Arrhythmia in Neurologic Disease

Autonomic Nervous System and Neuronal Networks

The key link between neurologic stress and secondary cardiac dysfunction is the autonomic nervous system (ANS). By sending regulatory signals from brain centers to the heart through the sympathetic and/or parasympathetic nervous systems (SNS and PNS, respectively), the ANS drives the cardiac response to neurogenic stress. The appropriate balance between SNS and PNS is fundamental for desired physiologic responses, which are fine-tuned via feedback inhibition pathways. The actual ANS pathways are highly complex and their description goes beyond the scope of this chapter. ^, In brief, a loop including the insular cortex, amygdala, and hypothalamic nuclei regulates the autonomic response. ^, There is evidence for lateralization of the autonomic system with the SNS thought to be regulated in the right insular cortex and the PNS by the left insula. ^, In addition to its role in visceral motor regulation, the insular cortex is integral to the response to emotional stressors, such as fear or anxiety, through dense connections with the limbic/paralimbic system. As such, the insular cortex is key in mounting the cardiac response to physiologic, environmental, and emotional stress, such as fear or anxiety. Clinical evidence of this close relationship between heart and insular cortex is seen in patients suffering from middle cerebral artery strokes involving the insula. These patients display profound autonomic dysregulation, rhythm disturbance, and arrhythmias leading to SCD. The hypothalamus, in turn, plays a role as an integration center of autonomic stimuli and as a regulator of cardiovascular response at the posterolateral and paraventricular nuclei. At the subcortical level, postganglionic fibers exit the spine via upper thoracic roots to the stellate and superior cervical ganglia, ending in the cardiac muscle where the ANS regulates heart rhythm, blood pressure, and the contractility and excitability of the heart. A recent study showed reduced functional connectivity between the various central autonomic nuclei resulting in dysregulation of the limbic system, which could explain the pathologic catecholamine surge in response to stress.

Pathophysiology of Neurogenic Heart Disease

Several theories regarding the pathophysiology of cardiac injury during neurologic stress have been hypothesized. Multivessel coronary spasm and microvascular dysfunction have been proposed as mediators for ST segment elevations and cardiac enzyme level elevations seen in NHD, which mirror ischemic manifestations. In the face of normal coronary arteries and in normal myocardial perfusion seen on contrast echocardiography, however, the “catecholamine toxicity hypothesis” has gained traction in explaining the underlying cardiac damage in NHD. Neurologic, physiologic, and emotional stress are all associated with a systemic elevation in plasma catecholamine levels, which persists beyond the acute insult. The concentration of epinephrine and norepinephrine was positively correlated with serum cardiac enzyme levels, and sympathetic blockade was shown to be cardioprotective in the setting of stress. Nevertheless, mild stress-induced myocardial injury still occurs despite bilateral adrenalectomy, and in models subjected to artificially produced intracranial hypertension, complete denervation of the heart prevented myocardial injury. This suggests that neurogenic myopathy is at least partially incurred by norepinephrine released locally at the sympathetic myocardial nerve terminals rather than by circulating catecholamines. At the cellular level, hypercalcemia is common and may explain the cytotoxicity of catecholamines. Increased binding of norepinephrine causes opening of the calcium channels leading to excessive entry of calcium and release of potassium from the cardiac cell, hence the hyperkalemic pattern seen on ECG (peaked T waves). Actin is continuously bound to myosin under the effect of calcium causing hypercontraction of the sarcomeres. Eventually, this leads to cell death with leakage of the cell content and cardiac enzymes into the blood. In addition, the metabolism of catecholamines produces reactive oxygen species contributing to cell membrane disruption. ^, These changes occur within 2 to 4 μm from the nerve ending, reinforcing the cytolytic role of locally released norepinephrine. Grossly, these changes are predominantly seen in the endocardium neighboring the conduction system. This, in addition to the high level of catecholamines, may explain the propensity for arrhythmia, conduction block, and SCD in these patients.

Pathology

The classic pathologic finding observed in patients with NHD is myofibrillary degeneration, also referred to as coagulative myocytolysis or contraction band necrosis. ^{, , ,} On light microscopy, mononuclear infiltrates are seen. Changes in the cardiac tissue range from increased eosinophilia with preservation of cross bands to complete distortion of the cellular structure with dense eosinophilic transverse bands. Myocardial fibers are in a hypercontracted state. Of note, myocytolysis can be distinguished from ischemic coagulation necrosis by the relaxed fibers, the relative absence of contraction bands, the polymorphonuclear response elicited, and the delayed calcification, all seen in the latter.

Cardiac Manifestations

Stress-induced cardiomyopathy, also known as apical ballooning syndrome or takotsubo cardiomyopathy (TTC), is a well-described syndrome of cardiac dysfunction resulting from severe neurologic stress. ^, It is most common among postmenopausal women over the age of 50 years. ^, Common triggers include acute emotional stress; physical stress; exposure to catecholaminergic agents such as cocaine, dobutamine, and epinephrine; and acute neurologic events, such as subarachnoid hemorrhage, epilepsy, intracerebral hemorrhage, encephalitis/meningitis, head trauma, and acute ischemic stroke. Although a catecholamine “storm” and an exaggerated hyperadrenergic response to stress are clearly involved in this condition, the susceptibility of individual patients remains unexplained. A study in women with a history of TTC showed that these patients, long after their initial episode, still exhibit the characteristic dysautonomia of excessive sympathetic and reduced parasympathetic tone and abnormal vagal modulation of the heart. This dysautonomia potentially predisposes these women for the disease, but more studies are necessary to replicate these findings.

Clinically, the presentation mimics that of an acute coronary syndrome, namely chest pain, dyspnea on exertion, or syncope. ECG abnormalities typical of myocardial ischemia are detected with ST segment elevation seen in virtually all the cases, characteristically in the precordial leads but also in the inferior leads and are usually accompanied by T wave inversion. Bundle branch blocks, prolonged p wave (interatrial block), and prolonged corrected QT (QTc) were also reported and may portend a worse prognosis. ^, Mild to moderate elevations in creatine kinase myocardial bound (CK-MB) and troponin T are seen, albeit at lower levels than in myocardial infarction (MI). ^, On echocardiography, the syndrome is characterized by reversible wall motion abnormalities that extend beyond the distribution of a single coronary artery. In the typical form, the LV apex and midventricular segments show moderate to severe impaired function with apparent hypercontractility of the base. Atypical presentations can present as inverted takotsubo (hypokinesis of the base and/or the midventricle with sparing of the apex), localized takotsubo, or as a biventricular cardiomyopathy. ^{, , ,} No significant coronary artery obstruction or plaque rupture are seen on angiography, and autopsy typically shows mononuclear interstitial infiltrates and contraction band necrosis as described previously.

A large study reported a 26% incidence of arrhythmias in patients with TTC, including supraventricular tachycardia, atrial fibrillation (AF)/flutter (AFL), and ventricular tachycardia/fibrillation (VT/VF). In particular, new-onset atrial arrhythmias arise in patients with more severe presentations and are associated with increased short-term and long-term mortality. Prolonged QTc-segment with or without bradycardia can lead to torsades de pointes (TdP) and is associated with worse clinical outcomes. Other mechanical complications of the disease include acute left heart failure, pulmonary edema, respiratory failure, cardiogenic shock, acute mitral regurgitation, ventricular mural thrombus, ventricular free-wall rupture, arrhythmias, and sudden cardiac death. ^, Sudden cardiac arrest was reported in 2% of patients and in-hospital mortality was increased in patients who developed arrhythmias. The mortality rate is 5% to 6% per patient-year with a survival rate of approximately 95% at 1 year. ^,

Management

The management of the disease itself is primarily supportive and dependent on the occurrence of complications previously mentioned. Given the sympathetic “storm” underlying the pathophysiology of the disease, adrenergic blockers (mostly β-blockers) are the most appropriate first-line medications in the absence of frank cardiogenic shock. Aggressive diuresis, angiotensin inhibitors, and hemodynamic support with an intraaortic balloon pump or ventricular assist device may be required in cases of profound LV dysfunction. Coronary angiography is commonly performed in the acute setting to rule out acute thrombus or plaque rupture along with the administration of aspirin, heparin, and β-blockers. Short-term anticoagulation with vitamin K antagonists should be considered to prevent the development of mural thrombi because of apical akinesis. Close monitoring in a hospital setting is favored to detect fatal arrhythmias and hemodynamic collapse and patients should be monitored with serial echocardiograms until recovery of cardiac function and even afterward because TTC may recur in some cases. Abnormalities on echocardiography are expected to recover spontaneously within days to weeks. The prognosis is favorable with an in-hospital mortality of 1% to 4%. ^, Pacemakers are indicated with advanced conduction disturbances because studies have shown that severe conduction abnormalities persist on follow-up. In contrast, life-threatening ventricular arrhythmias only occur in the acute setting with low long-term recurrence rate, a risk that can likely be managed with a temporary wearable defibrillator until LV function recovers. ^,

Cardiac Manifestations

Cardiac injury in the setting of neurologic insult is common especially after acute stroke, subarachnoid hemorrhage (SAH), and intracranial hemorrhage (ICH). It manifests as repolarization abnormalities, arrhythmias, or sudden death. The typical ECG pattern consists of large inverted “cerebral” T waves (T wave inversion of ≥5mm depth in ≥4 contiguous precordial leads), prolonged QTc interval, and large U waves. In addition, ST-T segment changes in a nonvascular distribution, ectopic ventricular beats, and variable atrioventricular (AV) block can also be seen in the absence of preexisting heart disease. ^, LV hypertrophy (LVH), diagnosed by ECG criteria, has been reported in 14% to 40% of patients after SAH. The prevalence of these abnormalities is variable among observational studies, but a recent systematic review reports higher occurrence of ECG changes in SAH (75%) than ischemic stroke and ICH (30%–50%). The incidence of ECG changes in patients with SAH has been shown to correlate with the amount of intracranial blood. ECG changes indicate a worse outcome after cerebrovascular disease, especially when the insular cortex is involved, pointing to the previously discussed role of ANS dysregulation in NHD. Cardiac enzymes are often elevated and portend worse long-term outcomes. Echocardiography may show global ventricular hypokinesis or regional wall motion abnormalities.

Arrhythmias are well known to occur in the setting of acute cerebrovascular disease with a reported incidence of 20% to 40% in the setting of ischemic stroke or ICH and reaching 100% in some series of patients with SAH, the most common of which are sinus bradycardia and tachycardia, complete heart block, AFL, AF, supraventricular tachycardia, VT (including TdP), and VF. AF, with a reported incidence of 14%, is the most common arrhythmia secondary to stroke. It is certainly possible, however, that some AF diagnoses after stroke actually represent a new diagnosis of an asymptomatic but preexisting arrhythmia that actually led to the stroke. Life-threatening ventricular arrhythmias occur in 5% after SAH, whereas sudden death has been reported in 12% of patients with SAH.

Management

Arrhythmias in these patients are to be managed according to the appropriate clinical guidelines. Neurogenic ECG changes do not warrant any primary intervention. Nevertheless, appropriate investigations should be made to detect and correct any coexistent conditions with similar ECG manifestations such as hereditary long QT syndromes, electrolyte disturbances (particularly hypokalemia and hypomagnesemia), medication side effects, and acute MI. β-blockers may have a cardioprotective role in the setting of neurogenic cardiac injury given the role of the SNS in the disease and have demonstrated mortality benefit. As for the prognosis of the NHD, ECG changes and arrhythmias are associated with a poor outcome after cerebrovascular events. ^,

Cardiac Manifestations

Traumatic brain injury (TBI), in the absence of obvious cerebral bleed on imaging, can lead to neurogenic cardiac injury secondary to ANS impairment. The most commonly reported ECG abnormality is transient ST segment elevation or depression reflecting myocardial injury in the absence of coronary abnormalities or preexisting structural heart disease. ^, These changes were seen even in the pediatric population, excluding ischemic coronary disease as a possible etiology. Other electrical abnormalities reported in TBI are peaked P and T waves, short PR interval, prolonged QTc interval, sinus tachycardia, ventricular premature beats, and VT/VF. These changes are often accompanied by transient, mild to moderate elevation of cardiac enzymes such as CK-MB and troponin T. Global or local impairment of ventricular function can be seen on echocardiography. TBI can also cause TTC in its typical or atypical forms. On autopsy, contraction band necrosis has been reported and confirms the neurogenic etiology of cardiac injury. In most cases, cardiac changes are reversible within 2 to 7 days of intensive care and close monitoring.

Another manifestation of dysautonomia in TBI occurs in up to 15% of patients who develop sudden onset of severe and paroxysmal episodes of sympathetic hyperactivity. Symptoms are typical of catecholamine excess and consist of paroxysms of increased blood pressure, respiratory rate, and heart rate. Hyperthermia, decreased level of consciousness, diaphoresis, and sympathetic overreactivity to normally nonpainful stimuli are also seen. These clinical features persist for at least 2 weeks and have been reported to last up to a year after TBI. Pathophysiology is based on ANS dysfunction with an imbalance between SNS and PNS. Although associated with poor outcomes, this condition is treatable with opioids, gabapentin, benzodiazepines, centrally acting α-agonists, and β-antagonists.

Cardiac Manifestations

The prevalence of migraine is estimated at 30 million individuals in the United States alone. Most of the common symptoms experienced during a migraine episode are related to dysfunction of the ANS. Hence, a wide array of electrophysiologic abnormalities are reported during migraine episodes, including sinus bradycardia, AV blocks, bundle branch blocks, S-T and T wave changes, AF, premature ventricular beats, and VTs. In addition, P wave and QTc interval dispersion, which are predictors of AF and ventricular arrhythmia, respectively, tend to increase during migraine episodes compared with pain-free periods. In a case of sudden death after migraine, autopsy showed contraction band necrosis, the hallmark of neurogenic cardiac injury from excessive SNS activation. Migraines can also lead to TTC. Furthermore, some medications commonly prescribed for the treatment of migraine (such as triptans and ergotamine) have been reported to cause serious arrhythmias, including VT and VF, but epidemiologic data do not support a definite risk.

Cardiac Manifestations

Arrhythmias in the setting of meningitis/encephalitis are rare, but cases are reported. ECG changes that have been described include sinus bradycardia, advanced AV block (including complete heart block), monomorphic or polymorphic VTs (including TdP), QTc segment prolongation, ST segment changes, and sick sinus syndrome. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune encephalitis with particularly high burden of temporary but severe dysrhythmias, such as bradycardia and sinus arrest. These are usually temporary and resolve with treatment of the underlying disease with antibiotics or immunotherapy.

Cardiac Manifestations

Central sleep apnea (SA), mediated by respiratory control dysregulation, may be caused by a variety of diseases including Rett syndrome, Prader-Willi syndrome, myotonic dystrophy, Arnold-Chiari malformation, heart failure, or ischemic stroke. Arrhythmias are common cardiovascular complications of SA. Potential mediators are thought to include repetitive hypoxemia, hypercapnia, and changes in intrathoracic pressure leading to increases in sympathetic activation and circulating catecholamines, potentiation of the sensitivity of peripheral chemoreceptors, spikes of blood pressure creating mechanical stress on the heart and vessels, inflammation, oxidative stress, and atrial remodeling. The most commonly reported arrhythmia is AF, but nonsustained VT, AV block, bradyarrhythmias, and asystole have also been described. ^, It has been reported that more than 60% of patients with a high burden of AF have sleep-disordered breathing, and patients with SA were less likely to respond to antiarrhythmic medication. The risk for nocturnal SCD is higher in patients with SA compared with the general population.

Management

Continuous positive airway pressure (CPAP) can reduce the burden of pauses and bradycardia and significantly reduce AF recurrence after cardioversion or catheter ablation. In patients with severe heart failure, treatment of coexisting SA with CPAP improves cardiac function and reduces the frequency of ventricular premature beats during sleep, potentially reducing the incidence of fatal ventricular arrhythmias. ^, In patients with congenital SA syndromes, like Prader-Willi, oxygen therapy has been efficacious. In contrast, in patients with Cheyne-Stokes respiration in heart failure, adaptive seroventilation failed to show definite benefit in survival and remains a controversial treatment. ^,

Cardiac Manifestations

Epilepsy is the most common serious neurologic disease. Patients with epilepsy have a 24-fold increase in the risk for sudden death compared with the general population. Sudden unexplained/unexpected death in patients with epilepsy (SUDEP) has been reported during or shortly after seizures. The incidence of SUDEP is reported to be between 0.1 to 9.3 per 1000 patient-years depending on the population studied. Although potential mechanisms of SUDEP are numerous, the occurrence of arrhythmia in the setting of epilepsy is commonly reported to increase mortality and morbidity.

ECG abnormalities are found both during and after seizure episodes and are more common in patients with generalized tonic-clonic seizures than in patients with complex partial seizures. ECG and biochemical markers of cardiac injury can be detected in the peri-ictal period, including QTc prolongation, ST changes, T wave inversion, and elevated troponin levels, and are significant predictors of sudden death. Seizure duration was greater in patients with electrical cardiac abnormalities than in those without, likely reflecting increased myocardial damage because of prolonged autonomic stress. ^, In SUDEP, reported histopathologic changes on autopsy are interstitial fibrosis, cardiomyocyte atrophy, myofibrillar degeneration, leukocytic infiltration, and edema of the conduction system tissue. ^, This picture converges with the aforementioned neurogenic myocardial injury mediated by the ANS. Studies have demonstrated dysfunction of the ANS in epileptic patients, particularly in those with a higher burden of seizures and a longer duration of the disease. Generalized seizures are indeed the second most common neurologic etiology of TTC with a reported incidence of 1 in 1000 epilepsy-related hospitalizations. ^,

Sinus tachycardia is universally present during seizures. Peri-ictal asystole, bradycardia, AV block, AF, AFL, and VF have all been reported. Ictal asystole, bradycardia, and AV block are self-limited and do not correlate with SUDEP. Such events occur predominantly during focal dyscognitive seizures (formerly known as complex partial seizures ) involving the temporal or frontal lobes. In contrast, postictal asystole, AF, and VT/VF are more common after convulsive seizures and are associated with SUDEP. Epilepsy is associated with a threefold increase in the risk for SCD, but the exact mechanism remains elusive. ^, Early repolarization is more common in patients with epilepsy compared with matched controls, but its relationship with SUDEP needs further investigation. Activation of carotid chemoreceptors because of hypercapnia and hypoxia may lead to vagal stimulation, bradycardia, and asystole. Studies have shown increased odds of arrhythmias with prolonged oxygen desaturation episodes. The link between the ANS and the cardiac conduction system could potentially explain the disturbance in rhythm observed in epilepsy. Other suggested mechanisms for arrhythmogenesis in seizures include myocardial ischemia, electrolyte derangements, conduction system abnormalities, arrhythmogenic antiepileptic drugs like carbamazepine or lacosamide, and underlying structural heart disease. ^,

Management

Because most peri-ictal arrhythmias are reversible, the first-line management of these patients is close observation, optimization of antiepileptic regimen, epilepsy surgery, and discontinuation of proarrhythmic and conduction-slowing drugs. In rare cases when asystole or conduction block does not remit, pacing is indicated as per guidelines on bradyarrhythmia management and was shown to reduce morbidity and falls.

Cardiac-induced syncope and seizures can be clinically indistinguishable. Cerebral hypoxia induced by VF or asystole may trigger tonic-clonic jerking movements mimicking convulsive seizures. Hence long-QT syndrome, arrhythmogenic right ventricular (RV) dysplasia, AV nodal reentry tachycardia, bradycardia, and sinus node disease can be misdiagnosed as epilepsy. This underscores the importance of a comprehensive personal and family history, 12-lead ECGs or continuous rhythm monitoring, and evaluation of prior ECGs when available.

Pathophysiology and Clinical Presentation

Guillain-Barré syndrome (GBS), also known as acute inflammatory demyelinating polyneuropathy, has an estimated incidence of 1 to 2 per 100,000 individuals per year. It is an autoimmune disorder where an aberrant immune response develops against the motor, sensory, or autonomic peripheral nerves because of antigen cross-reactivity, leading to demyelination. It is often preceded by a respiratory or gastrointestinal (GI) infection that triggers the immune response. The most common organism observed in GBS is Campylobacter jejuni, but viral infections with cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human immunodeficiency virus (HIV) have all been reported. It presents with symmetrical progressive ascending weakness accompanied by loss of reflexes, variable sensory loss, and paresthesias. The presentation can be acute or subacute and respiratory failure can occur despite treatment.