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Persistent cortical blindness after cyclosporine leukoencephalopathy
CASE REPORTS
Persistent Cortical Blindness After Cyclosporine Leukoencephalopathy Bonaventura Casanova,* Martin Prieto,† Elena Deya,* Carmen Gisbert,† Jose´ Mir,‡ Joaquin Berenguer,† and Juan Jesu´s Vilchez* Cyclosporine A (CyA)-related cortical blindness is an uncommon complication of CyA therapy in patients undergoing liver transplantation. Characteristically, neurological symptoms associated with CyA treatment usually regress after cyclosporine withdrawal. We present a case of a liver transplant recipient in whom discontinuation of CyA therapy has resulted in only partial clinical
improvement, and cortical blindness remains after 1 year of follow-up. The evolution of cerebral magnetic resonance imaging (MRI) findings over time in this form of CyA leukoencephalopathy is also described. Copyright r 1997 by the American Association for the Study of Liver Diseases
C
sions, or alcohol abuse. Immunosuppression was started immediately after transplantation as follows. One gram of intravenous methylprednisolone was administered intraoperatively. Postoperatively, the dose of corticosteroids was tapered from 200 mg methylprednisolone on day 1 to 20 mg on day 6. Azathioprine was administered at a dose of 2 mg · kg21 · day21 once a day during the first 2 postoperative months. At the end of day 1, an infusion of CyA was begun (2 mg/kg for 3 hours twice a day); whole-blood trough levels were measured by a specific monoclonal radioimmunoassay. During the following days, this dose had to be increased to a dose of 240 mg twice a day to maintain adequate therapeutic levels between 250 and 350 ng/mL. At day 10, the T-tube was clamped, and the method of CyA administration was changed from intravenous to oral. At the time of OLT, the patient’s total serum cholesterol levels were 108 mg/dL (normal range, 180-240 mg/dL) and remained low during the first 2 weeks after OLT. A hepatic biopsy performed at day 21 confirmed an acute rejection episode that was resolved after a course of increased corticosteroids. He was discharged from the hospital 36 days after transplantation. Two months after liver transplantation the patient was admitted to the hospital because of the sudden onset of complete blindness and headache. Four days after admission, he experienced complex partial and generalized seizures; hydantoins were administered without response, and the patient had to be transferred to the Intensive Care Unit. On admission, his blood pressure was 130/80 mm Hg. Serum sodium, creatinine, and magnesium levels were within the normal range. The serum CyA level was 212 ng/mL. Serum liver tests were within normal limits. A lumbar puncture was performed: Cytochemical and microbiological studies in the cerebrospinal fluid (including HIV, cytomegalovirus, and polymerase chain reaction for JC virus [progressive multiple leukoencephalopathy virus]) were either normal or nega-
yclosporine A (CyA) leukoencephalopathy is a well-defined complication after orthotopic liver transplantation (OLT) that is characterized by cortical blindness, confusion that eventually leads to coma, seizures, and bilateral white matter lesions in the occipital lobes and other cerebral regions.1 In a recent study, Stein et al2 stressed the importance of a rapid CyA withdrawal as soon as this complication is suspected to reverse these symptoms. We describe a patient with CyA leukoencephalopathy after OLT in whom cortical blindness and cerebral lesions visible on magnetic resonance imaging (MRI) persist 1 year after CyA treatment has been discontinued, although the other neurological symptoms have disappeared or greatly improved.
Case Report A 53-year-old man underwent OLT in September 1992 for end-stage cirrhosis secondary to hepatitis C virus infection. Before transplantation, he had been admitted several times to the hospital for treatment of ascites. The patient had no history of hepatic encephalopathy, variceal bleeding, or spontaneous bacterial peritonitis. He had no history of surgical procedures, blood transfu-
From the *Neurology Service, †Hepatogastroenterology Service, and ‡Liver Transplantation Unit, Hospital Universitari La Fe, Vale`ncia, Spain. Address reprint requests to B. Casanova, MD, Servicio de Neurologia, Hospital Universitari La Fe, Avenida Campanar 21, Vale`ncia 46009, Spain. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0306-0014$3.00/0
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Liver Transplantation and Surgery, Vol 3, No 6 (November), 1997: pp 638-640
Persistent Cortical Blindness
tive. Serial electroencephalograms showed slowing background without periodic lateralized epileptiform discharges or focal signs. A computed tomography scan of the head was performed and found to be normal. Although the convulsive state was finally controlled, the patient’s neurological status continued to decline during the following days; in addition to blindness, spatial disorientation, right hemiplegia, and stupor progressing to coma developed. A cerebral MRI was performed that showed multiple symmetrical hyperintense white matter lesions in the occipital lobes and in the centropontine region on the T2-weighted magnetic resonance images. With the suspicion of CyA-related neurological toxicity, CyA therapy was withheld 22 days after the onset of the blindness. After 1 year of follow-up, a progressive recovery of the encephalopathy and motor manifestations has been observed, but complete blindness is still present. An MRI of the head was repeated in November 1993 that showed severe corticosubcortical atrophy with persistent white matter lesions in the occipital lobes but no centropontine lesion (Fig. 1).
Discussion This patient experienced a typical CyA-related leukoencephalopathy, including cortical blindness,
Figure 1. T2-weighted axial magnetic resonance images through middle pons (1.5 T). Protuberancial slice shows disappearance of the white matter lesions.
639
seizures, right hemiplegia, stupor, drowsiness, coma, and multiple white matter lesions in MRI with improvement of all neurological manifestations except for cortical blindness and occipital white matter lesions after CyA withdrawal. Some cases of persistent visual defects have been reported,3 but to our knowledge, this is the first case of persistent cortical blindness after CyA leukoencephalopathy. In our case, CyA was discontinued on day 22; in patients 1 and 2 of the study by De Groen et al,4 CyA was changed to a low-dose CyA regimen on days 6 and 2 after CyA toxicity was suspected, and on days 10 and 11 CyA was lowered and administered orally. In the case with persistent visual defects, the time of withdrawal of the CyA had not been recorded.3 Some of the clinical features and MRI findings of this case are similar to those reported in central pontine myelinolysis with extrapontine myelinolysis after OLT.5 However, the reversibility of some but not all clinical and MRI findings and the normal serum sodium levels after transplantation argue against the diagnosis of sodium-related central pontine myelinolysis with extrapontine myelinolysis in this patient. Actually, MRI changes persisted in the occipital regions that proved to be more sensitive to metabolic and drug-induced toxic insults.6 Neurological complications, in particular CyA leukoencephalopathy, are more common in liver transplant recipients compared with other transplant recipients.7,8 The presence of a damaged blood-brain barrier before liver transplantation has been suggested to explain, at least in part, the higher prevalence of neurological complications after liver transplantation.9 Additional factors that have been implicated in the pathogenesis of CyArelated leukoencephalopathy include low total serum cholesterol levels after OLT4 and the presence of a hyperosmolar state after transplantation.8 All of these factors facilitate the accumulation of CyA in the brain, where it exerts a direct toxic effect on cellular processes or a relative ischemia secondary to disturbance of the prostacyclin thrombohexane metabolism.2 This patient’s low total serum cholesterol levels in the first 2 weeks after OLT may have facilitated the development of severe central nervous system toxicity associated with CyA treatment. In conclusion, CyA-related leukoencephalopathy is an uncommon complication of CyA treatment after liver transplantation. Although recovery is the rule with discontinuation or a reduction in
640
Casanova et al
the dose of CyA,10 a persistent neurological deficit may occur. Prolonged maintenance of CyA therapy after appearance of neurological symptoms may result in the persistence of these deficits. A cerebral MRI must be performed and CyA treatment promptly discontinued as soon as severe CyAinduced neurological toxicity is suspected.
References 1. Lloveras JJ, Larrue V, Suc E, Fourtanier G, Durand D. Leukoencephalopathy after cyclosporine in a liver transplant. Clin Transplant 1990;4:58-62. 2. Stein DP, Lederman RJ, Vogt DP, Carey WD, Broughan TA. Neurological complications following liver transplantation. Ann Neurol 1992;31:644-649. 3. Moreno E, Go´mez SR, Gonzalez I, Loinaz C, Garcı´a I, Perez A, et al. Neurologic complications in liver transplantation. Acta Neurol Scand 1993;87:25-31.
4. De Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RAF. Central nervous system toxicity after liver transplantation. N Engl J Med1987;317:861-866. 5. Wszolek ZK, McComb RD, Pfiffer RF, Steg RE, Wood RP, Shaw BW Jr, Marin RS. Pontine and extrapontine myelinolisis following liver transplantation: Relation to serum sodium. Transplantation 1989;48:1006-1012. 6. Truwit CL, Denaro CP, Lake JR, DeMarco T. MR imaging of reversible cyclosporine A-induced neurotoxicity. AJNR Am J Neuroradiol 1991;12:651-659. 7. Tollerman J, Ringden O, Ericzon BG, Tyden G. Letter. N Engl J Med 1988;318:788. 8. Vogt DP, Lederman RJ, Carey WD, Broughan TA. Neurologic complications of liver transplantation. Transplantation 1988;45:1057-1061. 9. Grant D, Wall W, Duff J, Ghent C, Keown O. Adverse effects of cyclosporin therapy following liver trasplantation. Transplant Proc 1987;19:3463. 10. Rubin AL, Kang H. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 1987;37:10721076.
Persistent Cortical Blindness After Cyclosporine Leukoencephalopathy Bonaventura Casanova,* Martin Prieto,† Elena Deya,* Carmen Gisbert,† Jose´ Mir,‡ Joaquin Berenguer,† and Juan Jesu´s Vilchez* Cyclosporine A (CyA)-related cortical blindness is an uncommon complication of CyA therapy in patients undergoing liver transplantation. Characteristically, neurological symptoms associated with CyA treatment usually regress after cyclosporine withdrawal. We present a case of a liver transplant recipient in whom discontinuation of CyA therapy has resulted in only partial clinical
improvement, and cortical blindness remains after 1 year of follow-up. The evolution of cerebral magnetic resonance imaging (MRI) findings over time in this form of CyA leukoencephalopathy is also described. Copyright r 1997 by the American Association for the Study of Liver Diseases
C
sions, or alcohol abuse. Immunosuppression was started immediately after transplantation as follows. One gram of intravenous methylprednisolone was administered intraoperatively. Postoperatively, the dose of corticosteroids was tapered from 200 mg methylprednisolone on day 1 to 20 mg on day 6. Azathioprine was administered at a dose of 2 mg · kg21 · day21 once a day during the first 2 postoperative months. At the end of day 1, an infusion of CyA was begun (2 mg/kg for 3 hours twice a day); whole-blood trough levels were measured by a specific monoclonal radioimmunoassay. During the following days, this dose had to be increased to a dose of 240 mg twice a day to maintain adequate therapeutic levels between 250 and 350 ng/mL. At day 10, the T-tube was clamped, and the method of CyA administration was changed from intravenous to oral. At the time of OLT, the patient’s total serum cholesterol levels were 108 mg/dL (normal range, 180-240 mg/dL) and remained low during the first 2 weeks after OLT. A hepatic biopsy performed at day 21 confirmed an acute rejection episode that was resolved after a course of increased corticosteroids. He was discharged from the hospital 36 days after transplantation. Two months after liver transplantation the patient was admitted to the hospital because of the sudden onset of complete blindness and headache. Four days after admission, he experienced complex partial and generalized seizures; hydantoins were administered without response, and the patient had to be transferred to the Intensive Care Unit. On admission, his blood pressure was 130/80 mm Hg. Serum sodium, creatinine, and magnesium levels were within the normal range. The serum CyA level was 212 ng/mL. Serum liver tests were within normal limits. A lumbar puncture was performed: Cytochemical and microbiological studies in the cerebrospinal fluid (including HIV, cytomegalovirus, and polymerase chain reaction for JC virus [progressive multiple leukoencephalopathy virus]) were either normal or nega-
yclosporine A (CyA) leukoencephalopathy is a well-defined complication after orthotopic liver transplantation (OLT) that is characterized by cortical blindness, confusion that eventually leads to coma, seizures, and bilateral white matter lesions in the occipital lobes and other cerebral regions.1 In a recent study, Stein et al2 stressed the importance of a rapid CyA withdrawal as soon as this complication is suspected to reverse these symptoms. We describe a patient with CyA leukoencephalopathy after OLT in whom cortical blindness and cerebral lesions visible on magnetic resonance imaging (MRI) persist 1 year after CyA treatment has been discontinued, although the other neurological symptoms have disappeared or greatly improved.
Case Report A 53-year-old man underwent OLT in September 1992 for end-stage cirrhosis secondary to hepatitis C virus infection. Before transplantation, he had been admitted several times to the hospital for treatment of ascites. The patient had no history of hepatic encephalopathy, variceal bleeding, or spontaneous bacterial peritonitis. He had no history of surgical procedures, blood transfu-
From the *Neurology Service, †Hepatogastroenterology Service, and ‡Liver Transplantation Unit, Hospital Universitari La Fe, Vale`ncia, Spain. Address reprint requests to B. Casanova, MD, Servicio de Neurologia, Hospital Universitari La Fe, Avenida Campanar 21, Vale`ncia 46009, Spain. Copyright r 1997 by the American Association for the Study of Liver Diseases 1074-3022/97/0306-0014$3.00/0
638
Liver Transplantation and Surgery, Vol 3, No 6 (November), 1997: pp 638-640
Persistent Cortical Blindness
tive. Serial electroencephalograms showed slowing background without periodic lateralized epileptiform discharges or focal signs. A computed tomography scan of the head was performed and found to be normal. Although the convulsive state was finally controlled, the patient’s neurological status continued to decline during the following days; in addition to blindness, spatial disorientation, right hemiplegia, and stupor progressing to coma developed. A cerebral MRI was performed that showed multiple symmetrical hyperintense white matter lesions in the occipital lobes and in the centropontine region on the T2-weighted magnetic resonance images. With the suspicion of CyA-related neurological toxicity, CyA therapy was withheld 22 days after the onset of the blindness. After 1 year of follow-up, a progressive recovery of the encephalopathy and motor manifestations has been observed, but complete blindness is still present. An MRI of the head was repeated in November 1993 that showed severe corticosubcortical atrophy with persistent white matter lesions in the occipital lobes but no centropontine lesion (Fig. 1).
Discussion This patient experienced a typical CyA-related leukoencephalopathy, including cortical blindness,
Figure 1. T2-weighted axial magnetic resonance images through middle pons (1.5 T). Protuberancial slice shows disappearance of the white matter lesions.
639
seizures, right hemiplegia, stupor, drowsiness, coma, and multiple white matter lesions in MRI with improvement of all neurological manifestations except for cortical blindness and occipital white matter lesions after CyA withdrawal. Some cases of persistent visual defects have been reported,3 but to our knowledge, this is the first case of persistent cortical blindness after CyA leukoencephalopathy. In our case, CyA was discontinued on day 22; in patients 1 and 2 of the study by De Groen et al,4 CyA was changed to a low-dose CyA regimen on days 6 and 2 after CyA toxicity was suspected, and on days 10 and 11 CyA was lowered and administered orally. In the case with persistent visual defects, the time of withdrawal of the CyA had not been recorded.3 Some of the clinical features and MRI findings of this case are similar to those reported in central pontine myelinolysis with extrapontine myelinolysis after OLT.5 However, the reversibility of some but not all clinical and MRI findings and the normal serum sodium levels after transplantation argue against the diagnosis of sodium-related central pontine myelinolysis with extrapontine myelinolysis in this patient. Actually, MRI changes persisted in the occipital regions that proved to be more sensitive to metabolic and drug-induced toxic insults.6 Neurological complications, in particular CyA leukoencephalopathy, are more common in liver transplant recipients compared with other transplant recipients.7,8 The presence of a damaged blood-brain barrier before liver transplantation has been suggested to explain, at least in part, the higher prevalence of neurological complications after liver transplantation.9 Additional factors that have been implicated in the pathogenesis of CyArelated leukoencephalopathy include low total serum cholesterol levels after OLT4 and the presence of a hyperosmolar state after transplantation.8 All of these factors facilitate the accumulation of CyA in the brain, where it exerts a direct toxic effect on cellular processes or a relative ischemia secondary to disturbance of the prostacyclin thrombohexane metabolism.2 This patient’s low total serum cholesterol levels in the first 2 weeks after OLT may have facilitated the development of severe central nervous system toxicity associated with CyA treatment. In conclusion, CyA-related leukoencephalopathy is an uncommon complication of CyA treatment after liver transplantation. Although recovery is the rule with discontinuation or a reduction in
640
Casanova et al
the dose of CyA,10 a persistent neurological deficit may occur. Prolonged maintenance of CyA therapy after appearance of neurological symptoms may result in the persistence of these deficits. A cerebral MRI must be performed and CyA treatment promptly discontinued as soon as severe CyAinduced neurological toxicity is suspected.
References 1. Lloveras JJ, Larrue V, Suc E, Fourtanier G, Durand D. Leukoencephalopathy after cyclosporine in a liver transplant. Clin Transplant 1990;4:58-62. 2. Stein DP, Lederman RJ, Vogt DP, Carey WD, Broughan TA. Neurological complications following liver transplantation. Ann Neurol 1992;31:644-649. 3. Moreno E, Go´mez SR, Gonzalez I, Loinaz C, Garcı´a I, Perez A, et al. Neurologic complications in liver transplantation. Acta Neurol Scand 1993;87:25-31.
4. De Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RAF. Central nervous system toxicity after liver transplantation. N Engl J Med1987;317:861-866. 5. Wszolek ZK, McComb RD, Pfiffer RF, Steg RE, Wood RP, Shaw BW Jr, Marin RS. Pontine and extrapontine myelinolisis following liver transplantation: Relation to serum sodium. Transplantation 1989;48:1006-1012. 6. Truwit CL, Denaro CP, Lake JR, DeMarco T. MR imaging of reversible cyclosporine A-induced neurotoxicity. AJNR Am J Neuroradiol 1991;12:651-659. 7. Tollerman J, Ringden O, Ericzon BG, Tyden G. Letter. N Engl J Med 1988;318:788. 8. Vogt DP, Lederman RJ, Carey WD, Broughan TA. Neurologic complications of liver transplantation. Transplantation 1988;45:1057-1061. 9. Grant D, Wall W, Duff J, Ghent C, Keown O. Adverse effects of cyclosporin therapy following liver trasplantation. Transplant Proc 1987;19:3463. 10. Rubin AL, Kang H. Cerebral blindness and encephalopathy with cyclosporin A toxicity. Neurology 1987;37:10721076.