Altered Mental Status After Liver Transplant

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1 REVIEW Altered Mental Status After Liver Transplant Helen S. Te, M.D. Mental status alteration occurs in up to 70% of liver transplant (LT) recipients in the early postoperative period and leads to longer hospitalizations and higher mortality rates. 1 It is more frequent among patients who had alcoholic cirrhosis as the indication for LT, 2,3 metabolic liver diseases, Model for End-Stage Liver Disease (MELD) scores above 15, and were on mechanical ventilation before LT. 3 Causes cover a wide spectrum and can be multifactorial, including residual hepatic encephalopathy (HE), metabolic derangements, immunosuppressive agents and other drugs, including sedatives and narcotics, infections, renal failure, hypoxia, hemodynamic instability, and graft dysfunction (Table 1). These conditionscanalsoleadtoseizures,whichbythemselvesare also frequently accompanied by altered mental status. This review focuses on etiologies of altered mental status that are specific and applicable to LT recipients. HE is a common manifestation of decompensated cirrhosis that results from inadequate metabolism of ammonia and other toxins by the failing liver and/or from significant shunting of the portal blood away from the liver through collateral vessels. It is an independent predictor of neurological complications after LT, but it typically resolves fairly rapidly within the first few days after LT in the setting of a functioning graft. In a few patients, however, early allograft dysfunction or persistence of large spontaneous portosystemic shunts may promote persistent HE after LT, until graft function improves or the shunts are ligated or embolized. Patients who undergo LT with severe HE, alcohol-related liver disease, or high MELD scores may have slower resolution of HE after LT, 4 but failure of a patient to awaken after LT should prompt a thorough investigation. Immunosuppressive agents administered after LT can cause alterations in mental status, and concomitant drugs that inhibit their metabolism may exacerbate this complication. Corticosteroids can cause confusion, mood disturbances, manic states, or psychosis, which improve Abbreviations: CNS, central nervous system; CPM, central pontine myelinolysis; FLAIR, fluid attenuation inversion recovery; HE, hepatic encephalopathy; LT, liver transplant; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; ODS, osmotic demyelination syndrome; PRES, posterior reversible leukoencephalopathy syndrome. From the Center for Liver Diseases, University of Chicago Medicine, Chicago, IL. Potential conflict of interest: Nothing to report. Received 11 May 2017; accepted 22 June 2017 View this article online at wileyonlinelibrary.com VC 2017 by the American Association for the Study of Liver Diseases 36 CLINICAL LIVER DISEASE, VOL 10, NO 2, AUGUST 2017 An Official Learning Resource of AASLD

2 TABLE 1. RISK FACTORS FOR ALTERED MENTAL STATUS AFTER LT Clinical Manifestation or Syndrome HE CPM or ODS Confusion, mood disturbances, mania, psychosis Encephalopathy, seizures, PRES Diffuse CNS involvement with meningitis, encephalitis, or focal brain involvement Sepsis-associated delirium Wernicke s encephalopathy Metabolic encephalopathy Ischemic stroke Intracranial hemorrhage Underlying Condition Graft dysfunction, large spontaneous portosystemic shunt, history of alcohol abuse, donor transmission of urea cycle disorders Chronic hyponatremia Corticosteroids Immunosuppressive agents Opportunistic infection Sepsis History of alcohol abuse Metabolic derangements, donor transmission of metabolic diseases such as acute intermittent porphyria Diabetes, older age, valvular heart disease Thrombocytopenia, coagulopathy FIG 1 MRI images of PRES. Areas of low signal in the white matter of the bilateral occipital lobes and bilateral frontal convexities on T 1 images (A) correspond to high hyperintense signal on T 2 (B) and on fluid attenuation inversion recovery (FLAIR) (C) images, consistent with PRES. A follow-up MRI image (D) obtained 4 weeks after a change of immunosuppression from tacrolimus to cyclosporine demonstrates resolution of the abnormal signals. Courtesy of Christopher M. Straus, M.D. 37 CLINICAL LIVER DISEASE, VOL 10, NO 2, AUGUST 2017 An Official Learning Resource of AASLD

3 FIG 2 MRI images of CPM or ODS. Mildly to moderately hypointense signal with no enhancement is seen in the pons and thalamic areas on T 1 images (A), with corresponding hyperintensity with sparing of the periphery and corticospinal tracts on T 2 (B) and T 2 fluid attenuation inversion recovery (FLAIR) (C) images. Courtesy of Christopher M. Straus, M.D. with dose reduction or drug discontinuation. Calcineurin inhibitors (cyclosporine and tacrolimus) can cause posterior reversible leukoencephalopathy syndrome (PRES), particularly when given intravenously or when serum levels are high, although it can also occur within therapeutic serum levels. There have also been rare reports of PRES attributed to sirolimus and mycophenolate mofetil. PRES is a syndrome characterized by alterations in perfusion of the brain caused by vasoconstriction (Fig. 1), typically occurring in patients with underlying arterial hypertension exacerbated by the immunosuppressive agent. Symptoms include nausea, emesis, headache, cortical blindness, and in severe cases, seizures and altered consciousness. Cerebral magnetic resonance imaging (MRI) shows vasogenic brain edema in occipital and parietal areas. Most patients respond to management of the blood pressure and dose reduction or, preferably, drug discontinuation. 2,4,5 Tacrolimus and cyclosporine do not have the same exact mechanism for causing PRES, and one drug can be substituted for the other when PRES occurs. 1 Outside of PRES, calcineurin inhibitors can also cause other mental symptoms, including psychosis, hallucinations, akinetic mutism, seizures, and encephalopathy. Seizures, if present, should be treated with antiepileptic agents, and drugs available in parenteral form include phenytoin, fosphenytoin, levetiracetam, and lacosamide. 4 Phenytoin levels must be closely monitored in LT recipients because of its affinity for albumin, which tends to be low in this population, and its drug interaction with immunosuppressive agents. Central pontine myelinolysis (CPM) or osmotic demyelination syndrome (ODS) may occur in up to 1% to 4% of LT recipients, 4-6 with susceptible patients typically having prolonged hyponatremia before LT, which is inadvertently corrected too rapidly during the massive fluid 38 CLINICAL LIVER DISEASE, VOL 10, NO 2, AUGUST 2017 An Official Learning Resource of AASLD

4 TABLE 2. CAUSATIVE MICROORGANISMS OF CNS INFECTIONS IN THE EARLY POST-LT PERIOD Bacteria Streptococcus pneumonia Neisseria meningitidis Listeria monocytogenes Nocardia asteroides Mycobacterium tuberculosis Viruses Cytomegalovirus Herpes simplex virus Varicella zoster virus Epstein-Barr virus Human herpes virus 6 JC polyoma virus Adenovirus Rabies West Nile virus Fungi Cryptococcus neoformans Aspergillus fumigatus Candida species Pneumocystis jiroveci Protozoa Toxoplasma gondii Amoeba shifts that occur within the perioperative period. It is characterized by symmetrical loss of myelin in the base of the pons and other areas of the brain, with relative preservation of axons and neuronal bodies, resulting from rapid osmolar shifts in the brain. The most common clinical manifestation is fluctuating levels of consciousness, but it can progress to pseudobulbar palsy and quadriparesis, sometimes leading to a quadriparetic locked-in syndrome state. MRIs of the brain typically demonstrate hypointense T 1 and hyperintense T 2 and diffusion-weighted lesions in the central pons 5,6 (Fig. 2). Serum sodium correction before, during, and in the postoperative period should be done with caution at a goal of <10 meq/l increments per day. 2 Patients with CPM/ ODS are managed with supportive care, but it usually leads to lifelong disability or death. Anecdotal improvements with thyroid-releasing hormones, hyperbaric oxygen therapy, corticosteroids, plasmapheresis, and intravenous immunoglobulins have been reported but remain to be proved. 6 Infections of the central nervous system (CNS) have become infrequent in LT recipients because of advances in surveillance and prophylactic measures. Acquired infections within the first 30 days are often related to pretransplant colonization, surgical procedures, or rarely, donor-to-recipient disease transmission either by blood products or by allograft. Most common causative organisms are bacteria, fungi, viruses, and less likely, protozoa (Table 2). Patients may present with signs of meningitis or meningoencephalitis, or with more focal deficits suggestive of a fungal or bacterial abscess or focal involvement of specific brain regions by viruses. New-onset severe back pain may herald a spinal abscess. 5 A timely diagnosis and early treatment with the appropriate antimicrobial agents is key, and abscesses may require drainage. Progressive multifocal leukoencephalopathy is characterized by progressive neurological decline caused by demyelination, with plaquelike nonenhancing white matter lesions on neuroimaging studies. This is attributed to reactivation of the JC virus within the CNS that often leads to death because it has no known effective treatment. 4 Other rare causes of altered mental status include cerebrovascular events such as ischemic strokes in 0% to 3% and intracranial hemorrhage in 1% to 7% of LT recipients. 6 Predisposed individuals for ischemic strokes are diabetics, older recipients, and those with valvular heart disease and/or cardiac arrhythmias. 5,6 A stroke from air embolism related to venovenous bypass during LT surgery may occur but is uncommon. Coagulopathy and thrombocytopenia that commonly accompany advanced cirrhosis predispose LT recipients to intracranial hemorrhage in the immediate post-lt period. Hypoxia, hypotension, extreme glucose levels, and electrolyte derangements (such as hypercalcemia, hypermagnesemia, hyponatremia, hypernatremia, hyposmolarity, and hyperosmolarity) can contribute to altered mentation. Although occurrences are rare, altered mental status may also result from donor transmission of metabolic diseases with neuropsychiatric complications such as urea cycle disorders and acute intermittent porphyria. 7 The management of altered mental status is rooted in making the timely diagnosis (Fig. 3) and appropriate treatment of the underlying cause, including optimization of metabolic disturbances. Adequate blood oxygenation and circulation must be maintained, and 39 CLINICAL LIVER DISEASE, VOL 10, NO 2, AUGUST 2017 An Official Learning Resource of AASLD

5 FIG 3 An approach to the evaluation of altered mental status in the early post-lt period. electrolyte derangements must be corrected. Caution must be exercised in correcting hyponatremia too quickly to avoid the development of CPM/ODS. Neuroimaging studies should be obtained early to allow for appropriate diagnosis of cerebrovascular events, focal brain abnormalities in those suspected to have CNS infections, CPM/ODS, or PRES. Treatment is directed toward the identified cause. Nonetheless, if agitation interferes with the patient s medical care or poses a risk to the patient s safety, symptomatic treatment with antipsychotic agents may be helpful. Haloperidol is a classic drug with the longest clinical experience and is quite effective; it can be given intravenously at 0.5 to 1.0 mg per dose, but limit to a total of 5 mg/day to avoid extrapyramidal side effects. Newer agents such as quetiapine, olanzapine, ziprasidone, and risperidone have been found to be as effective as haloperidol with fewer side effects. 2,6,8 Benzodiazepines should be avoided because they can perpetuate the delirium, unless alcohol withdrawal is the underlying cause. 8 In summary, alterations in mentation after LT can have various causes that may overlap, and a search for the underlying cause is critical in the management. Consultation with a neurologist and a psychiatrist can be valuable when the underlying cause is not easily identified or in the multidisciplinary management of the patient. Symptomatic treatment of delirium while addressing the root cause can improve the medical care and safety of the patient. CORRESPONDENCE Helen S. Te, M.D., Center for Liver Diseases, University of Chicago Medicine, 5841 S. Maryland Ave., MC7120, Chicago, IL hte@medicine.bsd.uchicago.edu REFERENCES 1) Senzolo M, Ferronato C, Burra P. Neurologic complications after solid organ transplantation. Transpl Int 2009;22: ) Chavarria L, Cordoba J. Encephalopathy and liver transplantation. Metab Brain Dis 2013;28: CLINICAL LIVER DISEASE, VOL 10, NO 2, AUGUST 2017 An Official Learning Resource of AASLD

6 3) Kanwal F, Chen D, Ting L, Gornbein J, Saab S, et al. A model to predict the development of mental status changes of unclear cause after liver transplantation. Liver Transpl 2003;9: ) Shah M. Inpatient neurologic consultation in solid organ transplant patients. Semin Neurol 2015;35: ) Zivkovic SA. Neurologic complications after liver transplantation. World J Hepatol 2013;5: ) Pustavoitau A, Bhardwaj A, Stevens R. Neurological complications of transplantation. J Intensive Care Med 2011;26: ) Tan A, Florman SS, Schiano TD. Genetic, hematological, and immunological disorders transmissible with liver transplantation. Liver Transpl 2017;23: ) Dyrud J Jr. Posttransplantation delirium: a review. Curr Opin Organ Transplant 2004;9: CLINICAL LIVER DISEASE, VOL 10, NO 2, AUGUST 2017 An Official Learning Resource of AASLD