Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 10

Neurologic complications of arrhythmia treatment MEGAN C. LEARY1, JEFFREY S. VELUZ2, AND LOUIS R. CAPLAN3* Department of Neurology, Harvard Clinical Research Institute, Boston, MA, USA

1 2

Cardiothoracic Surgery, St. Luke’s Hospital and Health Network, Bethlehem, PA, USA

3

Division of Stroke and Cerebrovascular Disease, Beth Israel Deaconess Medical Center, Boston, MA, USA

DIRECT NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA An arrhythmia is defined as an abnormal heart rhythm. Certain arrhythmias have much higher rates of neurologic complications, including stroke, cognitive impairment, and dementia. According to the Stroke Data Bank, which divided potential causes of cardioembolic brain embolism into strong and weak sources, both atrial fibrillation and sick sinus syndrome are considered to be strong sources of cardiogenic stroke (Kittner et al., 1992; Leary and Caplan, 2009).

Stroke and cerebrovascular disease ATRIAL FIBRILLATION Persistent and paroxysmal atrial fibrillation is a potent predictor of first and recurrent stroke, with > 75 000 attributed cases annually. Cardiogenic cerebral embolism is responsible for approximately 20% of ischemic strokes, and there is a history of nonvalvular atrial fibrillation in roughly half of these patients (Wolf et al., 1987; Bogousslavsky et al., 1988; Cerebral Embolism Task Force, 1989; Fuster and Halperin, 1989; Bogousslavsky et al., 1991; Sacco et al., 2006). Risk of embolism due to atrial fibrillation varies depending on many factors. For example, associated heart disease, age, duration, chronic versus intermittent fibrillation, and atrial size all influence the embolic risk in patients with atrial fibrillation. In general, atrial fibrillation has an annual estimated stroke rate of 4.5% (Wozakowska-Kaplon et al., 2009). In individuals over 80 years atrial fibrillation is

the single leading cause of major stroke. Moreover, about 25% of patients with atrial fibrillation in the absence of neurologic deficits have computed tomography (CT) signs of one or more silent brain infarcts (Wozakowska-Kaplon et al., 2009). Restoration of sinus rhythm in patients with atrial fibrillation is a logical strategy to prevent the neurologic complications of this dysrhythmia. The most common means of restoring sinus rhythm is pharmacologic antiarrhythmic therapy with or without electrical cardioversion. Five randomized clinical trials compared rhythm to rate-control strategies in patients with atrial fibrillation. These trials examined mortality, thromboembolic complications, exercise tolerance, quality of life, hospital admissions, and drug-related adverse reactions. Hospital admissions and drug-related adverse events were increased in the rhythm-control subjects. Stroke and systemic emboli occurred more often in the rhythm-control subjects, many of whom had been withdrawn from anticoagulation. Rhythm control offered no advantage compared with rate control for patients with atrial fibrillation at increased risk for stroke. One explanation for this finding is that those patients thought to have been successfully converted to sinus rhythm in fact had asymptomatic paroxysmal episodes of atrial fibrillation increasing their risk of stroke because they were unprotected by anticoagulation. Pharmacologic attempts to restore atrial fibrillation to sinus rhythm do not improve mortality or reduce stroke. All patients with atrial fibrillation at increased risk for stroke should be continued on long-term anticoagulation even if they appear to have been successfully restored to sinus rhythm (Sherman, 2007).

*Correspondence to: Louis R. Caplan, M.D., Division of Stroke and Cerebrovascular Disease, Palmer 125, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. Tel: þ1-617-632-8910, Fax: þ1-617-632-8920, E-mail: [email protected]

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SICK SINUS SYNDROME Sick sinus syndrome is the name given to several conditions in which the sinus node does not function normally. It affects about three out of every 10 000 persons, and it becomes more common with advancing age. Drugs used for other cardiac conditions often may worsen or cause the development of sick sinus syndrome. In addition, patients with sick sinus syndrome are at high risk for cardioembolic stroke (Fairfax et al., 1976; Bathen et al., 1978). The annual stroke incidence rate in nonpaced sick sinus syndrome patients might approach 8–10% (Radford and Julian, 1974; Abdon and Johnsson, 1979).

MULTIFOCAL PREMATURE VENTRICULAR CONTRACTIONS

Premature ventricular complexes (PVCs) on a 2 minute electrocardiogram are a common, largely asymptomatic finding associated with increased risk of coronary heart disease and death. They may reflect atherosclerosis or other pathogenic pathways that predispose to arrhythmias and stroke. Agarwal et al. (2010) conducted a prospective evaluation of the Atherosclerosis Risk In Communities (ARIC) study cohort (n ¼ 14 783) of middle-aged men and women to assess whether the presence of PVCs at study baseline influenced the risk of incident stroke over several years. PVCs were seen in 6.1% of the participants at baseline, and 4.9% had incident stroke. The unadjusted cumulative proportion of incident stroke in individuals with any PVC was 6.6% compared with 4.1% in those without PVC. Among individuals without hypertension and diabetes at baseline, PVCs were independently associated with incident stroke. Surprisingly, when participants had hypertension or diabetes at baseline, the presence of PVCs did not increase the hazard ratio for stroke compared with participants without PVCs. The association was stronger for noncarotid embolic stroke than for thrombotic stroke, and there was a marked increase in stroke risk in those participants with  4 PVCs in a 2 minute recording. The increased stroke risk was observed irrespective of gender and race (Agarwal et al., 2010). It is unclear how PVCs influence stroke risk (Worthington et al., 2010). PVCs could represent a “culprit arrhythmia” (Bhushan and Asirvatham, 2009) or an early sign of accumulating end organ damage as a result of identified or unidentified risk factors shared with stroke. The ARIC investigators posit that PVCs may be intimately related to the development of new-onset atrial fibrillation, a major risk factor for stroke (Agarwal et al., 2010; Worthington et al., 2010). During follow-up, new-onset atrial fibrillation was identified in 15% of people with PVCs, accounting for 34% of stroke

cases in this group. Atrial fibrillation diagnosis can be elusive, and the reported atrial fibrillation prevalence may be an underestimate. An association between PVCs and atrial fibrillation may explain the preponderance of “embolic stroke of noncarotid origin” in those with PVCs (Agarwal et al., 2010; Worthington et al., 2010). A 2 minute rhythm strip is not a routine test but is simple and feasible in a wide range of clinical settings. PVCs detected on a rhythm strip appear to be a newly identified marker, if not risk factor, for stroke. Most importantly, PVCs may identify stroke risk in middle-aged men and women without hypertension, diabetes, and other established risk factors. If the ARIC findings are replicated with further research, a rhythm strip may be a useful tool in identifying those most likely to benefit from close surveillance as well as lifestyle and pharmacologic interventions (Worthington et al., 2010).

SUPRAVENTRICULAR TACHYCARDIA Unlike adults, a cardiac illness causing stroke is unusual in an otherwise healthy child. However, supraventricular tachycardia has been reported as a cause of stroke in children (Atluru et al., 1985; Zapson et al., 1995). Interestingly, there is no reported link between supraventricular tachycardia and risk of stroke in adults (Aronow et al., 1996).

WOLFF–PARKINSON—WHITE SYNDROME The prevalence of Wolff–Parkinson–White (WPW) syndrome among patients with MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) and the A3243G mutation is much higher than in the normal population. While strokes and other neurologic issues associated with MELAS are probably not caused by the arrhythmia, it is important to note that WPW may manifest much earlier than neurologic symptoms. Patients with WPW syndrome should be monitored over time for the development of neurologic abnormalities consistent with MELAS, including seizures, deafness, short stature, and stroke. If neurologic symptoms occur, patients should be screened for the A3243G mutation (Sproule et al., 2007).

Disorders of cognition COGNITIVE IMPAIRMENT Wozakowska-Kapon et al. (2009) investigated whether cognitive function in patients with permanent atrial fibrillation was worse than in patients with sinus rhythm. Subjects were aged > 65 years, without previous stroke or dementia, with permanent arrhythmia lasting > 12 months. Of their 51 patients, 51% had hypertension, 37% coronary artery disease, 12% with concomitant sick

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 131 sinus syndrome or atrioventricular advanced block with irreversibly damaged by ischemic-anoxic damage a VVI pacemaker implanted. Patients in the normal sinus (Caplan, 1999a). Cardiologists must become very rhythm control group had a lower-risk profile and familiar with the pathology, signs, and prognosis of received antithrombotic therapy less often than the atrial brain dysfunction after periods of circulatory failure fibrillation group. However, a significant proportion of (Leary and Caplan, 2009). patients, particularly in the atrial fibrillation group, Different brain regions have selective vulnerability to received less than optimal prophylactic treatment with hypoxic-ischemic damage. Regions that are remote and anticoagulants. Cognitive status was found to be signifat the edges of major vascular supply are more liable to icantly worse in the atrial fibrillation group, compared hypoperfusion injury. Hypoperfusion injuries in these with the sinus rhythm group (p < 0.05), with cognitive areas are usually referred to as border zone or watershed impairment diagnosed in 43% of patients in the atrial cerebral infarction. In the cerebral cortex, these border fibrillation group and 14% in the sinus rhythm group. zone regions are between the anterior cerebral artery Permanent atrial fibrillation in patients older than 65 (ACA) and middle cerebral artery (MCA), and between years is clearly associated with lower Mini Mental State the MCA and posterior cerebral artery (PCA) (Leary and Examination (MMSE) scores compared with individuals Caplan, 2009). When hypoxia and ischemia are especially with sinus rhythm (Puccio et al., 2009; Wozakowskasevere, the spinal cord may also be damaged (Silver and Kapon et al., 2009) Interestingly, studies have shown Buxton, 1974; Caronna and Finklestein 1978). If cortical that patients with paroxysmal atrial fibrillation have damage is severe, cytotoxic edema causes massive brain worsened cognitive performance than patients with perswelling, cessation of blood flow, and brain death manent atrial fibrillation, suggesting a possible micro(Leary and Caplan, 2009). embolic pathogenesis. Anticoagulation therapy could The initial neurologic findings and their course are helpplay a protective role; however, more evidence is needed. ful in predicting neurologic outcome. Among patients who have meaningful responses to pain at 1 hour after resusciDEMENTIA tation, almost all survivors have preserved intellectual function. Patients who do not respond to pain by 24 hours Ettorre et al. (2009) studied the relationship between typically either die or remain in a vegetative state (Bell and atrial fibrillation and various types of dementia, includHodgson, 1974; Levy et al., 1985). In one study of out-ofing vascular dementia, Alzheimer’s disease, and mixed hospital cardiac arrests, patients who did not awaken died dementia. In women – but not men – a statistically sigon average 3.5 days after arrest. Of 459 patients, 40% nificant association was found between the triad of never awakened. Among those who did awaken, 33% MMSE score, clinical dementia rating score, and atrial had persistent neurologic deficits. Prognosis could be fibrillation occurrence. Unexpectedly, atrial fibrillation made by analysis of pupillary light reflexes, eye movewas associated with Alzheimer’s disease more often than ments, and motor responses (Longstreth et al., 1983a, b). with vascular dementia, becoming a possible risk factor Myoclonus also occurs after resuscitation and is a sign for this neurodegenerative disease. The authors note that of poor prognosis as well (Leary and Caplan, 2009). their results are supported by many studies that posit that With severe hypoperfusion ACA-MCA border-zone brain hypoperfusion has a pathogenetic role in causing cerebral infarction, there is weakness of the arms and sporadic Alzheimer’s disease, and they argue that proximal lower extremities with preservation of face, impaired cerebral perfusion may be the primary trigger leg, and foot movement (also referred to as the “man in developing this disease. Moreover, the mildly favorin a barrel” syndrome). With MCA-PCA ischemia, the able treatment response in patients with Alzheimer’s dissymptoms and signs are predominantly visual, and can ease to therapy that improves cerebral blood flow is also include difficulty seeing and integrating the features a consistent finding (Ettorre et al., 2009). In addition to of large objects or scenes despite retained capacity to the higher prevalence of atrial fibrillation observed in see small objects in some parts of their visual fields. patients with dementia ( p ¼ 0.0131), ventricular tachyReading may be impossible (Hecaen and Ajuriaguerra, cardia ( p ¼ 0.0156) and gaps ( p ¼ 0.0347) have also been 1954; Caplan, 1999a; Leary and Caplan, 2009). Formation reported (De Pedis et al., 1987). of new memories is difficult and patchy; retrograde amnesia can also be present. The amnesia may not be NEUROLOGIC COMPLICATIONS reversible, can be accompanied by visual abnormalities, OFARRHYTHMIA TREATMENT: apathy, and confusion, or may be isolated (Leary and CARDIOPULMONARY RESUSCITATION Caplan, 2009). It has been suggested that half of the Unfortunately, patients with arrhythmia can require long-term survivors of aborted sudden cardiac death cardiopulmonary resuscitation (CPR). After CPR, the are cognitively intact 6 months after resuscitation but heart often recovers in individuals whose brains are that 25% have moderate to severe impairment in

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memory, which could hamper and/or preclude the resumption of prearrest roles (Sauve´ et al., 1996). Aphasia, dyskinesias, abnormal motor function, and praxis have also been observed in survivors of arrhythmic cardiac arrest (Maryniak et al., 2008).

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT: DRUGS Antiarrhythmics Many antiarrhythmic drugs that are given to patients with cardiac disease have possible neurologic side-effects

(Caplan, 1999b). It is important to remember that virtually all of these neurologic complications are reversible with the discontinuation of the offending agent (Meschia and Biller, 1998). Potential neurologic side-effects from antiarrhythmic medications are listed in Table 10.1. Dizziness and headache, in particular, are common. Adenosine In patients with known migraines, intravenous adenosine has been reported to precipitate severe headaches (Brown and Waterer, 1995; Guieu et al., 1998; Meschia and Biller, 1998). Adenosine has also been associated with headaches in healthy subjects. While regional cerebral blood flow and middle cerebral artery flow

Table 10.1 Neurologic complications from antiarrhythmic medication Side-effect

Medications

Ataxia Anticholinergic effects Autonomic neuropathy Carpal tunnel Confusion/delirium

Amiodarone, mexiletine, propafenone, tocainide Disopyramide, quinidine Amiodarone Metoprolol Amiodarone, digoxin, diltiazem, disopyramide, esmolol, lidocaine, metoprolol, propafenone, quinidine, sotalol, tocainide, verapamil Diltiazem, dofetilide, dronedarone, encainide, esmolol, flecainide, ibutilide, isoprenaline (isoproterenol), metoprolol, propafenone, quinidine, sotalol, tocainide, verapamil Encainide, flecainide, mexiletine, propafenone, tocainide Amiodarone Flecainide Encainide, flecainide, propranolol, sotalol, verapamil Adenosine, dofetilide, dronedarone, encainide, esmolol, flecainide, ibutilide, isoprenaline (isoproterenol), metoprolol, propafenone, quinidine, sotalol, tocainide, verapamil Amiodarone Metoprolol, propafenone Encainide, metoprolol, mexiletine, tocainide Encainide Diltiazem (Eaton–Lambert), procainamide, propranolol, propafenone, quinidine Amiodarone, diltiazem, propafenone, verapamil Amiodarone, diltiazem, procainamide, propranolol Propranolol Amiodarone, tocaininde Amiodarone Amiodarone, disopyramide, esmolol, flecainide, propranolol, propafenone, sotalol, verapamil Amiodarone, diltiazem, verapamil Amiodarone, disopyramide, flecainide, procainamide, propafenone Amiodarone Diltiazem, esmolol, flecainide, lidocaine, propranolol, propafenone, quinidine, tocainide, verapamil Diltiazem, propafenone Amiodarone, metoprolol Propafenone, quinidine Propafenone Amiodarone, encainide, flecainide, isoprenaline (isoproterenol), mexiletine, propafenone, tocainide Amiodarone, digoxin, flecainide, metoprolol, mexiletine, quinidine Amiodarone, isoprenaline (isoproterenol), propranolol, propafenone, quinidine

Dizziness Dysarthria Dyskinesia Dystonia Fatigue Headache Hemiballism Language disturbance Memory impairment Myalgia Myasthenic syndrome Myoclonus Myopathy Myotonia Nystagmus Optic neuropathy Paresthesias Parkinsonism Peripheral neuropathy Pseudotumor cerebri Seizure Sensory loss Stroke Tinnitus Transient global amnesia Tremor Visual symptoms Weakness

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT velocities remain unchanged in this group of patients, a significant dilation of the superficial temporal artery occurs and is associated with a “pressing sensation” headache (Birk et al., 2005). Amiodarone A variety of neurologic symptoms have been attributed to amiodarone use. Some combination of tremor, ataxia, and peripheral neuropathy typically occurs in 10–50% of all patients on this medication (Fogoros et al., 1983; Charness et al., 1984; Palakurthy et al., 1987; Coulter et al., 1990; Meschia and Biller, 1998). These side-effects may be disabling and result in decreasing or ceasing amiodarone treatment in an estimated 5% of patients. Nystagmus has been reported. Amiodarone can also cause weakness, paresthesias, a distal generalized sensorimotor polyneuropathy, autonomic neuropathy, visual symptoms due to ischemic optic neuropathy and pseudotumor cerebri, myopathy with or without neuropathy, and occasionally delirium. Lastly, amiodarone has been associated with causing abnormal movements including: ataxia, a parkinsonianlike syndrome, myoclonus, hemiballism, and dyskinesias. Thromboembolic stroke (in a nonanticoagulated patient) due to chemical cardioversion with amiodarone has also been reported. Monitoring of amiodarone therapy should include assessment of the central and peripheral nervous system, especially in older patients (Fogoros et al., 1983; Charness et al., 1984; Pellissier et al., 1984; Anderson et al., 1985; Jacobs and Costa-Jussa`, 1985; Grogan and Narkun, 1987; Manolis et al., 1987; Palakurthy et al., 1987; Werner and Olanow, 1989; Coulter et al., 1990; Fernando Roth et al., 1990; Yapa and Green, 1990; Borruat and Regli 1993; Collaborative Group for the Study of Polyneuropathy, 1994; Dotti and Federico, 1995; Meschia and Biller, 1998; Krauser et al., 2005; Kashyap et al., 2006; Purvin et al., 2006; Wei et al., 2007; Younge, 2007; Hindle et al., 2008; Mindel, 2008; Leary and Caplan, 2009; Mahitchi et al., 2009; Ishida et al., 2010). Digoxin Digoxin can cause visual hallucinations, including Charles Bonnet syndrome, and general confusion (Volpe and Soave, 1979; Closson, 1983; G€ odeckeKoch et al., 2002). It has also been identified as a distorter of color vision: causing both blue and yellow vision (Durakovic´ et al., 1992; Leary and Caplan, 2009). People receiving large and repeated doses of this drug often see the world with a yellow-green tint. Interestingly, Vincent van Gogh, the Dutch PostImpressionist painter with a complex medical history (automutilation, depression, insanity, and suicide), characterized many of his paintings with halos and the color yellow during the last few years of his life. Critics have ascribed these aberrations to innumerable causes, one of which may be digitalis intoxication side-effects. Individuals with digitalis intoxication often complain of seeing yellow spots surrounded by coronas, much like those in The Starry Night. The artist’s physician, Paul-Ferdinand

133

Fig. 10.1. Portrait of Dr. Gachet, by Vincent van Gogh, 1890.

Gachet, may have treated van Gogh’s mania or epilepsy with digitalis, a common practice at that time. In one of van Gogh’s three portraits of Gachet, the physician holds a stem of Digitalis purpurea, the purple foxglove from which the drug is extracted (Fig. 10.1). It has been suggested that the toxic effects of digitalis may have, in part, dictated van Gogh’s technique in his later years (Lee, 1981; Wolf, 2001). Interestingly, the digitalis level does not need to be excessively elevated to cause these neurologic issues, and the symptoms disappear with drug cessation. In the setting of toxic doses of digoxin, a digoxin-specific Fab fragment antidote may be potentially useful (Meschia and Biller, 1998; Wijdicks, 2009). Diltiazem There are rare case reports of significant neurological complications with diltiazem. Myoclonus, myopathy, Lambert–Eaton syndrome, and parkinsonism have been associated with diltiazem use (Dick and Barold, 1989; Ueno and Hara, 1992; Ahmad, 1993; Graham and Stewart-Wynne, 1994; Pathirana and Hidelaratchi, 2004). Sensory loss associated with skin thickening of both feet has also been reported (Ilia et al., 1992). CNS depression secondary to hemodynamic instability can occur following a significant overdose. Effects observed during overdose include drowsiness, confusion, lethargy, and lightheadedness (Verbrugge and van Wezel, 2007). Seizures resulted from a 10.8 g ingestion of diltiazem in a 58-year-old man with a history

134 M.C. LEARY ET AL. of idiopathic epilepsy (Malcolm et al., 1986). A second Esmolol Generalized tonic-clonic seizure activity case report described generalized tonic-clonic seizures was described in an 89-year-old man while receiving in a 51-year-old man approximately 18 hours after ingestintravenous esmolol for the treatment of atrial tachycaring 1.8–3.6 g of slow-release diltiazem, as well as paradia. Termination of the infusion resulted in seizures. cetamol, aspirin, isosorbide nitrate, and alcohol The patient was rechallenged with esmolol infusion (Meschia and Biller, 1998; Isbister, 2002). 5 minutes later, again resulting in drowsiness and hyporDisopyramide A slowly reversible peripheral neuesponsiveness. The infusion was again discontinued and ropathy characterized by dysesthesias has been reported seizures did not recur. This patient had no previous seiwith this drug (Dawkins and Gibson, 1978; Briani et al., zure activity and esmolol was given in therapeutic doses. 2002). Additionally, anticholinergic effects, painful Careful monitoring for sedation or other neurologic dysesthesias, paresthesias, psychosis, hallucinations, signs should be routine in esmolol-treated patients, parand delusions are described with disopyramide use ticularly the elderly (Das and Ferris, 1988). Other, more (Teichman et al., 1987). common neurologic symptoms with esmolol infusion Dofetilide About 11% of patients develop headache include: dizziness and somnolence in 3% of patients, after oral dofetilide administration, and dizziness occurs headache, confusion, and agitation in 2% of patients, in some 8% of patients receiving oral dofetilide (Prod and paresthesia, asthenia, depression, anxiety, and seiInfo TIKOSYN(R) oral capsules, 2004). Headache assozures have occurred in less than 1% of patients receiving ciated with syncope and vasodilatation has also been esmolol (Prod Info Brevibloc(R), 2004). reported following a high oral dose of dofetilide Flecainide A common neurologic adverse effect (Allen et al., 2000). of flecainide is dizziness, occurring in about 30% of Dronedarone In the ATHENA trial (a placebopatients treated both chronically and in short-term studcontrolled, double-blind, parallel arm trial to assess the ies. Dizziness results in drug withdrawal in 5.7% of efficacy of dronedarone 400 mg twice daily for the prepatients receiving the drug short term and in 3.7% of vention of cardiovascular hospitalization or death from patients receiving the drug over long periods. Dizziness any cause in patients with atrial fibrillation/atrial flutis most likely related to the effect of the drug on the CNS ter), neurologic events reported in association with dro(Gentzkow and Sullivan, 1984). Neurologic effects of nedarone use included dizziness and headache. However, chronic flecainide dosing are headache (10%), asthenia these neurologic adverse events did not occur signifi(6%), fatigue (6%), tremor (4%), paresthesia (1%), and cantly more often in the dronedarone group compared hypoesthesia (3%). These effects resulted in drug withto the placebo group (Hohnloser et al., 2009). In a pooled drawal in less than 1% of patients treated (Gentzkow analysis of five controlled studies in patients with atrial and Sullivan, 1984). Less commonly, flecainide has been fibrillation or atrial flutter, asthenic conditions were associated with peripheral neuropathy (Palace et al., reported in 7% of patients who received dronedarone 1992), dystonia (Kennerdy et al., 1989; Linazasoro et al., hydrochloride 400 mg twice daily (n ¼ 3282) compared 1991; Miller and Jankovic, 1992; Meschia and Biller, with 5% of patients who received placebo (n ¼ 2875) over 1998), and seizures (Kennerdy et al., 1989; Meschia and a mean duration of 12 months (Prod Info MULTAQ oral Biller, 1998). Dysarthria in association with visual hallucitablets, 2009). nation has also been reported (Ramhamadany et al., 1986). Encainide A 10% incidence of neurologic adverse Ibutilide Headache has been observed occasionally effects was found in 140 patients evaluated with oral after intravenous ibutilide (3.6% of patients) (Prod Info encainide therapy. These symptoms of fatigue, memory Corvert(R), 2002). Stroke was reported in 0.9% of impairment, tremors, and dysarthria were considered patients who received up to two 10 minute intravenous mild in severity and improved with dose reduction. infusions of ibutilide 1 mg for atrial fibrillation or atrial Headache was also reported. The average drug dose flutter (Abi-Mansour et al., 1998). Ibutilide has also been and blood level of encainide in patients experiencing associated with dizziness (Li et al., 2007). adverse effects were not significantly different from Isoprenaline/isoproterenol Isoprenaline/isoproterenol those in patients who did not report neurologic sympuse may worsen a physiologic tremor (Perucca et al., toms (Tordjman et al., 1986). Dizziness was the most fre1981; Pickles et al., 1981; Tera¨va¨inen, 1984). Dizziness, headquent adverse reaction during therapeutic use of ache, nervousness, tremor, and weakness have also encainide, and this symptom appeared to be dose-related occurred during isoprenaline/isoproterenol therapy (Berchtold-Kanz et al., 1984). In one report, dizziness (Dukes, 1975). occurred in 26% of patients (Soyka, 1986). A patient with Lidocaine Patients may become acutely comatose myalgia associated with fever and chills has also been while being treated with intravenous lidocaine. This reported, and symptoms resolved with drug cessation effect has been associated with the accidental adminis(Goli-Bijanki et al., 1989; Meschia and Biller, 1998). tration of very large lidocaine doses, while the more

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 135 common CNS effects of a less extreme toxicity can Procainamide can also rarely cause a myopathy (Sayler include sedation, delirium, irritability, and twitching and DeJong, 1991; Venkayya et al., 1993; Agius et al., (Leary and Caplan, 2009). As part of their delirium, 1998). The creatine phosphokinase (CPK) levels in patients can show “doom anxiety,” an apprehension of procainamide-induced myopathy can be normal or death that can reach delusional proportions (Marke greater than 10 000 IU per liter (Meschia and Biller, et al., 1987; Meschia and Biller, 1998). Twitching can pro1998). Lastly, procainamide can aggravate myasthenic gress to partial or generalized seizures accompanied by symptoms in myasthenia gravis patients (Drachman respiratory depression (Meschia and Biller, 1998; Leary and Skom, 1965; Godley et al., 1990; Meschia and and Caplan, 2009). Seizures precipitated by lidocaine Biller, 1998) and even cause myasthenic-like symptoms usually occur when plasma levels exceed 9 mg per mL such as severe bulbar, limb, and respiratory weakness (Meschia and Biller, 1998) and have been reported with in nonmyasthenic patients in high doses (Niakan et al., topical, subcutaneous, and intravenous administration 1981; Oh et al., 1986; Miller et al., 1993; Meschia and (Boston Collaborative Drug Surveillance Program, Biller, 1998). 1972; Pelter et al., 1989; Meschia and Biller, 1998; Dorf Propanolol Common neurologic adverse effects et al., 2006; Brown et al., 2009). The Boston Collaboraassociated with propranolol therapy include paresthesia, tive Drug Surveillance Program found a convulsion rate fatigue, and insomnia. Propranolol-induced parestheof 5.7 per 1000 patients treated with intravenous lidosia has been reported to occur with an incidence of caine for arrhythmias (Boston Collaborative Drug 0.13–1.5%. Most patients with propranolol-induced paresSurveillance Program, 1972; Meschia and Biller, 1998). thesia tend to respond to a reduction in dose or discontinMetoprolol Dizziness has been reported in about uation of therapy (Prod Info propranolol hcl injection, 10% of patients receiving metoprolol. Metoprolol has 2006). Tonic-clonic seizures have also been reported also been reported to cause delirium, confusion, disoriin a patient with acute propranolol intoxication who entation, agitation, aggression, paranoid delusions, vivid had an acute psychotic episode that preceded the seizure dreams, headache, insomnia, short-term memory loss, as activity by several hours (Love and Handler, 1995). A well as complex visual and auditory hallucinations (Prod small number of case reports have associated propranolol Info Lopressor(R) 1999; Prod Info Toprol XL(R) 2001; with aggravation of myasthenia gravis or development of Fisher et al., 2002; van der Vleuten et al., 2005). Lana reversible myasthenic syndrome. Propranolol should guage disturbance has been reported as well (Fisher be used with caution in patients with known myasthenia et al., 2002). All symptoms resolved with termination gravis (Herishanu and Rosenberg, 1975). Rare cases of metoprolol therapy. Metoprolol has also been of myotonia and muscle weakness in both arms and reported to increase the risk of stroke after noncardiac legs have been reported following several months to years surgery (Roberts, 2008). Lastly, cases of carpal tunnel of propranolol therapy (Blessing and Walsh, 1977; Satyasyndrome associated with long-term (8–11 years) metoMurti et al., 1977; Turkewitz et al., 1984). prolol therapy have been reported. Symptoms typically Propafenone Some of the adverse effects of proresolved over 8–10 weeks following discontinuation of pafenone are neurologic in nature, including dizziness treatment (Emara and Saadah, 1988). (12.5%), ataxia (1.6%), tremor (1.4%), vertigo, and headMexiletine Commonly reported side-effects ache (4.5%) (Prod Info Rythmol(R), 2004). Severe bilatinclude tremor, ataxia, dysarthria, visual blurring, memeral symmetric ataxia occurred in three elderly patients ory impairment, and diplopia (Meschia and Biller, 1998). receiving propafenone. Their symptoms included Visual hallucinations can occur 2–3 days after initiation unclear speech, altered hand coordination, gait impairof therapy and resolve 8–12 hours after drug discontinment, and tremor with movement. Symptoms completely uation. Patients typically remain fully oriented during resolved in all within 3–6 days after discontinuation or a these hallucinations (Campbell et al., 1973; Holt, 1988; dose reduction of propafenone (Odeh et al., 2000). Coma, Meschia and Biller, 1998). Roughly 5% of patients need numbness, paresthesias, vertigo, seizures, and tinnitus to discontinue mexiletine use due to neurologic sidehave been reported in less than 1% of patients receiving effects (Nygaard et al., 1986; Campbell, 1987; Meschia propafenone (Siddoway et al., 1984; Ravid et al., 1987; and Biller, 1998). Prod Info Rythmol(R), 2004). Propafenone has also been Procainamide Neurologic side-effects due to associated with reversible generalized myoclonus (Chua procainamide can be localized to the nerve, muscle, or et al., 1994), myasthenia exacerbation (Lecky et al., neuromuscular junction. Patients with a procainamide1991), peripheral neuropathy (Galasso et al., 1995), and induced, lupus-like reaction can develop a distal sensotransient global amnesia (Jones et al., 1995; Meschia rimotor polyneuropathy. This neuropathy improves and Biller, 1998). In a large multicenter study of 774 with both drug discontinuation and steroids (Sahenk patients on long-term therapy, 21% had a central nervous et al., 1977; Ahmad 1982; Meschia and Biller, 1998). system side-effect (Ravid et al., 1987).

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Quinidine Quinidine is known to cause a neurologic syndrome known as cinchonism, named after cinchona bark, the original crude preparation of quinidine. Cinchonism occurs in an estimated 1% of patients taking quinidine (Cohen et al., 1977; Meschia and Biller, 1998) with symptoms of headache, flushing, mydriasis, delirium, and a visual change similar to retinal transient ischemia (Fisher, 1981; Meschia and Biller, 1998). If quinidine is taken with digoxin, quinidine can result in delirium even in the setting of normal serum concentrations (Eisenman and McKegney, 1994; Meschia and Biller, 1998). Some have asserted that quinidineassociated delirium is an anticholinergic syndrome that may be reversed with physostigmine (Summers et al., 1981; Meschia and Biller, 1998). Additionally, quinidine has been associated with seizures, coma, vertigo, tinnitus, and visual blurring (Leary and Caplan, 2009). Lastly, quinidine can also exacerbate weakness in myasthenics (Kornfeld et al., 1976; Meschia and Biller, 1998). Sotalol The most frequently reported adverse reactions at any dose level of sotalol include fatigue (20%), dizziness (20%), asthenia (13%), and lightheadedness (12%), leading to discontinuation of therapy in up to 2–4% of patients. Other commonly reported CNS effects of sotalol include headache and sleep disturbances in 8%, excessive perspiration in 6%, with 4% incidence of altered consciousness and paresthesia (Zanetti, 1993; Prod Info Betapace(R), 2001). Hemifacial edema followed by atrophy has also been described in one patient on sotalol after exposure to cold weather (Aho and Haapa, 1982; Meschia and Biller, 1998). Tocainide Neurologic side-effects associated with tocainide include tremor, restlessness, dizziness, paranoid psychosis, dysarthria, giddiness, and delirium (Streib, 1986; Bikadoroff, 1987; Meschia and Biller, 1998; Prod Info Tonocard(R), 2001). These symptoms are dose-related and resolve with stopping the medication (Horn et al., 1980; Meschia and Biller, 1998). Seizures and coma have also been rarely reported, usually in the setting of overdose (Clark and El-Mahdi, 1984; Forrence et al., 1986; Sperry et al., 1987; Meschia and Biller, 1998). One study reported memory loss to be a common side-effect (Maloney et al., 1980), and headaches have been reported in 4.6% of patients receiving tocainide (Prod Info Tonocard(R), 2001). In long-term controlled clinical trials nystagmus was reported in 1% and ataxia was reported in 3% of patients. (Prod Info Tonocard(R), 2001). Observed tremors are useful as clinical indicators that the maximum dose of tocainide is being approached. In long-term controlled studies, tremor was reported in 8% of patients and increased to 22% in patients receiving 1800 mg/day or more (Prod Info Tonocard(R), 2001).

Verapamil Verapamil has been associated with minimal central nervous system toxicity. Infrequent episodes of dizziness, headache, lassitude, drowsiness, and fatigue have been reported following oral administration (Moyer, 1972; Singh et al., 1976; Greif et al., 1977). Pooled results from trials of controlled-onset extended-release verapamil in 1049 patients noted an incidence of dizziness of 5.9% compared to a 2.1% placebo rate (n ¼ 379), while headache was noted in 10.1% compared to an 8.4% placebo rate (White et al., 2001). Additionally, perceptual disorders described as painful coldness and numbness or bursting feelings (especially in the legs) have been reported in association with chronic oral verapamil therapy. In the three patients with this disorder, all were rechallenged and had a return of symptoms (Kumana and Mahon, 1981). Verapamil has also been implicated in unmasking a parkinsonian syndrome (Garcia-Albea et al., 1993). Symptoms of tremor and leg dragging developed in a 55-year-old man 3–4 hours after verapamil was begun for hypertension. These symptoms progressed and worsened to where a diagnosis of Parkinson’s disease was made 4 years later. However, treatment with carbidopa/levodopa, trihexyphenidyl, and propranolol were only minimally effective. Within 3 months after verapamil was withdrawn, the parkinsonism was markedly improved. Lastly, similar to diltiazem, effects observed during verapamil overdose may include drowsiness, confusion, lethargy, and lightheadedness (Candell, 1979). Coma and cerebral infarction have been observed in rare cases of overdose (Moroni et al., 1980; Samniah and Schlaeffer, 1988; Shah and Passalacqua, 1992; Tuka et al., 2009). Both myoclonic and tonic-clonic seizure activity have been reported after ingestion of large verapamil doses (Passal and Crespin, 1984; Vadlamudi and Wijdicks, 2002). In conclusion, a variety of possible neurologic sideeffects, many of which are rare, can occur with antiarrhythmic drug therapy. However, while many of these reactions are uncommon, it is important to recognize if a neurologic condition is potentially drug-related, because virtually all of these complications can resolve with the discontinuation of the offending agent (Meschia and Biller, 1998).

Hematologic agents Anticoagulant and antiplatelet medications are commonly prescribed drugs in cardiac patients, particularly those with arrhythmia. Although the potential benefit of these medicines in reducing the risk of stroke is great, there is an inherent risk of hemorrhagic complication as well (Williams and Biller, 1998). Potential neurologic

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT Table 10.2 Neurologic complications from hematologic medications Side-effect

Medications

Carotid occlusion associated with heparin-induced thrombocytopenia (HIT) Carpal tunnel syndrome Cerebral venous sinus thrombosis (with HIT) Epidural hematoma Femoral neuropathy Hematomyelia Intracerebral hemorrhage

Unfractionated heparin

Neuropathy Spinal hematoma

Subdural hematoma Transient global amnesia (with HIT)

Warfarin Unfractionated heparin Unfractionated heparin Warfarin Warfarin Unfractionated heparin, warfarin, dabigatran Warfarin Unfractionated heparin, low molecular weight heparin, warfarin Unfractionated heparin, warfarin Unfractionated heparin

side-effects from hematologic agents are listed in Table 10.2. Unfractionated heparin Unfractionated heparin is the most commonly used parenteral anticoagulant in the US and is frequently used in ischemic stroke patients with atrial fibrillation. Intracerebral hemorrhage has been often noted in stroke patients anticoagulated with heparin. The interval between stroke onset and intracerebral hemorrhage was less than 72 hours in 80% of the patients, with intracerebral hemorrhage occurring 24 hours or less after heparin was started in 80% of the patients. The APTT closest to the time of hemorrhage was greater than two times control in seven patients. The findings suggest that heparin-related intracerebral hemorrhage occurs early after stroke onset, usually with moderate-sized or large infarcts, and with excessive anticoagulation in some patients. In theory, then, while heparin is generally safe to use in ischemic stroke patients, physicians should be cautious utilizing this drug in patients with moderate to large infarcts (Babikian et al., 1989). Heparin-induced thrombocytopenia (HIT) is a lifethreatening thrombotic disorder caused by antibodies (HITAb) against a complex of heparin and platelet factor 4 (Visentin et al., 1994; Pohl et al., 2000). There are 10 case reports in the English literature of heparin-induced thrombocytopenia-related cerebral venous sinus thrombosis (Fesler et al., 2011). In a series from the Mayo

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Clinic, 33% of postendarterectomy carotid occlusions occurred in patients with HIT (Atkinson et al., 1988). HIT-induced carotid occlusion has also been reported after endovascular repair of high cervical extracranial internal carotid artery (ICA) aneurysms (van Sambeek et al., 2000). Transient global amnesia has also been reported in two patients who had disorientation, anterograde amnesia, and retrograde amnesia 30 minutes after receiving intravenous heparin 5000 U. Interestingly, both patients also had HIT. Platelet counts normalized after discontinuation of heparin with resolution of amnesia after 24 hours (Warkentin et al., 1995). Although rare, both spinal and epidural hematomas have occurred in patients given neuraxial anesthesia during heparin thromboprophylaxis. In order to reduce this risk, stopping heparin for a minimum of 10–12 hours before neuraxial block and 1–2 hours afterwards has been recommended (Parnass et al., 1990; Schneider et al., 1997). In the case report of epidural hematoma, complete paraplegia developed over 3 hours (Parnass et al., 1990). Surgery to improve the deficit was unsuccessful in one patient who had a normal APTT, PT, and platelet count before the procedure was performed, which suggests that even minimally dosed heparin may carry a risk. Low molecular weight heparins There is a paucity of data regarding indications for, and risk–benefit ratio of, low molecular weight heparin “bridging” for cardioembolic stroke prevention in patients with atrial fibrillation until their INR levels are in therapeutic range (Billett et al., 2010). Although perhaps safer than heparin, low molecular weight heparins have also rarely been associated with central nervous system bleeding complications (Sternlo and Hybbinette, 1995; Williams and Biller, 1998). Warfarin Warfarin is associated with many neurologic complications, including various types of neuropathy. Carpal tunnel syndrome due to hematoma in the carpal canal has been reported. Complete resolution of symptoms occurred following carpal tunnel release surgery (Bonatz and Seabol, 1993). Femoral neuropathy has also been reported in association with the therapeutic use of warfarin, usually caused by retroperitoneal bleeding in and around the psoas muscle. Most patients have had sudden onset severe groin pain, pain in the lower thigh area, inguinal area pain, and hip pain. Numbness or weakness of the thigh and leg follows, as well as paresthesias. The knee jerk is lost as an early diagnostic sign. Recovery has occurred but permanent disability has been reported in several cases. Immediate surgical decompression may be necessary to prevent residual disability (Butterfield et al., 1972; Susens, 1974; Michel and Alevizatos, 1975; Brantigan et al., 1976; King and Bechtold, 1985). Spinal hematomas have been reported with the therapeutic use of warfarin, including epidural hematoma, extradural hematoma, and meningeal hematoma

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(Dabbert et al., 1970; Harik et al., 1971; Lederle et al., 1996). Hematomyelia, an uncommon occurrence, has also been reported following warfarin therapy. Symptoms include paresis, back or neck pain, and urinary incontinence(Murphy and Nye, 1991; Liebeschuetz et al., 1994; Pullarkat et al., 2000). Intracranial hemorrhage is a well-known serious adverse event associated with the use of warfarin (Kase et al., 1985; Hylek and Singer, 1994). Patients with atrial fibrillation, who are at a higher risk of thromboembolism and thus stand to benefit more from anticoagulation, appear also to have a higher risk of intracerebral hemorrhage with warfarin treatment (Table 10.3) (Williams and Biller, 1998). Information from several clinical trials estimated the risk of intracerebral hemorrhage at from 0% to 1.8% per patient-year treated (Williams and Biller, 1998). Headache and altered consciousness were common presenting symptoms in patients with intracerebral hemorrhage (Volans, 1998). An increase in prothrombin time ratio (PTR) above 2.0 increases the risk for an intracranial hemorrhage, as does

increasing age. In one study, the risk for a subdural hemorrhage doubled with each 10 year increase in age. These two risk factors indicate the necessity of careful control of anticoagulation with warfarin, especially among elderly patients (Hylek and Singer, 1994). Additionally, based on multivariate analysis, a study of 68 cases and 204 matched controls identified international normalized ratio (INR) above 4.5, short (1 year or less) duration of oral anticoagulant therapy, hypertension, alcohol abuse, and a history of cerebral vascular disease as independent risk factors for intracranial hemorrhage (Berwaerts and Webster, 2000). Irbesartan The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE) evaluated the safety and efficacy of the combination of aspirin plus clopidogrel in atrial fibrillation patients who were unsuitable candidates for vitamin K antagonist therapy. In those patients, the addition of clopidogrel to aspirin did reduce the risk of major vascular events, especially stroke, but also increased the risk of major hemorrhage (ACTIVE Investigators, 2009).

Table 10.3 Risk of intracranial hemorrhage in warfarin-treated atrial fibrillation patients*

Study

Special characteristics

Treatment

SPAF I

Atrial fibrillation (AF)

SPAF II

AF Age  75 AF Age > 75 AF and one thromboembolic risk factor

1. 2. 3. 1. 2. 1. 2. 1.

SPAF II SPAF III

EAFT

AF and TIA or minor stroke

VA

AF, males only

Pooled data{

AF

Warfarin Aspirin 325 mg Placebo Warfarin Aspirin 325 mg Warfarin Aspirin 325 mg Warfarin (fixed) and aspirin 325 mg 2. Warfarin (adjusted)

1. 2. 3. 1. 2. 1. 2. 3. 4.

Warfarin Aspirin 300 mg Placebo Warfarin Placebo Warfarin Placebo Aspirin 75–300 mg Placebo

Target/mean INR or PTR for warfarin Target PTR 1.3–1.8 Mean PTR 1.45 Target INR 2.0–4.5 Mean INR 2.7 Target INR 2.0–4.5 Mean INR 2.6 1.Target INR 1.2–1.5 Mean INR 1.3 2.Target INR 2.0–3.0 Mean INR 2.4 Target INR 2.5–4.0

Target PTR 1.2–1.5 Target INR 2.0–4.2 Target PTR 1.2–1.5

% Intracranial hemorrhages per patient-year 1. 2. 3. 1. 2. 1. 2. 1.

0.8 0.3 0.3 0.6 0.2 1.8 0.8 0.9

2. 0.5 1. 2. 3. 1. 2. 1. 2. 3. 4.

0 0.2 0.1 0.2 0 0.5 0.1 – –

*Adapted from Biller. { Data from: Atrial Fibrillation, Aspirin, Anticoagulation Study (AFASAK); Boston Area Trial For Atrial Fibrillation Study; Canadian Atrial Fibrillation Anticoagulation Study; SPAF, and VA. (Adapted from Atrial Fibrillation Investigators, 1994.) INR, international normalized ratio; PTR, prothrombin time ratio.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 139 recently, intracardiac direct-current electrical shock of Direct thrombin inhibitors variable energies is delivered. Elective direct-current car1. Ximelagatran was voluntarily withdrawn from the dioversion can now be carried out externally with chest European market and further development was terelectrodes (transthoracic) or endocardially using elecminated because of liver toxicity in clinical trials trode catheters or leads. (Lazo-Langner et al., 2009). EXTERNAL CARDIOVERSION 2. Dabigatran is a different oral direct thrombin inhibitor that has been compared to warfarin in a The initial shock energy may be as low as 50 J depending noninferiority trial. In this trial, 18 113 patients with on the type of arrhythmia and the hemodynamic stability atrial fibrillation were assigned to either 110 mg of the patient. After shock delivery, the rhythm is noted, dabigatran twice daily, 150 mg dabigatran twice and if conversion is unsuccessful, repeat direct-current daily, or adjusted-dose warfarin. Dabigatran was cardioversion is attempted with higher energy. This found, at the 110 mg dose, to have similar rates of can be repeated until the arrhythmia terminates or a decistroke and systemic embolism as well as lower rates sion is made to abandon direct-current cardioversion of major hemorrhage when compared to warfarin. (Tracy et al., 2000). The 150 mg dose had lower rates of stroke and The most common arrhythmia subjected to elective embolism, but similar rates of major hemorrhage. direct-current cardioversion is atrial fibrillation (Tracy However, the rate of MI was slightly higher in both et al., 2000). Electrical cardioversion of atrial fibrillation dabigatran groups. Theoretically, if dabigatran is associated with an increased risk of stroke, and its were FDA approved, potentially the dose could be appropriate prevention is still debated. Besides dislodgetailored to specific patient risk factors (Connolly ment of pre-existing intra-atrial thrombi, the “stunned” et al., 2009). atrium after cardioversion is an important cause of thrombus formation and subsequent embolism (Nabavi Orally available antagonists of factor Xa New et al., 2001). Stroke as a direct result of cardioversion medications for the prevention of stroke in atrial fibrilhas been estimated to occur in 1.3% of patients lation patients are also being tested. Seven compounds (Arnold et al., 1992). The patients with the highest risk including rivaroxaban, apixaban, betrixaban, and eribaxof embolism are those who are older than 55 years of aban are orally available direct inhibitors of activated age, those who have coronary artery disease, and those factor X now in development for thromboprophylaxis who have a pre-existing cardiomyopathy (Weinberg in patients with atrial fibrillation or following an acute and Mancini, 1989; Adams, 1998). Embolism is not precoronary syndrome. Trials comparing the efficacy of dicted by a history of prior stroke, an enlarged left rivaroxaban or apixaban to standard therapy for stroke atrium, diabetes mellitus, or hypertension (Arnold prophylaxis in patients with atrial fibrillation are in proet al., 1992). Anticoagulation before and after cardiovercess. Rivaroxaban, the sentinel compound in this class, is sion lowers the risk of embolism (Arnold et al., 1992; already approved in the European Union and Canada. It Ewy, 1992; Manning et al., 1993; Adams, 1998). is likely to be approved for use in the US in 2010. The The following protocol has been advocated by the neurologic complications from these agents are not well American College of Cardiology for stroke prevention known at present (Morell et al., 2010). and is considered standard of care (Tracy et al., 2000):

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT: CARDIOLOGY PROCEDURES Patients with arrhythmias are diagnosed, treated, and sometimes cured with a variety of cardiac procedures. Although the implicit goal with any cardiac intervention is to improve a patient’s quality of life, these procedures carry a risk as well as a possible benefit.

Electrical cardioversion Since the introduction of direct current transthoracic electrical shock, its use has become fairly routine for the termination of tachycardias (Lown et al., 1962; Tracy et al., 2000). A variety of clinical scenarios are now encountered in which transthoracic and, more

1.

2.

3.

Individuals with atrial fibrillation of > 48 hours’ duration should receive warfarin therapy for  3 weeks before cardioversion. In patients in whom earlier cardioversion is desired, anticoagulation with heparin can be initiated and transesophageal echocardiography can be performed (use of transesophageal echocardiography has been advocated to identify small atrial thrombi that are not visible on transthoracic echocardiography). If no clots are seen, cardioversion can be undertaken. Routine anticoagulation must still be maintained after cardioversion (Silverman and Manning, 1998; Tracy et al., 2000).

While postponing cardioversion if there is transesophageal evidence of a thrombus is recommended

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(Ewy, 1992; Manning et al., 1993; Klein et al., 1997; Adams, 1998), the value of transesophageal echocardiography (TEE) to prevent cardioversion-related stroke in patients with atrial fibrillation and left atrial thrombus is unclear (Saeed et al., 2006). In patients with atrial fibrillation, left atrial thrombus, and effective anticoagulation, Saeed et al. found no difference in the risk of clinical thromboembolism between direct-current cardioversion with or without follow-up TEE. The absence of atrial thrombi at TEE does not exclude the possibility of thromboembolic complications of cardioversion conducted without anticoagulant therapy (Missault et al., 1994; Preobrazhenskiı˘ et al., 2005). Consistent with the American College of Cardiology/American Heart Association Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion, many physicians prefer to delay cardioversion until the patient has received anticoagulants for at least 4 weeks (Prystowsky, 1997; Adams, 1998). An INR goal of 2.5 (range 2.0–3.0) is recommended for most patients undergoing external cardioversion. For high-risk patients such as those with mechanical heart valves, an INR goal of 3 (range 2.5–3.5) is recommended to prevent brain embolism. The routine use of warfarin therapy in arrhythmias other than atrial fibrillation is still controversial (Tracy et al., 2000). The benefits of warfarin are thought to be related to thrombus resolution and prevention of new thrombus formation (Saeed et al., 2006). This appears to be confirmed by the findings of Nabavi et al. (2001), who investigated whether cardioversion of atrial fibrillation was associated with occurrence of circulating microemboli. A total of 29 patients with valvular or nonvalvular atrial fibrillation were studied. All but one had been prescribed oral anticoagulation (with an INR > 2.0) for at least 3 weeks before and 4 weeks after successful cardioversion. In all patients, exclusion of internal carotid artery stenosis and atrial thrombus was performed before cardioversion. Five unilateral 1 hour transcranial Doppler monitorings for microemboli over the middle cerebral artery were performed: (1) before cardioversion, and (2) immediately, (3) 4–6 h, (4) 24 h, and (5) 2–4 weeks after cardioversion. A complete absence of circulating microemboli was found before cardioversion as well as during a cumulative monitoring time of 115 h after successful cardioversion, showing that cardioversion of atrial fibrillation after at least 3 weeks of effective anticoagulation is not associated with occurrence of cerebral circulating microemboli (Nabavi et al., 2001).

INTERNAL CARDIOVERSION In those patients for whom external direct-current cardioversion is unsuccessful, an internal shock using

electrode catheters can be effective (Schmitt et al., 1996; Levy et al., 1997). The primary indication for internal cardioversion is atrial fibrillation when external shock fails or to assess the feasibility of an implantable atrial defibrillator (Levy et al., 1992; Schmitt et al., 1996; Sra et al., 1996; Levy et al., 1997). Because of the potential risk of bleeding, warfarin therapy is usually withheld and resumed after the procedure. Temporary anticoagulation before and after the procedure can be accomplished with heparin. Preprocedural and postprocedural antiarrhythmic therapy considerations are similar to those for external cardioversion. The possible risks of right heart catheterization with electrode catheters and the fact that direct-current shock is delivered within the myocardial structures adds to specific complications. However, recent studies suggest that stroke, and transient ischemic attack complication rates are similar for both external and internal cardioversion procedures (Ozdemir et al., 2006).

Pacemakers BRADYCARDIA Ventricular single chamber permanent cardiac pacing undoubtedly eliminates symptoms related to the extremely low cardiac rate in bradycardic patients. However, it also contributes to neurologic morbidity as it results in the onset of permanent atrial fibrillation. Many studies have shown the superiority of atrial and dual chamber cardiac pacing in reducing atrial fibrillation risk and in preventing the related embolic complications. Saccomanno et al.’s analysis of 690 chronically paced patients found that the total incidence of permanent atrial fibrillation was 51.4% in the ventricular pacemaker group and 11.4% in the dual chamber pacemaker group (p < 0.05). After 7 years from implant, permanent atrial fibrillation was present in 90% of ventricular-paced patients and 20% of dual chamber pacemaker patients (p < 0.001). A significantly higher occurrence of stroke and transient ischemic attack occurred in the ventricular pacemaker group (p < 0.05) (Saccomanno et al., 1999).

SINUS NODE DYSFUNCTION Greenspon et al. (2004) investigated the effects of dualchamber versus single-chamber ventricular pacing on subsequent stroke in patients with sinus node dysfunction. A total of 2010 patients with sinus node dysfunction were randomized to ventricular or dual-chamber pacing and followed for a median of 33.1 months. During 5664 patient-years of follow-up, 90 strokes (11 hemorrhagic) occurred. The rate of stroke was 2.2% at 1 year and 5.8% at 4 years. The incidence of stroke was not significantly different in dual-chamber (4%) compared

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT 141 with ventricular-paced patients (4.9%). Multivariable ventricular-demand pacemaker might represent highanalysis showed that significant predictors of stroke risk groups for stroke. However, patients who have sick after pacemaker insertion included prior stroke or transinus syndrome even without atrial fibrillation still have sient ischemic attack, Caucasian race, hypertension, a significant risk of stroke after pacemaker insertion. prior systemic embolism, and New York Heart AssociaMattioli et al. (1999) analyzed 100 consecutive patients tion functional class III or IV (p < 0.05); pacing mode with sick sinus syndrome without atrial fibrillation remained nonsignificant after adjustment for these facwho received either dual chamber or ventricular pacetors ( p ¼ 0.37). Similar to bradycardic patients with makers. Cerebral ischemia occurred in 18 of the 100 pacemakers, developing atrial fibrillation after impatients. Univariate predictors for cerebral embolism plantation is a significant risk factor for stroke in this were age > 65 years ( p < 0.001), low atrial ejection force cohort after adjustment for other predictors of stroke ( p < 0.01) and a dilated left atrium with spontaneous (Greenspon et al., 2004). echo contrast ( p < 0.05) (Mattioli et al., 1999). The role of antithrombotic medications for the prevention of stroke still needs further clarification. Clinical SICK SINUS SYNDROME trials to assess the efficacy of antithrombotic medicaSick sinus syndrome (SSS), a common cardiac rhythm tions, perhaps including a subgroup treated with aspirin, disorder in the elderly, is now the most common inin reducing stroke risk might be necessary in paced sick dication for permanent cardiac pacemaker insertion sinus syndrome patients (Fisher et al., 1988). (Kaplan, 1978). The stroke risk in sick sinus syndrome before cardiac pacemaker insertion is substantial and probably remains so after pacemaker insertion (Fisher Implantable defibrillators et al., 1988). The first implantable defibrillation device used was the The precise stroke risk after cardiac pacemaker inserMetrix system, a stand-alone atrial defibrillator (without tion remains uncertain, but strokes have been observed ventricular defibrillation) which was found to be safe in 4.5–23% of paced sick sinus syndrome patients who and effective in selected groups of patients. Unfortuare followed for 2–3 years (Stone et al., 1982; nately, this device is no longer marketed. Only doubleRosenqvist et al., 1986; Fisher et al., 1988). Data from chamber defibrillators with pacing capabilities are now long-term follow-up of paced sick sinus syndrome available: the Medtronic GEM III AT, an updated verpatients indicates that the incidence of stroke is 3% at sion of the Jewel AF, and the Guidant PRIZM AVT. 1 year, 5% at 5 years, and 13% at 10 years (Sgarbossa These devices can be patient activated or programmed et al., 1993). The development of chronic atrial to deliver automatically, once atrial tachyarrhythmias fibrillation and stroke in paced patients with sick sinus are detected, therapies including pacing or/and shocks. syndrome is strongly determined by clinical variables Attempts to define the group of patients who might benand secondarily by the pacing modality. Independent efit from these devices are described; however, the predictors for stroke were history of cerebrovascular respective roles of atrial defibrillators versus other nondisease, ventricular pacing mode, and history of paroxpharmacologic therapies for atrial fibrillation, such as ysmal atrial fibrillation. Stroke has been reported in surgery and radiofrequency catheter ablation, remain paced sick sinus syndrome patients with ventricularto be determined (Le´vy, 2005). demand, dual-chamber, and atrial-inhibited pacemaker. Cardioversion of atrial fibrillation carries a risk of Ventricular pacing mode does predict chronic atrial thromboembolic complications and stroke (Przybylski fibrillation in patients with preimplant paroxysmal et al., 2002). As a result, anticoagulation therapy is rouatrial fibrillation but not in those without it (Sgarbossa tinely given before and after this procedure. In patients et al., 1993). with permanent atrial fibrillation who undergo implantaAtrial pacing or atrial-ventricular sequential pacing tion of cardioverter-defibrillator (ICD), anticoagulants has been posited to be better than ventricular-demand are usually withdrawn during the perioperative period. pacing in reducing the risk of subsequent embolic epiHowever, in some patients sinus rhythm may be restored sodes (Rosenqvist et al., 1986; Sgarbossa et al., 1993). during defibrillation threshold testing which potentially The role of anticoagulants in reducing stroke risk has may increase the risk of thromboembolic complications not been assessed, but Radford and Julian (1974) recomand stroke. Przybylski et al. noted that sinus rhythm was mend their use after pacemaker insertion in sick sinus restored in 21.7% of patients with permanent atrial fibrilsyndrome patients. Stroke in sick sinus syndrome after lation who underwent ICD implantation. Temporary pacemaker insertion is not rare, and pacing does not withdrawal of anticoagulation therapy did not increase appear to be protective. Sick sinus syndrome patients the risk of stroke (Przybylski et al., 2002). who convert to atrial fibrillation or who have a

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Electrophysiologic procedures STROKE Thromboembolic stroke can be a complication of cardiac electrophysiologic procedures, including radiofrequency catheter ablation of arrhythmia. Multicenter data are limited; however, the stroke risk appears to be < 2%, with a range from 1% to 5% (DiMarco et al., 1982; Tanel et al., 1997; Adams, 1998; Alvarez and Merino 2002; Borger van der Burg et al., 2002; Di Biase et al., 2010). The thromboembolic risk during and after cardioversion and ablation of atrial flutter is higher than previously recognized and anticoagulation therapy decreases this risk (Reithmann et al., 2007). Di Biase et al. (2010) developed a prospective database to evaluate the prevalence of stroke over time in patients undergoing ablation of atrial fibrillation. Patients were divided into three groups: ablation with an 8 mm catheter off warfarin (group 1), ablation with an open irrigated catheter off warfarin (group 2), and ablation with an open irrigated catheter on warfarin (group 3). Outcome data on stroke/transient ischemic attack and bleeding complications during and early after the procedures were collected. Among 6454 consecutive patients, periprocedural stroke/transient ischemic attack occurred in 1.1% in group 1 and 0.9% in group 2. Despite a higher prevalence of nonparoxysmal atrial fibrillation and more patients with CHADS2 (congestive heart failure, hypertension, age > 75 years, diabetes mellitus, and prior stroke or transient ischemic attack) score > 2, no stroke/transient ischemic attack was reported in group 3. The authors concluded that a combination of an open irrigation ablation catheter and periprocedural therapeutic anticoagulation with warfarin reduces the risk of periprocedural stroke without increasing the risk of pericardial effusion or other bleeding complications (Di Biase et al., 2010). Because periprocedural stokes can occur several hours postprocedure, overnight in-hospital observation is warranted for patients who undergo radiofrequency ablation of a left-sided accessory pathway or an accessory pathway in a patient with the ability to shunt right to left. If an ischemic stroke is detected, case studies have reported that tPA was an effective and safe drug to use following a cerebral thromboembolic event occurring after a cardiac catheterization procedure (Cannon et al., 2001).

PHRENIC NERVE INJURY While epicardial catheter ablation can cure arrhythmia resistant to endocardial ablation (Sosa et al., 1996), the risk of collateral damage to adjacent structures is increased with the epicardial approach. From a neurologic standpoint, this risk of complications includes left phrenic nerve injury, given its close contact to the left

lateral ventricular wall (Rumbak et al., 1996). Studies suggest that during electrophysiologic interventions, the left phrenic nerve is particularly at risk when cardiac ablation procedures are performed in the vicinity of the left atrial appendage, the high left ventricular wall, the right superior pulmonary vein, and the superior vena cava (Sacher et al., 2006; Sa´nchez-Quintana et al., 2009). Sacher et al. (2006) reported that of the 3755 consecutive patients undergoing ablation to treat atrial fibrillation, phrenic nerve injury was noted as a rare complication (0.48%) of the procedure. Symptoms in patients with phrenic nerve injury vary broadly from asymptomatic to dyspnea, and even to respiratory insufficiency requiring temporary mechanical ventilation support (Bai et al., 2006). Coughing, hiccupping, and/ or sudden diaphragmatic elevation have also been reported (Sacher et al., 2006). Dyspnea is often noted after exertion. Some patients with transient phrenic nerve injury resolve quickly after the procedure and others within months. Some studies suggest that phrenic nerve injury caused by catheter ablation functionally recovers over time regardless of the energy sources used for the procedure (Bai et al., 2006). Other studies note that complete (66%) or partial (17%) recovery is observed in the majority of patients; however, some patients do continue to have permanent sequelae (Sacher et al., 2006).

Percutaneous closure of the left atrial appendage In patients with nonvalvular atrial fibrillation, ischemic stroke is often attributed to left atrial appendage clot formation and subsequent embolization. The difficulties of using anticoagulants, as well as the increased risk of hemorrhage, have resulted in the exploration of alternative stroke prevention treatment options. Some investigators have assessed whether occlusion of the left atrial appendage could potentially become an alternative to warfarin. One multicenter, randomized noninferiority trial found that percutaneous closure of the left atrial appendage was noninferior to warfarin treatment. In the future, closure of the left atrial appendage might provide an alternative to chronic warfarin for stroke prevention in patients with nonvalvular atrial fibrillation (Holmes et al., 2009). A second study, by Block et al., assessed percutaneous closure of the left atrial appendage in patients who were nonwarfarin candidates (Block et al., 2009). They reported the first long-term results after transcatheter left atrial appendage occlusion with the PLAATO device in 64 patients enrolled in the former PLAATO multicenter study. Their findings are encouraging: only one major adverse event (tamponade) was related to the procedure. The annualized stroke/TIA rate in this study was 3.8%, which was almost half of the

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT actual expected stroke/TIA rate based on CHADS (2) scores of 6.6% per year (Block et al., 2009). No major adverse neurologic complications directly due to percutaneous closure of the left atrial appendage have been reported to date. The PROTECT AF study compared the efficacy and safety of the WATCHMAN device, an umbrella-like left atrial appendage closure device, to warfarin treatment in patients with nonvalvular atrial fibrillation (Holmes et al., 2009). A total of 707 eligible patients with atrial fibrillation at risk for cerebral embolism were randomly assigned to receive warfarin with a target INR of 2–3 or percutaneous WATCHMAN implantation and subsequent discontinuation of coumadin. The WATCHMAN percutaneous closure device was not inferior to anticoagulation for the primary efficacy endpoints of ischemic stroke, hemorrhagic stroke, cardiovascular or unexplained death, and systemic embolization. There was a slightly higher risk of ischemic stroke in the device group, with a total of five ischemic strokes (three from air embolism) that occurred at the time of the implantation procedure. Device closure of the left atrial appendage was associated with a significant reduction in the hemorrhagic stroke risk compared to warfarin, meeting superiority criteria. All-cause stroke outcomes in the group undergoing WATCHMAN implantation were noninferior to the warfarin group. Death occurred at similar proportions. The WATCHMAN device had a higher rate of adverse safety events, mainly from periprocedural complication (7.4 per 100 patient-years versus 4.4 per 100 patient safety-years). The teofold increase in safety events in the device group was mainly due to non-neurologic causes such as pericardial effusion. Additionally, these safety events decreased over time with procedural modifications. The probability of WATCHMAN device noninferiority was greater than 99.9%. The authors suggest that closure of the left atrial appendage may provide an alternative strategy to chronic warfarin therapy for stroke prophylaxis in patients with nonvalvular atrial fibrillation (Holmes et al., 2009). The most important impact of the PROTECT AF trial may actually be on the subgroup of atrial fibrillation patients who have contraindications to long-term anticoagulation, especially in those individuals with contraindications due to bleeding complication or noncompliance.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT: CARDIOVASCULAR SURGERY THE MAZE PROCEDURE In the “Maze” operation introduced by Cox, several small incisions are made in the atria to interrupt atrial fibrillation re-entry pathways (Cox et al., 1991). The Cox-Maze III operation, “cut and sew Maze,” or simply

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Maze procedure is now the gold standard for surgical treatment of atrial fibrillation. The operation may be performed alone or in conjunction with other cardiac surgical procedures, such as mitral valve repair or coronary artery bypass grafting (Gillinov, 2007). In a report of 197 patients who underwent the Maze procedure, the mean rate of freedom from atrial fibrillation was 89% after 10 years of follow-up (Gaynor et al., 2005). Despite these good results, the Maze procedure is seldom used because it is complicated and time-consuming. Operations that were modified from the original Maze procedure were shown to be less effective than the original procedure (Barnett and Ad, 2006). Complications of the Maze operation include different types of atrial arrhythmias as a possible consequence of partial denervation of the sympathetic and parasympathetic systems of the heart. Most importantly, it does not reduce the risk of embolic events, including stroke, so patients must continue with anticoagulation therapy. As with other cardiac surgical procedures, abnormalities of intellectual function and behavior can occur (Barbut and Caplan, 1997; Wolman et al., 1999). Although it carries a low risk of stroke, perioperative stroke has been reported in conjunction with the Maze procedure (Gammie et al., 2009). A particular patient’s risk of perioperative stroke may be estimated using the Society of Thoracic Surgeons 2008 cardiac surgery risk models, which include outcomes for stroke as well as other morbidities. Several variables were forced into each model to ensure face validity (for example, the permanent stroke model includes atrial fibrillation as a variable) (O’Brien et al., 2009; Shahian et al., 2009a, b).

EPICARDIAL RADIOFREQUENCY ATRIAL AND/OR PULMONARY VEIN ISOLATION AND GANGLIONATED PLEXUS ABLATION

Several new procedures have been developed that attempt to mimic the Maze procedure using a variety of energy sources to create conduction block rather than cardiac incisions. These procedures appear to provide effective treatment for atrial fibrillation, with 75% subjects overall and 87.5% subjects with paroxysmal or persistent atrial fibrillation having a successful procedure (defined as freedom from atrial fibrillation and antiarrhythmic agents throughout 1 year of follow-up) (McClelland et al., 2007). A second study with 6 months of follow-up showed freedom from atrial fibrillation in 93% of patients (Mehall et al., 2007). Specific neurologic complications from this procedure have not yet been reported. Ganglionated ablation directs an energy source onto the cardiac plexi usually located on the epicardial surface of the main pulmonary veins. Specific risks from these procedures are yet to be determined; however, a

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postprocedure requirement for permanent pacemaker is not insignificant, with the pacemaker-neurologic risk as previously mentioned.

OTHER CARDIAC SURGICAL PROCEDURES Preoperative arrhythmia has been shown to affect neurologic outcome after cardiac surgery. Preoperative atrial fibrillation increases the risk of cardiac surgical postoperative complications, including delirium, stroke, and death. The pilot study of the CODACS trial (COnsciousness Disorders After Cardiac Surgery) prospectively assessed 260 patients admitted for open-heart surgery. Preoperative atrial fibrillation was diagnosed on the basis of multiple electrocardiograms and confirmed by 24 hour Holter monitoring. Diagnosis of delirium following surgical intervention was based on DSM-IV criteria. Preoperative atrial fibrillation was an independent predictor of postoperative delirium (p < 0.001), increasing its risk of occurrence over sevenfold. Atrial fibrillation also increased the risk of other postoperative neurologic complications including stroke (8.7% versus 1.3%, p < 0.001). These results and data from available studies suggest that preoperative atrial fibrillation should be considered an important predictor of postoperative neurologic outcome (Banach et al., 2008).

CONCLUSION There are many causes of neurologic complications in arrhythmia patients. Certain arrhythmias have direct complications, such as stroke, cognitive impairment, and dementia. Other individuals with arrhythmia develop neurologic problems as an indirect result of their diagnosis or treatment. It is important to recognize these patients, because some of these neurologic complications can be prevented and others can be reversed with the discontinuation of the offending agent.

REFERENCES Abdon NJ, Johnsson BM (1979). High risk of embolization in episodic sick sinus syndrome. In: Proceedings of the VIth World Symposium on Cardiac Pacing, PACESYMP, Montreal, pp. 11–14. Abi-Mansour P, Carberry PA, McCowan RJ, Henthorn RW, Dunn GH, Perry KT (1998). Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Study Investigators. Am Heart J 136: 632–642. ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG et al. (2009). Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Eng J Med 360: 2066–2078. Adams HP (1998). Neurologic complications of cardiovascular procedures. In: J Biller (Ed.), Iatrogenic Neurology. Butterworth-Heinemann, Boston, pp. 51–61.

Agarwal SK, Heiss G, Rautaharju PM et al. (2010). Premature ventricular complexes and the risk of incident stroke: the Atherosclerosis Risk In Communities (ARIC) Study. Stroke 41: 588–593. Agius MA, Zhu S, Fairclough RH (1998). Antirapsyn antibodies in chronic procainamide-associated myopathy (CPAM). Ann N Y Acad Sci 841: 527–529. Ahmad S (1982). Procainamide and peripheral neuropathy. South Med J 74: 509–510. Ahmad S (1993). Diltiazem myopathy. Am Heart J 126: 1494–1495. Aho K, Haapa K (1982). Facial atrophy during sotalol treatment. J Neurol Neurosurg Psychiatry 45: 179. Allen MJ, Nichols DJ, Oliver SD (2000). The pharmacokinetics and pharmacodynamics of oral dofetilide after twice daily and three times daily dosing. Br J Clin Pharmacol 50: 247–253. Alvarez M, Merino JL (2002). Spanish registry on catheterablation: 1st official report of the working group on electrophysiology and arrhythmias of the Spanish Society of Cardiology (Year 2001). Rev Esp Cardiol 55: 1273–1285. Anderson NE, Lynch NM, O’Brien KP (1985). Disabling neurological complications of amiodarone. Aust N Z J Med 15: 300–304. Arnold AZ, Mick MJ, Mazurek RP et al. (1992). Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 19: 851–855. Aronow WS, Ahn C, Mercando AD et al. (1996). Correlation of paroxysmal supraventricular tachycardia, atrial fibrillation, and sinus rhythm with incidences of new thromboembolic stroke in 1476 old-old patients. Aging 8: 32–34. Atkinson JL, Sundt TM Jr, Kazmier FJ et al. (1988). Heparininduced thrombocytopenia and thrombosis in ischemic stroke. Mayo Clin Proc 63: 353–361. Atluru VL, Epstein LG, Gootman N (1985). Childhood stroke and supraventricular tachycardia. Pediatr Neurol 1: 54–56. Atrial Fibrillation Investigators (1994). Risk factors for stroke and efficacy of antithrombotic therapy in atrialfibrillation. Analysis of pooled data from five, randomized controlled trials. Arch Intern Med 154: 1449. Babikian VL, Kase CS, Pessin MS et al. (1989). Intracerebral hemorrhage in stroke patients anticoagulated with heparin. Stroke 20: 1500–1503. Bai R, Patel D, Di Biase L et al. (2006). Phrenic nerve injury after catheter ablation: should we worry about this complication? J Cardiovasc Electrophysiol 17: 944–948. Banach M, Kazmierski J, Kowman M et al. (2008). Atrial fibrillation as a nonpsychiatric predictor of delirium after cardiac surgery: a pilot study. Med Sci Monit 14: CR286–CR291. Barbut D, Caplan LR (1997). Brain complications of cardiac surgery. Curr Probl Cardiol 22: 455–476. Barnett SD, Ad N (2006). Surgical ablation as treatment for the elimination of atrial fibrillation: a meta-analysis. J Thorac Cardiovasc Surg 131: 1029–1035. Bathen J, Span S, Rokseth R (1978). Embolism in sinoatrial disorder. Acta Med Scand 203: 7–11. Bell JA, Hodgson HJ (1974). Coma after cardiac arrest. Brain 97: 361–372.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT Berchtold-Kanz E, Schwarz G, Hust M et al. (1984). Increased incidence of side effects after encainide: a newly developed antiarrhythmic drug. Clin Cardiol 7: 493–497. Berwaerts J, Webster J (2000). Analysis of risk factors involved in oral-anticoagulant-related intracranial haemorrhages. Q J Med 93: 513–521. Bhushan M, Asirvatham SJ (2009). The conundrum of ventricular arrhythmia and cardiomyopathy: which abnormality came first? Curr Heart Fail Rep 6: 7–13. Bikadoroff S (1987). Mental changes associated with tocainide, a new antiarrhythmic. Can J Psychiatry 32: 219–221. Billett HH, Scorziello BA, Giannattasio ER et al. (2010). Low molecular weight heparin bridging for atrial fibrillation: is VTE thromboprophylaxis the major benefit? J Thromb Thrombolysis 30: 479–485. Birk S, Petersen KA, Kruuse C et al. (2005). The effect of circulating adenosine on cerebral haemodynamics and headache generation in healthy subjects. Cephalalgia 25: 369–377. Blessing W, Walsh JC (1977). Myotonia precipitated by propranolol therapy. Lancet 1: 73–74. Block PC, Burstein S, Casale PN et al. (2009). Percutaneous left atrial appendage occlusion for patients in atrial fibrillation suboptimal for warfarin therapy: 5-year results of the PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion) study. J Am Coll Cardiol Intv 2: 594–600. Bogousslavsky J, Van Melle G, Regli F (1988). The Lausanne Stroke Registry: analysis of 1000 consecutive patients with first strokes. Stroke 19: 1083–1092. Bogousslavsky J, Cachin C, Regli F et al. (1991). Cardiac sources of embolism and cerebral infarction: clinical consequences and vascular concomitants. The Lausanne Stroke Registry. Neurology 41: 855–859. Bonatz E, Seabol KE (1993). Acute carpal tunnel syndrome in a patient taking coumadin: case report. J Trauma 35: 143–144. Borger van der Burg AE, de Groot NM, van Erven L et al. (2002). Long-term follow-up after radiofrequency catheter ablation of ventricular tachycardia: a successful approach? J Cardiovasc Electrophysiol 13: 424–426. Borruat FX, Regli F (1993). Pseudotumor cerebri as a complication of amiodarone therapy. Am J Ophthalmol 116: 776–777. Boston Collaborative Drug Surveillance Program [no authors listed] (1972). Drug-induced convulsions. Report from Boston Collaborative Drug Surveillance Program. Lancet 2: 677–679. Brantigan JW, Owens ML, Moody FG (1976). Femoral neuropathy complicating anticoagulant therapy. Am J Surg 132: 108–109. Briani C, Zara G, Negrin P (2002). Disopyramide-induced neuropathy. Neurology 58: 663. Brown SGA, Waterer GW (1995). Migraine precipitated by adenosine. Med J Aust 162: 389–391. Brown C, Bachmann G, Ling FW (2009). Differential diagnosis of seizure associated with topical lidocaine in a patient with vestibulodynia. J Low Genit Tract Dis 13: 51. Butterfield WC, Neviaser RJ, Roberts MP (1972). Femoral neuropathy and anticoagulants. Ann Surg 176: 58–61. Campbell RW (1987). Mexiletine. N Engl J Med 316: 29–34.

145

Campbell NP, Kelly JG, Shanks RG et al. (1973). Mexiletine (K€ o 1173) in the management of ventricular dysrhythmias. Lancet 2: 404–407. Candell J, Valle V, Soler M et al. (1979). Acute intoxication with verapamil. Chest 75: 200–201. Cannon BC, Kertesz NJ, Friedman RA et al. (2001). Use of tissue plasminogen activator in a stroke after radiofrequency ablation of a left-sided accessory pathway. J Cardiovasc Electrophysiol 12: 723–725. Caplan LR (1999a). Cardiac arrest and other hypoxic-ischemic insults. In: LR Caplan, JW Hurst, MI Chimowitz (Eds.), Clinical Neurocardiology, Marcel Dekker, New York, pp. 1–34. Caplan LR (1999b). Encephalopathies and neurological effects of drugs used in cardiac patients. In: LR Caplan, JW Hurst, MI Chimowitz (Eds.), Clinical Neurocardiology. Marcel Dekker, New York, pp. 186–225. Caronna JJ, Finkelstein S (1978). Neurological syndromes after cardiac arrest. Stroke 9: 517–520. Cerebral Embolism Task Force (1989). Cardiogenic brain embolism: the second report of the Cerebral Embolism Task Force. Arch Neurol 46: 727–743. Charness ME, Morady F, Scheinman MM (1984). Frequent neurologic toxicity associated with amiodarone therapy. Neurology 34: 669–671. Chua TP, Farrell T, Lipkin DP (1994). Myoclonus associated with propafenone. BMJ 308: 113. Clark CWF, El-Mahdi EO (1984). Fatal tocainide overdosage. BMJ 288: 760. Closson RG (1983). Visual hallucinations as the earliest symptom of digoxin intoxication. Arch Neurol 40: 386. Cohen IS, Jick H, Cohen SI (1977). Adverse reactions to quinidine in hospitalized patients: findings based on data from the Boston Collaborative Drug Surveillance Program. Prog Cardiovasc Dis 20: 151–163. Collaborative Group for the Study of Polyneuropathy (1994). Antiarrhythmic drugs and polyneuropathy. J Neurol Neurosurg Psychiatry 57: 340. Connolly SJ, Ezekowitz MD, Yusuf S et al. (2009). Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361: 1139–1151. Coulter DM, Edwards IR, Savage RL (1990). Survey of neurological problems with amiodarone in the New Zealand Intensive Medicines Monitoring Programme. N Z Med J 103: 98–100. Cox JL, Canavan TE, Schuessler RB et al. (1991). The surgical treatment of atrial fibrillation. II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg 101: 406–426. Dabbert O, Freeman DG, Weis AJ (1970). Spinal meningeal hematoma, warfarin therapy, and chiropractic adjustment. JAMA 214: 2058. Das G, Ferris JC (1988). Generalized convulsions in a patient receiving ultrashort-acting beta-blocker infusion. Drug Intell Clin Pharm 22: 484–485. Dawkins KD, Gibson J (1978). Peripheral neuropathy with disopyramide. Lancet 1: 329. De Pedis G, Hedner K, Johansson BW et al. (1987). Cardiac arrhythmia in geriatric patients with organic dementia. Compr Gerontol A 1: 115–117.

146

M.C. LEARY ET AL.

Di Biase L, Burkhardt JD, Mohanty P et al. (2010). Periprocedural stroke and management of major bleeding complications in patients undergoing catheter ablation of atrial fibrillation: the impact of periprocedural therapeutic international normalized ratio. Circulation 121: 2550–2556. Dick RS, Barold SS (1989). Diltiazem-induced parkinsonism. Am J Med 87: 95–96. DiMarco JP, Garan H, Ruskin JN (1982). Complications in patients undergoing cardiac electrophysiologic procedures. Ann Intern Med 97: 490–493. Dorf E, Kuntz AF, Kelsey J et al. (2006). Lidocaine-induced altered mental status and seizure after hematoma block. J Emerg Med 31: 251–253. Dotti MT, Federico A (1995). Amiodarone-induced parkinsonism: a case report and pathogenetic discussion. Mov Disord 10: 233–234. Drachman DA, Skom JH (1965). Procainamide – a hazard in myasthenia gravis. Arch Neurol 13: 316–320. Dukes MN (Ed.), (1975). In Meyler’s Side Effects of DrugsVol. VIII. Excerpta Medica, Amsterdam. Durakovic´ Z, Plavsic´ F, Smalcelj A et al. (1992). Blue color vision as a sign of digitalis poisoning. Lijec Vjesn 114: 132–134. Eisenman DP, McKegney FP (1994). Delirium at therapeutic serum concentrations of digoxin and quinidine. Psychosomatics 35: 91–93. Emara MK, Saadah AM (1988). The carpal tunnel syndrome in hypertensive patients treated with beta-blockers. Postgrad Med J 64: 191–192. Ettorre E, Cicerchia M, De Benedetto G et al. (2009). A possible role of atrial fibrillation as a risk factor for dementia. Arch Gerontol Geriatr 49 (Suppl 1): 71–76. Ewy GA (1992). Optimal technique for electrical cardioversion of atrial fibrillation. Circulation 86: 1645–1647. Fairfax AJ, Lambert CD, Leathan MA (1976). Systemic embolization in chronic sinoatrial disorder. N Engl J Med 295: 190–192. Fernando Roth R, Itabashi H, Louie J et al. (1990). Amiodarone toxicity: myopathy and neuropathy. Am Heart J 119: 1223–1225. Fesler MJ, Creer MH, Richart JM et al. (2011). Heparininduced thrombocytopenia and cerebral venous sinus thrombosis: case report and literature review. Neurocrit Care 15: 161–165. Fisher CM (1981). Visual disturbances associated with quinidine and quinine. Neurology 31: 1569–1571. Fisher M, Kase CS, Stelle B et al. (1988). Ischemic stroke after cardiac pacemaker implantation in sick sinus syndrome. Stroke 19: 712–715. Fisher AA, Davis M, Jeffery I (2002). Acute delirium induced by metoprolol. Cardiovasc Drugs Ther 16: 161–165. Fogoros RN, Anderson KP, Winkle RA et al. (1983). Amiodarone: clinical efficacy and toxicity in 96 patients with recurrent, drug-refractory arrhythmias. Circulation 68: 88–94. Forrence E, Covinsky JO, Mullen C (1986). A seizure induced by concurrent lidocaine-tocainide therapy – is it just a case of additive toxicity? Drug Intell Clin Pharm 20: 56–59.

Fuster V, Halperin JL (1989). Left ventricular thrombi and cerebral embolism. N Engl J Med 320: 392–394. Galasso PJ, Stanton MS, Vogel H (1995). Propafenone-induced peripheral neuropathy. Mayo Clin Proc 70: 469–472. Gammie JS, Didolkar P, Krowsoski LS et al. (2009). Intermediate-term outcomes of surgical atrial fibrillation correction with the CryoMaze procedure. Ann Thorac Surg 87: 1452–1458. Garcia-Albea E, Jimenez-Jimenez FJ, Ayuso-Peralta L et al. (1993). Parkinsonism unmasked by verapamil. Clin Neuropharmacol 16: 263–265. Gaynor SL, Schuessler RB, Bailey MS et al. (2005). Surgical treatment of atrial fibrillation: predictors of late recurrence. J Thorac Cardiovasc Surg 129: 104–111. Gentzkow GD, Sullivan JY (1984). Extracardiac adverse effects of flecainide. Am J Cardiol 53: 101B–105B. Gillinov AM (2007). Advances in surgical treatment of atrial fibrillation. Stroke 38: 618–623. G€ odecke-Koch T, Schlimme J, Rada D et al. (2002). Charles Bonnet syndrome in an elderly patient with bilateral vision loss, hyperthyroidism and relative digitalis overdose. Nervenarzt 73: 471–474. Godley PJ, Morton TA, Karboski JA et al. (1990). Procainamideinduced myasthenic crisis. Ther Drug Monit 12: 411–414. Goli-Bijanki R, Nair CK, Nair N et al. (1989). Previously unreported adverse reaction to encainide. Chest 96: 688–689. Graham DF, Stewart-Wynne EG (1994). Diltiazem-induced acute parkinsonism. Aust N Z J Med 24: 70. Greenspon AJ, Hart RG, Dawson D et al. (2004). MOST Study Investigators. Predictors of stroke in patients paced for sick sinus syndrome. J Am Coll Cardiol 43: 1617–1622. Greif S, Roth F, Harnoncourt K (1977). The treatment of angina pectoris with a fixed combination of a beta-receptor and a long-acting nitrate. Praxis 66: 1554–1559. Grogan WA, Narkun DM (1987). Pseudotumor cerebri with amiodarone. J Neurol Neurosurg Psychiatry 50: 651. Guieu R, Devaux C, Henry H et al. (1998). Adenosine and migraine. Can J Neurol Sci 25: 55–58. Harik SI, Raichle ME, Reis DJ (1971). Spontaneously remitting spinal epidural hematoma in a patient on anticoagulants. N Engl J Med 284: 1355–1357. Hecaen H, Ajuriaguerra J (1954). Balint’s syndrome and its minor forms. Brain 77: 373–400. Herishanu Y, Rosenberg P (1975). Beta-blockers and myasthenia gravis (letter). Ann Intern Med 83: 834–835. Hindle JV, Ibrahim A, Ramaraj R (2008). Ataxia caused by amiodarone in older people. Age Ageing 37: 347–348. Hohnloser SH, Crijns HJ, van Eickels M et al. (2009). Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 360: 668–678. Holmes DR, Reddy VY, Turi ZG et al. (2009). Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial. Lancet 374: 534–542. Holt P (1988). Visual hallucinations. N Z Med J 101: 29.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT Horn HR, Hadidian Z, Johnson JL et al. (1980). Safety evaluation of tocainide in the American Emergency Use Program. Am Heart J 100: 1037–1040. Hylek EM, Singer DE (1994). Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 120: 897–902. Ilia R, Goldfarb B, Gueron M (1992). Skin thickening and sensory loss of the feet during diltiazem therapy. Int J Cardiol 35: 115. Isbister GK (2002). Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation with high dose intravenous calcium. Emerg Med J 19: 355–357. Ishida S, Sugino M, Hosokawa T et al. (2010). Amiodaroneinduced liver cirrhosis and parkinsonism: a case report. Clin Neuropathol 29: 84–88. Jacobs JM, Costa-Jussa` FR (1985). The pathology of amiodarone neurotoxicity. II. Peripheral neuropathy in man. Brain 108: 753–769. Jones RJ, Brace SR, Vander Tuin EL (1995). Probable propafenone-induced transient global amnesia. Ann Pharmacother 29: 586–590. Kaplan BM (1978). Sick sinus syndrome. Arch Intern Med 138: 28. Kase CS, Robinson RK, Stein RW et al. (1985). Anticoagulant-related intracerebral hemorrhage. Neurology 35: 943–948. Kashyap AS, Anand KP, Kashyap S (2006). Severe ataxia caused by amiodarone. Am J Cardiol 97: 1550–1551. Kennerdy A, Thomas P, Sheridan DJ (1989). Generalized seizures as the presentation of flecainide toxicity. Eur Heart J 10: 950–954. King RB, Bechtold DL (1985). Warfarin-induced iliopsoas hemorrhage with subsequent femoral nerve palsy. Ann Emerg Med 14: 362–364. Kittner SJ, Sharkness CM, Sloan M et al. (1992). Infarcts with a cardiac source of embolism in the NINDS Stroke Data Bank: neurologic examination. Neurology 42: 299–302. Klein AL, Grimm RA, Black IW et al., for the ACUTE Investigators (1997). Cardioversion guided by transesophageal echocardiography. The ACUTE Pilot Study. A randomized, controlled trial. Ann Intern Med 126: 200–209. Kornfeld P, Horowitz SH, Genkins G et al. (1976). Myasthenia gravis unmasked by antiarrhythmic agents. Mt Sinai J Med 43: 10–14. Krauser DG, Segal AZ, Kligfield P (2005). Severe ataxia caused by amiodarone. Am J Cardiol 96: 1463–1464. Kumana CR, Mahon WA (1981). Bizarre perceptual disorder of extremities in patients taking verapamil. Lancet 1: 1324–1325. Lazo-Langner A, Rodger MA, Wells PS (2009). Lessons from ximelagatran: issues for future studies evaluating new oral direct thrombin inhibitors for venous thromboembolism prophylaxis in orthopedic surgery. Clin Appl Thromb Hemost 15: 316–326. Leary MC, Caplan LR (2009). Cerebrovascular disease and neurologic manifestations of heart disease. In: RA O’Rourke, RA Walsh, V Fuster (Eds.), Hurst’s The Heart: Manual of Cardiology. 12th edn. McGraw-Hill, New York, pp. 640–647, ch. 35.

147

Lecky BR, Weir D, Chong E (1991). Exacerbation of myasthenia by propafenone. J Neurol Neurosurg Psychiatry 54: 377. Lederle FA, Cundy KV, Farinha P et al. (1996). Spinal epidural hematoma associated with warfarin therapy. Am J Med 100: 237–238. Lee TC (1981). Van Gogh’s vision. Digitalis intoxication? JAMA 245: 727–729. Le´vy S (2005). Internal defibrillation: where we have been and where we should be going? J Interv Card Electrophysiol 13 (Suppl 1): 61–66. Levy D, Carrona JJ, Singer BH et al. (1985). Predicting outcome from hypoxicischemic coma. JAMA 253: 1420–1426. Levy S, Lauribe P, Dolla E et al. (1992). A randomized comparison of external and internal cardioversion of chronic atrial fibrillation. Circulation 86: 1415–1420. Levy S, Ricard P, Lau CP et al. (1997). Multicenter low energy transvenous atrial defibrillation (XAD) trial results in different subsets of atrial fibrillation. J Am Coll Cardiol 29: 750–755. Li Y, Tian L, Huang Y et al. (2007). Pharmacokinetic and pharmacodynamic properties of a single intravenous dose of ibutilide fumarate: a phase I, randomized, open-label, increasing-dose study in healthy Chinese men. Clin Ther 29: 1957–1966. Liebeschuetz S, Baddeley H, Thomas DJB (1994). Haematomyelia following warfarin therapy. Br J Clin Pharmacol 48: 105–106. Linazasoro G, Martı´-Masso´ JF, Urtasun M et al. (1991). Paroxysmal dystonia induced by exercise secondary to flecainide. Neurologia 6: 344. Longstreth WT, Inui TS, Cobb LA et al. (1983a). Neurologic recovery after out-of-hospital cardiac arrest. Ann Intern Med 38: 588–592. Longstreth WT, Diehr P, Inui TS (1983b). Prediction of awakening after out-of-hospital cardiac arrest. N Engl J Med 308: 1378–1382. Love JN, Handler JA (1995). Toxic psychosis: an unusual presentation of propranolol intoxication. Am J Emerg Med 13: 536–537. Lown B, Amarasingham R, Neuman J (1962). New method for terminating cardiac arrhythmias: use of synchronized capacitor discharge. JAMA 182: 548–555. Mahitchi E, Balague´ F, Waldburger M (2009). What is your diagnosis? Myopathy due to hypothyroidism aggravated by amiodarone. Praxis 98: 999–1000. Malcolm N, Callegari P, Goldberg J et al. (1986). Massive diltiazem overdosage: clinical and pharmacokinetic observations. Drug Intell Clin Pharm 20: 888. Maloney JD, Nissen RG, McColgan JM (1980). Open clinical studies at a referral center: chronic maintenance tocainide therapy in patients with recurrent sustained ventricular tachycardia refractory to conventional antiarrhythmia agents. Am Heart J 100: 1023–1030. Manning WJ, Silverman DI, Gordon SP et al. (1993). Cardioversion from atrial fibrillation without prolonged anticoagulation with use of transesophageal echocardiography to exclude the presence of atrial thrombi. N Engl J Med 328: 750–755.

148

M.C. LEARY ET AL.

Manolis AS, Tordjman T, Mack KD et al. (1987). Atypical pulmonary and neurologic complications of amiodarone in the same patient. Report of a case and review of the literature. Arch Intern Med 147: 1805–1809. Marke J, Steinberg MD, Rabiner CJ (1987). “Doom anxiety” and delirium in lidocaine toxicity. Am J Psychiatry 144: 159–163. Maryniak A, Bielawska A, Walczak F et al. (2008). Long-term cognitive outcome in teenage. Resuscitation 77: 46–50. Mattioli AV, Tarabini Castellani E, Mattioli G (1999). Stroke in paced patients with sick sinus syndrome: influence of left atrial function and size. Cardiology 91: 150–155. McClelland JH, Duke D, Reddy R (2007). Preliminary results of a limited thoracotomy: new approach to treat atrial fibrillation. J Cardiovasc Electrophysiol 18: 1289–1295. Mehall JR, Kohut RM Jr, Schneeberger EW et al. (2007). Intraoperative epicardial electrophysiologic mapping and isolation of autonomic ganglionic plexi. Ann Thorac Surg 83: 538–541. Meschia JF, Biller J (1998). Complications of cardiovascular drugs. In: J Biller (Ed.), Iatrogenic Neurology. Butterworth-Heinemann, Boston, pp. 379–396. Michel RH, Alevizatos AC (1975). Femoral neuropathy: a complication of anticoagulation. Md Med J 24: 57. Miller LG, Jankovic J (1992). Persistent dystonia possibly induced by flecainide. Mov Disord 7: 62–63. Miller CD, Oleshansky MA, Gibson KF et al. (1993). Procainamide-induced myasthenia-like weakness and dysphagia. Ther Drug Monit 15: 251–254. Mindel JS (2008). Amiodarone and optic neuropathy. Am Heart J 156: 411–413. Missault L, Jordaens L, Gheeraert P et al. (1994). Embolic stroke after unanticoagulated cardioversion despite prior exclusion of atrial thrombi by transoesophageal echocardiography. Eur Heart J 15: 1279–1280. Morell J, Sullivan B, Khalabuda M et al. (2010). Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban. J Clin Pharmacol 50: 986–1000. Moroni F, Mannaioni PF, Dolara A et al. (1980). Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning. Clin Toxicol 17: 395–400. Moyer RR (1972). Verapamil, an anti-anginal agent. Minn Med 55: 1043–1045. Murphy MA, Nye DH (1991). Thoracic intramedullary haematoma as a complication of warfarin: case report and literature review. Aust N Z J Surg 61: 789–792. Nabavi DG, Allroggen A, Reinecke H et al. (2001). Absence of circulating microemboli in patients with atrial fibrillation undergoing electric cardioversion. Cerebrovasc Dis 11: 95–99. Niakan E, Bertorini TE, Acchiardo SR et al. (1981). Procainamide-induced myasthenia-like weakness in a patient with peripheral neuropathy. Arch Neurol 38: 378–379. Nygaard TW, Sellers TD, Cook TS et al. (1986). Adverse reactions to antiarrhythmic drugs during therapy for ventricular arrhythmias. JAMA 256: 55–57.

O’Brien SM, Shahian DM, Filardo G et al. (2009). The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 2. Isolated valve surgery. Ann Thorac Surg 88: S23–S42. Odeh M, Seligmann H, Oliven A (2000). Propafenone-inducedataxia: report of three cases. Am J Med Sci 320: 151–153. Oh SJ, Elmore RS, Sarala PK et al. (1986). Procainamide-induced myasthenia-like syndrome. Muscle Nerve 9: 670–672. Ozdemir M, T€ urkoglu S, Kaya MG et al. (2006). Prospective randomized trial of transthoracic versus low-energy internal cardioversion in persistent atrial fibrillation: long term follow-up. Int Heart J 47: 753–762. Palace J, Shah R, Clough C (1992). Flecainide induced peripheral neuropathy. BMJ 305: 810. Palakurthy PR, Iyer V, Meckler RJ (1987). Unusual neurotoxicity associated with amiodarone therapy. Arch Intern Med 147: 881–884. Parnass SM, Rothenberg DM, Fischer RL et al. (1990). Spinal anesthesia and mini-dose heparin (letter). JAMA 263: 1496. Passal DB, Crespin FH (1984). Verapamil poisoning in an infant. Pediatrics 73: 543–545. Pathirana KD, Hidelaratchi MD (2004). Exacerbation of symptoms due to diltiazem in a patient with Lambert–Eaton myasthenic myopathic syndrome. Ceylon Med J 49: 130–131. Pellissier JF, Pouget J, Cros D et al. (1984). Peripheral neuropathy induced by amiodarone chlorhydrate. A clinicopathological study. J Neurol Sci 63: 251–266. Pelter MA, Vollmer TA, Blum RL (1989). Seizure-like reaction associated with subcutaneous lidocaine injection. Clin Pharm 8: 767–768. Perucca E, Pickles H, Richens A (1981). Effect of atenolol, metoprolol, and propranolol on isoproterenol-induced tremor and tachycardia in normal subjects. Clin Pharmacol Ther 29: 425–433. Pickles H, Perucca E, Fish A et al. (1981). Propranolol and sotalol as antagonists of isoproterenol-enhanced physiologic tremor. Clin Pharmacol Ther 30: 303–310. Pohl C, Harbrecht U, Greinacher A et al. (2000). Neurologic complications in immune-mediated heparin-induced thrombocytopenia. Neurology 54: 1240–1245. Preobrazhenskiı˘ DV, Sidorenko BA, Kiktev VG et al. (2005). Stroke and other thromboembolic complications of atrial fibrillation. Part VII. Prevention of cardioversion related thromboembolism. Kardiologiia 45: 78–82. Prystowsky EN (1997). Management of atrial fibrillation. Simplicity surrounded by controversy. Ann Intern Med 126: 244–246. Przybylski A, Sterli nski M, Lewandowski M et al. (2002). Risk of thromboembolic complications in patients with permanent atrial fibrillation undergoing cardioverter-defibrillator implantation. Kardiol Pol 57: 306–312. Puccio D, Novo G, Baiamonte V et al. (2009). Atrial fibrillation and mild cognitive impairment: what correlation? Minerva Cardioangiol 57: 143–150. Pullarkat VA, Kalapura T, Pincus M et al. (2000). Intraspinal hemorrhage complicating oral anticoagulant therapy. Arch Intern Med 160: 237–240. Purvin V, Kawasaki A, Borruat FX (2006). Optic neuropathy in patients using amiodarone. Arch Ophthalmol 124: 696–701.

NEUROLOGIC COMPLICATIONS OF ARRHYTHMIA TREATMENT Radford DJ, Julian DG (1974). Sick sinus syndrome: experience of a cardiac pacemaker clinic. Br Med J 3: 504–507. Ramhamadany E, Mackenzie S, Ramsdale DR (1986). Dysarthria and visual hallucinations due to flecainide toxicity. Postgrad Med J 62: 61–62. Ravid S, Podrid PJ, Novrit B (1987). Safety of long-term propafenone therapy for cardiac arrhythmia: experience with 774 patients. J Cardiovasc Electrophysiol 6: 580–590. Reithmann C, Hahnefeld A, Fiek M et al. (2007). Invasive electrophysiology: complications, nightmares and their management. Herzschrittmacherther Elektrophysiol 18: 204–215. Roberts R (2008). Metoprolol prevented myocardial infarction but increased risk of stroke and death after non-cardiac surgery. Evid Based Med 13: 175. Rosenqvist M, Brandt J, Sch€ uller H (1986). Atrial versus ventricular pacing in sinus node disease: a treatment comparison study. Am Heart J 111: 292–297. Rumbak MJ, Chokshi SK, Abel N et al. (1996). Left phrenic nerve paresis complicating catheter radiofrequency ablation for Wolff–Parkinson–White syndrome. Am Heart J 132: 1281–1285. Sacco RL, Adams R, Albers G et al. (2006). Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke – co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 37: 577–617. Saccomanno G, Fraticelli A, Marini M et al. (1999). Permanent ventricular and dual chamber cardiac stimulation: role of pacing mode in relation to chronic atrial fibrillation risk and stroke development. Arch Gerontol Geriatr 29: 61–74. Sacher F, Monahan KH, Thomas SP et al. (2006). Phrenic nerve injury after atrial fibrillation catheter ablation: characterization and outcome in a multicenter study. J Am Coll Cardiol 47: 2498–2503. Saeed M, Rahman A, Afzal A et al. (2006). Role of transesophageal echocardiography guided cardioversion in patients with atrial fibrillation, previous left atrial thrombus and effective anticoagulation. Int J Cardiol 113: 401–405. Sahenk Z, Mendell JR, Rossio JL et al. (1977). Polyradiculoneuropathy accompanying procainamide-induced lupus erythematosus: evidence for drug-induced enhanced sensitization to peripheral nerve myelin. Ann Neurol 1: 378–384. Samniah N, Schlaeffer F (1988). Cerebral infarction associated with oral verapamil overdose. Clin Toxicol 26: 365–369. Sa´nchez-Quintana D, Ho SY, Climent V et al. (2009). Anatomic evaluation of the left phrenic nerve relevant to epicardial and endocardial catheter ablation: implications for phrenic nerve injury. Heart Rhythm 6: 764–768. Satya-Murti S, Heiman T, Martinez LB (1977). Possible propranolol myotonin association. N Engl J Med 297: 223–224. Sauve´ MJ, Doolittle N, Walker JA et al. (1996). Factors associated with cognitive recovery after cardiopulmonary resuscitation. Am J Crit Care 5: 127–139.

149

Sayler DJ, DeJong DJ (1991). Possible procainamide-induced myopathy. DICP 25: 436. Schmitt C, Alt E, Plewan A et al. (1996). Low energy intracardiac cardioversion after failed conventional external cardioversion of atrial fibrillation. J Am Coll Cardiol 28: 994–999. Schneider MC, Caliezi C, Seeberger MD (1997). Antiplatelet therapy or low-dose heparin and neuraxial anesthaesia. Acta Anaesthesiol Scand 41: 219–221. Sgarbossa EB, Pinski SL, Maloney JD et al. (1993). Chronic atrial fibrillation and stroke in paced patients with sick sinus syndrome. Relevance of clinical characteristics and pacing modalities. Circulation 88: 1045–1053. Shah AR, Passalacqua BR (1992). Case report: sustainedrelease verapamil overdose causing stroke: an unusual complication. Am J Med Sci 304: 357–359. Shahian DM, O’Brien SM, Filardo G et al. (2009a). The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1. Coronary artery bypass grafting surgery. Ann Thorac Surg 88: S2–S22. Shahian DM, O’Brien SM, Filardo G et al. (2009b). The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 3. Valve plus coronary artery bypass grafting surgery. Ann Thorac Surg 88: S43–S62. Sherman DG (2007). Stroke prevention in atrial fibrillation: pharmacological rate versus rhythm control. Stroke 38 (2 Suppl): 615–617. Siddoway LA, Roden DM, Woosley RL (1984). Clinical pharmacology of propafenone: pharmacokinetics, metabolism and concentration-response relations. Am J Cardiol 54: 9D–12D. Silver JR, Buxton PH (1974). Spinal stroke. Brain 97: 539–550. Silverman DI, Manning WJ (1998). Role of echocardiography in patients undergoing elective cardioversion of atrial fibrillation. Circulation 98 (Suppl I): 479–486. Singh A, Singh P, Singh P (1976). Oral use of low dosage schedule Isoptin verapamil in cardiac arrhythmias. Indian J Med Sci 30: 7–11. Sosa E, Scanavacca M, d’Avila A et al. (1996). A new technique to perform epicardial mapping in the electrophysiology laboratory. J Cardiovasc Electrophysiol 7: 531–536. Soyka LF (1986). Safety of encainide for the treatment of ventricular arrhythmias. Am J Cardiol 58: 96C–103C. Sperry K, Wohlenberg N, Standefer JC (1987). Fatal intoxication by tocainide. J Forensic Sci 32: 1440–1446. Sproule DM, Kaufmann P, Engelstad K et al. (2007). Wolff– Parkinson–White syndrome in patients with MELAS. Arch Neurol 64: 1625–1627. Sra JS, Maglio C, Dhala A et al. (1996). Feasibility of atrial fibrillation detection and use of a preceding synchronization interval as a criterion for shock delivery in humans with atrial fibrillation. J Am Coll Cardiol 28: 1532–1538. Sternlo JE, Hybbinette CH (1995). Spinal subdural bleeding after attempted epidural and subsequent spinal anaesthesia in a patient on thromboprophylaxis with low molecular weight heparin. Acta Anaesthesiol Scand 39: 557–559.

150

M.C. LEARY ET AL.

Stone JM, Bhakta RD, Lutgen J (1982). Dual chamber sequential pacing management of sinus node dysfunction: advantages over single chamber pacing. Am Heart J 104: 1319–1326. Streib EW (1986). Successful treatment with tocainide of recessive generalized congenital myotonia. Ann Neurol 19: 501–504. Summers WK, Allen RE, Pitts FN Jr (1981). Does physostigmine reverse quinidine delirium? West J Med 135: 411–414. Susens GP (1974). Femoral neuropathy. Arch Intern Med 133: 171. Tanel RE, Walsh EP, Triedman JK et al. (1997). Five-year experience with radiofrequency catheter ablation: implications for management of arrhythmias in pediatric and young adult patients. J Pediatr 131: 878–887. Teichman SL, Ferrick A, Kim SG et al. (1987). Disopyramidepyridostigmine interaction: selective reversal of anticholinergic symptoms with preservation of antiarrhythmic effect. J Am Coll Cardiol 10: 633–641. Tera¨va¨inen H (1984). Beta-blockers in isoproterenolenhanced essential tremor. Acta Neurol Scand 69: 125–127. Tordjman T, Podrid PJ, Raeder E et al. (1986). Safety and efficacy of encainide for malignant ventricular arrhythmias. Am J Cardiol 58: 87C–95C. Tracy CM, Akhtar M, DiMarco JP et al. (2000). American College of Cardiology/American Heart Association clinical competence statement on invasive electrophysiology studies, catheter ablation, and cardioversion: a report of the American College of Cardiology/American Heart Association/American College of Physicians – American Society of Internal Medicine Task Force on Clinical Competence. Circulation 102: 2309–2320. Tuka V, Ricarova B, Janota T et al. (2009). Surprisingly delayed escalation of severe verapamil poisoning. Eur J Emerg Med 16: 100–102. Turkewitz LJ, Sahgal V, Spiro A (1984). Propranolol-induced myotonia. Mt Sinai J Med 51: 207. Ueno S, Hara Y (1992). Lambert–Eaton myasthenic syndrome without anti-calcium channel antibody: adverse effect of calcium antagonist diltiazem. J Neurol Neurosurg Psychiatry 55: 409–410. Vadlamudi L, Wijdicks EFM (2002). Multifocal myoclonus due to verapamil overdose. Neurology 58: 984–985. van der Vleuten PA, van den Brink E, Schoonderwoerd BA et al. (2005). Delirium attributed to the use of metoprolol. Ned Tijdschr Geneeskd 149: 2183–2186. van Sambeek MR, Segeren CM, van Dijk LC et al. (2000). Endovascular repair of an extracranial internal carotid artery aneurysm complicated by heparin-induced thrombo cytopenia and thrombosis. J Endovasc Ther 7: 353–358. Venkayya RV, Poole RM, Pentz WH (1993). Respiratory failure from procainamide-induced myopathy. Ann Intern Med 119: 345–346. Verbrugge LB, van Wezel HB (2007). Pathophysiology of verapamil overdose: new insights in the role of insulin. J Cardiothorac Vasc Anesth 21: 406–409.

Visentin GP, Ford SE, Scott JP et al. (1994). Thrombotic complications from HIT can include cerebral infarction, which often occurs 5–15 days after the start of heparin. J Clin Invest 93: 81–88. Volans AP (1998). The risks of minor head injury in the warfarinised patient. J Accid Emerg Med 15: 159–161. Volpe BT, Soave R (1979). Formal visual hallucinations as digitalis toxicity. Ann Intern Med 91: 868–869. Warkentin TE, Levine MN, Hirsh J et al. (1995). Heparininduced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332: 1330–1335. Wei L, Li XQ, Liu ZH (2007). Myopathy induced by amiodarone treatment: a case report. Zhonghua Xin Xue Guan Bing Za Zhi 35: 93. Weinberg DM, Mancini J (1989). Anticoagulation for cardioversion of atrial fibrillation. Am J Cardiol 63: 745–746. Werner EG, Olanow CW (1989). Parkinsonism and amiodarone therapy. Ann Neurol 25: 630–632. White WB, Johnson MF, Anders RJ et al. (2001). Safety of controlled-onset extended-release veapamil in middleaged and older patients with hypertension and coronary artery disease. Am Heart J 142: 1010–1015. Wijdicks E (2009). Neurologic complications of drug overdose, poisoning, and terrorism. In: E Wijdicks (Ed.), Neurologic Complications of Critical Illness. 3rd edn. Oxford University Press, New York, pp. 316–333. Williams LS, Biller J (1998). Neurologic complications of anticoagulant and antiplatelet drugs. In: J Biller (Ed.), Iatrogenic Neurology. Butterworth-Heinemann, Boston, pp. 379–396. Wolf P (2001). Creativity and chronic disease, Vincent van Gogh (1853–1890). West J Med 175: 348. Wolf PA, Abbot RD, Kannel WB (1987). Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study. Arch Intern Med 147: 1561–1564. Wolman RL, Nussmeier NA, Aggarwal A et al. (1999). Cerebral injury after cardiac surgery: identification of a group at extraordinary risk. Stroke 30: 514–522. Worthington JM, Gattellari M, Leung DY (2010). “Where there’s smoke . . .” Are premature ventricular complexes a new risk factor for stroke? Stroke 41: 572–573. Wozakowska-Kapłon B, Opolski G, Kosior D et al. (2009). Cognitive disorders in elderly patients with permanent atrial fibrillation. Kardiol Pol 67: 487–493. Yapa RS, Green GJ (1990). Embolic stroke following cardioversion of atrial fibrillation to sinus rhythm with oral amiodarone therapy. Postgrad Med J 66: 410. Younge BR (2007). Amiodarone and ischemic optic neuropathy. J Neuroophthalmol 27: 85–86. Zanetti LA (1993). Sotalol: a new class III antiarrhythmic agent. Clin Pharm 12: 883–891. Zapson DS, Riviello JJ Jr, Bagwell S (1995). Supraventricular tachycardia leading to stroke in childhood. J Child Neurol 10: 239–241.