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Drug-Induced Disorders of the Nervous System
Adverse drug reactions are a common and important cause of morbidity and hospital admission and are a major burden on the healthcare budget. Drug reactions commonly involve the nervous system, causing a variety of disorders that may be serious and even life-threatening, and may mimic naturally occurring neurologic disorders. Unlike many of these, most drug-induced disorders are readily reversible if the offending agent is identified early and withdrawn. It is therefore essential that the possibility of an iatrogenic condition should be considered in any patient presenting with neurologic symptoms, and a full drug history should always be obtained with this in mind. The spectrum of drug-induced disorders is diverse, as discussed in this chapter.
Headache
Drugs can cause headache through a number of different mechanisms, such as by inducing cerebral vasodilation or vasoconstriction, raised intracranial pressure, or aseptic meningitis. Moreover, medication may exacerbate a pre-existing headache disorder such as migraine or tension-vascular headache.
Vascular Headaches
Many drugs cause headaches by inducing vasodilation or reversible cerebral vasoconstriction. These include sympathomimetics, amyl nitrate, nitroglycerin, antihistamines, nicotinic acid, pentoxifylline, nifedipine, theophylline, aminophylline, terbutaline, and dipyridamole. Headache may also occur during treatment with cyclosporine, bromocriptine, dopamine, and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., naproxen, ketoprofen, diclofenac, alclofenac, ibuprofen), and in patients taking H 2 -receptor antagonists (e.g., cimetidine and ranitidine) and proton pump inhibitors (e.g., omeprazole and lansoprazole).
Headache is common during intravenous immunoglobulin infusions, which may induce reversible cerebral vasoconstriction, and may also occur with the use of illicit drugs such as amphetamines, cannabis, cocaine, 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 one of the most common causes of disabling headache in clinical practice and often goes unrecognized. A paradoxical increase in headache frequency commonly occurs in migraine or cluster headache patients consuming excessive quantities of ergotamine preparations or triptans on a regular basis. Treatment involves gradual withdrawal of the offending drugs and commencement of an alternative prophylactic medication. Chronic analgesic dependency may have a similar effect in chronic tension-vascular headache sufferers, leading to rebound headaches and contributing to the syndrome of chronic daily headache.
Idiopathic Intracranial Hypertension
A number of drugs may cause the idiopathic intracranial hypertension syndrome, characterized by headache, papilledema, diplopia, and visual impairment. These include oral contraceptives, estrogens and progestational agents, growth hormone, anabolic steroids, antibiotics (e.g., tetracyclines, minocycline, ampicillin, nalidixic acid, nitrofurantoin), nonsteroidal anti-inflammatory medications (e.g., naproxen, ibuprofen, indomethacin), vitamin A and retinoids (isotretinoin, etretinate), danazol, amiodarone, thyroxine, ketamine, nitrous oxide, and corticosteroids or corticosteroid withdrawal.
Aseptic Meningitis
Aseptic meningitis may be caused by a variety of drugs including NSAIDs and cotrimoxazole, particularly in patients with systemic connective tissue diseases, and occasionally by other antimicrobials such as sulfasalazine, penicillin, amoxicillin, ciprofloxacin, and cephalosporins; and by carbamazepine and pentoxifylline. Aseptic meningitis may also develop after intravenous immunoglobulin therapy and treatment with other immunomodulatory agents such as infliximab, leflunomide, azathioprine, and monoclonal antibodies such as muromonab-CD3. Intrathecal anesthetics, contrast media, methylprednisolone, methotrexate, and cytarabine may also cause aseptic meningitis.
Stroke
Women taking oral contraceptives have an increased risk of ischemic stroke and cerebral venous thrombosis, but the absolute risk is small in healthy young women without other stroke risk factors who are on low-dose estrogen-progestin preparations. The risk of ischemic stroke is higher in women with migraine and high blood pressure and in smokers and those taking higher-dose contraceptive pills. Oral contraceptives are not thought to increase the risk of hemorrhagic stroke, but have been implicated in subarachnoid hemorrhage, particularly in smokers. The risk of stroke may also be increased by postmenopausal hormone replacement therapy, particularly if commenced more than 5 years after the menopause. Women with breast cancer treated with tamoxifen have an increased risk of ischemic stroke and of other types of stroke including venous sinus thrombosis. There is also a modest increase in the risk of ischemic stroke and myocardial infarction in men on testosterone replacement therapy, particularly in the first 2 years of treatment.
Overmedication with antihypertensive drugs is an important potential cause of iatrogenic ischemic stroke, especially in the elderly and in patients with severe cerebrovascular disease. Patients taking anticoagulants have an increased risk of intracerebral and other forms of intracranial hemorrhage, particularly with long-term or poorly controlled therapy; and there is an increased risk of ischemic stroke in patients with heparin-induced thrombocytopenia. The use of aspirin and other antiplatelet drugs for primary or secondary stroke prevention is also a risk factor for intracerebral hemorrhage.
Intracerebral or subarachnoid hemorrhage may occur following intravenous, oral, or intranasal administration of amphetamines and related compounds that cause acute blood pressure elevation. Recreational use of methamphetamine is an important risk factor for intracerebral hemorrhage and is associated with a fivefold increase in the risk of hemorrhagic stroke, which can occur at an earlier age and has a poorer outcome than in nonusers. Intracranial hemorrhage may also occur in patients taking diet pills, decongestants, and stimulants containing phenylpropanolamine or pseudoephedrine. Intracerebral hemorrhage or ischemic stroke may occur in individuals taking high doses of ephedrine-containing preparations or taking cocaine, amphetamines, methylphenidate, or heroin. These drugs, as well as phenylpropanolamine, pseudoephedrine, oxymetazoline, allopurinol, penicillin, and ergot alkaloids, have also been implicated in causing cerebral vasculitis in some patients.
Seizures
Many drugs can induce seizures in healthy individuals, and especially in those with pre-existing epilepsy or a low seizure threshold ( Table 32-1 ). It has been estimated that up to 6 percent of new-onset seizures are drug related and that approximately 10 percent of cases of status epilepticus presenting to an emergency department result from drug toxicity. Some drugs are more likely than others to cause seizures, particularly those that cross the blood–brain barrier and those administered in high doses intravenously or intrathecally. The following classes of drugs have been reported repeatedly to induce seizures, in decreasing order of frequency: antidepressants, stimulants, anticholinergics, and other medications such as baclofen, antihistamines, antipsychotics, naproxen, meperidine, local anesthetics, isoniazid, propoxyphene, methylphenidate, lithium, cyproheptadine, acetylsalicylic acid, and glipizide. With a number of the drugs listed in Table 32-1 , seizures have been reported only rarely and the association therefore remains circumstantial.
Table 32-1
Drugs Associated with the Occurrence of Seizures
| Antidepressants | Tricyclics, monoamine oxidase inhibitors, SSRIs |
| Antipsychotics | Phenothiazines, butyrophenones, lithium, clozapine, olanzapine |
| Analgesics | Fentanyl, alfentanil, morphine, meperidine, pentazocine, propoxyphene, mefenamic acid |
| Local Anesthetics | Lidocaine, mepivacaine, procaine, bupivacaine |
| General Anesthetics | Ketamine, halothane, enflurane, methohexital, propofol, isoflurane |
| Antimicrobials | Penicillins, ampicillin, cephalosporins, imipenem, metronidazole, nalidixic acid, isoniazid, cycloserine, pyrimethamine, acyclovir, ganciclovir, foscarnet |
| Antineoplastics | Chlorambucil, vincristine, methotrexate, cytarabine, misonidazole, carmustine |
| Bronchodilators | Aminophylline, theophylline |
| Sympathomimetics | Ephedrine, terbutaline, phenylpropanolamine |
| Other Drugs | Antihistamines, anticholinergics, anticonvulsants, chloroquine, baclofen, cyclosporine, azathioprine, β-adrenergic blockers, flumazenil, disopyramide, bromocriptine, domperidone, phencyclidine, amphetamines, methylphenidate, famotidine, isotretinoin, ondansetron, allopurinol, oxytocin, erythropoietin |
A number of factors predispose to drug-induced seizures, including a family history of epilepsy and a genetically determined low seizure threshold. Penicillin-induced seizures are more likely to occur with high-dose intravenous or intrathecal administration, and in patients with impaired renal failure who have high blood levels of the drug. Other drugs that may cause seizures when they accumulate as a result of reduced renal excretion include meperidine, imipenem, nalidixic acid, cephalosporins, cimetidine, lithium, and erythropoietin. Seizures have also been reported in patients treated with cyclosporine, especially in renal or liver transplant patients who have high blood levels of the drug.
A number of therapeutic agents such as oxytocin, carbamazepine, and the SSRIs can cause seizures by inducing hyponatremia. Withdrawal of benzodiazepines, barbiturates, tricyclic antidepressants, alcohol, or baclofen is another important cause of seizures, particularly if the withdrawal is too abrupt. Withdrawal of anticonvulsant drugs in epileptic patients is also an important cause of seizures or even status epilepticus, and should always be gradual.
Conversely, excessively high doses and serum concentrations of certain anticonvulsants may aggravate epilepsy or induce new seizure types or even status epilepticus. Carbamazepine may aggravate absences and myoclonic or atonic seizures. Benzodiazepines may induce tonic seizures and status epilepticus in patients with the Lennox–Gastaut syndrome. Valproic acid and vigabatrin may occasionally induce status epilepticus. Gabapentin may have an adverse effect on myoclonic epilepsy, as may topiramate on focal epilepsy, and tiagabine may induce nonconvulsive status epilepticus.
The convulsant effects of certain drugs, such as isoniazid, aminophylline, local anesthetics, phencyclidine, and meperidine, are dose related, but other drugs may cause seizures even with therapeutic doses and blood levels. These include theophylline, tricyclic antidepressants, and phenothiazines. The aliphatic phenothiazines chlorpromazine, promazine, and prochlorperazine are more likely to induce seizures than the piperazine group, such as fluphenazine and trifluoperazine. Seizures have also been reported with the atypical neuroleptics clozapine, olanzapine, risperidone, and sertindole. Most classes of antidepressant may induce seizures, including SSRIs, SNRIs, tricyclics, bupropion, mirtazapine, reboxetine, and trazodone, although the risk is low. Lithium-induced seizures are well known and generally occur when plasma levels exceed 3.0 mEq/L.
Encephalopathy
Certain drugs such as lithium and acyclovir may cause a diffuse disturbance of cerebral function leading to tremor, asterixis, myoclonus, seizures, ataxia, confusion, and obtundation. Such a syndrome may be caused by lithium toxicity, but it sometimes occurs even when blood levels of the drug are within the recommended therapeutic range.
A severe diffuse encephalopathy with associated focal neurologic features has recently been recognized in patients with various forms of malignancy undergoing chimeric antigen receptor T-cell therapy.
High doses of penicillin and cephalosporins may also cause an acute encephalopathy, particularly in patients with impaired renal function, as may a variety of other drugs including lidocaine, tocainide, benzodiazepines, vigabatrin, valproic acid, phenytoin, carbamazepine, baclofen, isoniazid, levodopa, mefloquine, sulfonamides, podophyllin, l -asparaginase, thymidine, 5-fluorouracil, carmustine (BCNU), mechlorethamine, N -phosphonacetyl- l -aspartic acid (PALA), cytarabine, fludarabine, doxorubicin, and intrathecal metrizamide. In the past, a myoclonic encephalopathy was recognized in patients with prolonged exposure to bismuth-containing preparations or with aluminum toxicity in those undergoing hemodialysis (“dialysis encephalopathy”), and with carisoprodol overdosage.
A progressive leukoencephalopathy characterized by dementia, dysarthria, ataxia, and paralysis, at times followed by seizures, coma, and death, may occur in patients treated with high-dose intrathecal, intraventricular, or intravenous methotrexate, particularly after cranial or craniospinal radiotherapy. A posterior leukoencephalopathy with headache, seizures, cortical blindness, and parieto-occipital lesions has been increasingly recognized in patients treated with cyclosporine ( Fig. 32-1 ). The condition is often associated with hypertension and high blood drug levels and is usually reversible. Other drugs that have been associated with the development of a leukoencephalopathy include capecitabine, cisplatin, cytarabine, 5-fluorouracil, fludarabine, ifosfamide, amphotericin B, interferons, interleukin-2, levamisole, tacrolimus, melarsoprol, and bevacizumab, as well as heroin, synthetic cannabinoids, and other drugs of addiction.
There is increasing awareness of the higher risk of developing the JC virus–associated disorder progressive multifocal leukoencephalopathy (PML) in individuals treated with immunomodulatory biologics such as natalizumab (anti-α4-integrin) and rituximab (anti-CD20).
Drug-Induced Coma
Drugs are a common and important cause of coma resulting from accidental or self-administered overdosage. The drugs can be classified into those that have a direct depressant effect on the brain such as hypnotics, sedatives, antidepressants, analgesics, or various drug combinations, and those that cause coma through indirect effects, such as insulin, antihypertensives, and antiarrhythmics. Other drugs that may cause depression of consciousness include phenothiazines, salicylates, acetaminophen (which can cause severe hepatic damage), paraldehyde, acyclovir, and valproic acid.
Certain neurologic findings are characteristic of drug-induced coma. The pupils are typically small and reactive, but may be dilated and fixed in severe barbiturate intoxication or pinpoint in opiate poisoning. The corneal reflexes are preserved but may be lost in profound drug-induced coma. Both spontaneous and reflex eye movements are depressed early, particularly with barbiturate, tricyclic, and phenytoin intoxication, with the eyes being fixed and divergent, without spontaneous roving eye movements, and with impaired or absent oculocephalic and oculovestibular reflexes. Muscle tone is often reduced and the tendon reflexes are depressed, with flexor plantar responses, but there may be hypertonia, hyperreflexia, decerebrate posturing, and extensor plantar responses, particularly if there has been superadded cerebral hypoxia. Muscle twitching, choreoathetosis, myoclonus, and seizures may all occur in coma caused by tricyclic agents or lithium toxicity.
The electroencephalogram (EEG) can sometimes provide a clue to identifying the causative drug. In drug-induced coma it usually shows diffuse slowing, but with barbiturate or benzodiazepine intoxication there is typically a predominance of beta activity (“beta coma”). Alpha-pattern coma, or mixed alpha and beta rhythms, may also occur with benzodiazepine or with chlormethiazole intoxication.
Neuropsychiatric Disorders
Psychiatric adverse drug reactions are common in clinical practice and may take various forms.
Behavioral Toxicity
A variety of nonspecific symptoms including 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 and may be the prelude to a more florid delirious state, but usually subside with withdrawal of the drug or dose reduction. Such symptoms are encountered most frequently with tricyclic agents, lithium, amphetamines, phenothiazines, barbiturates, glucocorticoids, cholinergic drugs, levodopa, antihistamines, and acetylcholinesterase inhibitors, as well as some anticonvulsants. Similar symptoms may also occur following withdrawal of certain medications such as benzodiazepines and SSRIs.
Delirium and Confusional States
Drugs are an important cause of delirium and confusional states, particularly in the elderly. Various drugs may cause such reactions, including sedatives, tranquilizers, hypnotics, narcotics, antihistamines, and anticholinergics. Other important causes include antiparkinsonian drugs and antidepressants, in particular the SSRIs and SNRIs, which have been associated with the serotonin syndrome (discussed later), as well as interactions between serotonergic drugs and monoamine oxidase inhibitors or tricyclic agents and other drugs. Abrupt withdrawal of SSRI drugs may also precipitate a confusional or delirious state with associated twitching, hypertonia, and sensory symptoms. Less frequent causes of drug-induced delirium include cephalosporin and macrolide and fluoroquinolone antibiotics. Delirious states with associated motor hyperactivity have also been reported frequently with the influenza antiviral agent oseltamivir.
Mood Disorders
Drug-induced depressive reactions are common. Reserpine and α-methyldopa were among the first drugs recognized to cause depression, but depression is uncommon with the newer generations of antihypertensive agents. Mood disturbance with manic features is the most common psychiatric side effect of corticosteroids, and depression is the most common psychiatric symptom in patients taking levodopa. Depression may also occur in patients on a variety of other medications, including oral contraceptives, anabolic steroids, tetrabenazine, digoxin, indomethacin, naproxen, disulfiram, sulfonamides, cycloserine, retinoids, antineoplastics, antiepileptics, baclofen, barbiturates, benzodiazepines, phenothiazines, butyrophenones, and interferons. It may also follow benzodiazepine, amphetamine, or fenfluramine withdrawal.
Although euphoria is a common drug-induced side effect, manic or hypomanic reactions are uncommon. Such reactions may however occur with a variety of drugs including glucocorticoids, corticotropin, anabolic steroids, thyroxine, captopril, chloroquine, isoniazid, ranitidine and cimetidine, dopaminergic agents, baclofen, opiates, pentazocine, monoamine oxidase inhibitors, tricyclic agents, iproniazid, cyclosporine, sympathomimetic amines, amphetamines, benzodiazepines, procyclidine, phenylpropanolamine, and hallucinogens. Antidepressants may also induce mania, especially in individuals with bipolar disorder. Increased risk of a manic episode has been reported with tricyclic antidepressants and monoamine oxidase inhibitors, but not with standard doses of SSRIs.
Psychoses
Various drugs have been reported to cause paranoid or 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 psychotic disorder subsequently.
Hallucinatory States
Various drugs can cause hallucinations without other features of delirium or psychosis. The hallucinations usually tend to be visual, extremely vivid and colored, and often of animals, sometimes having microptic or Lilliputian dimensions. The most common causative drugs are tricyclic agents, benzodiazepines, vigabatrin, bromides, methylphenidate, atropine and other anticholinergic drugs after parenteral or even topical administration into the eye, ephedrine, amantadine, bromocriptine, pergolide, levodopa, digoxin, diltiazem, prazosin, captopril, disopyramide, pentazocine, buprenorphine, indomethacin, salicylates, cimetidine, aminophylline, acyclovir, and cyproheptadine, as well as cannabis and LSD. Auditory and less often visual hallucinations are also a feature of withdrawal from alcohol, barbiturates, benzodiazepines, and baclofen.
Cognitive Impairment
Various drugs may cause transient memory impairment, including baclofen, pregabalin, benzhexol, isoniazid, propranolol, antidepressants (SSRIs and tricyclics), and statins. More severe, but reversible, cognitive impairment, which may mimic dementia, can also develop with chronic intake of benzodiazepines, barbiturates, bromides, and chlorpromazine, with anticonvulsant overdosage, and with glucocorticoid and interleukin administration. These medications may also aggravate cognitive functions in patients who already have mild cognitive impairment and should therefore be administered with caution.
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 drugs. The newer antiepileptics gabapentin, lamotrigine, vigabatrin, tiagabine, remacemide, topiramate, and levetiracetam have fewer cognitive effects.
Several lines of evidence, including pretrial safety and tolerability testing, postmarketing surveillance, and multiple case reports have linked statins to short-term reversible cognitive impairment, particularly in relation to short-term memory. However, this was not confirmed in a systematic review and meta-analysis of randomized controlled trials. In spite of this, it does appear that memory impairment can occur in a small proportion of people taking statins and that the risk may be greater in individuals on the more potent lipophilic statins, atorvastatin and simvastatin. Further prospective studies are required to determine whether certain subpopulations of statin users are at greater risk and to identify other patient-specific factors that may allow such individuals to be identified.
Movement Disorders
Several drugs, in particular dopamine-receptor blocking antipsychotics and antiemetics, may induce involuntary movements or abnormalities of movement, posture, or gait that may resemble naturally occurring extrapyramidal disorders. These same drugs may also aggravate pre-existing extrapyramidal disorders such as Parkinson disease and should therefore be used with caution in such patients. There is marked individual variability in the susceptibility to these reactions, some patients developing side effects even with small doses of a drug, whereas others on much higher doses are unaffected. Sex, age, and genetic factors may all play a part in determining individual susceptibility.
Akathisia
Akathisia is a state of motor restlessness characterized by an uncontrollable urge to move about, pace, or even run incessantly. The condition typically occurs in patients taking dopamine-blocking agents such as phenothiazine derivatives and less frequently with butyrophenones, benzodiazepines, tricyclic agents, SSRIs, levodopa, lithium, monoamine oxidase inhibitors, and vigabatrin. The reported incidence of akathisia with antipsychotic drugs ranges from 20 to 75 percent and is less frequent with the atypical antipsychotics. It usually remits within days or weeks of withdrawal of the neuroleptic drug, but may persist for several months and is occasionally permanent.
The most effective treatment for akathisia is to withdraw or lower the dose of the causative drug. Benztropine or diphenhydramine is usually effective in controlling akathisia when given intramuscularly or intravenously, and propranolol, clonazepam, and amantadine may also be beneficial.
Acute Dystonic-Dyskinetic Reactions
Acute dystonic reactions are a well-recognized side effect of antipsychotic or antiemetic drugs, in particular the phenothiazines (fluphenazine, prochlorperazine) and butyrophenones (haloperidol), metoclopamide, and, less frequently, promethazine, tricyclic antidepressants and SSRIs, phenytoin, carbamazepine, propranolol, ondansetron, flunarizine, and cinnarizine. The onset is usually within the first few days of starting treatment, but can be almost immediate, and may be quite abrupt. The dystonia may be confined to the head and neck, causing facial grimacing, jaw spasms and trismus, abnormal tongue movements, blepharospasm, oculogyric crises, orofacial dyskinesias, and torticollis or retrocollis. In some cases the dystonia is more generalized, with slow writhing movements or prolonged tonic spasms of the limb and axial muscles resulting in carpopedal spasm, opisthotonos, lordosis, tortipelvis, and a bizarre gait. Rarely laryngospasm may occur. Because of their bizarre and protean nature, the movements can be mistaken for hysteria. The differential diagnosis also includes hyperventilation, tetany, tetanus, strychnine poisoning, and epilepsy. Despite their dramatic and at times alarming nature, the acute dystonic reactions are self-limiting and will usually remit once the drug is withdrawn. Severe reactions can be terminated by intravenous or intramuscular benztropine or promethazine, or intravenous diazepam.
Tardive Dyskinesia and Other Tardive Syndromes
Tardive dyskinesia and other tardive syndromes may occur in patients treated with a variety of dopamine antagonists. They are most commonly seen in patients with schizophrenia or schizoaffective or bipolar disorder treated with antipsychotic medications for long periods, but may also occur with prolonged administration of metoclopramide, chlorpromazine, thioridazine, promethazine, prochlorperazine, amoxapine, perphenazine, trifluoperazine, flunarizine, cinnarizine, and antidepressants. Early studies found tardive dyskinesia in up to 50 percent of patients treated with the older antipsychotic drugs, but the frequency has declined since the introduction of the second- and third-generation antipsychotics. Tardive dyskinesia usually develops after more than 12 months of continuous therapy, although it has been reported with periods as short as 3 months. It may present after cessation of therapy. The condition is more common and is often more severe in the elderly, in whom it is less likely to remit.
The dyskinesia typically takes the form of an orobuccal dyskinesia 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 may interfere with speaking and swallowing. In some cases more generalized choreoathetotic movements of the limbs and trunk and repetitive foot-tapping movements 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. Akathisia or parkinsonism may also occur.
Tardive dystonia is less common and tends to occur in younger individuals, particularly men. It is distinguished from tardive dyskinesia by the more sustained abnormal movements and postures, which may be focal or more generalized and may involve the jaw, neck, limbs, or trunk. Tardive dystonia is often more disabling than tardive dyskinesia. Other tardive syndromes include akathisia, chorea, myoclonus, tremor, tics, and oculogyric crises.
The severity of tardive dyskinesia is variable and it may remit in up to 40 percent of cases, even on continued therapy. Occasionally remission may occur even several years after withdrawal of antipsychotic medications. Interruption of therapy when dyskinesia first develops may be beneficial, but there is some evidence that repeated interruptions may actually increase the risk of persistence.
The treatment of tardive dyskinesia is problematic. Many medications have been used in the past, including dopaminergic agents (tetrabenazine, bromocriptine, and levodopa) and drugs with a cholinergic action, such as choline and deanol. Other drugs reported to be beneficial include amantadine, clonazepam, baclofen, propranolol, diazepam, tocopherol, Ginkgo biloba , levetiracetam, and calcium-channel blockers. None has been consistently effective. More recently, the VMAT2 inhibitors deutetrabenazine and valbenazine have become established as evidence-based therapies for tardive syndromes.
In cases of focal or segmental tardive dystonia or orobuccal dyskinesia, botulinum toxin injections may be effective. Deep brain stimulation may need to be considered in medically refractory cases.
Levodopa-Induced Dyskinesias
Choreoathetotic dyskinetic reactions involving the face, tongue, limbs, and trunk are common in patients with Parkinson disease treated with levodopa and other dopaminergic agents, developing in about 50 percent of patients after 4 to 5 years of treatment, usually starting on the side of the body that is more affected by the disease. Levodopa-induced dyskinesias are thought to be due to nonphysiologic phasic stimulation of dopamine receptors in the striatum and are dose-dependent. In some patients they develop early during treatment with levodopa or dopamine agonists and usually respond to a reduction in drug dose. With prolonged treatment, dyskinesias become an increasing problem, tending to occur at times of peak response to levodopa (peak-dose dyskinesia) but sometimes occurring as blood levels decline (biphasic dyskinesia) and alternating with periods of akinesia and severe rigidity (the so-called 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 often helpful in alleviating this common complication of prolonged levodopa therapy. Other medications that can be beneficial include amantadine and leviracetam, and a number of novel pharmacologic approaches are under development. However, severe and disabling dyskinesias are usually an indication for deep brain stimulation.
Chorea and Choreoathetosis
A number of drugs may cause chorea, which is characterized by multifocal, nonstereotyped, “fidgety” or jerky movements and may co-exist with the slower movements of athetosis or with dystonia. Chorea or choreoathetosis has been reported with many drugs including anticonvulsants in high doses (e.g., phenytoin, ethosuximide, valproic acid, carbamazepine, phenobarbital), clonazepam withdrawal, anticholinergic drugs (e.g., high doses of benzhexol), tricyclic agents, fluoxetine, amphetamines, methylphenidate, amoxapine, pemoline, cimetidine, theophylline, aminophylline, lithium, methadone, antihistamines, cyclosporine, oxymetholone, intrathecal baclofen, and certain oral contraceptives. Chorea has also been well described with cocaine use (“crack dancing”).
Tics
A condition resembling Gilles de la Tourette syndrome has been reported in children after the administration of dextroamphetamine, methylphenidate, or pemoline. Other antipsychotic drugs as well as opiates, clonazepam, carbamazepine, phenobarbital, and fluoxetine have also been reported to cause tics.
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