INTRACARDIAC GANGLIONITIS AND SUDDEN DEATH. HERPES OF THE HEART? THOMAS N. JAMES, M.D. BIRMINGHAM, ALABAMA
Most now believe that sudden unexpected death, especially when unexplainable by the usual careful necropsy examination, is due to some form of lethal instability of the electrical activity of the heart. Although ventricular fibrillation is one of the more familiar forms of such instability, this is less valuable information (for the sake of prevention) than knowing what some of the precursors or predisposing factors were which terminated in fibrillation. Too little is known of either the anatomical or physiological substrate upon which fibrillation begins and persists. Furthermore, most sudden and unexplained deaths occur in circumstances where the terminal rhythm of the heart was not recorded and one can only guess what were the initiating electrical events, the sequence of changes or the exact final rhythm. Actually, what may be more surprising than the rare example of electrical instability of any form is the fact that the heart can maintain an effective and stable rhythm under such a wide variety and continuing barrage of physiological challenges. For rapid adjustment to such challenges the autonomic neural control of the heart is an essential factor which not only permits the heart quickly to change its rate but can also powerfully alter AV (atrioventricular) conduction, myocardial contractility, coronary flow and electrical repolarization. Rather little attention has been paid to either the normal or abnormal anatomy of neural elements within the heart. From a continuing personal study of this subject, including examinations of the hearts of victims of sudden unexpected death (1-4), it has become apparent that the nerves and ganglia are not spared during myocardial infarction, myocarditis, amyloidosis, collagen diseases and other such processes known to damage myocardium. All of these may be considered secondary forms of cardioneuropathy. However, in a number of recent cases of sudden unexpected death the cardioneuropathy was the sole or singularly prevalent pathoFrom the Department of Medicine, University of Alabama Medical Center, Birmingham, Alabama 35294. This work was supported by the National Heart, Lung and Blood Institute (Program Project Grant HL 11,310 and SCOR on Ischemic Heart Disease No. 1 P17 HL 17,667) and by the Rast Fund for Medical Research. Address for correspondence: Thomas N. James, M.D., Department of Medicine, University of Alabama Medical Center, Birmingham, Alabama 35294. 177
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logical finding and other portions of the heart were essentially normal (5, 6). This report will deal with nine such cases. CLINICAL DATA AND NECROPSY FINDINGS All nine of these individuals died suddenly and unexpectedly although each had previously been considered to be in good health. Five of the deaths were witnessed as sudden collapses either during minor physical activity or while at rest, and resuscitative efforts failed. Two of these five deaths were due to documented ventricular fibrillation but the terminal rhythm is not known for the other three. Two deaths occurred while the victim was walking alone and happened no more than two hours after having been in the company of others. Two deaths occurred during sleep and each victim retired in apparent good health without any physical complaint; the interval between retiring and being found dead was two hours for one and five hours for the other, and there was no evidence of life when either was discovered. In none of the nine deaths was there any evidence of violence or of either poisons or intoxicating substances. Six were male and three were female. Their ages ranged from 12 years to 31 years. Three of the nine had a family history of one or more sudden unexpected deaths, but none of the present victims was related to any other. Their homes were in widely distributed geographic locations, extending from California to Indiana to Northern Ireland. In all respects these nine victims of sudden unexpected death were characteristic of an all too familiar set of circumstances and routine findings. Postmortem examination failed to demonstrate cerebral hemorrhage, pulmonary embolism or any of the other usual entities known to cause death suddenly. Each of the hearts was grossly normal in appearance; there were no significant valvular lesions or septal defects, and the major coronary arteries were normally distributed and widely patent. As part of the routine procedure to study such hearts in my laboratory, the regions of the sinus node and AV (artioventricular) junction were excised intact for special examination of the conduction system. The block containing the sinus node included 1 to 2 cm of attached superior vena cava and a similar margin of free wall of the right atrium beyond the crista terminalis (7). The block from AV junction included at least 2 cm each of interatrial and interventricular septa, extended from the noncoronary sinus of the aorta to the diaphragmatic surface of the heart and contained the entire AV node, His bundle and proximal portions of the right and left bundle branches (8). In addition to the elements of the conduction system just identified, these blocks also contained the local nutrient arteries and most of the regional nerves and ganglia, the latter normally being especially abundant at the posterior margin of the sinus
CARDIAC GANGLIONITIS AND SUDDEN DEATH
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node and between the AV node and coronary sinus (9, 10). Each of the two blocks was cut serially into 2 mm slices which were then embedded in paraffin. From each paraffin block at least 10 serial sections (each 8 microns thick) were prepared and stained with the Goldner trichrome method. Additional sections were cut wherever indicated, and in every heart some sections were prepared with periodic acid Schiff, Verhoeff van Gieson elastic, and Holmes or similar silver impregnation stains. Several hundred slides were examined from each of the nine hearts. Some non-neural abnormality of the conduction system was present in 4 of the 9 hearts and included fetal dispersion of the AV node or His bundle (11) in two and focal fibromuscular dysplasia of either the sinus node artery or AV node artery (12, 13) in the two others. Possible functional significance of such changes has been discussed in the cited previous publications. However, in all 9 of these hearts the more impressive abnormality was the cardioneuropathy, particularly in the nerves and ganglia near the sinus node but also within the interatrial septum and scattered throughout the ventricular myocardium. Directly over the sinus node there was focal epicardial edema and inflammation with some thickening of the pericardium, but this could not be identified in any place separate from local neural abnormalities; furthermore, there was no pericarditis or pericardial abnormality over the rest of the heart, and there was no significant valvulitis. There were scattered small inflammatory foci in various portions of the heart, but nearly all of these contained neural elements. Those few foci in which no nerves could be identified contained sufficient nonspecific debris or degeneration so that prior presence of nerves remained a possibility, particularly given the more abundant similar examples where nerves were found. To identify nerves or fragments of ganglia within foci of inflammation or degeneration, serial sections were essential. Without them, many foci observed in any single slide could not have been interpreted correctly as being perineural or juxtaneural. Furthermore, some neural elements which appeared normal or nearly so in one section could be seen to contain distinct abnormalities only a few sections away, each section being only 8 microns thick. Ganglionitis was characterized by Nissl degrandulation, by polychromasia and anisocytosis of neurons, and by local infiltration of lymphocytes and macrophages (Figures 1-3). Possible inclusion bodies were only rarely identified. Focal hemorrhage surrounded a few ganglia, while fatty replacement could be seen within other ganglia. Edema or proteinaceous material was present within and around various neural elements. Abnormalities which were found in many nerves included degenerative disruption of neurofibrils, lymphocytic infiltration and focal vesiculation (Figure 4). Except when vesicles directly disrupted the continuity of a
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H'IG. I. inese pnotomicrograpns mustrate ganguionitis rouna near tne sinus noae oi a woman 22 years old who died suddenly and unexpectedly. The ganglion boxed in A is seen at higher magnification in B, where the inflammation is indicated with arrqws. Neurons in this ganglion vary in size and in staining depth. One neuron in a different ganglion is indicated with a black arrow in A and exhibits both unusual pallor and swollen size with Nissl degranulation. Other details of this case have been presented elsewhere (6). Goldner trichrome stain here and in all subsequent photomicrographs. All magnifications indicated with reference bars. nerve, they could readily be mistaken for fat cells which normally surround most nerves of the heart. Foci of vesicular neuritis suggested varicose distortion of a nerve; if of viral origin, these vesicles may be a
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counterpart to vesicular dermal or mucocutaneous lesions. It was not possible to determine whether the degeneration of nerves preceded that of ganglia or the reverse. Some nerves were scarred and fibrotic (Figure 5), as if they had been the site of remote injury now healed. There was also thickening of the pericardium focally over the sinus node, a region where nerves and ganglia abound, and this pericardial fibrosis may have been secondary to the same disease which caused old injury to nerves in
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FIG. 3. Another example of ganglionitis adjacent to the sinus node (SN) is presented here from a second case of sudden unexpected death, occurring in an 18 year old man. Ganglion boxed in A is seen at higher magnification in B, where two (of several) abnormally shrunken neurons are marked with arrows. The ganglionitis depicted with this case and with that shown in Figures 1 and 2 is characteristic of the findings in all nine hearts.
those locations. The possibility of concomitant or independent pericarditis seems unlikely since there was no pericardial disease over the ventricles or elsewhere except near the sinus node. Focal neural abnormalities were present within ventricular myocardium and more rarely in
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ventricular epicardium, but not in the abundance with which they were found around the sinus node. In one heart the area near the sinus node in which ganglionitis was found to be present (Figure 6) was excised from the paraffin block with
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FIG. 5. Scarred nerve (boxed in A) within thickened pericardium over sinus node is illustrated from the same case as Figures 1, 2 and 4. Identity of this structure as a nerve was established with serial sections.
a scalpel, the paraffin then was dissolved and the specimen re-embedded in plastic for examination with the electron microscope in a search for viral particles. Viral particles were present (Figure 7).
CARDIAC GANGLIONITIS AND SUDDEN DEATH
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FIG. 6. These two low power photomicrographs are from the same paraffin block of sinus node, A being from a microscopic slide prepared before excision of tissue from this block for electron microscopy and B from a slide made after such a specimen had been cut out of the paraffin with a scalpel. The oval superimposed within epicardium over sinus node (SN) in A marks the area of ganglionitis seen in more detail in Figure 3 (same case). CT is the crista terminalis cut in cross section.
DISCUSSION
From these findings alone one can neither say what the functional signiticance of these neural abnormalities truly was nor what their etiology may be. However, given the probable regulatory importance of the
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nerves of the heart, particularly for the preservation of its electrical stability, logic would dictate that loss of neural effectiveness must favor electrical instability. This could take the form of transient excitatory influence within some neural elements early during inflammation, with subsequent loss of that neural control when damage became worse. Depending on whether these nerves were vagal or sympathetic (undetermined in the present study), the transient excitatory influence could have led to either vagal slowing or sympathetic acceleration of the sinus node. Eventual loss of the same nerves would lead to inappropriate response by the sinus node during any cardiovascular reflex. However, the anatomical proximity of the cardioneuropathy to the sinus node does not necessarily mean that the distribution of those nerves was locally, or locally alone, since some nerves travel great distances within the heart. Some of the perinodal nerves could be followed on serial sections as they distributed within the sinus node, but others were lost in such searches and may have coursed far away, including distribution into the ventricular myocardium. In addition, there were scattered neural abnormalities present within the ventricular myocardium of each heart. Focal loss of such neural influence could readily distort the normal pattern of repolarization
CARDIAC GANGLIONITIS AND SUDDEN DEATH
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(14). The potential effect which ventricular cardioneuropathy might have in the pathogenesis of lethal arrhythmias has been previously described in subjects with the long QT syndromes (5). In each of these 9 hearts ganglionitis was present. It is possible that all of the other neural abnormalities were secondary to the ganglionitis, perhaps representing Wallerian degeneration, but there are several reasons to doubt this explanation. For example, the neural degeneration was focal when assessed with serial sections, as might be expected with direct viral or similar invasion, rather than uniform along an entire nerve length as would be expected secondary to "denervation" injury. Furthermore, there was a wide variety of histological abnormalities along any involved nerve, with some foci of lymphocytic infiltration in one segment, then vesicular degeneration without inflammation in some other segment, and apparently normal nerve trunk in between. It seems more likely that damage had occurred separately in both the nerves and the ganglia, although some secondary degeneration may have occurred as a consequence of primary injury in either place. Although the etiology of the ganglionitis is still uncertain, there are several reasons to place the herpes varicella-zoster virus high on a list of suspicions. For example, none of these victims of sudden death gave any clinical complaint to friends or family which could have been interpreted as a general viral illness. Even though serious viral illnesses can have an explosive onset not preceded by myalgia, headache or gastrointestinal complaints, that is not the clinical pattern most often encountered. On the other hand, the varicella-zoster virus is known to be harbored by seemingly normal individuals for years or decades before making its presence known clinically. Furthermore, its propensity for attack on a single ganglion (trigeminal, for example) is well known and it has a special affinity for thoracic sensory ganglia, as seen with shingles. The varicellazoster virus is, incidentally, a well known but rare cause of myocarditis, although how often nerves are incorporated in the process (or are even a special target of the virus) is unknown. In the 9 hearts of the present study there was usually one ganglion most damaged near the sinus node, forming almost a sentinel lesion. If the functional consequences of this form of sentinel ganglionitis near the sinus node could be compared in intensity to the pain known to occur from sensory ganglionitis in shingles, it would be neural activity of a very high order indeed, but of course this is quite speculative. There are a number of other etiological possibilities to consider, such as some form of hereditary neural degeneration, or damage caused by an ingested or inhaled toxin. However, the similarity of the histological abnormalities in all nine victims, who were from widely separated parts of the world, and the lack of any clinical clues from associated neuro-
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muscular or musculoskeletal abnormalities in the victims or their family members, make either an inherited or toxic etiology less appealing hypotheses. Many other viruses or pathogens (e.g., toxoplasmosis) deserve careful consideration. It is known that the herpes simplex virus can lie dormant but potentially active in man (15, 16), and these intracardiac neural lesions could represent its activation. Demonstration of viral particles (Figure 7) in one of the present hearts does not prove that those particles had anything to do with the ganglionitis in that heart, although they were in the same anatomic vicinity. Herpes of the heart or cardiac canker or syncopal shingles each has a nice alliterative ring to it, but the concept remains now only a hypothetical consideration. What is clear from the present study is that the nerves and ganglia in and near the conduction system are distinctly abnormal in all nine of these cases of sudden unexpected death, and the nature of the cardioneuropathy is generally similar in all nine. The lesions may or may not have been the consequence of a single cause, such as the herpes varicella-zoster virus. But whatever the true etiology may be and whatever functional significance may be found for such abnormalities, it is apparent that the neural elements of the heart deserve more careful postmortem study than they usually receive. While specific destruction of intracardiac ganglia by the varicella-zoster virus has not to my knowledge been previously proposed, the known affinity of this virus for discrete anatomic locations within the thorax, its latent prevalence in most of the adult and younger population, and its potentially devastating influence on the electrical stability of the heart all lead one to suspect it as a possible cause of some previously unexplained sudden deaths. REFERENCES
1. JAMES, T. N. AND REYNOLDS, E. W., JR.: Pathology of the cardiac conduction system in a case of diphtheria associated with atrial arrhythmias and heart block. Circulation 28: 263, 1963. 2. JAMES, T. N., FROGGATT, P. AND MARSHALL, T. K.: Sudden death of young athletes. Ann. Intern. Med. 67: 1013, 1967. 3. JAMES, T. N.: Sudden death related to myocardial infarction. Circulation 45: 205, 1972. 4. JAMES, T. N.: De Subitaneis Mortibus. XXVIII. Apoplexy of the heart. Circulation 57: 385, 1978. 5. JAMES, T. N., FROGGATT, P., ATKINSON, W. J., LURIE, P. R., McNAMARA, D. G., MILLER, W. W., SCHLOSS, G. T., CARROLL, J. F. AND NORTH, R. L.: De Subitaneis Mortibus. XXX. Observations on the pathophysiology of the long QT syndromes with special reference to the neuropathology of the heart. Circulation 57: 1221, 1978. 6. JAMES, T. N., ZIPES, D. P., FINEGAN, R. E., EISELE, J. W. AND CARTER, J. E.: Cardiac ganglionitis associated with sudden unexpected death. Ann. Intern. Med., in press. 7. JAMES, T. N.: Anatomy of the human sinus node. Anat. Rec. 141: 109, 1961. 8. JAMES, T. N.: Morphology of the human atrioventricular node with remarks pertinent to its electrophysiology. Am. Heart. J. 62: 756, 1961.
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9. JAMES, T. N.: Cardiac innervation: Anatomic and pharmacologic relations. Bull. New York Acad. Med. 43: 1041, 1967. 10. SHERF, L. AND JAMES, T. N.: Fine structure of cells and their histological organization within the internodal pathways of the heart: Clinical and electrocardiographic impli-
cations. Am. J. Cardiol. 44: 345, 1979. 11. JAMES, T. N. AND MARSHALL, T. K.: De Subitaneis Mortibus. XVIII. Persistent fetal dispersion of AV node and His bundle within central fibrous body. Circulation 53: 1026, 1976. 12. JAMES, T. N. AND MARSHALL, T. K.: De Subitaneis Mortibus. XVII. Multifocal stenoses due to fibromuscular dysplasia of the sinus node artery. Circulation 53: 736, 1976. 13. JAMES, T. N., HACKEL, D. B. AND MARSHALL, T. K.: De Subitaneis Mortibus. V. Occluded AV node artery. Circulation 49: 772, 1974. 14. YANOWITZ, F., PRESTON, J. B. AND ABILDSKOV, J. A.: Functional distribution of right and left stellate innervation to the ventricles: Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circ. Res. 18: 416, 1966. 15. WARREN, K. G., BROWN, S. M., WROBLEWSKA, Z., GILDEN, D., KOPROWSKI, H. AND SUBAK-SHARPE, J.: Isolation of latent herpes simplex virus from the superior cervical and vagus ganglions of human beings. New Eng. J. Med. 298: 1068, 1978. 16. Buss, D. H. AND SCHARYJ, M.: Herpesvirus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance. Am. J. Med. 66: 457, 1979. DISCUSSION DR. UTz (Washington, D.C.): Tom, I'd like to compliment you on this intriguing idea. You know, I'm sure, that herpes simplex can be grown in a number of cell cultures and herpes zoster will grow in human embryonic fibroblasts. Have you had the chance to do any viral cultures? DR. JAMES (Birmingham): We're just beginning to explore this with colleagues in microbiology at our institution who are expert in this work. There is published experience on growth of herpes simplex virus from the superior cervical ganglion in man. There's also been identification of the varicella-zoster virus in esophagus in man so you are correct that there are some attractive possibilities here. DR. Ross (Baltimore): Tom, have you any more information about family history than what you told us? You have all these cases. Are there any siblings who've had ventricular fibrillation and been resuscitated? DR. JAMES: One young nurse's sister had ventricular fibrillation and was resuscitated. A different case, that came from California, had a series of members of the family who had had fainting attacks. That particular young woman (27 years old) was riding with her brother in a pickup truck on a farm. He thought she'd gone to sleep when she slumped against the door. It was only after several more minutes that he realized it was something more serious and rushed her to the hospital. She was found to be having ventricular fibrillation. There is a theme of familial fit for this kind of thing-documented multiple episodes of ventricular arrhythmia. DR. HOOK (Charlottesville): I wonder about the possibility of histologic changes of this type with deaths not associated with unexpected arrhythmias? Do we know that these changes do not exist if you use the same amount of energy in looking for these lesions in other individuals? In addition, most patients with herpes zoster give a history of chicken pox. How about a previous history of chicken pox in these patients or evidence of herpes infection at other sites? DR. JAMES: Very good question. As you might anticipate, many of these sudden unexpected deaths have not only very little information about the patient but almost no
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available information about family. So, I'm sorry, we don't have any leads of recurring fever blisters or recent exposure to chicken pox or this kind of thing. Regarding the first question, what about controls? It's a difficulty always faced in a project based on post mortem studies, because all of these are dead people and if they're dead, then they're not true controls. They're dead. To say, if ganglionitis existed it had nothing to do with death, would not be too logical. I will say that I was startled when I first saw this in that first case. It was the first case in which I'd seen such ganglionitis. I've looked much more carefully at subsequent cases and have found it in a number. But in a larger number, and in all the previous hundreds I've looked at I've not recognized it. I'll admit I didn't look before with the care I have in the recent ones. I would simply say that if this exists with deaths not associated with arrhythmia, in my experience it is quite rare. DR. WRIGHT (New York): I am particularly interested in other manifestations of herpes in members of the family. I am also interested in whether there was any evidence of herpes encephalitis in any of these families. That is also a rare neurological manifestation of herpes. DR. JAMES: It's the one form of the family history concerning which we have fair confidence, because that's such a dramatic experience. We have no evidence that encephalitis existed in these families, and we're fairly confident that had it existed we would have known about it. DR. SANFORD (Bethesda): Tom, you mentioned a 22-year old and an 18-year old. What were the ages of the 7 other individuals, since varicella-zoster would be anticipated to occur more frequently in older individuals than it would in younger individuals. If the others were older age, one might lean more toward thinking herpes simplex than of varicella-zoster virus. DR. JAMES: The age was 12-31 years. All young people, and that's been characteristic of the ones we've seen with the cardioneuropathy. You're perfectly correct that the usual recrudescence is at an older age, but we also know that there are rare examples (particularly of varicella myocarditis) which occur in relatively young people. DR. WHALEN (Durham): This is a very exciting and eye-opening observation. I recognize the speculative nature of the observation. Would you like to speculate a little further in terms of the possibility that this may be one of the etiologies of the so-called prolonged QT syndrome with sudden death that we see? Why do you think if this is part of the process of the QT syndrome, that stellate ganglionectomy may play a beneficial role in stopping the episodes of ventricular fibrillation. It seems to in maybe two-thirds of the cases. DR. JAMES: Thank you, Bob. The long QT syndrome is a little different. We studied 8 examples of that and all of them did have neural disease and some had ganglionitis, but the predominant neural lesions in those hearts were in the ventricular myocardium as one would teleologically expect if the distortion is principally of ventricular repolarization. There was neural disease in the vicinity of the sinus node which would fit with the prevalent sinus bradycardia we see in those patients. Now the beneficial effect of ganglionectomy is something of which I am not as persuaded as some have been. I helped Arthur Moss in studying the first patient in whom ganglionectomy was done. She's still well, I believe. But, as we all know, physicians are more reluctant to report failures than successes and a very large number of failures are specifically known to me because people write and discuss this long QT syndrome. I would inject a word of caution regarding that particular treatment, because if cardioneuropathology really is an important aspect of the etiology in patients with the long QT syndrome, ganglionectomy may benefit some patients but harm others. Furthermore, suppose that the cardioneuropathy progresses after ganglionectomy initially helped. Then the problem might become worse still, since both ganglionectomy and progressive cardioneuropathy would be acting to distort adrenergic neural symmetry.
Most now believe that sudden unexpected death, especially when unexplainable by the usual careful necropsy examination, is due to some form of lethal instability of the electrical activity of the heart. Although ventricular fibrillation is one of the more familiar forms of such instability, this is less valuable information (for the sake of prevention) than knowing what some of the precursors or predisposing factors were which terminated in fibrillation. Too little is known of either the anatomical or physiological substrate upon which fibrillation begins and persists. Furthermore, most sudden and unexplained deaths occur in circumstances where the terminal rhythm of the heart was not recorded and one can only guess what were the initiating electrical events, the sequence of changes or the exact final rhythm. Actually, what may be more surprising than the rare example of electrical instability of any form is the fact that the heart can maintain an effective and stable rhythm under such a wide variety and continuing barrage of physiological challenges. For rapid adjustment to such challenges the autonomic neural control of the heart is an essential factor which not only permits the heart quickly to change its rate but can also powerfully alter AV (atrioventricular) conduction, myocardial contractility, coronary flow and electrical repolarization. Rather little attention has been paid to either the normal or abnormal anatomy of neural elements within the heart. From a continuing personal study of this subject, including examinations of the hearts of victims of sudden unexpected death (1-4), it has become apparent that the nerves and ganglia are not spared during myocardial infarction, myocarditis, amyloidosis, collagen diseases and other such processes known to damage myocardium. All of these may be considered secondary forms of cardioneuropathy. However, in a number of recent cases of sudden unexpected death the cardioneuropathy was the sole or singularly prevalent pathoFrom the Department of Medicine, University of Alabama Medical Center, Birmingham, Alabama 35294. This work was supported by the National Heart, Lung and Blood Institute (Program Project Grant HL 11,310 and SCOR on Ischemic Heart Disease No. 1 P17 HL 17,667) and by the Rast Fund for Medical Research. Address for correspondence: Thomas N. James, M.D., Department of Medicine, University of Alabama Medical Center, Birmingham, Alabama 35294. 177
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logical finding and other portions of the heart were essentially normal (5, 6). This report will deal with nine such cases. CLINICAL DATA AND NECROPSY FINDINGS All nine of these individuals died suddenly and unexpectedly although each had previously been considered to be in good health. Five of the deaths were witnessed as sudden collapses either during minor physical activity or while at rest, and resuscitative efforts failed. Two of these five deaths were due to documented ventricular fibrillation but the terminal rhythm is not known for the other three. Two deaths occurred while the victim was walking alone and happened no more than two hours after having been in the company of others. Two deaths occurred during sleep and each victim retired in apparent good health without any physical complaint; the interval between retiring and being found dead was two hours for one and five hours for the other, and there was no evidence of life when either was discovered. In none of the nine deaths was there any evidence of violence or of either poisons or intoxicating substances. Six were male and three were female. Their ages ranged from 12 years to 31 years. Three of the nine had a family history of one or more sudden unexpected deaths, but none of the present victims was related to any other. Their homes were in widely distributed geographic locations, extending from California to Indiana to Northern Ireland. In all respects these nine victims of sudden unexpected death were characteristic of an all too familiar set of circumstances and routine findings. Postmortem examination failed to demonstrate cerebral hemorrhage, pulmonary embolism or any of the other usual entities known to cause death suddenly. Each of the hearts was grossly normal in appearance; there were no significant valvular lesions or septal defects, and the major coronary arteries were normally distributed and widely patent. As part of the routine procedure to study such hearts in my laboratory, the regions of the sinus node and AV (artioventricular) junction were excised intact for special examination of the conduction system. The block containing the sinus node included 1 to 2 cm of attached superior vena cava and a similar margin of free wall of the right atrium beyond the crista terminalis (7). The block from AV junction included at least 2 cm each of interatrial and interventricular septa, extended from the noncoronary sinus of the aorta to the diaphragmatic surface of the heart and contained the entire AV node, His bundle and proximal portions of the right and left bundle branches (8). In addition to the elements of the conduction system just identified, these blocks also contained the local nutrient arteries and most of the regional nerves and ganglia, the latter normally being especially abundant at the posterior margin of the sinus
CARDIAC GANGLIONITIS AND SUDDEN DEATH
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node and between the AV node and coronary sinus (9, 10). Each of the two blocks was cut serially into 2 mm slices which were then embedded in paraffin. From each paraffin block at least 10 serial sections (each 8 microns thick) were prepared and stained with the Goldner trichrome method. Additional sections were cut wherever indicated, and in every heart some sections were prepared with periodic acid Schiff, Verhoeff van Gieson elastic, and Holmes or similar silver impregnation stains. Several hundred slides were examined from each of the nine hearts. Some non-neural abnormality of the conduction system was present in 4 of the 9 hearts and included fetal dispersion of the AV node or His bundle (11) in two and focal fibromuscular dysplasia of either the sinus node artery or AV node artery (12, 13) in the two others. Possible functional significance of such changes has been discussed in the cited previous publications. However, in all 9 of these hearts the more impressive abnormality was the cardioneuropathy, particularly in the nerves and ganglia near the sinus node but also within the interatrial septum and scattered throughout the ventricular myocardium. Directly over the sinus node there was focal epicardial edema and inflammation with some thickening of the pericardium, but this could not be identified in any place separate from local neural abnormalities; furthermore, there was no pericarditis or pericardial abnormality over the rest of the heart, and there was no significant valvulitis. There were scattered small inflammatory foci in various portions of the heart, but nearly all of these contained neural elements. Those few foci in which no nerves could be identified contained sufficient nonspecific debris or degeneration so that prior presence of nerves remained a possibility, particularly given the more abundant similar examples where nerves were found. To identify nerves or fragments of ganglia within foci of inflammation or degeneration, serial sections were essential. Without them, many foci observed in any single slide could not have been interpreted correctly as being perineural or juxtaneural. Furthermore, some neural elements which appeared normal or nearly so in one section could be seen to contain distinct abnormalities only a few sections away, each section being only 8 microns thick. Ganglionitis was characterized by Nissl degrandulation, by polychromasia and anisocytosis of neurons, and by local infiltration of lymphocytes and macrophages (Figures 1-3). Possible inclusion bodies were only rarely identified. Focal hemorrhage surrounded a few ganglia, while fatty replacement could be seen within other ganglia. Edema or proteinaceous material was present within and around various neural elements. Abnormalities which were found in many nerves included degenerative disruption of neurofibrils, lymphocytic infiltration and focal vesiculation (Figure 4). Except when vesicles directly disrupted the continuity of a
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H'IG. I. inese pnotomicrograpns mustrate ganguionitis rouna near tne sinus noae oi a woman 22 years old who died suddenly and unexpectedly. The ganglion boxed in A is seen at higher magnification in B, where the inflammation is indicated with arrqws. Neurons in this ganglion vary in size and in staining depth. One neuron in a different ganglion is indicated with a black arrow in A and exhibits both unusual pallor and swollen size with Nissl degranulation. Other details of this case have been presented elsewhere (6). Goldner trichrome stain here and in all subsequent photomicrographs. All magnifications indicated with reference bars. nerve, they could readily be mistaken for fat cells which normally surround most nerves of the heart. Foci of vesicular neuritis suggested varicose distortion of a nerve; if of viral origin, these vesicles may be a
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FIG. 2. Another ganglion from the case illustrated in Figure 1 is shown here from an adjacent histological section of sinus node. Two neurons appear to "spill" together, with Nissl degranulation in one of them. Boxed area in A is seen at higher magnification in B, where an open arrow indicates a possible inclusion body.
counterpart to vesicular dermal or mucocutaneous lesions. It was not possible to determine whether the degeneration of nerves preceded that of ganglia or the reverse. Some nerves were scarred and fibrotic (Figure 5), as if they had been the site of remote injury now healed. There was also thickening of the pericardium focally over the sinus node, a region where nerves and ganglia abound, and this pericardial fibrosis may have been secondary to the same disease which caused old injury to nerves in
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FIG. 3. Another example of ganglionitis adjacent to the sinus node (SN) is presented here from a second case of sudden unexpected death, occurring in an 18 year old man. Ganglion boxed in A is seen at higher magnification in B, where two (of several) abnormally shrunken neurons are marked with arrows. The ganglionitis depicted with this case and with that shown in Figures 1 and 2 is characteristic of the findings in all nine hearts.
those locations. The possibility of concomitant or independent pericarditis seems unlikely since there was no pericardial disease over the ventricles or elsewhere except near the sinus node. Focal neural abnormalities were present within ventricular myocardium and more rarely in
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FIG. 4. Vesicular neural degeneration within the sinus node is depicted from the same case presented in Figures 1 and 2. Blebs and leucocytic response involve much of the nerve, marked with open arrows. These two sections of the same nerve are made 16 microns apart. Similar neural vesiculation was found in all nine hearts.
ventricular epicardium, but not in the abundance with which they were found around the sinus node. In one heart the area near the sinus node in which ganglionitis was found to be present (Figure 6) was excised from the paraffin block with
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FIG. 5. Scarred nerve (boxed in A) within thickened pericardium over sinus node is illustrated from the same case as Figures 1, 2 and 4. Identity of this structure as a nerve was established with serial sections.
a scalpel, the paraffin then was dissolved and the specimen re-embedded in plastic for examination with the electron microscope in a search for viral particles. Viral particles were present (Figure 7).
CARDIAC GANGLIONITIS AND SUDDEN DEATH
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FIG. 6. These two low power photomicrographs are from the same paraffin block of sinus node, A being from a microscopic slide prepared before excision of tissue from this block for electron microscopy and B from a slide made after such a specimen had been cut out of the paraffin with a scalpel. The oval superimposed within epicardium over sinus node (SN) in A marks the area of ganglionitis seen in more detail in Figure 3 (same case). CT is the crista terminalis cut in cross section.
DISCUSSION
From these findings alone one can neither say what the functional signiticance of these neural abnormalities truly was nor what their etiology may be. However, given the probable regulatory importance of the
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nerves of the heart, particularly for the preservation of its electrical stability, logic would dictate that loss of neural effectiveness must favor electrical instability. This could take the form of transient excitatory influence within some neural elements early during inflammation, with subsequent loss of that neural control when damage became worse. Depending on whether these nerves were vagal or sympathetic (undetermined in the present study), the transient excitatory influence could have led to either vagal slowing or sympathetic acceleration of the sinus node. Eventual loss of the same nerves would lead to inappropriate response by the sinus node during any cardiovascular reflex. However, the anatomical proximity of the cardioneuropathy to the sinus node does not necessarily mean that the distribution of those nerves was locally, or locally alone, since some nerves travel great distances within the heart. Some of the perinodal nerves could be followed on serial sections as they distributed within the sinus node, but others were lost in such searches and may have coursed far away, including distribution into the ventricular myocardium. In addition, there were scattered neural abnormalities present within the ventricular myocardium of each heart. Focal loss of such neural influence could readily distort the normal pattern of repolarization
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(14). The potential effect which ventricular cardioneuropathy might have in the pathogenesis of lethal arrhythmias has been previously described in subjects with the long QT syndromes (5). In each of these 9 hearts ganglionitis was present. It is possible that all of the other neural abnormalities were secondary to the ganglionitis, perhaps representing Wallerian degeneration, but there are several reasons to doubt this explanation. For example, the neural degeneration was focal when assessed with serial sections, as might be expected with direct viral or similar invasion, rather than uniform along an entire nerve length as would be expected secondary to "denervation" injury. Furthermore, there was a wide variety of histological abnormalities along any involved nerve, with some foci of lymphocytic infiltration in one segment, then vesicular degeneration without inflammation in some other segment, and apparently normal nerve trunk in between. It seems more likely that damage had occurred separately in both the nerves and the ganglia, although some secondary degeneration may have occurred as a consequence of primary injury in either place. Although the etiology of the ganglionitis is still uncertain, there are several reasons to place the herpes varicella-zoster virus high on a list of suspicions. For example, none of these victims of sudden death gave any clinical complaint to friends or family which could have been interpreted as a general viral illness. Even though serious viral illnesses can have an explosive onset not preceded by myalgia, headache or gastrointestinal complaints, that is not the clinical pattern most often encountered. On the other hand, the varicella-zoster virus is known to be harbored by seemingly normal individuals for years or decades before making its presence known clinically. Furthermore, its propensity for attack on a single ganglion (trigeminal, for example) is well known and it has a special affinity for thoracic sensory ganglia, as seen with shingles. The varicellazoster virus is, incidentally, a well known but rare cause of myocarditis, although how often nerves are incorporated in the process (or are even a special target of the virus) is unknown. In the 9 hearts of the present study there was usually one ganglion most damaged near the sinus node, forming almost a sentinel lesion. If the functional consequences of this form of sentinel ganglionitis near the sinus node could be compared in intensity to the pain known to occur from sensory ganglionitis in shingles, it would be neural activity of a very high order indeed, but of course this is quite speculative. There are a number of other etiological possibilities to consider, such as some form of hereditary neural degeneration, or damage caused by an ingested or inhaled toxin. However, the similarity of the histological abnormalities in all nine victims, who were from widely separated parts of the world, and the lack of any clinical clues from associated neuro-
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muscular or musculoskeletal abnormalities in the victims or their family members, make either an inherited or toxic etiology less appealing hypotheses. Many other viruses or pathogens (e.g., toxoplasmosis) deserve careful consideration. It is known that the herpes simplex virus can lie dormant but potentially active in man (15, 16), and these intracardiac neural lesions could represent its activation. Demonstration of viral particles (Figure 7) in one of the present hearts does not prove that those particles had anything to do with the ganglionitis in that heart, although they were in the same anatomic vicinity. Herpes of the heart or cardiac canker or syncopal shingles each has a nice alliterative ring to it, but the concept remains now only a hypothetical consideration. What is clear from the present study is that the nerves and ganglia in and near the conduction system are distinctly abnormal in all nine of these cases of sudden unexpected death, and the nature of the cardioneuropathy is generally similar in all nine. The lesions may or may not have been the consequence of a single cause, such as the herpes varicella-zoster virus. But whatever the true etiology may be and whatever functional significance may be found for such abnormalities, it is apparent that the neural elements of the heart deserve more careful postmortem study than they usually receive. While specific destruction of intracardiac ganglia by the varicella-zoster virus has not to my knowledge been previously proposed, the known affinity of this virus for discrete anatomic locations within the thorax, its latent prevalence in most of the adult and younger population, and its potentially devastating influence on the electrical stability of the heart all lead one to suspect it as a possible cause of some previously unexplained sudden deaths. REFERENCES
1. JAMES, T. N. AND REYNOLDS, E. W., JR.: Pathology of the cardiac conduction system in a case of diphtheria associated with atrial arrhythmias and heart block. Circulation 28: 263, 1963. 2. JAMES, T. N., FROGGATT, P. AND MARSHALL, T. K.: Sudden death of young athletes. Ann. Intern. Med. 67: 1013, 1967. 3. JAMES, T. N.: Sudden death related to myocardial infarction. Circulation 45: 205, 1972. 4. JAMES, T. N.: De Subitaneis Mortibus. XXVIII. Apoplexy of the heart. Circulation 57: 385, 1978. 5. JAMES, T. N., FROGGATT, P., ATKINSON, W. J., LURIE, P. R., McNAMARA, D. G., MILLER, W. W., SCHLOSS, G. T., CARROLL, J. F. AND NORTH, R. L.: De Subitaneis Mortibus. XXX. Observations on the pathophysiology of the long QT syndromes with special reference to the neuropathology of the heart. Circulation 57: 1221, 1978. 6. JAMES, T. N., ZIPES, D. P., FINEGAN, R. E., EISELE, J. W. AND CARTER, J. E.: Cardiac ganglionitis associated with sudden unexpected death. Ann. Intern. Med., in press. 7. JAMES, T. N.: Anatomy of the human sinus node. Anat. Rec. 141: 109, 1961. 8. JAMES, T. N.: Morphology of the human atrioventricular node with remarks pertinent to its electrophysiology. Am. Heart. J. 62: 756, 1961.
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9. JAMES, T. N.: Cardiac innervation: Anatomic and pharmacologic relations. Bull. New York Acad. Med. 43: 1041, 1967. 10. SHERF, L. AND JAMES, T. N.: Fine structure of cells and their histological organization within the internodal pathways of the heart: Clinical and electrocardiographic impli-
cations. Am. J. Cardiol. 44: 345, 1979. 11. JAMES, T. N. AND MARSHALL, T. K.: De Subitaneis Mortibus. XVIII. Persistent fetal dispersion of AV node and His bundle within central fibrous body. Circulation 53: 1026, 1976. 12. JAMES, T. N. AND MARSHALL, T. K.: De Subitaneis Mortibus. XVII. Multifocal stenoses due to fibromuscular dysplasia of the sinus node artery. Circulation 53: 736, 1976. 13. JAMES, T. N., HACKEL, D. B. AND MARSHALL, T. K.: De Subitaneis Mortibus. V. Occluded AV node artery. Circulation 49: 772, 1974. 14. YANOWITZ, F., PRESTON, J. B. AND ABILDSKOV, J. A.: Functional distribution of right and left stellate innervation to the ventricles: Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone. Circ. Res. 18: 416, 1966. 15. WARREN, K. G., BROWN, S. M., WROBLEWSKA, Z., GILDEN, D., KOPROWSKI, H. AND SUBAK-SHARPE, J.: Isolation of latent herpes simplex virus from the superior cervical and vagus ganglions of human beings. New Eng. J. Med. 298: 1068, 1978. 16. Buss, D. H. AND SCHARYJ, M.: Herpesvirus infection of the esophagus and other visceral organs in adults. Incidence and clinical significance. Am. J. Med. 66: 457, 1979. DISCUSSION DR. UTz (Washington, D.C.): Tom, I'd like to compliment you on this intriguing idea. You know, I'm sure, that herpes simplex can be grown in a number of cell cultures and herpes zoster will grow in human embryonic fibroblasts. Have you had the chance to do any viral cultures? DR. JAMES (Birmingham): We're just beginning to explore this with colleagues in microbiology at our institution who are expert in this work. There is published experience on growth of herpes simplex virus from the superior cervical ganglion in man. There's also been identification of the varicella-zoster virus in esophagus in man so you are correct that there are some attractive possibilities here. DR. Ross (Baltimore): Tom, have you any more information about family history than what you told us? You have all these cases. Are there any siblings who've had ventricular fibrillation and been resuscitated? DR. JAMES: One young nurse's sister had ventricular fibrillation and was resuscitated. A different case, that came from California, had a series of members of the family who had had fainting attacks. That particular young woman (27 years old) was riding with her brother in a pickup truck on a farm. He thought she'd gone to sleep when she slumped against the door. It was only after several more minutes that he realized it was something more serious and rushed her to the hospital. She was found to be having ventricular fibrillation. There is a theme of familial fit for this kind of thing-documented multiple episodes of ventricular arrhythmia. DR. HOOK (Charlottesville): I wonder about the possibility of histologic changes of this type with deaths not associated with unexpected arrhythmias? Do we know that these changes do not exist if you use the same amount of energy in looking for these lesions in other individuals? In addition, most patients with herpes zoster give a history of chicken pox. How about a previous history of chicken pox in these patients or evidence of herpes infection at other sites? DR. JAMES: Very good question. As you might anticipate, many of these sudden unexpected deaths have not only very little information about the patient but almost no
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available information about family. So, I'm sorry, we don't have any leads of recurring fever blisters or recent exposure to chicken pox or this kind of thing. Regarding the first question, what about controls? It's a difficulty always faced in a project based on post mortem studies, because all of these are dead people and if they're dead, then they're not true controls. They're dead. To say, if ganglionitis existed it had nothing to do with death, would not be too logical. I will say that I was startled when I first saw this in that first case. It was the first case in which I'd seen such ganglionitis. I've looked much more carefully at subsequent cases and have found it in a number. But in a larger number, and in all the previous hundreds I've looked at I've not recognized it. I'll admit I didn't look before with the care I have in the recent ones. I would simply say that if this exists with deaths not associated with arrhythmia, in my experience it is quite rare. DR. WRIGHT (New York): I am particularly interested in other manifestations of herpes in members of the family. I am also interested in whether there was any evidence of herpes encephalitis in any of these families. That is also a rare neurological manifestation of herpes. DR. JAMES: It's the one form of the family history concerning which we have fair confidence, because that's such a dramatic experience. We have no evidence that encephalitis existed in these families, and we're fairly confident that had it existed we would have known about it. DR. SANFORD (Bethesda): Tom, you mentioned a 22-year old and an 18-year old. What were the ages of the 7 other individuals, since varicella-zoster would be anticipated to occur more frequently in older individuals than it would in younger individuals. If the others were older age, one might lean more toward thinking herpes simplex than of varicella-zoster virus. DR. JAMES: The age was 12-31 years. All young people, and that's been characteristic of the ones we've seen with the cardioneuropathy. You're perfectly correct that the usual recrudescence is at an older age, but we also know that there are rare examples (particularly of varicella myocarditis) which occur in relatively young people. DR. WHALEN (Durham): This is a very exciting and eye-opening observation. I recognize the speculative nature of the observation. Would you like to speculate a little further in terms of the possibility that this may be one of the etiologies of the so-called prolonged QT syndrome with sudden death that we see? Why do you think if this is part of the process of the QT syndrome, that stellate ganglionectomy may play a beneficial role in stopping the episodes of ventricular fibrillation. It seems to in maybe two-thirds of the cases. DR. JAMES: Thank you, Bob. The long QT syndrome is a little different. We studied 8 examples of that and all of them did have neural disease and some had ganglionitis, but the predominant neural lesions in those hearts were in the ventricular myocardium as one would teleologically expect if the distortion is principally of ventricular repolarization. There was neural disease in the vicinity of the sinus node which would fit with the prevalent sinus bradycardia we see in those patients. Now the beneficial effect of ganglionectomy is something of which I am not as persuaded as some have been. I helped Arthur Moss in studying the first patient in whom ganglionectomy was done. She's still well, I believe. But, as we all know, physicians are more reluctant to report failures than successes and a very large number of failures are specifically known to me because people write and discuss this long QT syndrome. I would inject a word of caution regarding that particular treatment, because if cardioneuropathology really is an important aspect of the etiology in patients with the long QT syndrome, ganglionectomy may benefit some patients but harm others. Furthermore, suppose that the cardioneuropathy progresses after ganglionectomy initially helped. Then the problem might become worse still, since both ganglionectomy and progressive cardioneuropathy would be acting to distort adrenergic neural symmetry.
