Iatrogenic neurology.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 107

Iatrogenic neurology LUCIANO A SPOSATO1 AND OSVALDO FUSTINONI2,3* Department of Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada

1

2 3

INEBA Institute of Neurosciences, Buenos Aires, Argentina

Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina

INTRODUCTION Disease due to healthcare interventions is an important clinical problem that has remained unchanged for decades (Darchy et al., 1999). Iatrogenic disease due to drugs (60%), surgical (22%) and medical acts (18%) accounts for more than 12% of admissions in intensive care, with a 13% fatality rate and important financial costs, and equals noniatrogenic disease in severity, mortality, and length of stay. Advanced age and the number of prescribed drugs are the salient risk factors, with a rate of preventable disease of 51% (Darchy et al., 1999). Although iatrogenic neurologic disease may be more devastating due to the higher potential irreversibility of nervous system involvement, it has only been addressed in more recent years (Biller, 1998). This chapter will describe iatrogenic neurologic adverse effects and disorders induced by the administration of pharmacological agents prescribed for the clinical treatment and prevention of medical disease.

NEUROLOGIC ADVERSE EFFECTS OF CARDIOVASCULAR AND ANTITHROMBOTIC DRUGS Antihypertensive agents Aggressive blood pressure lowering in the course of stroke or malignant hypertension may induce neurologic worsening by hypoperfusion of brain ischemic areas (Choi et al., 2008). Current AHA/ASA Guidelines for early stroke management recommend “a cautious approach

to the treatment of arterial hypertension (Class I, Level of Evidence C),” and that “medications should be withheld unless the systolic blood pressure is greater than 220 mm Hg or the diastolic blood pressure less than 120 mm Hg (Class I, Level of Evidence C) (Adams et al., 2007). b-Adrenergic blockers often induce bradycardia and consequent symptoms of low cerebral blood flow (somnolence, unsteadiness, blurred vision, confusion, syncope). All other antihypertensive drugs may cause similar symptoms as a consequence of relative hypotension, which may appear even at therapeutic doses if the patient’s cerebral blood flow autoregulation curve is shifted to the right. Other less frequent and specific neurologic adverse effects of the most commonly used antihypertensive agents appear in Table 107.1. The neurologic side-effects of diuretics are almost invariably caused by their effect on electrolyte metabolism, such as hyponatremia (seizures and encephalopathy), hypokalemia (hypokalemic periodic paralysis), hyperkalemia (hyperkalemic periodic paralysis in the case of potassium-sparing agents such as spironolactone), and hypomagnesemia (myalgias, muscle cramps, tetany, carpopedal spasm, seizures). More specifically, loop diuretics and distal convoluted tubule agents (thiazides), produce hypokalemic, hypochloremic, metabolic alkalosis that responds to potassium chloride, and hyponatremia, which may cause permanent neurologic damage. Dose-related reversible or irreversible ototoxicity may complicate treatment with loop agents. Carbonic anhydrase inhibitors

*Correspondence to: Osvaldo Fustinoni, M.D., Professor of Neurology, Buenos Aires University Medical School, Chief, Cerebrovascular Diseases, INEBA - Instituto de Neurociencias, Buenos Aires, Guardia Vieja 4435, C1192AAW Buenos Aires Argentina. Tel/Fax: þ54-11-4867-7700/7735, 4805-8897, E-mail: [email protected]

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L.A. SPOSATO AND O. FUSTINONI

Table 107.1 Neurologic adverse effects of most commonly used antihypertensive agents Group

Drug

Adverse effects

a-Adrenergic blockers

Prazosin

b-Adrenergic blockers

Propranolol Atenolol

Cataplexy in narcoleptics (Guilleminault et al., 1988) Myotonia (Satya-Murti et al., 1977) Delirium (Arber, 1988) Visual effects (Kummar and Clooney, 1990) Fulminant myasthenia gravis (Confavreux et al., 1990) Rhabdomyolysis (Willis et al., 1990) Tingling and micturition impairment (Bailey, 1977) Delirium (Hoffmann and Ladogana, 1981) Myalgias (Schwarz, 1987) Parkinsonism and chorea (Yamadori and Albert, 1972) Myoclonic dystonia (De Medina et al., 1986) Magnesium sulphate neuromuscular blockade worsening (Snyder and Cardwell, 1989) Myopathy (Phillips and Muller, 1998) Parkinsonism (Teive et al., 2002) Parkinsonism (Dick and Barold, 1989) Myoclonus (Jeret et al., 1992) Myopathy (Ahmad, 1993) Lambert–Eaton syndrome (Ueno and Hara, 1992) Parkinsonism (Padrell et al., 1995) Worsening of neuromuscular diseases (Swash and Ingram, 1992) Carbamazepine toxicity (Macphee et al., 1986) Peripheral neuropathy (Hormigo and Alves, 1992) Pseudopolymyalgia rheumatica (Leloe¨t et al., 1989) Parkinsonism (Sarma et al., 2008) Delirium, encephalopathy, thiocyanate poisoning (Harmon and Wohlreich, 1995)

Acebutolol Labetalol a2-Adrenergic agonists

Clonidine Methyldopa

Calcium channel blockers

Nifedipine

Amlodipine Diltiazem

Verapamil

Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers Vasodilators

Enalapril Losartan Sodium nitroprusside

(acetazolamide) produce less hypokalemia and volume depletion but commonly induce often symptomatic metabolic acidosis. The potassium-sparing agents also limit proton excretion, and spironolactone may produce metabolic acidosis (Greenberg, 2000).

Antiarrythmics, inotropes, and coronary artery dilators The various neurologic adverse effects of antiarrythmics are thought to be a consequence of their interference with central or peripheral nervous conduction. Cardiac inotropes influence the force of myocardial muscular contraction, either by increasing it (positive inotropes), or decreasing it (negative inotropes). Common positive inotropes include glycosides (digitalis) and catecholamines (dopamine, dobutamine, isoproterenol, adrenaline/epinephrine and noradrenaline/ norepinephrine). Negative inotropes include diltiazem,

verapamil, quinidine, procainamide and flecainide, all antiarrythmic agents as well. Coronary vasodilators are mainly represented by nitroglycerin-derived nitrates, which are potent vasodilators and may also decrease blood pressure (nitroprusside). The frequent headaches induced by nitrates are attributed to associated vasodilation of the intracranial vessels. The neurotoxic effects of the most commonly used antiarrythmics, inotropes, and coronary artery dilators are listed in Table 107.2.

Antilipemic drugs: HMG-CoA reductase inhibitors (statins) and other antilipemic drugs The most salient and severe side-effect of statins is rhabdomyolysis, thought to be due to increased membrane fluidity caused by reduction of the cholesterol content of the sarcolemmal phospholipid bilayer. Myalgias occur in less than 1%, and severe myopathy in less than 0.1% of

IATROGENIC NEUROLOGY

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Table 107.2 Neurologic adverse effects of most commonly used antiarrythmics, inotropes and coronary artery dilators Group

Drug

Adverse effects

Antiarrythmics

Amiodarone

Peripheral neuropathy (Fraser et al., 1985) Myopathy (Roth et al., 1990) Optic neuropathy (Feiner et al., 1987) Pseudotumor cerebri (Grogan and Narkun, 1987) Parkinsonism and movement disorders (Werner and Olanow, 1989) Ataxia (Krauser et al., 2005) Peripheral neuropathy (Palace et al., 1992) Dystonia (Miller and Jankovic, 1992) Neuromuscular weakness (Ferrick and Power, 1990) Seizures (Kennedy et al., 1989) Dysarthria and visual hallucinations (Ramhamadany et al., 1986) Ataxic-myoclonic encephalopathy (Ghika et al., 1994) Seizures and encephalopathy (Crampton and Oriscello, 1968) “Doom anxiety” and delirium (Saravay et al., 1987) Tremor, ataxia, diplopia, blurred vision, visual hallucinations (Campbell, 1987) “Cinchonism”: headache, flushing, mydriasis, visual changes (Fisher, 1981) Myasthenia gravis worsening (also with propafenone and procainamide) (Kornfield et al., 1976) Delirium (Marriott, 1968) Photopsias (Oishi et al., 2006) Dyschromatopsias, acquired color vision deficiency (Lawrenson et al., 2002) Visual acuity decrease (Nagai et al., 2001) Trigeminal neuralgia (Bernat and Sullivan, 1979) Chorea (Wedzicha et al., 1984) Bilateral retinal infarction (Opremcak and Davidorf, 1985) Headache (Mueller and Meienberg, 1983) Intracranial hypertension (Ahmad, 1991)

Flecainide

Lidocaine Mexiletine Quinidine

Inotropes

Glycosides (digitalis) Dopamine

Coronary artery vasodilators

Nitrates

patients treated. Risk factors for myopathy are advanced age, impaired general or nutritional status, comorbidities, intercurrent surgery, and associated treatment with multiple medications. Associated drugs or nutrients that increase the risk include fibrates, nicotinamide, ciclosporin, azoles, macrolid antibiotics, erythromycin, clarithromycin, HIV-protease inhibitors, nefazodone, verapamil, amiodarone, alcohol, grapefruit juice. This is due to their interaction with cytochrome P450 and other hepatic uptake transporters which also metabolize statins (Neuvonen et al., 2006). Serum lipid, creatine kinase (CK) levels, and hepatic function should be assessed before starting treatment. Patients should be monitored for the risk of rhabdomyolysis with clinical follow-up, serum CK and thyroid-stimulating hormone (TSH) levels, especially if muscle symptoms develop. Statins should be discontinued if CK normal levels increase beyond 10 times The intensity of cytotoxicity, which is independent of their cholesterol-lowering effect, has been described as high for cerivastatin and simvastatin, intermediate for atorvastatin, and low for rosuvastatin and pravastatin The incidence of rhabdomyolisis is higher

with statins oxidized by cytochrome P450 3A4 (CYP3A4), such as simvastatin or atorvastatin, than with those not oxidized by CYP3A4, such as pravastatin or fluvastatin. In large systematic reviews, there is no excess of hepatic, renal, or cerebral disease with statins, although an increased incidence of peripheral neuropathy has been reported (Law and Rudnicka, 2006). Less common neurologic adverse effects of statins and other antilipemic drugs are listed in Table 107.3.

Thrombolytics The most salient neurologic complication of thrombolytic therapy, whether indicated for cardiovascular or cerebrovascular disease, is intracranial hemorrhage (IH). Ischemic stroke (IS) may also occur. The average frequency of stroke after therapeutic thrombolysis for noncerebral thrombotic disease, mainly acute myocardial infarction (AMI), was not higher than 2.5% in the 1990s (Sloan, 1998), and has since decreased. Several thrombolytic agents have been implicated:

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Table 107.3 Other neurologic adverse effects of most commonly used antilipemic drugs Group

Drug

Adverse effects

HMG-CoA reductase inhibitors (statins)

Lovastatin Pravastatin Simvastatin Clofibrate Gemfibrozil Ezetimibe

Parkinsonism (Muller et al., 1995) Mitochondrial myopathy (England et al., 1995) Mitochondrial myopathy, MELAS (Chariot et al., 1993) Myopathy, cardiomyopathy (Smals et al., 1977) Myopathy (Magarian et al., 1991) Myopathy (Havranek et al., 2006) Polymyositis (Garcıá-Valladares and Espinoza, 2010)

Fibrates Cholesterol intestinal absorption inhibitors

streptokinase (SK), recombinant tissue plasminogen activator (rt-PA, alteplase), reteplase, tenecteplase, and others. A higher stroke risk has been reported for alteplase and reteplase, with no difference in overall mortality (Dundar et al., 2003). Risk factors for IH after cardiac thrombolysis include age, hypertension, type and dosage of thrombolytic agent, associated antithrombotic therapy, prior cranial trauma and prior cerebrovascular disease, and for IS, age, hypertension, prior coronary artery disease or bypass graft (CABG), diabetes, and prior stroke. The American College of Chest Physicians has recommended against the administration of thrombolytic therapy in patients with AMI and with any history of intracranial hemorrhage, closed head trauma, or ischemic stroke within the previous 3 months (Menon et al., 2004). Thrombolysis administered for IS is associated with a higher rate of intracerebral hemorrhage (ICH), due to the intrinsic risk of spontaneous hemorrhagic transformation of the cerebral infarct (hemorrhagic infarction). Currently, rt-PA is the only approved thrombolytic agent for acute IS. Streptokinase is not recommended due to its high risk of ICH and death. Urokinase did not attain FDA approval status in the US. Other agents for the specific treatment of ischemic stroke are under investigation. By intravenous (systemic) infusion, rt-PA has been approved worlwide for the treatment of acute IS up to 4.5 hours from its onset, and is beneficial under strict inclusion/exclusion criteria (Del Zoppo et al., 2009). The treatment carries nevertheless a 10-fold higher risk of symptomatic ICH (overall risk around 5%, varying on the definitions used). If the established inclusion/ exclusion criteria are not met, the risk is higher. There is, however, no increase in mortality. Other less common complications of thrombolytic therapy are spinal epidural hematoma (Sawin et al., 1995), low back pain (Fishwick et al., 1995), angioneurotic orolingual edema (Hill et al., 2000), Guillain–Barre´ syndrome (Barnes and Hughes, 1992) and neuromuscular complications due to local hematoma (Cadman, 1995).

Anticoagulants Bleeding is the salient risk of any anticoagulant therapy, and ICH is the most frequent severe bleeding complication of anticoagulation.

HEPARINS AND HEPARINOIDS In acute stroke, subcutaneous unfractionated heparin (UFH) significantly decreases its recurrence, but causes a threefold increase in ICH (IST Collaborative Group, 1997). Consequently, heparin and urgent anticoagulation in general are currently not recommended for the treatment of acute stroke (Adams et al., 2007). The ICH risk of intavenous heparin for the treatment of AMI and deep vein thrombosis is less than 1% (Handley et al., 1972). Heparin may cause thrombocytopenia. Late heparininduced thrombocytopenia (HIT), appearing several days after initiation of treatment and often undiagnosed, may result in secondary platelet activation causing venous and arterial thrombotic events (Otis and Zehnder, 2010). Alternative nonheparin anticoagulants that inhibit thrombin directly, such as argatroban and lepirudin, are approved treatment options for HIT (Hook and Abrams, 2010). Other agents are under study. In the prevention of deep vein thrombosis and venous thromboembolism, low molecular weight heparins (LMWH) (enoxaparin, dalteparin, nadroparin, ardeparin, certoparin), compared to UFH, significantly reduce thrombosis, major hemorrhage, and mortality. Although hemorrhage with LMWH can still occur, fixed dose LMWH is more effective and safer than adjusted dose UFH in this setting (Erkens and Prins, 2010).

COUMARINS Coumarin drugs (warfarin, dicumarol, phenprocoumon, acenocumarol), interfering with vitamin K-dependent coagulation factors, are of benefit in the prevention of thromboembolic events when indicated, but concomitantly increase hemorrhagic risk. Coumarin-related ICH

IATROGENIC NEUROLOGY is a dreaded complication with a poor prognosis, that may occur even at therapeutic levels of anticoagulation. It is generally rapidly evolving, multilocular, and confluent and, characteristically, shows a liquid level in brain imaging studies. Risk factors for ICH in coumarin-treated patients are age, hypertension, diabetes, intensity of anticoagulation, stroke of arterial mechanism, amyloid angiopathy, and symptomatic intracranial arterial stenosis. Other rarer central nervous system bleeds can occur. A growing concern, especially when anticoagulation is an issue, is the finding of cerebral microbleeds in brain MRI echogradient-sequences of asymptomatic elderly individuals. Microbleeds are more prevalent in the presence of hypertension, lacunes, and white matter changes (Roob et al., 1999). However, the hemorrhagic risk of anticoagulation in such patients has not been established. Warfarin, unlike heparin, crosses the placenta and is teratogenic, causing bone disease (chondrodystrophia punctata), mental retardation, optic atrophy, hydrocephalus, schizencephaly, and the Dandy–Walker malformation (Ginsberg et al., 1989). Urgent reversal of anticoagulation is obtained with fresh frozen plasma or dose-adjusted protamine sulphate, in the case of heparin, or fresh frozen plasma and vitamin K, in the case of coumarins. Prothrombin complex concentrate of factors II, VII, IX, X, proteins C and S may also reverse warfarin anticoagulation.

DIRECT THROMBIN AND FACTOR XA INHIBITORS Direct thrombin and factor Xa inhibitors (DTIs and DFXaIs) inhibit thrombin and coagulation factor Xa directly, without modifying the hepatic synthesis of coagulation factors, and may thus overcome the limitations of conventional anticoagulants, especially the need of INR monitoring. At the time of writing, lepirudin, desirudin, bivalirudin, and argatroban are the FDAapproved DTIs in North America. New oral direct inhibitors are most promising as they may eventually replace conventional vitamin K antagonists for chronic oral anticoagulation. Dabigatran etexilate, apixaban, and rivaroxaban are currently the most studied drugs in this emerging group. DTI dabigatran, as well as DFXaIs rivaroxaban and apixaban, have been recently approved by the US Food and Drug Administration (FDA) for stroke prevention in atrial fibrillation. All have been found to be at least as effective as warfarin with comparable or even better bleeding risks. A recent meta-analysis comparing DTIs (ximelagatran, dabigatran, and desirudin) versus vitamin K antagonists or LMWH for prevention of venous thromboembolism after orthopedic replacements concluded that DTIs are as effective as LMWH and vitamin K antagonists, but show higher mortality and cause more bleeding

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(ximelagatran especially, but not desirudin) than LMWH (although not warfarin) (Salazar et al., 2010).

Antiplatelet agents Aspirin is an anticyclooxygenase platelet inhibitor of proven benefit in the prevention of IS and AMI. When indicated following acute IS, it does not cause a major risk of ICH at a daily maximum dose of 300 mg (Sandercock et al., 2008). Up to a quarter of complying patients on treatment may be at persistent risk of vascular events because of lack of response to aspirin (aspirin “resistance”) (Krasopoulos et al., 2008). Dipyridamole is a platelet phosphodiesterase and adenosine reuptake inhibitor of proven benefit for the prevention of IS, in an extended release formulation, in association with aspirin. It may cause headache as a side-effect, prevailing in women, normotensives, and nonsmokers (Halkes et al., 2009). Ticlopidine and clopidogrel are thienopyridines that inhibit the ADP-dependent activation of platelet aggregation, and prevent IS and other thrombotic events with a somewhat higher benefit than aspirin. Individually they do not increase the risk of ICH, but clopidogrel in association with aspirin has been shown to increase both systemic and ICH (ACTIVE Investigators, 2009). This association (so-called “dual” antiplatelet therapy) has not otherwise proven to be of further benefit in the prevention of IS. Clopidogrel “resistance” has also been documented and linked to an increased vascular risk (Sofi et al., 2010). The recently approved thienopyridine prasugrel is a more consistent platelet inhibitor than clopidogrel. Although it has not been formally studied in cerebrovascular disease, prasugrel has been related to a higher risk of ICH and should presently be avoided in patients with prior stroke (Testa et al., 2010). Glycoprotein (GP) IIb-IIIa inhibitors (abciximab, tirofiban, eptifibatide) block the binding of fibrinogen to platelets, thereby inhibiting aggregation. They have shown some benefit in the treatment of acute coronary syndromes, but with higher risk of major bleeding, including ICH. The efficacy of these agents in stroke has not been proven (De Luca et al., 2009). There are as yet no data regarding the risk/benefit of triple antiplatelet therapy (adding GPIIb/IIIa inhibitors to a dual antiplatelet regimen) in preventing IS.

NEUROLOGIC ADVERSE EFFECTS OFANTIEPILEPTIC AND ANTISPASTIC DRUGS Antiepileptic drugs The neurologic adverse effects of most commonly used antiepileptic drugs (AEDs) are presented in Table 107.4.

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Table 107.4 Neurologic adverse effects of most commonly used anticonvulsant drugs Drug

Adverse effects

Benzodiazepines Phenytoin

Cognitive impairment (Stewart, 2005) Cerebellar atrophy (Ney et al., 1994) Peripheral neuropathy (Shorvon and Reynolds, 1982) Mania (Drake and Peruzzi, 1986) Oculogyric crisis (Gorman and Barkley, 1995) Neurologic consequences of hyponatremia (Lahr, 1985) Hyperactivity (Wolf and Forsythe, 1978) Irritability and sleep disturbances (Camfield et al., 1979) Depression (Brent et al., 1987) Tremor (Karas et al., 1983) Hyperammonemic encephalopathy (Sunkavalli et al., 2011) Hearing loss (Hori et al., 2003) Dyskinesia and akathisia (Ehyai et al., 1978) Lupus with cerebral involvement (Casteels et al., 1998) Depression (Phabphal and Udomratn, 2010) Speech disturbances (Cramer et al., 1999) Peripheral visual field deficit (Willmore et al., 2009) Psychiatric and behavioral changes (Guberman, 1996) Agitation, confusion, and hallucinations (Beran and Gibson, 1998) Aggressive behavior (Litzinger et al., 1995) Neurologic consequences of hyponatremia (Van Amelsvoort et al., 1994) Depression (Andersohn et al., 2010) Irritability and behavioral changes (Mula et al., 2003) Tremor (Schachter, 1999) Psychomotor agitation (Chadwick and Marson, 2005)

Carbamazepine

Phenobarbital

Valproic acid

Ethosuximide Topiramate Vigabatrin Lamotrigine Gabapentin Oxcarbazepine Levetiracetam Tiagabine Zonisamide

Cognitive impairment is shared by most anticonvulsant drugs, an important issue since cognitive dysfunction is common among epileptic patients. Gabapentin, tiagabine, lamotrigine, oxcarbazepine, and levetiracetam are not associated with significant deleterious changes on cognitive functions. Movement disorders including parkinsonism, chorea, dystonia, asterixis, dyskinesias, hemiballism, and athetosis are less frequently found but can be seen with most anticonvulsant drugs: phenytoin, carbamazepine, valproic acid, ethosuximide, lamotrigine, and gabapentin (Kennedy and Lhatoo, 2008). Seizure exacerbation has also been described in children and adults as a consequence of clonazepam, phenytoin, carbamazepine, valproic acid, ethosuximide, topiramate, gabapentin, lamotrigine, oxcarbazepine, and tiagabine (Kennedy and Lhatoo, 2008).

Antispastic drugs There are several drugs with antispastic effect. Benzodiazepines, gabapentin, baclofen, tizanidine, and clonidine are centrally acting drugs. Dantrolene and botulinum toxin type A have peripheral action.

The efficacy of antispastic agents is marginal and adverse effects are so common that this can limit their usefulness. Antispastic drugs act by decreasing muscle tone, thus one of the most frequent adverse effects is impaired movement performance. Drowsiness is the most frequent adverse symptom in patients treated with tizanidine, dantrolene is associated with weakness, drowsiness, and malaise, while baclofen produces sedation, dizziness, and muscle weakness (Montane´ et al., 2004). Botulinum toxin type A is injected locally. This exotoxin of the anaerobic bacterium Clostridium botulinum is irreversibly bound to the presynaptic neuron at the neuromuscular junction and disrupts peptides necessary for the release of acetylcholine, causing a flaccid muscle paralysis. Common neurologic indications include blepharospasm, cervical dystonia, hemifacial spasm, and spasticity. Following injection, muscular function recovers after 4–6 months. The most frequent neurologic adverse effect of botulinum toxin type A is muscle weakness, generally due to local extension of the antispastic effect to the wrong or undesired muscles, inducing ptosis, diplopia, lack of eyelid occlusion, or cervical, facial or limb

IATROGENIC NEUROLOGY weakness, depending on the site of injection. It can sometimes spread to cause generalized weakness, dysphagia, dysarthria, and dyspnea (Bhatia et al., 1999).

NEUROLOGIC ADVERSE EFFECTS OFANTIPARKINSONIAN, ANTIDEPRESSANT, AND COGNITION DRUGS

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Table 107.5 Other neurologic adverse effects of commonly used antiparkinsonian drugs Drug

Adverse effects

Dopamine agonists

Compulsive behavior (i.e., pathological gambling) (Dodd et al., 2005) Uncontrollable somnolence (Avorn et al., 2005) Insomnia (Horn and Stern, 2004) Dizziness (Etminan et al., 2003) Orthostatic hypotension (Horn and Stern, 2004) Levodopa phobia (Kurlan, 2005) Serotonin syndrome (Bainbridge et al., 2008) Headache, dizziness, somnolence (Horn and Stern, 2004) Somnolence/insomnia (Horn and Stern, 2004) Confusion (Horn and Stern, 2004) Insomnia (Thornton et al., 1980) Headache (Horn and Stern, 2004) Serotonin syndrome (Bainbridge et al., 2008) Confusion (Horn and Stern, 2004)

Antiparkinsonian drugs Almost every antiparkinsonian agent, including levodopa, dopamine agonists, MAO B inhibitors, anticholinergics, and amantadine, can produce hallucinations, mostly visual (Burn and Tr€oster, 2004). They are considered benign when insight is preserved. When there is no insight they are regarded as malignant and a manifestation of psychosis. They may also be accompanied by delusional symptoms. Psychosis is present in up to a quarter of patients with Parkinson’s disease and constitutes the main predictor of institutionalization. Patients treated with antiparkinsonian drugs are at much higher risk of developing psychosis than nontreated patients. All the centrally acting drugs used to treat motor symptoms in Parkinson’s disease have been associated with psychosis (Goetz, 1999). Anticholinergic treatment is associated with chronic cognitive impairment (Cooper et al., 1992). Dopaminergic drugs (dopamine agonists and levodopa) can improve cognitive performance in early Parkinson’s disease but a relative “hyperdopaminergic” state may impair cognitive functioning in later stages (Kulisevsky, 2000). Amantadine and selegiline may also be associated with cognitive dysfunction (Elmer, 2004). Dopamine dysregulation syndrome, in patients treated with dopaminergic agents, is characterized by a compulsive use of drugs, beyond that needed to achieve relief of motor symptoms, resulting in harmful consequences, such as stereotypies or punding, euphoria, hypomania, delusions, paranoia, aggressive behavior, social or relationship breakdown, seeking/craving or hoarding medication, and withdrawal symptoms (Burn and Tr€ oster, 2004). Dyskinesias are common complications of dopaminergic treatment of Parkinson’s disease. They comprise ballism, chorea, dystonia, myoclonus, and tics. They can occur in coincidence with peak blood levels of dopaminergic drugs (peak dose dyskinesias), with rising and falling blood concentrations (diphasic dyskinesias), or when levels are low (off dyskinesias). Motor fluctuations are also common with the use of levodopa. Wearing off is the predictable recurrence of parkinsonian motor and nonmotor symptoms that

Levodopa COMT inhibitors Anticholinergics MAO B inhibitors

Amantadine

precedes and usually improves after the scheduled intake doses of antiparkinsonian medication. The “onoff” phenomenon is characterized by rapid and mostly random periods of change from a medication-related motor state to a parkinsonian state. Symptoms of parkinsonian autonomic dysfunction such as orthostatic hypotension, constipation, urinary retention, and abnormal salivation can be exacerbated by dopaminergic agents, amantadine, anticholinergics, and COMT inhibitors (Dewey, 2004). Other frequent neurologic adverse effects of most commonly used antiparkinsonian drugs are shown in Table 107.5.

Antidepressant drugs (See Table 107.6.)

Cognition drugs They comprise the agents used for the treatment of degenerative and vascular dementias. There are currently two groups of drugs available for the treatment of dementias: (1) cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), and (2) NMDA receptor antagonists (memantine).

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Table 107.6

Table 107.7

Common neurologic adverse effects of most antidepressants

Common neurologic adverse effects of cognition drugs

Drug

Adverse effects

Tricyclics

Confusion (Uher et al., 2009) Cognitive dysfunction (Uher et al., 2009) Orthosthatic hypotension (Uher et al., 2009) Blurred vision (Uher et al., 2009) Seizures (Kumlien and Lundberg, 2010) Serotonin syndrome (Bainbridge et al., 2008) Aggressive behavior (Moore et al., 2010) Decreased lacrimation (Malone et al., 1992) Insomnia (Papakostas and Fava, 2006)

MAOA inhibitors

SSRI

SNRI

SNRB

NRI NDRI

Trazodone and nefazodone

Agomelatine

Serotonin syndrome (Bainbridge et al., 2008) Orthostatic hypotension (Nair et al., 1995) Insomnia (Nair et al., 1995) Extrapyramidal symptoms (Gerber and Lynd, 1998) Sexual dysfunction (Montejo et al., 2001) Isomnia (Uher et al., 2009) Seizures (Kumilen and Lundberg, 2010) Serotonin syndrome (Mason et al., 2000) Hallucinations (Capaldi and Carr, 2010) Suicidal ideation (Mann et al., 2006) Aggressive behavior (Moore et al., 2010) Oculogyric dystonic reaction (Patel and Simon, 2006) Insomnia (Perahia et al., 2006) Serotonin syndrome (Hadikusumo and Ng, 2009) Aggressive behavior (Moore et al., 2010) Somnolence (Papakostas, 2007) Insomnia (Papakostas et al., 2008a) Aggressive behavior (Moore et al., 2010) Insomnia (Papakostas et al., 2008b) Seizures (Kumilen and Lundberg, 2010) Insomnia (Thase et al., 2005) Serotonin syndrome (Thorpe et al., 2010) Aggressive behavior (Moore et al., 2010) Priapism (Davis et al., 1997) Insomnia (Beasley et al., 1991) Serotonin syndrome (Bainbridge et al., 2008) Aggressive behavior (Moore et al., 2010) Confusion (Davis et al., 1997) Visual disturbances (Davis et al., 1997) Palinopsia (Hughes and Lessell, 1990) Insomnia (Green, 2011) Headache (Green, 2011)

Drug

Adverse effects

Donepezil

Seizures (Kumlien and Lundberg, 2010) Agitation (Turon-Estrada et al., 2003) Insomnia (Hogan et al., 2008) Headache (Hogan et al., 2008) Hallucinations (Sobow and Kloszewska, 2006) Vertigo (Sobow and Kloszewska, 2006) Seizures (Kumlien and Lundberg, 2010) Headache (Hogan et al., 2008) Insomnia (Kavirajan and Schneider, 2007) Headache (Hogan et al., 2008) Headache (Hogan et al., 2008) Confusion (Hogan et al., 2008) Seizures (Babai et al., 2010)

Rivastigmine Galantamine Memantine

Dizziness has been reported with the use of cholinesterase inhibitors and memantine (Hogan et al., 2008). Adverse events of cholinesterase inhibitors and memantine are shown in Table 107.7.

NEUROLOGIC ADVERSE EFFECTS OFANTIPSYCHOTICS, SEDATIVES, AND HYPNOTICS Antipsychotics and dopamine receptor-blocking drugs The salient clinical features and management of antipsychotics and dopamine receptor-blocking drugs (DRBDs) are listed in Table 107.8. Antipsychotics may also cause or worsen cognitive impairment and induce anticholinergic side-effects. Clozapine requires blood cell count monitoring for possible agranulocytosis. Other atypical antipsychotic adverse effects include hyperglycemia and dyslipidemia (mostly clozapine and olanzapine), hyperprolactinemia (mostly amisulpride, risperidone), prolongation of heart rate-corrected QT interval (all, but mostly ziprasidone, sertindole), weight gain (mostly clozapine, olanzapine), postural hypotension and seizures (mostly clozapine) (Haddad and Sharma, 2007). Nonantipsychotic DRBDs such as metoclopramide, domperidone, and droperidol (see digestive tract drugs), and promethazine, cinarizine and flunarizine (Mangone and Herskovits, 1989) may have similar though usually milder adverse effects.

Table 107.8 Dopamine receptor-blocking drugs: adverse effects, salient features, and management DRBD adverse effect

Salient features

Management

Acute dystonia

Usually begins early after commencing DRBD Tongue “thickness” or protrusion, brisk jaw or head movements, grimacing, twisted or crooked posturing (“Pisa” syndrome), oculogyric crisis, throat “tightness,” laryngeal spasm

Akathisia (“acute” akathisia)

Generally begins after weeks/months of DRBD Restlessness, fidgetiness, jumpiness, compulsion to move, pacing, foot-tapping or shifting, stomping, swinging Improves with DRBD removal

Neuroleptic malignant syndrome

Begins tipically after a few weeks of DRBD Fever, rigidity, tremor, confusion, dysautonomia (sweating, hypotension, arrhythmias, incontinence) High CK (>1000 U) and GPT, proteinuria, myoglobinuria Eventually, rhabdomyolysis, disseminated intravascular coagulation, acute renal failure Also seen in Parkinson’s disease, after withdrawal of dopaminergic drugs, dehydration, infections and “wearing off” (Ikebe et al., 2003) Generally begins after weeks/months of DRBD Common parkinsonism features, but symmetric “Rabbit” syndrome Appears mostly after months/years, or on discontinuation or dose reduction of DRBD Several clinical syndromes: Classic: oral-lingual: tongue pressing or rolling (“bonbon” sign), protruding (“fly-catcher’s” sign), chewing, cheek blowing Stereotypic: pelvic: “copulatory” rocking respiratory: panting, puffing, gasping, wheezing vocal: moaning, humming finger: “piano playing” chorea Withdrawal-emergent syndrome: transient chorea after sudden removal of DRBD Tardive akathisia: worsens with DRBD removal Tardive dystonia: face, neck, trunk, often painful Other: myoclonus, tremor, tics, orogenital pain

Discontinuation of DRBD Biperiden 2–8 mg/day Benztropine 1–2 mg IV Diphenhydramine 10–50 mg IV Diazepam 5–10 mg IV Discontinuation of DRBD Change to other neuroleptics Propranolol 40–120 mg/day Biperiden 2–8 mg/day Trihexyphenidyl 2–10 mg/day Consider related conditions: catatonia (Vesperini et al., 2010), serotonin syndrome (Carbone, 2000) Discontinuation of DRBD Oral dantrolene sodium 200–400 mg/day Bromocriptine 10–30 mg/day Dopaminergics resumption if due to its withdrawal Alkalinize urine to prevent myoglobinuria

Neuroleptic-induced parkinsonism Tardive dyskinesia

DRBD, dopamine receptor-blocking drug; CK, creatine kinase; GTP, glutamic-pyruvic transaminase; IV, intravenous.

Discontinuation of DRBD or dopamine-depleting (reserpine, tetrabenazine) drug Anticholinergics Discontinuation of DRBD Initial worsening, thenceforth slow improvement through months, may persist Avoid anticholinergics

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Sedatives and hypnotics Barbiturates and benzodiazepines may cause varying and well known dose-dependent degrees of sedation: slowed thinking, cognitive impairment, somnolence or drowsiness, incoordination, ataxia, hypotonia, dysarthria, nystagmus, delirium, coma. Benzodiazepine dependence may occur with therapeutic doses, through the appearance of withdrawal symptoms upon abrupt discontinuation (anxiety, tremor, eventually seizures) that may be controlled by progressive dose tapering (O’Brien, 2005). Carbamazepine as an adjunctive therapy has shown some benefit in reducing benzodiazepine withdrawal severity, significantly improving drug-free outcome (Denis et al., 2006). Benzodiazepines may specifically cause anterograde amnesia, especially for events occurring near the time of their peak plasma concentrations (Buffett-Jerrott and Stewart, 2002). Paradoxical aggressive reactions (physical aggression, rape, impulsive decision making, violence, and autoaggressiveness) may also occur (Saıäs and Gallarda, 2008).

NEUROLOGIC ADVERSE EFFECTS OF PSYCHOSTIMULANTS AND RELATED DRUGS The clinical effects of psychostimulants include increased alertness, wakefulness, activity and drive, enhanced attention, concentration, and memory, and mood improvement. Adverse effects include insomnia, restlessness, agitation, tremor, irritability and aggression, anxiety or panic, malaise, dizziness, nausea or vomiting, abdominal pain, headache, anorexia and weight loss. Associated adrenergic effects include mydriasis, dry mouth, hypertension, tachycardia, hyperthermia and hyperhydrosis. Most psychostimulants act by inhibiting the reuptake of selective neurotransmitters, such as epinephrine, norepinephrine, dopamine, and serotonin. The most commonly used drugs with psychostimulant-like effect today include atomoxetine, methylphenidate, bupropion, and modafinil. Atomoxetine, introduced as “the first nonstimulant for the management of ADHD,” is thought to enhance noradrenergic function via selective inhibition of the presynaptic norepinephrine transporter (Corman et al., 2004). Pemoline, introduced in the 1980s to treat attention deficity hyperactivity disorder (ADHD), has been discontinued in the US and several other countries because of liver toxicity, and overwhelmingly replaced by methylphenidate, and, increasingly, atomoxetine for that indication (Garnock-Jones and Keating, 2009). Bupropion is mainly a norepinephrine reuptake inhibitor which has shown

benefit for smoking cessation. Modafinil increases monoamine release and hypothalamic histamine levels. Exacerbation of the tics in Tourette’s syndrome has been linked to the use of psychostimulants indicated for the frequent coexistence of ADHD. However, whereas individual patients may eventually undergo an increase in tics, group data have not shown a significant adverse effect. Psychostimulants, used with caution, are therefore not considered today contraindicated in persons with tics and ADHD (Erenberg, 2005). Reported adverse effects of psychostimulants also include chorea (Weiner et al., 1978), growth retardation (Correll and Carlson, 2006), and hypomania (Masand et al., 1995). However, mania and other possible psychiatric effects, such as “behavioral rebound,” withdrawal risk, and psychosis are presently controversial. Concerns have been raised whether to continue or withdraw psychostimulants in adult patients treated for ADHD since childhood, and showing other psychiatric symtpoms (Ashton et al., 2006). On the other hand, the belief that stimulants are contraindicated in mania has been challenged. ADHD and mania share symptoms or pathogenetic mechanisms. Patients with features of both ADHD and psychosis (“ADHD psychosis”) do benefit from treatment with psychostimulants, possibly by improvement of frontal lobe dysfunction (Opler et al., 2001). Psychostimulants have a low risk and might thus even be a treatment option for mania (Hegerl et al., 2010). Other specific neurologic adverse efects of psychostimulants appear in Table 107.9. Recreationally used or abused psychostimulants, such as amfetamines (dextramfetamine, methamfetamine, MDMA or “ecstasy”, MDEA or “eve”), sympathomimetics (phenylpropanolamine, ephedrine), and cocaine may cause movement disorders, seizures, ischemic and hemorrhagic stroke, and severe withdrawal symptoms, other than the general neuropsychiatric and cardiovascular effects mentioned above.

NEUROLOGIC ADVERSE EFFECTS OF ANTIBACTERIAL, ANTIVIRAL, ANTIFUNGAL, ANTIPARASITIC DRUGS, AND VACCINES Antibacterial agents (antibiotics) About 80% of the adverse effects of antibacterial agents are the result of allergic reactions. Neurologic complications, mostly ototoxicty and seizures, are much less frequent. Serious neurologic complications are generally related to inadequate dose management in patients with renal failure. Imipenem and cefepime are the antibacterial agents with the highest neurotoxic risk.

IATROGENIC NEUROLOGY Table 107.9

Antiparasitic agents

Other neurologic adverse effects of most commonly used psychostimulants and related drugs Drug

Adverse effects

Methylphenidate

Stuttering (Burd and Kerbeshian, 1991) Paroxysmal kinesigenic dystonia (Gay and Ryan, 1994) Cerebral arteritis Priapism (Schwartz and Rushton, 2004) Akathisia (Almeida et al., 2006) Rabbit syndrome (Mendhekar and Duggal, 2006) Orofacial and extremity dyskinesia (Bala´zs et al., 2007) Enuresis (Ghanizadeh, 2008) Bruxism (Mendhekar and Andrade, 2008) Excessive talking (Ghanizadeh, 2009) Complex visual hallucinations (Halevy and Shuper, 2009) Acute urinary retention (Desarkar and Sinha, 2006) Suicidal ideation (Bangs et al., 2008) Bruxism worsening (Mendhekar and Lohia, 2009) Priapism (Levenson, 1995) Rhabdomyolysis (David and Esquenazi, 1999) Tactile hallucinations (Charuvastra and Yaeger, 2006) Acute dystonia (Wang et al., 2007) Neck and shoulder pain (Sansone and Sansone, 2009) Seizures (Starr et al., 2009) Serotonin syndrome (Thorpe et al., 2010) Cataplexy worsening (Poza, 2003) Hyperkinetic nondystonic movement disorder (Luborzewski et al., 2006) Visual and cenesthetic hallucinations (Oulis et al., 2008)

Atomoxetine

Bupropion

Modafinil

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The neurologic adverse effects of the most frequently used antibacterial agents are shown in Table 107.10.

Antiviral agents The neurologic adverse effects of the most frequently used antiviral agents are shown in Table 107.11.

Systemic antifungal agents The most frequently encountered adverse effects of systemic antifungal agents are shown in Table 107.12.

The salient neurologic adverse effects of the most frequently used antiparasitic agents are shown in Table 107.13.

Vaccines The reported neurologic adverse effects of the most frequently used vaccines are shown in Table 107.14, but it must be pointed out that no clear causal association could be confirmed for some of the adverse effects shown.

NEUROLOGIC ADVERSE EFFECTS OF ANTINEOPLASTIC AND IMMUNOMODULATORY DRUGS Antineoplastic drugs The most prevalent neurologic complication of chemotherapy is peripheral neuropathy. Encephalopathy is also relatively frequent, especially after repeated intrathecal administration. The most common adverse effects of antineoplastic agents are shown in Table 107.15.

Immunomodulatory drugs Common adverse effects of immunomodulatory agents are shown in Table 107.16.

NEUROLOGIC ADVERSE EFFECTS OF ANTI-INFLAMMATORY, ANALGESIC, AND ANTIALLERGIC DRUGS Anti-inflammtory and analgesic drugs CORTICOSTEROIDS Corticosteroids or glucocorticoids commonly used as anti-inflammatory agents have a central stimulating effect and may cause well-known behavioral changes, such as insomnia, hyperactivity, logorrea, hallucinations, agressiveness, mania, and delirium (“steroid psychosis”). Longer treatment with corticosteroids can induce dose-dependent depression and memory decline, often during the first few weeks of therapy, with changes in the temporal lobe detected by structural, functional, and spectroscopic imaging. Lithium and phenytoin may prevent the mood symptoms, whereas lamotrigine and memantine can partially reverse the memory changes. Both alterations may also revert with dose reduction or discontinuation. The symptoms and treatment response have been likened to those of bipolar disorder (Brown, 2009).

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Table 107.10 Neurologic adverse effects of the most frequently used antibacterial drugs Group

Adverse effects

Penicillins

Seizures (Meropol et al., 2008) Penicillin psychosis (Hoigne’s syndrome) (Rao, 1999) Aseptic meningitis (Prieto-Gonza´lez et al., 2011) Delirium (Tong et al., 2004) Benign intracranial hypertension (Schmitt and Krivit, 1969) Seizures (Chow et al., 2005) Delirium (Chow et al., 2003) Encephalopathy (Roncon-Albuquerque et al., 2009) Dysgeusia (Noel et al., 2008) Agitation and confusion (Slaker and Danielson, 1991) Elevated creatine phosphokinase (Talbot et al., 2007) Vestibular toxicity (Sennesael et al., 1982) Psychosis, aphasia, and dizziness (Mitropoulos et al., 2007) Headache (Dauner et al., 2010) Aseptic meningitis (Nakajima et al., 2007) Hearing loss (Schmutzhard et al., 1995) Seizures (Schranz, 1998) Headache (Bazan et al., 2009) Stroke-like symptoms and delirium (Duquaine et al., 2011) Hearing loss (Schmutzhard et al., 1995) Vertigo (Duque et al., 1991) Insomnia (Matthews and Lancaster, 2009) Encephalopathy (Fernańdez-Torre et al., 2004) Paresthesiae (Gotuzzo et al., 1994) Hearing loss (Pedrajas et al., 1993) Hearing loss (Moore et al., 1984) Vestibular toxicity (Darlington and Smith, 2003) Neuromuscular blockade (Snavely and Hodges, 1984) Musical hallucinations (Tanriverdi et al., 2001) Psychosis (Kane and Byrd, 1975) Polyneuropathy/encephalopathy (Bischoff et al., 1977) Aseptic meningitis (Granowitz and Brown, 2008) Optic neuritis (Bucy, 1937) Confusion (Lehr, 1957) Psychosis Multiple peripheral neuropathy (Blankenhorn, 1938) Seizures (Meropol et al., 2008) Vertigo (Granowitz and Brown, 2008) Pseudotumor cerebri (Tabibian and Gutie´rrez, 2009) Headache (Doan et al., 2006) Vestibular dysfunction (Fanning et al., 1977) Visual disturbances (Aagaard and Hansen, 2010) Neuromuscular blockade (Bezzi and Gessa, 1961) Hearing loss (Ress and Gross, 2000) Headache and dizziness (Hopkins, 1991) Dysgeusia (Snyman et al., 2009) Hallucinations and seizures (Schiff et al., 2010) Psychosis, anxiety, confusion, and restlessness (Aagaard and Hansen, 2010) Headache and dizziness (Nguyen and Chung, 2005) Dysgeusia (Kasbekar and Acharya, 2005)

Cephalosporins

Carbapenems

Monobactams Aminoglycosides

Sulfonamides

Tetracyclines

Macrolides

Ketolides


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Table 107.10 Continued Group

Adverse effects

Glycopeptides

Hearing loss (Farber and Moellering, 1983) Headache and dizziness (Noel et al., 2008) Dysgeusia (Leonard and Rybak, 2008) Seizures (Aagaard and Hansen, 2010) Elevated creatine phosphokinase (Cantoń et al., 2010) Headache, drowsiness, and dizziness (Radner, 1973) Headache, insomnia, and seizures (Owens and Ambrose, 2005) Dysgeusia and seizures (Noel, 2009) Seizures (Walton et al., 1997) Dysgeusia (Geddes, 1999) Peripheral neuropathy (Lode, 2010) Psychosis and anxiety (Stahlmann and Lode, 2003) Delirium (Slobodin et al., 2009) Dizziness (Anzueto et al., 2002) Neuromuscular blockade (Tang and Schroeder, 1968), Headache, insomnia, and dizziness (Fung et al., 2001)

Lipopeptides Rifamycins Fluoroquinolones

Lincosamides Oxazolidinone Other agents Metronidazole

Chloramphenicol

Polymyxin

Isoniazid

Trimethoprim

Cerebellar dysfunction (Kusumi et al., 1980) Peripheral neuropathy (Coxon and Pallis, 1976) Seizures (Frytak et al., 1978) Optic neuritis (Lasky et al., 1957) Peripheral neuropathy (Wallenstein and Snyder, 1952) Ophthalmoplegia (Hill and Armstrong, 1950) Neuromuscular blockade (Fogdall and Miller, 1974) Hearing loss, visual disturbances, paresthesiae, vertigo, confusion, hallucinations, seizures, and ataxia (Falagas and Kasiakou, 2006) Seizures (Sullivan et al., 1998) Optic neuritis (Kass et al., 1957) Peripheral neuropathy (Goldman and Braman, 1972) Encephalopathy (Adams and White, 1965) Aseptic meningitis (Granowitz and Brown, 2008)

By an uncertain mechanism, corticosteroids may induce exacerbation of myasthenia gravis symptoms, especially at initiation of therapy, in up to 50% of patients. Predictors of exacerbation appear to be old age, predominant bulbar symptoms, and clinical severity of the disease, rather than a high initial dose (Bae et al., 2006). Proximal progressive lower limb girdle myopathy is a frequent complication of prolonged steroid therapy. It may extend to upper limbs, and occasionally present as an acute quadriplegic myopathy after high intravenous doses (Hirano et al., 1992). Other rarer reported adverse effects of steroids are optic neuropathy with fluprednisolone (Teus et al., 1991) and pseudotumor cerebri on steroid withdrawal (Lessell, 1992).

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Non-selective COX inhibitors Aspirin has antiplatelet effects that have been dealt with earlier in this chapter. Its most common side-effect is gastrointestinal bleeding linked to inhibition of anticyclooxygenase-1 (COX-1). Aspirin administered in children with high fever may cause Reye syndrome believed to be due to impaired oxidation on the long chain hydroxyacyl-CoA dehydrogenase enzyme (Glasgow, 2006). However, the cause– effect relationship between aspirin and Reye syndrome has recently been put into question (Schr€or, 2007). Reye syndrome has also been linked to the use of phenothiazines and antiemetics (Casteels-Van Daele et al., 2000).

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Table 107.11 Neurologic adverse effects of the most frequently used antiviral drugs Drug Nonretroviral agents: Anti-herpesviridae agents

Anti-influenza agents*

Antihepatitis agents*{{ Other nonretroviral agents Retroviral agents: Nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Fusion inhibitors CCR5 antagonists

Adverse effects

Delirium (Revankar et al., 1995) Encephalopathy (Onuigbo et al., 2009) Seizures (Fan-Harvard et al., 2009) Aseptic meningitis (Olin and Gugliotta, 2003) Psychosis (Yang et al., 2007) Headache, insomnia, peripheral neuropathy, and paresthesia (Curran and Noble, 2001) Depression (Sirota et al., 1988) Confusion and ataxia (Martinez-Diaz and Hsia, 2011) Headache (Dutkowski et al., 2010) Dizziness (Choo et al., 2011) Insomnia and hallucinations (Jefferson et al., 2006) Depression (Chung and Joung, 2010) Myopathy (Tak et al., 2010) Tetany secondary to hypocalcemia or hypomagnesemia (Muller et al., 2007) Psychosis (Quarantini et al., 2006) Psychosis (Maxwell et al., 1988) Depression (Foster et al., 2004) Migraine and mood changes (Colebunders et al., 2002) Sleep disturbances and peripheral neuropathy (Sharma et al., 2008) Seizures (D’Silva et al., 1995) Psychosis (Wise et al., 2002) Cognitive impairment (Prime and French, 2001) Insomnia, vivid dreams, and night terrors (Cespedes and Aberg, 2006) Mania (Shah and Balderson, 2003) Delirium and behavioral changes (de la Garza et al., 2001) Depression Insomnia, peripheral neuropathy, and headache (Fung and Guo, 2004) Dizziness and insomnia (Lieberman-Blum et al., 2008)

*Adverse effects of interferons and amantadine have been addressed in other sections. { Adverse effects of lamivudine are included in the NRTI group. { Ribavirin is included in the group of other nonretroviral agents.

Acute aspirin/salicylate intoxication, accidental or voluntary, presents as hyperpnea, sweating, tinnitus, deafness, encephalopathy (confusion, stupor, seizures) and metabolic acidosis, and can be confirmed by measuring plasma salicylate concentrations. Gastric emptying, forced alkaline diuresis, and eventually hemodialysis are accepted therapeutic interventions (Pearlman and Gambhir, 2009). Consensus management guidelines have been published (Chyka et al., 2007). Aspirin and salicylates are ototoxic, causing usually reversible tinnitus, high frequency hearing loss, and alterations of perceived sounds. Salicylates act as competitive inhibitors of Cl-anions at the anion-binding site of prestin, the motor protein of the outer hair cell. Regular use of aspirin, non-steroidal antiinflammatory

drugs (NSAIDs), and acetaminophen/paracetamol may cause hearing loss (Curhan et al., 2010). Aseptic ibuprofen-induced meningitis, often recurrent, may occur with therapeutic doses, especially in patients with an autoimmune connective tissue disorder. It presents as an acute meningeal or meningoencephalopathic syndrome, sometimes with focal neurologic signs (Agus et al., 1990). The cerebrospinal fluid shows elevated neutrophils and protein, and, unlike acute bacterial meningitis, normal glucose. Symptoms abate on discontinuation. Screening for autoimmune disease has been recommended in previously healthy patients with ibuprofen-related meningoencephalitis (Rodrı´guez et al., 2006). Diclofenac is a NSAID inhibiting COX-1, COX-2, and prostaglandin synthesis. Nonselective COX inhibitors


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Table 107.12

Selective COX-2 inhibitors

Neurologic adverse effects of most frequently used antifungal drugs

Selective COX-2 inhibitors, especially rofecoxib, have been associated with an increased risk of thromboembolic vascular events, possibly stroke, either through prothrombotic effects or blood pressure destabilization (Farkouh and Greenberg, 2009). Other COX-2 inhibitors include celecoxib, parecoxib, valdecoxib, etoricoxib, and lumiracoxib.

Drug

Adverse effects

Polyenes

Benign intracranial hypertension (Heudier et al., 1992) Seizures (Aruna et al., 2000) Delirium and depression (Weddington, 1982) Headache and dizziness (Bodhe et al., 2002) Visual loss (Li and Lai, 1989) Recurrent hemiparesis (Devuyst et al., 1995) Myelopathy (Carnevale et al., 1980) Leukoencephalopathy (Liu et al., 1995) Anxiety, confusion, and insomnia Visual disturbances (Herbrecht et al., 2002) Hallucinations (Cleveland and Campbell, 1995) Vertigo (Costa et al, 1994) Headache and dizziness (Tucker et al., 1990) Sexual dysfunction (Terrell, 1999) Cerebellar syndrome (Cubo Delgado et al., 1997) Headache (Mayr et al., 2011) Dizziness (Menichetti, 2009) Insomnia (Hiemenz et al., 2005) Sexual dysfunction (Hull and Vismer, 1992)

Triazoles

Pyrimidine analogs Echinocandins

Allylamines

may have an increased risk of cardiovascular thromboembolic adverse effects, and diclofenac-related stroke has been reported (Kornowski et al., 1995). Other neurologic or neurologically related adverse effects induced by diclofenac include myoclonus/myoclonic encephalopathy (Sańchez Valiente, 1995), corneal disorders either with oral or topical use of the drug (Zanini et al., 2006), and, in association with mefenamic acid, another NSAID, pediatric posterior reversible leukoencephalopathy (Yokobori et al., 2006). Naproxen, a nonselective COX inhibitor, has been reported to cause hearing loss, sometimes irreversible (Chapman, 1982). Both naproxen and phenylbutazone, another NSAID now in scant use because of agranulocytosis risk, in combination with misoprostol, a prostaglandin E1 analog preventing the development of NSAID-induced gastric ulcers, have been reported to cause ataxia and other neurosensory effects (Huq, 1990).

OPIATES AND OPIOIDS Both opiates and opioids have narcotic and analgesic effects. Opioids, predominantly, are as a rule used today for the treatment of chronic pain, mostly related to cancer, but also to selected cases of headache, neuralgias, facial, radicular, rheumatic, and low back pain. Drowsiness, somnolence, stupor, shallow respiration, pinpoint pupils, bradycardia, and hypothermia are classic narcotic effects of opioids. Opioid withdrawal symptoms, also well known, include agitation, sweating, shivering, piloerection, abdominal pain, vomiting and diarrhea. Naloxone may reverse the narcotic symptoms as well as precipitate withdrawal. Sedation and cognitive changes can occur on initiation of therapy with opioids (Swegle and Logemann, 2006). Cognitive changes have been reported in patients on long-term therapy (Larsen et al., 1999), but psychological measures and pain severity seem to be more predictive of cognitive decrements than specific opioids or daily dose (Brown et al., 2006). Opioid-induced dose-related myoclonus may appear with various agents, including methadone (Ito and Liao, 2008). It occurs particularly in the perioperative setting, in patients on chronic opioid therapy, and with coexisting dehydration or renal disease (Mercadante, 1998). Prolonged opioid treatment may result in opioidinduced hyperalgesia, with worsening pain despite accelerating opioid doses, and abnormal pain sensitivity and symptoms such as allodynia (Mitra, 2008). Intrathecal use of opioids may increase the likelihood of adverse events (Ruan, 2007).

FLUPIRTINE Flupirtine, an aminopyridine, is a centrally acting nonopioid, non-NSAID, nonsteroidal analgesic, a selective neuronal potassium channel opener and NMDA receptor antagonist, used in Europe for treating fibromyalgia and other types of back pain. It is not commercialized in the U.S.A. Reported cases of flupirtine-induced neurologic toxicity include “paradoxical cerebral cortical

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Table 107.13 Neurologic adverse effects of most frequently used antiparasitic drugs Drug

Adverse effects

Benzimidazoles

Vertigo (Knopp et al., 2010) Headache and dysgeusia (Can˜ete et al., 2006) Encephalopathy (Blum et al., 2001) Dizziness (Keystone and Murdoch, 1979) Blurred vision, optic neuritis, and seizures (Bagheri et al., 2004) Post-ivermectin Loa loa encephalopathy (Kamgno et al., 2008) Myalgia, dizziness, and headache (Bussaratid et al., 2005) Optic neuritis (Bagheri et al., 2004) Neuromuscular blockade (Ojewole, 1984) Headache and myalgia (Pani et al., 2005) Sleepiness, headache, and dizziness (Bagheri et al., 2004) Seizures (Hewagama et al., 2010) Vertigo and headache (Yangco et al., 1987) Psychosis (Zaki et al., 2009) Ototoxicity (Bortoli and Santiago, 2007) Seizures (Marquardt and Albertson, 2001) Cinchonism (Wolf et al., 1992) Dizziness, sleep disturbances, anxiety, and psychosis (Toovey, 2009) Fatigue and dysgeusia (Fung and Doan, 2005) Headache and dysgeusia (Kapoor et al., 1999)

Avermectins

Other anthelmintics

Antimalarials

Agents for other parasitic infections

hyperexcitability” entailing an increased risk of seizures (Hoffmann et al., 2004), and, more specifically, a clinical syndrome of headache, blurred vision, confusion, ataxia, syncope, and, characteristically, green urine (Hufschmidt et al., 2009).

OTHER ANTI-INFLAMMATORY AND ANALGESIC DRUGS Acute colchicine poisoning causes abdominal pain, vomiting, metabolic acidosis, pancytopenia, lifethreatening cardiac arrythmias, hypotension, respiratory distress, and hypocalcemia. Rhabdomyolysis, peripheral neuropathy, and ascending paralysis may occur a few days after exposure (Maxwell et al., 2002). Longer use of colchicine may induce axonal peripheral neuropathy and associated vacuolar myopathy with elevated CK levels (colchicine myoneuropathy), especially in patients with altered renal function, that may resolve on discontinuation of the drug (Kuncl et al., 1987). Gold salts can cause peripheral neuropathy, sometimes with segmental demyelination and axonal degeneration, a Guillain–Barre´-type syndrome, cranial nerve palsies, encephalopathy showing white matter lesions on contrast CT, and associated myokimia or generalized muscle fasciculations. Both symptoms and lesions revert on withdrawal (Schlumpf et al., 1983; Fam et al., 1984; Perry and Jacobsen, 1984).

ANTIMIGRAINE AGENTS Ergotamine Long-term use of ergotamine may cause the so called “ergotism,” characterized by headache and an intensive generalized, even gangrenous, vasoconstriction of small and large blood vessels. Angiography may show arterial narrowing, tapering, or segmented stenosis in different vascular territories (Ruano-Calderoń and ZermenõPohls, 2005). Ergot vasospasm and ischemia may involve the cerebral arteries, producing various ischemic syndromes with neurologic and neuropsychiatric manifestations. Convulsive ergotism, with generalized tonic-clonic seizures, may be due to ischemia or other unclear mechanisms. Neurologic adverse effects of ergotamine toxicity are summarized in Table 107.17. Patients taking ergotamine, ergotamine derivatives and other vasoconstrictive medications may undergo a specific reversible cerebral vasoconstriction (“Call– Fleming”) syndrome. Patients present with sudden, severe, and recurrent (“thunderclap”) headache, and may have seizures, focal motor signs, bilateral paramedian hyperintense diffuse lesions on MRI with a nonvascular distribution, and characteristic (“string of beads”) vasospasm on angiography, mostly resolving spontaneously or on withdrawal of the medication. Localized cortical subarachnoid hemorrhages and later cerebral ischemic events may occur (Ducros, 2010).


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Table 107.14 Reported neurologic adverse effects of vaccines included in recommended immunization schedules Drug

Adverse effects

Hepatitis B

Guillain–Barre´ syndrome and optic neuritis (Shaw et al., 1998) Multiple sclerosis (Herroelen et al., 1991) Ototoxicity (DeJonckere and de Surge`res, 2001) Cerebellar ataxia (Deisenhammer et al., 1994) Transverse myelitis (Tartaglino et al., 1995) Irritability (Cheuvart et al., 2009) Guillain–Barre´ syndrome (Pollard and Selby, 1978) Encephalomyelitis (Schwarz et al., 1988) Transverse myelitis (Whittle and Robertson, 1977) Optic neuritis and myelitis (Topaloglu et al., 1992) Peripheral neuropathy (Baust et al., 1979) Febrile and afebrile seizures (Barlow et al., 2001) Seizures (Kulenkampff et al., 1974) Hypotonic/hyporesponsive episodes (DuVernoy and Braun, 2000) Guillain–Barre´ syndrome (Gervaix et al., 1993) Giant cell arteritis (Perez et al., 2000) Seizures, encephalopathy, ataxia, insomnia, meningitis, and hypotonic/hyporesponsive episodes (Wise et al., 2004) Paralytic poliomyelitis (Nathanson and Kew, 2010) Guillain–Barre´ syndrome (Kinnunen et al., 1989) Encephalitis (Landrigan and Witte, 1973) Subacute sclerosing panencephalitis (Modlin et al., 1977) Febrile and afebrile seizures (Griffin et al., 1991) Cranial neuropathy (Chan et al., 1980) Optic neuritis (Kazarian and Gager, 1978) Peripheral neuropathy (Schaffner et al., 1974) Aseptic meningitis (Fujinaga et al., 1991) Transverse myelitis and optic neuritis (Kline et al., 1982) Encephalitis (Gilden et al., 2000) Behavioral changes and delirium (George and Benonis, 2003) Encephalitis (Goulleret et al., 2010) Herpes zoster ophthalmicus and encephalitis (Chouliaras et al., 2010) Headache (Mick, 2010) Meningitis and Guillain–Barre´ syndrome (De Wals et al., 2009)

Rotavirus DT and DTP

Haemophilus influenzae type b4 Pneumococcal Poliovirus Measles, mumps, and rubella

Varicella Hepatitis A Zoster

Meningococcal

Triptans The most salient potential complication of triptans is coronary spasm and acute myocadial infarction. Concerns have been raised about the risk of serotonin syndrome when triptans are used in association with selective serotonin reuptake inhibitors (SSRIs), usually indicated for affective disorders, and the FDA in the US has suggested that fatal serotonin syndrome (SS) is possible in that case. However, the evidence for this risk is uncertain and such a concern has recently been put into question (Gillman, 2010). Rare reported neurologic side-effects of triptans have included triptan-induced daily headache (G€ obel et al., 1996), axial dystonia (Oterino and Pascual,

1998), postpartum cerebral angiopathy in association with dihydroergotamine (Granier et al., 1999) and acute pathologic laughter (Barbanti et al., 2008).

Antiallergic drugs: antihistamines (H1-receptor antagonists) Diphenhydramine poisoning may induce a central anticholinergic syndrome with clouding of consciousness, optical/acoustic hallucinatory psychosis, fever, and dry skin and mouth (Lang et al., 1995). The most common neurologic symptoms for fatal cases of diphenhydramine intoxication have been seizures and/or sympathetic pupil responses (Nine and Rund, 2006). Other rarer toxic

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Table 107.15 Common neurologic adverse effects of antineoplastic agents Group

Adverse effects

Alkylating agents

Seizures (Salloum et al., 1997) Blurred vision (Kende et al., 1979) Confusion (Tashima, 1975) Retinal hemorrhages and diplopia (Burns, 1992) Visual loss (Shapiro et al., 1992) Myoclonus (Wyllie et al., 1997) Hallucinations (Walsh et al., 1984) Encephalopathy (Nicolao and Giometto, 2003) Peripheral neuropathy (Patel et al., 1997) Headache (Middleton et al., 2000) Seizures (Tfayli et al., 1999) Visual disturbances (Ostrow et al., 1978) Encephalopathy (Lyass et al., 1998) Peripheral neuropathy (Roelofs et al., 1984) Cranial neuropathy (Bokemeyer et al., 1998) Muscle cramps (Siegal and Haim, 1990) Stroke (Doll et al., 1986) Hearing loss (Extra et al., 1998) Paraparesis and quadriparesis (Cheson et al., 1994) Cerebellar dysfunction (Herzig et al., 1987) Aseptic meningitis (Nelson and Frank, 1981) Locked-in syndrome (Kleinschmidt-DeMasters and Yeh, 1992) Encephalopathy (Hwang et al., 1985) Myeloencephalopathy (Resar et al., 1993) Leukoencephalopathy (Lien et al., 1991) Posterior reversible encephalopathy (Russell et al., 2001) Peripheral neuropathy (Dormann et al., 1998) Stroke-like syndrome (Yim et al., 1991) Encephalopathy (Nieto et al., 1999) Coma (Whittaker et al., 1973) Cortical blindness (Byrd et al., 1981) Hallucinations (Ghosh et al., 1994) Lethargy (Brown et al., 2000) Transient dysarthria (Baz et al., 2001) Peripheral neuropathy (Hilkens et al., 1996) Cranial neuropathy (Delaney, 1982) Autonomic disturbances (Carmichael et al., 1970) Optic neuropathy (Capri et al., 1994) Myalgias (McGuire et al., 1989) Stroke (Kukla et al., 1982) Myeloencephalopathy (Arico et al., 1990) Encephalopathy (Pisoni et al., 2001) TIA (Schachter and Freeman, 1982) Stroke (Doll and Yarbro, 1992) Encephalopathy (Pirzada et al., 2000) Multifocal inflammatory leukoencephalopathy (Hook et al., 1992) Subacute leucoencephalopathy (Kuzuhara et al., 1987) Wernicke–Korsakoff-like syndrome (Heier et al., 1986) Cerebellar dysfunction (Riehl and Brown, 1964) Optic neuropathy (Adams et al., 1984) Focal dystonia (Brashear and Siemers, 1997) Acute parkinsonian syndrome (Bergevin et al., 1975) Stroke (Doll and Yarbro, 1992)

Platinum-based agents

Antimetabolites

Plant alkaloids

Antitumor antibiotics

Fluorinated pyrimidines


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Table 107.15 Continued Group

Adverse effects

Tyrosine kinase inhibitors Bortezomib

Headache (Giampaglia et al., 2010) Peripheral neuropathy (Richardson et al., 2006) Stroke (Guo et al., 2010) Encephalopathy (Leonard and Kay, 1986) Ischemic and hemorrhagic stroke (Feinberg and Swenson, 1988) Headache and idiopathic intracranial hypertension (Bigby and Stern, 1988) Cerebellar dysfunction (Bernstein and Leventhal-Rochon, 1996) Depression and suicide (Jacobs et al., 2001) Myalgias/rhabdomyolysis (Trauner and Ruben, 1999) Stroke (Royer et al., 2002) Peripheral neuropathy (La Rocca et al., 1990) Disorientation, visual and hearing loss (Hussain et al., 2000) Stroke (Laterra et al., 2004) Somnolence (Singhal et al., 1999) Peripheral neuropathy (Molloy et al., 2001) Seizures (Fine et al., 2000) Stroke (Ortin et al., 2006)

L-Asparaginase Retinoids

Suramin

Lenalidomide/thalidomide

Table 107.16 Common neurologic adverse effects of immunomodulatory agents Group

Adverse effects

Interferons

Encephalopathy and parkinsonism (Meyers et al., 1991a) Confusion, lethargy, and dizziness (Weiss, 1998) Depression and suicide (Jonasch and Haluska, 2001) Paranoid psychosis (Schafer and Schwaiger, 2003) Cognitive impairment (Valentine et al., 1998) Hearing loss (Kanda et al., 1994) Oculomotor nerve paralysis (Bauherz et al., 1990) Peripheral neuropathy (Bernsen et al., 1988) Spastic diplegia (Barlow et al., 1998) Seizures and vegetative state (Meyers et al., 1991b) Encephalopathy (Siegel and Puri, 1991) Acute fatal leukoencephalopathy (Vecht et al., 1990) Transient visual loss (Bernard et al., 1990) Peripheral neuropathy (Loh et al., 1992) Cerebellar dysfunction (Meyers and Yung, 1993). Transient dysarthria (Baz et al., 2001) Multifocal inflammatory leukoencephalopathy (Kimmel et al., 1995) Insomnia, headache and dizziness (Parkinson et al., 1977) Progressive multifocal leukoencephalopathy (Carson et al., 2009) Hemorrhagic stroke (Ranpura et al., 2010) Hypophysitis (Blansfield et al., 2005) Uveitis (Weber et al., 2008) Cerebral aspergillosis (Amadori et al., 2010)

Interleukins

Levamisole

Monoclonal antibodies

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Table 107.17 Neurologic adverse effects of ergotamine toxicity Drug

Adverse effects

Ergotamine tartrate

Coma (Hudgson and Hart, 1964) Peroneal nerve palsy (Merhoff and Porter, 1974) Transient monocular blindness (Merhoff and Porter, 1974) Headache (Wainscott et al., 1974) Homonymous hemianopia, hemiplegia, uninhibited behavior (Senter et al., 1976) Neuropsychiatric symptoms (Fl€ ugel et al., 1977) Paraplegia (Lenger, 1984) Bilateral focal cortical atrophy/ infarcts (Fincham et al., 1985) Carotid artery territory infarct (Berlit et al., 1986) Bilateral ischemic optic neuropathy (Sommer et al., 1998) Dystonia and reflex sympathetic dystrophy (Merello et al., 1991)

effects observed have been rhabdomyolysis (Emadian et al., 1996) and opsoclonus (Irioka et al., 2009). Cetirizine has been reported to cause sedation and mental performance changes (Spangler and Brunton, 2006), oculogyric crises (Fraunfelder and Fraunfelder, 2004), and dystonia (Esen et al., 2008). Cyproheptadine may cause anticholergic delirium (Scott et al., 2007). Choreoathetosis has also been observed (Samie and Ashton, 1989).

NEUROLOGIC ADVERSE EFFECTS OF HORMONES, HORMONE-RELATED AND METABOLISM DRUGS Hormones and hormone-related drugs Estrogens given in contraceptive doses may have prothrombotic effects and increase stroke risk, both ischemic and hemorrhagic, whether in higher (more than 50 mg per pill) or lower doses (Collaborative Group, 1973; Stadel, 1981). Smoking and migraine increase this risk (Tzourio et al., 1995). Progestogens increase the hazard of venous thromboembolism and may contribute to stroke risk (Jick et al., 1995). There has been a long-standing controversy about the benefit of hormone replacement therapy in postmenopausal women, through possible vascular and cognition protective effects. However, an excess risk of stroke, cognitive decline and dementia was observed with

combined estrogen/progestogen replacement therapy in large randomized studies (Shumaker et al., 2003; Wassertheil-Smoller et al., 2003), and the US Preventive Services Task Force has discouraged or not recommended its use (Humphrey et al., 2002). Oral contraceptives are also known to cause chorea (Nausieda et al., 1979). Agents that inhibit or block natural endogenous hormones and have neurologic side-effects are listed in Table 107.18. Sildenafil may cause headache and eventually cluster headache (de L Figuerola et al., 2006). Visual adverse effects have been described in some patients, such as increased brightness of lights, blue-tinged or blurry vision (Laties and Sharlip, 2006). They are usually transient, appear after higher doses, and are attributed to associated inhibition of the retinal PDE6. Serious ophthalmic side-effects may occur, generally after longer exposure to the drug: branch retinal artery occlusion (Tripathi and O’Donnell, 2000), central serous chorioretinopathy (Allibhai et al., 2004), anterior and posterior ischemic optic neuropathy (Pomeranz and Bhavsar, 2005; Su et al., 2008), acute angle-closure glaucoma (Ramasamy et al., 2007), optic atrophy (Sowka et al., 2007), and stepwise decline in visual field (Pepin and Pitha-Rowe, 2008). Priapism (Sur and Kane, 2000), tonic-clonic seizures (Gilad et al., 2002), vestibular dysfunction (Hamzavi et al., 2002), and amnesia and aggressive behavior (Milman and Arnold, 2002) have also been reported. Intracerebral hemorrhage (McGee et al., 2005), sudden sensorineural hearing loss (Snodgrass et al., 2010) and epileptic seizures (Koussa et al., 2006) have been linked to vardenafil, and transient global amnesia to tadalafil (Schiefer and Sparing, 2005), both sildenafil-related drugs.

Metabolism drugs Long-term ingestion of allopurinol may rarely cause axonal peripheral neuropathy, receding after discontinuation (Azulay et al., 1993). Oral glucose lowering drugs include sulfonylureas and biguanides. Their most frequent side-effect is hypoglycemia. Hypoglycemic encephalopathy can develop insidiously and result in disabling residual neurologic deficits if not recognized in time (Turkington, 1977). Chlorpropamide can cause optic neuropathy (Wymore and Carter, 1982). Biguanides may induce lactic acidosis and encephalopathy, but encephalopathy without lactic acidosis has also been reported (Jung et al., 2009). Vitamins may be neurotoxic (Snodgrass, 1992). Pseudotumor cerebri (benign intracranial hypertension) linked to vitamin A (Drouet and Valance, 1998) and pyridoxine-generated peripheral neuropathy (Scott


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Table 107.18 Neurologic adverse effects of most commonly used antihormonal drugs Group

Drug

Adverse effects

Antithyroid agents

Methimazole

Prolactin blocking agents

Bromocriptine Cabergoline

Anti-osteoporotic agents (diphosphonates) Antiandrogens and antigonadotrophin-releasing agents Antiestrogens

186Re-HEDP

Optic neuritis (Sponzilli et al., 1979) Cerebral vasculitis (Tripodi et al., 2008) Postpartum cerebral angiopathy (Chartier et al., 1997) Puerperal seizures (von Werder, 1996) Cerebrospinal fluid leakage (Netea-Maier et al., 2006) SUNCT syndrome (Jimeńez Caballero, 2007) Pathological gambling and hypersexuality (Falhammar and Yarker, 2009) Chiasmal herniation and secondary deterioration of visual field (Raverot et al., 2009) Priapism (De La Penã Zarzuelo et al., 2010) Transient cranial neuropathy (de Klerk et al., 1996)

Leuprolide

Atypical absence seizures (Akaboshi and Takeshita, 2000)

Tamoxifen

Retinopathy (Nayfield and Gorin, 1996) Cerebral venous sinus thrombosis (Bushnell and Goldstein, 2004)

et al., 2008) are well-established neurologic adverse effects of vitamins. The initiation of vitamin B12 treatment for cyanocobalamin deficiency has been reported to eventually induce seizures (Benbir et al., 2007) and involuntary movements (tremor, myoclonus) (Ozdemir et al., 2010). Vitamin D has also been related to pseudotumor cerebri (Alpan et al., 1991). Prolonged vitamin D administration may result in muscle calcinosis due to hypercalcemia (Chiricone et al., 2003). Drug-induced hypercalcemia is caused by increased bone resorption (vitamin D and vitamin A intoxication), increased gastrointestinal absorption (vitamin D intoxication, excessive calcium intake) or increased renal tubule reabsorption (thiazide diuretics) of calcium (Sato, 2006). The administration of high levels of vitamin E is contraindicated in subjects who are receiving vitamin K antagonists as anticoagulant therapy (Machlin, 1989).

NEUROLOGIC ADVERSE EFFECTS OF RESPIRATORY TRACT DRUGS Bronchodilators with b-stimulating adrenergic effect may cause classic adrenergic reactions. Tremor may sometimes be intense and disabling (Ozog and Lerner, 1989). Posterior reversible encephalopathy has been observed in relation to pseudoephedrine (Ebbo et al., 2010). Theophylline may induce seizures and nonconvulsive status epilepticus (Paloucek and Rodvold, 1988; Krieger and Takeyasu, 1999).

Dextromethorphan, alone or in association, has been observed to cause distonic reaction (Warden et al., 1997), agitated psychosis, and ataxia (Roberge et al., 1999; Price and Lebel, 2000).

NEUROLOGIC ADVERSE EFFECTS OF GENITOURINARY AND DIGESTIVE TRACT DRUGS Smooth muscle spasmolytic drugs with anticholinergic antimuscarinic action all entail a risk of anticholinergic delirium: sudden confusion, distractibility, dysarthria, logorrhea, dry mouth, restlessness, tremor, and visual hallucinations (Lipowski, 1990). Agents stimulating uterine contractility to induce labor have been associated with postpartum cerebral angiopathy and hypertensive encephalopathy (Garre´ et al., 1978; Chartier et al., 1997; Sato et al., 2004). Antiemetic and gastroprokinetic drugs may cause extrapiramidal side-effects. Related antiemetic agents with an indirect parasympathomimetic effect may also induce extrapyramidal toxicity. The neurologic adverse effects of antiemetics appear in Table 107.19. Gastric H2-receptor inhibitors have been associated with some neurologic side-effects, including confusion (Sonnenblick and Yinnon, 1986), extrapyramidal and cerebellar syndrome with encephalopathy (Handler et al., 1982), and hemiballism (Elzinga-Huttenga et al., 2006). Gastric protonic pump inhibitors have been associated with central fever with severe myalgia (Grattagliano

1656


Table 107.19 Neurologic adverse effects of most commonly used antiemetic drugs Drug

Adverse effects

Metoclopramide

Myoclonus (Hyser and Drake, 1983) Parkinsonism, tardive dyskinesia, tardive dystonia, akathisia (Miller and Jankovic, 1989) Acute dyskinesia (Andrejak et al., 1990) Dystonic reaction (Guala et al., 1992) Oculogyric crisis (Lou and Abou-Zeid, 2006) Oculogyric crisis (Shafrir et al., 1985) Acute dyskinesia (Andrejak et al., 1990) Acute dystonia (Yamada et al., 2010) Syncope associated with QT prolongation (Gray, 1998) Akathisia, abnormal movements (Elzinga-Huttenga et al., 2006) Transient dyskinesia (Martıńez-Martıń, 1993) Parkinsonism, tardive dyskinesia (Sempere et al., 1994) Acute dystonic reaction (Sprung et al., 2003) Oromandibular/limb dystonia, oculogyric crisis, multifocal encephalopathy (Ritter et al., 2003)

Domperidone Droperidol Cisapride Clebopride Ondansetron

et al., 2005), myopathy (Clark and Strandell, 2006), and panic attacks and confusion (Polimeni et al., 2007).

CONCLUSION Almost every drug can produce neurologic adverse effects. The compelling evidence of the frequency of iatrogenic pharmacologic disease is large enough to warrant its consideration as a differential diagnosis when assessing the neurologically ill patient.

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