Handbook of Clinical Neurology, Vol. 120 (3rd series) Neurologic Aspects of Systemic Disease Part II Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 46

Neurotoxicity of commonly used hepatic drugs CHRISTINE L. AHRENS AND EDWARD M. MANNO* Neurological Intensive Care Unit, Cleveland Clinic, Cleveland, OH, USA

INTRODUCTION The increased need for and utility of organ transplantation including liver transplantation has increased the use of immunosuppressive agents to prevent rejection. Neurologic complications are common with many of these medications (Table 46.1). The neurologist, surgeon, or intensivist will often be confronted with a variety of these complications. Similarly, the use of interferons has improved the care of patients with hepatitis C and other hepatic infections. This chapter will review the medications used to treat hepatic infections and to prevent liver rejection posttransplantation. Neurologic complications commonly encountered will be emphasized.

CALCINEURIN INHIBITORS Calcineurin inhibitors are a class of immunosuppressant drugs that decrease lymphocytic proliferation through the inhibition of a phophatase calcineurin. The two commonly employed drugs are ciclosporin and tacrolimus (previously referred to as FK506). These drugs represent the mainstay of immunosuppression after orthotopic liver transplantation (OLT).

MECHANISM OF ACTION The lymphocytic response to an antigen is mediated through antigenic binding of the T-helper membrane receptor. This results in the opening of calcium channels which facilitates calcium influx into the cell. Intracellular calcium subsequently binds to calmodulin. This complex stimulates calcineurin (a phosphatase) which activates various transcription factors (primarily IL-2). These factors lead to a clonal expansion of new lymphocytes while inhibiting the apoptosis of existing lymphocytic lines.

This process of antigen-induced clonal expansion is inhibited by ciclosporin. Ciclosporin binds to a cytosolic protein named cyclophilin. This complex inhibits calcineurin-mediated activation of several transcriptases. Tacrolimus inhibits calcineurin through binding to FK-binding protein which in turn inhibits the function of calcineurin (Rang et al., 2003).

NEUROTOXICITY The range of neurologic signs and symptoms attributable to the use of calcineurin inhibitors is considerable. Symptoms can vary from mild headache, paresthesias, and confusion to psychosis and coma. Neurologic signs include tremor, visual disturbances, and seizures. Other reported neurologic complications include speech apraxia, cortical blindness, hemiparesis, parkinsonism, peripheral neuropathy, and ocular motor difficulties (Muellar et al., 1994; Wijdicks et al., 1994, 1995; Bechstein, 2000). The incidence of neurologic complications reported after liver transplantation ranges between 10% and 47% with most studies limiting the range between 20% and 30% (Saner et al., 2007, 2009, 2010). The exact incidence of side-effects attributable to calcineurin inhibitors is difficult to assess. Pre-existing or posttransplant encephalopathy can complicate the evaluation of immunosuppressant medications. Drug interactions with glucocorticoids can confuse which medication is the source of the problem. Other complications can include issues attributable to electrolyte disturbances, infections, sepsis, or sedative medications. Thus, neurotoxicity attributable to calcineurin inhibitors is often a diagnosis of exclusion (Bechstein, 2000). Neurotoxicity attributable to calcineurin inhibitors is often classified as mild, moderate, or severe. The most common side-effect is tremor, seen in up to 40% of

*Correspondence to: Edward M. Manno, M.D., Head, Neurocritical Care, Cleveland Clinic, 9500 Euclid Ave, HB-105, Cleveland, OH 44195, USA. Tel: þ1-216-445-1624, E-mail: [email protected]



Table 46.1 Potential central nervous system adverse effects of immunosuppresent medications Medication Immunosuppressants Calcineurin inhibitors (ciclosporin, tacrolimus) Sirolimus Mycophenolate mofetil Antihepatitis therapies Interferons Ribavirin Lamivudine Adefovir dipivoxil Entecavir Telbivudine

Central nervous system adverse effects

Headache, paresthesias, confusion, tremor, visual disturbances, apraxia, parkinsonism, peripheral neuropathy, ocular motor difficulties, psychosis, coma seizures, hemiparesis, cortical blindness, leukoencephalopathy Headache, arthralgias, insomnia, dizziness, neuropathy, confusion, abnormal vision, leukoencephalopathy (rare) Headache, insomnia, dizziness, anxiety, pain, psychosis, seizure Depression, asthenia, myalgia, psychosis, insomnia, irritability Headache, fatigue Headache, fatigue, insomnia, neuropathy Headache, asthenia Headache, fatigue, dizziness Headache, dizziness, insomnia, peripheral neuropathy (occurs in combination with pegylated interferon (peg-IFN))

patients. This can resolve spontaneously but usually requires dose reduction. Paresthesias can respond similarly to dose adjustments. Headache, neuralgia, and peripheral neuropathies are also quite common. Severe complications such as psychosis, coma or a leukoencephalopathy occur in approximately 5% of patients and may not be amenable to dose reduction or discontinuation of the calcineurin inhibitor (Bechstein, 2000; Saner et al., 2009).

MECHANISM OF NEUROTOXICITY The mechanism of neurologic cellular dysfunction after the initiation of calcineurin inhibitors is not completely understood. There are, however, several observations and findings that are common to both tacrolimus and ciclosporin toxicity. Both animal models and clinical studies suggest that calcineurin inhibitors increase sympathetic outflow and nerve activity (Scherrer et al., 1990; Lyson et al., 1993). The exact localization of this process is unknown but probably involves both central and peripheral mechanisms (Sander et al., 1996; Bechstein, 2000). Increased sympathetic activity may also be modulated through both pre- and postsynaptic effects on excitatory and inhibitory amino acid receptors. Ciclosporin may decrease GABA-mediated inhibition. In rat brain slice models a ciclosporin–cyclophilin complex can desensitize GABA receptors (Martina et al., 1996). Similarly, tacrolimus has been shown to increase NMDA-induced transmitter release (Lu et al., 1996). Calcineurin inhibition may also be selectively toxic to white matter. In vitro studies of cells incubated with ciclosporin suggest selective toxicity of glial cells

(Stoltenburg-Didinger and Boegner, 1992). Similarly, ciclosporin induces apoptosis in oligodendrocytes (McDonald et al., 1996). Cell lines with the highest density of calcineurin appear to be most affected. These effects increase with the length of exposure, possibly accounting for the delayed development of a leukoencephalopathy seen in some patients (Bechstein, 2000). The white matter changes commonly seen on computed tomography (CT) and magnetic resonance imaging (MRI) may represent vascular injury. Ciclosporin and tacrolimus induced white matter changes on MRI, typically in the occipital white matter and border zone areas similar to those areas encountered during hypoperfusion (Bartynski et al., 1994). Tacrolimus can also affect the thalami and produce vascular injury in animal models (Frank et al., 1993). Patients after liver transplant will develop cortical hyperintensities involving the cingulate gyrus and the occipital lobes noted on proton density-weighted imaging (Jansen et al., 1996). This may represent ciclosporin-induced changes to the vascular basement membrane (Sloane et al., 1985).

SPECIFIC COMPLICATIONS Mild symptoms of calcineurin inhibition include tremor, sleep disturbances, mood alterations, headaches, and confusion. These are commonly encountered and may even have a higher incidence than reported if a thorough neurologic and mental status examination is performed. Moderate and severe symptoms of cortical blindness, seizures, coma, and encephalopathy are found in a smaller percentage of patients and may be more common with tacrolimus (Muellar et al., 1994). The incidence of

NEUROTOXICITY OF COMMONLY USED HEPATIC DRUGS these complications appears to be higher for liver transplantation compared to other solid organ transplants (Muellar et al., 1994) and may be related to high plasma concentration of tacrolimus. The leukoencephalopathy encountered with calcineurin use is difficult to predict or characterize. Clearly white matter tracts are involved as central pontine myelinolysis can occur with devastating effects (Saner et al., 2007). Calcineurin effects on MRI can occur early but also in a delayed fashion after several weeks or months (Saner et al., 2009). Interestingly, MRI changes in white matter do not necessarily correlate with neurologic symptoms (Wijdicks et al., 1995). Seizures are seen most commonly immediately posttransplant. Early studies had suggested that calcineurin inhibition-induced seizures had a poor outcome (Adams et al., 1987; Estol et al., 1989). Wijdicks, however, in a retrospective analysis of post liver transplant patients, suggested that this may not be accurate. In the Mayo series, most seizures occurred during the time of initiation or adjustment of ciclosporin or tacrolimus. All patients had supratherapeutic levels and did not have further seizures with dose reduction (Wijdicks et al., 1996). Hypertension has been shown to be an independent risk factor for developing seizures post-transplant (Erer et al., 1996), and seizures may be associated with hypomagnesemia (Thompson et al., 1989). The significance of calcineurin-induced neurotoxicity post liver transplant is unclear. Mild symptoms probably have little significance; however, older literature has suggested that patients with late onset or severe neurologic complications have worse outcome (Wszolek et al., 1991; Muellar et al., 1994). It is difficult, however, to discern if late neurologic complications are due to calcineurin inhibitors or a late complication of a failing transplant (Bechstein, 2000). There are a number of predisposing factors that can increase the risk to post-transplant patients of calcineurin inhibition toxicity. Liver failure can lead to blood–brain barrier disruption and increased access of ciclosporin and tacrolimus to the brain (Freise et al., 1993). Intravenous administration of drug, concurrent use of prednisone, and hypocholesterolemia can increase the total and unbound level of calcineurin inhibitors, thus increasing brain uptake of the drug used (Freise et al., 1991, 1993; Bechstein, 2000).

TREATMENT OF COMPLICATIONS The correlation between neurotoxicity and calcineurin inhibitor drug levels is weak and routine monitoring of drug levels is usually not indicated. A simple dose response relationship does not exist and discontinuation


of drug does not always reverse symptomatology. Severe toxicity, however, does occur with higher drug levels. Toxicity may be mediated through ciclosporin and tacrolimus metabolites which can cross the blood– brain barrier. Impaired hepatic function can also increase these metabolites. Monitoring of these metabolites to assess for neurotoxicity has been suggested but has not gained wide acceptance (Trull et al., 1989). In some instances maneuvers designed to decrease drug levels can help with symptomatology. These can include lowering the dose, switching to oral therapy (Wijdicks et al., 1999), or treating renal failure. Lipid supplementation with soybean oil has been used in five patients post liver transplant to prevent lipophillic calcineurin inhibtors from crossing the blood–brain barrier (Ide et al., 2007). Several antibiotics can have drug interactions which can increase ciclosporin or tacrolimus levels. The use of combined immunosuppressant regimens can be used to lower the levels of any individual drug (Bechstein, 2000). Treatment of post liver transplant hypertension is important to decrease the incidence of neurologic complications. Drug-induced blood–brain barrier and vascular membrane disruption may impair cerebral autoregulation rendering the brain susceptible to a form of malignant hypertension. This may account for the MRI changes commonly encountered which resemble the posterior reversible encephalopathy syndrome (PRES). Seizure control post liver transplant can be difficult. Management involves dose reduction and the initiation of anticonvulsants. Phenytoin, phenobarbital, and carbamazepine will decrease ciclosporin levels. Valproate or levetiracetam may be preferred. Levetiracetam dosing will need to be adjusted based on renal function. Early post-transplant seizures do not appear to affect long-term outcome; however, status epilepticus and epiletiform activity on EEG monitoring has an ominous prognosis (Wszolek et al., 1991; Wijdicks et al., 1996).

OTHER MEDICATIONS USED FOR IMMUNOSUPPRESION AFTER ORTHOTOPIC LIVER TRANSPLANTATION Sirolimus Sirolimus is the generic name for a drug also known as rapamycin. It has a similar mechanism of action to tacrolimus in that sirolimus binds to the intracellular FK-12 protein but inhibits a regulatory kinase (mTOR) which leads to the suppression of T cell proliferation. No evidence of direct central neurotoxicity could be attributed to sirolimus use in a review of over 200 transplant patients (Maramattom and Wijdicks, 2004). A demyelinating



sensorimotor polyneuropathy, however, has been described (Bilodeau et al., 2008).

Mycophenolate mofetil (CellCept) Mycophenolate mofetil is a prodrug which is hydrolyzed to mycophenolic acid. Mycophenolic acid is a noncompetitive inhibitor of inosine monophosphate dehydrogenase, an enzyme required for B and T cell proliferation (Krensky et al., 2006). The toxicity for this drug is primarily GI and hematopoietic. Use can lead to hyperlipidemia, thrombocytopenia, and leukopenia. Levels can be increased with ingestion of grapefruit juice. A review of 191 liver transplant patients treated with mycophenolate did not report any neurologic complications (Pfitzmann et al., 2003). Mycophenolate has been used for rescue therapy in patients that have developed neurotoxicty from calcineurin inhibitors (Klupp et al., 1997). Two studies have suggested that mycophenolate is a safe and useful adjuvant for immunosuppression in post liver transplant patients (Freise et al., 1993; Klupp et al., 1997).

INTERFERONS, RIBAVIRIN AND NUCLEOSIDE AND NUCLEOTIDE ANALOGS USED IN THE TREATMENT OF HEPATITIS B AND C VIRUS There are a select number of medications available for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) (Lok and McMahon, 2009). Interferons, ribavirin, lamivudine, entecavir, tenofovir, telbivudine, and adefovir make up the armamentarium of commonly used antivirals considered in the treatment of hepatitis. Interferon monotherapy or in combination with ribavirin are the recommended medications for the treatment of chronic hepatitis C virus (HCV). Not all patients with HBV and/or HCV receive pharmacologic treatment. However, for those appropriately selected candidates who do, there exists a potential for adverse effects related to these therapies. Particular adverse events to some of these therapies are the primary reason patients discontinue therapy. Understanding the potential for these effects to occur and patient counseling may reduce discontinuation or denial of therapy (Ghany et al., 2009).

Interferons Interferons (INF) are a class of cytokines which have antiviral, immunomodulating, and antiproliferative effects (Lok and McMahon, 2009). Three classes of human IFNs exist (a, b, and g) with significant antiviral activity; however, only recombinant a and b IFNs are clinically utilized. Standard IFNs were first available for the treatment of HBV and HCV but have been

replaced by the newer pegylated interferons (peg-IFN). Certain advantages exist with peg-IFNs compared to the standard formulations, including a reduction in the severity of side-effects. Commercially available IFNs used in the treatment of HBV are standard IFN-a2b (Intron®A) and peg-IFN-a2a (PEGASYS®) and IFN-a 2b, peg-IFN-a2a, peg-IFN-a2b (PegIntron®), and IFN alfacon-1 (Infergen®).

MECHANISM OF ACTION IFNs activate the JAK-STAT signal-transduction pathway on the surface of target cells leading to nuclear translocation of a cellular protein complex that binds to genes containing an IFN-specific response element. This leads to synthesis of over two dozen proteins that contribute to viral resistance mediated at a different stage of viral penetration. IFN-induced proteins can inhibit protein synthesis in the presence of double-stranded RNA. IFN also induces a phosphodiesterase which cleaves a portion of transfer RNA thus preventing peptide elongation. IFNs may modify the immune response to infection as well through enhancement of the lytic effects of cytotoxic T lymphocytes (Pegasys, 2011).

NEUROTOXICITY Pegylated interferons have several, undesirable adverse effects. Nearly every patient treated with the combination therapy (peginterferon and ribavirin) will experience one or more adverse effects, potentially resulting in discontinuation of therapy. The two most common adverse effects are influenza-like symptoms (fatigue, headache, fever, rigors), asthenia, myalgia, and psychiatric effects, specifically depression, irritability, and insomnia. The incidence of depression is approximately 30% and occurs typically in the first few months of therapy (Lok and McMahon, 2009). An exact causative mechanism for interferon-induced depression has not been fully elucidated. Risk factors linked to the development of depression include a premorbid presence of mood and anxiety symptoms. To a lesser extent, history of depression, higher doses of interferon, and female gender are also considered risk factors. Two syndromes describe interferon-induced depression: a depression-specific syndrome characterized by mood, anxiety, and cognitive complaints and a neurovegetative syndrome characterized by fatigue, anorexia, pain, and psychomotor slowing. Preassessment for neuropsychiatric conditions should be completed prior to initiating interferon therapy. Selective serotonin reuptake inhibitors (SSRIs) have been studied in both prevention and treatment of symptoms associated with depression-specific syndromes. Some centers

NEUROTOXICITY OF COMMONLY USED HEPATIC DRUGS have a low threshold for initiating SSRIs, even prior to interferon therapy. While debatable, consideration of prophylactic antidepressants use should be given for patients with risk factors for the development of depression. Use of certain antidepressants (citalopram, fluoxetine, imipramine, nortriptyline, paroxetine, sertraline) has over an 85% success rate in treating interferon-induced depression. Consideration should be given to which antidepressant to use, based on the particular adverse effects of these agents (Lok and McMahon, 2009).

Ribavirin Ribavirin is indicated for the treatment of chronic hepatitis C in combination with interferon a-2B (pegylated and nonpegylated) in patients with compensated liver disease. (Rebetol®, 2013) (ribavirin) monotherapy is not effective for the treatment of hepatitis C (37).

MECHANISM OF ACTION Ribavirin is a neucleoside analog and has antiviral activity against multiple RNA viruses. However, its mechanism in the treatment of hepatitis C has not been fully elucidated. It is proposed that ribavirin has effects on the host immune response (Lau et al., 2002).

NEUROTOXICITY The most concerning adverse effect associated with ribavirin use is hemolytic anemia. Other adverse effects include fatigue, leukopenia, pruritis, rash, and gout. Ribavirin is a well known teratogenic drug and is US Food and Drug Administration (FDA) pregnancy category X. Clear recommendations on use in women of childbearing age are outlined within the prescribing information (Epivir-HBV, 2011).

Lamivudine ®

Lamivudine (Epivir-HBV ) is approved for the treatment of chronic hepatitis B and may be considered as initial therapy for patients with compensated liver disease. This indication is supported by 1 year data of histologic and serologic responses in adult patients. Advantages of this therapy over IFN-a or adefovir as first line include lower cost and tolerability. Disadvantages are the potential for increased resistance and worsening of hepatic disease.

MECHANISM OF ACTION Lamivudine is a synthetic nucleoside analog and is incorporated into viral DNA by HBV polymerase resulting in premature DNA termination (Lau et al., 2002).


NEUROTOXICITY Lamivudine is generally well tolerated. A black box warning within the prescribing information states lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Female gender, obesity, pregnancy, and prolonged exposure may increase the risk of these occurring. While these adverse effects are rare, there should be heightened consideration of encephalopathy related to these metabolic processes in critically ill patients presenting on lamivudine. In addition, severe acute exacerbations of hepatitis B have been reported in patients who have discontinued antihepatitis B therapy, including Epivir-HBV®. Less severe CNS effects include headache (21%), fatigue and malaise (24%), and insomnia (11%). Musculoskeletal pain (12%), neuropathy (12%), and myalgias (8–14%) also commonly occurred. In clinical trials of lamivudine for HBV, increases in creatine kinase levels were observed in 9% of patients (Lau et al., 2002; Lai et al., 2006).

Adefovir dipivoxil (Hepsera®) Adefovir dipivoxil is a prodrug of adefovir, a nucleotide analog of adenosine monophosphate. Hepsera® is approved for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases or histologically active disease (Hepsera, 2009).

MECHANISM OF ACTION Adefovir is phosphorylated to its active metabolite, adefovir diphosphate, which inhibits HBV DNA polymerase resulting in inhibition of viral replication.

NEUROTOXICITY Adefovir has multiple black box warnings within its prescribing information, including lactic acidosis and severe hepatomegaly with steatosis; severe, acute exacerbation of hepatitis B upon discontinuation; and cautious use in patients with renal dysfunction since chronic administration may result in nephrotoxicity. CNS toxicities associated with adefovir are minimal. In clinical studies adefovir had a similar side-effect profile to placebo. More commonly occurring central nervous system effects are headache (25%) and asthenia (13%). These adverse effects, however, have not been reported to significantly result in discontinuation of patient therapy. If patients experience headache, it is recommended they consult their healthcare provider for appropriate selection of analgesic therapy (Hadziyannis et al., 2003; Marcellin et al., 2003).



Entecavir (Baraclude®) Entecavir is approved for the treatment of hepatitis B infection with compensated or decompensated liver disease in adults with evidence of active viral replication and either evidence of persistent transaminase elevations or histologically active disease. Entecavir can also be used for patients with lamivudine-resistant viremia. Adjustment in dosing should be considered for patients with CrCl < 50 mL/min (Baraclude, 2010).

MECHANISM OF ACTION Entecavir is a guanosine nucleoside analog. Intracellularly it is phosphorylated to guanosine triphosphate which competes with natural substrates to inhibit HBV reverse transcriptase in three activities: (1) base priming, (2) reverse transcription of the negative strand DNA from the pregenomic messenger RNA, (3) synthesis of the positive strand of HBV DNA (Baraclude, 2010).

NEUROTOXICITY The adverse effect profile of entecavir is similar to lamivudine, including the same black box warnings (Sherman et al., 2006; Baraclude, 2010). Common CNS effects include pyrexia (14% with decompenstated liver disease), headache (2–4%), fatigue (1–3%), and dizziness. In preclinical animal trials, there was a higher incidence of solid tumors with high-dose, prolonged administration of entecavir (Baraclude, 2010). Studies are ongoing to evaluate long-term treatment effects with entecavir.

Telbivudine (Tyzeka®) Telbivudine is indicated for the treatment of chronic HBV in adult patients. It is well tolerated and has been shown to be more efficacious compared to lamivudine and adefovir in treating compensated chronic HBV (Chan et al., 2007; Lai et al., 2007; Liaw et al., 2009). Its use in special populations, such as patients with renal insufficiency, has not been reported.

MECHANISM OF ACTION Telbivudine is a synthetic thymidine nucleoside analog reverse transcriptase inhibitor. Intracellularly it is phosphorylated to its active triphosphate form which competes with naturally occurring thymidine triphosphate for HBV viral DNA elongation. This incorporation into viral DNA results in DNA chain termination (Bryant et al., 2001).

NEUROTOXICITY The same boxed warning which exists for other nucleoside analogs is included in the prescribing information

for telbivudine. In clinical trials comparing telbivudine to lamivudine, side-effects were similar with the exception of increased creatinine kinase levels in the telbivudine patients (Liaw et al., 2009). During these trials, the most commonly occurring neurologic adverse effects seem with telbivudine included headache (10%), dizziness (4%), and insomnia (3%) (Baraclude, 2010). Peripheral neuropathy has been reported with telbivudine either as monotherapy (

Neurotoxicity of commonly used hepatic drugs.

Neurologic complications are common side-effects of immunosuppressive medications used in the prevention of graft rejection after organ transplantatio...
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