Psychosomatics 39:124-133, April 1998
© 1998 The Academy of Psychosomatic Medine
Immunosuppressant Neurotoxicity in Liver Transplant Recipients
Clinical Challenges for the Consultation-Liaison Psychiatrist
Thomas B. Strouse, M.D.,
Suzie M. El-Saden, M.D.,
Nancy E.M. Glaser, M.D.,
Curley Bonds, M.D.,
Natalie Ayars, M.D., and
Ronald W. Busuttil, M.D., Ph.D.
Received February 24, 1997; revised April 16, 1997; accepted July 8, 1997. From the University of California, Los Angeles (UCLA)–Dumont/Cedars-Sinai Combined Liver Transplant Program (TBS, NEMG, RWB); and the Departments of Psychiatry (TBS, NEMG, CB, NA), Radiology (SME), and Surgery (RWB), School of Medicine, UCLA. Address reprint requests to Dr. Strouse, Director, Psychosocial Services, Cedars-Sinai Comprehensive Cancer Center, 8700 Beverly Blvd., Los Angeles, CA 90048. e-mail: tstrouse{at}csccc.salick.com
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ABSTRACT
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Neuropsychiatric problems are common among liver transplant recipients, and immunosuppressant neurotoxicity is an important etiologic factor in the posttransplant period. Four typical cases of immunosuppressant neurotoxicity are presented from the clinical experience of the University of California, Los Angeles–Dumont Liver Transplant program. All patients presented with acute behavioral symptoms and received urgent psychiatric consultation; each proved to be suffering from a variant of immunosuppressive-related neurotoxicity. Correlative neuroimaging studies and descriptions of clinical course are included. Psychiatrists are urged to become familiar with the signs, symptoms, differential diagnosis, neuroimaging findings, and management of immunosuppressive neurotoxicity and secondary psychiatric disorders in solid organ recipients.
Key Words: Immunosuppressant • Neurotoxicity • Liver Transplants • Transplantation • Organ Donation
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INTRODUCTION
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It is now widely accepted that among organ transplant patients, liver recipients have the highest rates of a broad spectrum of neuropsychiatric symptoms and syndromes before transplant, in the acute postoperative period, and during long-term clinical follow-up.1 Common problems for liver patients before transplant include frank hepatic encephalopathy, prevalent at rates of 20%–30% in prospectively studied liver transplant candidates,2 as well as more subtle abnormalities of motor function, concentration and memory, mood, energy, and sleep-wake cycle. Common posttransplant problems include delirium, visual disturbances, seizures, secondary mood and anxiety disorders, cognitive problems, and complex movement disorders.3–5 This cluster of pre- and posttransplant problems might be best understood as an interaction of clinical variables, such as the patient's neuropsychiatric status before the onset of chronic organ dysfunction (e.g., prior neurological/psychiatric factors); the added effects upon the central nervous system of organ failure (e.g., chronic hyperammonemia); the biopsychosocial provocation of transplant surgery itself (e.g., veno-venous bypass, sleep deprivation, pain, fear); and the travails of the postoperative course (e.g., potent immunosuppression, infection, rejection, and prolonged intensive care unit [ICU] stays).6
When persistent, posttransplant neuropsychiatric problems are associated with decreased quality of life for patients; suboptimal physical, vocational, and social rehabilitation after technically successful liver transplantation; extended hospital stays; and, more rarely, catastrophic outcomes such as neurological death.7,8
Psychiatrists, meanwhile, know transplant patients well over time and are often the most "brain-oriented" physicians involved routinely in the spectrum of transplant candidate selection, hospital management in the postoperative period, and long-term follow-up. The clinical continuity afforded by the regular presence of a psychiatrist allows for initial assessment of neuropsychiatric problems before transplant, observation of their natural course, and, when necessary, informed acute diagnosis and management. While a growing base of knowledge about these neuropsychiatric problems has been accumulating in the general medical and transplant literature over the last decade, this additional knowledge has not made its way into the psychiatric literature as quickly as transplant recipients have made their way into university hospital-psychiatry clinics and even community psychiatrists' freestanding offices. This clinical correlation case series is meant to provide consultation-liaison psychiatrists with some illustrative examples of acute neuropsychiatric syndromes occurring in liver transplant recipients presenting to psychiatrists at a large university-hospital program.
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Case Reports
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Case 1. Ms. A. is a 36-year-old woman who underwent orthotopic liver transplantation (OLT) for congenital polycystic disease. Six months after a technically successful liver transplantation, she presented to our medical center from her home out of state with a 2-week history of treatment-refractory headaches.
Her neurological and physical examination at admission, vital signs, and laboratories, including serum cyclosporine levels and electrolytes, were unremarkable.
The morning after admission, she awoke feeling "odd," exhibited rightward involuntary neck torsion and right-arm movements, and then reported to staff that she could not see. A noncontrast head computed tomography (CT) (Figure 1) performed a few hours later appeared normal. The surgical house staff strongly suspected a conversion reaction but were persuaded to order a magnetic resonance imaging (MRI) scan (Figure 2) by the psychiatrist, who was impressed mainly by the patient's appropriate distress about her loss of vision.
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FIGURE 1. Case 1. Selective transaxial images of the brain from a noncontrast computed tomography scan demonstrating normal density throughout the parietal-occipital region
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FIGURE 2. Case 1. Axial T2-weighted MRI images obtained within 12 hours of the computed tomography scan through the same region as Figure 1. clearly demonstrate increased signal intensity indicative of acute edema in the parietal and occipital lobes. This patient was 6 months out from liver transplant.
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Upon recognition of her occipital brain edema, a known complication of cyclosporine therapy, the patient's cyclosporine doses were held for 36 hours, and her vision returned in parallel with the MRI resolution of her occipital edema.
Re-challenge with lower daily oral doses of cyclosporine did not lead to recurrent headache or blindness.
Case 2. Ms. B., a 48-year-old Asian-American woman, was re-admitted to the transplant unit 4 months after undergoing an uncomplicated liver transplant for hepatitis B. The reason for admission was 2 weeks of increasingly bizarre behavior characterized by dense insomnia, irritability, explosive outbursts, and paranoia. A non-English–speaking native Korean, Ms. B.'s speech was unintelligible to Korean-speaking family and hospital interpreters who noted her to be pressured and having apparent phonation and elocution problems.
Soon after admission, she became mute and akinetic, and developed choreoathetoid movements of her hands, mouth, and tongue, although she had not received antipsychotics or anticholinergics. Admission laboratory tests, including cyclosporine blood level, electrolytes, complete blood count, tests of liver graft function, blood cultures, and a metabolic screen, were unremarkable. A brain MRI (Figure 3) showed focal pontine T2 hyperintensity and more diffuse T2 hyperintensity within the cerebral white matter. With the diagnosis of central pontine myelinolysis (CPM), a known complication of cyclosporine immunosuppression, her cyclosporine was stopped and held for 6–8 weeks, with attendant increases in immuran and prednisone. Her akinesia slowly resolved, but she continued to be irritable and explosive, with pathological speech modulation. She was started on carbamazepine and showed partial clinical improvement, such that she was able to return home and live with her family, though requiring supervision. Follow-up MRI scans 3 months later (Figure 4) showed incomplete resolution of her pontine lesions.
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FIGURE 3. Case 2. Axial T2-weighted MRI image demonstrating subtle, diffuse signal intensity throughout the pons in a patient 4 months status-postliver transplant. Upper images through the brain (not shown) revealed increased signal intensity throughout much of the cerebral white matter.
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FIGURE 4. Case 2. Axial T2-weighted MRI images through the same level of the pons, as in Figure 3, obtained 4 months later, now demonstrate residual signal abnormalities consistent with gliosis
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Case 3. Ms. C. underwent OLT at age 59 for chronic active hepatitis C contracted decades earlier from a blood transfusion. Despite excellent graft function and low therapeutic blood levels of FK506 in the ICU, she had a protracted postoperative course characterized by staphylococcal sepsis, confusion, little verbal output, and psychomotor retardation. During this period, her serum sodium was corrected from 125 to 140 over 36 hours.
An MRI of the brain (Figure 5) performed 18 days after transplant showed myelinolysis of the pons and thalamus. FK506 dosing was reduced, and the patient improved slowly, but she required transfer to a nursing facility 2 months after transplant with cognitive function worse than before transplant, marked deconditioning, and poor nutritional status. The next year was characterized by continued failure to thrive, infectious complications, and a more clearly declared clinical syndrome of dementia and depression. A repeat brain MRI (Figure 6) performed 10 months after that shown in Figure 5 shows persistent pontine lesions.
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FIGURE 5. Case 3. Axial proton density and T2-weighted MRI images through the pons reveal increased signal thought to represent myelinolysis in this patient 18 days after transplant
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FIGURE 6. Case 3. Follow-up MRI scan obtained 10 months after Figure 5 demonstrates residual disease in the pons associated with mild tissue-volume loss now consistent with chronic gliosis
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Case 4. Ms. D. underwent OLT at age 54 for chronic active hepatitis C with cirrhosis. She had suffered moderate nonpsychotic hepatic encephalopathy in the weeks before transplant. On Postoperative Day 2, she was extubated and reported intense paranoia and florid visual and auditory hallucinations in the context of a clear sensorium.
Despite excellent graft function and normal FK506 levels, she quickly developed respiratory failure, required reintubation, developed adult respiratory distress syndrome and sepsis, and spent the next 3 weeks in the ICU, where she remained agitated, affectively labile, and perseverative. Though recommended to rule out CPM, MRI brain imaging was initially delayed by the logistics of ventilator dependence. When the patient was noted upon extubation to be dysarthric, dysphagic, and disinhibited, urgently performed MRI scanning showed multiple lesions within the pons (Figure 7 and Figure 8), and her FK506 regimen was immediately changed to cyclosporine. Her dysarthria, dysphagia, and emotional lability improved over 4 weeks of neurological rehabilitation and with 2 mg/day of risperidone. At the time of this writing, she continues in neurological rehabilitation.
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FIGURE 7. Case 4. Axial T2-weighted images through the brain at the level of the pontomedullary junction, midpons, and midbrain, demonstrating abnormal, diffusely increased signal in the white matter of the brain stem, isolated to the posterior fossa and sparing the corticospinal tracts
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FIGURE 8. Case 4. Axial T2-weighted images through the brain at the level of the pontomedullary junction, midpons, and midbrain, demonstrating abnormal, diffusely increased signal in the white matter of the brain stem, isolated to the posterior fossa and sparing the corticospinal tracts (continued)
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DISCUSSION
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The four patients described here presented with prominent behavioral signs and symptoms of central nervous system toxicity related to transplant immunosuppressives. One recovered completely from her cyclosporine-related cortical blindness after a brief drug holiday (Case 1); one showed moderate recovery from her cyclosporine-related CPM and secondary maniaform illness after an extended drug holiday (Case 2), requiring maintenance therapy with anticonvulsants; one showed progressive cognitive decline and multiple hospital readmissions following FK506-related CPM and lower dose drug-maintenance therapy despite rehabilitation efforts (Case 3); and 1 patient appears to have had rapid improvement in her FK506-related pontine myelinolysis with a change in primary immunosuppressant therapy to cyclosporine, with neurological rehabilitation ongoing at the time of this writing (Case 4).
As noted in this article's introduction, a growing literature implicates the immunosuppressives cyclosporine and FK506 in the pathophysiology of a range of neuropsychiatric syndromes seen in transplant recipients.9–17 These syndromes (Table 1) include multiple manifestations of delirium, seizures, akinetic mutism with CPM, cortical blindness or "reversible posterior leukoencephalopathy syndrome," secondary mood, anxiety, and thought disorders; extrapyramidal syndromes, orofacial dyskinesias, tremors, and myoclonus; cerebellar ataxia syndromes, pseudobulbar palsies, dysarthria, and other problems.18–22 In studies from the late 1980s, large centers reported from 25% to 40% of liver transplant patients had some degree of cyclosporine neurotoxicity8–10 in the acute perioperative phase, although due to superior postoperative management these numbers may now be overestimates. A recently published series on 44 OLT recipients documented CPM in 5 cases.23
Despite early enthusiasm to the contrary, recent prospective trials have unfortunately concluded that FK506 may be associated with greater, rather than less, neurotoxicity than cyclosporine.13–15 A recent, prospective, 1-year, randomized trial of FK506 vs. cyclosporine in patients transplanted for hepatitis C showed nearly twice the rates of neurotoxicity (35% vs. 17%) in the FK506-treated group,24 and a consecutive series of 100 OLT recipients treated with FK506 and prospectively followed by Burkhalter and colleagues from the time of transplant to first hospital discharge had similar rates of "severe" posttransplant neurotoxicity, including CPM, of 34%.25 A recent study of 31 OLT recipients evaluated cognitively at 1 week after transplant showed no significant differences between patients randomized to FK-506 vs. cyclosporine,26 suggesting that differences in primary immunosuppressant-related neurotoxicity may occur in relation to duration of exposure.
The mechanism(s) and mediators of immunosuppressive neurotoxicity in transplant recipients remain largely speculative (Table 2). A variety of metabolic potentiators have been proposed, including disruptions of the blood-brain barrier, cytokines associated with occult infection, regional brain ischemia, coagulopathy, rejection and its treatment, other organ failure, hypertension, hypomagnesemia, hypocholesterolemia, elevated aluminum levels, hypoactive donor organ P450 isoenzyme genotypes, seizures, air emboli, serum osmolarity, and other factors.1,5,6,27–29
The role of rapid correction of hyponatremia during transplant surgery has long been advanced as another pathophysiologic mechanism for some neurotoxicity, in particular CPM.30 Indeed, intracellular sodium flux during "over-rapid" correction of hyponatremia has been implicated as a cause of CPM in patients who are not transplant recipients,31,32 although this mechanism is debated. CPM was originally described as a specific syndromal triad of quadraparesis, bulbar palsy, and coma that was almost always fatal; in the pre-MRI era it was confirmed histologically at autopsy. Contemporary descriptions of a wider range of symptoms (see Table 3) correlated with both MRI images and autopsy specimens suggest that CPM may be a more common, more protean, less catastrophic syndrome with multiple etiologies.33–35(see also Fryer et al.23). As demonstrated in Cases 1 and 2, we have seen demyelination/posterior leukoencephalopathy months or longer after transplant in medically/surgically stable patients in whom no hyponatremia or other metabolic embarrassment has been known to exist. The correction of hyponatremia in Case 3 occurred in a gradual enough fashion so as to be unlikely to have caused CPM, even if this mechanism were accepted as a definitive one. Other reports from around the world confirm a late-onset pattern consistent with our cases,13,36 although incidence rates are unknown.
We believe these case reports contain a number of important points for psychiatrists. First and foremost, these dramatic neuropsychiatric syndromes occur with prominent behavioral symptoms, and psychiatric consultants at our center are often the "first on the scene." Immunosuppressive-mediated acute syndromes are best understood as contemporary examples of secondary psychiatric disorders; therefore, the syndromes need to be added to the list of differential diagnostic considerations in the psychiatric assessment of transplant recipients and others on immunosuppressives.
From the point of view of practical patient care, the psychiatrist can help direct cost-effective medical assessment of these clinical problems. The noncontrast CT scan initially ordered for Patient 1, for example, was probably a wasted expense; a knowledgeable consultant would have advised the house staff to dispense with a CT scan, since it is inferior to MRI in imaging demyelination and cerebral edema. The psychiatrist may also be an advocate for low-cost, common-sense measures such as drug holidays or primary immunosuppressant switchovers. (Other treatment strategies are summarized in Table 4.) Rapid recognition of immunosuppressive neurotoxicity by the psychiatric consultant may also lead to better clinical outcomes and shorter hospital stays by avoiding misdirected efforts at treating these disorders as primary psychiatric illnesses.
In addition, the psychiatrist is well suited to helping manage the consequences of these acute syndromes. Our patients who have had complete recovery (e.g., Patient 1) are still frightened by their experiences and have subjectively benefited from surveillance follow-up care. For patients without complete recovery—perhaps the majority of those afflicted with immunosuppressant neurotoxicity—high-quality psychiatric care is necessary in the management of what are essentially new-onset chronic disorders.
Other potential benefits include the avoidance of psychiatric hospital admissions when excellent psychiatric care is provided in the medical center and reduction in the stigmatization of highly symptomatic patients by the transplant-unit staff. Indeed, the transplant-unit staff's ability to recognize complex behavioral symptoms as a potential complication of transplant immunosuppression facilitates rapid diagnosis and continuity of care.
Immunosuppressive neurotoxicity in transplant recipients occupies a watershed area between neurology and psychiatry. Familiarity with the range of clinical syndromes is an important part of the base of knowledge for psychiatrists seeing patients who are medically ill. The ability to recognize and treat these problems in persons who have received solid organ transplants may serve to reify an important clinical role for psychiatrist-physicians of the future.
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ABSTRACT
INTRODUCTION
