occurs at doses normally used in man for prophylaxis, diagnosis, therapy of a disease, or modification of physiological function.

Side effect. Any unintended effect of a pharmaceutical related to the pharmacological properties of the drug and occurring at doses normally used in humans.

In the first half of the 20th century, increasing attention was given to adverse drug reactions, partly because of the increased rate of therapeutic development. For example, polyneuropathy as a complication of serum therapy was described in 1934 (02), and encephalopathy as a complication of pertussis vaccination was described in 1949 (11). In the late 20th century, there were attempts at conceptualizing, categorizing, and systematizing complications of treatment of neurologic disorders as well as neurologic complications resulting from treatment of diseases of other systems (28; 19; 07). Increasingly sophisticated surveillance systems have been developed for collection and analysis of adverse drug reactions.

Clinical significance

Drug-induced neurologic disorders can mimic neurologic disorders due to other causes; however, when a reasonable suspicion exists of association with a drug or a known or plausible pathogenetic mechanism for drug-induced neurologic disorders, the drug should be considered in the differential diagnosis. Questionnaires, algorithms, and computer-based approaches have been used to assess the causal relationship of the drugs to the adverse drug reactions. None of these methods have found universal application because they are tedious, time consuming, and expensive. In clinical practice, causality is usually assessed by global judgment (ie, opinion of the causal relation of the drug to the event after taking into consideration the available relevant information, as shown in Table 1).

Table 1. Global Evaluation of Causal Relationship of a Drug to an Adverse Event

(1) Is there a plausible biological explanation (pathogenetic mechanism)?

(2) Is the adverse event temporally related to the drug?

(3) Do the symptoms subside after discontinuation of the drug? (positive dechallenge)

(4) Do the symptoms recur after resumption of the drug? (positive rechallenge)

(5) Is the event already known and documented?

(6) Is the adverse event known to occur in the course of the natural disease?

(7) Is the adverse event known with the concomitant therapy?

The answers are taken into consideration to allocate the adverse drug reactions to the following categories: (1) probable, (2) possible, and (3) unlikely. These are approximate terms, and the term "definite" is rarely used. "Possible" means that such a reaction can take place with the drug, and sometimes this term is used because the possibility cannot be excluded. Sufficient information for assessment may not be available in some cases.

Anecdotal reports of suspected adverse drug reactions involving the nervous system are common in the medical literature but are generally of limited value because, by themselves, they cannot establish causality, nor can they provide an indication of the magnitude of the risk. This anecdotal information is not even systematically incorporated into commonly used drug information sources.

Epidemiology

Adverse effects of drugs involving the nervous system form only a small proportion of all neurologic disorders, but they are under-recognized and under-reported. Adverse drug reactions, both from clinical trials and post-marketing surveillance, are usually reported to the manufacturers of the product involved. Manufacturers make the initial assessment of these reports and file the adverse drug reactions with the health authorities of the countries involved according to regulatory requirements (Food and Drug Administration [FDA] in the United States). The World Health Organization also maintains a database for adverse drug reactions.

FDA-approved drug labeling is defined by the Code of Federal Regulations (1 CFR) of the United States and contains several distinct sections (03). Each section provides specific information such as drug safety, efficacy, patient information, target populations, and clinical as well as nonclinical data. To promote the safe use of drug products and protect public health, adverse drug reaction information is collected from clinical trials and post-marketing surveillance data and summarized in FDA-approved drug labeling as boxed warnings and precautions with different levels of severity and coverage. Serious warnings are about adverse drug reactions that lead to death or serious injury whereas warnings describe clinically significant adverse drug reactions.

The Medical Dictionary for Regulatory Activities (MedDRA) is the standard medical terminology developed by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and is used worldwide to facilitate the sharing of regulatory information for medical products. MedDRA is used for coding adverse events in the FDA’s Adverse Event Reporting System. MedDRA is widely applied in analyzing adverse drug reactions report data and in mining public health data for potential safety concerns. MedDRA terminology has been successfully used to code and investigate adverse drug reactions. MedDRA has also been used to analyze adverse drug reactions in FDA drug labeling, but it may not provide an adequate assessment of drug toxicity and severity, potentially undermining the utility of drug labeling.

Combining MedDRA standard terminologies with data mining techniques facilitated computer-aided adverse drug reaction analysis of drug labeling and highlighted the importance of labeling sections that differ in seriousness and application in drug safety (27). Using adverse drug reactions primarily related to boxed warning sections, a prototype approach for computer-aided adverse drug reaction monitoring and studies can be applied to other public health documents.

The incidence of adverse drug reactions in hospitalized patients was determined by a meta-analysis of 39 prospective studies from American hospitals. The overall incidence of serious adverse drug reactions was 6.7%, and fatal adverse drug reactions was 0.3%, making these the fourth leading cause of death in the United States after heart disease, cancer, and stroke (16). The incidence is much higher than that assumed from the spontaneous reporting system, which identifies only about 1 in 20 adverse drug reactions. In a study of 18,820 hospital admissions in the United Kingdom, 1225 were related to an adverse drug reaction, giving a prevalence of 6.5%, with the adverse drug reaction directly leading to the admission in 80% of cases (20). Assessment of 1263 consecutive admissions to the neurology unit of a Swiss university hospital over 1 year revealed drug-related problems in 29% of cases, and these were the cause of admission in 0.8% (25).

A systematic review of the incidence of adverse drug reactions in primary care reviewed studies published from 1990 to the end of 2018 and found that the CNS was the body system with the most adverse drug reactions reported (15). The most frequent adverse drug reactions were fatigue (55%), dizziness (18%), and tremor (16%).

Small numbers of the adverse drug reactions are published in case reports, and many adverse drug reactions are not observed in clinical trials of new drugs. Most of the information received by the pharmaceutical companies is inadequate for establishing the diagnosis of drug-induced neurologic disorders, but it is used for answering questions from physicians and for making decisions for inclusions of adverse drug reactions in basic drug information and package inserts.

Most of the products listed in the Physicians' Desk Reference mention at least one untoward effect that relates to the nervous system. Entries in the list of adverse drug reactions are not always based on medical judgment but may be a measure to protect the manufacturer against legal liability by having declared that such an adverse drug reaction has been reported. The adverse effects reported may not be causally related to the drug.

The frequency of occurrence of adverse events in clinical trials can be calculated and compared with that in the placebo group. An adverse event is an adverse drug reaction only if the relation to the drug is proven or suspected. The size of clinical trials is limited and seldom involves more than 500 patients and, therefore, rare adverse drug reactions cannot be expected to show up in these trials. Post-marketing surveillance continues for the lifetime of a drug to detect such adverse drug reactions. The frequency of occurrence of adverse drug reactions in this phase is difficult to determine because of generally poor, typically variable, and often biased reporting and lack of knowledge of the denominator. The number of patients exposed to the drug is sometimes estimated from the quantity of the drug sold and the standard dose for a patient. These figures are not reliable because the amount of drug used by individual patients varies a great deal, and all the drugs sold are not administered to (or actually taken) by the patients.

A Swedish study showed that fatal adverse drug reactions accounted for approximately 3% of all deaths in the general population, and two thirds of these were due to hemorrhages, of which 29% involved the CNS (26). Antithrombotic agents were implicated in more than half of the fatal adverse drug reactions.

Pharmaceutical drug neurotoxicity ratings. Spencer and Schaumburg provided a simple but useful categorization of neurotoxicity ratings that they applied to both pharmaceutical drugs and to toxins of all kinds. The ratings will be applied here for some categories of pharmaceutical drugs: A, strong association between the drug and the adverse drug reaction; B, a suspected and plausible but still unproven association; C, the association is not likely to be causal (Spencer and Schaumburg 2000). In the absence of specified ratings, the substance can be assumed to be "category A."

Table 2. Pharmaceutical Drug Neurotoxicity Ratings

Drugs associated with psychobiological reactions
	• Amphetamines
	• Corticosteroids
	• Indomethacin
	• L-dopa
	• Mefloquine (anti-parasitic agent)
	• Methylxanthines (eg, theophylline)
	• Quinacrine (antiprotozoal, antirheumatic, and an intrapleural sclerosing agent; unavailable in the U.S. since 2020)
	• Reserpine
	• Tricyclic antidepressants
	• "Z-drugs" (eg, zolpidem, zopiclone, eszopiclone, zaleplon)
Drugs associated with acute encephalopathy
	A rating
		• Acetylsalicylic acid
		• Acyclovir
		• Amphetamines
		• Atropine
		• Baclofen
		• Barbiturates
		• Benzodiazepines
		• Bromide
		• Carbamazepine
		• Chloral hydrate
		• Cimetidine
		• Cinnarizine (sedating antihistamine, used for motion sickness and nausea/vomiting post-chemotherapy)
		• Cyclobenzaprine
		• Cyclopentolate (mydriatic)
		• Cycloserine (GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis)
		• Cytarabine (cytosine arabinoside; chemotherapeutic agent)
		• Digitalis
		• Ergot alkaloids
		• Fentanyl
		• Flecainide (antiarrhythmic)
		• Fludarabine (chemotherapeutic agent)
		• Fluorouracil (chemotherapeutic agent)
		• "Gold salts" (sodium aurothiomalate; antirheumatic)
		• Ifosfamide (chemotherapeutic agent)
		• Indomethacin
		• Mechlorethamine (chemotherapeutic agent)
		• Meperidine
		• Methadone
		• Methaqualone (sedative hypnotic)
		• Methotrexate
		• Metrizamide (non-ionic, iodine-based, radiocontrast agent)
		• Metronidazole
		• Morphine
		• Nalidixic acid (synthetic quinolone antibiotic)
		• Nicotine
		• Pemoline (stimulant)
		• Pentazocine (opioid)
		• Pertussis vaccine
		• Propranolol
		• Quinacrine (antiprotozoal, antirheumatic, and an intrapleural sclerosing agent; unavailable in the U.S. since 2020)
		• Reserpine
		• Valproic acid
	B rating
		• Amantadine
		• Aminocaproic acid (clotting promoter)
		• Bromocriptine
		• Cephalosporins
		• Chloramphenicol
		• Chloroquine
		• Clonidine
		• Clozapine
		• Disulfiram
		• Enflurane (halogenated ether; induction and maintenance of general anesthesia)
		• Ethionamide (anti-tuberculous agent)
		• Fluoroquinolones
		• Ganciclovir (antiviral)
		• Griseofulvin
		• Interferon alpha
		• Methysergide
		• Mitotane (chemotherapeutic agent)
		• Nitroprusside
		• Quinine
		• Sulfonamides
		• Trihexyphenidyl (antimuscarinic/antispasmodic)
		• Vidarabine (antiviral)
		• Vinca alkaloids (antineoplastic/antimitotic)
Drug-induced seizures
	• Atropine
	• Baclofen
	• Butyrophenones (eg, haloperidol and droperidol)
	• Carbamazepine
	• Cephalosporins
	• Chlorpromazine and other neuroleptics
	• Clozapine
	• Cycloserine (GABA transaminase inhibitor and an antibiotic, used to treat tuberculosis)
	• Enflurane (halogenated ether; induction and maintenance of general anesthesia)
	• Isoniazid
	• Mefloquine (anti-parasitic agent)
	• Nalidixic acid (synthetic quinolone antibiotic)
	• Penicillins
	• Tacrolimus (immunosuppressive drug)
	• Tricyclic antidepressants
Drug-induced movement disorders
	• Tremor
		- Postural/kinetic (eg, enhanced physiological tremor)
			-- Amiodarone
			-- Amphetamines
			-- Beta agonists, nonselective (eg, epinephrine, isoproterenol/isoprenaline)
			-- Beta2 agonists (eg, albuterol, fenoterol, levalbuterol, metaproterenol, pirbuterol, terbutaline)
			-- Bupropion
			-- Caffeine
			-- Corticosteroids
			-- Cyclosporine
			-- Levothyroxine
			-- Methylphenidate
			-- Nicotine
			-- Phenylpropanolamine
			-- Procainamide
			-- Pseudoephedrine
			-- Selective serotonin reuptake inhibitors
			-- Tacrolimus
			-- Theophylline
			-- Tricyclic antidepressants
		- Rest (see parkinsonism)
		- Intention (see cerebellar syndromes/ataxia)
		- Mixed
			-- Amiodarone (mixed tremor with postural, intention, and possibly components)
		-- Lithium (mixed tremor, typically kinetic/postural, but may be intention)
		-- Thalidomide (dose-dependent mixed tremor, typically kinetic/postural, but may be rest)
		-- Valproic acid (dose- and duration-dependent mixed tremor, typically kinetic/postural, but may be rest)
	• Parkinsonism
		- Typical antipsychotic dopamine D2 receptor antagonists
			-- Phenothiazines (eg, chlorpromazine, fluphenazine, mesoridazine, perphenazine, prochlorperazine, promazine, thioridazine, trifluoperazine, and triflupromazine)
			-- Butyrophenones (eg, haloperidol)
			-- Thioxanthenes
			-- Other chemical classes
		- Atypical antipsychotic dopamine receptor antagonists
		- Antiemetic dopamine D2 receptor antagonists (eg, droperidol, metoclopramide, prochlorperazine)
		- Dopamine-depleting drugs (eg, reserpine, tetrabenazine)
		- Alpha-methyldopa
		- Amphotericin B
		- Calcium channel blockers (eg, flunarizine, cinnarizine)
	• Acute akathisia
		- Antipsychotic drugs (particularly older antipsychotics)
			-- Chlorpromazine
			-- Fluphenazine
			-- Haloperidol
			-- Loxapine
			-- Perphenazine
			-- Pimozide
			-- Prochlorperazine
			-- Thioridazine
			-- Thiothixene
			-- Trifluoperazine
		- Antiemetics [In a prospective study, akathisia caused by the antiemetic (and antidopaminergic) prochlorperazine was found in 5% of cancer patients (14).]
			-- Droperidol
			-- Prochlorperazine
		- Calcium channel blockers
		- Selective serotonin reuptake inhibitors (SSRIs)
		- Tricyclics antidepressants
	• Acute dystonia (see medication list for drug-induced parkinsonism)
	• Tardive dyskinesia (see medication list for drug-induced parkinsonism)
	• Tics
		- Aripiprazole (?)
		- Carbamazepine (uncommon)
		- Lamotrigine (uncommon)
		- Methylphenidate (?, controversial)
		- Mirtazapine (uncommon)
		- Montelukast
		- Risperidone (?)
		- Tramadol (uncommon)
		- Venlafaxine (uncommon)
	• Myoclonus
		- Opiates (full agonists and, less commonly, with partial agonist–antagonists; with initial administration, change, or withdrawal)
		- Antidepressants
			-- Lithium
			-- Selective serotonin-reuptake inhibitors (SSRIs)
			-- Tricyclic antidepressants
		- Antipsychotics (typical and less commonly with atypical)
		- Antibiotics
			-- Aminoglycosides (uncommon)
			-- Beta-lactams
			-- Quinolones
		- Antiemetics
		- Antiepileptics
			-- Gabapentin
			-- Lamotrigine (uncommon)
			-- Pregabalin
			-- Valproic acid
		- Antiparkinsonian
			-- Amantadine
			-- Dopamine agonists
			-- L-dopa
		- Benzodiazepines
		- Dementia-related
			-- Cholinesterase inhibitors
			-- Memantine
		- General anesthetics
	• Cerebellar syndromes/ataxia
		- Antiepileptic drugs
			-- Benzodiazepines (especially in children with epilepsy)
			-- Carbamazepine
			-- Ezogabine
			-- Felbamate
			-- Fosphenytoin
			-- Gabapentin
			-- Lacosamide
			-- Lamotrigine
			-- Oxcarbazepine
			-- Phenobarbital
			-- Phenytoin (common)
			-- Rufinamide
			-- Valproic acid (especially with hyperammonemia)
			-- Zonisamide
		- Antimicrobials
			-- Metronidazole (high doses associated with ataxia and development of cerebellar hyperintensities on T2-weighted MRI)
			-- Piperazine (antihelminthic agent)
		- Antineoplastics
			-- Cyclosporine (usually mild and transient)
			-- Cytarabine (typical onset 2-4 days after first dose and typically resolves within weeks)
			-- Tacrolimus (usually mild and transient)
		- Psychiatric medications
			-- Benzodiazepines (especially in children and the elderly)
			-- Lithium (intention tremor with chronic use and toxicity, particularly with SILENT)
			-- SSRIs (?)
Drug-induced intracranial hypertension (pseudotumor cerebri)
	• Growth hormone (recombinant)
	• Lithium
	• Tetracycline-class antibiotics
		- Doxycycline
		- Minocycline
		- Tetracycline
		- Tigecycline
	• Vitamin A vitamers (retinoids)
		- All-trans retinoic acid
		- Isotretinoin
		- Vitamin A (at doses > 25,000 IU daily)
Demyelinating neuropathies
	• Amiodarone
	• Dichloroacetate
	• Immune checkpoint inhibitors
	• Levamisole
	• Tumor necrosis factor-alpha antagonists
Drug-induced progressive multifocal leukoencephalopathy
	• Corticosteroids
	• Cyclophosphamide
	• Dimethyl fumarate
	• Fingolimod
	• Monoclonal antibodies (eg, alemtuzumab, natalizumab, rituximab)
	• Mycophenolate mofetil
Drug-induced vasculitis
	Large-vessel vasculitis
		• Anti-tumor necrosis factor-alpha agents
			- Adalimumab
			- Etanercept
		• Granulocyte colony-stimulating factor
			- Chemotherapy plus granulocyte colony-stimulating factor
			- Pegfilgrastim
	Antineutrophil cytoplasmic antibody (ANCA)–associated (small vessel) vasculitis (AAV)
		• Antibiotics
			- Aminopenicillins
			- Cefotaxime
			- Minocycline
			- Penicillin
			- Quinolones
			- Sulfonamides
		• Anti-thyroid drugs
			- Benzylthiouracil
			- Carbimazole
			- Methimazole
			- Prophythiouracil
		• Anti-tumor necrosis factor-alpha agents
			- Adalimumab
			- Etanercept
			- Infliximab
		• Psychoactive agents
			- Clozapine
			- Thioridazine
		• Miscellaneous drugs
			- Allopurinol
			- D-penicillamine
			- Hydantoins (phenytoin, fosphenytoin, dantrolene)
			- Hydralazine
			- Levamisole
			- Sulfasalazine
			- Thiazides
Drug-induced headaches
	• Dipyridamole
	• Isosorbide mononitrate
	• Lithium
	• Nitric oxide
	• Nitroglycerine
	• Oral contraceptives
Drugs associated with optic neuropathy/retinopathy
	• Amiodarone
	• Bisphosphonates
	• Bromocriptine (C)
	• Chloramphenicol
	• Chloroquine and hydroxychloroquine (B)
	• Cimetidine (B)
	• Clioquinol (antifungal and antiprotozoal drug)
	• Corticosteroids (C)
	• Cyclo-oxygenase (COX)-2 inhibitors (C)
	• Cyclophosphamide (C)
	• Cyclosporine
	• Digitalis (C)
	• Disulfiram (B)
	• Ethambutol
	• Fluorouracil (C)
	• Interferon
	• Isoniazid (C)
	• Isotretinoin and other retinoids
	• Linezolid (antibiotic)
	• Lithium (C)
	• Mellaril (pigmentary retinopathy)
	• Methotrexate
	• Metronidazole
	• Naproxen (C)
	• Omeprazole (ie, nutritional optic neuropathy from chronic omeprazole use)
	• Oral contraceptives (C)
	• Paroxetine (C)
	• Phosphodiesterase type 5 (PDE-5) inhibitors (eg, sildenafil)
	• Quetiapine (C)
	• Quinine (B)
	• Streptomycin (C)
	• Sulfonamides (C)
	• Tamoxifen (B)
	• Tetracyclines (C)
	• Topiramate (C)
	• Vigabatrin
	• Vincristine (B)
	• Vinca alkaloids (C) (antineoplastic/antimitotic)
Drugs associated with ototoxicity/vestibulotoxicity
	• Acetylsalicylic acid
	• Aminoglycoside antibiotics
	• Chlorhexidine gluconate (for gingivitis)
	• Chloroquine
	• Cisplatin
	• Erythromycin
	• Ethacrynic acid
	• Furosemide
	• Naproxen
	• Quinidine
	• Quinine
Drugs associated with peripheral neuropathy
	A rating
		• Amiodarone
		• Capsaicin
		• Chloramphenicol
		• Cisplatin
		• Colchicine
		• Dapsone
		• Ethambutol
		• "Gold salts" (sodium aurothiomalate; antirheumatic)
		• Hexachlorophene
		• Hydralazine
		• Isoniazid
		• Metronidazole
		• Nitrofurantoin
		• Nitrous oxide
		• Perhexiline (prophylactic antianginal agent used primarily in Australia and New Zealand)
		• Pyridoxine
		• Rabies vaccine
		• Suramin (treatment of African sleeping sickness and river blindness)
		• Tacrolimus
		• Taxoids [derivatives from taxol (ie, paclitaxel) developed for their anticancer chemotherapeutic properties]
		• Thalidomide
		• L-tryptophan (impure)
		• Vidarabine (antiviral)
		• Vinca alkaloids (antineoplastic/antimitotic)
	B rating
		• Chloroquine
		• Cytarabine
		• Disulfiram
		• Ethionamide (anti-tuberculous agent)
		• Glutethimide (sedative hypnotic)
		• Hexamethylmelamine (altretamine; chemotherapeutic agent)
		• Lidocaine
		• Methaqualone
		• Naproxen
		• Penicillamine
		• Phenytoin
		• Rubella vaccine
		• Sulfasalazine
		• Sulfonamides
Drug-associated sensory neuronopathy
	• Platinum-based chemotherapy
	• Pyridoxine
Drug-associated neuromuscular transmission syndromes
	• Aminoglycoside antibiotics
	• Botulinum neurotoxin
	• Interferon alpha
	• Lincomycin (antibiotic)
	• Penicillamine
	• Polymyxin
	• Quinine
	• Succinylcholine
	• Tetracyclines
	• Trimethaphan
	• Tubocurarine
	• Vecuronium
Drug-associated myopathies
	• Necrotizing myopathies
		- Aminocaproic acid (clotting promoter)
		- Clofibrate
		- Corticosteroids (acute)
		- Gemfibrozil
		- Hypervitaminosis E (uncontrolled self-medication)
		- Isotretinoin
		- Statins (eg, lovastatin, pravastatin, simvastatin)
	• Hypokalemic myopathy
		- Amphotericin B
		- Carbenoxolone (treatment of peptic, esophageal, and oral ulceration and inflammation)
		- Diuretics
		- Laxatives
	• Amphophilic cationic drug myopathy (lysosomal storage, "lipidosis")
		- Amiodarone
		- Chloroquine/hydroxychloroquine
		- Perhexiline (prophylactic antianginal agent used primarily in Australia and New Zealand)
		- Plasmocid (antimalarial)
		- Quinacrine (antiprotozoal, antirheumatic, and an intrapleural sclerosing agent; unavailable in the U.S. since 2020)
	• Myopathy associated with impaired protein synthesis
		- Ipecac syrup/emetine (surreptitious use in individuals with eating disorders)
	• Antimicrotubular myopathy
		- Colchicine
		- Vincristine
	• Inflammatory myopathy
		- D-penicillamine
		- Procainamide
	• Eosinophilia-myalgia syndrome (fasciitis, perimyositis, microangiopathy)
		- Tryptophan (synthetic, impure?)
	• Mitochondrial myopathy
		- Zidovudine
	• Steroid myopathy (chronic)
	• Malignant hyperthermia
		- Induction of anesthesia with halogenated hydrocarbon inhalation anesthetic and depolarizing skeletal muscle relaxants
Source: Modified from (Spencer and Schaumburg 2000)

Pathophysiology

Pathogenetic mechanisms of drug-induced neurologic disorders can be categorized by the primary organ or system affected:

(1) Direct neurotoxicity or primary neurotoxicity
(2) Indirect mechanisms or secondary neurotoxicity (ie, neurotoxicity due to drug-induced disturbances of other organs)
(3) Predisposing or risk factors for drug-induced neurologic disorders

A toxidrome or toxic syndrome can be defined as a constellation of findings that are evident either from the physical examination of the patient or from ancillary testing, which may result from drug overdose or withdrawal or exposure to a toxin.

Direct neurotoxicity. Drugs may produce direct neurotoxicity by multiple different mechanisms, including actions on neurotransmitters or their receptors; ion channels; neuronal metabolism; glial metabolism; or neuronal proteins. Examples include the following: (1) dystonic reactions and tardive dyskinesia with dopamine-receptor antagonists, most often antipsychotic drugs; (2) SILENT (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity) with lithium neurotoxicity (01); (3) levodopa-induced dyskinesias; (4) augmentation and impulse control disorders with dopaminergic medications (eg, in restless legs syndrome); (5) neuroleptic malignant syndrome; and (6) serotonin syndrome.

For direct neurotoxic effects, the drugs must either act on the peripheral nervous system or they must cross the blood-brain barrier. Despite this barrier, lipid-soluble molecules (eg, benzodiazepines) readily enter the brain. Damage to the blood-brain barrier facilitates the passage of drugs that normally do not cross the blood-brain barrier; in particular, diseases in which the blood-brain barrier is damaged (eg, multiple sclerosis, malignant brain tumors, and meningitis) may facilitate direct neurotoxic drug effects. Drugs may also cross the blood-brain barrier by being introduced into the ventricles or intrathecal space (eg, instillation of antibiotics via intraventricular catheter, myelography contrast dye).

Various direct mechanisms of neurotoxicity have been established for different drugs. These include (1) disturbances of brain energy metabolism (and sequelae); (2) uncoupling of oxidative phosphorylation (eg, aspirin, indomethacin); (3) disturbances of oxygen consumption; (4) enzymatic dysfunction; (5) ion channel disturbances; (6) mitochondrial dysfunction (eg, zidovudine-induced mitochondrial myopathy); (7) neurotransmitter disturbances (eg, atropine produces memory impairment by reducing CNS acetylcholine); (8) toxic metabolites (Trojan horse medication); (9) disturbance of the proteome; (10) drug-induced apoptosis; etc.

Secondary drug-induced neurologic disorders. The nervous system may be secondarily affected by adverse drug reactions affecting other body systems. Examples of such secondary drug-induced neurologic disorders include (1) dizziness, syncope, and cerebral ischemia from drug-induced cardiac arrhythmias, hypotension, or orthostatic hypotension; (2) cerebral hemorrhage with anticoagulation, especially over-anticoagulation; (3) encephalopathy from drug-induced renal or hepatic failure; (4) convulsions from drug-induced hyponatremia, hypocalcemia, or hypoglycemia; and (5) tremor or myopathy from drug-induced hyperthyroidism (iatrogenic or surreptitious).

Predisposing conditions for drug-induced neurologic disorders. Risk factors that predispose a patient to the development of drug-induced neurologic disorders include (1) genetic predisposition (ie, pharmacogenetic factors); (2) old age; (3) compromised brain function (eg, degenerative, mass lesions, stroke, head injury); (4) systemic diseases (eg, organ failure, AIDS); (5) noncompliance; and (6) pregnancy (teratogens).

Pharmacogenetics. Pharmacogenetics investigates the influence of genetic factors on the action of drugs. Existing drug development does not incorporate genetic variability in pharmacokinetics and pharmacodynamics of new drug candidates, with the potential for serious, but seemingly idiosyncratic, drug-gene interactions resulting in severe adverse drug reactions. Polymorphisms in the genes that code for drug-metabolizing enzymes, drug transporters, drug receptors, and ion channels can affect the efficacy of drug treatment and the likelihood of developing an adverse drug reaction. Examples of adverse drug reactions with a pharmacogenetic basis are malignant hyperthermia and extrapyramidal movement disorders in psychiatric patients on neuroleptic therapy.

P450 enzymes. Enzymes controlling drug metabolism are relevant to pharmacogenetics. The cytochrome P450 enzyme system consists of a large family of proteins that are involved in the synthesis or degradation of a vast number of endogenous compounds as well as the metabolism of exogenous toxins. P450 enzymes can alter, abolish, or enhance drug metabolism. Most clinically used drugs are cleared through the action of P450 enzymes: CYP2D6, CYP3A4, and CYP2C19. For example, drugs used in neurology and psychiatry practice, which are metabolized by the CYP2D6 enzyme, include tricyclic antidepressants, antipsychotics, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and opioid analgesics.

CYP2C19 is the gene encoding S-mephenytoin hydroxylase, and its mutations lead to poor metabolism of various drugs that include amitriptyline, citalopram, clomipramine, diazepam, imipramine, and mephenytoin.

Epigenetic factors. Gene regulation by genetics involves a change in the DNA sequence whereas epigenetic regulation involves alteration in chromatin structure and methylation of the promoter region, representing a means of inheritance without associated DNA sequence alterations (05). Epigenetic factors may explain changes in gene expression that persist long after drug exposure has ceased. One hypothesis proposes that some iatrogenic diseases, such as tardive dyskinesia, are epigenetic in nature.

Drug-drug interactions. Drug-to-drug interactions contribute significantly to adverse drug reactions. There may be unpredictable potentiation of synergistic effect resulting in neurotoxicity if two drugs with similar mechanisms of action are used concomitantly. The interaction of a drug acting on the nervous system with a drug acting on another system that interferes with the metabolism of the CNS drug may lead to neurotoxicity. Anticonvulsants have clinically significant interactions with other drugs used in brain tumor patients. A drug interaction resulted in elevated phenytoin levels after initiation of erlotinib therapy in a patient who was receiving phenytoin (12).

In polypharmacy there may be a combination of drug-drug and drug-disease interactions. An example is serotonin syndrome that developed after the use of tramadol and ziprasidone in a patient with an indwelling deep brain stimulator for Parkinson disease (06).

Systemic diseases. Patients suffering from systemic diseases are more prone to develop adverse drug reactions. In particular, drug-induced neurologic disorders are more likely to develop in patients with diseases of the kidneys and liver. Several cases of neurotoxicity resulting from treatment of herpes zoster with acyclovir or valacyclovir have been reported in patients with renal failure, whereas this is a rare side effect of these drugs in patients with normal renal function (22).

Risk factors related to drugs. Factors related to the drugs that influence neurotoxicity are:

Dose. Some of the neurotoxic effects are dose-related, and some occur only as an overdose effect. Management of non-neurotoxic side effects of drugs enables higher doses of these drugs to be given, leading to neurotoxicity. An example of this is high-dose chemotherapy enabled by the addition of granulocyte colony stimulating factor (filgrastim), which counteracts neutropenia. Eventually, neurotoxicity becomes the limiting factor with this approach.

Rate of drug delivery. Faster rates of intravenous delivery of some drugs may produce transient neurologic disturbances.

Route of administration. Some drugs, which usually do not cross the blood-brain barrier, have neurotoxic effects only when applied directly to the CNS such as by intrathecal or intraventricular routes.

Drug interactions. Interactions may occur with concomitant medications.

Drug-disease interaction. Drugs may unfavorably influence the course of the neurologic condition being treated.

Drug withdrawal. Withdrawal of drugs after prolonged use may produce neurologic disorders.

Principles of management of drug-induced neurologic disorders

Clinical diagnosis. A careful history of drug use and a high index of suspicion are the most important factors in the diagnosis of drug-induced neurologic disorders. The physician should obtain a complete list of current medications and medications the patient has taken previously (from at least several months before the onset of the condition that is possibly drug-induced) and should consider other possible offending medications that might be available from family members and other sources. Drugs most likely to cause such disorders should be considered first.

Diagnostic procedures. Laboratory studies of patients with neurologic disorders induced by drugs are like those used for nondrug-induced disorders.

MRI lesions of the splenium can develop in some epileptic patients after rapid anticonvulsant withdrawal. CAR-T-cell therapy-induced neurologic deficits are not always easily observable clinically and MRI is mostly normal, but diagnostic studies that more directly evaluate neuronal functioning, like EEG and PET scan, can reliably detect and predict neurologic dysfunction (21).

Detection of biomarkers of neurotoxicity may be useful for detection of toxic effects of drugs in the absence of clinical features or any clues in routine laboratory studies and imaging procedures. Detection of genetic biomarkers associated with neurotoxicity induced by single-agent and combination platinum chemotherapy can be useful in reducing the adverse effects of chemotherapy for cancer (17).

Prevention. This is the most important approach to reduce the incidence of adverse drug reactions. When several therapeutic alternatives are available, the one with the least neurotoxicity should be selected, particularly in susceptible patients with risk factors. Dose-related adverse effects may be reduced by slow, stepwise increases in dosage.

Epidemiological studies indicate that antithrombotic agent-associated cerebral hemorrhages constitute a significant proportion of adverse drug reactions. Preventive measures should be considered to reduce these fatalities.

Treatment. Usually, the first step is discontinuation of the responsible drug in case of severe adverse drug reactions. Symptomatic treatment may be given for persisting symptoms.

Special considerations

Patients with preexisting neurologic disorders, renal insufficiency, and advanced age may be particularly susceptible to the neurotoxicity of antibiotics, and this can be reduced by dosage adjustments in high-risk populations (13).

Developmental toxicity. Developmental toxicity refers to adverse effects on the developing organism that result from exposure prior to conception during the prenatal period or postnatally up to the time of sexual maturity. Adverse developmental outcomes include the following groups of developmental toxicities (10).

Mortality. Mortality resulting from developmental toxicity may occur at any time from early conception to post-weaning (eg, embryo-fetal death is a subset of mortality resulting from developmental toxicity). This incorporates pre- or peri-implantation loss, early or late resorption, abortion (including miscarriage), stillbirth, neonatal death, and peri-weaning loss.

Dysmorphogenesis (structural abnormalities). Dysmorphogenic effects are generally seen as malformations or variations of the skeleton or soft tissues of the offspring and are commonly referred to as structural abnormalities. Dysmorphology includes malformations, variations, deformations, and disruptions.

Alterations to growth. Alterations to growth are generally seen as growth retardation, although excessive growth or early maturation may also be considered alterations to growth. Body weight is the most common measurement for assessing growth rate, but crown-rump length and anogenital distance may also be measured. Sometimes it may not be clear if an effect is a direct structural alteration or an inhibition of growth (eg, reduced ossification could be either). A distinction must be made on review of all relevant data.

Functional impairment. Functional toxicities could include any persistent alteration of normal physiologic or biochemical function, but typically only developmental neurobehavioral effects and reproductive function are measured. Common assessments include locomotor activity, learning and memory, reflex development, time to sexual maturation, mating behavior, and fertility. Functional toxicity includes such outcomes as neurodevelopmental effects, deafness, endocrinopathy, and impairment of reproduction.

Teratogens. A teratogenic drug has the potential to cause developmental malformations or birth defects to a fetus when taken by a pregnant woman. Common central nervous system birth defect prevalence at birth in the United States (from selected states) is shown in the Table 3.

Table 3. Central Nervous System Birth Defect Surveillance Data from Selected States (1995–1999)*

Birth defect	Range in rates (per 10,000 live births)
Anencephalus	0.00 – 4.92
Anophthalmia/microphthalmia	0.39 – 3.73
Anotia/microtia	0.19 – 6.43
Hydrocephalus without spina bifida	0.59 – 19.34
Microcephalus	0.51 – 15.65
Spina bifida without anencephalus	1.36 – 8.08
*Rates represent data contributed to the National Birth Defects Prevention Network from 30 states. Rates for most of the states were based on 5 years of data from 1995–1999. However, four states provided data for only 1 to 3 years. Not all states reported data for all defects. State birth defect surveillance programs vary considerably in their methodologies, definitions, and inclusion criteria. Because of these differences, the data cannot be combined to give overall rates for the United States; therefore, data are presented as a range of rates. Sources: (18; 08).

The Swedish system for the classification of fetal risk of drugs was the first of its kind when it was implemented in 1978 (23). In Sweden, drugs for use in pregnant women are classified in four general categories (A to D). The U.S. Food and Drug Administration (FDA) introduced a classification system in 1979 (A to D, and X). However, the definitions differed considerably between the Swedish system and the FDA system, producing a different allocation of drugs to the various categories. Although the Swedish system was widely accepted, the FDA system proved more controversial, in part because of shortcomings in the category definitions. For example, the FDA system required an unrealistically high quality of data to be available, including the availability of controlled studies in pregnant women that fail to demonstrate a risk to the fetus, before a drug could be assigned to category A. Consequently, most drugs on the U.S. market were allocated to category C and interpreted as "risk cannot be ruled out."

Table 4. The Swedish System for Classification of Drugs Used During Pregnancy

	Category A: Drugs have been extensively used and/or there are reliable clinical data indicating no evidence of disturbance of the reproductive process.
	Category B: Drugs for which data from pregnant women are insufficient to make any solid estimation of human teratogenic risk, and classification is, therefore, based on animal data, with allocation to three subgroups.
	Category C: The pharmacological action of the drug may have undesirable effects on the human fetus or newborn infant.
	Category D: Drugs for which human data indicate an increased incidence of malformations.
	(23)

Table 5. The FDA System for Classification of Drugs Used During Pregnancy (1979–2015)

	Category A: Adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters). If animal reproduction studies are also available and they fail to demonstrate a risk to the fetus, the labeling must indicate this. Example drugs include levothyroxine and folic acid. The required drug labeling indicated that: "Studies in pregnant women have not shown that [the drug] increases the risk of fetal abnormalities if administered during the first (second, third, or all) trimester(s) of pregnancy. If this drug is used during pregnancy, the possibility of fetal harm appears remote. Because studies cannot rule out the possibility of harm, however, [the drug] should be used during pregnancy only if clearly needed. ... Reproduction studies have been performed in [specified animals and doses] and have revealed no evidence of impaired fertility or harm to the fetus due to [the drug]."
	Category B: Either (1) animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; or (2) animal reproduction studies have shown an adverse effect (other than decrease in fertility), but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus during the first trimester of pregnancy (and there is no evidence of a risk in later trimesters). Example drugs include metformin, hydrochlorothiazide, cyclobenzaprine, and amoxicillin. The required drug labeling indicated either: (1) "Reproduction studies have been performed in [specified animals and doses] and have revealed no evidence of impaired fertility or harm to the fetus due to [the drug]. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed." (2) "Reproduction studies in [specified animals] have shown [specified findings at specified doses]. Studies in pregnant women, however, have not shown that [the drug] increases the risk of abnormalities when administered during the first (second, third, or all) trimester(s) of pregnancy. Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy. Nevertheless, because the studies in humans cannot rule out the possibility of harm, [the drug] should be used during pregnancy only if clearly needed."
	Category C: Either (1) animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks; or (2) there are no animal reproduction studies and no adequate and well-controlled studies in humans. Example drugs include gabapentin, amlodipine, and trazodone. The required drug labeling indicated either of the following: (1) "[The drug] has been shown to be teratogenic (or to have an embryocidal effect or other adverse effect) in [specified animals] when given [at specified doses]. There are no adequate and well-controlled studies in pregnant women. [The drug] should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus." (2) "Animal reproduction studies have not been conducted with [the drug]. It is also not known whether [name of drug] can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. [The drug] should be given to a pregnant woman only if clearly needed."
	Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. Example drugs include losartan. The required drug labeling indicated the following: "[The drug] can cause fetal harm when administered to a pregnant woman. ... If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus."
	Category X: Studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit. Example drugs include atorvastatin, simvastatin, methotrexate, and finasteride. The required drug labeling indicated the following: "[The drug] may (can) cause fetal harm when administered to a pregnant woman. ... [The drug] is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus."
	(09)

Based on critiques of the prior FDA system since the early 1990s, the FDA instituted a new system in 2015. Clinicians and patients were often confused by the meaning of the pregnancy risk categories because the system was overly simplistic, led to misinformation, and did not adequately address the available information.

The FDA's A, B, C, D, and X risk categories, in use since 1979, have now been replaced with narrative sections and subsections. The Pregnancy subsection provides information about dosing and potential risks to the developing fetus and registry information that collects and maintains data on how pregnant women are affected when they use the drug or biological product. The Lactation subsection includes drugs that should not be used during breastfeeding, known human or animal data regarding active metabolites in milk, as well as clinical effects on the infant. Other information may include pharmacokinetic data like metabolism or excretion, a risk and benefit section, as well as timing of breastfeeding to minimize infant exposure. In the subsection entitled "Females and Males of Reproductive Potential," relevant information on pregnancy testing or birth control before, during, or after drug therapy and a medication’s effect on fertility or pregnancy loss are provided when available.

Neonatal abstinence syndrome. Maternal intake of opioids, antidepressants, antiepileptics, and antipsychotics may cause neonatal withdrawal syndromes ("neonatal abstinence syndrome"), which are caused by the birth-related discontinuation of fetal exposure to the responsible drug(s). Symptoms may occur within a few hours to 1 month after delivery and may include feeding disorders, tremors, irritability, hypotonia/hypertonia, vomiting, and persistent crying (04). Neonatal neurologic and behavioral effects can also be caused by residual pharmacological effects of drugs that have accumulated in neonatal tissues.

Geriatric age group. The elderly who are frequently on multidrug therapy and are 2 to 3 times more likely to experience adverse drug reactions than young people. Five to 20% of all hospital admissions are related to adverse drug reactions in older people, among which 40% to 70% could be prevented, but identifying these is challenging because they often present as common geriatric problems, such as falls or delirium, that are often attributed to the aging process or underlying diseases (29).

The brain is an especially sensitive drug target in old age. Elderly patients are particularly prone to adverse effects of psychotropic agents, including benzodiazepines, because of the altered pharmacokinetics. Memory and psychomotor impairment are more pronounced in the elderly on benzodiazepine treatment as compared with younger controls. The elderly are also more susceptible to antimuscarinic effects of some antidepressants and neuroleptic drugs and may manifest agitation, confusion, and delirium. These drugs should be used sparingly in elderly patients. If their use is essential, the dosage should be slowly titrated to a clearly defined clinical or biochemical therapeutic goal starting from a low initial dose.