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Neurologic conditions affecting the cardiovascular system
Albert C. Cuetter, M.D., received his medical degree in 1963 from the University of Cartagena, Colombia, and took his residency training in neurology and a fellowship in electrodiagnosis from 1965 to 2969 at Northwestern University Medical School, Chicago. He has been engaged in the full-time practice of neurology in teaching hospitals of the United States Army for the past 20 years. He is a Professor of Neurology at Texas Tech School of Medicine, El Paso, Texas.
William Pearl, M.D., received his medical degree from the State University of New York at Brooklyn in 1970. He took his residency training in pediatrics at New York HospitalCornell Medical Center, and a fellowship in pediatric cardiology at the Albert Einstein College of Medicine, both in New York City. He has been enagaged in the full-time practice of pediatric cardiology in teaching hospitals of the United States Army for the past 15 years. He is a fellow of both the American Academy of Pediatrics and the American College of Cardiology, and is a Clinical Associate Professor of Pediatrics at TeFas Tech University School of Medicine.
Victor J. Ferrans, M.D., Ph.D., graduated from the Tulane University School of Medicine in 1960, and received a Ph.D. in anatomy from the Tulane University Graduate School in 1963. After completing training in internal medicine and cardiology at Tulane, he joined the Pathology Branch of the National Heart, Lung, and Blood Institute at the National Institutes of Health, where he is Chief of the Ultrastructure Section. His research interests are centered on the pathology of cardiovascular, pulmonary, and meta-
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NEUROLOGIC CONDITIONS THE CARDIOVASCULAR
AFFECTING SYSTEM
We present a survey of neurologic conditions affecting the cardiovascular system. One of the motivations to carry out a comprehensive review of this subject is the difficulty encountered by students and residents trying to find this information in conventional textbooks. Apart from interesting clinical features, the cardiovascular manifestations and complications of neurologic conditions are important because they dramatically alter the prognosis of the basic neurologic problem. Therefore, recognition and prompt treatment of a cardiovascular manifestation or complication of a neurologic disease are indispensable steps toward attaining better results in the management of a neurologic illness. We classify neurologic conditions affecting the cardiovascular system as: autonomic nervous system dysfunctions; myopathies; metabolic disorders; malformations of the central nervous system; hereditary and degenerative diseases; paroxysmal conditions (seizures, sleep apnea); miscellaneous vascular conditions; and neurologic medications prone to produce cardiovascular complications.
AUTONOMIC
NERVOUS
SYSTEM DYSFUNCTION
The autonomic nervous system is a mediator in the genesis of a number of cardiovascular abnormalities encountered during the course of neurologic diseases. A paradigm of this mediation is the Cushing phenomenon, which shows that an increase in intracranial pressure is followed by an increase in systemic blood pressure, presumably as a protective response to ensure cerebral perfusi0n.l
CARDZAC
CHANGES
IN ACUTE
INTZSACRANL4L
Central nervous system (CNS) lesions produce tonomic activity with consequent hemodynamic
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DISEASE
disturbances in auchanges, and clini-
479
TABLE 1. Cardiovascular Abnormalities Subarachnoid Hemorrhage
in
Electrocardiographic changes: large upright T waves Long QT interval Q waves and ST depression Rhythm disturbances Supraventricular tachycardia Atrial flutter-fibrillation Sinus bradycardia Arrest, nodal rhythms AV block or dissociation Premature ventricular contractions Ventricular flutter-fibrillation4
cal, electrocardiographic, and pathologic evidence of myocardial damage .’ Subarachnoid hemorrhage produces significant effects on cardiac function as a result of autonomic nervous system involvement (Table 1). Electrocardiographic and pathologic changes in the heart occur more frequently in subarachnoid hemorrhage than in any other intracranial catastrophe.3 Serious ventricular ectopy, myocardial necrosis, and subendocardial hemorrhages4 occur in a significant number of patients with acute cerebrovascular accidents of any type when compared with a control group of patients.4-7 This does not seem to reflect the presence of preexisting heart disease, The electrocardiographic changes associated with subarachnoid hemorrhage include atrial and ventricular arrhythmias and changes suggestive of myocardial ischemia.4 The latter include alterations in QRS configuration, QT interval prolongation, T wave abnormalities, and ST segment elevation. The mechanism of the electrocardiographic changes in subarachnoid hemorrhage has not been explained satisfactorily. Vagal stimulation, hypothalamic stimulation, and stimulation or destruction of the sympathetic nerves can produce electrocardiographic and myocardial damage in experimental animals .4 b D. MCCALL: As the authors point out, electrocardiographic abnormalities are common in the setting of subarachnoid hemorrhage and other cerebrovascular accidents. In experimental animals, similar changes can be produced by stimulation or ablation of one of the stellate ganglia, with a resultant imbalance of sympathetic stimulation to the anterior and posterior myocardial wall. The authors rightly emphasize the role of the autonomic nervous system in the genesis of these electrocardiographic findings and cardiac arrhythmias associated with intracerebral hemorrhage. This is further emphasized by the observation that, in patients with intracranial lesions, the most common ECG abnormalities (T-wave 480
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inversion and QT prolongation) can be corrected by the infusion no1 to produce uniform sympathetic stimulation of the ventricular
of isoproteeemyocardium.
Transmurally scattered foci of damaged myocardial fibers were seen in 62% of patients with intracranial lesions compared with 26% of control patients.’ Focal myocardial damage requires at least 6 hours to develop after the onset of an acute neurologic event and is not observed after the second week. This damage is associated with intracranial lesions which produce a rapid increase in intracranial pressure
and
is usually
absent
in patients
with
slowly
enlarging
or
small cerebral lesions.’ Postulated mechanisms of cardiac damage in patients with acute cerebral lesions include an increase in the level of plasma catecholamines secondary to a rapid increase in intracranial pressure8 and ischemic irritation of the hypothalamus.3 Whatever the mechanism, there is clinical evidence that a sudden increase in the intracranial pressure gives rise to diencephalic compression which in turn produces: (a) massive vagal discharges leading to sinus bradycardia, sinus arrest, sinus arrhythmias, and atrioventricular block; and (b) massive sympathetic discharges which may lead to supraventricular tachycardia, bigeminal rhythm, and ventricular tachycardia.3, ’ It has been suggested that the cerebral cortex of the orbital surface of the frontal lobe, which contains the cortical representation of the vagus nerve, is stimulated either by the blood in the subarachnoid space or by the local effects of a nearby aneurysm. Focal transient ischemic attacks of the brain caused by carotid atherosclerosis are reflections of either cerebral or cardiovascular disease. Patients with recurrent transient ischemic attacks of the brain seem to be at great risk of suffering a myocardial infarct.l’ The s-year cumulative rate of myocardial infarction or sudden death in these patients is 2l%, a rate only slightly less than that of fatal or nonfatal cerebral infarction (22.7% 1.ll Furthermore, cardiovascular disease is the leading cause of death in long-term survivors of stroke. A person who recovers from a stroke has a greater risk of suffering a heart attack than a second stroke.” A lesion anywhere in the CNS can produce an acute elevation of arterial blood pressure? Hypertension is especially common following compression, ischemia, or distortion of the medulla oblongata (Fig 1),13 and with hypothalamic lesions.’ Such abnormalities are thought to produce an imbalance in the neural control system that normally regulates blood pressure, with subsequent cardiovascular of the changes and hypertension,13’ I4 but there is no explanation mechanism involved. Neurogenic pulmonary edema occurs in association with CNS disease without underlying cardiopulmonary pathologic problems.” Neurogenic pulmonary edema may complicate intracerebral and Cm-r Probl
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FIG 1. Schematic drawing of neurovascular compression simulator in baboons. Neurogenic hypertension is induced by experimental pulsatile compression of the ventrolateral aspect of the medulla oblongata. (From Jannetta PM, Segal R, Wolfson SK Jr: Ann Surg 1985; 202:253-261. Used by permission.)
subarachnoid hemorrhage in patients in whom no pie-existing left ventricular dysfunction can be identified.16 Nearly 52% of patients who die of acute traumatic or spontaneous intracerebral hemorrhage have pulmonary edema, compared to 29% of patients who die from other causes. In neurogenic pulmonary edema, there are alterations in the pulmonary microvascular pressure and pulmonary capillary permeability resulting from the influence of neurogenic mechanisms.17 But the factors involved in the activation of these neurogenic mechanisms are controversial and poorly understood. In experimental animals, pulmonary edema can be produced by discrete bilateral lesions in the preoptic hypothalamic region. Nevertheless, histologic studies in patients in whom pulmonary edema occurred during the course of a subarachnoid hemorrhage have failed to demonstrate consistent hypothalamic lesions. Furthermore, ante-
482
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rior hypothalamic lesions (foci of necrosis, perivascular microhemorrhages), which are found in 60% of patients with ruptured intracranial aneurysms, do not correlate with the presence of pulmonary edema. Neurogenic pulmonary edema also has been described with lesions of the medulla oblongata.15 Catecholamine secretion is markedly elevated in patients with subarachnoid or intracranial hemorrhage. This indicates, intense sympathetic nervous system activity.2”8 The increase of sympathetic activity gives rise to vasoconstriction, central pooling of blood, left ventricular failure, and pulmonary edema.“# 2o In turn, the resulting sustained refractory hypertension may give rise not only to rebleeding, but also to congestive heart failure and pulmonary edema. Exactly what triggers the excessive catecholamine secretion after intracranial hemorrhage is not known. But studies of paroxysmal hypertension and increased catecholamine levels in patients with intracranial lesions suggest that the increased catecholamines and the consequent stimulation of the sympathoadrenal pathways are a result of excitation of the vasomotor centers in the posterior hypothalamus and medulla oblongata.21’ 23 b S. H. RAHIMTOOLX It is important to remember that pulmonary edema occurs in association with diseases of the central nenrous system in the absence of cardiopulmonary disease. The incidence of neurogenic pulmonary edema in patients who die of acute traumatic or spontaneous intracerebral hemorrhage is very high. TRANSIENT CARDZOVASCUZAR INJECTIONS OF HYPERTONIC SUBARACHNOID SPACE
CHANGES SOLUTIONS
DURING THERAPEUTIC IN THE
The injections of hypertonic solution into the subarachnoid space (lumbar, cisternall are used for the relief of intractable pain. There are transient cardiovascular changes in about 10% of patients receiving these injections.= Lumbar intrathecal injections presumably lead to sympathetic stimulation, increase the heart rate, and may induce ventricular ectopic beats. A direct osmotic effect on intradural sympathetic nerve fibers is suggested to explain these electrocardiographic changes. Cisternal injections are thought to produce a direct vagal stimulation at the level of the brain stem. Cisternal injections have been shown to produce slowing of the heart rate, junctional rhythm, and atrial or ventricular ectopic beats, or both (Table 21. Transient hypotension is noted in less than z%.~~ There are no dangerous cardiac arrhythmias, and the electrocardiographic changes, which occur within 5 minutes of the injection, return to normal in all patients within 30 minutes of the injection. Curr
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TRANSIENT CARDIOVAsCULAR PERClJ7%VEOUS TRZGEMINAL
CHANGES DURING RHIZOTOMY
Percutaneous retrogasserian radiofrequency electrocoagulation rhizotomy and glycerol rhizolysis are often performed for the management of trigeminal neuralgia. Depending on the procedure, either an electrocoagulation needle or a spinal needle is inserted through the foramen ovale into the retrogasserian cistern of Meckel’s cavity, using intravenous methohexital for light general anesthesia. The procedure is then performed with the patient under sedation and local anesthesia. Standard cardiopulmonary monitoring is used continuously. Stimulation of the trigeminal ganglion during percutaneous retrogasserian radiofrequency rhizotomy can trigger a transient increase in mean arterial blood pressurez5 and premature ventricular ectopic beats during the period of elevated blood pressure (see Table 2). A case of bradycardia and asystole, and another case of coronary artery spasm with myocardial infarction during percutaneous retrogasserian glycerol rhizolysis have been reported.“’ ” However, other studies of 60, 100, and 681 patients who underwent percutaneous retrogasserian trigeminal procedures did not report any cardiac complications.28’ ”
TABLE TRANSIENT DURING
2. CARDIOVASCUlAR CHANGES THERAPEUTIC INJECTIONS OF
HYPERTONIC SOLUTIONS IN THE SIJBARACHNOID SPACE’t Lumbar injections: Sympathetic stimulation? Increased heart rate Ventricular ectopy Cisternal injections: Vagal Slowing of heart rate Junctional Hypotension
Transient pressure
stimulation?
rhythm
increase (29% 1
in mean
arterial
blood
*Data t?om Lucas JT, Ducker TB, Pemx PL Jr: Adverse reactions to intrathecal saline injection for control of pain. J h’eurosurg 1975; 42557-561; and tSweet WII, Poletti CE, Roberts JT: Dangerous rises in blood pressure upon heating of trigeminal motlets; increased bleeding times in patients with trigemioal neuralgia. Neurosurgery 1985; 17: 643-844.
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Age and preexisting cardiac disease are undoubtedly factors in the risk of cardiac complications during these procedures. It should also be pointed out that most of these patients with trigeminal neuralgia had been taking carbamazepine, which prolongs atrioventricular conduction. All patients who present for percutaneous trigeminal rhizotomy or rhizolysis should undergo preoperative electrocardiography, and the electrocardiogram should be monitored continuously during the procedure. Premeditation with atropine should be considered.26 b S. H. ~HIMTOOLA: An indication for routine preoperative percutaneous trigeminal rhizotomy or rhizolysis. Ideally, also be monitored during the procedure.
CARDIOVASCULAR
CHANGES
DURING
electrocardiogram is these patients should
CAROTID
ENDARTERECTOMY
Fluctuations in blood pressure occur in about 47% of patients during or after carotid endarterectomy and are believed to reflect an alteration in the baroreceptors in the neck. A sustained increase in blood pressure was observed in 29% of 90 unilateral procedures and in 38% of 104 bilateral operations.30 Carotid sinus stimulation during carotid endarterectomy decreases blood pressure and carotid sinus denervation increases it. These changes undoubtedly contribute to the occurrence of perioperative complications. Transient hypotension occurs in about one fourth of carotid endarterectomies with the lowest blood pressure occurring about 5 hours after surgery. This hypotension is relatively benign and can be prevented by careful manipulation of tissues during the dissection of the carotid vessels. Infiltration of the carotid bulb with 1% lidocaine prior to surgery is effective in preventing postoperative hypotension. Vasopressor therapy can be complicated by myocardial infarction.31 About 19% of patients undergoing carotid endarterectomy have hypertension in the early postoperative period with the maximum blood pressure occurring about 2.3 hours postoperatively.32 Preoperative hypertension is the single most important determinant of postoperative hypertension in patients undergoing carotid artery surgery.“’ Sustained postoperative hypertension increases the risk of intracerebral hemorrhage. A postoperative neurologic deficit occurs in 10% of patients with postoperative hypertension.3z The most important principles of treatment are the preoperative control of hypertension, and the appropriate modification of anesthesia procedures. In most patients, the elevation in blood pressure following endarterectomy is self-limited, and preoperative readings are reached
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within 4 hours3’ Sustained hypertension may be treated with fastacting antihypertensive medications. The use of potent antihypertensive drugs such as nitroprusside should be avoided if possible because they may increase the risk of myocardial or cerebral ischemia.30 Striking electrocardiographic changes simulating subendocardial infarction have been observed after bilateral carotid endarterectomy in patients without clinical evidence of myocardial infarction.33 These electrocardiographic changes occur within 48 hours of surgery and disappear within 3 months. Likewise, myocardiaf infarction occurs within 72 hours of carotid endarterectomy in 0.5% of patients without preexisting heart disease, and in 4.9% of patients with preexisting heart disease.34 Animal experiments suggest that electrocardiographic changes and myocardial damage result from carotid sinus denervation and alterations in cardiac sympathetic activity.35 Vasopressor drugs, which are used to increase perfusion pressure at the time of carotid clamping during endarterectomy, seem to be well tolerated by patients without preexisting heart disease (the incidence of myocardial infarction in these patients is 0.5% regardless whether vasopressors are used or not).34 But in patients with preexisting heart disease (angina, congestive heart failure, previous myocardial infarction, arrhythmias), the use of vasopressor drugs during carotid endarterectomy is associated with an increased incidence of myocardial infarction (8.1% in those receiving vasopressors vs. 2.9% in those not receiving vasopressors).34 Because of the risk of myocardial damage associated with the use of vasopressors, many surgeons prefer other methods to increase cerebral perfusion during carotid surgery. b S. H. RAHIMTOOLA:Blood pressure monitoring during and after carotid endarterectomies appears to be very impomt. Transient hypotension is common; the lowest blood pressure occurs about 5 hours after surgery. Hypertension is also common, the maximum blood pressure elevation occurs about 2 to 2% hours after the procedure. CARDlOV’CULAR
ChYANGES AFTER MINOR HEAD INJURIES
Recurrent cardiac arrhythmias are known to occur following minor head injuries. A trivial head injury without the occurrence of unconsciousness may be followed within minutes by either asystole requiring prompt cardiorespiratory resuscitation, or by an abnormal cardiac rhythm such as ventricular fibrillation or severe junctional bradycardia.3” These observations stress the fact that reactive syncope secondary to a minor head injury may be due to a severe cardiac arrhythmia resulting from excessive autonomic disturbance . 486
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b S. H. RAHIMTOOLA: It is important to recognize may be followed shortly by serious arrhythmia ment and even cardiopulmonary resuscitation.
vxtwwT ANGINA HEADACHES
(PRINZMETAL
that even trivial head injuries that requires immediate treat-
ANGINA) AND MlGk41~i-3
There are individuals who may or may not have obstructive coronary atherosclerosis, all of whom suffer a variant form of angina called Prinzmetal angina pectoris. This angina is thought to be associated with focal spasm of the coronary arteries, often is not associated with exercise or stress, may occur at rest or even during sleep,37 and may be a result of altered adrenergic activity. There are several similarities and dissimilarities between variant angina and migraine headaches. For example, in both conditions, arterial vasospasms play a major role, and there is abnormal platelet function. Also, there is a high prevalence of migraine in patients with variant angina (26% of patients, compared with 10% in a control group of healthy subjects).38 There are dissimilarities in the response to pharmacologic agents in patients with these two conditions. For example, migraine attacks can be prevented with propranolol, aborted with ergotamine, and induced by nitroglycerine. Conversely, propranolol often is not beneficial in variant angina, but ergotamine can cause anginal attacks, and nitroglycerin is therapeutic in angina.3s It is interesting that calcium antagonist drugs are the therapy of choice in the treatment of variant angina, and that these same drugs are being used with increasing frequency in the prophylactic treatment of migraine. Many aspects of the cerebral oligemia and the painful phase of migraine, as well as the vasospasm of variant angina remain unexplained.
HEMODMVAMK HYPOTENSION DYSFUNCTION
DISTURBANCES AND ORTHOSTATlC DUE TO AUTONOMIC NERVOUS SYSTEM
Autonomic nervous system dysfunction often is associated with orthostatic hypotension. When the cause of the autonomic nervous system dysfunction is not known the orthostatic hypotension is called primary; when the cause is known it is called secondary (Table 3). Primary orthostatic hypotension can occur either alone or with concomitant diffuse neurologic involvement. Shy-Drager syndrome (progressive autonomic failure) is an example of primary orthostatic hypotension with diffuse neurologic involvement. There is convincCurr
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487
TABLE
3.
Hemodynamic Autonomic
Disturbances Nervous Svstem
Pmduced Dvsfunction
by
Primary Ckthostatic Hypotension In prugressive autonomic failure (Shy-Drager syndrome), familial dysautonomia, and dysautonomia associated with mitral valve prolapse Secondary Orthostatic Hypotension Secondary to diseases that produced autonomic neumpathy (diabetes, amyloidosis, porphyria, Guillain-Barr4 syndrome, alcoholism) Secondary to transection of spinal cord, syringomyelia, and tabes dorsalis
ing evidence that primary ence of diffuse neurologic Shy-Drager syndrome.
Shy-Draper
orthostatic hypotension impairment represents
without the presan early stage of
Syndrome
In the Shy-Drager syndrome,40 there is degeneration of central motor tracts korticobulbar, corticospinal, extrapyramidal), cell loss in the nuclei of the brain stem and cerebellum, and degeneration of preganglionic sympathetic neurons and intermediolateral column cells of the spinal cord.41 Clinically, there is a severe autonomic neuropathy (orthostatic hypotension, lightheadedness, syncope, impotence, bladder disturbances) and extrapyramidal abnormalities. The cardiovascular system is no longer able to activate its compensatory mechanisms in response to changes in body position.42 This results in a major disturbance in the control of blood pressure, even in the supine position. The extrapyramidal syndrome resembles Parkinson’s disease. There is also evidence of long tract and cerebellar signs. Other symptoms and signs reported include iris atrophy, Homer’s syndrome, abnormal pupillary responses, nystagmus, and sleep apnea.43 There is no specific treatment, but symptomatic treatments (elastic stockings, tludrocortisone acetate, dihydroergotamine) produce some relief of the orthostatic hypotension in some patients.
Familial Dysautonomia
(Riley-Day Syndrome)
This is another primary disease of the autonomic nervous system. It is an autosomal recessive disease that affects predominantly children of Ashkenazi (Eastern European) Jewish ancestry. The features of familial dysautonomia have been summarized by Riley et al.44: absence of overflow tears, impairment of the regulatory mechanism of blood pressure control, postural hypotension, erratic temperature 4.9s
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control, excessive perspiration over the head, difficulty swallowing, episodic vomiting, absence of fungiform papillae on the tongue, impaired sensations of pain and taste, corneal anesthesia, hypomflexia, poor coordination, developmental delay, decreased esophageal motility, and an abnormal histamine skin test. Although familial dysautonomia is a distinct clinical entity, its biochemical basis has not been elucidated. Recent studies have implicated a lack of nerve growth factor during embryogenesis that may account for the marked reduction of neurons in sensory and autonomic ganglia.45 The sural nerve shows a loss of unmyelinated and small myelinated fibers.43 The diagnosis must be made on clinical grounds, and symptoms can usually be traced back to infancy.
Dysautonomia
and Mitral
Valve Prolapse
A subset of patients with mitral valve prolapse have faulty autonomic regulation of cardiac and vascular fLmctions.46’ 47 This autonomic dysfunction can slow neural circulatory controls necessary for rapid adaptive changes and anticipatory adjustments, with consequent symptoms of both chronic adrenergic hyperactivity and exaggerated parasympathetic response.4”‘47 Adrenergic activation in mitral valve prolapse may give rise to inappropriate tachycardia, arrhythmias, and increased catecholamine levels. The latter can cause a volume contracted state, increased venous and arterial constriction, increased peripheral vascular resistance, and increased orthostatic intolerance.4”848 The increased vascular tone in both the arterial and venous systems may further decrease total blood volume.46 Most patients respond to reassurance, dietary salt loading, an exercise fitness program, or low doses of clonidine.4” Individuals with an exaggerated parasympathetic response may experience syncope or near syncope without demonstrable cardiac dysrhythmias.47 Weisman et a1.4s reported orthostatic hypotension in 17% of patients with mitral valve prolapse, and Santos et ak5’ reported hypotension, lightheadedness, and syncope in 12% of their patients. Phenobarbital suppresses the exaggerated parasympathetic response .47 Possible explanations for the episodic nature of the symptoms, the etiopathogenesis of the autonomic dysregulation, and the similarities of these autonomic dysfunctions with the somatic expressions of anxiety are extensively reviewed by Gaffney and Blomqvist4” and Coghlan.47
Secondary
Orthostatic
Secondary orthostatic that produce peripheral orthostatic hypotension Cur-r Probl
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Hypotension hypotension is associated with diseases and autonomic neuropathy. For example, occurs in diabetes, amyloidosis,51 chronic 1990
489
alcoholism,52 acute porphyria,42 and Guillain-Barr% syndrome. The orthostatic hypotension in these diseases is probably due to an impairment of vasomotor innervation of blood vessels with the consequent loss of activating reflexes necessary to maintain the blood pressure upon standing. The autonomic neuropathy in porphyria can explain certain features of the acute attack such as abdominal pain, constipation, tachycardia, and blood pressure changes.53’ 54 But the latter may occur in the absence of autonomic neuropathy suggesting other causes.55 Autonomic neurons seem to be more susceptible to the biochemical changes of porphyria than somatic neurons.53 In addition to orthostatic hypotension, patients with severe diabetic autonomic neuropathy seem to have defective vagal and sympathetic control of the heart. This lack of control is manifested by a poor cardiac rate response to autonomic blockade and by a diminished beat-to-beat variation on deep breathing.5” These abnormalities, which are attributed to cardiac denervation, are predisposing factors for the development of serious cardiac arrhythmias and sudden death. Destruction of the central sympathetic connections in the spinal cord by a myelopathic process induces orthostatic blood pressure abnormalities.57 These abnormalities are due to the inability to activate sympathetic vasoconstrictor reflexes during a change of position from recumbent to upright. Acute transection of the cervical spinal cord produces orthostatic hypotension as a result of disruption of pathways between the brain and the spinal cord. Likewise, head-up tilting in chronic paraplegic and tetraplegic patients is accompanied by a fall in systolic and diastolic blood pressures and an increase in heart rate. Return to the horizontal position is usually followed by a return of blood pressure to previous levels within a minute. Postural hypotension is more pronounced in patients with high cervical lesions and may be a serious limiting factor in the rehabilitation of these patients. Tetraplegic patients also have paroxysmal hypertension during defecation and micturition or after the application of painful or cold stimuli below the level of the lesion. This hypertension is thought to result from exaggerated reflex sympathetic activity in the isolated spinal cord.“’ Tracheal suctioning may cause vagal hyperactivity, resulting in bradycardia and cardiac arreSt.43 Tetraplegic patients devoid of autonomic cardiac control have a decrease in cardiac mass which limits the work capacity of the heart .59 In these patients, there is a decrease in the workload of the heart with subsequent cardiac atrophy.60 The left ventricular cavity is reduced in size, the shortening fraction may be normal, the stroke volume, cardiac output, and mean blood pressure are decreased, and the systemic vascular resistance is usually in the high normal 490
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range. In recent years, endurance training for cardiopulmonary reconditioning has become an important part of rehabilitation programs for tetraplegics and quadriplegics to improve the quality of living. Ordinary daily activities do not seem to be adequate to maintain cardiovascular fitness in such patients.5g Endurance training guidelines for the general population appear to be appropriate for the population with spinal cord injury; these guidelines can be followed during participation in wheelchair pushing, arm crank ergometry, aerobic swimming, ambulation training, canoeing, and wheelchair basketbal15’ Dicarlo”’ recommends an arm pedaling cycle ergometer for endurance training. Orthostatic hypotension is rare in syringomyelia. Aminoff and Wilcox”’ described a patient with syringomyelia in whom symptoms of autonomic dysfunction included orthostatic hypotension and inability to sweat. These autonomic symptoms were attributed to interruption of descending sympathetic fibers in the spinal cord by the syrinx. Tabes dorsalis interferes with atferent autonomic fibers in the dorsal root ganglia and dorsal roots. In addition, infarction and cavitation of the spinal cord (seen in other syphilitic, nontabetic spinal syndromes) also interfere with the function of preganglionic sympathetic neurons in the intermediolateral column cell. Orthostatic hypotension may be present not only in tabes dorsalis, but also in other syphilitic nontabetic spinal syndromes. Orthostatic hypotension is an accompanying sign in patients with volume depletion associated with shock syndrome, excessive vomiting, prolonged water restriction, acidosis, excessively high external temperatures (with loss of large amount of water through skin and lungs), and adrenal cortical insufficiency. The clinical investigation of disorders of the autonomic nervous system is summarized by McLeod et al.43 Some of the tests include: (a) blood pressure and heart rate response after change of posture, after isometric exercises, or during inspiration and expiration; (b) tests of sweating; (c) plasma noradrenaline and other biochemical tests; (d) tests of peripheral vasomotor control; and [e) tests of pupillary innervation. Symptomatic treatment of orthostatic hypotension is initially carried out with fludrocortisone and tight-fitting elastic garments. Other medications recommended are ephedrine, indomethacin, and dihydroergotamine.42’ 63
Guillain-Barr6
Syndrome
About 10% of patients with Guillain-Barr6 syndrome have a much more severe illness and a poorer prognosis than those patients with typical Guillain-Barr6 syndrome. In this variant of the disease, there is a rapidly devastating illness in which the patients become quadriplegic necessitating ventilator-y assistance in 2 to 5 days from the onCurr
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491
set of the illness.“4 Death due to cardiovascular collapse may occur in as many as 14% of these patients, and autopsies show marked axonal degeneration in nerve roots and distal nerves.65, 66 Cardiovascular changes in Guillain-Ban+ syndrome, which are attributed to anoxia and autonomic nervous system dysfunction,“7 include hypertension (particularly diastolic), episodes of flushing, diaphoresis, hypotension, cardiac arrhythmias, and electrocardiographic changes (Table 4). The most common cardiac arrhythmias in patients with GuillainBarr6 syndrome are sinoatrial arrest, atrioventricular block, and supraventricular and ventricular tachyarrhythmias.68 Resting heart rates are significantly higher in patients with Guillain-B& syndrome than in control subjects, sometimes exceeding 100 beats per minute.6g In healthy people, there is a beat-to-beat (R-R) variation of the heart rate that can be used as a measure of normal autonomic function. Persson and Solders” demonstrated that this R-R variation is diminished in Guillain-Barn5 syndrome. The R-R interval can be easily monitored during the critical period of the illness, can be used to select patients at risk, and may aid in deciding which patients are in need of intensive care. The reduction of the R-R variation in GuillainBar& syndrome follows the progression of the clinical course. Accordingly, reduction of the R-R interval variation is observed a few days after the onset of symptoms, and the variation returns to normal with clinical improvement. There is no correlation between the diminished R-R variation and motor conduction velocity or cerebrospinal fluid proteins in Guillain-Barr6 syndrome. Patients with Guillain-Barr6 syndrome should be observed carefully for signs of autonomic dysfunction. During the critical period of the illness, continuous electrocardiographic and arterial pressure TABLE 4. Cardiovascular Guillain-Barr&
Changes Syndrome*
in Severe
Type
of
Cardiovascular collapse in 3% to 14% Diastolic hypertension Hypotension Cardiac arrhythmias Sinus arrest Atrioventricular block Supraventricular and ventricular arrhythmias Resting heart rate higher than 100 beats per minute No beat-to-beat variation *Data
492
from
mferences
66, 68, and
70
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monitoring are helpful in detecting early signs of impending cardiovascular collapse.“6 It is important to stress that medical complications occurring during the course of the Guillain-Barr6 syndrome, such as pulmonary embolism, pneumonia, pneumothorax, electrolyte imbalance, and focal myocarditis, also can induce cardiac arrhythmias.“8 Therefore, these medical complications should be suspected in patients with Guillain-Barn? syndrome who develop cardiac arrhythmias.
Stress and Disturbance
of Cardiac Rhythm
Psychological stimulation frequently changes the rate and the rhythm of the heart. There is a significant association between overwhelming emotional stimulation and sudden death. Although largely anecdotal, evidence suggests that psychological stress can evoke neural impulses from higher centers. These neural impulses, acting on the myocardium, either alter the electrokinesis of cardiac muscle, or destabilize an underlying occlusive atherosclerotic process in the coronary arteries, giving rise to disturbances of heart rhythm, and less frequently, to cardiac necrosis. This belief is compatible with the fact that experimental stimulation of the hypothalamus, the amygdala, or the midbrain reticular formation evokes arrhythmias . Lown71 demonstrated that stress markedly reduces the threshold for ventricular fibrillation. For this demonstration, he occluded the anterior ‘descending coronary artery in dogs. Once the infarcts were considered to be old, the dogs were placed in a sling where they received a single electric shock on three successive days. Though no further shocks were administered, each time the dogs were placed in the sling, the ventricular fibrillation threshold was markedly reduced. Arrhythmias occurred without having to resort to electrical stimulation of the myocardium. These results were different from those obtained in a tranquil cage environment, where electrical stimulation of the myocardium was necessary to induce ventricular fibrillation in the same animals. Therefore, psychological stress appears to be an important factor in the initiation of ventricular fibrillation in the ischemic heart. In this respect, Skinner and Reed72 demonstrated that blockade of the frontocortical-brain stem pathways (cryogenic blockade of the forebrain, posterior hypothalamus, or fields of Fore11 prevents the lethal consequences of myocardial ischemia in stressed animals.” G. A. BELLER: Acute psychological stress or a sudden “adrenergic trigger” such as a sharp telephone ring that awakens someone from sleep can trigger acute ventricular tachycardia (usually polymorphic) and even fibrillation in patients with hereditary prolonged QT syndrome. Such patients may merely present as having seizures. Often there is a family history of premature death or similar “seizures” in siblings. Ambulatory ECG monitoring during these episodes usu-
b
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ally shows speeding of the sinus rate and appearance of ventricular ectopic beats falling on the T wave with prolongation of the Q-T interval. Beta blockers are the class of drugs that are most effective in preventing these arrhythmias. MYOPATHIES
In most respects, the myocardium seems to share with skeletal muscle a vulnerability to both hereditary and acquired diseases. The cardiac abnormalities of many hereditary skeletal myopathies contribute to the morbidity and mortality of those myopathies. In certain patients, cardiac involvement may manifest before the generalized myopathy.7” MYOTONIC
DYSTROPHY
Myotonic dystrophy is a hereditary myopathy with features of a systemic disease. As in other myopathies, affected patients have muscular weakness, but there is a peculiar atrophy of the temporalis muscles. These patients also have myotonia, which is an inability to relax muscles after contraction. Myotonia can be easily elicited in these patients by tapping the thenar eminence. There are other characteristic findings such as baldness, cataracts, testicular atrophy, gastrointestinal smooth muscle abnormalities, alveolar hypoventilation, and cardiac abnormalities. In most cases, myopathic features are apparent long before any evidence of heart disease. But in some patients, the cardiac abnormalities are the predominant features.74 In other patients, there is no detectable myocardial ailment despite advanced skeletal muscular involvement.75 About 90% of patients with myotonic dystrophy have abnormalities on an electrocardiogram, ambulatory Holter monitoring, or an echocardiogram or radionuclide ventriculogram. (Table 5). Electrocardiographic abnormalities are found in about 70% of cases. Conduction disturbances, which are the most common abnormalities in myotonic dystrophy, are manifest by first degree atrioventricular block (33% 1 (Fig 2),75 and intraventricular conduction defects (20% 1 (Fig 3).75876 Evidence of disease in the entire conduction system has been obtained with intracardiac electrocardiography.77 Pathologically, there may be replacement of the myocardium and conducting system by fatty and fibrous tissue.75 These patients are prone to Stokes-Adams attacks, asystole, and ventricular fibrillation. Other cardiac abnormalities encountered in myotonic dystrophy are generalized cardiac enlargement and left ventricular dysfunction (70%).75 The association of mitral valve prolapse with myotonic dystrophy is sufficiently strong (37%) that it should be sought in all patients with myotonic dystrophy.75’ 78, 7g Since the presence of mitral 494
Curr
Probl
Cardiol,
September 1990
TABLE
5.
Cardiovascular
Abnormalities
in Muscular
Dystrophies*
Myotonic Dystrophy Replacement of myocardium and conducting system by fatty and fibmus tissue Conduction disturbances (Stokes-Adams attacks, AV block) Ventricular fibrillation Generalized cardiac enlargement Left ventricular dysfunction (70%) Mitral valve prolapse (37% I Duchenne Type Muscular Dystrophy Dilatation of left ventricle and mitral annulus Dysfunction of chordae tendineae and papillary muscles Replacement of muscle with connective tissue Myocardial infarctions Congestive heart failure Prolapse of mitral valve (50%) Electrocardiographic changes (90% of cases) Sinus tachycardia, atrial flutter Paroxysmal ventricular tachycardia Abnormally tall R waves in the lateral chest leads Deep, narrow waves in the lateral chest leads Inverted T waves over leads V5 and V6 Right axis deviation Shortened PR interval Bundle branch blocks QRS pmlongation Limb-Girole Muscular Dystrophy Disturbance in rhythm or conduction (Wolf-Parkinson-White syndrome, QRS prolongation, first degree heart block, intraventricular conduction defect, atrial flutter) Paroxysmal ventricular tachycardia Cardiomyopathy and congestive heart failure Electrocardiographic changes Minor T wave alterations Tall R waves in lead Vl, deep Q waves or a QS pattern on lead I, II, III, aVP, and V6 *Data fmm
references
75, 84, 90, 91
valve prolapse in patients with myotonic dystrophy represents a potential source of neurologic problems (particularly cerebral embolism), symptomatic supportive treatment of these patients should include periodic cardiac evaluations, and prophylaxis against infectious endocarditis at the time of oral surgery. The use of antiplatelet agents should be considered in patients over 40 years of age. Subclinical cardiac involvement in myotonic dystrophy may be responsible for sudden death in 4% of patients. Moorman recom-
Curr
frobl
Car&id,
September
1999
495
aVR
aVL
aVF
FIG 2. Full standard electrocardiogram ing first degree atrioventricular
LEAD”1
/ ; ;
from block.
a 41 -year-old
woman
with myotonic
dystrophy
show-
: I
LEAD II
BUNDLE OF HIS
CORONARV SINUS
---
FIG 3. Intracardiac prolonged
496
electrophysiologic HV interval (100
msec).
recording from patient with (Courtesy of Jerry Miller,
myotonic M.D.)
Cur-r Probl
Cardiol,
dystrophy
September
showing
1990
mends: (a) investigation of coronary artery disease in patients with myotonic dystrophy who have significant risk factors; lb) detailed evaluation of syncopal episodes in these patients; and (cl pacemaker and/or antiarrhythmic drug therapy if indicated. The symptomatic relief of myotonia is sometimes achieved with procainamide or phenytoin. If a drug should be used in the symptomatic treatment of myotonia, phenytoin, which shortens the P-R interval, is preferred over procainamide, which lengthens the P-R intenal.77 In addition, procainamide may induce a lupus-like syndrome with adverse effects on the heart.”
NONMYOTONZC
MUSCULAR
DYSTROPHY
The spectrum of heart disease in nonmyotonic muscular dystrophy has been studied extensively (see Table 5). Heart disease is not only frequent, but it is easy to detect in the classic sex-linked recessive type of Duchenne. It is rare in facioscapular humeral dystrophy. Cardiac involvement in Becker’s muscular dystrophy and limb-girdle muscular dystrophy is of intermediate prevalence. In Becker’s muscular dystrophy, the incidence of cardiac involvement increases progressively after adolescence, but it is seldom severe before the third decade, at which time the incidence of cardiac involvement is 80% .‘O In this myopathy, which is less severe than the Duchenne type, there may be severe myocardial involvements1 Mitral valve prolapse has also been reported.” Duchenne muscular dystrophy is the most severe of all muscular dystrophies. It is also known as pseudohypertrophic muscular dystrophy because of the enlargement of the calf and other muscles from the deposition of fat (see Fig 31. Although patients with Duchenne muscular dystrophy generally succumb to inanition and infection before the age of 20 years, the concomitant presence of cardiomyopathy (which is aggravated by the weakness of the respiratory muscles) is also an important cause of death. The heart disease of Duchenne muscular dystrophy is progressive and directly pmportional to the severity of skeletal muscle dysfunction.83 There is dilatation of the left ventricle and mitral annulus, dysfunction of chordae tendineae and papillary muscles, and replacement of myocardial fibers with connective tissue. Cardiac degenerative changes are more severe in the postembasal region of the left ventricular free wall. It has been suggested that this selective distribution accounts for the characteristic electrocardiographic changes. It is interesting that the myocardial fibrosis usually involves the subepicardial areas (Fig 4), in contrast to the subendocardial fibrosis that occurs in most other types of cardiac disease. The large extramural coronary arteries are normal, although the small intramural coronary arteries Cum
Probl
Cardiol,
September
1990
497
FIG 4. Histologic Duchene
section showing type of muscular
severe dystrophy,
subepicardial x40.
fibrosis
in left ventricle
of patient
with
show luminal narrowing due to fibromuscular intimal proliferation; these changes may be pronounced in the arteries to the sinoatrial and atrioventricular nodes. Clinical myocardial infarctions have been reported in young patients with Duchenne muscular dystrophy.84 Congestive heart failure and many cardiac arrhythmias have been observed in Duchenne muscular dystrophy. Electrocardiographic abnormalities, which are found in about 90% of cases, do not correlate with the degree of systemic skeletal disability.85 Electrocardiographic changes include sinus tachycardia, atrial flutter, paroxysmal ventricular tachycardia, abnormally tall R waves in lead Vl, shallow S waves in leads Vl and VZ, deep narrow Q waves in the lateral chest leads, inverted T waves in leads V5 and V6, right axis deviation, shortened P-R interval, and bundle branch blocks (Fig 5). These electrocardiographic changes are rarely seen in carriers of Duchenne muscular dystrophy. But in carriers, the sum of the R and S waves in leads Vl and VZ is significantly greater than that in women who are not carriers.85 Mitral valve prolapse can be identified in nearly 50% of patients with Duchenne muscular dystrophy and in about 30% of carrierss2 Duchenne muscular dystrophy presents risk during general anesthesia. Cardiac arrest following inhalation induction86-88 and the occurrence of malignant hyperthermiaSs have been reported. Cardiac involvement in limb-girdle muscular dystrophy is manifest by disturbances in rhythm and conduction (Wolff-ParkinsonWhite syndrome, QRS prolongation, first degree heart block, intra49s
Curr
Probl
Cardiol,
September
19x)
5
v3
v2
aVR
aVL
aVF
%
v5
'6
FIG 5. Full standard electrocardiogram phy. Note high voltages and
deep
from an 8-year-old narrow Q waves
boy with Duchene muscular dystroin the inferior and lateral leads.
ventricular conduction defects, atrial flutter, paroxysmal ventricular tachycardia), minor T-wave alterations, cardiomyopathy, and congestive heart faib.ue7” go,” Other electrocardiographic changes include tall R waves in lead Vl, and deep Q waves or a QS pattern in leads I, II, III, aVF, and V6.‘l Cardiac abnormalities in facioscapular humeral muscular dystrophy may not be clinically evident, but subclinical cardiac dysfunction can be detected in some patients. Permanent paralysis of the atria may occur.76 CONGENITAL
h4YOPATHIES
These myopathies are present at birth and are either nonprogressive or slowly progressive. In severe cases of congenital myopathies there is significant weakness at birth leading to death in infancy, childhood, or adolescence. But most patients with mild forms of these diseases remain almost asymptomatic in early childhood.s2 Curr
Probl
Cat-did,
September
1990
499
These myopathies seem to affect specific muscular structures, without the destructive changes of other myopathies. They derive their names from some of their pathologic changes. Symptoms include skeletal weakness, hypotonia, and external ophthalmoparesis. Congenital myopathies may give rise to myocardial abnormalities as a reflection of a diffuse muscular dysfunction (Table 6). Obstructive hypertrophic cardiomyopathy with cardiomegaly has been reported in patients with mitochondrial myopathies. In these patients, histologic examination showed abnormal mitochondrial aggregates TABLE 6. Cardiovascular Myopathies
Abnormalities
in Other
Congenital Myopathies Mitochondrial Obstructive cardiomyopathy Cardiomegaly Nemaline Bicuspid aortic valve Aortic regurgitation Left ventricular hypertrophy Diaphragmatic paralysis Centmnuclear Cardiac fibrosis with dilation and compensatory focal hypertmphy Progressive External Ophthalmoplegia-plus (Kearns-Sayre syndrome, Refsum’s syndrome, progressive external ophthalmoplegia, abetalipopmteinemia) Atrioventricular and intraventricular block ST changes Heart enlargement Carnitine Deficiency Extensive deposits of lipids in cardiac muscle cells Endocardial fibmelastosis Cardiomyopathy Congestive heart failure Polymyositis Myocarditis 30% Diffuse interstitial infiltrate similar to that in the skeletal muscle Congestive heart failure 45% Atrial arrhythmias Ventricular arrhythmias Atrioventricular and intraventricular conductive defects ST changes *Data
from references
92-lOO, llO-113,
X20-123.
Curr
Probl
Cardiol,
September
1990
in the skeletal muscless3’ s4 and hearts5 Likewise, bicuspid aortic valve, aortic regurgitation, left ventricular hypertrophy, dilated cardiomyopathy, and biventricular failure have been reported in nemaline myopathy?” s6 In a patient with nemaline myopathy and left ventricular hypertrophy who died of congestive heart failure, necropsy demonstrated a patent ductus arteriosus, mild infundibular pulmonic stenosis, anomalous papillary muscles, and myocardial scarrings There are a few reports of adult-onset nemaline myopathy presenting with diaphragmatic paralysis. This is important to clinicians since these patients present with pulmonary symptoms rather than muscular weakness.s7 Centronuclear (myotubular) myopathy may be either sporadic, or have a sex-linked, autosomal recessive, or autosomal dominant mode of inheritance.s8 Central nuclei are present in fetal muscle through the first 15 weeks of gestation, suggesting that centronuclear myopathy may represent an arrest of muscle development.” Although most patients do not have an associated cardiomyopathy, cardiac fibrosis with dilation and compensatory focal hypertrophy does OCCU~.~~’loo Patients with cardiomyopathy have variable electrocardiograms. Deep S waves in the lateral leads and abnormal axes are frequent (Fig 6). PROGKL?SSlVE EXTERNAL OPHTHALMOPLEGlA-PLUS The simultaneous occurrence of neuromuscular and cardiac disease is also found in a group of diseases which are lumped together under the name of ophthalmoplegia-plus (see Table 6).‘01 These syndromes are numerous, and the ones most commonly recognized are: Kearns-Sayre syndrome, Refsum’s syndrome, progressive external ophthalmoplegia, and abetalipoproteinemia. A common feature in these syndromes is involvement of the extraocular muscles. The presence of a wide variety of other clinical abnormalities differentiates one syndrome from another, but the classification of these syndromes remains uncertain. The resemblance that these syndromes share and the lack of distinct etiopathogenesis justify grouping them under the term ophthalmoplegia-plus. Kearns-Sayre Syndrome Kearns-Sayre syndrome features external ophthalmoplegia retinitis pigmentosa and varying degrees of atrioventricular heart block.“’ Additional clinical abnormalities include subnormal mentation, hearing loss, impaired growth, proximal weakness of the extremities, cerebellar abnormalities, and increased protein in the cerebrospinal fluid. Biopsy specimens of skeletal muscle show ultrastructural mitochondrial abnormalities.‘03 “Ragged-red fibers” are recognized Cut-r ~robl
Car-did,
September
1990
501
Vl
aVL
aVF
v4
VI5
‘6
l/2 STANDARD
-.I
V3
V2 I
FIG 6. Electrocardiogram
from
a 21.year-old
woman
with centronuclear
myopathv.
with modified Gomori trichrome stain. These findings, which are not specific for Kearns-Sayre syndrome, are also seen in congenital myopathies, in other neuromuscular conditions, and even in normal muscle1”3; but they are useful in the diagnosis of Kearns-Sayre syndrome. This disease is sometimes classified with the mitochodrial “encephalomyopathies.“104 Genetic factors seem to play a role in the pathogenesis of this syndrome.lO” Some patients with Kearns-Sayre syndrome have hypertrophic cardiomyopathy. Many patients present without cardiac symptoms, while others suffer from palpitations and life-threatening AdamsStokes attacks, which may necessitate the implantation of an artificial cardiac pacemaker. Evidence is accumulating to show that Kearns-Sayre syndrome is a metabolic disease caused by defective mitochondrial function.lo6 502
Curr
Probl
Cardiol,
September
1990
Refsum’s Syndrome Refsum’s syndrome is the result of inability to metabolize phytanic acid and is associated with intraventricular and atrioventricular conductive defects, ST changes, and various arrhythmias. Other features of the disease include retinitis pigmentosa, ocular myopathy, peripheral neuropathy, ataxia, and changes in the skin and bones. Progressive E,xternal Ophthalmoplegia This is manifest by progressive weakness of the external ocular muscles and ptosis. When the pharyngeal muscles are also involved, the syndrome is called oculopharyngeal dystrophy. The most common electrocardiographic abnormalities are atrioventricular conduction defects. Abetalipoproteinemia (Acanthocytosis; Bassen-Kornzweig Syndrome) This disease is an inherited error of lipoprotein metabolism manifest by gastrointestinal symptoms (resembling celiac disease), retinitis pigmentosa, external ophthalmoplegia, oropharyngeal weakness, ataxia (due to progressive degeneration of posterior column and cerebellum), distal weakness (due to peripheral neuropathy),107’ lo8 abnormally low absorption of lipids from the intestinal tract, a near absence of P-lipoprotein in the serum, and spiny red blood cells.10g The heart may be enlarged, and mural thrombosis and serious arrhythmias occur.11o* “I Cardiac failure is a common cause of death, and interstitial myocardial fibrosis occurs.111 CARNZTZNE DEFICIENCY SYNDROME Carnitine deficiency is considered to be a disorder of fat metabolism in which both skeletal muscle myopathy and cardiomyopathy may occur. The disease becomes clinically manifest during the first four decades of life. Traditionally, two syndromes are recognized. In the systemic form, the deficiency of carnitine is generalized due to defective hepatic biosynthesis, and carnitine levels are decreased in plasma, liver, skeletal muscle, and myocardium.‘123 ‘13 Because carnitine is necessary for the transport of long-chain fatty acids into the inner mitochondrial compartment where they undergo P-oxidation and become a major source of energy, deficiency of carnitine may result in impairment of lipid oxidation. This leads to the excessive use of carbohydrates as a source of energy.‘14 Thus, these patients can experience episodes of liver dysfunction and acidosis. In the muscular form of carnitine deficiency, the mechanism of active transport of carnitine into skeletal and cardiac muscle is beCwr
Probl
Cardiol,
September
1990
503
lieved to be defective. Carnitine levels are normal in plasma but decreased in muscle.1*5’ ‘Iti Carroll et al.lZ7 reported a patient who demonstrated features of both systemic and muscular carnitine deficiency, suggesting that the current classification of carnitine deficiencies may need revision. The systemic (generalized) form of carnitine deficiency is characterized clinically by a premyopathic phase in which patients have recurrent, spontaneous episodes of nausea, vomiting, acidosis, and stupor. This presentation is followed by progressive muscular weakness, muscular atrophy, and hepatic insufficiency. The muscular form of carnitine deficiency is manifested mainly by progressive muscular weakness and atrophy.‘13 Systemic carnitine deficiency can be primary, when there is no evidence of another systemic illness that might deplete tissue carnitine stores, or secondary, when the carnitine deficiency is a result of a recognized condition such as glutaric aciduria type II, methylmalonic aciduria, abnormalities of folate metabolism, or cytochrome-c oxidase deficiency.‘18 The histologic and ultrastructural appearance of skeletal muscle is similar in both forms, with lipid storage (in the form of numerous droplets free in the sarcoplasm) in type I fiber and atrophy in type II fibers. Lipid deposits also have been found in the cytoplasm of pericytes, fibroblasts, and venules. Crystalline inclusions and other nonspecific abnormalities have been found in skeletal muscle mitochondria.l*’ Lipid deposits also occur in the kidneys and liver in the systemic form.112, ‘I3 The lipid deposits in skeletal muscle consist mainly of triglycerides with smaller amounts of diglycerides and free fatty acids.l13 Clinical evidence of cardiac involvement is found in some patients with each of the two forms of carnitine deficiency (Table 6).l*’ Waber et a1.l” studied a boy with a family history of cardiomyopathy who presented at 3% years with congestive heart failure, skeletal muscle weakness, lipid myopathy on a skeletal muscle biopsy specimen, and reduced muscle and plasma carnitine levels. In this patient, therapy with L-carnitine (174 mgkgday) improved cardiac function and muscle strength.l” Likewise, Tripp et al.lzl studied a family of four girls and one boy in whom cardiomyopathy developed in four of five, three of whom died suddenly. Autopsy in these children showed endocardial fibroelastosis. The surviving child and autopsy results of her brother showed a severe decrease in plasma and tissue carnitine levels. Treatment of the affected child with oral L-carnitine (3 g per day) markedly improved myocardial function and reduced the heart size.lzl In other pathologic reports, at least two patients had extensive lipid deposits in cardiac myocytes.112’113 In another patient the cardiac myocytes were vacuolated and the myofibrils were widely sep604
Curr
probl
Cardiol,
September
1990
arated by aggregates of mitochondria (a nonspecific finding), but lipid deposits were not found.l18 Oral carnitine supplementation may be followed by improvement in some patients, but not in others, perhaps depending on the condition of the tissue carnitine receptor.*l’ POLYhJYOSITZS Polymyositis
inflammatory myopathy clinically weakness, characteristic electromyographic abnormalities, elevated serum enzyme levels, and abnormal muscle histologic findings. In some cases, polymyositis may occur in conjunction with other collagen diseases. In other cases, it may be associated with a malignancy. A muscle biopsy specimen shows degeneration and regeneration of skeletal muscle with a predominantly mononuclear inflammatory infi1trate.l” Symptomatic cardiac involvement in polymyositis is rare, but clinicopathologic studies have shown that cardiac involvement may be far more common than previously recognized (see Table 61. Denbow et al.‘“” found myocarditis (30% 1, congestive heart failure (45% 1, and electrocardiographic abnormalities (72%) in a clinicopathologic study of 20 autopsies. The myocarditis was characterized by a diffuse interstitial and perivascular mononuclear cell infiltrate, similar to the inflammatory changes seen in the affected skeletal muscle. There was also muscle fiber degeneration, regeneration, and fibrosis.12”. 123
manifested
is an acquired
by proximal
muscular
The presence of fibrosis in the conduction system of the heart may explain the conductive abnormalities observed in polymyositis. There may be encroachment on the lumina of small vessels by medial smooth muscle hyperplasia with little or no intimal pmliferation. Electrocardiographic changes most commonly seen in polymyositis are atrial and ventricular arrhythmias, intraventricular and atrioventricular conduction defects,lz4 and ST changes characteristic of myocardial ischemia.lz5 Corticostemids are beneficial in most cases of polymyositis. A permanent pacemaker may be necessary in patients with heart block. b G. A. BELLER: Polymyositis involving the myocardium can present with findings similar to those encountered in acute myocardial infarction. However, one sees enormous elevations in serum creatine kinase levels which are sustained, rather than exhibiting the usual rise-and-fall characteristic 6f an acute coronary artery occlusion. CK levels can exceed 4,000 IU with minimal percent MB. b D. MCCALL: The association between skeletal muscle myopathies and myopathies of cardiac muscle remains of great clinical and research interest. While the association may have a readily explicable basis in certain types, e.g., those asso-
Curr
Pmbl
Cardiol,
September
1990
SOS
ciated with carnitine deficiency and abetalipoproteinemia, such is not the case in the more common hereditary myopathies. No common, genetically determined, perturbation of muscle biochemistry or physiology has as yet been defined. The relationship is so strong, however, that the clinician should always be mindful of the possibility of an underlying skeletal myopathy when confronted with the young patient with otherwise unexplained heart failure. This is especially true since, not infrequently, the cardiac manifestations may demand clinical scrutiny prior to there being overt skeletal muscle involvement. b S. H. RAHIMTOOW: system involvement. cluding malignant
Patients with myositis may have myocardial and conduction As a result, they may develop various cardiac problems arrhythmias that require treatment.
METABOLIC DISORDERS THAT INVOLVE AND THE CENTRAL NERVOUS SYSTEM
BOTH
in-
THE HEART
Inborn errors of metabolism with a wide range of neurologic and cardiovascular abnormalities are discussed as follows. Likewise, neurologic syndromes associated with alcohol and thiamine deficiency are also included here. GLYCOGEN STORAGE DISEASES The glycogen storage diseases are autosomal recessive abnormalities characterized by the accumulation of glycogen as a result of deficiencies of different enzymes of glycogen metabolism. Only those affecting the heart are mentioned (Table 7). 7@e II Glycogenosis (Acid Maltase Dejkiency) The name Pompe’s disease is used for the infantile form of type II glycogenosis. This is a generalized disease in which there is increased storage of glycogen in the CNS, skeletal muscle, and myocardium (Fig 7) as a result of a deficiency of acid maltase. The infantile form presents several weeks to several months after birth with generalized weakness, marked hypotonia, respiratory difficulties, and cardiomegaly. The latter helps in the separation of Pompe’s disease from other causes of infantile muscular weakness such as WerdnigHoffmann disease, congenital myopathies, and myasthenia gravis. In some patients, severe myocardial thickening is associated with small ventricular cavities and obstruction to ventricular outflow.1ZG8 lz7 Electrocardiographic changes include high voltage QRS complexes in all leads, a shortened P-R interval, and cardiac arrhythmias.127*128 Death occurs by the age of 12 months from either respiratory or cardiac failure. The severe infiltrative cardiomyopathy and respiratory muscle weakness pose a special problem in the anesthetic management of these patients.lz8, lzy 506
Curr
J+obl
Cardiol,
September
1990
TABLE 7. Cardiovascular Abnormalities Storage Disease*
in Glycogen
Glycogenosis Type II (acid maltase deficiency) Infantile form (Pompe’s disease) Myocardial thickening, small cardiac cavities, obliteration of ventricular flow, cardiomegaly, cardiac failure Electrocardiographic changes: tall QRS complexes in all leads, short P-R interval, cardiac arrhythmias Late infantile form and adult form Cardiac involvement is minimal Electrocardiographic changes have been‘reported Glycogenosis Type III (Cori’s disease) Cardiomegaly Thickening of ventricular myocardium Nonspecific electrocardiographic abnormalities Glycogenosis Type IV Cardiomegaly Congestive heart failure Glycogenosis Type V (McArdle’s disease) Electrocardiographic changes lsinus arrhythmia, prolongation of the P-R interval, intraventricular conduction defects, and T wave changes) ‘Data fmmreferences
126-128,130,132,133.
Patients with late infantile acid maltase deficiency have progressive weakness simulating muscular dystrophy, but symptomatic cardiac involvement is minimal. However, electrocardiographic changes are common in this type and in the adult form. For example, Francesconi and Auff13’ reported a X)-year-old woman with the adult form of Pompe’s disease who had ventricular complexes shaped like those of Wolff-Parkinson-White syndrome, often in combination with second-degree atrioventricular block. 7&e XII Glycogenosis (Debrancher Deficiency [Cori’s Disease]) This is milder form of glycogen storage disease that results from debrancher enzyme deficiency. Glycogen of abnormal structure accumulates in the liver, muscle, and heart, resulting in hepatomegaly, myopathy, and cardiomegaly. Clinically, growth retardation, seizures, hypoglycemic episodes, and muscular weakness with wasting electrocardiographic abnormaliare seen.131 There are nonspecific ties, but clinical cardiac difficulties are usually not striking, although Cut-r Probl
Cardiol,
September
1990
so7
FIG 7. Vacuolated appearance of muscle Pompe’s disease. (Hematoxylin-eosin
cells in histologic [HE], x300.)
section
of heart
from
a child
with
there is sometimes massive cardiomegaly.*32 Olson et a1.13” reported a 25year-old woman with glycogenosis type III who had marked thickening of the ventricular myocardium on echocardiography with normal systolic function and no outflow tract obstruction. 7&e N Glycogenosis (Brancher Dejkiency) This is a rare form of glycogen storage disease due to deficiency of the brancher enzyme. Neurologic manifestations include failure to thrive and hypotonia. There is also progressive cirrhosis of the liver. Death occurs before the age of 4 years. Clinical manifestations of heart disease are uncommon, but cardiac enlargement may be seen.lz6 Servidei et a1.134 reported a child with congestive heart failure in whom an endomyocardial biopsy specimen showed hypertrophy of muscle fibers, marked fibrosis, and abundant cytoplasmic deposits that were periodic acid-Schiff positive and diastase resistant. There were similar inclusions in the muscle, skin, and liver. Figure 8 shows basophilic deposits of abnormal glycogen filling central portions of the cytoplasm of myocytes in an endocardial biopsy specimen from a 4-year-old child with type IV glycogenosis. In this patient, cardiomyopathy was the predominant clinical feature of branching enzyme deficiency. There is a report of a clinicopathological syndrome with morphologic, histochemical, and ultrastructural findings similar to those of glycogenosis type IV but without enzymatic concordance.‘35
Curt- Probl
Cardiol,
September
1990
7jpe V Glycogenosis (McArdle’s Disease, Phosphorykse Dejkiency) In McArdle’s disease, there is a deficiency of muscle phosphorylase. This deficiency gives rise to a defect in degradation of glycogen with subsequent high muscle glycogen concentrations and a decreased production of lactic acid. Although patients are normal at rest and well developed, they suffer muscle cramps during strenuous exercise. Muscle damage is clinically detected by the presence of elevated creatine phosphokinase in the blood and myoglobin in the urine. Symptoms often begin in childhood, although onset as late as the fifth decade is seen. These patients do not have clinical cardiac problems, but frequently they have electrocardiographic changes including prolongation of the P-R interval, intraventricular conduction defects, and T wave changes. A useful test for McArdle’s disease is the demonstration that venous lactate levels from a limb performing anaerobic exercise fail to increase.131 Other: Lafora’s Disease Lafora’s disease is considered a form of progressive myoclonic epilepsy in which there are carbohydrate deposits in many organs including the nervous system and the heart. These deposits consist of intracytoplasmic basophilic inclusions in the neurons (Lafora’s bodies), retina, spinal nerves, and cytoplasm of cardiac muscles.136 This inclusion material is a glycoprotein-acid mucopolysaccharide complex and is probably a product of some as yet unidentified derange-
FIG 8. Basophilic deposits of abnormal cytes In endomyocardial biopsy SIS (HE, x500.)
Curr
Probl
Car&d,
September
glycogen specimen
1990
filling central portions of the cytoplasm of myofrom a 4-year-old child with type IV glycogeno-
509
ment of carbohydrate metabolism. In Lafora’s disease, grand mal seizures and myoclonic seizures, which begin during the second decade of life, are accompanied by rapid and severe mental deterioration, often with psychotic symptoms and short survi~al.~~~ Clinical cardiologic abnormalities are not well studied. The diagnosis depends on the detection of the characteristic periodic acid-Schiff (PAS) positive inclusions in the brain.138’13s PAS-positive deposits in other organs are nonspecific and nondiagnostic.
MUCOPOLYSACCHARIDOSI The mucopolysaccharidosis (MPS) are characterized by deficiencies of lysosomal enzymes involved in the degradation of various acid mucopolysaccharides. The clinical and pathologic manifestations of these diseases reflect not only the effects of the storage of mucopolysaccharides within lysosomes, but also the presence of a complex abnormality in the organization of the extracellular elements of connective tissue. The latter abnormalities are responsible for the various anatomic changes that occur in the cardiac valves, skin, cartilages, and bone.lz6 Echocardiographic changes are encountered in many patients with mucopolysaccharidosis, even in the absence of clinical cardiac involvement (Table 8).14’ There are six separate types of mucopolysaccharidoses, and some of these are further subdivided. As a group, patients with mucopolysaccharidoses have coarse facies, short stature, and skeletal dysplasia.14* MPS I (Hurler, Scheie’s, Hurler-Scheie Syndromes) This is an a-L idurodinase deficiency with three clinically distinct subtypes: Hurler syndrome, Scheie’s syndrome, and the HurlerScheie syndrome. Hurler syndrome is a severe progressive disorder with autosomal recessive inheritance that usually leads to death before the age of 10 years. Clinically, mental retardation, dwarfism, coarse facies, large head, cloudy corneas, protruding abdomen, hepatosplenomegaly, upper lumbar kyphos, and other skeletal malformations are seen.14’ Over production of collagen is perhaps responsible in part for restricted motion in the shoulder, elbows, and fingers, for the presence of bilateral carpal tunnel syndrome, and for thickening of the leptomeninges with the subsequent production of hydrocephalus .142 Cardiac involvement may be lethal. The cardiac valves, endocardium, myocardium, coronary arteries, and large systemic arteries are diffusely thickened as a result of increased amounts of fibroelastic connective tissue containing intracellular storage material (Fig 9).143 The left-sided cardiac valves are more severely affected.14’ 510
Cut-r Probl
Cardio!,
September
1990
TABLE
8.
Cardiac Involvement Mucouolvsaccharidosis
in (MPS)*
MPS I and V: Thickening of cardiac valves, endocardium, myocardium, coronary arteries, and large systemic arteries; calcification of mitral valve; intimal plaques in aorta and major blood vessels. Clinical abnormalities include angina, myocardial infarction, cardiomegaly, mitral regurgitation, heart murmurs, and congestive heart failure. MPS II: Thickening of cardiac valves, endocardium, and myocardium; diminished left ventricular ejection fraction. MPS III: Rigidity and thickening of mitral valve, shortening of chordae tendineae, dilatation of ventricles, and slight sclerosis of the conxary arteries and aorta. Asymmetric valve involvement on echocardiogram. MI’S IV: Cardiomegaly, endocardial thickening, cardiac valve thickening, calcification of pulmonary and aortic valve rings, intimal thickening in the aorta, pulmonary trunk, and coronary arteries; aorZic regurgitation; mitral stenosis. MPS VI: Endocardial thickening; mitral and tricuspid valve thickening, mitral valve calcification, and stenosis; aortic stenosis and regurgitation; cardiomegaly; congestive heart failure; premature death from cardiac reasons. MPS VII: Systemic hypertension, aortic regurgitation, obstructive lesions in the aorta and major blood vessels. Mucolipidosis II and III: Cardiac valve, endocardial, pericardial, and coronary artery thickening; accumulation of foam cells in the ruyocardium: cardiomegaly, aortic regurgitation from valve prolapse, (JJ prolongation, ST depression. ‘Data
Cur-r Probl
Cardiol,
September
from t~felwxes
1990
126, 140-145,
147-151.
511
FIG 9. Severe intimal thickening by cells with clear, foamy cytoplasm nal narrowing in this large, extramural coronary artery from (Movat pentachrome stain, x30.)
has produced marked lumia child with Hurler syndrome.
Calcification of the mitral valve ring may be apparent on roentgenograms. The large extramural coronary arteries are rigid and thickened, and their lumina are severely narrowed.12”’ 144 The aorta and other large systemic arteries have raised intimal p1aques.l’” Clinical cardiovascular disease is present in more than 70% of patients with Hurler syndrome. This includes angina, myocardial infarction, cardiomegaly, mitral regurgitation, mitral stenosis, and congestive heart failure.‘45 Scheie’s syndrome features severe cloudiness of the corneas, pigmentary degeneration of the retinas, and glaucoma. These abnormalities lead to severe visual impairment. Patients with this syndrome also have deformities in the hands, stiff joints, entrapment neuropathies of the median nerve at the wrist, and normal intelligence. Aortic stenosis and regurgitation have been observed clinically.142 Cardiomegaly, thickening of the cardiac valves and endocardium, and thickening and narrowing of the coronary arteries also have been reported.‘46 In Hurler-Scheie syndrome, the abnormalities are more severe than those in Scheie’s syndrome, but milder than those in Hurler syndrome. Affected children have mental retardation and involvement of the heart and liver. Mitral stenosis and regurgitation, aortic regurgitation, and calcification of the mitral and aortic valves have been reported.14” 512
Cur-r
Probl
Cardiol,
September
19SO
MPS ZZ (Hunter’s Syndrome) This sex-linked recessive disorder is distinguished from Hurler syndrome by the lack of cornea1 cloudiness and by a longer survival sulfatase. Reported time .14’ There is a deficiency of sulfoiduronate cardiac abnormalities include infiltration by clear cells and thickening of cardiac valves, endocardium, and myocardium, with a diminished left ventricular ejection fraction.lz6 MPS ZZZ(Sanfllippo’s Syndrome) Sanfilippo’s syndrome occurs in two forms according to the enzymatic defect: deficiency of heparan sulfatase in type A, and deficiency of N-acetyl-alpha-D glycosaminidase in type B. Progressive mental retardation and relatively mild skeletal abnormalities are noted at school age, but can be seen as early as 2 years of age. Cardiovascular abnormalities reported in type A include rigidity and thickening of the mitral valve and shortening of the chordae tendineae. In type B, dilatation of both ventricles, numerous tiny nodules of fibrous connective tissue on the aortic and mitral valves, and slight sclerosis of the coronary arteries and aorta are encountered.lz6 An asymmetric valve involvement is noted on an echocardiogram.14’ MPS ZV (Morquio Syndrome) The prominent clinical features are skeletal abnormalities and their effects on the nervous system. The enzymatic defect is a deficiency of hexosamine-6-sulfatase. The trunk and neck are short, the sternum is prominent, and the head appears to lie directly on the shoulders. Growth ceases at about 7 years of age.14’ Cervical myelopathy is associated with the presence of atlantoaxial subluxation resulting from hypoplasia of the odontoid process.142 Cardiac pathologic conditions include cardiomegaly, endocardial thickening, cardiac valve thickening, calcification of pulmonary and aortic valve rings, and intimal thickening in the aorta, pulmonary trunk, and coronary arteries.“” Sometimes, there is clinical evidence of aortic regurgitation.‘45 Mitral stenosis has also been reported.141 MPS V MPS V is now classified
with mucopolysaccharidosis
I.
MPS VI (Maroteau)r-Lamy Syndrome) Maroteaux-Lamy syndrome is caused by a deficiency of arylsulfatase B. Retardation of growth, skeletal deformities, restriction of joint movement, flexion contractures of the knees, and corneal clouding are encountered. Myelopathy results from hypoplasia and subluxation of the odontoid process.‘4” cur-r Probl
Cardiol,
September 1990
513
Aortic stenosis147 and regurgitation are the prominent findings noted clinically. Endocardial thickening, mitral and tricuspid valve thickening, and calcific mitral valve stenosis have been observed.148’ I49 Cardiomegaly, congestive heart failure, and premature death from cardiac disease are also encountered.14’ MPS VZZ(@Glucoronidase Deficiency) This is a rare disease that results from a deficiency of B-glucuronidase. It is manifest by skeletal deformities, growth impairment, a protruding abdomen, hepatosplenomegaly, and slow mentation. Systemic hypertension, aortic regurgitation, and obstructive lesions in the aorta and other major blood vessels have been reported.150 Mucolipidosis ZZand ZZZ These conditions are characterized deficiencies of several lysosomal hydrolases which are active in the degradation of lipids and mucopolysaccharides.12” Mucolipidosis II (I-cell disease) resembles Hurler syndrome, but the former has an earlier onset, and may even be evident at birth. Mucolipidosis III (pseudo-Hurler polydystrophy) becomes manifest at 2 to 4 years of age and resembles juvenile rheumatoid arthritis.14’ Coarse facies, cloudy corneas, joint stiffness, retarded growth, skeletal changes, and slow mentation are seen. Thickening of the cardiac valves, endocardium, pericardium, and coronary arteries, and accumulation of foam cells in the myocardium are seen? 15’ There are prominent clinical, electrocardiographic, and echocardiographic signs of myocardial involvement. These changes include cardiomegaly, aortic regurgitation, mitral valve prolapse, QT segment prolongation, and ST segment depression.151 THE SPHZNGOLZPZDOSZS A wide variety of clinical syndromes results from the excessive accumulation of sphingolipids in nerve cells. In the following syndromes, the nervous system is primarily involved, but cardiovascular abnormalities may also be apparent (Table 9). Fabry’s Disease (Angiokeratoma Corporis Dijgirsum) Fabry’s disease is caused by a deficiency of lysosomal a-galactosidase A. Being the only known sex-linked recessive lipid storage disease, it occurs primarily in men. The disease becomes clinically apparent during childhood or early adolescence. Manifestations include proteinuria, skin lesions (angiokeratomas), corneal dystrophy, burning pains, paresthesias, and attacks of fever.15’ The cardiovascular involvement is directly related to the cumula614
Cur-r
Probl
Cardid,
September
1990
TABLE
9.
Cardiovascular
Abnormalities
in the Sphyngolipodosis’
Fably’s disease (angiokeratoma corporis diffusum) Deposition of sphingolipids in small arteries, myocardial cells, and valvular fibroblasts. Clinical: Anginal chest pains, myocardial infarctions, congestive heart failure, cardiomegaly, valvular involvement, hypertension, hypertrophic obstructive cardiomyopathy. Farber disease Granulomas in cardiac valves, chordae tendineae, coronary arteries, pericardium, aorta, and pulmonary arteries; cardiac enlargement. Gaucher’s disease Pulmonary hypertension, intrapericardial hemorrhages, constrictive pericarditis. Niemann-Pick disease Occasional accumulation of sphingolipids in the endothelium of blood vessels and myocardium interstitium. GM1 gangliosidosis Infantile: Diffuse, nodular thickening of the mitral and tricuspid valves; cardiomegaly. Juvenile: Cardiomegaly, mitral and aortic regurgitation. GM2 ganghosidosis Tay Sachs disease: Accumulation of GM2 ganglioside in the heart tissue, nonspecific electrocardiographic changes (QRS-T angle, QT prolongation, abnormal T waves). Sandhoff disease: Lipid deposits in the heart, cardiomegaly, thickening of the mitral and tricuspid valve leaflets, thickening and fusion of the chordae tendineae, thickening of the aortic and pulmonary valves. ‘Data liom refe1ences
126, 145, 152, 1.53, 157, 159, 162, 163.
tive deposition of glycosphingolipid in small arteries, arterioles, cardiac myocytes, and valvular fibroblasts (Fig 10). Cardiomegaly, angina, premature myocardial infarctions, congestive heart failure, valvular involvement,lz6. IS2 hypertrophic obstructive cardiomyopathy,153 and hypertension have been reported. Electrocardiographic and echocardiographic changes are consistent with the structural cardiac abnormalities. In addition to the vascular lesions mentioned above, areas of ectasis develop in small blood vessels of the skin and other organs. Microaneurysms are prominent in ocular vessels.154 Cerebral complications are associated with both premature cerebrovascular disease and long standing hypertension. The resulting neurologic manifestations, which vary with the site and extent of lesions, include alterations of consciousness, aphasia, seizures, hemiplegia, and hemisensory defects.l”” Alterations in consciousness may be secondary to an electrolyte imbalance associated with renal involvement. Women heterozygous for the disease can be clinically affected.“’ In both homozygotes and heterozygotes, there is deposition of glycosphingolipids in the neuronal cytoplasm of peripheral nerves, neurons of the autonomic nervous system, and subcortical nuclei of the CNS.l”’ The conduction velocity of peripheral nerves is Curr
Probl
Cardiol,
September
1990
515
FIG 10. Fabry’s disease. Histologic sections showing marked vacuolization of cardiac muscle cells A, and smooth muscle cells B, in the wall of an artery. (HE, each x2.50.) C, darkly stained lamelle composed of glycolipid material fill the cytoplasm of the cardiac muscle cells. One-micron thick section of plastic-embedded tissue, alkaline toluidine blue stain, xl ,000. D, electron micrograph showing membrane-limited group of lamellae composed of alternating dense and light bands. (Uranyl acetate and lead citrate stain, x92,000.)
slowed.*5e Hypohydrosis and gastrointestinal disturbances ondary to autonomic nervous system disturbances.
are sec-
Farber Disease (Lipogranulomatosis) This is an autosomal recessive disease. It results from accumulation of ceramide and acid mucopolysaccharides in a variety of cell types and from the subsequent formation of granulomas with lipidfilled histiocytes. These granulomas give rise to the clinical symptoms of hoarseness, markedly swollen painful joints, periarticular subcutaneous nodules, pulmonary infiltrates, and respiratory dis516
Curr
Probl
Cardiol,
September
1990
tress. Mental deterioration occurs in the late stages of the severe form of this illness.157 But the most prominent neurologic involvement occurs in the peripheral nervous system with areflexia and electromyographic signs of denervation. Cogan et al.15’ reported color changes in the retina around the foveal area with a cherry red center, but without disturbance of vision. Patients are severely disabled early in childhood and usually die of pulmonary infections. Heart murmurs and cardiomegaly result from the formation of granulomas in cardiac valves, chordae tendineae, coronary arteries, pericardium, aorta, and pulmonary arteries.f26’ 157
Gaucher’s
Disease
This is an autosomal recessive disease caused by a deficiency of a lysosomal glucocerebrosidase. Gaucher’s disease is the most common of the sphingolipidosis. Three forms of the disease have been described: the acute neuronopathic form (nemologic involvement during infancy), the subacute neuronopathic form (nemologic involvement after infancy), and the chronic non-neuronopathic form (adult type without cerebral involvement) .15’ Visceral abnormalities such as enlargement of the liver and spleen and involvement of the lungs are found in all three forms. Occlusion of alveolar capillaries by Gaucher’s cells may predispose to pneumonia. A few patients develop pulmonary hypertension,15’ and a few Gaucher’s cells may appear in the myocardium.15s Hypersplenism produces both anemia and thrombocytopenia. A bleeding diathesis frequently results from the thrombocytopenia and may lead to intrapericardial hemorrhage and subsequent constrictive pericarditis . Neurologic involvement in the acute neuronopathic form is present at birth or shortly after birth. The infant fails to thrive, and has strabismus, laryngeal stridor, a feeble cry, seizures, and spasticity. The latter progresses to decerebrate rigidity. Death occurs around 9 months of age from pulmonary infections.l”’ In the subacute neuronopathic form (juvenile form), the neurologic involvement occurs after infancy and patients may survive to adulthood. The chronic non-neuronopathic form is characterized by the lack of neurologic involvement. However, there are several reports of neurologic involvement in this form. For example, Miller et al. reported two adult siblings with proven Gaucher’s disease who presented with a nemologic picture characterized by seizures, mental deterioration, disturbance of extraocular movements, and abnormal electroencephalograms.160 The diagnosis of Gaucher’s disease rests on the presence of splenomegaly, hepatomegaly, Gaucher’s cells in bone marrow, and a deficiency of glucocerebrosidase.15g Curr
Probl
Cardiol,
September
1990
517
Niemann-Pick
Disease
This is an autosomal recessive disorder in which sphingomyelin accumulates in body tissue as a consequence of a deficiency of sphingomyelinase. The onset of symptoms is usually between 3 and 9 months of age, and hepatomegaly and splenomegaly are early clinical signs. The most common form is the infantile type. This is characterized by regression of acquired motor and intellectual functions, macular degeneration, and seizures. Occasionally, sphingolipids also accumulate in the endothelium of blood vessels and myocardial interstitium, but as a rule, the heart and blood vessels show no significant involvement in any of the types of Niemann-Pick disease.“’
GM1 Gangliosidosis Generalized GM1 gangliosidosis @galactosidase deficiency) exists in clinically distinct infantile and juvenile forms, Both forms are associated with accumulation of GM1 ganglioside and its asialoderivative in the CNS and of a keratan sulfatase-like proteoglycan in visceral organs. The infantile form is characterized by coarse facial features, hepatomegaly, splenomegaly, dysostosis multiplex, progressive mental and motor retardation, tonic-clonic seizures, ineffective sucking and swallowing, and malnutrition. If the patient survives beyond the first year of life, the clinical picture is that of decerebrate rigidity, blindness, deafness, and unresponsiveness. Cardiovascular lesions include diffuse, nodular thickening of the mitral and tricuspid valves and cardiomegaly. In the juvenile type of GM1 gangliosidosis, visceromegaly is much less pronounced than in the infantile type, and survival may extend to 10 years of age. Cardiovascular lesions in the juvenile type include cardiomegaly and aortic and mitral regurgitati0n.l’”
GM2 Gangliosidosis The two types of generalized GM2 gangliosidosis, Tay-Sachs disease and Sandhoff disease, are clinically very similar, despite differences in the metabolic derangement. In Sandhoff disease, there is a reduction in the activity of both A and B forms of G-N-acetylhexosaminidase, whereas in Tay-Sachs disease only the A form is affected. Progressive mental and motor deterioration begins between 3 and 6 months of age.161 After 18 months of age, deafness, blindness, convulsions, and spasticity are apparent. Death occurs by 3 years of age. Lipidosis of the cerebral cortex neurons and ganglion cells of the autonomic nervous system of the intestinal tract and other organs is seen. Patients with Tay-Sachs disease have no clinical manifestations of cardiovascular disease, but exhibit nonspecific electrocardiographic changes, and accumulation of a GM2 ganglioside in heart 618
Cum Probl
Cardid,
September
1990
tissue similar to that found in excessive amounts in the brain.“’ Electrocardiographic changes occasionally seen include a wide QRST angle, Q-T interval prolongation, and abnormal T waves.14’ Cardiomegaly and mitral regurgitation are clinically prominent in some patients with Sandhoff disease. Anatomic studies of the heart in this disease have shown left atrial and left ventricular enlargement, thickening of the mitral and tricuspid valve leaflets with thickening and fusion of the chordae tendineae, and thickening of the aortic and pulmonic valves.163 Histologic and ultrastructural studies have disclosed lipid deposits in endocardial fibroblasts, connective tissue of the heart valves, endothelial cells, cardiac muscle cells, smooth muscle cells of the blood vessels, and neural elements of the epicardium.lti3 D. MCCALL: In the extensive variety of inherited infiltrative disorders described by the authors, there is intramyocardial accumulation of abnormal products of metabolism. This is particularly true of the glycogeneses and mucopolysaccharidoses. When extensive, this intramyocardial accumulation may result in impaired systolic contractile performance; the patient presenting with symptoms and signs of a dilated cardiomyopathy. Many times, however, the infiltrate causes a reduction in ventricular compliance, impairing ventricular filling and resulting in a restrictive cardiomyopathy. Such patients will frequently present with symptoms and signs of predominantly right-sided failure, and in many ways, the clinical picture may resemble that of constrictive pericarditis. Noninvasive testing, including echocardiography and radionuclide angiography, is useful in establishing the functional abnormality, and endomyocardial biopsy may be used to provide the exact pathologic diagnosis. Because of the patchy nature of the infiltrate, however, biopsy may be negative in up to 50% of cases and the clinician must rely upon other markers of the disease in order to establish the diagnosis.
b
OTHER
METABOLIC
DZSZQISES
OF THE
NERVOUS SYSTEM
The following diseases affect both the nervous system and the cardiovascular system with significant frequency (Table 10). Homocystinuria
Homocystinuria is caused by a defect in the activity of cystathionine synthetase, which converts homocysteine to cystathionine. This defect results in increased plasma levels of homocysteine and methionine, and increased urinary excretion of homocysteine. Individuals with this metabolic defect have mental retardation seizures, skeletal deformities, ectopia lentis, and occlusive vascular disease. The latter, which is a frequent cause of death, seems to be related to low antithrombin activity,1”4 increased platelet consumption, decreased platelet survival time, and pronounced fragility of the vascular endothelium.lz6 The occlusive vascular disease gives rise to cerebral thromboembolic episodes, myocardial infarctions, aortic thromCurt- Probl
Cardiol,
September 1990
619
TABLE
10.
Cardiovascular Abnormalities Menke’s Disease and Familial
in Homocystinuria, Periodic Paralvsis*
Tangier
Disease,
Wilson’s
Disease,
Homocystinuria Low antithmmbin activity and pronounced fragility of the vascular endothelium, myocardial infarction, aortic thrombosis, peripheral arterial occlusions, venous thrombosis, pulmonary and systemic emboli. Tangier disease Congenital pulmonary stenosis, ischemic heart disease, mitral regurgitation, aortic insufficiency. Wilson’s disease Increaqed copper concentration in the heart, cardiac hypertmphy, dilated cardiomyopathy, electrocardiographic abnormalities (34% 1 of left ventricular hypertmphy and biventricular hypertrophy, early repolarization, ST depression, T wave inversion, premature atria1 and ventricular contractions, atrial fibrillation, sinoatrial block, and Mobitz type 1 atrioventricular block, orthostatic hypotension (19761, congestive cardiomyopathy. Menke’s (kinky-hair) syndrome Body copper deficiency, patchy degenerative changes in arterial walls, tortuous and dilated blood vessels, aneurysm formation. Familial periodic paralysis Cardiac dysfunction during episodes of flaccid paralysis (cardiac arrhythmias, bradycardia, left ventricular dysfunction), fixed electrocardiographic changes (ectopic heart beats, ventricular tachycardia), intermyofibrillary glycogen in the myocardium. ‘Datafiwn
references
boses, peripheral cerebral cortical emboli.lZ”, 165
126,164,165,167,168,172-175,178-182.
arterial occlusions, venous thromboses),
Familial Lipoprotein
Deficiency
venous thromboses (including and pulmonary and systemic
(Tangier Disease)
This disease is clinically characterized by enlarged yellow-orange tonsils, corneal opacities, relapsing peripheral neuropathies, low plasma cholesterol levels, and storage of cholesterol esters in various tissues. The neuropathy is manifested by sensory symptoms and asymmetric proximal and distal motor weakness. All the symptoms progress slowly or fluctuate in intensity through the years.16” Cardiovascular abnormalities are rare, but congenital pulmonary stenosis, ischemic heart disease, mitral regurgitation, and aortic insufficiency have been reported.l”, lG7,lfix There is focal cholesterol ester deposition in the mitral and tricuspid valvesl” and the pulmonary arteries.17o
Wilson’s Disease (Hepatolenticular
Degeneration)
Wilson’s disease is an autosomal recessive disorder characterized by cirrhosis of the liver and degenerative changes of the brain, especially the basal ganglia. A deficiency of ceruloplasmin allows Su)
Curr
Probl
Cardiol,
September
1990
the loosely bound serum copper to deposit in many organs. Clinically, Wilson’s disease exists in two forms, the juvenile type (with early onset and rapid evolution if not treated) and the chronic type (with onset between 20 and 30 years of age and a slower course). Clinical abnormalities include liver disease, Kayser-Fleischer corneal rings, emotional disturbances, failure to make progress in school, dementia if the disease remains untreated, dysphagia, dysarthria, incoordination, tremor, and postural abnormalities?‘l Heart involvement has been recognized as an important aspect of the disease. Electrocardiographic abnormalities, which occur in about 34% of patients, include left ventricular and biventricular hypertrophy, early repolarization, ST depression, T wave inversion, premature atrial or ventricular contractions, atrial fibrillation, sinoatrial block, and Mobitz. type I atrioventricular block.172 Orthostatic hypotension occurs in about 19% of patients. Two cardiac deaths occurred among 53 patients as a result of congestive cardiomyopathy in one and ventricular fibrillation in the other.17’ Cardiac hypertrophy and dilatation, and an increased copper concentration in the heart are common.172-174 Serum ceruloplasmin levels are decreased, serum copper levels are low, urinary copper excretion may be increased or normal, liver function tests are abnormal, and a liver biopsy specimen demonstrates cirrhosis. The treatment of choice is o-penicillamine.
Menke’s (Kinky-hair)
Syndrome
This syndrome is inherited as a sex-linked recessive trait and is caused by a defect in the intestinal absorption of copper. The clinical manifestations are a result of copper deficiency. Copper is a cofactor required for lysyl oxidase, the enzyme responsible for the formation of crosslinks between lysine residues in elastic and collagen tissues.12” The disease presents early in life with convulsions, hypothermia, mental and growth retardation, spasticity, and a peculiar appearance of the face and hair. Copper deficiency seems to be responsible for widespread, patchy degenerative changes in the arterial walls. Arteries show premature degenerative changes with elongation, aneurysmal dilatation, rupture, stenosis, intimal proliferation, intimal thickening, and thrombosis. The internal elastic lamina demonstrates fragmentation, disruption, and duplication.‘75 Aneurysm formation often involves major arteries and veins.lz6 Cerebrovascular insufficiency induced by involvement of the cerebral arteries is the probable cause of gliosis and cystic degeneration seen in the brain. Arteriograms show elongation and tortuosity of major arteries with areas of localized dilatation and narrowing.17’ The heart in Menke’s syndrome is normal, but superficial vessels often appear tortuous or dilated. Cut-r Probl
Cat-did,
September 1990
521
Lead Poisoning The symptoms and signs of lead poisoning in adults are different from those seen in children. While progressive motor weakness due to peripheral axonal neuropathy occurs in the adult, there is an acute encephalopathy in children. This encephalopathy in children is manifest by alterations of consciousness, signs of increased intracranial pressure, and convulsions. Although recovery takes place in mild and moderate cases of lead poisoning, there may be permanent damage to the nervous system. Other organs besides the nervous system can be involved. Myocarditis, which occurs in chronic lead intoxication, is characterized by interstitial fibrosis with a serous exudate and relatively few inflammatory cells.176 Bertel et a1.‘77 reported a patient in whom severe lead poisoning appeared to have caused rapid development of arterial hypertension and elevation of plasma catecholamine concentrations with reduced P-adrenoceptor responses similar to those observed in low-renin essential hypertension.
Familial Periodic
Paralysis
There are three varieties of this disease: the hypokalemic, normokalemic, and hyperkalemic forms. They resemble each other, but differ in that each may be precipitated by different factors. Hyperkalemic periodic paralysis sometimes is accompanied by clinical and electromyographic myotonia, which can be precipitated by exposure to cold. Common to all three forms are the occurrence of attacks at rest, the increased frequency of attacks when exposed to cold, and the ability of patients to abort incipient attacks with mild exercise. While the hypokalemic form can be precipitated by carbohydrate ingestion or by the administration of insulin, hydrocortisone, or sodium chloride, the hyperkalemic form may be provoked by ingestion of potassium. The hypokalemic form is alleviated by the administration of potassium, the hyperkalemic form is alleviated by epinephrine, amphetamine, or calcium chloride. Cardiac arrhythmias occur during attacks of hypokalemic, hyperkalemic,178 and normokalemic17s periodic paralysis. Although cardiac arrhythmias between attacks are not a feature of any of the commonly encountered varieties of familial periodic paralysis, fixed electrocardiographic abnormalities occur infrequently after the disease has existed for many years. The electrocardiographic changes include ectopy, most commonly manifested as bigeminy,17’ and ventricular tachycardia. Most commonly, the electrocardiogram is normal between attacks. During attacks, electrocardiographic changes are associated with the variation of the potassium concentration in cardiac the bloodlao and should not be taken as a sign of permanent dysfunction. Evidence of cardiac dysfunction during an episode of flaccid pa622
Curr
Probl
Cardiol,
September
1990
ralysis was reported by Kramer et al.“* in a patient with familial hypokalemic periodic paralysis. This patient had an elevated serum creatinine phosphokinase level with an increased myocardial fraction of this enzyme (myocardial band), alterations in the lactic dehydrogenase isoenzyme pattern, severe bradycardia, and evidence of left ventricular dysfunction. Likewise, patients with the combination of paroxysmal muscular weakness due to hyperkalemic periodic paralysis and cardiac arrhythmias have also been reported.17’ In patients with hypokalemic periodic paralysis who have developed permanent muscular weakness, a careful noninvasive screening failed to show evidence of cardiac involvement.“’ Nevertheless, subtle abnormalities of cardiac muscle cannot be ruled out completely in these patients. In this respect, ultrastructural examination of tissue obtained from the left ventricle in a patient with hypokalemic periodic paralysis showed an unusual amount of intermyofibrillary glycogen resembling the increase of glycogen found in the skeletal biopsy specimen obtained from the same patient.“’ Idiopathic infantile Hypercalcemia (Williams Syndrome) This syndrome, in which idiopathic hypercalcemia coexists with congenital cardiac abnormalities, is probably a result of deranged vitamin D metabolism. Children with this illness have mental subnormality, unusual facial features (elfin face), dental malformations, and aortic stenosis is found in more than strabismus.183 Supravalvular 80% of patients.ls3 Other arteriopathies include peripheral pulmonary stenosis (58%), and stenosis of innominate, common carotid, subclavian, coronary, superior mesenteric, and renal arteries. Less frequently, there are atria1 and ventricular septal defects, and juxtaductal coarctation of the aorta.ls3 NEUROLOGIC SYNDROMES ASSOCIATED AND THIAMINE DEFICIENCY
WITH ALCOHOL ABUSE
The clinical picture of chronic alcoholism with malnutrition involving the nervous system varies from the classic features of pellagra (mental changes, vertigo, deafness, long tract involvement, tremor, ataxia, peripheral neuropathy) and beriberi (polyneuropathy, congestive heart failure) to a simple peripheral neuropathy or nutritional optic atrophy. Neurologic conditions resulting from prolonged and severe dietary restriction of thiamine intake occur in prisoners of war and persons with beriberi or pellagra. All these entities seem to be part of a broad spectrum of neurologic symptom-complexes caused primarily by nutritional deficiency and chronic alcoholism. In chronic alcoholism, repeated acute heavy alcohol consumption may cause congestive cardiomyopathy, acute left ventricular failure, and atria1 fibrillation.1x4-*8” Beriberi and Wernicke’s encephalopathy Cur-r Probl
Cardiol,
September
1990
523
TABLE
11.
Cardiovascular Abnormalities in Syndromes Associated With Alcohol Abuse and Thiamine Deficiency* Beriberi Cardiac enlargement Congestive heart failure Cardiocirculatory failure Wernicke’s encephalopathy Tachycardia Tachypnea Increase in cardiac output T wave changes Orthostatic hypotension *Data from
referances
1X7-193.
are associated with thiamine deficiency, tem is involved in both (Table 11).
and the cardiovascular
sys-
Beriberi Cardiac circulatory
enlargement, congestive heart failure, and severe cardiofailure occur in the wet and acute (shoshin) forms of befi,,efi.187, 188 A rise in serum pyruvate and lactate concentrations leads to a blockade of carbohydrate metabolism and metabolic acidosis.ls8 The mechanism whereby the heart is involved in beriberi is not clear, but there may be more than one cause: (a) concomitant presence of autonomic neuropathy, anemia, and other unknown factors may lead to lowering of systemic vascular resistance with peripheral blood shunting, increased venous return to the heart, and high output heart failurel”; (b) elevated splanchnic flow, reduction of renal blood flow, and reduction of glomerular filtration; (cl direct impairment of myocardial energy production, since thiamine is no longer available as a cofactor for energy production in the Krebs cycle; and (d) a direct effect of alcohol on the myocardium, with the production of alcoholic cardiomyopathy.lsgj lso Treatment with thiamine and abstention from alcohol are effective in relieving the symptoms in the early stages.‘88’ Is9
Wernicke’s
Encephalopathy
The occurrence of lesions in the hypothalamus and brain stem in patients with Wernicke’s encephalopathy explains not only the alteration of consciousness, extraocular movement abnormalities, and ataxia seen in this syndrome, but also the occurrence of respiratory and cardiovascular difficulties. Tachypnea, tachycardia, increased cardiac output, and postural hypotension are present in over half the patients suffering from acute Wernicke’s encephalopathy. Pos524
Curr
Probl
Cardiol,
September
1990
tural hypotension may be due to a defect in efferent sympathetic nervous outflow and decreased peripheral vascular resistance,l’l or to a disorder of central vasomotor contro1.192 A concomitant peripheral neuropathy with autonomic nervous system involvement may also play a role in the genesis of the orthostatic hypotension. Electrocardiographic changes in Wernicke’s encephalopathy include sinus tachycardia, and flattened, isoelectric, diphasic, inverted, or peaked T waves.ls3 Improvement in neurologic and cardiovascular abnormalities takes place after treatment with thiamine. MALFORMATIONS
OF THE CNS
Cardiovascular anomalies are among the malformations found in association with dysraphism (posterior midline defects of development), faciotelencephalopathy (anterior midline defects of development), and disorders of cellular migration and proliferation. Immediately after the neural tube closes at the fourth week of gestation, its lining of immature ependymal cells secretes a proteinaceous neural tube fluid, and the resulting distention of the tube helps to shape not only the embryonic brain and spinal cord, but also the bordering mesodermal cells.ls4 Gardner hypothesized that a hypersecretion of neural tube fluid during this critical period will lead to overdistention of the neural tube and infiltration of fluid into the mesoderm, damaging not only the neural tube, but also the cells that are destined to form mesodermal organs such as the heart. Cardiovascular anomalies associated with malformations of the CNS are best studied in chromosome disorders, the Dandy-Walker syndrome, and fetal alcohol syndrome. CHROMOSOME
ABERRATIONS
The chromosome aberrations associated with nervous system and cardiac abnormalities are summarized in Table 12. DANDY-WALKER
SYNDROME
In the Dandy-Walker syndrome, there is a cystic deformity of the fourth ventricle and agenesis or hypoplasia of the cerebral vermis.‘s7 In more than half of the patients with Dandy-Walker syndrome, there are other associated neurologic anomalies such as hydrocephalus, agenesis of the corpus callosum, cerebral and cerebellar heterotopias, polymicrogyria, aqueductal stenosis, microcephaly, infundibular hamartomata, syringomyelia, and occipital meningocele .1s7-1ss Clinical manifestations include mental retardation, seizures, changes in the size of the head, spastic quadriparesis, ocular Curr
Probl
Cardiol,
September
1990
5.25
TABLE
12.
Cardiovascular Chromosome
Abnormalities Aberrations*
Trisomy 21 (Down syndrome) Endocardial cushion defect Ventricular septal defect Atrial septal defect Tetralogy of Fallot Patent ductus arteriosus Trisomy 13 (Patau’s syndrome) Ventricular septal defect Patent ductus arteriosus Atria1 septal defect Dextrocardia ‘Transposition of great vessels Double outlet right ventricle Trisomy 18 (Edward’s syndrome1 Ventricular septal defect Atria1 septal defect Patent ductus arteriosus Aortic and pulmonic stenosis 4p-Wolf syndrome) Atria1 septal defect Ventricular septal defect 5p-(cri du chat syndrome) Ventricular septal defect Patent ductus arteriosus Aortic stenosis 13q-syndrome Tetralogy of Fallot Ventricular septal defect lSp-syndrome Tetralogy of Fallot Transposition with pulmonic Patent ductus arteriosus Ventricular septal defect Ventricular hypertmphy Dextroversion Congestive heart failure lSq-ICarp mouth syndmmet Ventricular septal defect X0 Wurner’s syndrome, Coarctation of the aorta Aortic stenosis Atria1 septal defect XXXXY syndrome Patent ductus arteriosus Atria1 septal defect XXX syndrome Patent ductus arteriosus ‘Data horn rt?ferences
526
in
(variable)
stenosis
195, 196.
Curr
Probl
Cardiol,
September
1999
findings, cerebellar ataxia, apneic spells, and several other clinical signs of brain stem and cerebellar dysfunction. About 25% of patients with the Dandy-Walker syndrome have anomalies outside of the nervous system.l” Reported anomalies include cleft palate, facial angiomas, vertebral abnormalities, polydactylism-syndactylism, polycystic kidneys, and cardiovascular abnormalities.lg7’ ‘O” Heart defects reported in association with the Dandy-Walker syndrome are septal defects, patent ductus arteriosus, subaortic stenosis, infundibular pulmonary stenosis, bicuspid aortic valve, coarctation of the aorta, ventricular aneurysm, cardiomegaly, tetralogy of Fallot, single ventricle, and dextrocardia.1g7’ 1ss--204The association of facial and cardiovascular anomalies favors the hypothesis that the onset of the Dandy-Walker syndrome occurs between the formation and the migration of the cells of the neural crest (between the third and fourth postovulatory week) .‘O” FETAL
ALCOHOL
SYNDROME
Delayed development, mental deficiency, facial, limb, and cardiovascular defects have been reported in children born to women who are alcoholics. Among these abnormalities, the most consistent are prenatal and postnatal growth deficiencies, microcephaly, dysmorphic features, hyperactivity, learning disabilities, mental retardation, and urogenital deformities. Cardiac malformations include ventricular septal defect (30% to 65%), atrial septal defect (lo%), pulmonic stenosis (lo%), patent ductus arteriosus (lo%), tetralogy of Fallot (10% to 16%), aortic stenosis (7% 1, coarctation of the aorta (5%), and transposition of the great arteries (5%).205-207 The syndrome occurs in about one infant per 1,000 live births. The syndrome is not well defined, and it is possible that other drugs used in conjunction with alcohol by these women may also exert teratogenic effects. Acute alcoholic intoxication may produce changes in myocardial contractility. Experimental studies in animals have shown that maternal alcohol intoxication causes a rapid depression of fetal myocardial contractility that is maintained several hours after cessation of alcohol ingestion.20x Other studies in animals showed abnormalities of heart and great vessel development following ethanol exposure.e.2”9 OTHER HEREDITARY NERVOUS SYSTEM Five classic neurologic able clinical significance. Curr
Probl
Cardiol,
September
AND DEGENERATIVE diseases have cardiac
1990
DISEASES involvement
OF THE of vari-
527
FRIEDREZCH’S
ATMZA
Most commonly transmitted as an autosomal recessive and rarely as a sex-linked abnormality, Friedreich’s ataxia chiefly involves the spinocerebellar and pyramidal tracts, dorsal columns, peripheral nerves, and optic nerves. It also involves the skeletal and cardiovascular systems. Probably more than 55% of patients with Friedreich’s ataxia have major clinical cardiac abnormalities (anginal pain, cardiac enlargement, congestive heart failure). In a clinical study of 75 patients, one or more cardiac abnormalities were detected in 95% of patients utilizing the combination of scalar electrocardiography, Mmode echocardiography, and two-dimensional echocardiography.“” Cardiac involvement is present at necropsy in all patients.‘ll Heart disease may present in some patients prior to the development of neurologic symptoms.212 Left ventricular hypertrophy is more common in slightly to moderately disabled patients; right ventricular hypertrophy predominates in severely affected patients.‘l” Gross anatomic changes in the heart include ventricular hypertrophy with or without dilatation, patchy or diffuse interstitial fibrosis, and less frequently, endocardial thickening and mural thrombosis.214 A high incidence of hypertrophic cardiomyopathy with asymmetric thickening of the ventricular septum has been shown by echocardiographic and angiographic studies to occur in Friedreich’s ataxia.215-218 Both obstructive and nonobstructive forms of hypertrophic cardiomyopathy have been described.21”-Z20 Fibrous replacement of the myocardium is widespread, especially in subendocardial and subepicardial areas. Fatty infiltration may be prominent. The cardiac muscle cells show hypertrophy, but the valves and the conduction system usually are normal. The large extramural coronary arteries are not affected, but all stages of intimal proliferation can be found in small coronary arteries, which may be occluded. Brumback et alzzl reported a 27year-old woman with Friedreich’s ataxia in whom the cardiac abnormalities included ventricular subendocardial fibroelastosis, occlusion of the coronary sinus ostium, individual myofiber loss, myofiber disarray, and enlarged hyperchromatic myofiber nuclei. Electrocardiographic changes, which may be present at the onset of neurologic signs in Friedreich’s ataxia, are seen in two thirds of patients?l”, 222 These changes reflect the anatomic cardiac abnormalities and include widespread inversion of T waves, changes consistent with left ventricular hypertrophy,76’ ‘I2 atria1 fibrillation, and atria1 flutter. Serial electrocardiograms, recorded over periods of up to 32 years, showed that these abnormalities may develop in patients with Friedreich’s ataxia at any time up to 20 years after the onset of neurologic symptoms.21” ST changes characteristic of ischemia do not occur2” and disturbances of conduction are rare.“” 528
Curr
Probl
Cardiol,
September
1990
b D. MCCALL: It is of interest to note that cardiac abnormalities may be present in the parents of patients affEcted by Friedreich’s ataxia. These individuals, because of their heteruzygous state, have no clinical manifestations of the disease, but will occasionally have both electticardiographic abnormalities and asymmetric septal hypertrophy, on echocardiographic evaluation. PERONEAL SENSORY
MUSCULAR NEUROPATHY;
ATROPHY (HEREDITARY CHARCOT-MARIE-TOOTH
MOTOR AND DISEASE)
Peroneal muscular atrophy is a slowly progressive neurogenic atrophy affecting mainly the distal muscles of the legs and sometimes the intrinsic muscles of the hands. It is related to Friedreich’s ataxia. Isolated cases of Friedreich’s ataxia occur in families with peroneal muscular atrophy, and the two diseases have been described in the same individual. Cardiomyopathy is not characteristically associated with peroneal muscular atrophy.223 But there are a few reports associating peroneal muscular atrophy with heart disease.2z28 224--226A myocardial biopsy specimen from a 42-year-old man with familial heart block and peroneal muscular atrophy revealed ultrastructural changes similar to those described in simple myocardial hypertrophy and hypertrophic obstructive cardiomyopathy.“’ Little?z4 described the coexistence of cardiac conduction defects and peroneal muscular atrophy in a family in which ten members of three generations were affected (three manifested both conditions, six had the cardiac defect alone, and one had only the neurologic disorder). Thus, it seems likely that some cases of peroneal muscular atrophy have conductive cardiac defects and cardiomyopathy. TUBEROUS
SCLEROSIS
(BOURNEVZLLE’S
DISEASE)
The inheritance of this disease fits an autosomal dominant pattern. A commonly encountered triad of adenoma sebaceum, seizures, and mental retardation are the clinical characteristics of this disease, but visceral anomalies are not uncommon. In this regard, tuberous sclerosis is associated with cardiac rhabdomyoma in about 37% to 50% of cases.z27 Two-dimensional echocardiography is particularly well suited for detecting rhabdomyomas, which are the most common cardiac tumors in infancy and childhood (Fig 11). These tumors of infancy can be single or multiple; intracavitary OI intramural. Intracavitary rhabdomyomas may be found in stillborn infants or in infants who died suddenly, suggesting that an obstruction of intracardiac blood flow might have occurred. Intramural tumors may produce arrhythmias and atrioventricular block due to invasion of the conduction system by the tumor. Thus, syncope can occur in patients with cardiac rhabdomyomas not only from obCurr
Probl
Car-did,
September
1990
529
FIG 11. Two-dimensional echocardiograms showing right ventricular born. LA = left atrium, LV = left ventricle, RA = right atrium.
rhabdomyoma
(T) in a new-
struction of intracardiac blood flow, but also as a result of atrioventricular conduction block. Attacks of syncope should not be confused with generalized epileptic seizures which occur frequently in tuberous sclerosis. Cardiac rhabdomyomas may also give rise to cardiac enlargement and congestive heart failure. Apart from rhabdomyomas, another cardiovascular abnormality rarely reported in tuberous sclerosis is stenosis of the great vessels. NElJROFZBROh4ATOSZS
WON
RECZUZNGHAUSEN’S
DISEASE)
The incidence of pheochromocytoma in neurofibromatosis is greater than that in the general population, and it is possible that patients with both conditions can develop cardiac ailments due to systemic arterial hypertension. Myocardial rhabdomyosarcomas producing systemic and cerebral emboli also have been reported in patients with neurofibromatosis.“’ This association may represent one of the features common to the neurocutaneous syndromes and behooves the clinican to suspect cardiac tumors, not only in patients with tuberous sclerosis, but also in those with other neurocutaneous syndromes.
530
Cut-r
Probl
Cardiol,
September
1990
KUGELBERG-WELANDER
SMVDROME
Kugelberg-Welander syndrome, also known as the juvenile form of progressive spinal muscular atrophy, begins in infancy as a lower motor neuron disease (flaccid muscular weakness, muscular wasting, fasciculations, absent muscle stretch reflexes, and electromyographic evidence of a neuronal disease). Familial cases fit autosomal recessive, dominant, and X-linked patterns. This disease runs a rapid, fatal course. The weakness is most pronounced in the proximal muscles of the extremities. Kugelberg-Welander syndrome is associated with cardiomyopathy, atrial arrhythmias, atrioventricular conductive defects, and congestive heart failure.z2s No cardiac necropsy data have been reported in patients with this syndrome, but endomyocardial biopsy specimens from three patients showed right atrial and right ventricular fibrosisz2’* 230 as well as degenerative changes in the muscle cells of the right ventricular wall.230 PAROXYSMAL
CONDITIONS
Among paroxysmal neurologic conditions, nea are of relevance to this review.
seizures
and sleep ap-
SEIZURES Cardiac arrhythmias and death may occur during a generalized tonic-clonic seizure: (a) in those epileptic patients with antecedent severe coronary artery disease23” 232; (b) in elderly patients with cardiopulmonary disease during intravenous injection of phenytoinZ33-235; and (19 in otherwise healthy patients with epilepsy as a result of cardiorespiratory depression induced by repeated intravenous injections of different drugs such as phenobarbital and diazepam. Although underlying cardiac disease plays an important role in most patients who die during a tonic-clonic seizure, a small percentage of patients with epilepsy die during or shortly after a tonicclonic seizure with neither an obvious clinical cause nor elucidative anatomic findings on postmortem examination.z31’ 236 The incidence of unexpected death among epileptic patients is 1 in 370 to 1 in 1,000.237 A review of deaths in epilepsy indicates that in 3% to 31% of cases, death is sudden and unexpected.231 Unexpected deaths among patients with epilepsy occur in individuals with a longstanding history of generalized seizures who abuse alcohol and who have poor compliance with the prescribed regimen of anticonvulsant medicines.237 Most patients with epilepsy who die suddenly show subtherapeutic or no levels of anticonvulsant medications in blood their blood at autopsy.‘“” 238 This suggests that an inadequate Curr
Probl
Cardiol,
September
1990
531
level of anticonvulsant medication is an important risk factor and emphasizes the need to monitor patient compliance by measuring blood levels of medications. Hypoxia, the depressant effects of anticonvulsant drugs on the myocardium, the concomitant use of alcohol with anticonvulsant drugs, and the development of cardiac arrhythmias during seizures have been proposed as possible causes of sudden unexplained death in patients with epilepsy. Simultaneous 24-hour electroencephalographic and electrocardiographic recordings have produced several important observations: 1. Interictal cardiac arrhythmias in epileptics and nonepileptics are related to a preexisting cardiovascular disease rather than to a primary cerebral disorder.Z3s These cardiac arrhythmias can lead to cerebral hypoxia and consequent cerebral symptoms including seizures . 2. Electrographic seizures, either lateralized or generalized, are frequently accompanied by tachycardia.23s’ 240 Ictal tachycardia of more than 100 beats per minute is seen in 93% of seizures, more than 120 beats per minute in 76%, and more than 150 beats per minute in 48% .240 The onset of tachycardia occurs several seconds before or after the seizure and often persists for several minutes after termination of the discharge. 3. Simultaneous 24-hour electroencephalographic and electrocardiographic studies should be obtained in all neurologic patients referred for long-term electroencephalographic recordings.23s 4. High-risk ictal cardiac arrhythmias are uncommon.Z4” In a study of 338 patients with epilepsy, simultaneous electroencephalographic and electrocardiographic monitoring showed a 5.3% incidence of dangerous cardiac arrhythmias,241 which does not differ from that of the general population.24z However, in a review of the literature, Jay and Leestmaz31 found many reported cases of patients with epilepsy free from hypertension and heart disease, who suffered transient cardiac arrhythmias of various types and severity during tonic-clonic seizures. Likewise, a case is described in which simultaneous ambulatory electroencephalographic and electrocardiographic studies revealed periods of asystole coinciding with epileptic seizures. In this patient, insertion of a cardiac pacemaker did not prevent the seizures.z43 It is assumed that such patients have cardiac irregularities induced by the epileptic fit, via autonomic nervous system pathways and by the increase of blood catecholamines during the seizure.23”, 237,244--246 Also, cardiovascular abnormalities can be found in association with partial complex seizures.24”-248 Devinski et a1.248 described 6 patients with partial complex seizures in whom the most prominent 532
Curt- Probl
Cardiol,
September
1999
manifestations of the cerebral dysrhythmia were chest pain, sinus tachycardia, and sinus bradycardia leading to syncope. Likewise, Kiok et al.245 reported a 2%year-old man who had a 9 second sinus arrest during a partial complex seizure. Marshall et aLz4” reported 12 patients in whom partial complex seizures recorded by electroencephalography and video monitoring were accompanied by marked tachycardia. The causal relationship between partial complex seizures and these cardiovascular abnormalities is demonstrated by the absence of preexisting heart disease, the presence of electroencephalographic abnormalities, and a therapeutic response to anticonvulsant, rather than antianginal, medications for the cardiac symptoms.248 However, it is necessary to point out that cardiac arrhythmias may lead to fainting spells, which could be mistaken for epileptic seizures. We had the opportunity to examine a 17-year-old man who had been treated for epilepsy since he was 4 years of age. Ambulatory electrocardiographic monitoring demonstrated severe bradycardia during one of these spells (Fig 12). The placement of a permanent electronic cardiac pacemaker cured the condition. b D. MCCALL: The authors point out here an interesting symptom complex, of which we are becoming increasingly aware. Not infrequently, bradycardia-related syncope may be the only manifestation of partial complex seizure activity, although the causal relationship has as yet to be defined. These individuals, usually young males, are frequently misdiagnosed as having a sick sinus syndrome. Holter monitor recordings obtained during the syncopal episode have shown progressive slowing of the sinus rate, rather than the abrupt changes that occur in the setting of sinus node dysfunction. The sinus slowing is also frequently associated with other manifestations of heightened vagal tone, such as nausea. The appearance of bradycardia-related syncope in a young adult should, therefore, alert the clinician to this possibility and to the need for a careful neurologic evaluation, including e1ectroencephalograph.y.
The occurrence of neurogenic pulmonary edema in patients who die during generalized tonic-clonic seizures suggests that in some patients death does not occur immediately after the seizure.23”,24g Cardiac arrhythmias and hypoxic cardiomyopathy’ may play a role in deaths occurring in epileptic patients during a generalized seizure. The depressant effect of alcohol on the myocardium com-
FIG 12. Holter lepsy
Curr
recording from for 13 years. Probl
a 17.year-old
Cardiol, September 1990
boy
who
had
carried
the erroneous
diagnosis
of epi-
533
bined with anticonvulsant medications is another contributing factor.237 There is a genetic association between a familial history of seizures and hereditary prolongation of a Q-T interval (Fig 13) with sudden death.“’ Gospe and Chop reported two siblings with an autosomal dominant familial long Q-T interval syndrome in whom the cardiac abnormality was recorded many years before the diagnosis was recognized. The importance of calculating the corrected Q-T interval on electrocardiograms cannot be overemphasized, as this simple test may prevent death in some patients with seizures. Hereditary prolongation of the Q-T interval may lead to cardiac arrhythmias, cerebral hypoperfusion, and seizure activity as in two families reported by Bricker et akz5’ Phenytoin is sometimes effective not only in controlling the seizures in these patients, but also in correcting the underlying Q-T interval prolongation. A family history of seizures should always generate suspicion of hereditary Q-T interval prolongation.252 SLEEP APNEA Chronic sleep apnea secondary to mechanical upper airway obstruction induces many types of cardiac arrhythmias. The latter are
FIG 13. Greatly 534
prolonged
Q-T
interval. Curr
Probl
Car-did,
September
1990
probably related to either increased vagal tone resulting from the persistent inspiratory effort against an obstructive airway or to falling oxygen saturation.2”3-25” In a study of 400 patients with sleep apnea, 193 patients (48%) had cardiac arrhythmias as shown by nocturnal polysomnography. Bradycardia, which appears initially following an attack of sleep apnea, can progress to atria1 fibrillation, atrial flutter, or high degrees of atrioventricular block.257 The major factor influencing the incidence of bradycardia is the duration of apnea,255 but cardiovascular disease facilitates ventricular arrhythmias during sleep-induced apneaz5’ Bradycardia can occur with any type of apnea. In apnea of short duration, there is a higher incidence of bradycardia in mixed and obstructive apnea than in central apnea.z55 Other significant cardiac arrhythmias during sleep apnea include ventricular tachycardia, sinus arrest lasting as long as 13 seconds, and premature seems to prevent ventricular contractions.254 Oxygen administration the bradycardia?” A tracheostomy may be effective in eliminating sleep apnea and in controlling the arrhythmias.254 G. A. BELLER: The bradyarrhythmias seen with sleep apnea may be mediated by increased myocardial adenosine levels induced by the hypoxemia. Infusion of adenosine into the sinus node artery in experimental animal models has produced sinus bradycardia and sinus arrest.
b
Chronic upper respiratory tract obstruction may lead to increased pulmonary vascular resistance, progressive pulmonary atria1 hypertension, right ventricular hypertrophy, and congestive heart failure. The development of pulmonary edema in patients with obstructive sleep apnea may result from high intrathoracic pressure during inspiration with a negative transpulmonary pressure, and the exudation of fluid from the capillaries into the interstitium.25s Systemic arterial hypertension is associated with obstructive sleep apnea.z60 About 60% of patients with sleep apnea syndrome have hypertension; while 22% of patients with essential hypertension have sleep apnea.261’ “’ Ross et al.‘“’ described two siblings with sleep apnea and systemic hypertension. These two patients had symmetric left ventricular hypertrophy, which was probably secondary to systemic hypertension. In these patients, treatment included a permanent tracheostomy, weight reduction, and the treatment of the systemic hypertension. Short periods of sleep apnea are normal in infants through 3 months of age. But periods of apnea longer than 20 seconds, which may induce bradycardia,2”3 have been considered part of a final common pathway in the sudden infant death syndrome.z64’ 265 The significance of increased pulmonary artery smooth muscle mass in the sudden infant death syndrome is unclear.z6” Another important pathologic finding in this syndrome is the presence of lymphocytic Curr
Prwbl
Cardid,
September 1990
535
infiltrates and areas of degeneration in the conductive system of the heart. This could be a source of lethal cardiac arrhythmias.z”7
MISCELLANEOUS
VASCULAR
CONDITIONING
This group includes temporal arteritis and two neurologic conditions: intracranial arteriovenous fistulas and ventriculovenous shunts.
TEMPORAL ARTERITIS Temporal arteritis is a form of giant cell arteritis seen in elderly persons. The incidence is 17 per 100,000 for those older than 50 years.268 The involvement of the cranial arteries produces the typical abnormalities of headaches, temporal artery and scalp tenderness, jaw and tongue claudication, transient ischemic attacks of the brain, amaurosis fugax,26s and blindness. Blindness occurs in one third of patients and is due to disease of the posterior ciliary and ophthalmic arteries with consequent anterior ischemic optic neuropadue thy. 270 The loss of vision is sudden, but mild visual disturbances to premonitory ischemic episodes in the retinal arteries may herald total vision loss. Commonly, there are systemic symptoms such as weight loss, malaise, fever, and polymyalgia rheumatica.z71 Headaches, which are due to involvement of the cranial arteries, may be the only symptom present. The typical pain is intense, constant, and unilateral. The temporal arteries are thick and tender. Extracephalic giant cell arteritis occurs in about 10% to 15% of patients with temporal arteritis, with the aorta and its branches most often involved.268 Giant cell arteritis in the aorta and its branches is encountered in 1.4% to 1.7% of unselected autopsies.“’ Granulomatous giant cell aortitis may give rise to progressive aortic aneurysmal dilatation, aortic valve ring dilation, and aortic regurgitation268,270,273 Occlusion of the branches of the aortic arch may result in cerebral ischemia and strokes. Occlusions of the coronary arteries by granulomatous giant cell arteritis may lead to ischemic heart disease and myocardial infarctions?68’ “‘, 2748275 The erythrocyte sedimentation rate is elevated during active stages of temporal arteritis is about 95% to 97% of cases. In the presence of strong clinical evidence, the diagnosis should not be dismissed just because the sedimentation rate is normal?76 Temporal and facial artery biopsy specimens are not always diagnostic due to the existence of isolated foci of arteritis which make an examination of multiple histologic sections necessary.27z Steroid therapy is essential in
636
Curr
Probl
Cardiol,
September
1990
giant cell arteritis. than conventional
Elderly people are likely to respond doses of steroids.
well to lower
) G. A. BELLER: Temporal arteritis is a disease entitv that is often missed in the &agnostic workup df a fever of unknoti origin. It should be considered in any patient presenting with recurrent fever, malaise, and a markedly elevated erythroc.yte sedimentation rate. INTRACRANIAL
ARTERIOVENOUS
FISTULA
Large, congenital intracranial arteriovenous fistulas produce a serious circulatory burden and are a cause of congestive heart failure in the newborn.277’ 278 Symptomatic arteriovenous malformations in the neonatal period are rare. A review of arteriovenous malformations in 156 infants less than 6 months of age showed 81 cases of CNS arteriovenous malformations, with a male to female ratio of 2:1.277 In 1987, Johnston et al. collected 245 cases of vein of Galen malformations from the literature. The lesions occur primarily in the vein of Galen (64%), cerebral hemispheres (7%), and superior sagittal sinus (6%).277 The usual clinical presentation of vein of Galen malformations in neonates includes
high-output
congestive
heart
failure
(45% 1, raised
intracranial
pressure secondary to hydrocephalus (38% ), cranial bruits (23% 1, focal neurologic deficits (15%), seizures (lo%), and bleeding (10%).
FIG 14. This vein
cerebral of Galen
Curr
Probl
contrast-enhanced of an infant born
Cardiol,
September
CT scan shows a large with massive cardiomegaly
1990
arteriovenous malformation of the and congestive heart failure.
537
High-output congestive heart failure is the most common cause of death in these patients.277 Congestive heart failure without any apparent cause in a baby suggests the existence of a large arteriovenous fistula.z7g The diagnosis is made by the presence of an audible bruit over the cranium, dilated scalp veins, associated vascular malformations over the head, hyperdynamic cardiac impulse, abnormal findings on a computed tomography (CT) scan (Fig 141, and the visualization of the arteriovenous malformation with arteriography (Fig. 15). Cranial ultrasound and cardiac investigative techniques are also helpful in the clinical diagnosis. Cardiac catheterization is of value through recognition of a wide pulse pressure in combination with a high oxygen saturation in the superior vena cava and rightsided chambersZ7’ Chest roentgenograms reveal an enlarged heart with increased pulmonary vascular markings (Fig 16). The electrocardiogram may show enlargement of the right atrium and either right ventricular or biventricular hypertrophy (Fig 17). Early combined medical and surgical therapy may increase the chances for a successful outcome. Treatments include surgical clipping, embolization, and progressive occlusion.z80J 28X Unfortunately, the outcome with any type of treatment is very disappointing and the mortality is greater than 50% .277
FIG 15. This lateral view from an angiogram made following selective injection of contrast material in the right carotid artery shows an arteriovenous malformation of the vein of Galen, dilated feeding arterial branches, and prominent venous draining. (Same patient whose CT scan is shown in Figure 14.) 538
Cur-r
Probl
Cardiol,
September
1990
FIG 16. Chest roentgenogram massive cardiomegaly roimaging appearance
from infant with vein of Galen arteriovenous malformation, showing and increased pulmonary vascular markings. (The cerebral neuof the arteriovenous malformation is shown in Figures 14 and 15.)
VENTRICULOVENOUS
SHUNTS
In performing extracranial shunting of cerebrospinal fluid to treat hydrocephalus, ventriculoperitoneal shunts are preferred over ventriculovenous shunts (ventriculojugular, ventriculoatrial) because of fewer complications, lower mortality rates, and a simpler operative procedure.28z Cardiopulmonary complications occur in about 7% of patients with ventriculoatrial shuntsZa3 The complications of vascular shunting procedures include thromboembolism, catheter migration with embolization, and perforation.z84 Ventriculovenous shunts are rarely performed today. Thromboembolism Thromboembolism is the most common cardiopulmonary complication.z83’ 284 The distal portion of the catheter is the site of thrombus formation. Over 50% of patients who die with ventriculovenous shunts have a thromboembolism in the pulmonary arteries.283’284 In about one fourth of patients with a ventriculoatrial shunt, chronic irritation of the atrium may result in a nidus for the implantation of bacteria and thrombus formation.283 A thrombus resembling a tumor may form around the distal end of the tubing in the right atrium.285 Pulmonary embolism can produce acute symptoms, but a chronic picture of right ventricular failure and car pulmonale may also follow repeated small embolizations.28”-z288 Cardiac and pulmonary Curr
Probl
Car&cd,
September
1990
539
;: : I.... fy trz-- . .. . ... -_.(. ... .. .. . . ::.. .. ... ..,. .. .. .....a k. .
aVR
aVL
aVF
FIG 17. Electrocardiogram giant P waves
and
from newborn left ventricular
with vein of Galen hypertrophy.
arteriovenous
malformation,
showing
thrombi or sepsis may occur as complications of infected ventriculoatrial shunts.283, “’ An unusual complication of a ventriculoatrial shunt is a mycotic aneurysm of the pulmonary artery.z8g Superior vena cava obstruction secondary to thrombus formation has been reported as a complication in 1% to 6% of ventriculoatrial shunts.“s0-2s2 Real time two-dimensional echocardiography to detect a right atrial thrombus may be used as a part of routine follow-up.285~287 Thromboembolism with or without heart failure is an indication for removal of the shunt catheter, and if continued cerebrospinal fluid drainage is necessary, it may be replaced with a ventriculoperitoneal 540
Curr
Probl
Cardiol,
September
1990
shunt ?’ Thromboembolectomy intracardiac thrombusz8’
may be necessary
to remove a large
Catheter Migration with Embolization The distal tubing of a ventriculovenous shunt may separate and migrate to the vena cava, right atrium, right ventricle, left atrium (via a patent foramen ovale), or the pulmonary arteries.‘&l’ “‘, 2g3 Migration of the tubing to the left atrium can give rise to cerebral embolization. The catheter can interfere with the function of the pulmanic valve and also give rise to arrhythmias, infections, pulmonary embolism, and pulmonary hypertension.284’ 2s4 Tubing can be removed via thoracotomy or transvenous snare techniques with fl~oros~opy.~~~ In one of the two cases reported by Hougen, the catheter was left in situ because of its location in the periphery of the lung and relatively insignikant hemodynamic disturbance, with no symptoms during a follow-up period of 8 years.284 Perforation Reported sites of perforation by the tubing include the venae cavae, right atrium, and right ventricle.284~2g1 Cardiac perforation is caused either by forceful introduction of the distal catheter during shunt placement or by too long a distal catheter that ulcerates through the cardiac wall. An impacted distal tubing in the cardiac wall can give rise to increased intracranial press~re.~~* Perforation of the myocardium with tamponade occurs in less than 1% of patients with ventriculoatrial shunts and necessitates immediate pericardiocentesis.“’ NEUROLOGIC MEDICATIONS PRONE CARDIOVASCULAR COMPLICATIONS
TO PRODUCE
Certain drugs used to treat neurologic disorders effects on the cardiovascular system. Fortunately, fects are infrequent and most of them disappear the medicine is reduced or when the medicine is
may have adverse these adverse efwhen the dose of discontinued.
LEVODOPA When it is converted to dopamine, levodopa has cardiac arrhythmogenic effects due to an increase in the release’ of endogenous norepinephrine from the peripheral sympathetic nerve endings in the heart. In early clinical studies, cardiac arrhythmias, particularly atrial or ventricular ectopic beats, were noted during treatment with
Cur-r
Probl
Cardiol,
September
1990
641
levodopa in 7% to 12% of patientszs5 But decarboxylase inhibitor, carbidopa, which is now used in conjunction with levodopa, decreases the arrhythmogenic effect of levodopa.2s6 Therapy with levodopa-carbidopa appears to pose little increased hazard to patients with most forms of heart disease. Nevertheless, levodopa should be used with caution in patients over 70 years of age with angina, a history of recent myocardial infarction, or residual atrial, nodal, or ventricular arrhythmias.2s5 In these patients, it may be a good idea to carry out inpatient observation at the beginning of therto stress that Parkinson’s disapy with levodopa.zg7 It is important ease and cardiac disease frequently coexist, particularly in older patients. Orthostatic hypotension is noted in about 20% of patients taking levodopa.2g5’ 2’S The maximum tolerated doses of levodopa induce a mean reduction in erect systolic blood pressure of 19 mm Hg without any significant changes in pulse rate. This hypotension is probably due to dopamine acting on adrenergic nerve endings or on the CNS itself. In some patients, the hypotension may be prevented by the concomitant administration of proprano101,2ss giving support to the views that levodopa exerts a P-adrenergic action.“’ Hypotension induced by levodopa is dose-dependent and disappears as treatment continues. The addition of the peripherally acting dopa-decarboxylase inhibitor has greatly decreased the hypotension induced by levodopa?” A persistent, severe hypotension may indicate another problem such as progressive autonomic failure.
z3oz3 RECEPTOR AGONISTS (RROMOCRZPTINE,PERGOLZDE) Dopa receptor agonists, such as bromocriptine and pergolide, are used as an adjunct to combined levodopa and carbidopa therapy in the symptomatic treatment of Parkinson disease. Combined with levodopa, these medications produce a therapeutic response equal to that of levodopa alone, but with fewer fluctuations and less peakdose dyskinesias.301 The administration of dopamine agonists permits a reduction in the daily dose of levodopa. Dopa agonists may produce several cardiovascular side effects, the most common one being orthostatic hypotension.301-303 The postural hypotension can be corrected by lowering the dose. At high doses, patients can experience frequent extrasystoles, which cease on termination of the medication.304
METHYSERGZDEMALEATE This is a serotonin antagonist used in the prophylactic treatment of cluster headaches. Reported complications of long-term therapy with methysergide maleate include retroperitoneal fibrosis and fi542
Cur-r Probl
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1990
brosis of the cardiac valves. Less frequently, the aorta and coronary ostia may show fibrotic thickening305 Fibrotic changes in the cardiac valves are due to the presence of collagen tissue plaques covering the valves.305 The occurrence of heart murmurs, constrictive pericarditis, congestive heart failure, and myocardial infarctions in people without a previous history of heart disease who have been receiving methysergide maleate for 6 months to several years suggests that the use of this medication is directly related to the appearance of the cardiac abnormalities.305’ 306 Undesirable clinical symptoms seen after prolonged therapy with methysergide maleate may include cold numb extremities, intermittent peripheral claudication, and the appearance or worsening of angina. Narrowing of peripheral arteries can be demonstrated on arteriography. ERGOTAMINE
TARTRATE
Ergotamine tartrate is an a-adrenergic blocking agent with a direct stimulating effect on the smooth muscle of the peripheral and cranial blood vessels. The drug can be used parenterally, orally, or sublingually, and it is a safe medication when prescribed in correct doses. Nausea and vomiting, which occur when the drug is ingested in excess or too frequently, can prevent the occurrence of serious complications. Among the cardiovascular side effects are precordial discomfort and pain, transient tachycardia or bradycardia, and symptoms and signs of peripheral vascular insufficiency. In addition, ergotamine tartrate may aggravate preexisting occlusive vascular disease and coronary artery insufficiency. EDROPHONWM
About 1% of patients given anticholinesterase drugs experience adverse cardiovascular effects.307 Edrophonium is a short-acting anticholinesterase agent used intravenously as an aid in the diagnotests, if performed sis of myasthenia gravis. Most edrophonium cautiously, are free from adverse reactions. However, the action of accumulated acetylcholine on the myocardium may result in bradycardia, decreased cardiac output, hypotension, and a variety of cardiac arrhythmias .307,3o8 Atropine sulfate, 0.6 mg or more intravenously, should be given immediately if a severe muscarinic reaction ensues.3o8 It is necessary to keep in mind that, if the test is performed in patients in cholinergic crises, the respiratory failure and hypoxia that result from a further decrease in patients’ strength may give rise to hypotension and cardiac irregularities, which are often reversed by the establishment of adequate pulmonary ventilation3” and the adCurr
Pmbl
Cardid,
September
1990
543
ministration of atropine. A baseline electrocardiogram should be obtained before the edrophonium test, and appropriate cardiac monitoring, conventional resuscitative equipment, and emergency treatment must be available. ANTICONVULSANT
DRUGS
Among all the anticonvulsant drugs, phenytoin sodium, carbamazepine, phenobarbital, and primidone have been studied most intensely with regard to effects on the cardiovascular system (Table 13). Phenytoin is primarily an anticonvulsant drug indicated for the control of tonic-clonic seizures. Phenytoin is also effective in the treatment of ventricular arrhythmias, particularly those due to digitalis intoxication. Carbamazepine is an anticonvulsant used in partial complex and generalized seizures and is also a specific analgesic for trigeminal neuralgia. Phenobarbital is a long-acting barbiturate used as adjunctive therapy in the treatment of all types of seizures. Primidone resembles phenobarbital in its chemical structure and in some of its anticonvulsant effects. The incidence of congenital heart disease in children of women with epilepsy taking anticonvulsant drugs (mainly phenytoin, phenobarbital, and primidone) seems to be significantly higher (43 in 1,000) than in the general population (5.7 to 8 in 1,000).30g However, as with other congenital malformations related to epilepsy, it is difficult to state for certain whether these congenital cardiac malformaTABLE Cardiac
13. Side Effects
of Anticonvulsants*
IV Phenytoin ICardiovascular complications in 3.5% J Tachyarrhythmias 12% J Bradycardia and hypotension (1.5% 1 Ventricular asystole Oral Phenytoin and Primidone Teratogenic effects over the heart (43 in 1000, compared to 5.7 to 8 in 1000 in general population) Interaction with oral anticoagulants and quinidine Phenobarbital Interaction with oral anticoagulants and quinidine Carbamazepine Prolongation of atrioventricular conduction ‘Data fmm references
644
233,
235, 309,
312-315.
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tions in babies of mothers who took anticonvulsants during the first trimester of pregnancy are a result of genetic factors associated with the seizure disorder or a result of the teratogenetic effects of the drug. Patients on prolonged therapy with phenytoin develop low serum folate levels, Because the active derivatives of folic acid are intimately involved in the synthesis of nucleic acids and proteins, a folic acid deficiency in pregnancy may affect rapidly growing trophoblastic and embryonic tissues with subsequent teratogenicity.3f0 But there are studies attributing malformations seen in children of mothers with epilepsy to genetic factors. For example, Shapiro et in offspring of faal. 311 reported a high incidence of malformations thers with epilepsy, suggesting that fetal damage, which is attributed to phenytoin and other anticonvulsants, may be due to epilepsy itself. Whatever the cause, children of mothers with epilepsy have an increased incidence of premature births, microcephaly, cleft lip, cleft palate, ocular hypertelorism, epicanthal folds, other facial malformations, phalangeal hypoplasia, hypoplasia of nails, and congenital heart disease (Fig 18).3os Reported cardiac malformations include atria1 and ventricular septal defects, coarctation of the aorta, tetralogy of Fallot, and patent ductus arteriosus.30s Intravenous phenytoin infusion during the treatment of status epilepticus produces cardiovascular complications in about 3.5% of the cases.235 Intravenous phenytoin depresses myocardial contractility, decreases peripheral vascular resistance, and can produce disturbances of cardiac rate and rhythm.236 These cardiovascular complications, which include tachyarrhythmias, bradycardia, atrioventricular block, asystole, and hypotension, seem to be related to the use of high concentrations of phenytoin given at a rapid rate. However, BarronZ34 found that the slow, intravenous injection of small doses of phenytoin also may produce sudden, marked sinus bradycardia, hypotension, and syncope in healthy persons. This suggests that hypersensitivity to intravenous phenytoin may be unrelated to the total dose and rate of administration. In fact, in some of the reports of deaths during intravenous phenytoin infusion, the patients had received only 100 to 250 mg of phenytoin at the time they developed ventricular asystole.z33 It seems that elderly patients with digitalis toxicity, advanced intraventricular conduction disturbances, and severe chronic restrictive or obstructive pulmonary disease are prone to develop cardiac arrhythmias during the intravenous injection of phenytoin.233 It also seems likely that patients with subclinical heart disease may develop cardiac arrhythmias during prolonged oral treatment with phenytoin3” Phenytoin and phenobarbital seem to interact with the metabolism of quinidine, resulting in an inadequate blood level of quinidine. Likewise, treatment with phenobarbital decreases the anticoagCurr
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1990
645
FIG 18. Twelve-month-old with primidone embryopathy, pulmonic stenosis, and a ventricular tal defect. Picture shows depressed nasal bridge, anteverted nares, epicanthal folds, set ears, a long philtrum, and a thin upper lip.
seplow-
ulant effect of warfarin sodium. This is a result of increased elimination of the anticoagulant due to induction of warfarin-metabolizing This interaction becomes clinically enzymes by the barbiturate.313 evident after the first week of warfarin therapy. Withdrawal of phenobarbital in patients taking a well-tolerated dose of oral anticoagulants may result in prothrombinopenic hemorrhage. This interaction appears to be a common cause of bleeding among hospitalized patients. A drug interaction also occurs between warfarin and phenytoin. Warfarin interferes with the metabolism of phenytoin in the liver, leading to increased serum levels of phenytoin and the appearance of toxic symptoms.314 These effects have clinical significance when patients with epilepsy taking phenytoin are in need of anticoagulant therapy. In these patients, toxic levels of phenytoin can be produced by standard doses of the anticonvulsant drug. 546
Cut-r
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19Sll
Phenytoin has been advocated as the drug of choice for myotonic dystrophy and it is preferred over procainamide because the latter lengthens the P-R interval, which in some patients with myotonic dystrophy is already prolonged. But Durelli et al. emphasize the need for careful monitoring of plasma levels and a thorough assessment of cardiac status before initiating phenytoin therapy in these patients.312 They report a patient with myotonic dystrophy and echocardiographic signs of subclinical cardiomyopathy in whom ventricular tachycardia was induced by oral treatment with phenytoin when the serum level rose over 27 p#mL. The cardiac arrhythmia disappeared when the drug concentration fell to the therapeutic range. Experience with carbamazepine in young patients with epilepsy has shown that the drug is relatively safe and effective. Most adverse cardiovascular effects of carbamazepine occur in elderly patients with heart disease, particularly those with conduction abnormalities. The drug prolongs atrioventricular conduction.312’ 315 Although age is a factor, conduction disturbances have been described in relatively young subjects taking carbamazepine for epilepsy.315 Durelli et al. reported two patients with myotonic dystrophy and subclinical cardiomyopathy (mitral valve prolapse and abnormal thickness of the left ventricular wall on echocardiogram, defective conduction as shown by a P-R interval at the upper limit of normal) in whom a reversible first-degree atrioventricular block developed at low serum carbamazepine levelsal’ The authors stated that a defective conduction system is a prerequisite for the development of atrioventricular block induced by carbamazepine. But many physicians believe that an underlying defect in conduction is not a prerequisite for carbamazepine-induced cardiac conduction disturbances.315 The conduction defect disappears after carbamazepine is discontinued.315 Because of the carbamazepine-induced conduction disturbances, treatment of patients with Stokes-Adams attacks misdiagnosed as epilepsy may have a deleterious effect. It is recommended that an electrocardiogram be obtained in elderly individuals prior to the institution of therapy with carbamazepine.315 The serum levels of valproic acid, phenytoin, and carbamazepine appear to increase when verapamil is used in patients taking any of Administration of verapamil to patients these anticonvulsants.3f6 taking carbamazepine significantly increases the total plasma level of carbamazepine by more than 40% and the free plasma level of carbamazepine by more than 30%.‘17 Therefore, the use of verapamil in patients previously stabilized on carbamazpine should be avoided.
Curr
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547
TRICYCLZC
ANTIDEPRESSANT
DRUGS
These drugs, widely regarded as effective adjunctive therapy for several neurologic problems, are safe medications at normal therapeutic levels in patients who have normal hearts.318 But occasionally these drugs produce arrhythmias in patients with cardiac disease, especially in those patients being treated with multiple medications. At therapeutic doses, imipramine prolongs intraventricular conduction and widens QR8 complexes.31s Psychotropic drugs, such as tricyclic antidepressants and thioridazine, prolong the Q-T interval. Patients with preexisting Q-T interval prolongation are at risk for lethal arrhythmias when treated with psychotropic drugs3” Because patients with psychic depression have Q-T interval prolongation more often than normal subjects, even in the absence of drug therapy, many authors emphasize the importance of electrocardiographic evaluation in patients with depression prior to the use of psychotropic drugs.32o Ventricular tachycardia, intraventricular conduction defects, and high-degree atrioventricular block are most likely to occur in patients with preexisting heart disease. Sudden, unexpected death has occurred more frequently during treatment with amitriptyline in patients with a history of heart disease than in patients without heart disease. Cardiac complications following tricyclic antidepressant overdosage include convulsions (12%), coma (30%), hypotension (7%), hypertension (9%), respiratory arrest (7%), and cardiac arrest (4% 1. Temporary electrocardiographic changes develop in 55% of cases.321 The most frequent electrocardiographic alterations are sinus tachycardia (12%), sinus bradycardia (4%), atrioventricular block (19%1, enlargement of QRS complexes (19 to 23% 1, T wave abnormalities (82% 1, prolonged Q-T interval (60% to 85%1, and ventricular tachycardia or fibrillation (4% 1.321 The vast majority of electrocardiographic changes in tricyclic antidepressant overdosage appear within the first 24 hours, and the clinical course of the intoxication is more severe in patients with electrocardiographic changes.321 Patients who develop electrocardiographic abnormalities in the course of the intoxication are more frequently unconscious and more often require assisted ventilation than those without electrocardiographic changes. In a prospective study of 49 patients with acute overdosage of tricyclic antidepressant drugs, Boehnert and Lovejoy3” found that serum drug levels failed to predict the risk of ventricular arrhythmias accurately, but ventricular arrhythmias were seen only with a QRS duration of 0.16 seconds or longer: They concluded that determination of the maximal limb-lead QRS duration predicts the risk of ventricular arrhythmias in acute overdoses with tricyclic antidepressants. Pro-
648
Cur-r Pmbl
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phylactic insertion of a temporary cardiac pacemaker may be necessary in patients with wide QRS complexes.321 Another frequent cardiovascular side effect of the tricyclic antidepressant drugs is orthostatic hypotension. The incidence of orthostatic hypotension is significantly higher among those patients with severe heart disease. Because adverse cardiovascular reactions cannot be predicted, it is helpful to monitor those patients who have cardiovascular disease while they are receiving tricyclic antidepressant drugs. In an acute overdose with tricyclic antidepressants, hypotension occurs in the absence of any significant cardiac arrhythmia and appears to be secondary to a fall in cardiac output as a result of a direct toxic effect of the drug on the myocardium. No hemodynamic problems occur after the first 12 hours of intoxication.321 Tricyclic antidepressant drugs interfere with the hypotensive action of guanethidine.323 The antihypertensive effect of guanethidine is mediated by adrenergic neuron blockade and is dependent on uptake of guanethidine in peripheral adrenergic neurons. This uptake is blocked by the tricyclic compounds. Perhaps by the same mechanism, tricyclic antidepressant drugs hamper the hypotensive action of clonidine; but other effects of the tricyclic medications are likely to play a role. The clinical implication is that the combination of a tricyclic antidepressant drug with guanethidine or clonidine must be carefully monitored for the development of a pharmacologic interaction.
PHENOTHLAZINES
Hypotension, the most common cardiovascular effect of phenothiazines, is due to vasodilatation that results not only from inhibition of centrally mediated pressor reflexes, but also from cw-adrenergic blockade. By their ability to compete with catecholamines for binding sites in the cell membrane, phenothiazines can block and even reverse the sympathomimetic effects of epinephrine. Therefore, the concomitant use of phenothiazines and epinephrine can induce hypotension and a shock-like state which may not be responsive to vasopressors. At the same time, the blockade of catecholamine binding sites by phenothiazines results in high blood levels of catecholamines. The increase in blood catecholamines may play a role in the genesis of electrocardiographic changes and cardiac’arrhythmias occasionally encountered after prolonged use of phenothiazines. Electrocardiographic changes during treatment with phenothiazines include prolongation of the P-R and Q-T intervals, depression of the ST segment, and flattening of T waves.
Curr
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1990
649
The anhythmogenic activity of therapeutic doses of phenothiazines administered for prolonged periods of time has been associated with sudden death in patients without preexisting cardiac disease. A review of the effects of prolonged administration of phenothiazines in seven young patients in whom cardiac arrhythmias, myocardial failure, and conduction abnormalities were attributed to the use of phenothiazines suggests that the insidious, cumulative toxicity of these drugs is capable of producing toxic cardiomyopathy. Further studies to quantity the risk of prolonged therapy with psychotropic drugs are needed. However, the interest in this subject seems to have declined with the advent of nonphenothiazine drugs that are free from cardiac toxicity. MONOAMINE
OXIDASE INHIBITORS
The potentiation of the effects of sympathomimetics by nonselective or type A-selective monoamine oxidase inhibitors may result in increased blood catecholamine levels, with resultant hypertensive crises and cardiac arrhythmias. Therefore, patients receiving these monoamine oxidase inhibitors should not be given methyldopa, levodopa, dopamine, epinephrine, norepinephrine, amphetamines, tricyclic antidepressant drugs, or substances containing tyramine, such as cheddar cheese, herring, burgundy wine, and beer. Deprenyl (selegiline hydrochloride) which is used in Parkinson’s disease, is a type B-selective monoamine oxidase inhibitor without adverse pressor effects when it is administered at the recommended dosage of 10 mg per day.324
LITHIUM
CABBONATE
Lithium carbonate is primarily used in the treatment of manic episodes of bipolar affective disorders. In neurologic practice, lithium carbonate is also used in the prevention of cluster headaches not responsive to conventional therapy. A statistically significant increase in the frequency of T wave depression and inversion occurs in the electrocardiograms of patients receiving therapeutic doses of lithium carbonate.325’ 326 Rarely, lithium may cause reversible, symptomatic sinus node dysfunction or ventricular arrhythmias.326, 327 Patients with lithium toxicity almost always present with hypotension, cardiovascular collapse, and alterations of consciousness. D. MCCALL: Both the tricyclic antidepressants been shown to have ant&rhythmic properties Electrophysiologic studies have shown that both overshoot of the action potential, decrease the
b
550
and the phenothiazines have similar to those of quinidine. groups of drugs decrease the maximal rate of rise during
Curr
Probl
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phase 0 of the action potential, decrease the duration and amplitude of phase 2 and prolong the repolarization phase, phase 3. These effects are identical to those of quinidine. This similarity, therefore, readily explains the electrocardiographic changes described by the authors. It also suggests that the arrhythmogeniticity of these drugs is similar to the proarrhythmic effect of quinidine, namely, facilitation of reentrant excitation as a result of decreased conduction velocity and temporal dispersion of action potential duration. Following accidental or intentional overdosage with these drugs, patients are at greatest risk for the development of serious ventricular arrhythmias during the first 24 to 72 hours, i.e., when serum drug levels are declining. It is possible that changing serum levels are associated with greater nonuniformity of action potential duration and hence greater susceptibility to reentrant arrhythmias. Regardless of the mechanism, however, this recovery phase has shown the greatest vulnerability to potentially lethal arrhythmias and careful electrocardiographic monitoring of these patients for up to 72 hours is essential.
Following free filtration -at the glomerulus, lithium is partially reabsorbed exclusively at proximal tubular sites in parallel with sodium. 328,32g Long-term thiazide treatment leads to a compensatory increase in sodium reabsorption at the proximal tubules, and lithium is also reabsorbed with sodium. Therefore, long-term use of thiazides gives rise to a decrease in lithium clearance, and an increase in serum levels of lithium.32s In patients who need both medications, Himmelhoch et al. recommend reduction in the daily lithium dose to compensate for the decrease in renal lithium clearance, making subsequent refinements in dose according to lithium serum levels and the clinical state of the patient.330 Proximal tubular reabsorption of sodium is increased in patients with hypertension. This perturbation of renal sodium handling in patients with hypertension also increases the proximal tubular fractional lithium reabsorption, for which reason lithium clearance is decreased in patients with essential hypertension.3z8 A decreased glomerular filtration rate, the presence of heart failure, and dietary salt restriction also reduce the renal clearance of lithium, leading to elevation of plasma lithium levels and increasing the possibility of toxic effects.32g* 330 Serum levels of lithium and renal function should be monitored carefully in patients with cardiac disease who are taking lithium carbonate. Lithium and verapamil have similar effects on the neurosecretory process, neurotransmitter dynamics, calcium metabolism, and calcium transport. A synergistic drug interaction can be encountered when combining lithium carbonate with verapamil.331’ 332 Profound bradycardia developed in two patients taking verapamil in combination with lithium carbonate.333 One of these two patients developed a fatal myocardial infarction. Valdiserri331 reported one patient who was receiving 900 mg per day of lithium carbonate who developed a significant extrapyramidal reaction when diltiazem treat angina pectoris. However, there are extrapyramidal Cur-r Probl
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1990
was
added abnormali-
to
651
ties such as cogwheel rigidity and tremor in more than half of the patients taking lithium carbonate alone for prolonged periods of time.334 At any rate, caution is advised in the use of lithium and verapamil together. Caution is also recommended when prescribing lithium carbonate for women of childbearing age. Approximately 7% of infants born to women receiving chronic lithium therapy will have serious cardiac defects.335 Ebstein’s anomaly, a usually rare defect, is common among these infants. b G. A. BELLER:Digitalis is another drug that has direct CNS effects that affect the heart. Digitalis excess can cause increased nerve traiBc along sympathetic nerves which may contribute to the genesis of digitalis-toxic ventricular rhythm disturbances. The noncardiac toxic manifestations of digitalis excess such as anorexia, nausea, and vomiting are also secondary to the nemoexcitatory effects of the drug. b S. H. BAHIMTOOIA:The occurrence of rhythm disorders with a variety of pharmaceutical agents, in addition to antiarrhythmic agents, needs to be emphasized. This is an exhaustive and excellent review of neurologic conditions that affect the cardiovascular system. It is a most valuable resource that is needed and will be referred to by all practicing clinicians. b D. MCCALL: The authors have provided an extensive review of the effect of a large variety of neurologic and neuromuscular diseases on the cardiovascular system. They have grouped the topics logically and conveniently and have pruvided an extensive bibliography for each condition described. The monograph plays an important role in bringing together this vast array of information and in providing a ready source of references for those who may want to explore any particular condition in greater depth. The authors are to be congratulated for their tremendous effort. ACKNOWLEDGMENTS
We thank Colonel Steve Stephenson, US Army Medical Corps, and Sue Lamonde, from the Department of Clinical Investigation, William Beaumont Army Medical Center, El Paso, Texas, for their assistance in the preparation of this review article. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or Department of Defense. REFERENCES 1. Thompson GE: Pulmonary edema complicating intrathecal hypertonic saline injection for intractable pain. Anesthesiology 1971; 35:425-427. 2. Talman WT: Cardiovascular regulation and lesions of the central nemous system. Ann New-01 1985; 18:1-12. 652
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rhythmias detected by ambulatory monitoring. Chest 1979; 75’565-568. 243. Howell SJL, Blumhardt LD: Cardiac asystole associated with epileptic seizures: A case report with simultaneous EEG and ECG. J New-01 Neurosurg Psychiatry 1989; 52:795-798. 244. Young RSK, Fripp RR, Yagel SK, et al: Cardiac dysfunction during status epilepticus in the neonatal pig. Ann Neural 1985; 18291-297. 245. Kiok MC, Terrence CF, Fromm GH, et al: Sinus arrest in epilepsy. Neurology 1986; 36:115-116. 246. Marshall DW, Westmoreland BF, Sharbrough FW: Ictal tachycardia during temporal lobe seizures. Mayo Clin Proc 1983; 58:443-446. 247. Pritchett ELC, Minamara JO, Gallagher JJ: Arrhythmogenic epilepsy: A hypothesis. Am Heart J 1980; 100:683-687. 248. Devisky 0, Price BH, Cohen SI: Cardiac manifestation of complex partial seizures. Am J Med 1986; 80:195-202. 249. Mulroy JJ, Mickell JJ, Tong TK, et al: Postictal pulmonary edema in children. Neurology 1985; 35:403-405. 250. Falconer B, Jovan R: Post-mortem findings of cardiac lesions in epileptics: A preliminary report. Forensic Sci 1976; 863-71. 251. Gospe SM Jr, Choy M: Hereditary long Q-T syndrome presenting as epilepsy: Electroencephalography laboratory diagnosis. Ann Neural 1989; 25: 514-516. 252. Bricker JT, Garson A, Gillette PC: A family history of seizures associated with sudden cardiac death. Am J Dis Child 1984; 138:866-868. 253. Zwillich C, Devlin T, White D, et al: Bradycardia during sleep apnea. J Clin Invest 1982;69:1286-1292. 254. Guilleminault C, Connolly SJ, Winkle RA: Cardiac arrhythmias and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 255. Henderson-Smart DJ, Butcher-Puech MC, Edwards DA: incidence and mechanism of bradycardia during apnoea in preterm infants. Arch Dis Child 1986;61227-232. 256. Orr WC: Sleep apnea, hypoxemia, and cardiac arrhythmias. Chest 1986; 89:1-2. 257. Kryger N, Quesney LF: The sleep deprivation syndrome of the obese patient. Am J Med 1974; 56:531-539. 258. Kawakami T, Otsuka K, Saito H, et al: Arrhythmogenesis during sleep-induced apnea. Am Heart J 1984; 108:1591- 1593. 259. Chaudhary BA, Ferguson DS, Speir WA: Pulmonary edema as a presenting feature of sleep apnea syndrome. Chest 1982; 82:122-124. 260. Ross RD, Daniels SR, Loggie JMH, et al: Sleep apnea-associated hypertension and reversible left ventricular hypertrophy. J Pediatr 1987; 111: 253-255. 261. Lavie P, Ben-Yosef R, Rubin AE: Prevalence of sleep apnea syndrome among patients with essential hypertension. Am Heart J 1984; 108:373-376. 262. Tirlapur VG: Sleep apnea and essential hypertension. Am Heart J 1985; 109:1409-1410. 263. Gabriel M, Albani M, Schulte FJ: Apneic spells and sleep states in pmterm infants. Pediatrics 1976; 57:142-147. 264. Steinschneider A: Prolonged apnea and the sudden infant death syndrome. Clinical and laboratory observations. Pediatrics 1972; 50:646-654. 265. Steinschneider A, Weinstein SL, Diamond E: The sudden infant death syndrome and apnea/obstruction during neonatal sleep and feeding. Pediatrics 1982; 70:858-863. 564
Curr Probl Cardiol, September 1990
266. Naeye RL: Pulmonary arterial abnormalities in sudden infant death syndrome.N Engl .I Med 1973;289:1167-1170. 267. Jankus A: The cardiac conduction system in sudden infant death syndrome. Pathology 1976; 8275-280. 268. Lie JT, Failoni DD, Davis DC: Temporal arteritis with giant cell aortitis, coronary arteritis, and myocardial infarction. Arch Path01 Lab Med 1986; 1101857-860. 269. Caselli RJ, Hunder GG, Whisnant JP: Neurological disease in biopsy-proven giant cell (temporal) arteritis. Neurology 1988; 38:352-359. 270. Klinkhoff AV, Reid GD, Moscovich M: Aortic regurgitation in giant cell arteritis. Arthritis Rheum 1985, 28582-585. 271. Mumenthaler M: Giant cell arteritis. J Neural 1978; 218219-236. 272. Paulley JW: Coronary ischaemia and occlusion in giant cell (temporal) arteritis. Acta Med Stand 1980; 208257-263. 273. Bowles C, Hunder GG: Aortic valve involvement in temporal arteritis. Arthritis Rheum 1984;27:86. 274. Lie JT: Coronary vasculitis: A review in the current scheme of classification of vasculitis. Arch Path01 lab Med 1987; 111224-233. 27.5. Bloch T, Wailer BF, Vakih ST: Giant cell arteritis of the coronary arteries. Indiana Med 1987; 80262-264. 276. Blumenthal HJ: Temporal arteritis without an elevated erythmcyte sedimentation rate. Am J Med 1987; 82:187. 277. Knudson RP, Alden ER: Symptomatic arteriovenous malformation in infants less than 6 months of age. Pediatrics 1979; 64238-241. 278. Fujishima M, Tanaka K, Omae T: Cerebral arteriovenous malformation as a cause of cardiac hypertrophy in adults. Jpn Heart J 1972; 13:471-477. 279. Cumming GR: Circulation in neonates with intracranial arteriovenous fistula and cardiac failure. Am 3 Cardiol 1980; 45:1019-1024. 280. Mickle JP, Quisling RG: The transocular embolization of vein of Galen aneurysms. J Neurosurg 1986; 65:731-735. 281. Vinuela F, Dion J, Lylyk P, et al: Update on interventional neumradiology. AJR 1989; 15323-33. 282. Olsen L, Frykberg T: Complications in the treatment of hydrocephalus in children. Acta Paediatr Stand 1983; 72:385-390. 283. Anderson FM: Ventriculocardiac shunts: Identification and control of practical problems in 143 cases. J Pediatr 1973; 82:222-227. 284. Hougen TG, Emmanoulides GC, Moss AJ: Pulmonary valvular dysfunction in children with ventriculovenous shunts for hydmcephalus: A previously unreported complication. Pediatrics 1975; 55:836-841. 285. Iqbal SM, Pezzella AT, Effler DB: Infection and right atria1 pseudotumor complicating a ventriculoatrial shunt for hydmcephalus. Am J Cardiol 1984; 54:668-670. 286. Greco R, Massari A, Colangeli M, et al: Grave complicanza di shunt liquorale ventricolo-atriale per idmcefalo infantile: I1 cuore pulmonare cmnico. Riv Neurobiol 1981; 27:501-508. 287. Schmaltz AA, Huenges R, Hell RP: Thrombosis and embolism complicating ventriculo-atria1 shunt for hydrocephalus: Echocardiographic findings. Br HeartJ 1980;43241-243. 288. Sperling DR, Patrick JR, Anderson FM, et al: Cor pulmonale secondary to ventriculoauriculostomy. Am J His Child 1964; 107:308-315. 289. Gelfand ET, Callaghan JC: Mycotic pulmonary artery aneurysm: An unusual complication of ventriculo-atria1 shunt. Cardiovascular disease. Bull Te,x Heart Inst 1981; 8:271-275. Curr
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290. Tsingoglou S, Forrest DM: Complications from Holter ventriculo-atria1 shunts. Br J Surg 1971; 58:372-377. 291. Forrest DM, Cooper DGW: Complications of ventriculo-atria1 shunts: A review of 455 cases. J Neurosurg 1968: 29506-512. 292. Guthkelch AN: The treatment of infantile hydrocephalus by the Holter valve. Br J Surg 1967; 54:665-673. 293. Daniele B, Colangelo M, Ruggiero R, et al: Migration of distal catheter of the ventriculo-atrial shunt into the right atrium: Case report. J Neurusurg Sci 1984; 28:41-42. 294. McLaurin RL: Infantile hydrocephalus, in Wilson CB, Hoff JT teds): Current Surgical Management of Neurological Disease. New York, Churchill Livingston, 1980, p 26. 235. Wener J, Rosenberg G, Grad B, et al: Cardiovascular effects of levodopa in aged versus younger patients with Parkinson’s disease. J Am Geriatr Sot 1976; 24:185- 188. 296. Watanabe AM, Parks LC, Kopin IJ, et al: Modification of the cardiovascular effects of L-dopa by decarboxylase inhibitors. J Clin Invest 1971; 50: 1322-1328. 297. Jenkins RB, Mendelson SH, Lamid S, et al: Levodopa therapy of patients with parkinsonism and heart disease. BF Med J 1972; 3512-514. 298. Rinne UK: Problems associated with long-term levodopa treatment of Parkinson’s disease. Acta Neural Stand 1983; 95:19-26. 299. Duvoisin RC: Hypotension caused by L-dopa (letter). Br Med J 1970; 3:47. 300. Sachs C, Berglund B, Kaijser L: Autonomic cardiovascular responses in parkinsonism: Effect of levodopa with dopa-decarboxylase inhibition. Acta Neural Stand 1985; 71:37-42. 301. Rinne UK: Combined bromocriptine-levodopa therapy early in Parkinson’s disease. Neurology 1985; 35:1196-1198. 302. Factor SA, Sanchez-Ramos JR, Weiner WJ: Parkinson’s disease: An open label trial of pergolide in patients failing bromocriptine therapy. J Neural Neurosurg Psychiatry 1988; 51:529-533. 303. Lorrain J, DiPaola ED, Lhoste F, et al: Effects of pergolide on the cardiovascular responses to sinoaortic deafferentation in dogs with intact or surgically decentralized adrenal glands. J Pharmacol E.“p Ther 1987; 240: 280-293. 304. Teychenne PF, Leigh PN, Reid JL, et al: Idiopathic parkinsonism treated with bromocriptine. Lancet 1975; 2:473-476. 305. Bana DS, MacNeal PS, LeCompte PM, et al: Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J 1974; 88:640-655. 306. Orlando RC, Moyer P, Barnett TB: Methysergide therapy and constrictive pericarditis. Ann Intern Med 1978; 88213-214. 307. Arsura EL, Brunner NG, Namba T, et al: Adverse cardiovascular effects of anticholinesterase medication. Am J Med Sci 1987; 293:18-23. 308. Taylor P: Anticholinesterase agents, in Gilman AG, Goodman LS, Rall TW, et al teds): The Pharmacological Basis of Therapeutics. New York, MacMillan Publishing Co, 1985, pp 110-127. 309. Annegers JF, Elveback LR, Hauser WA, et al: Do anticonvulsants have a teratogenic effect? Arch Neural 1974; 31:364-373. 310. Dansky LV, Andermann E, Rosenblatt D, et al: Anticonvulsants, folate levels, and pregnancy outcome: A prospective study. Ann Neurol 1987; 21: 176-182. St36
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311. Shapiro S, Hartz SC, Siskind V, et al: Anticonvulsants and parental epilepsy in the development of birth defects. Lancet 1976; 1272-275. 312. Durelli L, Mutani R, Sechi GP, et al: Cardiac side effects of phenytoin and carbamazepine. Arch Neurol 1985; 42:1067-1068. 313. Udall JA: Clinical implications of warfarin interaction with five sedatives. Am J Caro!iol 1975; 3567-71. 314. O’Reilly RA: Anticoagulant, antithrombotic, and thrombolytic drugs, in Gilman AG, Goodman LS, Rat1 TW, et al teds): The Pharmacological Basis of Therapeutics. New York, MacMillan Publishing Co, 1985, p 1349. 315. Benasi E, Bo G-P, Cocito L, et al: Carbamazepine and cardiac conduction disturbances. Ann Neural 1987; 22280-281. 316. Piepho RW, Culbertson VL, Rhodes RS: Drug interactions with the calciumentry blockers. Circulation 1987; 75:181- 194. 317. Macphee GJ, McInnes GT, Thompson GG, et al: Verapamil potentiates carbamazepine neurotoxicity: A clinically important inhibitory interaction. Lancet 1986;1:700-703. 318. Mahapatra RK, Paul SK, Mahapatra D, et al: Cardiovascular effects of polycyclic antidepressants. Angiology 1986; 37:709-717. 319. Burckhardt D: Clinical relevance of cardiovascular side-effects of tri- and tetracyclic antidepressants: Fear or facts. Int J Cardiol 1983; 2:387-389. 320. Flugelman MY, Tal A, Pollack S, et al: Psychotropic drugs and long QT syndromes: Case reports. J Clin Psychiatry 1985; 46290-291. 321. Pellinen TJ, Farkkila M, Heikkila J, et al: Electrocardiographic and clinical features of tricyclic antidepressant intoxication. Ann Clin Res 1987; 19:12-17. 322. Boehnert MT, Lovejoy FH: Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdosage of tricyclic antidepressants. N Engl J Med 1985; 313:474-479. 323. Leishman AW, Matthews HL, Smith AJ: Antagonism of guanethidine by imipramine. Lancet 1963; 1:112. 324. The Parkinson Study Group: Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engt J Med 1989; 321:1364-1371. 325. Bucht G, Smigan L, Wahlin A, et al: ECG changes during lithium therapy: A prospective study. Acta Med &and 1984; 216:101- 104. 326. Mitchell JE, MacKenzie TB: Cardiac effects of lithium therapy in man: A review. J Clin Psychiatry 1982; 43:47-51. 327. Wilson JR, Kraus EG, Bailas MM, et al: Reversible sinus-node abnormalities due to lithium carbonate therapy. N Engl J Med 1976; 294:1223-1224. 328. Weder AB, Fitzpatrick MA: Lithium-sodium countertransport: Physiological moorings for red cell transport disorders in hypertension. J Cardiovasc Pharmacol1986;8:76-81. 329. Petersen V, Hvidt S, Thomsen K, et al: Effect of prolonged thiazide treatment on renal lithium clearance. Br Med J 1974; 3:143-145. 336. Himmelhoch JM, Poust RI, MaRinger AG, et al: Adjustment of lithium dose during lithium-chlorothiazide therapy. Clin Pharmacol Ther 1977; 22: 225-227. 331. Valdiserri EV: A possible interaction between lithium and diltiazem: Case report. J C/in Psychiatry 1985; 46:540-541. 332. Price WA, Giannini AJ: Neurotoxicity caused by lithium-verapamil synergism. J Clin Pharmacol 1986; 26:717-719. 333. Dubovsky SL, Franks RD, Allen S: Verapamil: A new antimanic drug with potential interaction with lithium. J Clin Psychiat 1987; 48371-372. Curr
Pmbl
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334. Ghadirian AM, Lehmann HE: Neurological brain syndrome, seizures, extrapyramidal Compr Psychiatry 1980; 21:327-335. 335. Brady HR, Horgan JH: Lithium and 166- 168.
side effects of lithium: Organic side effects and EEG changes. the
heart.
Chest
1988;
93:
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William Pearl, M.D., received his medical degree from the State University of New York at Brooklyn in 1970. He took his residency training in pediatrics at New York HospitalCornell Medical Center, and a fellowship in pediatric cardiology at the Albert Einstein College of Medicine, both in New York City. He has been enagaged in the full-time practice of pediatric cardiology in teaching hospitals of the United States Army for the past 15 years. He is a fellow of both the American Academy of Pediatrics and the American College of Cardiology, and is a Clinical Associate Professor of Pediatrics at TeFas Tech University School of Medicine.
Victor J. Ferrans, M.D., Ph.D., graduated from the Tulane University School of Medicine in 1960, and received a Ph.D. in anatomy from the Tulane University Graduate School in 1963. After completing training in internal medicine and cardiology at Tulane, he joined the Pathology Branch of the National Heart, Lung, and Blood Institute at the National Institutes of Health, where he is Chief of the Ultrastructure Section. His research interests are centered on the pathology of cardiovascular, pulmonary, and meta-
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NEUROLOGIC CONDITIONS THE CARDIOVASCULAR
AFFECTING SYSTEM
We present a survey of neurologic conditions affecting the cardiovascular system. One of the motivations to carry out a comprehensive review of this subject is the difficulty encountered by students and residents trying to find this information in conventional textbooks. Apart from interesting clinical features, the cardiovascular manifestations and complications of neurologic conditions are important because they dramatically alter the prognosis of the basic neurologic problem. Therefore, recognition and prompt treatment of a cardiovascular manifestation or complication of a neurologic disease are indispensable steps toward attaining better results in the management of a neurologic illness. We classify neurologic conditions affecting the cardiovascular system as: autonomic nervous system dysfunctions; myopathies; metabolic disorders; malformations of the central nervous system; hereditary and degenerative diseases; paroxysmal conditions (seizures, sleep apnea); miscellaneous vascular conditions; and neurologic medications prone to produce cardiovascular complications.
AUTONOMIC
NERVOUS
SYSTEM DYSFUNCTION
The autonomic nervous system is a mediator in the genesis of a number of cardiovascular abnormalities encountered during the course of neurologic diseases. A paradigm of this mediation is the Cushing phenomenon, which shows that an increase in intracranial pressure is followed by an increase in systemic blood pressure, presumably as a protective response to ensure cerebral perfusi0n.l
CARDZAC
CHANGES
IN ACUTE
INTZSACRANL4L
Central nervous system (CNS) lesions produce tonomic activity with consequent hemodynamic
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1990
DISEASE
disturbances in auchanges, and clini-
479
TABLE 1. Cardiovascular Abnormalities Subarachnoid Hemorrhage
in
Electrocardiographic changes: large upright T waves Long QT interval Q waves and ST depression Rhythm disturbances Supraventricular tachycardia Atrial flutter-fibrillation Sinus bradycardia Arrest, nodal rhythms AV block or dissociation Premature ventricular contractions Ventricular flutter-fibrillation4
cal, electrocardiographic, and pathologic evidence of myocardial damage .’ Subarachnoid hemorrhage produces significant effects on cardiac function as a result of autonomic nervous system involvement (Table 1). Electrocardiographic and pathologic changes in the heart occur more frequently in subarachnoid hemorrhage than in any other intracranial catastrophe.3 Serious ventricular ectopy, myocardial necrosis, and subendocardial hemorrhages4 occur in a significant number of patients with acute cerebrovascular accidents of any type when compared with a control group of patients.4-7 This does not seem to reflect the presence of preexisting heart disease, The electrocardiographic changes associated with subarachnoid hemorrhage include atrial and ventricular arrhythmias and changes suggestive of myocardial ischemia.4 The latter include alterations in QRS configuration, QT interval prolongation, T wave abnormalities, and ST segment elevation. The mechanism of the electrocardiographic changes in subarachnoid hemorrhage has not been explained satisfactorily. Vagal stimulation, hypothalamic stimulation, and stimulation or destruction of the sympathetic nerves can produce electrocardiographic and myocardial damage in experimental animals .4 b D. MCCALL: As the authors point out, electrocardiographic abnormalities are common in the setting of subarachnoid hemorrhage and other cerebrovascular accidents. In experimental animals, similar changes can be produced by stimulation or ablation of one of the stellate ganglia, with a resultant imbalance of sympathetic stimulation to the anterior and posterior myocardial wall. The authors rightly emphasize the role of the autonomic nervous system in the genesis of these electrocardiographic findings and cardiac arrhythmias associated with intracerebral hemorrhage. This is further emphasized by the observation that, in patients with intracranial lesions, the most common ECG abnormalities (T-wave 480
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inversion and QT prolongation) can be corrected by the infusion no1 to produce uniform sympathetic stimulation of the ventricular
of isoproteeemyocardium.
Transmurally scattered foci of damaged myocardial fibers were seen in 62% of patients with intracranial lesions compared with 26% of control patients.’ Focal myocardial damage requires at least 6 hours to develop after the onset of an acute neurologic event and is not observed after the second week. This damage is associated with intracranial lesions which produce a rapid increase in intracranial pressure
and
is usually
absent
in patients
with
slowly
enlarging
or
small cerebral lesions.’ Postulated mechanisms of cardiac damage in patients with acute cerebral lesions include an increase in the level of plasma catecholamines secondary to a rapid increase in intracranial pressure8 and ischemic irritation of the hypothalamus.3 Whatever the mechanism, there is clinical evidence that a sudden increase in the intracranial pressure gives rise to diencephalic compression which in turn produces: (a) massive vagal discharges leading to sinus bradycardia, sinus arrest, sinus arrhythmias, and atrioventricular block; and (b) massive sympathetic discharges which may lead to supraventricular tachycardia, bigeminal rhythm, and ventricular tachycardia.3, ’ It has been suggested that the cerebral cortex of the orbital surface of the frontal lobe, which contains the cortical representation of the vagus nerve, is stimulated either by the blood in the subarachnoid space or by the local effects of a nearby aneurysm. Focal transient ischemic attacks of the brain caused by carotid atherosclerosis are reflections of either cerebral or cardiovascular disease. Patients with recurrent transient ischemic attacks of the brain seem to be at great risk of suffering a myocardial infarct.l’ The s-year cumulative rate of myocardial infarction or sudden death in these patients is 2l%, a rate only slightly less than that of fatal or nonfatal cerebral infarction (22.7% 1.ll Furthermore, cardiovascular disease is the leading cause of death in long-term survivors of stroke. A person who recovers from a stroke has a greater risk of suffering a heart attack than a second stroke.” A lesion anywhere in the CNS can produce an acute elevation of arterial blood pressure? Hypertension is especially common following compression, ischemia, or distortion of the medulla oblongata (Fig 1),13 and with hypothalamic lesions.’ Such abnormalities are thought to produce an imbalance in the neural control system that normally regulates blood pressure, with subsequent cardiovascular of the changes and hypertension,13’ I4 but there is no explanation mechanism involved. Neurogenic pulmonary edema occurs in association with CNS disease without underlying cardiopulmonary pathologic problems.” Neurogenic pulmonary edema may complicate intracerebral and Cm-r Probl
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481
FIG 1. Schematic drawing of neurovascular compression simulator in baboons. Neurogenic hypertension is induced by experimental pulsatile compression of the ventrolateral aspect of the medulla oblongata. (From Jannetta PM, Segal R, Wolfson SK Jr: Ann Surg 1985; 202:253-261. Used by permission.)
subarachnoid hemorrhage in patients in whom no pie-existing left ventricular dysfunction can be identified.16 Nearly 52% of patients who die of acute traumatic or spontaneous intracerebral hemorrhage have pulmonary edema, compared to 29% of patients who die from other causes. In neurogenic pulmonary edema, there are alterations in the pulmonary microvascular pressure and pulmonary capillary permeability resulting from the influence of neurogenic mechanisms.17 But the factors involved in the activation of these neurogenic mechanisms are controversial and poorly understood. In experimental animals, pulmonary edema can be produced by discrete bilateral lesions in the preoptic hypothalamic region. Nevertheless, histologic studies in patients in whom pulmonary edema occurred during the course of a subarachnoid hemorrhage have failed to demonstrate consistent hypothalamic lesions. Furthermore, ante-
482
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1990
rior hypothalamic lesions (foci of necrosis, perivascular microhemorrhages), which are found in 60% of patients with ruptured intracranial aneurysms, do not correlate with the presence of pulmonary edema. Neurogenic pulmonary edema also has been described with lesions of the medulla oblongata.15 Catecholamine secretion is markedly elevated in patients with subarachnoid or intracranial hemorrhage. This indicates, intense sympathetic nervous system activity.2”8 The increase of sympathetic activity gives rise to vasoconstriction, central pooling of blood, left ventricular failure, and pulmonary edema.“# 2o In turn, the resulting sustained refractory hypertension may give rise not only to rebleeding, but also to congestive heart failure and pulmonary edema. Exactly what triggers the excessive catecholamine secretion after intracranial hemorrhage is not known. But studies of paroxysmal hypertension and increased catecholamine levels in patients with intracranial lesions suggest that the increased catecholamines and the consequent stimulation of the sympathoadrenal pathways are a result of excitation of the vasomotor centers in the posterior hypothalamus and medulla oblongata.21’ 23 b S. H. RAHIMTOOLX It is important to remember that pulmonary edema occurs in association with diseases of the central nenrous system in the absence of cardiopulmonary disease. The incidence of neurogenic pulmonary edema in patients who die of acute traumatic or spontaneous intracerebral hemorrhage is very high. TRANSIENT CARDZOVASCUZAR INJECTIONS OF HYPERTONIC SUBARACHNOID SPACE
CHANGES SOLUTIONS
DURING THERAPEUTIC IN THE
The injections of hypertonic solution into the subarachnoid space (lumbar, cisternall are used for the relief of intractable pain. There are transient cardiovascular changes in about 10% of patients receiving these injections.= Lumbar intrathecal injections presumably lead to sympathetic stimulation, increase the heart rate, and may induce ventricular ectopic beats. A direct osmotic effect on intradural sympathetic nerve fibers is suggested to explain these electrocardiographic changes. Cisternal injections are thought to produce a direct vagal stimulation at the level of the brain stem. Cisternal injections have been shown to produce slowing of the heart rate, junctional rhythm, and atrial or ventricular ectopic beats, or both (Table 21. Transient hypotension is noted in less than z%.~~ There are no dangerous cardiac arrhythmias, and the electrocardiographic changes, which occur within 5 minutes of the injection, return to normal in all patients within 30 minutes of the injection. Curr
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483
TRANSIENT CARDIOVAsCULAR PERClJ7%VEOUS TRZGEMINAL
CHANGES DURING RHIZOTOMY
Percutaneous retrogasserian radiofrequency electrocoagulation rhizotomy and glycerol rhizolysis are often performed for the management of trigeminal neuralgia. Depending on the procedure, either an electrocoagulation needle or a spinal needle is inserted through the foramen ovale into the retrogasserian cistern of Meckel’s cavity, using intravenous methohexital for light general anesthesia. The procedure is then performed with the patient under sedation and local anesthesia. Standard cardiopulmonary monitoring is used continuously. Stimulation of the trigeminal ganglion during percutaneous retrogasserian radiofrequency rhizotomy can trigger a transient increase in mean arterial blood pressurez5 and premature ventricular ectopic beats during the period of elevated blood pressure (see Table 2). A case of bradycardia and asystole, and another case of coronary artery spasm with myocardial infarction during percutaneous retrogasserian glycerol rhizolysis have been reported.“’ ” However, other studies of 60, 100, and 681 patients who underwent percutaneous retrogasserian trigeminal procedures did not report any cardiac complications.28’ ”
TABLE TRANSIENT DURING
2. CARDIOVASCUlAR CHANGES THERAPEUTIC INJECTIONS OF
HYPERTONIC SOLUTIONS IN THE SIJBARACHNOID SPACE’t Lumbar injections: Sympathetic stimulation? Increased heart rate Ventricular ectopy Cisternal injections: Vagal Slowing of heart rate Junctional Hypotension
Transient pressure
stimulation?
rhythm
increase (29% 1
in mean
arterial
blood
*Data t?om Lucas JT, Ducker TB, Pemx PL Jr: Adverse reactions to intrathecal saline injection for control of pain. J h’eurosurg 1975; 42557-561; and tSweet WII, Poletti CE, Roberts JT: Dangerous rises in blood pressure upon heating of trigeminal motlets; increased bleeding times in patients with trigemioal neuralgia. Neurosurgery 1985; 17: 643-844.
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1990
Age and preexisting cardiac disease are undoubtedly factors in the risk of cardiac complications during these procedures. It should also be pointed out that most of these patients with trigeminal neuralgia had been taking carbamazepine, which prolongs atrioventricular conduction. All patients who present for percutaneous trigeminal rhizotomy or rhizolysis should undergo preoperative electrocardiography, and the electrocardiogram should be monitored continuously during the procedure. Premeditation with atropine should be considered.26 b S. H. ~HIMTOOLA: An indication for routine preoperative percutaneous trigeminal rhizotomy or rhizolysis. Ideally, also be monitored during the procedure.
CARDIOVASCULAR
CHANGES
DURING
electrocardiogram is these patients should
CAROTID
ENDARTERECTOMY
Fluctuations in blood pressure occur in about 47% of patients during or after carotid endarterectomy and are believed to reflect an alteration in the baroreceptors in the neck. A sustained increase in blood pressure was observed in 29% of 90 unilateral procedures and in 38% of 104 bilateral operations.30 Carotid sinus stimulation during carotid endarterectomy decreases blood pressure and carotid sinus denervation increases it. These changes undoubtedly contribute to the occurrence of perioperative complications. Transient hypotension occurs in about one fourth of carotid endarterectomies with the lowest blood pressure occurring about 5 hours after surgery. This hypotension is relatively benign and can be prevented by careful manipulation of tissues during the dissection of the carotid vessels. Infiltration of the carotid bulb with 1% lidocaine prior to surgery is effective in preventing postoperative hypotension. Vasopressor therapy can be complicated by myocardial infarction.31 About 19% of patients undergoing carotid endarterectomy have hypertension in the early postoperative period with the maximum blood pressure occurring about 2.3 hours postoperatively.32 Preoperative hypertension is the single most important determinant of postoperative hypertension in patients undergoing carotid artery surgery.“’ Sustained postoperative hypertension increases the risk of intracerebral hemorrhage. A postoperative neurologic deficit occurs in 10% of patients with postoperative hypertension.3z The most important principles of treatment are the preoperative control of hypertension, and the appropriate modification of anesthesia procedures. In most patients, the elevation in blood pressure following endarterectomy is self-limited, and preoperative readings are reached
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486
within 4 hours3’ Sustained hypertension may be treated with fastacting antihypertensive medications. The use of potent antihypertensive drugs such as nitroprusside should be avoided if possible because they may increase the risk of myocardial or cerebral ischemia.30 Striking electrocardiographic changes simulating subendocardial infarction have been observed after bilateral carotid endarterectomy in patients without clinical evidence of myocardial infarction.33 These electrocardiographic changes occur within 48 hours of surgery and disappear within 3 months. Likewise, myocardiaf infarction occurs within 72 hours of carotid endarterectomy in 0.5% of patients without preexisting heart disease, and in 4.9% of patients with preexisting heart disease.34 Animal experiments suggest that electrocardiographic changes and myocardial damage result from carotid sinus denervation and alterations in cardiac sympathetic activity.35 Vasopressor drugs, which are used to increase perfusion pressure at the time of carotid clamping during endarterectomy, seem to be well tolerated by patients without preexisting heart disease (the incidence of myocardial infarction in these patients is 0.5% regardless whether vasopressors are used or not).34 But in patients with preexisting heart disease (angina, congestive heart failure, previous myocardial infarction, arrhythmias), the use of vasopressor drugs during carotid endarterectomy is associated with an increased incidence of myocardial infarction (8.1% in those receiving vasopressors vs. 2.9% in those not receiving vasopressors).34 Because of the risk of myocardial damage associated with the use of vasopressors, many surgeons prefer other methods to increase cerebral perfusion during carotid surgery. b S. H. RAHIMTOOLA:Blood pressure monitoring during and after carotid endarterectomies appears to be very impomt. Transient hypotension is common; the lowest blood pressure occurs about 5 hours after surgery. Hypertension is also common, the maximum blood pressure elevation occurs about 2 to 2% hours after the procedure. CARDlOV’CULAR
ChYANGES AFTER MINOR HEAD INJURIES
Recurrent cardiac arrhythmias are known to occur following minor head injuries. A trivial head injury without the occurrence of unconsciousness may be followed within minutes by either asystole requiring prompt cardiorespiratory resuscitation, or by an abnormal cardiac rhythm such as ventricular fibrillation or severe junctional bradycardia.3” These observations stress the fact that reactive syncope secondary to a minor head injury may be due to a severe cardiac arrhythmia resulting from excessive autonomic disturbance . 486
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1990
b S. H. RAHIMTOOLA: It is important to recognize may be followed shortly by serious arrhythmia ment and even cardiopulmonary resuscitation.
vxtwwT ANGINA HEADACHES
(PRINZMETAL
that even trivial head injuries that requires immediate treat-
ANGINA) AND MlGk41~i-3
There are individuals who may or may not have obstructive coronary atherosclerosis, all of whom suffer a variant form of angina called Prinzmetal angina pectoris. This angina is thought to be associated with focal spasm of the coronary arteries, often is not associated with exercise or stress, may occur at rest or even during sleep,37 and may be a result of altered adrenergic activity. There are several similarities and dissimilarities between variant angina and migraine headaches. For example, in both conditions, arterial vasospasms play a major role, and there is abnormal platelet function. Also, there is a high prevalence of migraine in patients with variant angina (26% of patients, compared with 10% in a control group of healthy subjects).38 There are dissimilarities in the response to pharmacologic agents in patients with these two conditions. For example, migraine attacks can be prevented with propranolol, aborted with ergotamine, and induced by nitroglycerine. Conversely, propranolol often is not beneficial in variant angina, but ergotamine can cause anginal attacks, and nitroglycerin is therapeutic in angina.3s It is interesting that calcium antagonist drugs are the therapy of choice in the treatment of variant angina, and that these same drugs are being used with increasing frequency in the prophylactic treatment of migraine. Many aspects of the cerebral oligemia and the painful phase of migraine, as well as the vasospasm of variant angina remain unexplained.
HEMODMVAMK HYPOTENSION DYSFUNCTION
DISTURBANCES AND ORTHOSTATlC DUE TO AUTONOMIC NERVOUS SYSTEM
Autonomic nervous system dysfunction often is associated with orthostatic hypotension. When the cause of the autonomic nervous system dysfunction is not known the orthostatic hypotension is called primary; when the cause is known it is called secondary (Table 3). Primary orthostatic hypotension can occur either alone or with concomitant diffuse neurologic involvement. Shy-Drager syndrome (progressive autonomic failure) is an example of primary orthostatic hypotension with diffuse neurologic involvement. There is convincCurr
Probl
Car-did,
September 1990
487
TABLE
3.
Hemodynamic Autonomic
Disturbances Nervous Svstem
Pmduced Dvsfunction
by
Primary Ckthostatic Hypotension In prugressive autonomic failure (Shy-Drager syndrome), familial dysautonomia, and dysautonomia associated with mitral valve prolapse Secondary Orthostatic Hypotension Secondary to diseases that produced autonomic neumpathy (diabetes, amyloidosis, porphyria, Guillain-Barr4 syndrome, alcoholism) Secondary to transection of spinal cord, syringomyelia, and tabes dorsalis
ing evidence that primary ence of diffuse neurologic Shy-Drager syndrome.
Shy-Draper
orthostatic hypotension impairment represents
without the presan early stage of
Syndrome
In the Shy-Drager syndrome,40 there is degeneration of central motor tracts korticobulbar, corticospinal, extrapyramidal), cell loss in the nuclei of the brain stem and cerebellum, and degeneration of preganglionic sympathetic neurons and intermediolateral column cells of the spinal cord.41 Clinically, there is a severe autonomic neuropathy (orthostatic hypotension, lightheadedness, syncope, impotence, bladder disturbances) and extrapyramidal abnormalities. The cardiovascular system is no longer able to activate its compensatory mechanisms in response to changes in body position.42 This results in a major disturbance in the control of blood pressure, even in the supine position. The extrapyramidal syndrome resembles Parkinson’s disease. There is also evidence of long tract and cerebellar signs. Other symptoms and signs reported include iris atrophy, Homer’s syndrome, abnormal pupillary responses, nystagmus, and sleep apnea.43 There is no specific treatment, but symptomatic treatments (elastic stockings, tludrocortisone acetate, dihydroergotamine) produce some relief of the orthostatic hypotension in some patients.
Familial Dysautonomia
(Riley-Day Syndrome)
This is another primary disease of the autonomic nervous system. It is an autosomal recessive disease that affects predominantly children of Ashkenazi (Eastern European) Jewish ancestry. The features of familial dysautonomia have been summarized by Riley et al.44: absence of overflow tears, impairment of the regulatory mechanism of blood pressure control, postural hypotension, erratic temperature 4.9s
Curr
Probl
Car&$
September
1990
control, excessive perspiration over the head, difficulty swallowing, episodic vomiting, absence of fungiform papillae on the tongue, impaired sensations of pain and taste, corneal anesthesia, hypomflexia, poor coordination, developmental delay, decreased esophageal motility, and an abnormal histamine skin test. Although familial dysautonomia is a distinct clinical entity, its biochemical basis has not been elucidated. Recent studies have implicated a lack of nerve growth factor during embryogenesis that may account for the marked reduction of neurons in sensory and autonomic ganglia.45 The sural nerve shows a loss of unmyelinated and small myelinated fibers.43 The diagnosis must be made on clinical grounds, and symptoms can usually be traced back to infancy.
Dysautonomia
and Mitral
Valve Prolapse
A subset of patients with mitral valve prolapse have faulty autonomic regulation of cardiac and vascular fLmctions.46’ 47 This autonomic dysfunction can slow neural circulatory controls necessary for rapid adaptive changes and anticipatory adjustments, with consequent symptoms of both chronic adrenergic hyperactivity and exaggerated parasympathetic response.4”‘47 Adrenergic activation in mitral valve prolapse may give rise to inappropriate tachycardia, arrhythmias, and increased catecholamine levels. The latter can cause a volume contracted state, increased venous and arterial constriction, increased peripheral vascular resistance, and increased orthostatic intolerance.4”848 The increased vascular tone in both the arterial and venous systems may further decrease total blood volume.46 Most patients respond to reassurance, dietary salt loading, an exercise fitness program, or low doses of clonidine.4” Individuals with an exaggerated parasympathetic response may experience syncope or near syncope without demonstrable cardiac dysrhythmias.47 Weisman et a1.4s reported orthostatic hypotension in 17% of patients with mitral valve prolapse, and Santos et ak5’ reported hypotension, lightheadedness, and syncope in 12% of their patients. Phenobarbital suppresses the exaggerated parasympathetic response .47 Possible explanations for the episodic nature of the symptoms, the etiopathogenesis of the autonomic dysregulation, and the similarities of these autonomic dysfunctions with the somatic expressions of anxiety are extensively reviewed by Gaffney and Blomqvist4” and Coghlan.47
Secondary
Orthostatic
Secondary orthostatic that produce peripheral orthostatic hypotension Cur-r Probl
Car&d,
September
Hypotension hypotension is associated with diseases and autonomic neuropathy. For example, occurs in diabetes, amyloidosis,51 chronic 1990
489
alcoholism,52 acute porphyria,42 and Guillain-Barr% syndrome. The orthostatic hypotension in these diseases is probably due to an impairment of vasomotor innervation of blood vessels with the consequent loss of activating reflexes necessary to maintain the blood pressure upon standing. The autonomic neuropathy in porphyria can explain certain features of the acute attack such as abdominal pain, constipation, tachycardia, and blood pressure changes.53’ 54 But the latter may occur in the absence of autonomic neuropathy suggesting other causes.55 Autonomic neurons seem to be more susceptible to the biochemical changes of porphyria than somatic neurons.53 In addition to orthostatic hypotension, patients with severe diabetic autonomic neuropathy seem to have defective vagal and sympathetic control of the heart. This lack of control is manifested by a poor cardiac rate response to autonomic blockade and by a diminished beat-to-beat variation on deep breathing.5” These abnormalities, which are attributed to cardiac denervation, are predisposing factors for the development of serious cardiac arrhythmias and sudden death. Destruction of the central sympathetic connections in the spinal cord by a myelopathic process induces orthostatic blood pressure abnormalities.57 These abnormalities are due to the inability to activate sympathetic vasoconstrictor reflexes during a change of position from recumbent to upright. Acute transection of the cervical spinal cord produces orthostatic hypotension as a result of disruption of pathways between the brain and the spinal cord. Likewise, head-up tilting in chronic paraplegic and tetraplegic patients is accompanied by a fall in systolic and diastolic blood pressures and an increase in heart rate. Return to the horizontal position is usually followed by a return of blood pressure to previous levels within a minute. Postural hypotension is more pronounced in patients with high cervical lesions and may be a serious limiting factor in the rehabilitation of these patients. Tetraplegic patients also have paroxysmal hypertension during defecation and micturition or after the application of painful or cold stimuli below the level of the lesion. This hypertension is thought to result from exaggerated reflex sympathetic activity in the isolated spinal cord.“’ Tracheal suctioning may cause vagal hyperactivity, resulting in bradycardia and cardiac arreSt.43 Tetraplegic patients devoid of autonomic cardiac control have a decrease in cardiac mass which limits the work capacity of the heart .59 In these patients, there is a decrease in the workload of the heart with subsequent cardiac atrophy.60 The left ventricular cavity is reduced in size, the shortening fraction may be normal, the stroke volume, cardiac output, and mean blood pressure are decreased, and the systemic vascular resistance is usually in the high normal 490
Curr
Probl
Cardiol,
September
1390
range. In recent years, endurance training for cardiopulmonary reconditioning has become an important part of rehabilitation programs for tetraplegics and quadriplegics to improve the quality of living. Ordinary daily activities do not seem to be adequate to maintain cardiovascular fitness in such patients.5g Endurance training guidelines for the general population appear to be appropriate for the population with spinal cord injury; these guidelines can be followed during participation in wheelchair pushing, arm crank ergometry, aerobic swimming, ambulation training, canoeing, and wheelchair basketbal15’ Dicarlo”’ recommends an arm pedaling cycle ergometer for endurance training. Orthostatic hypotension is rare in syringomyelia. Aminoff and Wilcox”’ described a patient with syringomyelia in whom symptoms of autonomic dysfunction included orthostatic hypotension and inability to sweat. These autonomic symptoms were attributed to interruption of descending sympathetic fibers in the spinal cord by the syrinx. Tabes dorsalis interferes with atferent autonomic fibers in the dorsal root ganglia and dorsal roots. In addition, infarction and cavitation of the spinal cord (seen in other syphilitic, nontabetic spinal syndromes) also interfere with the function of preganglionic sympathetic neurons in the intermediolateral column cell. Orthostatic hypotension may be present not only in tabes dorsalis, but also in other syphilitic nontabetic spinal syndromes. Orthostatic hypotension is an accompanying sign in patients with volume depletion associated with shock syndrome, excessive vomiting, prolonged water restriction, acidosis, excessively high external temperatures (with loss of large amount of water through skin and lungs), and adrenal cortical insufficiency. The clinical investigation of disorders of the autonomic nervous system is summarized by McLeod et al.43 Some of the tests include: (a) blood pressure and heart rate response after change of posture, after isometric exercises, or during inspiration and expiration; (b) tests of sweating; (c) plasma noradrenaline and other biochemical tests; (d) tests of peripheral vasomotor control; and [e) tests of pupillary innervation. Symptomatic treatment of orthostatic hypotension is initially carried out with fludrocortisone and tight-fitting elastic garments. Other medications recommended are ephedrine, indomethacin, and dihydroergotamine.42’ 63
Guillain-Barr6
Syndrome
About 10% of patients with Guillain-Barr6 syndrome have a much more severe illness and a poorer prognosis than those patients with typical Guillain-Barr6 syndrome. In this variant of the disease, there is a rapidly devastating illness in which the patients become quadriplegic necessitating ventilator-y assistance in 2 to 5 days from the onCurr
Probl
Carcfiol,
September
1990
491
set of the illness.“4 Death due to cardiovascular collapse may occur in as many as 14% of these patients, and autopsies show marked axonal degeneration in nerve roots and distal nerves.65, 66 Cardiovascular changes in Guillain-Ban+ syndrome, which are attributed to anoxia and autonomic nervous system dysfunction,“7 include hypertension (particularly diastolic), episodes of flushing, diaphoresis, hypotension, cardiac arrhythmias, and electrocardiographic changes (Table 4). The most common cardiac arrhythmias in patients with GuillainBarr6 syndrome are sinoatrial arrest, atrioventricular block, and supraventricular and ventricular tachyarrhythmias.68 Resting heart rates are significantly higher in patients with Guillain-B& syndrome than in control subjects, sometimes exceeding 100 beats per minute.6g In healthy people, there is a beat-to-beat (R-R) variation of the heart rate that can be used as a measure of normal autonomic function. Persson and Solders” demonstrated that this R-R variation is diminished in Guillain-Barn5 syndrome. The R-R interval can be easily monitored during the critical period of the illness, can be used to select patients at risk, and may aid in deciding which patients are in need of intensive care. The reduction of the R-R variation in GuillainBar& syndrome follows the progression of the clinical course. Accordingly, reduction of the R-R interval variation is observed a few days after the onset of symptoms, and the variation returns to normal with clinical improvement. There is no correlation between the diminished R-R variation and motor conduction velocity or cerebrospinal fluid proteins in Guillain-Barr6 syndrome. Patients with Guillain-Barr6 syndrome should be observed carefully for signs of autonomic dysfunction. During the critical period of the illness, continuous electrocardiographic and arterial pressure TABLE 4. Cardiovascular Guillain-Barr&
Changes Syndrome*
in Severe
Type
of
Cardiovascular collapse in 3% to 14% Diastolic hypertension Hypotension Cardiac arrhythmias Sinus arrest Atrioventricular block Supraventricular and ventricular arrhythmias Resting heart rate higher than 100 beats per minute No beat-to-beat variation *Data
492
from
mferences
66, 68, and
70
Curr
Probl
Carcfioi,
September
1990
monitoring are helpful in detecting early signs of impending cardiovascular collapse.“6 It is important to stress that medical complications occurring during the course of the Guillain-Barr6 syndrome, such as pulmonary embolism, pneumonia, pneumothorax, electrolyte imbalance, and focal myocarditis, also can induce cardiac arrhythmias.“8 Therefore, these medical complications should be suspected in patients with Guillain-Barn? syndrome who develop cardiac arrhythmias.
Stress and Disturbance
of Cardiac Rhythm
Psychological stimulation frequently changes the rate and the rhythm of the heart. There is a significant association between overwhelming emotional stimulation and sudden death. Although largely anecdotal, evidence suggests that psychological stress can evoke neural impulses from higher centers. These neural impulses, acting on the myocardium, either alter the electrokinesis of cardiac muscle, or destabilize an underlying occlusive atherosclerotic process in the coronary arteries, giving rise to disturbances of heart rhythm, and less frequently, to cardiac necrosis. This belief is compatible with the fact that experimental stimulation of the hypothalamus, the amygdala, or the midbrain reticular formation evokes arrhythmias . Lown71 demonstrated that stress markedly reduces the threshold for ventricular fibrillation. For this demonstration, he occluded the anterior ‘descending coronary artery in dogs. Once the infarcts were considered to be old, the dogs were placed in a sling where they received a single electric shock on three successive days. Though no further shocks were administered, each time the dogs were placed in the sling, the ventricular fibrillation threshold was markedly reduced. Arrhythmias occurred without having to resort to electrical stimulation of the myocardium. These results were different from those obtained in a tranquil cage environment, where electrical stimulation of the myocardium was necessary to induce ventricular fibrillation in the same animals. Therefore, psychological stress appears to be an important factor in the initiation of ventricular fibrillation in the ischemic heart. In this respect, Skinner and Reed72 demonstrated that blockade of the frontocortical-brain stem pathways (cryogenic blockade of the forebrain, posterior hypothalamus, or fields of Fore11 prevents the lethal consequences of myocardial ischemia in stressed animals.” G. A. BELLER: Acute psychological stress or a sudden “adrenergic trigger” such as a sharp telephone ring that awakens someone from sleep can trigger acute ventricular tachycardia (usually polymorphic) and even fibrillation in patients with hereditary prolonged QT syndrome. Such patients may merely present as having seizures. Often there is a family history of premature death or similar “seizures” in siblings. Ambulatory ECG monitoring during these episodes usu-
b
Cut-r Probl
Car&o& September
1990
493
ally shows speeding of the sinus rate and appearance of ventricular ectopic beats falling on the T wave with prolongation of the Q-T interval. Beta blockers are the class of drugs that are most effective in preventing these arrhythmias. MYOPATHIES
In most respects, the myocardium seems to share with skeletal muscle a vulnerability to both hereditary and acquired diseases. The cardiac abnormalities of many hereditary skeletal myopathies contribute to the morbidity and mortality of those myopathies. In certain patients, cardiac involvement may manifest before the generalized myopathy.7” MYOTONIC
DYSTROPHY
Myotonic dystrophy is a hereditary myopathy with features of a systemic disease. As in other myopathies, affected patients have muscular weakness, but there is a peculiar atrophy of the temporalis muscles. These patients also have myotonia, which is an inability to relax muscles after contraction. Myotonia can be easily elicited in these patients by tapping the thenar eminence. There are other characteristic findings such as baldness, cataracts, testicular atrophy, gastrointestinal smooth muscle abnormalities, alveolar hypoventilation, and cardiac abnormalities. In most cases, myopathic features are apparent long before any evidence of heart disease. But in some patients, the cardiac abnormalities are the predominant features.74 In other patients, there is no detectable myocardial ailment despite advanced skeletal muscular involvement.75 About 90% of patients with myotonic dystrophy have abnormalities on an electrocardiogram, ambulatory Holter monitoring, or an echocardiogram or radionuclide ventriculogram. (Table 5). Electrocardiographic abnormalities are found in about 70% of cases. Conduction disturbances, which are the most common abnormalities in myotonic dystrophy, are manifest by first degree atrioventricular block (33% 1 (Fig 2),75 and intraventricular conduction defects (20% 1 (Fig 3).75876 Evidence of disease in the entire conduction system has been obtained with intracardiac electrocardiography.77 Pathologically, there may be replacement of the myocardium and conducting system by fatty and fibrous tissue.75 These patients are prone to Stokes-Adams attacks, asystole, and ventricular fibrillation. Other cardiac abnormalities encountered in myotonic dystrophy are generalized cardiac enlargement and left ventricular dysfunction (70%).75 The association of mitral valve prolapse with myotonic dystrophy is sufficiently strong (37%) that it should be sought in all patients with myotonic dystrophy.75’ 78, 7g Since the presence of mitral 494
Curr
Probl
Cardiol,
September 1990
TABLE
5.
Cardiovascular
Abnormalities
in Muscular
Dystrophies*
Myotonic Dystrophy Replacement of myocardium and conducting system by fatty and fibmus tissue Conduction disturbances (Stokes-Adams attacks, AV block) Ventricular fibrillation Generalized cardiac enlargement Left ventricular dysfunction (70%) Mitral valve prolapse (37% I Duchenne Type Muscular Dystrophy Dilatation of left ventricle and mitral annulus Dysfunction of chordae tendineae and papillary muscles Replacement of muscle with connective tissue Myocardial infarctions Congestive heart failure Prolapse of mitral valve (50%) Electrocardiographic changes (90% of cases) Sinus tachycardia, atrial flutter Paroxysmal ventricular tachycardia Abnormally tall R waves in the lateral chest leads Deep, narrow waves in the lateral chest leads Inverted T waves over leads V5 and V6 Right axis deviation Shortened PR interval Bundle branch blocks QRS pmlongation Limb-Girole Muscular Dystrophy Disturbance in rhythm or conduction (Wolf-Parkinson-White syndrome, QRS prolongation, first degree heart block, intraventricular conduction defect, atrial flutter) Paroxysmal ventricular tachycardia Cardiomyopathy and congestive heart failure Electrocardiographic changes Minor T wave alterations Tall R waves in lead Vl, deep Q waves or a QS pattern on lead I, II, III, aVP, and V6 *Data fmm
references
75, 84, 90, 91
valve prolapse in patients with myotonic dystrophy represents a potential source of neurologic problems (particularly cerebral embolism), symptomatic supportive treatment of these patients should include periodic cardiac evaluations, and prophylaxis against infectious endocarditis at the time of oral surgery. The use of antiplatelet agents should be considered in patients over 40 years of age. Subclinical cardiac involvement in myotonic dystrophy may be responsible for sudden death in 4% of patients. Moorman recom-
Curr
frobl
Car&id,
September
1999
495
aVR
aVL
aVF
FIG 2. Full standard electrocardiogram ing first degree atrioventricular
LEAD”1
/ ; ;
from block.
a 41 -year-old
woman
with myotonic
dystrophy
show-
: I
LEAD II
BUNDLE OF HIS
CORONARV SINUS
---
FIG 3. Intracardiac prolonged
496
electrophysiologic HV interval (100
msec).
recording from patient with (Courtesy of Jerry Miller,
myotonic M.D.)
Cur-r Probl
Cardiol,
dystrophy
September
showing
1990
mends: (a) investigation of coronary artery disease in patients with myotonic dystrophy who have significant risk factors; lb) detailed evaluation of syncopal episodes in these patients; and (cl pacemaker and/or antiarrhythmic drug therapy if indicated. The symptomatic relief of myotonia is sometimes achieved with procainamide or phenytoin. If a drug should be used in the symptomatic treatment of myotonia, phenytoin, which shortens the P-R interval, is preferred over procainamide, which lengthens the P-R intenal.77 In addition, procainamide may induce a lupus-like syndrome with adverse effects on the heart.”
NONMYOTONZC
MUSCULAR
DYSTROPHY
The spectrum of heart disease in nonmyotonic muscular dystrophy has been studied extensively (see Table 5). Heart disease is not only frequent, but it is easy to detect in the classic sex-linked recessive type of Duchenne. It is rare in facioscapular humeral dystrophy. Cardiac involvement in Becker’s muscular dystrophy and limb-girdle muscular dystrophy is of intermediate prevalence. In Becker’s muscular dystrophy, the incidence of cardiac involvement increases progressively after adolescence, but it is seldom severe before the third decade, at which time the incidence of cardiac involvement is 80% .‘O In this myopathy, which is less severe than the Duchenne type, there may be severe myocardial involvements1 Mitral valve prolapse has also been reported.” Duchenne muscular dystrophy is the most severe of all muscular dystrophies. It is also known as pseudohypertrophic muscular dystrophy because of the enlargement of the calf and other muscles from the deposition of fat (see Fig 31. Although patients with Duchenne muscular dystrophy generally succumb to inanition and infection before the age of 20 years, the concomitant presence of cardiomyopathy (which is aggravated by the weakness of the respiratory muscles) is also an important cause of death. The heart disease of Duchenne muscular dystrophy is progressive and directly pmportional to the severity of skeletal muscle dysfunction.83 There is dilatation of the left ventricle and mitral annulus, dysfunction of chordae tendineae and papillary muscles, and replacement of myocardial fibers with connective tissue. Cardiac degenerative changes are more severe in the postembasal region of the left ventricular free wall. It has been suggested that this selective distribution accounts for the characteristic electrocardiographic changes. It is interesting that the myocardial fibrosis usually involves the subepicardial areas (Fig 4), in contrast to the subendocardial fibrosis that occurs in most other types of cardiac disease. The large extramural coronary arteries are normal, although the small intramural coronary arteries Cum
Probl
Cardiol,
September
1990
497
FIG 4. Histologic Duchene
section showing type of muscular
severe dystrophy,
subepicardial x40.
fibrosis
in left ventricle
of patient
with
show luminal narrowing due to fibromuscular intimal proliferation; these changes may be pronounced in the arteries to the sinoatrial and atrioventricular nodes. Clinical myocardial infarctions have been reported in young patients with Duchenne muscular dystrophy.84 Congestive heart failure and many cardiac arrhythmias have been observed in Duchenne muscular dystrophy. Electrocardiographic abnormalities, which are found in about 90% of cases, do not correlate with the degree of systemic skeletal disability.85 Electrocardiographic changes include sinus tachycardia, atrial flutter, paroxysmal ventricular tachycardia, abnormally tall R waves in lead Vl, shallow S waves in leads Vl and VZ, deep narrow Q waves in the lateral chest leads, inverted T waves in leads V5 and V6, right axis deviation, shortened P-R interval, and bundle branch blocks (Fig 5). These electrocardiographic changes are rarely seen in carriers of Duchenne muscular dystrophy. But in carriers, the sum of the R and S waves in leads Vl and VZ is significantly greater than that in women who are not carriers.85 Mitral valve prolapse can be identified in nearly 50% of patients with Duchenne muscular dystrophy and in about 30% of carrierss2 Duchenne muscular dystrophy presents risk during general anesthesia. Cardiac arrest following inhalation induction86-88 and the occurrence of malignant hyperthermiaSs have been reported. Cardiac involvement in limb-girdle muscular dystrophy is manifest by disturbances in rhythm and conduction (Wolff-ParkinsonWhite syndrome, QRS prolongation, first degree heart block, intra49s
Curr
Probl
Cardiol,
September
19x)
5
v3
v2
aVR
aVL
aVF
%
v5
'6
FIG 5. Full standard electrocardiogram phy. Note high voltages and
deep
from an 8-year-old narrow Q waves
boy with Duchene muscular dystroin the inferior and lateral leads.
ventricular conduction defects, atrial flutter, paroxysmal ventricular tachycardia), minor T-wave alterations, cardiomyopathy, and congestive heart faib.ue7” go,” Other electrocardiographic changes include tall R waves in lead Vl, and deep Q waves or a QS pattern in leads I, II, III, aVF, and V6.‘l Cardiac abnormalities in facioscapular humeral muscular dystrophy may not be clinically evident, but subclinical cardiac dysfunction can be detected in some patients. Permanent paralysis of the atria may occur.76 CONGENITAL
h4YOPATHIES
These myopathies are present at birth and are either nonprogressive or slowly progressive. In severe cases of congenital myopathies there is significant weakness at birth leading to death in infancy, childhood, or adolescence. But most patients with mild forms of these diseases remain almost asymptomatic in early childhood.s2 Curr
Probl
Cat-did,
September
1990
499
These myopathies seem to affect specific muscular structures, without the destructive changes of other myopathies. They derive their names from some of their pathologic changes. Symptoms include skeletal weakness, hypotonia, and external ophthalmoparesis. Congenital myopathies may give rise to myocardial abnormalities as a reflection of a diffuse muscular dysfunction (Table 6). Obstructive hypertrophic cardiomyopathy with cardiomegaly has been reported in patients with mitochondrial myopathies. In these patients, histologic examination showed abnormal mitochondrial aggregates TABLE 6. Cardiovascular Myopathies
Abnormalities
in Other
Congenital Myopathies Mitochondrial Obstructive cardiomyopathy Cardiomegaly Nemaline Bicuspid aortic valve Aortic regurgitation Left ventricular hypertrophy Diaphragmatic paralysis Centmnuclear Cardiac fibrosis with dilation and compensatory focal hypertmphy Progressive External Ophthalmoplegia-plus (Kearns-Sayre syndrome, Refsum’s syndrome, progressive external ophthalmoplegia, abetalipopmteinemia) Atrioventricular and intraventricular block ST changes Heart enlargement Carnitine Deficiency Extensive deposits of lipids in cardiac muscle cells Endocardial fibmelastosis Cardiomyopathy Congestive heart failure Polymyositis Myocarditis 30% Diffuse interstitial infiltrate similar to that in the skeletal muscle Congestive heart failure 45% Atrial arrhythmias Ventricular arrhythmias Atrioventricular and intraventricular conductive defects ST changes *Data
from references
92-lOO, llO-113,
X20-123.
Curr
Probl
Cardiol,
September
1990
in the skeletal muscless3’ s4 and hearts5 Likewise, bicuspid aortic valve, aortic regurgitation, left ventricular hypertrophy, dilated cardiomyopathy, and biventricular failure have been reported in nemaline myopathy?” s6 In a patient with nemaline myopathy and left ventricular hypertrophy who died of congestive heart failure, necropsy demonstrated a patent ductus arteriosus, mild infundibular pulmonic stenosis, anomalous papillary muscles, and myocardial scarrings There are a few reports of adult-onset nemaline myopathy presenting with diaphragmatic paralysis. This is important to clinicians since these patients present with pulmonary symptoms rather than muscular weakness.s7 Centronuclear (myotubular) myopathy may be either sporadic, or have a sex-linked, autosomal recessive, or autosomal dominant mode of inheritance.s8 Central nuclei are present in fetal muscle through the first 15 weeks of gestation, suggesting that centronuclear myopathy may represent an arrest of muscle development.” Although most patients do not have an associated cardiomyopathy, cardiac fibrosis with dilation and compensatory focal hypertrophy does OCCU~.~~’loo Patients with cardiomyopathy have variable electrocardiograms. Deep S waves in the lateral leads and abnormal axes are frequent (Fig 6). PROGKL?SSlVE EXTERNAL OPHTHALMOPLEGlA-PLUS The simultaneous occurrence of neuromuscular and cardiac disease is also found in a group of diseases which are lumped together under the name of ophthalmoplegia-plus (see Table 6).‘01 These syndromes are numerous, and the ones most commonly recognized are: Kearns-Sayre syndrome, Refsum’s syndrome, progressive external ophthalmoplegia, and abetalipoproteinemia. A common feature in these syndromes is involvement of the extraocular muscles. The presence of a wide variety of other clinical abnormalities differentiates one syndrome from another, but the classification of these syndromes remains uncertain. The resemblance that these syndromes share and the lack of distinct etiopathogenesis justify grouping them under the term ophthalmoplegia-plus. Kearns-Sayre Syndrome Kearns-Sayre syndrome features external ophthalmoplegia retinitis pigmentosa and varying degrees of atrioventricular heart block.“’ Additional clinical abnormalities include subnormal mentation, hearing loss, impaired growth, proximal weakness of the extremities, cerebellar abnormalities, and increased protein in the cerebrospinal fluid. Biopsy specimens of skeletal muscle show ultrastructural mitochondrial abnormalities.‘03 “Ragged-red fibers” are recognized Cut-r ~robl
Car-did,
September
1990
501
Vl
aVL
aVF
v4
VI5
‘6
l/2 STANDARD
-.I
V3
V2 I
FIG 6. Electrocardiogram
from
a 21.year-old
woman
with centronuclear
myopathv.
with modified Gomori trichrome stain. These findings, which are not specific for Kearns-Sayre syndrome, are also seen in congenital myopathies, in other neuromuscular conditions, and even in normal muscle1”3; but they are useful in the diagnosis of Kearns-Sayre syndrome. This disease is sometimes classified with the mitochodrial “encephalomyopathies.“104 Genetic factors seem to play a role in the pathogenesis of this syndrome.lO” Some patients with Kearns-Sayre syndrome have hypertrophic cardiomyopathy. Many patients present without cardiac symptoms, while others suffer from palpitations and life-threatening AdamsStokes attacks, which may necessitate the implantation of an artificial cardiac pacemaker. Evidence is accumulating to show that Kearns-Sayre syndrome is a metabolic disease caused by defective mitochondrial function.lo6 502
Curr
Probl
Cardiol,
September
1990
Refsum’s Syndrome Refsum’s syndrome is the result of inability to metabolize phytanic acid and is associated with intraventricular and atrioventricular conductive defects, ST changes, and various arrhythmias. Other features of the disease include retinitis pigmentosa, ocular myopathy, peripheral neuropathy, ataxia, and changes in the skin and bones. Progressive E,xternal Ophthalmoplegia This is manifest by progressive weakness of the external ocular muscles and ptosis. When the pharyngeal muscles are also involved, the syndrome is called oculopharyngeal dystrophy. The most common electrocardiographic abnormalities are atrioventricular conduction defects. Abetalipoproteinemia (Acanthocytosis; Bassen-Kornzweig Syndrome) This disease is an inherited error of lipoprotein metabolism manifest by gastrointestinal symptoms (resembling celiac disease), retinitis pigmentosa, external ophthalmoplegia, oropharyngeal weakness, ataxia (due to progressive degeneration of posterior column and cerebellum), distal weakness (due to peripheral neuropathy),107’ lo8 abnormally low absorption of lipids from the intestinal tract, a near absence of P-lipoprotein in the serum, and spiny red blood cells.10g The heart may be enlarged, and mural thrombosis and serious arrhythmias occur.11o* “I Cardiac failure is a common cause of death, and interstitial myocardial fibrosis occurs.111 CARNZTZNE DEFICIENCY SYNDROME Carnitine deficiency is considered to be a disorder of fat metabolism in which both skeletal muscle myopathy and cardiomyopathy may occur. The disease becomes clinically manifest during the first four decades of life. Traditionally, two syndromes are recognized. In the systemic form, the deficiency of carnitine is generalized due to defective hepatic biosynthesis, and carnitine levels are decreased in plasma, liver, skeletal muscle, and myocardium.‘123 ‘13 Because carnitine is necessary for the transport of long-chain fatty acids into the inner mitochondrial compartment where they undergo P-oxidation and become a major source of energy, deficiency of carnitine may result in impairment of lipid oxidation. This leads to the excessive use of carbohydrates as a source of energy.‘14 Thus, these patients can experience episodes of liver dysfunction and acidosis. In the muscular form of carnitine deficiency, the mechanism of active transport of carnitine into skeletal and cardiac muscle is beCwr
Probl
Cardiol,
September
1990
503
lieved to be defective. Carnitine levels are normal in plasma but decreased in muscle.1*5’ ‘Iti Carroll et al.lZ7 reported a patient who demonstrated features of both systemic and muscular carnitine deficiency, suggesting that the current classification of carnitine deficiencies may need revision. The systemic (generalized) form of carnitine deficiency is characterized clinically by a premyopathic phase in which patients have recurrent, spontaneous episodes of nausea, vomiting, acidosis, and stupor. This presentation is followed by progressive muscular weakness, muscular atrophy, and hepatic insufficiency. The muscular form of carnitine deficiency is manifested mainly by progressive muscular weakness and atrophy.‘13 Systemic carnitine deficiency can be primary, when there is no evidence of another systemic illness that might deplete tissue carnitine stores, or secondary, when the carnitine deficiency is a result of a recognized condition such as glutaric aciduria type II, methylmalonic aciduria, abnormalities of folate metabolism, or cytochrome-c oxidase deficiency.‘18 The histologic and ultrastructural appearance of skeletal muscle is similar in both forms, with lipid storage (in the form of numerous droplets free in the sarcoplasm) in type I fiber and atrophy in type II fibers. Lipid deposits also have been found in the cytoplasm of pericytes, fibroblasts, and venules. Crystalline inclusions and other nonspecific abnormalities have been found in skeletal muscle mitochondria.l*’ Lipid deposits also occur in the kidneys and liver in the systemic form.112, ‘I3 The lipid deposits in skeletal muscle consist mainly of triglycerides with smaller amounts of diglycerides and free fatty acids.l13 Clinical evidence of cardiac involvement is found in some patients with each of the two forms of carnitine deficiency (Table 6).l*’ Waber et a1.l” studied a boy with a family history of cardiomyopathy who presented at 3% years with congestive heart failure, skeletal muscle weakness, lipid myopathy on a skeletal muscle biopsy specimen, and reduced muscle and plasma carnitine levels. In this patient, therapy with L-carnitine (174 mgkgday) improved cardiac function and muscle strength.l” Likewise, Tripp et al.lzl studied a family of four girls and one boy in whom cardiomyopathy developed in four of five, three of whom died suddenly. Autopsy in these children showed endocardial fibroelastosis. The surviving child and autopsy results of her brother showed a severe decrease in plasma and tissue carnitine levels. Treatment of the affected child with oral L-carnitine (3 g per day) markedly improved myocardial function and reduced the heart size.lzl In other pathologic reports, at least two patients had extensive lipid deposits in cardiac myocytes.112’113 In another patient the cardiac myocytes were vacuolated and the myofibrils were widely sep604
Curr
probl
Cardiol,
September
1990
arated by aggregates of mitochondria (a nonspecific finding), but lipid deposits were not found.l18 Oral carnitine supplementation may be followed by improvement in some patients, but not in others, perhaps depending on the condition of the tissue carnitine receptor.*l’ POLYhJYOSITZS Polymyositis
inflammatory myopathy clinically weakness, characteristic electromyographic abnormalities, elevated serum enzyme levels, and abnormal muscle histologic findings. In some cases, polymyositis may occur in conjunction with other collagen diseases. In other cases, it may be associated with a malignancy. A muscle biopsy specimen shows degeneration and regeneration of skeletal muscle with a predominantly mononuclear inflammatory infi1trate.l” Symptomatic cardiac involvement in polymyositis is rare, but clinicopathologic studies have shown that cardiac involvement may be far more common than previously recognized (see Table 61. Denbow et al.‘“” found myocarditis (30% 1, congestive heart failure (45% 1, and electrocardiographic abnormalities (72%) in a clinicopathologic study of 20 autopsies. The myocarditis was characterized by a diffuse interstitial and perivascular mononuclear cell infiltrate, similar to the inflammatory changes seen in the affected skeletal muscle. There was also muscle fiber degeneration, regeneration, and fibrosis.12”. 123
manifested
is an acquired
by proximal
muscular
The presence of fibrosis in the conduction system of the heart may explain the conductive abnormalities observed in polymyositis. There may be encroachment on the lumina of small vessels by medial smooth muscle hyperplasia with little or no intimal pmliferation. Electrocardiographic changes most commonly seen in polymyositis are atrial and ventricular arrhythmias, intraventricular and atrioventricular conduction defects,lz4 and ST changes characteristic of myocardial ischemia.lz5 Corticostemids are beneficial in most cases of polymyositis. A permanent pacemaker may be necessary in patients with heart block. b G. A. BELLER: Polymyositis involving the myocardium can present with findings similar to those encountered in acute myocardial infarction. However, one sees enormous elevations in serum creatine kinase levels which are sustained, rather than exhibiting the usual rise-and-fall characteristic 6f an acute coronary artery occlusion. CK levels can exceed 4,000 IU with minimal percent MB. b D. MCCALL: The association between skeletal muscle myopathies and myopathies of cardiac muscle remains of great clinical and research interest. While the association may have a readily explicable basis in certain types, e.g., those asso-
Curr
Pmbl
Cardiol,
September
1990
SOS
ciated with carnitine deficiency and abetalipoproteinemia, such is not the case in the more common hereditary myopathies. No common, genetically determined, perturbation of muscle biochemistry or physiology has as yet been defined. The relationship is so strong, however, that the clinician should always be mindful of the possibility of an underlying skeletal myopathy when confronted with the young patient with otherwise unexplained heart failure. This is especially true since, not infrequently, the cardiac manifestations may demand clinical scrutiny prior to there being overt skeletal muscle involvement. b S. H. RAHIMTOOW: system involvement. cluding malignant
Patients with myositis may have myocardial and conduction As a result, they may develop various cardiac problems arrhythmias that require treatment.
METABOLIC DISORDERS THAT INVOLVE AND THE CENTRAL NERVOUS SYSTEM
BOTH
in-
THE HEART
Inborn errors of metabolism with a wide range of neurologic and cardiovascular abnormalities are discussed as follows. Likewise, neurologic syndromes associated with alcohol and thiamine deficiency are also included here. GLYCOGEN STORAGE DISEASES The glycogen storage diseases are autosomal recessive abnormalities characterized by the accumulation of glycogen as a result of deficiencies of different enzymes of glycogen metabolism. Only those affecting the heart are mentioned (Table 7). 7@e II Glycogenosis (Acid Maltase Dejkiency) The name Pompe’s disease is used for the infantile form of type II glycogenosis. This is a generalized disease in which there is increased storage of glycogen in the CNS, skeletal muscle, and myocardium (Fig 7) as a result of a deficiency of acid maltase. The infantile form presents several weeks to several months after birth with generalized weakness, marked hypotonia, respiratory difficulties, and cardiomegaly. The latter helps in the separation of Pompe’s disease from other causes of infantile muscular weakness such as WerdnigHoffmann disease, congenital myopathies, and myasthenia gravis. In some patients, severe myocardial thickening is associated with small ventricular cavities and obstruction to ventricular outflow.1ZG8 lz7 Electrocardiographic changes include high voltage QRS complexes in all leads, a shortened P-R interval, and cardiac arrhythmias.127*128 Death occurs by the age of 12 months from either respiratory or cardiac failure. The severe infiltrative cardiomyopathy and respiratory muscle weakness pose a special problem in the anesthetic management of these patients.lz8, lzy 506
Curr
J+obl
Cardiol,
September
1990
TABLE 7. Cardiovascular Abnormalities Storage Disease*
in Glycogen
Glycogenosis Type II (acid maltase deficiency) Infantile form (Pompe’s disease) Myocardial thickening, small cardiac cavities, obliteration of ventricular flow, cardiomegaly, cardiac failure Electrocardiographic changes: tall QRS complexes in all leads, short P-R interval, cardiac arrhythmias Late infantile form and adult form Cardiac involvement is minimal Electrocardiographic changes have been‘reported Glycogenosis Type III (Cori’s disease) Cardiomegaly Thickening of ventricular myocardium Nonspecific electrocardiographic abnormalities Glycogenosis Type IV Cardiomegaly Congestive heart failure Glycogenosis Type V (McArdle’s disease) Electrocardiographic changes lsinus arrhythmia, prolongation of the P-R interval, intraventricular conduction defects, and T wave changes) ‘Data fmmreferences
126-128,130,132,133.
Patients with late infantile acid maltase deficiency have progressive weakness simulating muscular dystrophy, but symptomatic cardiac involvement is minimal. However, electrocardiographic changes are common in this type and in the adult form. For example, Francesconi and Auff13’ reported a X)-year-old woman with the adult form of Pompe’s disease who had ventricular complexes shaped like those of Wolff-Parkinson-White syndrome, often in combination with second-degree atrioventricular block. 7&e XII Glycogenosis (Debrancher Deficiency [Cori’s Disease]) This is milder form of glycogen storage disease that results from debrancher enzyme deficiency. Glycogen of abnormal structure accumulates in the liver, muscle, and heart, resulting in hepatomegaly, myopathy, and cardiomegaly. Clinically, growth retardation, seizures, hypoglycemic episodes, and muscular weakness with wasting electrocardiographic abnormaliare seen.131 There are nonspecific ties, but clinical cardiac difficulties are usually not striking, although Cut-r Probl
Cardiol,
September
1990
so7
FIG 7. Vacuolated appearance of muscle Pompe’s disease. (Hematoxylin-eosin
cells in histologic [HE], x300.)
section
of heart
from
a child
with
there is sometimes massive cardiomegaly.*32 Olson et a1.13” reported a 25year-old woman with glycogenosis type III who had marked thickening of the ventricular myocardium on echocardiography with normal systolic function and no outflow tract obstruction. 7&e N Glycogenosis (Brancher Dejkiency) This is a rare form of glycogen storage disease due to deficiency of the brancher enzyme. Neurologic manifestations include failure to thrive and hypotonia. There is also progressive cirrhosis of the liver. Death occurs before the age of 4 years. Clinical manifestations of heart disease are uncommon, but cardiac enlargement may be seen.lz6 Servidei et a1.134 reported a child with congestive heart failure in whom an endomyocardial biopsy specimen showed hypertrophy of muscle fibers, marked fibrosis, and abundant cytoplasmic deposits that were periodic acid-Schiff positive and diastase resistant. There were similar inclusions in the muscle, skin, and liver. Figure 8 shows basophilic deposits of abnormal glycogen filling central portions of the cytoplasm of myocytes in an endocardial biopsy specimen from a 4-year-old child with type IV glycogenosis. In this patient, cardiomyopathy was the predominant clinical feature of branching enzyme deficiency. There is a report of a clinicopathological syndrome with morphologic, histochemical, and ultrastructural findings similar to those of glycogenosis type IV but without enzymatic concordance.‘35
Curt- Probl
Cardiol,
September
1990
7jpe V Glycogenosis (McArdle’s Disease, Phosphorykse Dejkiency) In McArdle’s disease, there is a deficiency of muscle phosphorylase. This deficiency gives rise to a defect in degradation of glycogen with subsequent high muscle glycogen concentrations and a decreased production of lactic acid. Although patients are normal at rest and well developed, they suffer muscle cramps during strenuous exercise. Muscle damage is clinically detected by the presence of elevated creatine phosphokinase in the blood and myoglobin in the urine. Symptoms often begin in childhood, although onset as late as the fifth decade is seen. These patients do not have clinical cardiac problems, but frequently they have electrocardiographic changes including prolongation of the P-R interval, intraventricular conduction defects, and T wave changes. A useful test for McArdle’s disease is the demonstration that venous lactate levels from a limb performing anaerobic exercise fail to increase.131 Other: Lafora’s Disease Lafora’s disease is considered a form of progressive myoclonic epilepsy in which there are carbohydrate deposits in many organs including the nervous system and the heart. These deposits consist of intracytoplasmic basophilic inclusions in the neurons (Lafora’s bodies), retina, spinal nerves, and cytoplasm of cardiac muscles.136 This inclusion material is a glycoprotein-acid mucopolysaccharide complex and is probably a product of some as yet unidentified derange-
FIG 8. Basophilic deposits of abnormal cytes In endomyocardial biopsy SIS (HE, x500.)
Curr
Probl
Car&d,
September
glycogen specimen
1990
filling central portions of the cytoplasm of myofrom a 4-year-old child with type IV glycogeno-
509
ment of carbohydrate metabolism. In Lafora’s disease, grand mal seizures and myoclonic seizures, which begin during the second decade of life, are accompanied by rapid and severe mental deterioration, often with psychotic symptoms and short survi~al.~~~ Clinical cardiologic abnormalities are not well studied. The diagnosis depends on the detection of the characteristic periodic acid-Schiff (PAS) positive inclusions in the brain.138’13s PAS-positive deposits in other organs are nonspecific and nondiagnostic.
MUCOPOLYSACCHARIDOSI The mucopolysaccharidosis (MPS) are characterized by deficiencies of lysosomal enzymes involved in the degradation of various acid mucopolysaccharides. The clinical and pathologic manifestations of these diseases reflect not only the effects of the storage of mucopolysaccharides within lysosomes, but also the presence of a complex abnormality in the organization of the extracellular elements of connective tissue. The latter abnormalities are responsible for the various anatomic changes that occur in the cardiac valves, skin, cartilages, and bone.lz6 Echocardiographic changes are encountered in many patients with mucopolysaccharidosis, even in the absence of clinical cardiac involvement (Table 8).14’ There are six separate types of mucopolysaccharidoses, and some of these are further subdivided. As a group, patients with mucopolysaccharidoses have coarse facies, short stature, and skeletal dysplasia.14* MPS I (Hurler, Scheie’s, Hurler-Scheie Syndromes) This is an a-L idurodinase deficiency with three clinically distinct subtypes: Hurler syndrome, Scheie’s syndrome, and the HurlerScheie syndrome. Hurler syndrome is a severe progressive disorder with autosomal recessive inheritance that usually leads to death before the age of 10 years. Clinically, mental retardation, dwarfism, coarse facies, large head, cloudy corneas, protruding abdomen, hepatosplenomegaly, upper lumbar kyphos, and other skeletal malformations are seen.14’ Over production of collagen is perhaps responsible in part for restricted motion in the shoulder, elbows, and fingers, for the presence of bilateral carpal tunnel syndrome, and for thickening of the leptomeninges with the subsequent production of hydrocephalus .142 Cardiac involvement may be lethal. The cardiac valves, endocardium, myocardium, coronary arteries, and large systemic arteries are diffusely thickened as a result of increased amounts of fibroelastic connective tissue containing intracellular storage material (Fig 9).143 The left-sided cardiac valves are more severely affected.14’ 510
Cut-r Probl
Cardio!,
September
1990
TABLE
8.
Cardiac Involvement Mucouolvsaccharidosis
in (MPS)*
MPS I and V: Thickening of cardiac valves, endocardium, myocardium, coronary arteries, and large systemic arteries; calcification of mitral valve; intimal plaques in aorta and major blood vessels. Clinical abnormalities include angina, myocardial infarction, cardiomegaly, mitral regurgitation, heart murmurs, and congestive heart failure. MPS II: Thickening of cardiac valves, endocardium, and myocardium; diminished left ventricular ejection fraction. MPS III: Rigidity and thickening of mitral valve, shortening of chordae tendineae, dilatation of ventricles, and slight sclerosis of the conxary arteries and aorta. Asymmetric valve involvement on echocardiogram. MI’S IV: Cardiomegaly, endocardial thickening, cardiac valve thickening, calcification of pulmonary and aortic valve rings, intimal thickening in the aorta, pulmonary trunk, and coronary arteries; aorZic regurgitation; mitral stenosis. MPS VI: Endocardial thickening; mitral and tricuspid valve thickening, mitral valve calcification, and stenosis; aortic stenosis and regurgitation; cardiomegaly; congestive heart failure; premature death from cardiac reasons. MPS VII: Systemic hypertension, aortic regurgitation, obstructive lesions in the aorta and major blood vessels. Mucolipidosis II and III: Cardiac valve, endocardial, pericardial, and coronary artery thickening; accumulation of foam cells in the ruyocardium: cardiomegaly, aortic regurgitation from valve prolapse, (JJ prolongation, ST depression. ‘Data
Cur-r Probl
Cardiol,
September
from t~felwxes
1990
126, 140-145,
147-151.
511
FIG 9. Severe intimal thickening by cells with clear, foamy cytoplasm nal narrowing in this large, extramural coronary artery from (Movat pentachrome stain, x30.)
has produced marked lumia child with Hurler syndrome.
Calcification of the mitral valve ring may be apparent on roentgenograms. The large extramural coronary arteries are rigid and thickened, and their lumina are severely narrowed.12”’ 144 The aorta and other large systemic arteries have raised intimal p1aques.l’” Clinical cardiovascular disease is present in more than 70% of patients with Hurler syndrome. This includes angina, myocardial infarction, cardiomegaly, mitral regurgitation, mitral stenosis, and congestive heart failure.‘45 Scheie’s syndrome features severe cloudiness of the corneas, pigmentary degeneration of the retinas, and glaucoma. These abnormalities lead to severe visual impairment. Patients with this syndrome also have deformities in the hands, stiff joints, entrapment neuropathies of the median nerve at the wrist, and normal intelligence. Aortic stenosis and regurgitation have been observed clinically.142 Cardiomegaly, thickening of the cardiac valves and endocardium, and thickening and narrowing of the coronary arteries also have been reported.‘46 In Hurler-Scheie syndrome, the abnormalities are more severe than those in Scheie’s syndrome, but milder than those in Hurler syndrome. Affected children have mental retardation and involvement of the heart and liver. Mitral stenosis and regurgitation, aortic regurgitation, and calcification of the mitral and aortic valves have been reported.14” 512
Cur-r
Probl
Cardiol,
September
19SO
MPS ZZ (Hunter’s Syndrome) This sex-linked recessive disorder is distinguished from Hurler syndrome by the lack of cornea1 cloudiness and by a longer survival sulfatase. Reported time .14’ There is a deficiency of sulfoiduronate cardiac abnormalities include infiltration by clear cells and thickening of cardiac valves, endocardium, and myocardium, with a diminished left ventricular ejection fraction.lz6 MPS ZZZ(Sanfllippo’s Syndrome) Sanfilippo’s syndrome occurs in two forms according to the enzymatic defect: deficiency of heparan sulfatase in type A, and deficiency of N-acetyl-alpha-D glycosaminidase in type B. Progressive mental retardation and relatively mild skeletal abnormalities are noted at school age, but can be seen as early as 2 years of age. Cardiovascular abnormalities reported in type A include rigidity and thickening of the mitral valve and shortening of the chordae tendineae. In type B, dilatation of both ventricles, numerous tiny nodules of fibrous connective tissue on the aortic and mitral valves, and slight sclerosis of the coronary arteries and aorta are encountered.lz6 An asymmetric valve involvement is noted on an echocardiogram.14’ MPS ZV (Morquio Syndrome) The prominent clinical features are skeletal abnormalities and their effects on the nervous system. The enzymatic defect is a deficiency of hexosamine-6-sulfatase. The trunk and neck are short, the sternum is prominent, and the head appears to lie directly on the shoulders. Growth ceases at about 7 years of age.14’ Cervical myelopathy is associated with the presence of atlantoaxial subluxation resulting from hypoplasia of the odontoid process.142 Cardiac pathologic conditions include cardiomegaly, endocardial thickening, cardiac valve thickening, calcification of pulmonary and aortic valve rings, and intimal thickening in the aorta, pulmonary trunk, and coronary arteries.“” Sometimes, there is clinical evidence of aortic regurgitation.‘45 Mitral stenosis has also been reported.141 MPS V MPS V is now classified
with mucopolysaccharidosis
I.
MPS VI (Maroteau)r-Lamy Syndrome) Maroteaux-Lamy syndrome is caused by a deficiency of arylsulfatase B. Retardation of growth, skeletal deformities, restriction of joint movement, flexion contractures of the knees, and corneal clouding are encountered. Myelopathy results from hypoplasia and subluxation of the odontoid process.‘4” cur-r Probl
Cardiol,
September 1990
513
Aortic stenosis147 and regurgitation are the prominent findings noted clinically. Endocardial thickening, mitral and tricuspid valve thickening, and calcific mitral valve stenosis have been observed.148’ I49 Cardiomegaly, congestive heart failure, and premature death from cardiac disease are also encountered.14’ MPS VZZ(@Glucoronidase Deficiency) This is a rare disease that results from a deficiency of B-glucuronidase. It is manifest by skeletal deformities, growth impairment, a protruding abdomen, hepatosplenomegaly, and slow mentation. Systemic hypertension, aortic regurgitation, and obstructive lesions in the aorta and other major blood vessels have been reported.150 Mucolipidosis ZZand ZZZ These conditions are characterized deficiencies of several lysosomal hydrolases which are active in the degradation of lipids and mucopolysaccharides.12” Mucolipidosis II (I-cell disease) resembles Hurler syndrome, but the former has an earlier onset, and may even be evident at birth. Mucolipidosis III (pseudo-Hurler polydystrophy) becomes manifest at 2 to 4 years of age and resembles juvenile rheumatoid arthritis.14’ Coarse facies, cloudy corneas, joint stiffness, retarded growth, skeletal changes, and slow mentation are seen. Thickening of the cardiac valves, endocardium, pericardium, and coronary arteries, and accumulation of foam cells in the myocardium are seen? 15’ There are prominent clinical, electrocardiographic, and echocardiographic signs of myocardial involvement. These changes include cardiomegaly, aortic regurgitation, mitral valve prolapse, QT segment prolongation, and ST segment depression.151 THE SPHZNGOLZPZDOSZS A wide variety of clinical syndromes results from the excessive accumulation of sphingolipids in nerve cells. In the following syndromes, the nervous system is primarily involved, but cardiovascular abnormalities may also be apparent (Table 9). Fabry’s Disease (Angiokeratoma Corporis Dijgirsum) Fabry’s disease is caused by a deficiency of lysosomal a-galactosidase A. Being the only known sex-linked recessive lipid storage disease, it occurs primarily in men. The disease becomes clinically apparent during childhood or early adolescence. Manifestations include proteinuria, skin lesions (angiokeratomas), corneal dystrophy, burning pains, paresthesias, and attacks of fever.15’ The cardiovascular involvement is directly related to the cumula614
Cur-r
Probl
Cardid,
September
1990
TABLE
9.
Cardiovascular
Abnormalities
in the Sphyngolipodosis’
Fably’s disease (angiokeratoma corporis diffusum) Deposition of sphingolipids in small arteries, myocardial cells, and valvular fibroblasts. Clinical: Anginal chest pains, myocardial infarctions, congestive heart failure, cardiomegaly, valvular involvement, hypertension, hypertrophic obstructive cardiomyopathy. Farber disease Granulomas in cardiac valves, chordae tendineae, coronary arteries, pericardium, aorta, and pulmonary arteries; cardiac enlargement. Gaucher’s disease Pulmonary hypertension, intrapericardial hemorrhages, constrictive pericarditis. Niemann-Pick disease Occasional accumulation of sphingolipids in the endothelium of blood vessels and myocardium interstitium. GM1 gangliosidosis Infantile: Diffuse, nodular thickening of the mitral and tricuspid valves; cardiomegaly. Juvenile: Cardiomegaly, mitral and aortic regurgitation. GM2 ganghosidosis Tay Sachs disease: Accumulation of GM2 ganglioside in the heart tissue, nonspecific electrocardiographic changes (QRS-T angle, QT prolongation, abnormal T waves). Sandhoff disease: Lipid deposits in the heart, cardiomegaly, thickening of the mitral and tricuspid valve leaflets, thickening and fusion of the chordae tendineae, thickening of the aortic and pulmonary valves. ‘Data liom refe1ences
126, 145, 152, 1.53, 157, 159, 162, 163.
tive deposition of glycosphingolipid in small arteries, arterioles, cardiac myocytes, and valvular fibroblasts (Fig 10). Cardiomegaly, angina, premature myocardial infarctions, congestive heart failure, valvular involvement,lz6. IS2 hypertrophic obstructive cardiomyopathy,153 and hypertension have been reported. Electrocardiographic and echocardiographic changes are consistent with the structural cardiac abnormalities. In addition to the vascular lesions mentioned above, areas of ectasis develop in small blood vessels of the skin and other organs. Microaneurysms are prominent in ocular vessels.154 Cerebral complications are associated with both premature cerebrovascular disease and long standing hypertension. The resulting neurologic manifestations, which vary with the site and extent of lesions, include alterations of consciousness, aphasia, seizures, hemiplegia, and hemisensory defects.l”” Alterations in consciousness may be secondary to an electrolyte imbalance associated with renal involvement. Women heterozygous for the disease can be clinically affected.“’ In both homozygotes and heterozygotes, there is deposition of glycosphingolipids in the neuronal cytoplasm of peripheral nerves, neurons of the autonomic nervous system, and subcortical nuclei of the CNS.l”’ The conduction velocity of peripheral nerves is Curr
Probl
Cardiol,
September
1990
515
FIG 10. Fabry’s disease. Histologic sections showing marked vacuolization of cardiac muscle cells A, and smooth muscle cells B, in the wall of an artery. (HE, each x2.50.) C, darkly stained lamelle composed of glycolipid material fill the cytoplasm of the cardiac muscle cells. One-micron thick section of plastic-embedded tissue, alkaline toluidine blue stain, xl ,000. D, electron micrograph showing membrane-limited group of lamellae composed of alternating dense and light bands. (Uranyl acetate and lead citrate stain, x92,000.)
slowed.*5e Hypohydrosis and gastrointestinal disturbances ondary to autonomic nervous system disturbances.
are sec-
Farber Disease (Lipogranulomatosis) This is an autosomal recessive disease. It results from accumulation of ceramide and acid mucopolysaccharides in a variety of cell types and from the subsequent formation of granulomas with lipidfilled histiocytes. These granulomas give rise to the clinical symptoms of hoarseness, markedly swollen painful joints, periarticular subcutaneous nodules, pulmonary infiltrates, and respiratory dis516
Curr
Probl
Cardiol,
September
1990
tress. Mental deterioration occurs in the late stages of the severe form of this illness.157 But the most prominent neurologic involvement occurs in the peripheral nervous system with areflexia and electromyographic signs of denervation. Cogan et al.15’ reported color changes in the retina around the foveal area with a cherry red center, but without disturbance of vision. Patients are severely disabled early in childhood and usually die of pulmonary infections. Heart murmurs and cardiomegaly result from the formation of granulomas in cardiac valves, chordae tendineae, coronary arteries, pericardium, aorta, and pulmonary arteries.f26’ 157
Gaucher’s
Disease
This is an autosomal recessive disease caused by a deficiency of a lysosomal glucocerebrosidase. Gaucher’s disease is the most common of the sphingolipidosis. Three forms of the disease have been described: the acute neuronopathic form (nemologic involvement during infancy), the subacute neuronopathic form (nemologic involvement after infancy), and the chronic non-neuronopathic form (adult type without cerebral involvement) .15’ Visceral abnormalities such as enlargement of the liver and spleen and involvement of the lungs are found in all three forms. Occlusion of alveolar capillaries by Gaucher’s cells may predispose to pneumonia. A few patients develop pulmonary hypertension,15’ and a few Gaucher’s cells may appear in the myocardium.15s Hypersplenism produces both anemia and thrombocytopenia. A bleeding diathesis frequently results from the thrombocytopenia and may lead to intrapericardial hemorrhage and subsequent constrictive pericarditis . Neurologic involvement in the acute neuronopathic form is present at birth or shortly after birth. The infant fails to thrive, and has strabismus, laryngeal stridor, a feeble cry, seizures, and spasticity. The latter progresses to decerebrate rigidity. Death occurs around 9 months of age from pulmonary infections.l”’ In the subacute neuronopathic form (juvenile form), the neurologic involvement occurs after infancy and patients may survive to adulthood. The chronic non-neuronopathic form is characterized by the lack of neurologic involvement. However, there are several reports of neurologic involvement in this form. For example, Miller et al. reported two adult siblings with proven Gaucher’s disease who presented with a nemologic picture characterized by seizures, mental deterioration, disturbance of extraocular movements, and abnormal electroencephalograms.160 The diagnosis of Gaucher’s disease rests on the presence of splenomegaly, hepatomegaly, Gaucher’s cells in bone marrow, and a deficiency of glucocerebrosidase.15g Curr
Probl
Cardiol,
September
1990
517
Niemann-Pick
Disease
This is an autosomal recessive disorder in which sphingomyelin accumulates in body tissue as a consequence of a deficiency of sphingomyelinase. The onset of symptoms is usually between 3 and 9 months of age, and hepatomegaly and splenomegaly are early clinical signs. The most common form is the infantile type. This is characterized by regression of acquired motor and intellectual functions, macular degeneration, and seizures. Occasionally, sphingolipids also accumulate in the endothelium of blood vessels and myocardial interstitium, but as a rule, the heart and blood vessels show no significant involvement in any of the types of Niemann-Pick disease.“’
GM1 Gangliosidosis Generalized GM1 gangliosidosis @galactosidase deficiency) exists in clinically distinct infantile and juvenile forms, Both forms are associated with accumulation of GM1 ganglioside and its asialoderivative in the CNS and of a keratan sulfatase-like proteoglycan in visceral organs. The infantile form is characterized by coarse facial features, hepatomegaly, splenomegaly, dysostosis multiplex, progressive mental and motor retardation, tonic-clonic seizures, ineffective sucking and swallowing, and malnutrition. If the patient survives beyond the first year of life, the clinical picture is that of decerebrate rigidity, blindness, deafness, and unresponsiveness. Cardiovascular lesions include diffuse, nodular thickening of the mitral and tricuspid valves and cardiomegaly. In the juvenile type of GM1 gangliosidosis, visceromegaly is much less pronounced than in the infantile type, and survival may extend to 10 years of age. Cardiovascular lesions in the juvenile type include cardiomegaly and aortic and mitral regurgitati0n.l’”
GM2 Gangliosidosis The two types of generalized GM2 gangliosidosis, Tay-Sachs disease and Sandhoff disease, are clinically very similar, despite differences in the metabolic derangement. In Sandhoff disease, there is a reduction in the activity of both A and B forms of G-N-acetylhexosaminidase, whereas in Tay-Sachs disease only the A form is affected. Progressive mental and motor deterioration begins between 3 and 6 months of age.161 After 18 months of age, deafness, blindness, convulsions, and spasticity are apparent. Death occurs by 3 years of age. Lipidosis of the cerebral cortex neurons and ganglion cells of the autonomic nervous system of the intestinal tract and other organs is seen. Patients with Tay-Sachs disease have no clinical manifestations of cardiovascular disease, but exhibit nonspecific electrocardiographic changes, and accumulation of a GM2 ganglioside in heart 618
Cum Probl
Cardid,
September
1990
tissue similar to that found in excessive amounts in the brain.“’ Electrocardiographic changes occasionally seen include a wide QRST angle, Q-T interval prolongation, and abnormal T waves.14’ Cardiomegaly and mitral regurgitation are clinically prominent in some patients with Sandhoff disease. Anatomic studies of the heart in this disease have shown left atrial and left ventricular enlargement, thickening of the mitral and tricuspid valve leaflets with thickening and fusion of the chordae tendineae, and thickening of the aortic and pulmonic valves.163 Histologic and ultrastructural studies have disclosed lipid deposits in endocardial fibroblasts, connective tissue of the heart valves, endothelial cells, cardiac muscle cells, smooth muscle cells of the blood vessels, and neural elements of the epicardium.lti3 D. MCCALL: In the extensive variety of inherited infiltrative disorders described by the authors, there is intramyocardial accumulation of abnormal products of metabolism. This is particularly true of the glycogeneses and mucopolysaccharidoses. When extensive, this intramyocardial accumulation may result in impaired systolic contractile performance; the patient presenting with symptoms and signs of a dilated cardiomyopathy. Many times, however, the infiltrate causes a reduction in ventricular compliance, impairing ventricular filling and resulting in a restrictive cardiomyopathy. Such patients will frequently present with symptoms and signs of predominantly right-sided failure, and in many ways, the clinical picture may resemble that of constrictive pericarditis. Noninvasive testing, including echocardiography and radionuclide angiography, is useful in establishing the functional abnormality, and endomyocardial biopsy may be used to provide the exact pathologic diagnosis. Because of the patchy nature of the infiltrate, however, biopsy may be negative in up to 50% of cases and the clinician must rely upon other markers of the disease in order to establish the diagnosis.
b
OTHER
METABOLIC
DZSZQISES
OF THE
NERVOUS SYSTEM
The following diseases affect both the nervous system and the cardiovascular system with significant frequency (Table 10). Homocystinuria
Homocystinuria is caused by a defect in the activity of cystathionine synthetase, which converts homocysteine to cystathionine. This defect results in increased plasma levels of homocysteine and methionine, and increased urinary excretion of homocysteine. Individuals with this metabolic defect have mental retardation seizures, skeletal deformities, ectopia lentis, and occlusive vascular disease. The latter, which is a frequent cause of death, seems to be related to low antithrombin activity,1”4 increased platelet consumption, decreased platelet survival time, and pronounced fragility of the vascular endothelium.lz6 The occlusive vascular disease gives rise to cerebral thromboembolic episodes, myocardial infarctions, aortic thromCurt- Probl
Cardiol,
September 1990
619
TABLE
10.
Cardiovascular Abnormalities Menke’s Disease and Familial
in Homocystinuria, Periodic Paralvsis*
Tangier
Disease,
Wilson’s
Disease,
Homocystinuria Low antithmmbin activity and pronounced fragility of the vascular endothelium, myocardial infarction, aortic thrombosis, peripheral arterial occlusions, venous thrombosis, pulmonary and systemic emboli. Tangier disease Congenital pulmonary stenosis, ischemic heart disease, mitral regurgitation, aortic insufficiency. Wilson’s disease Increaqed copper concentration in the heart, cardiac hypertmphy, dilated cardiomyopathy, electrocardiographic abnormalities (34% 1 of left ventricular hypertmphy and biventricular hypertrophy, early repolarization, ST depression, T wave inversion, premature atria1 and ventricular contractions, atrial fibrillation, sinoatrial block, and Mobitz type 1 atrioventricular block, orthostatic hypotension (19761, congestive cardiomyopathy. Menke’s (kinky-hair) syndrome Body copper deficiency, patchy degenerative changes in arterial walls, tortuous and dilated blood vessels, aneurysm formation. Familial periodic paralysis Cardiac dysfunction during episodes of flaccid paralysis (cardiac arrhythmias, bradycardia, left ventricular dysfunction), fixed electrocardiographic changes (ectopic heart beats, ventricular tachycardia), intermyofibrillary glycogen in the myocardium. ‘Datafiwn
references
boses, peripheral cerebral cortical emboli.lZ”, 165
126,164,165,167,168,172-175,178-182.
arterial occlusions, venous thromboses),
Familial Lipoprotein
Deficiency
venous thromboses (including and pulmonary and systemic
(Tangier Disease)
This disease is clinically characterized by enlarged yellow-orange tonsils, corneal opacities, relapsing peripheral neuropathies, low plasma cholesterol levels, and storage of cholesterol esters in various tissues. The neuropathy is manifested by sensory symptoms and asymmetric proximal and distal motor weakness. All the symptoms progress slowly or fluctuate in intensity through the years.16” Cardiovascular abnormalities are rare, but congenital pulmonary stenosis, ischemic heart disease, mitral regurgitation, and aortic insufficiency have been reported.l”, lG7,lfix There is focal cholesterol ester deposition in the mitral and tricuspid valvesl” and the pulmonary arteries.17o
Wilson’s Disease (Hepatolenticular
Degeneration)
Wilson’s disease is an autosomal recessive disorder characterized by cirrhosis of the liver and degenerative changes of the brain, especially the basal ganglia. A deficiency of ceruloplasmin allows Su)
Curr
Probl
Cardiol,
September
1990
the loosely bound serum copper to deposit in many organs. Clinically, Wilson’s disease exists in two forms, the juvenile type (with early onset and rapid evolution if not treated) and the chronic type (with onset between 20 and 30 years of age and a slower course). Clinical abnormalities include liver disease, Kayser-Fleischer corneal rings, emotional disturbances, failure to make progress in school, dementia if the disease remains untreated, dysphagia, dysarthria, incoordination, tremor, and postural abnormalities?‘l Heart involvement has been recognized as an important aspect of the disease. Electrocardiographic abnormalities, which occur in about 34% of patients, include left ventricular and biventricular hypertrophy, early repolarization, ST depression, T wave inversion, premature atrial or ventricular contractions, atrial fibrillation, sinoatrial block, and Mobitz. type I atrioventricular block.172 Orthostatic hypotension occurs in about 19% of patients. Two cardiac deaths occurred among 53 patients as a result of congestive cardiomyopathy in one and ventricular fibrillation in the other.17’ Cardiac hypertrophy and dilatation, and an increased copper concentration in the heart are common.172-174 Serum ceruloplasmin levels are decreased, serum copper levels are low, urinary copper excretion may be increased or normal, liver function tests are abnormal, and a liver biopsy specimen demonstrates cirrhosis. The treatment of choice is o-penicillamine.
Menke’s (Kinky-hair)
Syndrome
This syndrome is inherited as a sex-linked recessive trait and is caused by a defect in the intestinal absorption of copper. The clinical manifestations are a result of copper deficiency. Copper is a cofactor required for lysyl oxidase, the enzyme responsible for the formation of crosslinks between lysine residues in elastic and collagen tissues.12” The disease presents early in life with convulsions, hypothermia, mental and growth retardation, spasticity, and a peculiar appearance of the face and hair. Copper deficiency seems to be responsible for widespread, patchy degenerative changes in the arterial walls. Arteries show premature degenerative changes with elongation, aneurysmal dilatation, rupture, stenosis, intimal proliferation, intimal thickening, and thrombosis. The internal elastic lamina demonstrates fragmentation, disruption, and duplication.‘75 Aneurysm formation often involves major arteries and veins.lz6 Cerebrovascular insufficiency induced by involvement of the cerebral arteries is the probable cause of gliosis and cystic degeneration seen in the brain. Arteriograms show elongation and tortuosity of major arteries with areas of localized dilatation and narrowing.17’ The heart in Menke’s syndrome is normal, but superficial vessels often appear tortuous or dilated. Cut-r Probl
Cat-did,
September 1990
521
Lead Poisoning The symptoms and signs of lead poisoning in adults are different from those seen in children. While progressive motor weakness due to peripheral axonal neuropathy occurs in the adult, there is an acute encephalopathy in children. This encephalopathy in children is manifest by alterations of consciousness, signs of increased intracranial pressure, and convulsions. Although recovery takes place in mild and moderate cases of lead poisoning, there may be permanent damage to the nervous system. Other organs besides the nervous system can be involved. Myocarditis, which occurs in chronic lead intoxication, is characterized by interstitial fibrosis with a serous exudate and relatively few inflammatory cells.176 Bertel et a1.‘77 reported a patient in whom severe lead poisoning appeared to have caused rapid development of arterial hypertension and elevation of plasma catecholamine concentrations with reduced P-adrenoceptor responses similar to those observed in low-renin essential hypertension.
Familial Periodic
Paralysis
There are three varieties of this disease: the hypokalemic, normokalemic, and hyperkalemic forms. They resemble each other, but differ in that each may be precipitated by different factors. Hyperkalemic periodic paralysis sometimes is accompanied by clinical and electromyographic myotonia, which can be precipitated by exposure to cold. Common to all three forms are the occurrence of attacks at rest, the increased frequency of attacks when exposed to cold, and the ability of patients to abort incipient attacks with mild exercise. While the hypokalemic form can be precipitated by carbohydrate ingestion or by the administration of insulin, hydrocortisone, or sodium chloride, the hyperkalemic form may be provoked by ingestion of potassium. The hypokalemic form is alleviated by the administration of potassium, the hyperkalemic form is alleviated by epinephrine, amphetamine, or calcium chloride. Cardiac arrhythmias occur during attacks of hypokalemic, hyperkalemic,178 and normokalemic17s periodic paralysis. Although cardiac arrhythmias between attacks are not a feature of any of the commonly encountered varieties of familial periodic paralysis, fixed electrocardiographic abnormalities occur infrequently after the disease has existed for many years. The electrocardiographic changes include ectopy, most commonly manifested as bigeminy,17’ and ventricular tachycardia. Most commonly, the electrocardiogram is normal between attacks. During attacks, electrocardiographic changes are associated with the variation of the potassium concentration in cardiac the bloodlao and should not be taken as a sign of permanent dysfunction. Evidence of cardiac dysfunction during an episode of flaccid pa622
Curr
Probl
Cardiol,
September
1990
ralysis was reported by Kramer et al.“* in a patient with familial hypokalemic periodic paralysis. This patient had an elevated serum creatinine phosphokinase level with an increased myocardial fraction of this enzyme (myocardial band), alterations in the lactic dehydrogenase isoenzyme pattern, severe bradycardia, and evidence of left ventricular dysfunction. Likewise, patients with the combination of paroxysmal muscular weakness due to hyperkalemic periodic paralysis and cardiac arrhythmias have also been reported.17’ In patients with hypokalemic periodic paralysis who have developed permanent muscular weakness, a careful noninvasive screening failed to show evidence of cardiac involvement.“’ Nevertheless, subtle abnormalities of cardiac muscle cannot be ruled out completely in these patients. In this respect, ultrastructural examination of tissue obtained from the left ventricle in a patient with hypokalemic periodic paralysis showed an unusual amount of intermyofibrillary glycogen resembling the increase of glycogen found in the skeletal biopsy specimen obtained from the same patient.“’ Idiopathic infantile Hypercalcemia (Williams Syndrome) This syndrome, in which idiopathic hypercalcemia coexists with congenital cardiac abnormalities, is probably a result of deranged vitamin D metabolism. Children with this illness have mental subnormality, unusual facial features (elfin face), dental malformations, and aortic stenosis is found in more than strabismus.183 Supravalvular 80% of patients.ls3 Other arteriopathies include peripheral pulmonary stenosis (58%), and stenosis of innominate, common carotid, subclavian, coronary, superior mesenteric, and renal arteries. Less frequently, there are atria1 and ventricular septal defects, and juxtaductal coarctation of the aorta.ls3 NEUROLOGIC SYNDROMES ASSOCIATED AND THIAMINE DEFICIENCY
WITH ALCOHOL ABUSE
The clinical picture of chronic alcoholism with malnutrition involving the nervous system varies from the classic features of pellagra (mental changes, vertigo, deafness, long tract involvement, tremor, ataxia, peripheral neuropathy) and beriberi (polyneuropathy, congestive heart failure) to a simple peripheral neuropathy or nutritional optic atrophy. Neurologic conditions resulting from prolonged and severe dietary restriction of thiamine intake occur in prisoners of war and persons with beriberi or pellagra. All these entities seem to be part of a broad spectrum of neurologic symptom-complexes caused primarily by nutritional deficiency and chronic alcoholism. In chronic alcoholism, repeated acute heavy alcohol consumption may cause congestive cardiomyopathy, acute left ventricular failure, and atria1 fibrillation.1x4-*8” Beriberi and Wernicke’s encephalopathy Cur-r Probl
Cardiol,
September
1990
523
TABLE
11.
Cardiovascular Abnormalities in Syndromes Associated With Alcohol Abuse and Thiamine Deficiency* Beriberi Cardiac enlargement Congestive heart failure Cardiocirculatory failure Wernicke’s encephalopathy Tachycardia Tachypnea Increase in cardiac output T wave changes Orthostatic hypotension *Data from
referances
1X7-193.
are associated with thiamine deficiency, tem is involved in both (Table 11).
and the cardiovascular
sys-
Beriberi Cardiac circulatory
enlargement, congestive heart failure, and severe cardiofailure occur in the wet and acute (shoshin) forms of befi,,efi.187, 188 A rise in serum pyruvate and lactate concentrations leads to a blockade of carbohydrate metabolism and metabolic acidosis.ls8 The mechanism whereby the heart is involved in beriberi is not clear, but there may be more than one cause: (a) concomitant presence of autonomic neuropathy, anemia, and other unknown factors may lead to lowering of systemic vascular resistance with peripheral blood shunting, increased venous return to the heart, and high output heart failurel”; (b) elevated splanchnic flow, reduction of renal blood flow, and reduction of glomerular filtration; (cl direct impairment of myocardial energy production, since thiamine is no longer available as a cofactor for energy production in the Krebs cycle; and (d) a direct effect of alcohol on the myocardium, with the production of alcoholic cardiomyopathy.lsgj lso Treatment with thiamine and abstention from alcohol are effective in relieving the symptoms in the early stages.‘88’ Is9
Wernicke’s
Encephalopathy
The occurrence of lesions in the hypothalamus and brain stem in patients with Wernicke’s encephalopathy explains not only the alteration of consciousness, extraocular movement abnormalities, and ataxia seen in this syndrome, but also the occurrence of respiratory and cardiovascular difficulties. Tachypnea, tachycardia, increased cardiac output, and postural hypotension are present in over half the patients suffering from acute Wernicke’s encephalopathy. Pos524
Curr
Probl
Cardiol,
September
1990
tural hypotension may be due to a defect in efferent sympathetic nervous outflow and decreased peripheral vascular resistance,l’l or to a disorder of central vasomotor contro1.192 A concomitant peripheral neuropathy with autonomic nervous system involvement may also play a role in the genesis of the orthostatic hypotension. Electrocardiographic changes in Wernicke’s encephalopathy include sinus tachycardia, and flattened, isoelectric, diphasic, inverted, or peaked T waves.ls3 Improvement in neurologic and cardiovascular abnormalities takes place after treatment with thiamine. MALFORMATIONS
OF THE CNS
Cardiovascular anomalies are among the malformations found in association with dysraphism (posterior midline defects of development), faciotelencephalopathy (anterior midline defects of development), and disorders of cellular migration and proliferation. Immediately after the neural tube closes at the fourth week of gestation, its lining of immature ependymal cells secretes a proteinaceous neural tube fluid, and the resulting distention of the tube helps to shape not only the embryonic brain and spinal cord, but also the bordering mesodermal cells.ls4 Gardner hypothesized that a hypersecretion of neural tube fluid during this critical period will lead to overdistention of the neural tube and infiltration of fluid into the mesoderm, damaging not only the neural tube, but also the cells that are destined to form mesodermal organs such as the heart. Cardiovascular anomalies associated with malformations of the CNS are best studied in chromosome disorders, the Dandy-Walker syndrome, and fetal alcohol syndrome. CHROMOSOME
ABERRATIONS
The chromosome aberrations associated with nervous system and cardiac abnormalities are summarized in Table 12. DANDY-WALKER
SYNDROME
In the Dandy-Walker syndrome, there is a cystic deformity of the fourth ventricle and agenesis or hypoplasia of the cerebral vermis.‘s7 In more than half of the patients with Dandy-Walker syndrome, there are other associated neurologic anomalies such as hydrocephalus, agenesis of the corpus callosum, cerebral and cerebellar heterotopias, polymicrogyria, aqueductal stenosis, microcephaly, infundibular hamartomata, syringomyelia, and occipital meningocele .1s7-1ss Clinical manifestations include mental retardation, seizures, changes in the size of the head, spastic quadriparesis, ocular Curr
Probl
Cardiol,
September
1990
5.25
TABLE
12.
Cardiovascular Chromosome
Abnormalities Aberrations*
Trisomy 21 (Down syndrome) Endocardial cushion defect Ventricular septal defect Atrial septal defect Tetralogy of Fallot Patent ductus arteriosus Trisomy 13 (Patau’s syndrome) Ventricular septal defect Patent ductus arteriosus Atria1 septal defect Dextrocardia ‘Transposition of great vessels Double outlet right ventricle Trisomy 18 (Edward’s syndrome1 Ventricular septal defect Atria1 septal defect Patent ductus arteriosus Aortic and pulmonic stenosis 4p-Wolf syndrome) Atria1 septal defect Ventricular septal defect 5p-(cri du chat syndrome) Ventricular septal defect Patent ductus arteriosus Aortic stenosis 13q-syndrome Tetralogy of Fallot Ventricular septal defect lSp-syndrome Tetralogy of Fallot Transposition with pulmonic Patent ductus arteriosus Ventricular septal defect Ventricular hypertmphy Dextroversion Congestive heart failure lSq-ICarp mouth syndmmet Ventricular septal defect X0 Wurner’s syndrome, Coarctation of the aorta Aortic stenosis Atria1 septal defect XXXXY syndrome Patent ductus arteriosus Atria1 septal defect XXX syndrome Patent ductus arteriosus ‘Data horn rt?ferences
526
in
(variable)
stenosis
195, 196.
Curr
Probl
Cardiol,
September
1999
findings, cerebellar ataxia, apneic spells, and several other clinical signs of brain stem and cerebellar dysfunction. About 25% of patients with the Dandy-Walker syndrome have anomalies outside of the nervous system.l” Reported anomalies include cleft palate, facial angiomas, vertebral abnormalities, polydactylism-syndactylism, polycystic kidneys, and cardiovascular abnormalities.lg7’ ‘O” Heart defects reported in association with the Dandy-Walker syndrome are septal defects, patent ductus arteriosus, subaortic stenosis, infundibular pulmonary stenosis, bicuspid aortic valve, coarctation of the aorta, ventricular aneurysm, cardiomegaly, tetralogy of Fallot, single ventricle, and dextrocardia.1g7’ 1ss--204The association of facial and cardiovascular anomalies favors the hypothesis that the onset of the Dandy-Walker syndrome occurs between the formation and the migration of the cells of the neural crest (between the third and fourth postovulatory week) .‘O” FETAL
ALCOHOL
SYNDROME
Delayed development, mental deficiency, facial, limb, and cardiovascular defects have been reported in children born to women who are alcoholics. Among these abnormalities, the most consistent are prenatal and postnatal growth deficiencies, microcephaly, dysmorphic features, hyperactivity, learning disabilities, mental retardation, and urogenital deformities. Cardiac malformations include ventricular septal defect (30% to 65%), atrial septal defect (lo%), pulmonic stenosis (lo%), patent ductus arteriosus (lo%), tetralogy of Fallot (10% to 16%), aortic stenosis (7% 1, coarctation of the aorta (5%), and transposition of the great arteries (5%).205-207 The syndrome occurs in about one infant per 1,000 live births. The syndrome is not well defined, and it is possible that other drugs used in conjunction with alcohol by these women may also exert teratogenic effects. Acute alcoholic intoxication may produce changes in myocardial contractility. Experimental studies in animals have shown that maternal alcohol intoxication causes a rapid depression of fetal myocardial contractility that is maintained several hours after cessation of alcohol ingestion.20x Other studies in animals showed abnormalities of heart and great vessel development following ethanol exposure.e.2”9 OTHER HEREDITARY NERVOUS SYSTEM Five classic neurologic able clinical significance. Curr
Probl
Cardiol,
September
AND DEGENERATIVE diseases have cardiac
1990
DISEASES involvement
OF THE of vari-
527
FRIEDREZCH’S
ATMZA
Most commonly transmitted as an autosomal recessive and rarely as a sex-linked abnormality, Friedreich’s ataxia chiefly involves the spinocerebellar and pyramidal tracts, dorsal columns, peripheral nerves, and optic nerves. It also involves the skeletal and cardiovascular systems. Probably more than 55% of patients with Friedreich’s ataxia have major clinical cardiac abnormalities (anginal pain, cardiac enlargement, congestive heart failure). In a clinical study of 75 patients, one or more cardiac abnormalities were detected in 95% of patients utilizing the combination of scalar electrocardiography, Mmode echocardiography, and two-dimensional echocardiography.“” Cardiac involvement is present at necropsy in all patients.‘ll Heart disease may present in some patients prior to the development of neurologic symptoms.212 Left ventricular hypertrophy is more common in slightly to moderately disabled patients; right ventricular hypertrophy predominates in severely affected patients.‘l” Gross anatomic changes in the heart include ventricular hypertrophy with or without dilatation, patchy or diffuse interstitial fibrosis, and less frequently, endocardial thickening and mural thrombosis.214 A high incidence of hypertrophic cardiomyopathy with asymmetric thickening of the ventricular septum has been shown by echocardiographic and angiographic studies to occur in Friedreich’s ataxia.215-218 Both obstructive and nonobstructive forms of hypertrophic cardiomyopathy have been described.21”-Z20 Fibrous replacement of the myocardium is widespread, especially in subendocardial and subepicardial areas. Fatty infiltration may be prominent. The cardiac muscle cells show hypertrophy, but the valves and the conduction system usually are normal. The large extramural coronary arteries are not affected, but all stages of intimal proliferation can be found in small coronary arteries, which may be occluded. Brumback et alzzl reported a 27year-old woman with Friedreich’s ataxia in whom the cardiac abnormalities included ventricular subendocardial fibroelastosis, occlusion of the coronary sinus ostium, individual myofiber loss, myofiber disarray, and enlarged hyperchromatic myofiber nuclei. Electrocardiographic changes, which may be present at the onset of neurologic signs in Friedreich’s ataxia, are seen in two thirds of patients?l”, 222 These changes reflect the anatomic cardiac abnormalities and include widespread inversion of T waves, changes consistent with left ventricular hypertrophy,76’ ‘I2 atria1 fibrillation, and atria1 flutter. Serial electrocardiograms, recorded over periods of up to 32 years, showed that these abnormalities may develop in patients with Friedreich’s ataxia at any time up to 20 years after the onset of neurologic symptoms.21” ST changes characteristic of ischemia do not occur2” and disturbances of conduction are rare.“” 528
Curr
Probl
Cardiol,
September
1990
b D. MCCALL: It is of interest to note that cardiac abnormalities may be present in the parents of patients affEcted by Friedreich’s ataxia. These individuals, because of their heteruzygous state, have no clinical manifestations of the disease, but will occasionally have both electticardiographic abnormalities and asymmetric septal hypertrophy, on echocardiographic evaluation. PERONEAL SENSORY
MUSCULAR NEUROPATHY;
ATROPHY (HEREDITARY CHARCOT-MARIE-TOOTH
MOTOR AND DISEASE)
Peroneal muscular atrophy is a slowly progressive neurogenic atrophy affecting mainly the distal muscles of the legs and sometimes the intrinsic muscles of the hands. It is related to Friedreich’s ataxia. Isolated cases of Friedreich’s ataxia occur in families with peroneal muscular atrophy, and the two diseases have been described in the same individual. Cardiomyopathy is not characteristically associated with peroneal muscular atrophy.223 But there are a few reports associating peroneal muscular atrophy with heart disease.2z28 224--226A myocardial biopsy specimen from a 42-year-old man with familial heart block and peroneal muscular atrophy revealed ultrastructural changes similar to those described in simple myocardial hypertrophy and hypertrophic obstructive cardiomyopathy.“’ Little?z4 described the coexistence of cardiac conduction defects and peroneal muscular atrophy in a family in which ten members of three generations were affected (three manifested both conditions, six had the cardiac defect alone, and one had only the neurologic disorder). Thus, it seems likely that some cases of peroneal muscular atrophy have conductive cardiac defects and cardiomyopathy. TUBEROUS
SCLEROSIS
(BOURNEVZLLE’S
DISEASE)
The inheritance of this disease fits an autosomal dominant pattern. A commonly encountered triad of adenoma sebaceum, seizures, and mental retardation are the clinical characteristics of this disease, but visceral anomalies are not uncommon. In this regard, tuberous sclerosis is associated with cardiac rhabdomyoma in about 37% to 50% of cases.z27 Two-dimensional echocardiography is particularly well suited for detecting rhabdomyomas, which are the most common cardiac tumors in infancy and childhood (Fig 11). These tumors of infancy can be single or multiple; intracavitary OI intramural. Intracavitary rhabdomyomas may be found in stillborn infants or in infants who died suddenly, suggesting that an obstruction of intracardiac blood flow might have occurred. Intramural tumors may produce arrhythmias and atrioventricular block due to invasion of the conduction system by the tumor. Thus, syncope can occur in patients with cardiac rhabdomyomas not only from obCurr
Probl
Car-did,
September
1990
529
FIG 11. Two-dimensional echocardiograms showing right ventricular born. LA = left atrium, LV = left ventricle, RA = right atrium.
rhabdomyoma
(T) in a new-
struction of intracardiac blood flow, but also as a result of atrioventricular conduction block. Attacks of syncope should not be confused with generalized epileptic seizures which occur frequently in tuberous sclerosis. Cardiac rhabdomyomas may also give rise to cardiac enlargement and congestive heart failure. Apart from rhabdomyomas, another cardiovascular abnormality rarely reported in tuberous sclerosis is stenosis of the great vessels. NElJROFZBROh4ATOSZS
WON
RECZUZNGHAUSEN’S
DISEASE)
The incidence of pheochromocytoma in neurofibromatosis is greater than that in the general population, and it is possible that patients with both conditions can develop cardiac ailments due to systemic arterial hypertension. Myocardial rhabdomyosarcomas producing systemic and cerebral emboli also have been reported in patients with neurofibromatosis.“’ This association may represent one of the features common to the neurocutaneous syndromes and behooves the clinican to suspect cardiac tumors, not only in patients with tuberous sclerosis, but also in those with other neurocutaneous syndromes.
530
Cut-r
Probl
Cardiol,
September
1990
KUGELBERG-WELANDER
SMVDROME
Kugelberg-Welander syndrome, also known as the juvenile form of progressive spinal muscular atrophy, begins in infancy as a lower motor neuron disease (flaccid muscular weakness, muscular wasting, fasciculations, absent muscle stretch reflexes, and electromyographic evidence of a neuronal disease). Familial cases fit autosomal recessive, dominant, and X-linked patterns. This disease runs a rapid, fatal course. The weakness is most pronounced in the proximal muscles of the extremities. Kugelberg-Welander syndrome is associated with cardiomyopathy, atrial arrhythmias, atrioventricular conductive defects, and congestive heart failure.z2s No cardiac necropsy data have been reported in patients with this syndrome, but endomyocardial biopsy specimens from three patients showed right atrial and right ventricular fibrosisz2’* 230 as well as degenerative changes in the muscle cells of the right ventricular wall.230 PAROXYSMAL
CONDITIONS
Among paroxysmal neurologic conditions, nea are of relevance to this review.
seizures
and sleep ap-
SEIZURES Cardiac arrhythmias and death may occur during a generalized tonic-clonic seizure: (a) in those epileptic patients with antecedent severe coronary artery disease23” 232; (b) in elderly patients with cardiopulmonary disease during intravenous injection of phenytoinZ33-235; and (19 in otherwise healthy patients with epilepsy as a result of cardiorespiratory depression induced by repeated intravenous injections of different drugs such as phenobarbital and diazepam. Although underlying cardiac disease plays an important role in most patients who die during a tonic-clonic seizure, a small percentage of patients with epilepsy die during or shortly after a tonicclonic seizure with neither an obvious clinical cause nor elucidative anatomic findings on postmortem examination.z31’ 236 The incidence of unexpected death among epileptic patients is 1 in 370 to 1 in 1,000.237 A review of deaths in epilepsy indicates that in 3% to 31% of cases, death is sudden and unexpected.231 Unexpected deaths among patients with epilepsy occur in individuals with a longstanding history of generalized seizures who abuse alcohol and who have poor compliance with the prescribed regimen of anticonvulsant medicines.237 Most patients with epilepsy who die suddenly show subtherapeutic or no levels of anticonvulsant medications in blood their blood at autopsy.‘“” 238 This suggests that an inadequate Curr
Probl
Cardiol,
September
1990
531
level of anticonvulsant medication is an important risk factor and emphasizes the need to monitor patient compliance by measuring blood levels of medications. Hypoxia, the depressant effects of anticonvulsant drugs on the myocardium, the concomitant use of alcohol with anticonvulsant drugs, and the development of cardiac arrhythmias during seizures have been proposed as possible causes of sudden unexplained death in patients with epilepsy. Simultaneous 24-hour electroencephalographic and electrocardiographic recordings have produced several important observations: 1. Interictal cardiac arrhythmias in epileptics and nonepileptics are related to a preexisting cardiovascular disease rather than to a primary cerebral disorder.Z3s These cardiac arrhythmias can lead to cerebral hypoxia and consequent cerebral symptoms including seizures . 2. Electrographic seizures, either lateralized or generalized, are frequently accompanied by tachycardia.23s’ 240 Ictal tachycardia of more than 100 beats per minute is seen in 93% of seizures, more than 120 beats per minute in 76%, and more than 150 beats per minute in 48% .240 The onset of tachycardia occurs several seconds before or after the seizure and often persists for several minutes after termination of the discharge. 3. Simultaneous 24-hour electroencephalographic and electrocardiographic studies should be obtained in all neurologic patients referred for long-term electroencephalographic recordings.23s 4. High-risk ictal cardiac arrhythmias are uncommon.Z4” In a study of 338 patients with epilepsy, simultaneous electroencephalographic and electrocardiographic monitoring showed a 5.3% incidence of dangerous cardiac arrhythmias,241 which does not differ from that of the general population.24z However, in a review of the literature, Jay and Leestmaz31 found many reported cases of patients with epilepsy free from hypertension and heart disease, who suffered transient cardiac arrhythmias of various types and severity during tonic-clonic seizures. Likewise, a case is described in which simultaneous ambulatory electroencephalographic and electrocardiographic studies revealed periods of asystole coinciding with epileptic seizures. In this patient, insertion of a cardiac pacemaker did not prevent the seizures.z43 It is assumed that such patients have cardiac irregularities induced by the epileptic fit, via autonomic nervous system pathways and by the increase of blood catecholamines during the seizure.23”, 237,244--246 Also, cardiovascular abnormalities can be found in association with partial complex seizures.24”-248 Devinski et a1.248 described 6 patients with partial complex seizures in whom the most prominent 532
Curt- Probl
Cardiol,
September
1999
manifestations of the cerebral dysrhythmia were chest pain, sinus tachycardia, and sinus bradycardia leading to syncope. Likewise, Kiok et al.245 reported a 2%year-old man who had a 9 second sinus arrest during a partial complex seizure. Marshall et aLz4” reported 12 patients in whom partial complex seizures recorded by electroencephalography and video monitoring were accompanied by marked tachycardia. The causal relationship between partial complex seizures and these cardiovascular abnormalities is demonstrated by the absence of preexisting heart disease, the presence of electroencephalographic abnormalities, and a therapeutic response to anticonvulsant, rather than antianginal, medications for the cardiac symptoms.248 However, it is necessary to point out that cardiac arrhythmias may lead to fainting spells, which could be mistaken for epileptic seizures. We had the opportunity to examine a 17-year-old man who had been treated for epilepsy since he was 4 years of age. Ambulatory electrocardiographic monitoring demonstrated severe bradycardia during one of these spells (Fig 12). The placement of a permanent electronic cardiac pacemaker cured the condition. b D. MCCALL: The authors point out here an interesting symptom complex, of which we are becoming increasingly aware. Not infrequently, bradycardia-related syncope may be the only manifestation of partial complex seizure activity, although the causal relationship has as yet to be defined. These individuals, usually young males, are frequently misdiagnosed as having a sick sinus syndrome. Holter monitor recordings obtained during the syncopal episode have shown progressive slowing of the sinus rate, rather than the abrupt changes that occur in the setting of sinus node dysfunction. The sinus slowing is also frequently associated with other manifestations of heightened vagal tone, such as nausea. The appearance of bradycardia-related syncope in a young adult should, therefore, alert the clinician to this possibility and to the need for a careful neurologic evaluation, including e1ectroencephalograph.y.
The occurrence of neurogenic pulmonary edema in patients who die during generalized tonic-clonic seizures suggests that in some patients death does not occur immediately after the seizure.23”,24g Cardiac arrhythmias and hypoxic cardiomyopathy’ may play a role in deaths occurring in epileptic patients during a generalized seizure. The depressant effect of alcohol on the myocardium com-
FIG 12. Holter lepsy
Curr
recording from for 13 years. Probl
a 17.year-old
Cardiol, September 1990
boy
who
had
carried
the erroneous
diagnosis
of epi-
533
bined with anticonvulsant medications is another contributing factor.237 There is a genetic association between a familial history of seizures and hereditary prolongation of a Q-T interval (Fig 13) with sudden death.“’ Gospe and Chop reported two siblings with an autosomal dominant familial long Q-T interval syndrome in whom the cardiac abnormality was recorded many years before the diagnosis was recognized. The importance of calculating the corrected Q-T interval on electrocardiograms cannot be overemphasized, as this simple test may prevent death in some patients with seizures. Hereditary prolongation of the Q-T interval may lead to cardiac arrhythmias, cerebral hypoperfusion, and seizure activity as in two families reported by Bricker et akz5’ Phenytoin is sometimes effective not only in controlling the seizures in these patients, but also in correcting the underlying Q-T interval prolongation. A family history of seizures should always generate suspicion of hereditary Q-T interval prolongation.252 SLEEP APNEA Chronic sleep apnea secondary to mechanical upper airway obstruction induces many types of cardiac arrhythmias. The latter are
FIG 13. Greatly 534
prolonged
Q-T
interval. Curr
Probl
Car-did,
September
1990
probably related to either increased vagal tone resulting from the persistent inspiratory effort against an obstructive airway or to falling oxygen saturation.2”3-25” In a study of 400 patients with sleep apnea, 193 patients (48%) had cardiac arrhythmias as shown by nocturnal polysomnography. Bradycardia, which appears initially following an attack of sleep apnea, can progress to atria1 fibrillation, atrial flutter, or high degrees of atrioventricular block.257 The major factor influencing the incidence of bradycardia is the duration of apnea,255 but cardiovascular disease facilitates ventricular arrhythmias during sleep-induced apneaz5’ Bradycardia can occur with any type of apnea. In apnea of short duration, there is a higher incidence of bradycardia in mixed and obstructive apnea than in central apnea.z55 Other significant cardiac arrhythmias during sleep apnea include ventricular tachycardia, sinus arrest lasting as long as 13 seconds, and premature seems to prevent ventricular contractions.254 Oxygen administration the bradycardia?” A tracheostomy may be effective in eliminating sleep apnea and in controlling the arrhythmias.254 G. A. BELLER: The bradyarrhythmias seen with sleep apnea may be mediated by increased myocardial adenosine levels induced by the hypoxemia. Infusion of adenosine into the sinus node artery in experimental animal models has produced sinus bradycardia and sinus arrest.
b
Chronic upper respiratory tract obstruction may lead to increased pulmonary vascular resistance, progressive pulmonary atria1 hypertension, right ventricular hypertrophy, and congestive heart failure. The development of pulmonary edema in patients with obstructive sleep apnea may result from high intrathoracic pressure during inspiration with a negative transpulmonary pressure, and the exudation of fluid from the capillaries into the interstitium.25s Systemic arterial hypertension is associated with obstructive sleep apnea.z60 About 60% of patients with sleep apnea syndrome have hypertension; while 22% of patients with essential hypertension have sleep apnea.261’ “’ Ross et al.‘“’ described two siblings with sleep apnea and systemic hypertension. These two patients had symmetric left ventricular hypertrophy, which was probably secondary to systemic hypertension. In these patients, treatment included a permanent tracheostomy, weight reduction, and the treatment of the systemic hypertension. Short periods of sleep apnea are normal in infants through 3 months of age. But periods of apnea longer than 20 seconds, which may induce bradycardia,2”3 have been considered part of a final common pathway in the sudden infant death syndrome.z64’ 265 The significance of increased pulmonary artery smooth muscle mass in the sudden infant death syndrome is unclear.z6” Another important pathologic finding in this syndrome is the presence of lymphocytic Curr
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infiltrates and areas of degeneration in the conductive system of the heart. This could be a source of lethal cardiac arrhythmias.z”7
MISCELLANEOUS
VASCULAR
CONDITIONING
This group includes temporal arteritis and two neurologic conditions: intracranial arteriovenous fistulas and ventriculovenous shunts.
TEMPORAL ARTERITIS Temporal arteritis is a form of giant cell arteritis seen in elderly persons. The incidence is 17 per 100,000 for those older than 50 years.268 The involvement of the cranial arteries produces the typical abnormalities of headaches, temporal artery and scalp tenderness, jaw and tongue claudication, transient ischemic attacks of the brain, amaurosis fugax,26s and blindness. Blindness occurs in one third of patients and is due to disease of the posterior ciliary and ophthalmic arteries with consequent anterior ischemic optic neuropadue thy. 270 The loss of vision is sudden, but mild visual disturbances to premonitory ischemic episodes in the retinal arteries may herald total vision loss. Commonly, there are systemic symptoms such as weight loss, malaise, fever, and polymyalgia rheumatica.z71 Headaches, which are due to involvement of the cranial arteries, may be the only symptom present. The typical pain is intense, constant, and unilateral. The temporal arteries are thick and tender. Extracephalic giant cell arteritis occurs in about 10% to 15% of patients with temporal arteritis, with the aorta and its branches most often involved.268 Giant cell arteritis in the aorta and its branches is encountered in 1.4% to 1.7% of unselected autopsies.“’ Granulomatous giant cell aortitis may give rise to progressive aortic aneurysmal dilatation, aortic valve ring dilation, and aortic regurgitation268,270,273 Occlusion of the branches of the aortic arch may result in cerebral ischemia and strokes. Occlusions of the coronary arteries by granulomatous giant cell arteritis may lead to ischemic heart disease and myocardial infarctions?68’ “‘, 2748275 The erythrocyte sedimentation rate is elevated during active stages of temporal arteritis is about 95% to 97% of cases. In the presence of strong clinical evidence, the diagnosis should not be dismissed just because the sedimentation rate is normal?76 Temporal and facial artery biopsy specimens are not always diagnostic due to the existence of isolated foci of arteritis which make an examination of multiple histologic sections necessary.27z Steroid therapy is essential in
636
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giant cell arteritis. than conventional
Elderly people are likely to respond doses of steroids.
well to lower
) G. A. BELLER: Temporal arteritis is a disease entitv that is often missed in the &agnostic workup df a fever of unknoti origin. It should be considered in any patient presenting with recurrent fever, malaise, and a markedly elevated erythroc.yte sedimentation rate. INTRACRANIAL
ARTERIOVENOUS
FISTULA
Large, congenital intracranial arteriovenous fistulas produce a serious circulatory burden and are a cause of congestive heart failure in the newborn.277’ 278 Symptomatic arteriovenous malformations in the neonatal period are rare. A review of arteriovenous malformations in 156 infants less than 6 months of age showed 81 cases of CNS arteriovenous malformations, with a male to female ratio of 2:1.277 In 1987, Johnston et al. collected 245 cases of vein of Galen malformations from the literature. The lesions occur primarily in the vein of Galen (64%), cerebral hemispheres (7%), and superior sagittal sinus (6%).277 The usual clinical presentation of vein of Galen malformations in neonates includes
high-output
congestive
heart
failure
(45% 1, raised
intracranial
pressure secondary to hydrocephalus (38% ), cranial bruits (23% 1, focal neurologic deficits (15%), seizures (lo%), and bleeding (10%).
FIG 14. This vein
cerebral of Galen
Curr
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contrast-enhanced of an infant born
Cardiol,
September
CT scan shows a large with massive cardiomegaly
1990
arteriovenous malformation of the and congestive heart failure.
537
High-output congestive heart failure is the most common cause of death in these patients.277 Congestive heart failure without any apparent cause in a baby suggests the existence of a large arteriovenous fistula.z7g The diagnosis is made by the presence of an audible bruit over the cranium, dilated scalp veins, associated vascular malformations over the head, hyperdynamic cardiac impulse, abnormal findings on a computed tomography (CT) scan (Fig 141, and the visualization of the arteriovenous malformation with arteriography (Fig. 15). Cranial ultrasound and cardiac investigative techniques are also helpful in the clinical diagnosis. Cardiac catheterization is of value through recognition of a wide pulse pressure in combination with a high oxygen saturation in the superior vena cava and rightsided chambersZ7’ Chest roentgenograms reveal an enlarged heart with increased pulmonary vascular markings (Fig 16). The electrocardiogram may show enlargement of the right atrium and either right ventricular or biventricular hypertrophy (Fig 17). Early combined medical and surgical therapy may increase the chances for a successful outcome. Treatments include surgical clipping, embolization, and progressive occlusion.z80J 28X Unfortunately, the outcome with any type of treatment is very disappointing and the mortality is greater than 50% .277
FIG 15. This lateral view from an angiogram made following selective injection of contrast material in the right carotid artery shows an arteriovenous malformation of the vein of Galen, dilated feeding arterial branches, and prominent venous draining. (Same patient whose CT scan is shown in Figure 14.) 538
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1990
FIG 16. Chest roentgenogram massive cardiomegaly roimaging appearance
from infant with vein of Galen arteriovenous malformation, showing and increased pulmonary vascular markings. (The cerebral neuof the arteriovenous malformation is shown in Figures 14 and 15.)
VENTRICULOVENOUS
SHUNTS
In performing extracranial shunting of cerebrospinal fluid to treat hydrocephalus, ventriculoperitoneal shunts are preferred over ventriculovenous shunts (ventriculojugular, ventriculoatrial) because of fewer complications, lower mortality rates, and a simpler operative procedure.28z Cardiopulmonary complications occur in about 7% of patients with ventriculoatrial shuntsZa3 The complications of vascular shunting procedures include thromboembolism, catheter migration with embolization, and perforation.z84 Ventriculovenous shunts are rarely performed today. Thromboembolism Thromboembolism is the most common cardiopulmonary complication.z83’ 284 The distal portion of the catheter is the site of thrombus formation. Over 50% of patients who die with ventriculovenous shunts have a thromboembolism in the pulmonary arteries.283’284 In about one fourth of patients with a ventriculoatrial shunt, chronic irritation of the atrium may result in a nidus for the implantation of bacteria and thrombus formation.283 A thrombus resembling a tumor may form around the distal end of the tubing in the right atrium.285 Pulmonary embolism can produce acute symptoms, but a chronic picture of right ventricular failure and car pulmonale may also follow repeated small embolizations.28”-z288 Cardiac and pulmonary Curr
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1990
539
;: : I.... fy trz-- . .. . ... -_.(. ... .. .. . . ::.. .. ... ..,. .. .. .....a k. .
aVR
aVL
aVF
FIG 17. Electrocardiogram giant P waves
and
from newborn left ventricular
with vein of Galen hypertrophy.
arteriovenous
malformation,
showing
thrombi or sepsis may occur as complications of infected ventriculoatrial shunts.283, “’ An unusual complication of a ventriculoatrial shunt is a mycotic aneurysm of the pulmonary artery.z8g Superior vena cava obstruction secondary to thrombus formation has been reported as a complication in 1% to 6% of ventriculoatrial shunts.“s0-2s2 Real time two-dimensional echocardiography to detect a right atrial thrombus may be used as a part of routine follow-up.285~287 Thromboembolism with or without heart failure is an indication for removal of the shunt catheter, and if continued cerebrospinal fluid drainage is necessary, it may be replaced with a ventriculoperitoneal 540
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1990
shunt ?’ Thromboembolectomy intracardiac thrombusz8’
may be necessary
to remove a large
Catheter Migration with Embolization The distal tubing of a ventriculovenous shunt may separate and migrate to the vena cava, right atrium, right ventricle, left atrium (via a patent foramen ovale), or the pulmonary arteries.‘&l’ “‘, 2g3 Migration of the tubing to the left atrium can give rise to cerebral embolization. The catheter can interfere with the function of the pulmanic valve and also give rise to arrhythmias, infections, pulmonary embolism, and pulmonary hypertension.284’ 2s4 Tubing can be removed via thoracotomy or transvenous snare techniques with fl~oros~opy.~~~ In one of the two cases reported by Hougen, the catheter was left in situ because of its location in the periphery of the lung and relatively insignikant hemodynamic disturbance, with no symptoms during a follow-up period of 8 years.284 Perforation Reported sites of perforation by the tubing include the venae cavae, right atrium, and right ventricle.284~2g1 Cardiac perforation is caused either by forceful introduction of the distal catheter during shunt placement or by too long a distal catheter that ulcerates through the cardiac wall. An impacted distal tubing in the cardiac wall can give rise to increased intracranial press~re.~~* Perforation of the myocardium with tamponade occurs in less than 1% of patients with ventriculoatrial shunts and necessitates immediate pericardiocentesis.“’ NEUROLOGIC MEDICATIONS PRONE CARDIOVASCULAR COMPLICATIONS
TO PRODUCE
Certain drugs used to treat neurologic disorders effects on the cardiovascular system. Fortunately, fects are infrequent and most of them disappear the medicine is reduced or when the medicine is
may have adverse these adverse efwhen the dose of discontinued.
LEVODOPA When it is converted to dopamine, levodopa has cardiac arrhythmogenic effects due to an increase in the release’ of endogenous norepinephrine from the peripheral sympathetic nerve endings in the heart. In early clinical studies, cardiac arrhythmias, particularly atrial or ventricular ectopic beats, were noted during treatment with
Cur-r
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1990
641
levodopa in 7% to 12% of patientszs5 But decarboxylase inhibitor, carbidopa, which is now used in conjunction with levodopa, decreases the arrhythmogenic effect of levodopa.2s6 Therapy with levodopa-carbidopa appears to pose little increased hazard to patients with most forms of heart disease. Nevertheless, levodopa should be used with caution in patients over 70 years of age with angina, a history of recent myocardial infarction, or residual atrial, nodal, or ventricular arrhythmias.2s5 In these patients, it may be a good idea to carry out inpatient observation at the beginning of therto stress that Parkinson’s disapy with levodopa.zg7 It is important ease and cardiac disease frequently coexist, particularly in older patients. Orthostatic hypotension is noted in about 20% of patients taking levodopa.2g5’ 2’S The maximum tolerated doses of levodopa induce a mean reduction in erect systolic blood pressure of 19 mm Hg without any significant changes in pulse rate. This hypotension is probably due to dopamine acting on adrenergic nerve endings or on the CNS itself. In some patients, the hypotension may be prevented by the concomitant administration of proprano101,2ss giving support to the views that levodopa exerts a P-adrenergic action.“’ Hypotension induced by levodopa is dose-dependent and disappears as treatment continues. The addition of the peripherally acting dopa-decarboxylase inhibitor has greatly decreased the hypotension induced by levodopa?” A persistent, severe hypotension may indicate another problem such as progressive autonomic failure.
z3oz3 RECEPTOR AGONISTS (RROMOCRZPTINE,PERGOLZDE) Dopa receptor agonists, such as bromocriptine and pergolide, are used as an adjunct to combined levodopa and carbidopa therapy in the symptomatic treatment of Parkinson disease. Combined with levodopa, these medications produce a therapeutic response equal to that of levodopa alone, but with fewer fluctuations and less peakdose dyskinesias.301 The administration of dopamine agonists permits a reduction in the daily dose of levodopa. Dopa agonists may produce several cardiovascular side effects, the most common one being orthostatic hypotension.301-303 The postural hypotension can be corrected by lowering the dose. At high doses, patients can experience frequent extrasystoles, which cease on termination of the medication.304
METHYSERGZDEMALEATE This is a serotonin antagonist used in the prophylactic treatment of cluster headaches. Reported complications of long-term therapy with methysergide maleate include retroperitoneal fibrosis and fi542
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1990
brosis of the cardiac valves. Less frequently, the aorta and coronary ostia may show fibrotic thickening305 Fibrotic changes in the cardiac valves are due to the presence of collagen tissue plaques covering the valves.305 The occurrence of heart murmurs, constrictive pericarditis, congestive heart failure, and myocardial infarctions in people without a previous history of heart disease who have been receiving methysergide maleate for 6 months to several years suggests that the use of this medication is directly related to the appearance of the cardiac abnormalities.305’ 306 Undesirable clinical symptoms seen after prolonged therapy with methysergide maleate may include cold numb extremities, intermittent peripheral claudication, and the appearance or worsening of angina. Narrowing of peripheral arteries can be demonstrated on arteriography. ERGOTAMINE
TARTRATE
Ergotamine tartrate is an a-adrenergic blocking agent with a direct stimulating effect on the smooth muscle of the peripheral and cranial blood vessels. The drug can be used parenterally, orally, or sublingually, and it is a safe medication when prescribed in correct doses. Nausea and vomiting, which occur when the drug is ingested in excess or too frequently, can prevent the occurrence of serious complications. Among the cardiovascular side effects are precordial discomfort and pain, transient tachycardia or bradycardia, and symptoms and signs of peripheral vascular insufficiency. In addition, ergotamine tartrate may aggravate preexisting occlusive vascular disease and coronary artery insufficiency. EDROPHONWM
About 1% of patients given anticholinesterase drugs experience adverse cardiovascular effects.307 Edrophonium is a short-acting anticholinesterase agent used intravenously as an aid in the diagnotests, if performed sis of myasthenia gravis. Most edrophonium cautiously, are free from adverse reactions. However, the action of accumulated acetylcholine on the myocardium may result in bradycardia, decreased cardiac output, hypotension, and a variety of cardiac arrhythmias .307,3o8 Atropine sulfate, 0.6 mg or more intravenously, should be given immediately if a severe muscarinic reaction ensues.3o8 It is necessary to keep in mind that, if the test is performed in patients in cholinergic crises, the respiratory failure and hypoxia that result from a further decrease in patients’ strength may give rise to hypotension and cardiac irregularities, which are often reversed by the establishment of adequate pulmonary ventilation3” and the adCurr
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1990
543
ministration of atropine. A baseline electrocardiogram should be obtained before the edrophonium test, and appropriate cardiac monitoring, conventional resuscitative equipment, and emergency treatment must be available. ANTICONVULSANT
DRUGS
Among all the anticonvulsant drugs, phenytoin sodium, carbamazepine, phenobarbital, and primidone have been studied most intensely with regard to effects on the cardiovascular system (Table 13). Phenytoin is primarily an anticonvulsant drug indicated for the control of tonic-clonic seizures. Phenytoin is also effective in the treatment of ventricular arrhythmias, particularly those due to digitalis intoxication. Carbamazepine is an anticonvulsant used in partial complex and generalized seizures and is also a specific analgesic for trigeminal neuralgia. Phenobarbital is a long-acting barbiturate used as adjunctive therapy in the treatment of all types of seizures. Primidone resembles phenobarbital in its chemical structure and in some of its anticonvulsant effects. The incidence of congenital heart disease in children of women with epilepsy taking anticonvulsant drugs (mainly phenytoin, phenobarbital, and primidone) seems to be significantly higher (43 in 1,000) than in the general population (5.7 to 8 in 1,000).30g However, as with other congenital malformations related to epilepsy, it is difficult to state for certain whether these congenital cardiac malformaTABLE Cardiac
13. Side Effects
of Anticonvulsants*
IV Phenytoin ICardiovascular complications in 3.5% J Tachyarrhythmias 12% J Bradycardia and hypotension (1.5% 1 Ventricular asystole Oral Phenytoin and Primidone Teratogenic effects over the heart (43 in 1000, compared to 5.7 to 8 in 1000 in general population) Interaction with oral anticoagulants and quinidine Phenobarbital Interaction with oral anticoagulants and quinidine Carbamazepine Prolongation of atrioventricular conduction ‘Data fmm references
644
233,
235, 309,
312-315.
Cur-r
Probl
Car-did,
September
1390
tions in babies of mothers who took anticonvulsants during the first trimester of pregnancy are a result of genetic factors associated with the seizure disorder or a result of the teratogenetic effects of the drug. Patients on prolonged therapy with phenytoin develop low serum folate levels, Because the active derivatives of folic acid are intimately involved in the synthesis of nucleic acids and proteins, a folic acid deficiency in pregnancy may affect rapidly growing trophoblastic and embryonic tissues with subsequent teratogenicity.3f0 But there are studies attributing malformations seen in children of mothers with epilepsy to genetic factors. For example, Shapiro et in offspring of faal. 311 reported a high incidence of malformations thers with epilepsy, suggesting that fetal damage, which is attributed to phenytoin and other anticonvulsants, may be due to epilepsy itself. Whatever the cause, children of mothers with epilepsy have an increased incidence of premature births, microcephaly, cleft lip, cleft palate, ocular hypertelorism, epicanthal folds, other facial malformations, phalangeal hypoplasia, hypoplasia of nails, and congenital heart disease (Fig 18).3os Reported cardiac malformations include atria1 and ventricular septal defects, coarctation of the aorta, tetralogy of Fallot, and patent ductus arteriosus.30s Intravenous phenytoin infusion during the treatment of status epilepticus produces cardiovascular complications in about 3.5% of the cases.235 Intravenous phenytoin depresses myocardial contractility, decreases peripheral vascular resistance, and can produce disturbances of cardiac rate and rhythm.236 These cardiovascular complications, which include tachyarrhythmias, bradycardia, atrioventricular block, asystole, and hypotension, seem to be related to the use of high concentrations of phenytoin given at a rapid rate. However, BarronZ34 found that the slow, intravenous injection of small doses of phenytoin also may produce sudden, marked sinus bradycardia, hypotension, and syncope in healthy persons. This suggests that hypersensitivity to intravenous phenytoin may be unrelated to the total dose and rate of administration. In fact, in some of the reports of deaths during intravenous phenytoin infusion, the patients had received only 100 to 250 mg of phenytoin at the time they developed ventricular asystole.z33 It seems that elderly patients with digitalis toxicity, advanced intraventricular conduction disturbances, and severe chronic restrictive or obstructive pulmonary disease are prone to develop cardiac arrhythmias during the intravenous injection of phenytoin.233 It also seems likely that patients with subclinical heart disease may develop cardiac arrhythmias during prolonged oral treatment with phenytoin3” Phenytoin and phenobarbital seem to interact with the metabolism of quinidine, resulting in an inadequate blood level of quinidine. Likewise, treatment with phenobarbital decreases the anticoagCurr
Probl
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September
1990
645
FIG 18. Twelve-month-old with primidone embryopathy, pulmonic stenosis, and a ventricular tal defect. Picture shows depressed nasal bridge, anteverted nares, epicanthal folds, set ears, a long philtrum, and a thin upper lip.
seplow-
ulant effect of warfarin sodium. This is a result of increased elimination of the anticoagulant due to induction of warfarin-metabolizing This interaction becomes clinically enzymes by the barbiturate.313 evident after the first week of warfarin therapy. Withdrawal of phenobarbital in patients taking a well-tolerated dose of oral anticoagulants may result in prothrombinopenic hemorrhage. This interaction appears to be a common cause of bleeding among hospitalized patients. A drug interaction also occurs between warfarin and phenytoin. Warfarin interferes with the metabolism of phenytoin in the liver, leading to increased serum levels of phenytoin and the appearance of toxic symptoms.314 These effects have clinical significance when patients with epilepsy taking phenytoin are in need of anticoagulant therapy. In these patients, toxic levels of phenytoin can be produced by standard doses of the anticonvulsant drug. 546
Cut-r
Probl
Cardid,
September
19Sll
Phenytoin has been advocated as the drug of choice for myotonic dystrophy and it is preferred over procainamide because the latter lengthens the P-R interval, which in some patients with myotonic dystrophy is already prolonged. But Durelli et al. emphasize the need for careful monitoring of plasma levels and a thorough assessment of cardiac status before initiating phenytoin therapy in these patients.312 They report a patient with myotonic dystrophy and echocardiographic signs of subclinical cardiomyopathy in whom ventricular tachycardia was induced by oral treatment with phenytoin when the serum level rose over 27 p#mL. The cardiac arrhythmia disappeared when the drug concentration fell to the therapeutic range. Experience with carbamazepine in young patients with epilepsy has shown that the drug is relatively safe and effective. Most adverse cardiovascular effects of carbamazepine occur in elderly patients with heart disease, particularly those with conduction abnormalities. The drug prolongs atrioventricular conduction.312’ 315 Although age is a factor, conduction disturbances have been described in relatively young subjects taking carbamazepine for epilepsy.315 Durelli et al. reported two patients with myotonic dystrophy and subclinical cardiomyopathy (mitral valve prolapse and abnormal thickness of the left ventricular wall on echocardiogram, defective conduction as shown by a P-R interval at the upper limit of normal) in whom a reversible first-degree atrioventricular block developed at low serum carbamazepine levelsal’ The authors stated that a defective conduction system is a prerequisite for the development of atrioventricular block induced by carbamazepine. But many physicians believe that an underlying defect in conduction is not a prerequisite for carbamazepine-induced cardiac conduction disturbances.315 The conduction defect disappears after carbamazepine is discontinued.315 Because of the carbamazepine-induced conduction disturbances, treatment of patients with Stokes-Adams attacks misdiagnosed as epilepsy may have a deleterious effect. It is recommended that an electrocardiogram be obtained in elderly individuals prior to the institution of therapy with carbamazepine.315 The serum levels of valproic acid, phenytoin, and carbamazepine appear to increase when verapamil is used in patients taking any of Administration of verapamil to patients these anticonvulsants.3f6 taking carbamazepine significantly increases the total plasma level of carbamazepine by more than 40% and the free plasma level of carbamazepine by more than 30%.‘17 Therefore, the use of verapamil in patients previously stabilized on carbamazpine should be avoided.
Curr
Probl
Cardiol,
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1990
547
TRICYCLZC
ANTIDEPRESSANT
DRUGS
These drugs, widely regarded as effective adjunctive therapy for several neurologic problems, are safe medications at normal therapeutic levels in patients who have normal hearts.318 But occasionally these drugs produce arrhythmias in patients with cardiac disease, especially in those patients being treated with multiple medications. At therapeutic doses, imipramine prolongs intraventricular conduction and widens QR8 complexes.31s Psychotropic drugs, such as tricyclic antidepressants and thioridazine, prolong the Q-T interval. Patients with preexisting Q-T interval prolongation are at risk for lethal arrhythmias when treated with psychotropic drugs3” Because patients with psychic depression have Q-T interval prolongation more often than normal subjects, even in the absence of drug therapy, many authors emphasize the importance of electrocardiographic evaluation in patients with depression prior to the use of psychotropic drugs.32o Ventricular tachycardia, intraventricular conduction defects, and high-degree atrioventricular block are most likely to occur in patients with preexisting heart disease. Sudden, unexpected death has occurred more frequently during treatment with amitriptyline in patients with a history of heart disease than in patients without heart disease. Cardiac complications following tricyclic antidepressant overdosage include convulsions (12%), coma (30%), hypotension (7%), hypertension (9%), respiratory arrest (7%), and cardiac arrest (4% 1. Temporary electrocardiographic changes develop in 55% of cases.321 The most frequent electrocardiographic alterations are sinus tachycardia (12%), sinus bradycardia (4%), atrioventricular block (19%1, enlargement of QRS complexes (19 to 23% 1, T wave abnormalities (82% 1, prolonged Q-T interval (60% to 85%1, and ventricular tachycardia or fibrillation (4% 1.321 The vast majority of electrocardiographic changes in tricyclic antidepressant overdosage appear within the first 24 hours, and the clinical course of the intoxication is more severe in patients with electrocardiographic changes.321 Patients who develop electrocardiographic abnormalities in the course of the intoxication are more frequently unconscious and more often require assisted ventilation than those without electrocardiographic changes. In a prospective study of 49 patients with acute overdosage of tricyclic antidepressant drugs, Boehnert and Lovejoy3” found that serum drug levels failed to predict the risk of ventricular arrhythmias accurately, but ventricular arrhythmias were seen only with a QRS duration of 0.16 seconds or longer: They concluded that determination of the maximal limb-lead QRS duration predicts the risk of ventricular arrhythmias in acute overdoses with tricyclic antidepressants. Pro-
648
Cur-r Pmbl
Cardiol,
September
1990
phylactic insertion of a temporary cardiac pacemaker may be necessary in patients with wide QRS complexes.321 Another frequent cardiovascular side effect of the tricyclic antidepressant drugs is orthostatic hypotension. The incidence of orthostatic hypotension is significantly higher among those patients with severe heart disease. Because adverse cardiovascular reactions cannot be predicted, it is helpful to monitor those patients who have cardiovascular disease while they are receiving tricyclic antidepressant drugs. In an acute overdose with tricyclic antidepressants, hypotension occurs in the absence of any significant cardiac arrhythmia and appears to be secondary to a fall in cardiac output as a result of a direct toxic effect of the drug on the myocardium. No hemodynamic problems occur after the first 12 hours of intoxication.321 Tricyclic antidepressant drugs interfere with the hypotensive action of guanethidine.323 The antihypertensive effect of guanethidine is mediated by adrenergic neuron blockade and is dependent on uptake of guanethidine in peripheral adrenergic neurons. This uptake is blocked by the tricyclic compounds. Perhaps by the same mechanism, tricyclic antidepressant drugs hamper the hypotensive action of clonidine; but other effects of the tricyclic medications are likely to play a role. The clinical implication is that the combination of a tricyclic antidepressant drug with guanethidine or clonidine must be carefully monitored for the development of a pharmacologic interaction.
PHENOTHLAZINES
Hypotension, the most common cardiovascular effect of phenothiazines, is due to vasodilatation that results not only from inhibition of centrally mediated pressor reflexes, but also from cw-adrenergic blockade. By their ability to compete with catecholamines for binding sites in the cell membrane, phenothiazines can block and even reverse the sympathomimetic effects of epinephrine. Therefore, the concomitant use of phenothiazines and epinephrine can induce hypotension and a shock-like state which may not be responsive to vasopressors. At the same time, the blockade of catecholamine binding sites by phenothiazines results in high blood levels of catecholamines. The increase in blood catecholamines may play a role in the genesis of electrocardiographic changes and cardiac’arrhythmias occasionally encountered after prolonged use of phenothiazines. Electrocardiographic changes during treatment with phenothiazines include prolongation of the P-R and Q-T intervals, depression of the ST segment, and flattening of T waves.
Curr
Probl
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1990
649
The anhythmogenic activity of therapeutic doses of phenothiazines administered for prolonged periods of time has been associated with sudden death in patients without preexisting cardiac disease. A review of the effects of prolonged administration of phenothiazines in seven young patients in whom cardiac arrhythmias, myocardial failure, and conduction abnormalities were attributed to the use of phenothiazines suggests that the insidious, cumulative toxicity of these drugs is capable of producing toxic cardiomyopathy. Further studies to quantity the risk of prolonged therapy with psychotropic drugs are needed. However, the interest in this subject seems to have declined with the advent of nonphenothiazine drugs that are free from cardiac toxicity. MONOAMINE
OXIDASE INHIBITORS
The potentiation of the effects of sympathomimetics by nonselective or type A-selective monoamine oxidase inhibitors may result in increased blood catecholamine levels, with resultant hypertensive crises and cardiac arrhythmias. Therefore, patients receiving these monoamine oxidase inhibitors should not be given methyldopa, levodopa, dopamine, epinephrine, norepinephrine, amphetamines, tricyclic antidepressant drugs, or substances containing tyramine, such as cheddar cheese, herring, burgundy wine, and beer. Deprenyl (selegiline hydrochloride) which is used in Parkinson’s disease, is a type B-selective monoamine oxidase inhibitor without adverse pressor effects when it is administered at the recommended dosage of 10 mg per day.324
LITHIUM
CABBONATE
Lithium carbonate is primarily used in the treatment of manic episodes of bipolar affective disorders. In neurologic practice, lithium carbonate is also used in the prevention of cluster headaches not responsive to conventional therapy. A statistically significant increase in the frequency of T wave depression and inversion occurs in the electrocardiograms of patients receiving therapeutic doses of lithium carbonate.325’ 326 Rarely, lithium may cause reversible, symptomatic sinus node dysfunction or ventricular arrhythmias.326, 327 Patients with lithium toxicity almost always present with hypotension, cardiovascular collapse, and alterations of consciousness. D. MCCALL: Both the tricyclic antidepressants been shown to have ant&rhythmic properties Electrophysiologic studies have shown that both overshoot of the action potential, decrease the
b
550
and the phenothiazines have similar to those of quinidine. groups of drugs decrease the maximal rate of rise during
Curr
Probl
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phase 0 of the action potential, decrease the duration and amplitude of phase 2 and prolong the repolarization phase, phase 3. These effects are identical to those of quinidine. This similarity, therefore, readily explains the electrocardiographic changes described by the authors. It also suggests that the arrhythmogeniticity of these drugs is similar to the proarrhythmic effect of quinidine, namely, facilitation of reentrant excitation as a result of decreased conduction velocity and temporal dispersion of action potential duration. Following accidental or intentional overdosage with these drugs, patients are at greatest risk for the development of serious ventricular arrhythmias during the first 24 to 72 hours, i.e., when serum drug levels are declining. It is possible that changing serum levels are associated with greater nonuniformity of action potential duration and hence greater susceptibility to reentrant arrhythmias. Regardless of the mechanism, however, this recovery phase has shown the greatest vulnerability to potentially lethal arrhythmias and careful electrocardiographic monitoring of these patients for up to 72 hours is essential.
Following free filtration -at the glomerulus, lithium is partially reabsorbed exclusively at proximal tubular sites in parallel with sodium. 328,32g Long-term thiazide treatment leads to a compensatory increase in sodium reabsorption at the proximal tubules, and lithium is also reabsorbed with sodium. Therefore, long-term use of thiazides gives rise to a decrease in lithium clearance, and an increase in serum levels of lithium.32s In patients who need both medications, Himmelhoch et al. recommend reduction in the daily lithium dose to compensate for the decrease in renal lithium clearance, making subsequent refinements in dose according to lithium serum levels and the clinical state of the patient.330 Proximal tubular reabsorption of sodium is increased in patients with hypertension. This perturbation of renal sodium handling in patients with hypertension also increases the proximal tubular fractional lithium reabsorption, for which reason lithium clearance is decreased in patients with essential hypertension.3z8 A decreased glomerular filtration rate, the presence of heart failure, and dietary salt restriction also reduce the renal clearance of lithium, leading to elevation of plasma lithium levels and increasing the possibility of toxic effects.32g* 330 Serum levels of lithium and renal function should be monitored carefully in patients with cardiac disease who are taking lithium carbonate. Lithium and verapamil have similar effects on the neurosecretory process, neurotransmitter dynamics, calcium metabolism, and calcium transport. A synergistic drug interaction can be encountered when combining lithium carbonate with verapamil.331’ 332 Profound bradycardia developed in two patients taking verapamil in combination with lithium carbonate.333 One of these two patients developed a fatal myocardial infarction. Valdiserri331 reported one patient who was receiving 900 mg per day of lithium carbonate who developed a significant extrapyramidal reaction when diltiazem treat angina pectoris. However, there are extrapyramidal Cur-r Probl
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ties such as cogwheel rigidity and tremor in more than half of the patients taking lithium carbonate alone for prolonged periods of time.334 At any rate, caution is advised in the use of lithium and verapamil together. Caution is also recommended when prescribing lithium carbonate for women of childbearing age. Approximately 7% of infants born to women receiving chronic lithium therapy will have serious cardiac defects.335 Ebstein’s anomaly, a usually rare defect, is common among these infants. b G. A. BELLER:Digitalis is another drug that has direct CNS effects that affect the heart. Digitalis excess can cause increased nerve traiBc along sympathetic nerves which may contribute to the genesis of digitalis-toxic ventricular rhythm disturbances. The noncardiac toxic manifestations of digitalis excess such as anorexia, nausea, and vomiting are also secondary to the nemoexcitatory effects of the drug. b S. H. BAHIMTOOIA:The occurrence of rhythm disorders with a variety of pharmaceutical agents, in addition to antiarrhythmic agents, needs to be emphasized. This is an exhaustive and excellent review of neurologic conditions that affect the cardiovascular system. It is a most valuable resource that is needed and will be referred to by all practicing clinicians. b D. MCCALL: The authors have provided an extensive review of the effect of a large variety of neurologic and neuromuscular diseases on the cardiovascular system. They have grouped the topics logically and conveniently and have pruvided an extensive bibliography for each condition described. The monograph plays an important role in bringing together this vast array of information and in providing a ready source of references for those who may want to explore any particular condition in greater depth. The authors are to be congratulated for their tremendous effort. ACKNOWLEDGMENTS
We thank Colonel Steve Stephenson, US Army Medical Corps, and Sue Lamonde, from the Department of Clinical Investigation, William Beaumont Army Medical Center, El Paso, Texas, for their assistance in the preparation of this review article. The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or Department of Defense. REFERENCES 1. Thompson GE: Pulmonary edema complicating intrathecal hypertonic saline injection for intractable pain. Anesthesiology 1971; 35:425-427. 2. Talman WT: Cardiovascular regulation and lesions of the central nemous system. Ann New-01 1985; 18:1-12. 652
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