Vascular Headaches

Many drugs cause headaches by inducing cerebral vasodilation or vasoconstriction. These include antihistamines, sympathomimetics, amyl nitrate, nitroglycerin, nicotinic acid, hydralazine, prazosin, pentoxifylline, cyclandelate, nifedipine, perhexiline, theophylline, aminophylline, terbutaline, and dipyridamole.

Headache may also occur during treatment with cyclosporine, bromocriptine, dopamine, and some nonsteroidal anti-inflammatory drugs such as naproxen, ketoprofen, diclofenac, alclofenac, and ibuprofen. Severe and persistent headache may also occur in some patients treated with H ₂ -receptor antagonists (e.g., cimetidine and ranitidine) and proton pump inhibitors (e.g., omeprazole and lansoprazole).

Headache is a common transient reaction with intravenous immunoglobulin therapy, particularly in migraine patients, perhaps due to reversible cerebral vasoconstriction syndrome. This syndrome has also been reported with illicit drugs such as cannabis, cocaine, amphetamines, and lysergic acid diethylamide (LSD). Selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), α-sympathomimetics, nasal decongestants, triptans, ergot alkaloid derivatives, nicotine patches, and herbal medications such as ginseng have also been implicated.

Medication Overuse Headache

Medication overuse headache is now recognized as the third most frequent form of headache encountered in clinical practice and one of the most costly neurologic disorders ; it is often unrecognized and is a significant contributor to health care costs. A paradoxical increase in headache frequency commonly occurs in migraine or cluster headache patients taking excessive ergotamine-containing preparations or triptans on a regular basis. Treatment involves gradual withdrawal of the offending medications and commencement of another prophylactic medication. Chronic analgesic dependency may have a similar effect in patients with primary headache disorders, leading to rebound headaches and chronic daily headache.

Idiopathic Intracranial Hypertension (Pseudotumor Cerebri)

A number of drugs may cause idiopathic intracranial hypertension (pseudotumor cerebri), characterized by headache, papilledema, diplopia, and visual impairment. These include oral contraceptives, estrogens and progestational agents, growth hormone, anabolic steroids, antibiotics (tetracyclines, minocycline, ampicillin, nalidixic acid, nitrofurantoin), nonsteroidal anti-inflammatory drugs (naproxen, ibuprofen, indomethacin), vitamin A, retinoids (isotretinoin, etretinate), danazol, amiodarone, perhexiline, thyroxine, ketamine, nitrous oxide, corticosteroids (or corticosteroid withdrawal), and intrathecal liposomal cytarabine.

Aseptic Meningitis

Drug-induced aseptic meningitis may occur with the use of nonsteroidal anti-inflammatory drugs or cotrimoxazole, particularly in patients with systemic connective tissue diseases, and occasionally with other antimicrobials, such as sulfasalazine, penicillin, amoxicillin, ciprofloxacin, and cephalosporins, and with carbamazepine and pentoxifylline. Aseptic meningitis may also develop after intravenous immunoglobulin therapy, and treatment with other immunomodulatory agents such as infliximab, leflunomide, azathioprine, and muromonab-CD3. Intrathecal anesthetics, contrast media, methylprednisolone, methotrexate, and cytarabine may also cause aseptic meningitis.

Behavioral Toxicity

Nonspecific symptoms such as drowsiness, insomnia, irritability, restlessness, anxiety, mood changes, vivid dreams and nightmares, and increased sensitivity to light and sound may occur with a wide range of medications. These symptoms may be the prelude to a more florid delirious state, and usually subside with dose reduction. They are encountered most frequently with tricyclic antidepressants, lithium, amphetamines, phenothiazines, barbiturates, glucocorticoids, cholinergic drugs, levodopa, anticonvulsants, some antihistamines, and acetylcholinesterase inhibitors. Similar symptoms may occur after withdrawal of drugs such as benzodiazepines and SSRIs.

Delirium and Confusional States

Drugs are an important cause of delirium and confusional states, particularly in the elderly. Although various drugs may cause such reactions, the sedatives and hypnotics are the most common. Other important causative agents include benzodiazepines, antiparkinsonian drugs, and antidepressants, including the SSRIs. SSRIs also can lead to the serotonin syndrome, which usually results from an interaction between serotonergic drugs and monoamine oxidase inhibitors or tricyclic agents and is characterized by an altered mental state with fever, confusion, agitation, tremor, myoclonus, shivering, hyperreflexia, and incoordination. Abrupt withdrawal of SSRI drugs may also result in a confusional or delirious state with twitching, hypertonia, and sensory symptoms. With the recent influenza epidemics and increased use of oseltamivir, delirious states with increased motor activity have been frequently reported.

Affective Disorders

Drug-induced depressive reactions are common and represent approximately 1 percent of reported adverse drug reactions. Reserpine and α-methyldopa were among the first drugs recognized to cause depression, but the newer antihypertensive agents do not commonly depress mood. Depression may occur in patients on corticosteroids, and is the most common psychiatric symptom in patients receiving levodopa. Oral contraceptives, anabolic steroids, digoxin, indomethacin and naproxen, sulfonamides, retinoids, disulfiram, cycloserine, antineoplastic and antiepileptic drugs, baclofen, barbiturates, benzodiazepines, phenothiazines, butyrophenones, interferons as well as withdrawal from benzodiazepines, amphetamines, and fenfluramines may also cause depression. A review of depression as an adverse drug reaction found that the best evidence supporting this association related to corticosteroids, contraceptive implants (progestin-releasing), gonadotropin-releasing hormone agonists, interferon-α, interleukin-2, mefloquine, and to a lesser extent propranolol.

Although euphoria is common in patients on various drugs, manic or hypomanic reactions are uncommon. Such reactions may occur with glucocorticoids or corticotropin, anabolic steroids, thyroid hormone, captopril, chloroquine, isoniazid, ranitidine and cimetidine, dopaminergic agents, baclofen, opiates, pentazocine, monoamine oxidase inhibitors, tricyclic antidepressants, iproniazid, cyclosporine, sympathomimetic amines, amphetamines, benzodiazepines, procyclidine, phenylpropanolamine, and hallucinogens. A mood disturbance with manic features is the commonest psychiatric condition caused by corticosteroids, considered responsible for 54 percent of cases of organic mania in one study. In another study it was found that 13 of 50 individuals receiving between 50 and 150 mg of methylprednisolone or fluocortolone developed manic-like episodes.

Antidepressants may induce mania in those who have bipolar affective disorder. An increased risk of a manic episode has been reported with the introduction of tricyclic antidepressants or monoamine oxidase inhibitors, but not with standard-dose SSRIs. Agitation and hypomania may also occur in the serotonin syndrome.

Psychoses

Various drugs have been reported to cause paranoid and schizophreniform psychotic reactions characterized by delusions, hallucinations, and emotional and thought disorder, particularly in the elderly. Although these drug-induced disorders closely resemble the naturally occurring psychoses, such individuals do not appear predisposed to develop a chronic psychotic condition.

Hallucinatory States

Various drugs may cause hallucinations without other features of delirium or psychosis. The hallucinations are usually visual, extremely vivid and colored, and often of animals, sometimes having microptic or lilliputian dimensions. The most common drugs are tricyclic antidepressants, benzodiazepines, vigabatrin, bromides, methylphenidate, atropine and other anticholinergic drugs after parenteral (or even topical) administration, ephedrine, amantadine, bromocriptine, pergolide, levodopa, digoxin, diltiazem, β-adrenergic blockers, prazosin, captopril, disopyramide, pentazocine, buprenorphine, indomethacin, salicylates, cimetidine, aminophylline, acyclovir, and cyproheptadine, as well as cannabis and LSD. Hallucinations, usually auditory and less often visual, are also a feature of withdrawal from alcohol, barbiturates, benzodiazepines, and baclofen.

Cognitive Impairment

A number of drugs may cause transient memory impairment, including clioquinol, isoniazid, baclofen, benzhexol, and antidepressant drugs that have a central anticholinergic action. More severe, but reversible, cognitive impairment that may mimic dementia sometimes develops with chronic use of benzodiazepines, barbiturates, bromides, and chlorpromazine, and with glucocorticoid and interleukin administration. A number of antiepileptic drugs may adversely affect cognitive functions. Early studies suggested that such effects were less frequent with carbamazepine or sodium valproate than with phenytoin or phenobarbital. However, more recent studies have shown that, at therapeutic serum concentrations, the adverse effects are comparable for these four drugs. The newer antiepileptics gabapentin, lamotrigine, vigabatrin, tiagabine, remacemide, topiramate, and levetiracetam likely have fewer cognitive effects. In a review of cognitive toxicity of agents used to treat social anxiety disorder, impairment was least with fluvoxamine, paroxetine, and escitalopram, moderate with propranolol, sertraline, and dothiepin, and more severe with pregabalin, amitriptyline, lorazepam, and mianserin.

Dystonic-Dyskinetic Reactions

Acute dystonic reactions are well recognized with neuroleptic drugs such as the phenothiazines and butyrophenones, metoclopamide, tricyclic antidepressants, and, less frequently, phenytoin, carbamazepine, propranolol, ondansetron, fluoxetine, flunarizine, and cinnarizine. The onset is usually within the first few days of starting treatment and may be abrupt. The dystonia may be confined to the head and neck, causing facial grimacing, trismus, abnormal tongue movements, oculogyric crises, orofacial dyskinesias, torticollis, and retrocollis, but may also be more generalized, with slow writhing movements of the limbs and more prolonged tonic contractions of the axial and limb muscles leading to opisthotonos, lordosis, tortipelvis, and bizarre gait. The character of the movements may lead to a mistaken diagnosis of hysteria, tetanus, tetany, or epilepsy. Such reactions occur in around 6 percent of patients exposed to typical neuroleptics and 1 to 2 percent of those taking atypical neuroleptics. Despite their dramatic and at times alarming nature, the acute dystonias are usually self-limited and remit once the drug is discontinued; severe reactions may be terminated by the intravenous administration of benztropine or diazepam.

Dyskinetic reactions involving the lips, face, and tongue, and at times the limbs and trunk, are common in parkinsonian patients treated with levodopa. These dyskinesias may develop early during the course of treatment with levodopa (or with various dopamine agonists) and respond to a reduction in dose. With prolonged treatment, dyskinesias become an increasing problem, tending to occur at times of maximal response to levodopa and alternating with periods of akinesia and severe rigidity (the “on-off” phenomenon). The administration of smaller, more frequent doses of levodopa, or a reduction in overall dose and the introduction of a dopamine agonist, is sometimes helpful in alleviating this common complication of chronic levodopa therapy. More severe cases may require alternative approaches including deep brain stimulation.

Akathisia

Akathisia is a state of motor restlessness characterized by an uncontrollable urge to move about, pace, or even run incessantly. The condition is typically seen in patients taking dopamine-blocking agents such as phenothiazine derivatives and less frequently with the butyrophenones, benzodiazepines, tricyclic antidepressants, SSRIs, levodopa, lithium, monoamine oxidase inhibitors, and vigabatrin. The reported incidence of akathisia with antipsychotic drugs has ranged from 20 to 75 percent and is less frequent with the atypical neuroleptics. It usually remits within days or weeks of withdrawal of the drug, but it may persist for several months and is occasionally permanent.

The most effective treatment for akathisia is to withdraw the offending drug or lower the dose. Benztropine or diphenhydramine is usually effective in controlling akathisia when given by the intramuscular or intravenous route. Propranolol, clonazepam, mirtazapine, amantadine, and mianserin may also be beneficial.

Tardive Dyskinesia and Other Disorders

Tardive dyskinesia is an involuntary movement disorder that occurs most frequently after prolonged treatment with dopamine antagonists, particularly antipsychotic drugs, but also with metoclopramide, promethazine, prochlorperazine, amoxapine, perphenazine, flunarizine, cinnarizine, and tricyclic antidepressants. Early studies found tardive dyskinesia in up to 50 percent of patients treated with antipsychotic drugs, but this frequency appears to be declining since the introduction of the atypical antipsychotic agents. Tardive dyskinesia usually develops after more than 12 months of continuous therapy, although it has been reported with periods as short as 3 months. The condition is more common and more severe in the elderly, in whom it is less likely to remit.

The condition typically takes the form of orobuccal dyskinesias with lip smacking and pursing; sucking; jaw opening and closing; protruding, side-to-side, or writhing movements of the tongue; and facial grimacing. The movements tend to be stereotyped and, when severe, may interfere with speech or swallowing. In some cases, more generalized choreoathetotic movements of the limbs and trunk and repetitive foot tapping are present, at times resembling Huntington chorea. Less frequently, dystonic posturing of the neck and myoclonic jerking of the distal extremities are present as well. Concomitant akathisia or parkinsonism may also occur. Dystonia or dyskinesia may also occur occasionally with abrupt withdrawal of clozapine and other neuroleptic agents.

The pathophysiologic basis for tardive dyskinesia has not been clearly established. The most widely held theory is that, as a result of prolonged dopamine receptor blockade in the corpus striatum, a state of hypersensitivity to endogenous dopamine develops owing to changes in receptor properties or numbers.

The severity of tardive dyskinesia is variable, and the condition is not often disabling. It may remit in up to 40 percent of cases, even on continued therapy, but in some cases the condition persists. Occasionally, remission may occur even several years after withdrawal of antipsychotic drugs. Interruption of therapy when dyskinesia first develops may be beneficial, but there is some evidence that repeated interruptions paradoxically may increase the risk of dyskinesia and its persistence.

The risks of developing tardive dyskinesia should be reduced by using the lowest effective dose of a neuroleptic for the shortest amount of time that is necessary. If tardive dyskinesia is diagnosed, the causative drug should be discontinued when possible. Many drugs have been used to treat established tardive dykinesia, including dopaminergic agents, such as tetrabenazine, bromocriptine, and levodopa, along with drugs with a cholinergic action such as choline, deanol, and lecithin. None has been consistently effective. Other drugs reported to be beneficial in individual cases include baclofen, propranolol, diazepam, tocopherol, levetiracetam, melatonin, and the calcium-channel blockers.

Tardive dystonia may be focal or more generalized and may involve the neck, jaw, limbs, or trunk. It is distinguished from the more frequent orobuccal dyskinesia by the dystonic nature of the disorder. It is often more disabling than tardive dyskinesia. Other tardive syndromes include akathisia, chorea, myoclonus, tremor, tics, or oculogyric crises.

Choreoathetosis

A number of drugs may cause chorea, which is characterized by multifocal, nonstereotyped, “fidgety” or jerky movements and may be associated with the slower movements of athetosis or with dystonia. Chorea has been reported with anticonvulsants (phenytoin overdose, ethosuximide, valproic acid, carbamazepine, phenobarbital), clonazepam withdrawal, anticholinergic drugs (e.g., high doses of benzhexol), tricyclic antidepressants, fluoxetine, amphetamines, methylphenidate, amoxapine, pemoline, cimetidine, theophylline, aminophylline, lithium, methadone, antihistamines, cyclosporine, oxymetholone, intrathecal baclofen, and oral contraceptives. Chorea has also been well described with cocaine use (“crack dancing”).

Parkinsonism

Drug-induced parkinsonism can occur at any age, but it is more common in the elderly and is probably the most common drug-induced movement disorder. It closely resembles idiopathic Parkinson disease. Bradykinesia is usually the most prominent feature, and may be accompanied by facial masking, rigidity, tremor, and gait disturbance. The incidence of tremor is lower than in idiopathic Parkinson disease but has been as high as 50 percent in some series. The drugs most frequently implicated are the phenothiazines, most frequently prochlorperazine, but not clozapine ; haloperidol; the tricyclic andtidepressants; metoclopramide; lithium; and the calcium-channel blockers cinnarizine, flunarizine, and verapamil. The condition is usually reversible after drug withdrawal or dose reduction. In a study of 36 cases of parkinsonism induced by calcium-channel blockers, most patients were found to improve after drug discontinuation, but tremor usually persisted.

In patients who need to continue on neuroleptic therapy, administration of anticholinergic agents such as benzhexol or benztropine may alleviate some of their parkinsonian symptoms; levodopa may aggravate the underlying psychotic disorder and is best avoided or used with caution. Consideration should be given to switching to a drug with fewer parkinsonian risks, such as clozapine.

In some cases, spontaneous improvement occurs even if the causative agent is continued. Prophylactic treatment with anticholinergic agents is not advocated, since it may predispose to the development of an irreversible form of tardive dyskinesia.

Neuroleptic Malignant Syndrome

The neuroleptic malignant syndrome is a serious and potentially lethal complication of treatment with antipsychotic drugs. It is characterized by hyperpyrexia, severe muscular rigidity, and elevated serum creatine kinase (CK) levels (which are considered major diagnostic criteria). Tachycardia, abnormal blood pressure, tachypnea, altered consciousness, diaphoresis, and leukocytosis also occur (and are minor diagnostic criteria). Three major criteria or two major and four minor criteria are considered very suggestive of the diagnosis in the correct clinical context. Other movement disorders associated with the neuroleptic malignant syndrome include tremor, myoclonus, and dystonia.

The drugs most frequently implicated are haloperidol, fluphenazine and other phenothiazines, thioxanthenes, olanzapine, clozapine, and combinations of these drugs either with each other or with lithium, metoclopramide, loxapine, or tricyclic antidepressants. The condition may occur with both high and low doses of either high- or low-potency neuroleptic drugs and may develop after neuroleptic therapy is begun, after an increase in dose, or after the introduction of a second more potent drug. A similar syndrome has been reported after abrupt levodopa withdrawal in patients with Parkinson disease.

In mild cases, complete recovery may occur within days or weeks of stopping the causative drug, but in severe cases metabolic acidosis, myoglobinuria, renal failure, coagulation defects, respiratory failure, shock, seizures, and coma can develop, leading to a mortality rate of up to 20 percent, with persistent neurologic sequelae in 10 percent of survivors.

The underlying pathophysiologic mechanism is uncertain, but the current view is that the condition relates to profound dopamine receptor blockade in the striatum and in the thermoregulatory and vasomotor centers of the hypothalamus.

Treatment involves discontinuation of the causative drug together with vigorous cooling, restoration of fluid and electrolyte balance, and management of any other complications. Specific medications that may be beneficial in reversing the rigidity and akinesia include levodopa, pancuronium, bromocriptine, dantrolene, or a combination of these drugs.

Tremor

Various drugs may cause or aggravate tremor. These include β-adrenergic agonists (e.g., salbutamol, salmeterol), sympathomimetic drugs (e.g., ephedrine, pseudoephedrine, phenylpropanolamine), antiepileptic agents (e.g., sodium valproate), antidepressants and mood stabilizers (e.g., tricyclic antidepressants, SSRIs, lithium), neuroleptic agents (e.g., phenothiazines, butyrophenones), anti-arrhythmics (e.g., amiodarone, procainamide, mexiletine), chemotherapeutic agents (e.g., doxorubicin, cytarabine, thalidomide), and immunosuppressants (e.g., cyclosporine, tacrolimus), as well as thyroxine, glucocorticoids, oral hypoglycemic drugs, levodopa, amphetamines, theophylline, and aminophylline.

A postural tremor of the hands, head, and trunk resembling essential tremor is not uncommon in patients treated with sodium valproate. The tremor develops over a period of several months and usually remits when the drug is stopped or the dose is reduced. Treatment with propranolol or amantadine may alleviate the tremor.

Postural or action tremor is an early manifestation of lithium intoxication and is common even at therapeutic doses. A postural tremor has been reported in up to 40 percent of patients on cyclosporine. A flapping tremor (asterixis) may occur in patients treated with phenytoin, phenobarbital, carbamazepine, sodium valproate, methyldopa, ceftazidime, lithium, or tocainide.

Tics

A syndrome resembling Gilles de la Tourette syndrome has been reported after the administration of dextroamphetamine, methylphenidate, pemoline, or haloperidol in children. Other antipsychotic drugs as well as opiates, clonazepam, carbamazepine, phenobarbital, and fluoxetine have also been reported to cause tics.

Myoclonus

Drug-induced myoclonus may occur in patients treated with antipsychotic and tricyclic antidepressant drugs or lithium. Myoclonus has been reported in patients treated with clozapine, propofol, vigabatrin, fluvoxamine, chlorambucil, opioids, antibiotics (e.g., penicillin, ticarcillin, carbenicillin, imipenem, cephalosporins), and calcium-channel blockers. A clinical picture resembling that of Creutzfeldt–Jakob disease with myoclonus, tremor, cerebellar and extrapyramidal manifestations, cognitive impairment, and periodic sharp-wave complexes on EEG has been reported in patients with lithium toxicity. Posturally induced myoclonic jerks in the upper limbs have been described in patients on phenytoin, and with long-term antipsychotic drug therapy; the myoclonus may also be associated with tardive dyskinesia.

Pupillary Changes

Parasympathomimetic drugs such as carbachol and neostigmine cause miosis, as can morphine, chloral hydrate, and phenothiazines. Mydriasis is more often drug-induced and potentially more serious as it may precipitate acute angle-closure glaucoma in susceptible individuals. Drugs that may cause mydriasis and cycloplegia with blurring of near vision include anticholinergics, antihistamines, monoamine oxidase inhibitors, tricyclic antidepressants, chlorpropamide, indomethacin, hexamethonium, fenfluramine, oral contraceptives, amphetamines, and LSD.

Refractive Changes

In addition to the drugs mentioned that may cause cycloplegia and induce hypermetropia, certain drugs cause a transient myopia as a result of fluid shifts between the lens and the aqueous humor. These include oral diuretics (chlorothiazide, hydrochlorothiazide, chlorthalidone, and acetazolamide), tetracyclines, sulfonamides, corticosteroids and corticotropin, stilbestrol, phenytoin, thiamine, bromocriptine, and arsenicals, as well as insulin and oral hypoglycemic agents.

Retinopathy

Chloroquine, hydroxychloroquine, mepacrine, and amodiaquine may cause a pigmentary maculopathy and retinopathy with central and peripheral field defects and impairment of central vision after prolonged administration. Patients taking these drugs should have regular neuro-ophthalmic examinations, electroretinography, and electro-oculography to detect early signs of retinopathy. Phenothiazines in high doses may produce a progressive choroidoretinopathy; cardiac glycosides, methylphenidate, and cephaloridine have also been reported to cause pigmentary retinopathy. Macular edema may be caused by fingolimod, a novel oral therapeutic agent for multiple sclerosis, with an incidence of around 0.5 percent; the edema normally resolves on cessation of treatment. Macular edema may also be caused by contraceptives and, rarely, by chlorothiazide and acetazolamide. Other drugs that may interfere with vision through retinal effects include indomethacin, quinine, tamoxifen, ethambutol, diethylcarbamazine, and vigabatrin, the latter of which has been found to cause symptomatic—or more commonly asymptomatic—visual field constriction.

Optic Neuropathy

Optic atrophy occurred as part of the subacute myelo-opticoneuropathy syndrome associated with clioquinol when it was in use for the treatment of enteric infections. A number of other antimicrobial agents including linezolid, chloramphenicol, isoniazid, paraminosalicylate, streptomycin, ethambutol, sulfonamides, griseofulvin, dapsone, and chlorpropamide may also cause optic neuropathy. In the case of chloramphenicol, this may be prevented by the prophylactic administration of vitamin B ₁₂ .

There have been case reports of tumor necrosis factor alpha (TNF-α) inhibitors infliximab, adalimumab, and entancercept causing optic neuritis with enhancement of the optic nerve on MRI in some cases; some patients have associated cerebral demyelinating lesions.

Other drugs implicated in causing optic neuropathy include amiodarone, chlorambucil, cisplatin, 5-fluorouracil, vincristine, penicillamine, disulfiram, phenylbutazone, indomethacin, ibuprofen, naproxen, benoxaprofen, morphine, monoamine oxidase inhibitors, retinoids, organic arsenicals, cardiac glycosides, ergotamine, dideoxyinosine, omeprazole, and interferon-α.

Disorders of Color Vision

Disturbances of color vision may result from the effects of various drugs on retinal cone receptors or from direct injury to the optic nerve. Xanthopsia (yellow vision) may be caused by sulfonamides, streptomycin, methaqualone, barbiturates, digitalis derivatives, thiazide diuretics, and the anthelmintic agent santonin. Other drugs that may cause altered color vision include nalidixic acid, oral contraceptives, cannabis, LSD, and the older anticonvulsants troxidone and paramethadione.

Cortical Blindness

Cortical blindness may rarely occur after episodes of severe hypotension during anesthesia or after aggressive treatment of hypertension. It has also been reported as a complication of chemotherapy during childhood; with excessive doses of salicylates or barbiturates; and in those treated with drugs such as cyclosporine causing a posterior reversible encephalopathy syndrome ( Fig. 32-1 ).

Diplopia

Certain drugs commonly cause diplopia through breakdown of a latent squint. These include benzodiazepines, indomethacin, chlorpropamide, quinine, methaqualone, fenfluramine, tricyclic antidepressants, and anticonvulsants.

Nystagmus

Drug-induced nystagmus is common in hospital practice. Horizontal vestibular nystagmus occurs in patients on high doses of barbiturates, benzodiazepines, anticonvulsants, and other sedative and hypnotic drugs. It is a useful sign of toxicity in patients on anticonvulsant therapy and may occur even with therapeutic serum levels. Other drugs reported to cause nystagmus include monoamine oxidase inhibitors, salicylates, gold, neostigmine, chlordiazepoxide, fenfluramine, and amitriptyline, as well as the ototoxic antibiotics. Lithium and various other drugs may cause downbeat nystagmus.