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Articles

Neurologic Complications of Cardiac Transplantation BRIAN T. ANDREWS, MD; JAMES J. HERSHON, MD; PHILIP CALANCHINI, MD; G. JAMES AVERY, II, MD; and J. DONALD HILL, MD, San Francisco

Between 1984 and 1989, orthotopic cardiac transplantations were done in 90 patients from 10 to 65 years of age for end-stage, refractory congestive cardiomyopathy. Two patients had had ischemic strokes 5 months and 18 years, respectively, before transplantation. Six patients (7%) suffered acute neurologic events perioperatively. Three patients suffered cerebral infarctions. In 1 case this occurred 10 days before transplantation-probably as a result of systemic hypoperfusion-with the placement of ventricular assist devices. Two others suffered infarctions 5 and 21 days, respectively, after transplantation, each of probable embolic origin. Two patients had an acute intracerebral hemorrhage 21 and 36 days, respectively, after transplantation; both were located within the basal ganglia and subcortical regions. Both patients had moderate to severe hypertension, and in 1, renal failure and a coagulopathy developed before hemorrhage. Tremor, seizures, and an altered level of consciousness developed in 1 patient as an apparent toxic reaction to cyclosporine treatment. Only 1 patient died as a result of the neurologic complication-of an acute intracerebral hemorrhage. Three patients recovered fully, 2 partially. Only the case of drug toxicity could be directly attributed to the transplantation procedure itself. We conclude that the risk of an acute neurologic insult with orthotopic cardiac transplantation is low but may result from drug toxicity, cerebral ischemia, or hemorrhagic mechanisms. (Andrews BT, Hershon JJ, Calanchini P, et al: Neurologic complications of cardiac transplantation. West J Med 1990 Aug; 153:146-148)

A transplantation by ,Alin 1967,' there was initially high enthusiasm for, fol-

fter the first human heart

Barnard

lowed by a waning in the use of, cardiac transplantation as the difficulties of patient selection, graft rejection, and low survival rates became recognized.2-4 With improved methods of immunosuppression, including the use of cyclosporine,5-7 there has been a nearly exponential increase in the number of transplantations done worldwide.8-10 As of 1989, a total of 9,139 orthotopic heart transplantations had been recorded by the Registry of the International Society for Heart Transplantation. In addition, there were 501 combined heart-lung transplantations and nearly 300 heterotopic heart transplantations.10 A similar dramatic rise has occurred in the number of medical centers doing these procedures: in 1989 there were 118 transplant centers in the United States.'0 Although the survival rate after heart transplantation has improved steadily, significant common complications remain, including graft rejection, infection, graft arteriosclerosis, malignancy, abdominal complications, and drug toxicity.4'5_11-'4 These problems have led to continued perioperative mortality of approximately 9% and a five-year survival rate of 74% to 82%.9 10 Less well recognized, but perhaps increasingly common, are neurologic complications associated with heart transplantation. We review the neurologic complications that have occurred over the course of 90 consecutive heart transplantations at a major metropolitan transplantation center. Patients and Methods Between 1984 and 1989, orthotopic cardiac transplantations were done in 90 patients for end-stage, refractory congestive cardiomyopathy. Included were 75 male and 15 female patients between 10 and 65 years of age (mean 43.5 years). The causes of cardiomyopathy are shown in Table 1.

The most common was myocardial ischemia due to coronary artery atherosclerosis. A retrospective chart review was done to delineate neurologic complications that occurred during the immediate preoperative period from those that developed over the first 60 days postoperatively. Two patients with a history of previous ischemic strokes, 5 months and 18 years, respectively, before transplantation were not included in this series. Late follow-up was carried out with all transplant recipients either directly or through their primary caretakers as part of their ongoing care, at which time the occurrence of delayed neurologic complications was noted. Results Six patients (7%) suffered acute neurologic events perioperatively (Table 2). Cerebral infarction developed in three patients. In one a right parietal infarction occurred ten days before transplantation after two episodes of cardiac arrest and prolonged systemic hypotension leading to the placement of ventricular assist devices. Cerebral infarction in the parieto-occipital region was probably a result of cerebral hypoperfusion. Two others suffered infarction following transplantation. In one patient right hemiparesis and aphasia began 21 days postoperatively, hours after the development of paroxysmal atrial fibrillation, suggesting a probable embolic origin. The second patient had no detectable arrhythmias or hypotension, but a sudden loss of vision developed, followed by a transient coma five days postoperatively. Magnetic resonance imaging subsequently showed bilateral abnormalities in the occipital region consistent with infarcts. A cardiac workup showed no evidence suggesting an embolic source, although emboli to the vertebrobasilar circulation were suspected. The patient was treated successfully with antiplatelet therapy alone, with eventual recovery of vision.

From the Departments of Neurological Surgery (Dr Andrews), Medicine (Dr Hershon), Cardiovascular Surgery (Drs Hershon, Avery, and Hill), and Neurology (Dr Calanchini), Pacific Presbyterian Medical Center, San Francisco. Reprint requests to Brian T. Andrews, MD, Department of Neurological Surgery, Pacific Presbyterian Medical Center, 2100 Webster St, Ste 110, San Francisco, CA

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Two patients suffered acute intracerebral hemorrhage 14 and 36 days, respectively, after transplantation. One was located primarily within the region of the putamen, and the other occurred within the basal ganglia and subcortical area. Both patients had intermittently severe hypertension, and renal failure, sepsis, and a coagulopathy developed in one patient before hemorrhage. In the latter patient, a mycotic aneurysm may have developed and subsequently ruptured as a result of hypertension combined with the coagulopathy. A myoclonic tremor, seizures, and an altered level of consciousness developed in one patient, probably as a toxic reaction to high-dose cyclosporine treatment. This patient had severe impairment of renal function preoperatively as a result of congestive heart failure, but azotemia had rapidly resolved after transplantation; azotemia was mild and resolving at the time of the central nervous system dysfunction. Two of the three patients with ischemic strokes recovered fully; the third was left with persistent dysphasia. One patient with an intracerebral hemorrhage had an incomplete recovery, and the other patient died as a direct result of the hemorrhage complicated by renal failure and a coagulopathy. The patient with a toxic reaction to cyclosporine recovered fully with a tapering in dosage of the medication.

tients receiving heart transplants, fatal strokes occurred in only 3.5 The details of these cases were not reported. In neither the 1987 nor 1989 registries of the International Society for Heart Transplantation were strokes listed as a cause of death after transplantation.9"10 Indeed, only one of the six neurologic complications in our series proved to be fatal, suggesting that the actual incidence of stroke, based on mortality figures, and hemorrhage may be much higher than the reports cited suggest. The causes of ischemic infarctions in our series included both systemic hypoperfusion related to cardiac arrest and embolism related to atrial fibrillation. Systemic hypoperfusion and cardiac arrest have been well documented to cause ischemic cerebral infarction in characteristic distributions at the boundary zones of irrigation between major cerebral arteries, occurring primarily at the parietal and parietooccipital regions.'6 l7 Reperfusion of these regions after the restoration of the blood pressure may result in the develop-

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Discussion By far the most common complications after cardiac transplantation have been acute and chronic graft rejection4 5'7 and infections, such as mediastinitis,'2 pulmonary abscesses, and pneumonia.5" 3 Other complications have been less frequent, including coronary graft atherosclerosis, malignant lesions related to immunosuppression,5 abdominal complications such as gastrointestinal hemorrhage and pancreatitis," and drug toxicities.74,15 Although it would seem that the hemodynamic instability, the potential for cardiac emboli, and the need for systemic anticoagulation in patients undergoing a cardiac transplantation would render the central nervous system at considerable risk for stroke and hemorrhage, such events have been infrequently reported. In a review of the experience at Stanford University Medical Center between 1968 and 1981, Jamieson and co-workers found that of 206 paTABLE 1.-Causes of Cardiomyopathy Among 90 Patients Patients, No.

Couse

Coronary artery disease ..........46 38 Idiopathic .................... Congenital...5 ....................r a jCtiongand 1 ................ and retransplantation Rejection

9

51 42 6 1

ment of hemorrhage within such infarctions.'6"

7

An embolic cause of stroke has long been described in association with atrial fibrillation.'8-20 The Framingham study reported a fivefold increase in the risk of stroke among patients with atrial fibrillation in the absence of rheumatic heart disease.'9 Aberg noted that at autopsy a left atrial thrombus was present in 15.8% of patients with atrial fibrillation.20 In one patient from our series, infarction occurred soon after the development of this arrhythmia. Mechanical support of the circulation has previously been associated with cerebral ischemia. Bregman and associates noted that a stroke developed in one of six patients requiring an intra-aortic balloon pump before transplantation, although the stroke occurred after transplantation and removal of the mechanical devices2'; the cause was not determined. Griffith and colleagues described the temporary use of the Jarvik-7 total artificial heart as a so-called bridge to transplantation in six patients,22 and although no strokes were documented, each heart contained areas of macroscopic aggregations of platelets and thrombi. Other potential sources of cardiac emboli that may occur before or during transplantation include an enlarged and hypokinetic left atrium or ventricle with mural thrombi,'8 intraoperative air embolism at the time of insertion and removal of cardiac bypass,'6"l7 and retained thrombi within the transplanted graft itself. Intracerebral hemorrhage in one patient from our series occurred as a probable result of a coagulopathy related to renal failure and sepsis. It is possible that a mycotic aneurysm developed because of sepsis and subsequently ruptured as a combined result of hypertension and the coagulation disorder. In the second patient the only apparent risk

TABLE 2.-Clinical Summaries for Six Patients With Neurologic Complications of Cardiac Transplantation Patient Age, yr

Cardiomyopathy 1 ... 50 Idiopathic

Complicotion

MCA distribution infarction

Parietal infarction Grand mal seizure; bilateral PCA infarctions Ischemic, Marfan's Putaminal hemorrhage

2 ... 53 Ischemic 3 ... 38 Idiopathic

4... 41

syndrome 5 ... 45 Ischemic

6 ... 23 Idiopathic

Cause Time, d -10 Hypoperfusion; after cardiac arrest; VAD +21 Embolic; atrial fibrillation +5 Embolic?

+14

Incomplete recovery Anticoagulation Antiplatelet therapy Complete recovery

Supportive

Incomplete recovery

Coagulopathy, renal failure,

Supportive

Brain death

Drug taper

Recovery

+36

Myoclonus, seizures, altered

+15 Toxic reaction to

sepsis; hypertension

MCA= middle cerebral artery, PCA- posterior communicating artery. VAD - ventricular assist device

Outcome

Complete recovery

Hypertension

Basal ganglia and subcortical hemorrhage mental state

Treatment

Supportive

cyclosporine

NEUROLOGIC COMPLICATIONS OF HEART TRANSPLANTS

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factor for hemorrhage 14 days after transplantation was hypertension. Hemorrhage occurred within the region of the putamen, the single most frequent site of intracerebral hemorrhage related to hypertension, accounting for 35% to 50% of such cases.23 Only one patient had an apparent toxic reaction to high doses of cyclosporine, consisting of myoclonus, seizures, and an altered level of consciousness, all of which resolved after a tapering of the cyclosporine dosage. Whereas acute and chronic renal failure has been described as the most common forms of cyclosporine toxicity,"4,5 and azotemia may result in secondary seizure activity and delirium, in our patient, renal function was severely impaired preoperatively but had rapidly improved after transplantation, and azotemia was mild and resolving when these symptoms occurred. Cyclosporine use has been reported to cause seizures in 3% to 5% of patients receiving solid organ transplants; additional central nervous system toxicity has also included tremor in 21% to 55% and headaches in 2% to 15%.24 It is of interest that except in the patient with cyclosporine toxicity, no complication was directly attributable to the transplantation procedure itself, but rather appeared to be more directly related to preoperative or postoperative cardiac dysfunction or hypertension, in one patient complicated by a coagulopathy. Despite the seemingly high theoretic risk of cardiac transplantation to the central nervous system, in fact the greater risk is that of the clinical setting in which the procedure is done. REFERENCES

1. Barnard CN: The operation-A human cardiac transplant: An interim report of a successful operation performed at Groote Schuur Hospital, Cape Town. South Afr Med J 1967; 41:2171-1274 2. Barnard CN: The present status of heart transplantation. South Afr Med J 1975; 49:213-217 3. Baumgartner WA, Reitz BA, Oyer PE, et al: Cardiac homotransplantation. Curr Probl Surg 1979; 16:3-61 4. Russell PS, Winn HJ: Transplantation. N Engl J Med 1970; 282:896-906 5. Jamieson SW, Oyer PE, Reitz BA, et al: Cardiac transplantation at Stanford. Heart Transplant 1982; 1:86-91

6. Rabin BS: Immunologic aspects of human cardiac transplantation. Heart Transplant 1983; 2:188-191 7. Griffith BP, Hardesty RL, Bahnson HT: Powerful but limited immunosuppression for cardiac transplantation with cyclosporine and low-dose steroid. J Thorac Cardiovasc Surg 1984; 87:35-42 8. Solis E, Kaye MP: The Registry of the International Society for Heart Transplantation: 3rd Official Report-June 1986, Vol 5. Chicago, International Society for Heart Transplantation, 1986, pp 2-5 9. Kaye MP: The Registry of the International Society for Heart Transplantation: 4th Official Report-1987, Vol 6, Chicago, International Society for Heart Transplantation, 1987, pp 63-67 10. Heck CF, Shumway SJ, Kaye MP: The Registry of the International Society for Heart Transplantation: 6th Official Report-1969, Vol 8. Chicago, International Society for Heart Transplantation, 1989, pp 271-276 11. Merrell SW, Ames SA, Nelson EW, et al: Major abdominal complications following cardiac transplantation-Utah Transplantation Affiliated Hospitals Cardiac Transplant Program. Arch Surg 1989; 124:889-894 12. Trento A, Dummer JS, Hardesty RL, et al: Mediastinitis following heart transplantation: Incidence, treatment and results. Heart Transplant 1984; 111:336-340 13. Mammana RB, Petersen EA, Fuller JK, et al: Pulmonary infections in cardiac transplant patients: Modes of diagnosis, complications, and effectiveness of therapy. Ann Thorac Surg 1983; 36:700-705 14. Myers BD, Ross J, Newton L, et al: Cyclosporine-associated chronic nephropathy. N Engl J Med 1984; 311:699-705 15. Greenberg A, Egel JW, Thompson ME, et al: Early and late forms of cyclosporine nephrotoxicity: Studies in cardiac transplant recipients. Am J Kidney Dis 1987; 9:12-22 16. Caronna JJ: Neurological syndromes following cardiac arrest and cardiac bypass surgey, Chap 36, In Barnett HJM, Mohr JP, Stein BM, et al (Eds): Stroke: Pathophysiology, Diagnosis, and Management. New York, Churchill Livingstone, 1986, pp 747-762 17. Branthwaite MA: Neurological damage related to open heart surgery: A clinical survey. Thorax 1972; 27:748-752 18. Gates PC, Barnett HJM, Silver MD: Cardiogenic stroke, chap 54, In Barnett HJM, Mohr JP, Stein BM, et al (Eds): Stroke: Pathophysiology, Diagnosis, and Management. New York, Churchill Livingstone, 1986, pp 1085-1109 19. Wolf PA, Dawber TR, Thomas HE, et al: Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The Framingham study. Neurology (Minneap) 1978; 28:973-977 20. Aberg H: Atrial fibrillation-I: A study of atrial thrombosis and systemic embolism in necropsy material. Acta Med Scand 1969; 185:373-379 21. Bregman D, Drusin R, Lamb J, et al: Heart transplantation in patients requiring mechanical circulatory support. Heart Transplant 1982; 1:154-157 22. Griffith BP, Hardesty RL, Kormos RL, etal: Temporary use oftheJarvik-7 total artificial heart before transplantation. N Engl J Med 1987; 316:130-134 23. Kase CS, Mohr JP: General features of intracerebral hemorrhage, chap 27, In Barnett HJM, Mohr JP, Stein BM, et al (Eds): Stroke: Pathophysiology Diagnosis, and Management. New York, Churchill Livingstone, 1986, pp 497-523 24. Barnhart ER: Cyclosporine: Product information, In Physicians' Desk Reference. Oradell, NJ, Medical Economics, 1989, pp 1892-1894

Neurologic complications of cardiac transplantation.

Between 1984 and 1989, orthotopic cardiac transplantations were done in 90 patients from 10 to 65 years of age for end-stage, refractory congestive ca...
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