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Cyclosporine-associated central neurotoxicity after heart transplantation
CASE REPORTS
Cyclosporine-Associated Central Neurotoxicity After Heart Transplantation Robert P. McManus, MD, Daniel P. O’Hair, MD, Jan Schweiger, RN, MSN, Jan Beitzinger, RN, BSN, and Ronald Siegel, MD Departments of Cardiothoracic Surgery and Cardiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Cyclosporine central neurotoxicity has been described after bone marrow, kidney, and liver transplantation but has not been well documented after heart transplantation. This case illustrates severe reversible neurotoxicity after heart transplantation with characteristic radiographic changes in magnetic resonance imaging. (Ann Thorac Surg 1992;53:326-7)
S
urvival after heart transplantation has increased dramatically since the introduction of cyclosporine [l]. Unfortunately, cyclosporine therapy can be toxic to many organs including the central nervous system [2]. Although several reports have documented cyclosporine central neurotoxicity in transplant recipients, information regarding this syndrome in heart recipients is limited. We report a case of severe, yet completely reversible, central nervous system toxicity associated with cyclosporine therapy that was documented by serial magnetic resonance imaging (MRI) after heart transplantation. A 57-year-old woman with a normal preoperative neurological and psychological evaluation underwent heart transplantation for end-stage dilated cardiomyopathy. The operation was uncomplicated. Immunosuppression consisted of 3 mgkg of cyclosporine twice daily, azathioprine, and methylprednisolone or prednisone. The patient awoke normally and was extubated, awake, alert, and appropriately answering questions 12 hours postoperatively. Over the next 24 to 48 hours, the patient became progressively lethargic, somnolent, and difficult to arouse. With concentration, however, the patient was oriented to person, place, and time but complained of overwhelming fatigue. Electroencephalography showed diffuse slowing with no epileptiform activity. The patient’s mental status stabilized over the next few days but on postoperative day 12 her mental status acutely worsened and she became comatose. At this time the blood urea nitrogen level was 25 mmoln (70 mg/dL) and the creatinine level was 239 pmoYL (2.7 mg/dL). The cyclosporine level was 325 ng/mL (target range, 100 to 300 ng/mL). Serum cholesterol level at this time was 3.44 mmol/L (133 mg/dL) with a low-density lipoprotein level Accepted for publication July 16, 1991. Address reprint requests to Dr McManus, Department of Cardiothoracic Surgery, Medical College of Wisconsin, 8700 West Wisconsin Ave, Milwaukee, WI 53226.
0 1992 by The Society of Thoracic Surgeons
of 1.58 mmol/L (61 mg/dL) and high-density lipoprotein of 0.85 mmolL (33 mg/dL). The serum magnesium level was within normal limits. An extensive neurological work-up was performed. Lumbar puncture was unremarkable. Computed tomographic scan of the head was normal, but an MRI scan revealed multiple areas of increased water uptake in the white matter of essentially the entire brain. Cyclosporine administration was empirically stopped when no other cause could be determined. Over the next 2 weeks the patient gradually improved to the point where she was able to carry on normal conversations with only slight impairment of cognitive function and shortterm memory. The improvement in mental status allowed a reinitiation of cyclosporine therapy. Within 2 days the patient again began to exhibit signs of increasing somnolence and lethargy. Another MRI scan was performed at that time. This scan, although markedly improved from the previous scan performed during her comatose state, did show substantial areas of increased water uptake in the white matter. The cyclosporine dose was again reduced, and the patient’s mental status again improved. Eight weeks after heart transplantation the patient was transferred to a rehabilitation service for intensive physical therapy. On a reduced dose of cyclosporine (2 mgkg per day) the neurological condition completely normalized. The muscle strength lost during her prolonged neurological illness was almost completely regained. An MRI scan performed on discharge, 11 weeks after transplantation, revealed near-complete resolution of previous findings. The patient is without sequelae 6 months after transplantation.
Comment The syndrome of cyclosporine-associated central neurotoxicity was initially reported after bone marrow [3] and kidney [4] transplantation and later described in detail in patients after liver transplantation [2]. The liver recipients demonstrated encephalopathy, seizures, and white matters changes and appeared to be at a higher risk when the total serum cholesterol level was low after transplantation. In a series of 48 patients, the 13 patients in whom central neurotoxicity developed had strikingly low levels of serum cholesterol compared with 35 patients without neurotoxicity. Although the incidence of cyclosporine neurotoxicity is not well established, the observed rate, 13 of 54 patients (approximately 25%), is consistent with a previous report by Adams and associates [5]. In patients undergoing heart transplantation, cyclosporine neurotox0003-4975/92/$5.00
Ann Thorac Surg
CASE REPORT McMANUS ET AL CYCLOSPORINE NEUROTOXICITY
1992;53:32&7
icity has been reported but the incidence is unknown and documentation is limited to a single report [ 6 ] . This isolated report included cerebral infarctions as neurotoxic events, lacked confirmatory MRI findings, and did not report serum cholesterol levels. The cause of the syndrome is unknown. Cyclosporine neurotoxicity has been associated with hypomagnesemia, which may lower the seizure threshold [7],but the predominant theory suggests that toxicity is related to intracellular transport of cyclosporine via the low-density lipoprotein receptor [8]. When total cholesterol or lowdensity lipoprotein levels are low, up-regulation of the low-density lipoprotein receptor occurs, intracellular transport of cyclosporine increases, and higher tissue levels of cyclosporine develop. Although the blood-brain barrier usually limits transport of cyclosporine, dysfunction of this membrane allows cyclosporine access to central nervous tissue with a relatively high density of low-density lipoprotein receptors, that is, the white matter. Although this complication can be devastating if unrecognized, the syndrome appears to be reversible. Furthermore, there appears to be a threshold dose in sensitive patients below which no serious central neurotoxicity occurs and cyclosporine therapy can be safely reinstituted. In summary, this case illustrates that patients with central neurologic dysfunction after heart transplantation who have been treated with cyclosporine should be promptly evaluated with MRI, and the possibility of cyclosporine-associated central neurotoxicity should be
327
considered. Patients with low serum cholesterol levels appear to be at increased risk for this syndrome. Withdrawal of cyclosporine and later reinitiation at a lower .dose appears to be safe treatment for this disorder, and full neurologic recovery is possible.
References 1. Heck CF, Shumway SJ, Kaye MP. Registry of the International Society for Heart Transplantation: sixth official report-1989. J Heart Transplant 1989;8:271-6. 2. DeGroen PC, Aksnait AJ, Rakela J, Forbes GS, Krom RAF. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Engl J Med 1987;317861-6. 3. Atkinson K, Biggs J, Darvenzia, et al. Cyclosporine-associated central-nervous-system toxicity after allogenic bone marrow transplantation. Transplantation 1984;38:34. 4. Wilczek H, Ringden 0, Tyden G. Cyclosporine-associated central nervous system toxicity after renal transplantation. Transplantation 1985;39:110. 5. Adams DH, Ponsford S, Gunson B, et al. Neurological complications following liver transplantation. Lancet 1987;l: 949-51. 6. Vasquez de Prada JA, Martin-Duran R, Garcia Monoco C, et al. Cyclosporine neurotoxicity in heart transplantation. J Heart Transplant 1989;9:581-3. 7. Thompson CB, June CH, Sullivan KM, Thomas ED. Association between cyclosporine neurotoxicity and hypomagnesemia. Lancet 1984;2:1116-20. 8. DeGroen PC. Cyclosporine, low density lipoprotein, and cholesterol. Mayo Clin Proc 1988;63:1012-21.
Cyclosporine-Associated Central Neurotoxicity After Heart Transplantation Robert P. McManus, MD, Daniel P. O’Hair, MD, Jan Schweiger, RN, MSN, Jan Beitzinger, RN, BSN, and Ronald Siegel, MD Departments of Cardiothoracic Surgery and Cardiology, Medical College of Wisconsin, Milwaukee, Wisconsin
Cyclosporine central neurotoxicity has been described after bone marrow, kidney, and liver transplantation but has not been well documented after heart transplantation. This case illustrates severe reversible neurotoxicity after heart transplantation with characteristic radiographic changes in magnetic resonance imaging. (Ann Thorac Surg 1992;53:326-7)
S
urvival after heart transplantation has increased dramatically since the introduction of cyclosporine [l]. Unfortunately, cyclosporine therapy can be toxic to many organs including the central nervous system [2]. Although several reports have documented cyclosporine central neurotoxicity in transplant recipients, information regarding this syndrome in heart recipients is limited. We report a case of severe, yet completely reversible, central nervous system toxicity associated with cyclosporine therapy that was documented by serial magnetic resonance imaging (MRI) after heart transplantation. A 57-year-old woman with a normal preoperative neurological and psychological evaluation underwent heart transplantation for end-stage dilated cardiomyopathy. The operation was uncomplicated. Immunosuppression consisted of 3 mgkg of cyclosporine twice daily, azathioprine, and methylprednisolone or prednisone. The patient awoke normally and was extubated, awake, alert, and appropriately answering questions 12 hours postoperatively. Over the next 24 to 48 hours, the patient became progressively lethargic, somnolent, and difficult to arouse. With concentration, however, the patient was oriented to person, place, and time but complained of overwhelming fatigue. Electroencephalography showed diffuse slowing with no epileptiform activity. The patient’s mental status stabilized over the next few days but on postoperative day 12 her mental status acutely worsened and she became comatose. At this time the blood urea nitrogen level was 25 mmoln (70 mg/dL) and the creatinine level was 239 pmoYL (2.7 mg/dL). The cyclosporine level was 325 ng/mL (target range, 100 to 300 ng/mL). Serum cholesterol level at this time was 3.44 mmol/L (133 mg/dL) with a low-density lipoprotein level Accepted for publication July 16, 1991. Address reprint requests to Dr McManus, Department of Cardiothoracic Surgery, Medical College of Wisconsin, 8700 West Wisconsin Ave, Milwaukee, WI 53226.
0 1992 by The Society of Thoracic Surgeons
of 1.58 mmol/L (61 mg/dL) and high-density lipoprotein of 0.85 mmolL (33 mg/dL). The serum magnesium level was within normal limits. An extensive neurological work-up was performed. Lumbar puncture was unremarkable. Computed tomographic scan of the head was normal, but an MRI scan revealed multiple areas of increased water uptake in the white matter of essentially the entire brain. Cyclosporine administration was empirically stopped when no other cause could be determined. Over the next 2 weeks the patient gradually improved to the point where she was able to carry on normal conversations with only slight impairment of cognitive function and shortterm memory. The improvement in mental status allowed a reinitiation of cyclosporine therapy. Within 2 days the patient again began to exhibit signs of increasing somnolence and lethargy. Another MRI scan was performed at that time. This scan, although markedly improved from the previous scan performed during her comatose state, did show substantial areas of increased water uptake in the white matter. The cyclosporine dose was again reduced, and the patient’s mental status again improved. Eight weeks after heart transplantation the patient was transferred to a rehabilitation service for intensive physical therapy. On a reduced dose of cyclosporine (2 mgkg per day) the neurological condition completely normalized. The muscle strength lost during her prolonged neurological illness was almost completely regained. An MRI scan performed on discharge, 11 weeks after transplantation, revealed near-complete resolution of previous findings. The patient is without sequelae 6 months after transplantation.
Comment The syndrome of cyclosporine-associated central neurotoxicity was initially reported after bone marrow [3] and kidney [4] transplantation and later described in detail in patients after liver transplantation [2]. The liver recipients demonstrated encephalopathy, seizures, and white matters changes and appeared to be at a higher risk when the total serum cholesterol level was low after transplantation. In a series of 48 patients, the 13 patients in whom central neurotoxicity developed had strikingly low levels of serum cholesterol compared with 35 patients without neurotoxicity. Although the incidence of cyclosporine neurotoxicity is not well established, the observed rate, 13 of 54 patients (approximately 25%), is consistent with a previous report by Adams and associates [5]. In patients undergoing heart transplantation, cyclosporine neurotox0003-4975/92/$5.00
Ann Thorac Surg
CASE REPORT McMANUS ET AL CYCLOSPORINE NEUROTOXICITY
1992;53:32&7
icity has been reported but the incidence is unknown and documentation is limited to a single report [ 6 ] . This isolated report included cerebral infarctions as neurotoxic events, lacked confirmatory MRI findings, and did not report serum cholesterol levels. The cause of the syndrome is unknown. Cyclosporine neurotoxicity has been associated with hypomagnesemia, which may lower the seizure threshold [7],but the predominant theory suggests that toxicity is related to intracellular transport of cyclosporine via the low-density lipoprotein receptor [8]. When total cholesterol or lowdensity lipoprotein levels are low, up-regulation of the low-density lipoprotein receptor occurs, intracellular transport of cyclosporine increases, and higher tissue levels of cyclosporine develop. Although the blood-brain barrier usually limits transport of cyclosporine, dysfunction of this membrane allows cyclosporine access to central nervous tissue with a relatively high density of low-density lipoprotein receptors, that is, the white matter. Although this complication can be devastating if unrecognized, the syndrome appears to be reversible. Furthermore, there appears to be a threshold dose in sensitive patients below which no serious central neurotoxicity occurs and cyclosporine therapy can be safely reinstituted. In summary, this case illustrates that patients with central neurologic dysfunction after heart transplantation who have been treated with cyclosporine should be promptly evaluated with MRI, and the possibility of cyclosporine-associated central neurotoxicity should be
327
considered. Patients with low serum cholesterol levels appear to be at increased risk for this syndrome. Withdrawal of cyclosporine and later reinitiation at a lower .dose appears to be safe treatment for this disorder, and full neurologic recovery is possible.
References 1. Heck CF, Shumway SJ, Kaye MP. Registry of the International Society for Heart Transplantation: sixth official report-1989. J Heart Transplant 1989;8:271-6. 2. DeGroen PC, Aksnait AJ, Rakela J, Forbes GS, Krom RAF. Central nervous system toxicity after liver transplantation. The role of cyclosporine and cholesterol. N Engl J Med 1987;317861-6. 3. Atkinson K, Biggs J, Darvenzia, et al. Cyclosporine-associated central-nervous-system toxicity after allogenic bone marrow transplantation. Transplantation 1984;38:34. 4. Wilczek H, Ringden 0, Tyden G. Cyclosporine-associated central nervous system toxicity after renal transplantation. Transplantation 1985;39:110. 5. Adams DH, Ponsford S, Gunson B, et al. Neurological complications following liver transplantation. Lancet 1987;l: 949-51. 6. Vasquez de Prada JA, Martin-Duran R, Garcia Monoco C, et al. Cyclosporine neurotoxicity in heart transplantation. J Heart Transplant 1989;9:581-3. 7. Thompson CB, June CH, Sullivan KM, Thomas ED. Association between cyclosporine neurotoxicity and hypomagnesemia. Lancet 1984;2:1116-20. 8. DeGroen PC. Cyclosporine, low density lipoprotein, and cholesterol. Mayo Clin Proc 1988;63:1012-21.