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Neurological complications after orthotopic liver transplantation
Digestive and Liver Disease 39 (2007) 740–747
Liver, Pancreas and Biliary Tract
Neurological complications after orthotopic liver transplantation P. Amodio a,∗ , A. Biancardi a , S. Montagnese a , P. Angeli a , P. Iannizzi a , U. Cillo b , D. D’Amico b , A. Gatta a a
Clinical Medicine 5 and Veneto Regional Reference Centre for Hepatic Diseases, University of Padova, Padova, Italy b Clinical Surgery I, Transplant Centre, University of Padova, Padova, Italy Received 13 November 2006; accepted 8 May 2007 Available online 3 July 2007
Abstract Background. The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. Aim. To review present knowledge on the neurological complications of orthotopic liver transplantation. Methods. The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. Results and conclusions. The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Encephalopathy; Immunosuppressants; Liver cirrhosis; Liver transplantation; Neurological complication; Neurotoxicity; OLTx
1. Introduction Orthotopic liver transplantation (OLTx) is the only radical treatment for end-stage liver disease. Due to increased safety and logistic facilities, the number of transplanted patients is continuously increasing. In Italy, 744 OLTx were performed between 1992 and 1994 and this number increased to 2161 between 2000 and 2002, with a 1-year survival rate of about 84.1% (Italian National Transplant Center: http://www.ministerosalute.it/trapianti). The increased frequency of this procedure justifies a great effort to reduce post-transplant complications, since these may impinge on both survival and quality of life. Of all the complications of OLTx, the neurological ones are particularly relevant, since
∗ Corresponding author at: Clinical Medicine 5, Via Giustiniani 2, 35128 Padova, Italy. Tel.: +39 049 8218677; fax: +39 049 8754179. E-mail address: [email protected] (P. Amodio).
they affect up to a third of transplanted patients, causing significant mortality and morbidity [1]. Nonetheless, they are often neglected in routine clinical practice. Herein, we provide a short, schematic characterization of the neurological complications of OLTx in order to increase the insight of the clinical hepatologist in this field. 2. Epidemiology Studies pertaining the neurological complications of OLTx in human adults were searched within two on-line databases (Medline, Embase) in the period 1988–2005, using the key words ‘liver transplantation and neuropsychiatric effects’, ‘calcineurin inhibitors and side effects’, ‘calcineurin inhibitors and pharmacokinetic and pharmacodynamic mechanism’. Further information was obtained by references of the published papers dealing with transplant complications. Only articles in English or Italian were considered.
1590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2007.05.004
P. Amodio et al. / Digestive and Liver Disease 39 (2007) 740–747 Table 1 Prevalence of neurological complications after OLTx Patients examined (n) Adams et al. [2] Burkhalter et al. [3] Guarino [4] Casanova [5] Bronster et al. [6] Lewis and Howdle [7] Wijdicks et al. [8] Fryer et al. [9] Yu et al. [10] Saner et al. [11] Total
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Table 2 Neurological complications of OLTx Prevalence
Minor complications
Major complications
52 100 114 126 464 627 430 44 142 168
33 (CI95% : 20–47) 34 (CI95% : 25–44) 42 (CI95% : 34–51) 39 (CI95% : 30–47) 20 (CI95% : 16–24) 27 (CI95% : 24–31) 11 (CI95% : 8–14) 25 (CI95% : 13–40) 41 (CI95% : 33–49) 27 (CI95% : 21–34)
Tremors Headache Sleep disorders Mood alterations Sensory peripheral neuropathy
Seizures Cerebellar syndromes Posterior leukoencephalopathy Central pontine myelinolysis Vegetative state
1957
25 (CI95% : 23–27)
Six hundred and forty papers were retrieved; 57 of these were strictly pertinent to the topic and freely available from our library. These were finally considered for this review. The overall prevalence of neurological symptoms or disorders after OLTx ranges from 11 to 42% and their aggregate prevalence is 25% (CI95% : 23–27) (Table 1). Interestingly, such prevalence far exceeds that of other transplanted organs, such as kidney (0.5%) and heart (3.6%) [12–14]. The reasons why liver transplant is associated with such a high risk of neurological complications is reasonably ascribable to (i) the complexity of the surgical procedure, (ii) the unfavourable clinical conditions of the patients awaiting transplantation (malnutrition, coagulopathy, low platelet count) and (iii) hepatic encephalopathy [6,15]. This can be inferred from the observation that a transplantation time longer than 10 h is a risk factor for the occurrence of neurological complications (OR = 2.6; p = 0.04), as well as a high Child-Pugh score before OLTx (Child B versus Child A: OR = 2.4, p = ns; Child C versus Child A: OR = 8.7, p = 0.006) [4] and clinical history of overt hepatic encephalopathy (OR = 2.4, p = 0.05) [4,16]. The neurological complications of OLTx can greatly reduce patients’ compliance to immunosuppressive therapy and, therefore, increase the risk of rejection [17,18]. Patients with neuropsychiatric complications of OLTx show a high mortality rate, especially when the complications occur in the first period after transplantation [4,15]. In addition, patients with neurological complications have longer hospitalization [3,10,19], higher need of re-transplation [3,7], more infections [5,7], lower self-sufficiency and social reintegration [20] than patients without neurological complications.
3. Clinical features The neurological complications usually occur in the first period (1–3 months) after OLTx [2,15,17,21–23] and are associated with significant mortality and morbidity [1]. Neurological complications after OLTx can be classified into minor and major complications (Table 2), on the basis of clinical findings and severity [24]. Minor complications usu-
Flaccid paralysis Consciousness alterations Toxic-metabolic encephalopathy with or without psychorganic syndromes
ally disappear spontaneously and, therefore, treatment, if any, is merely symptomatic. Their prognosis is good. In contrast, major complications usually have ominous consequences. 3.1. Minor complications 3.1.1. Tremor Tremor frequently appears after OLTx and its features resemble those of tremor due to sleep deprivation, stress or exciting substances. It is more intentional than postural and causes rhythmic oscillations of a frequency of about 10 Hz and an amplitude which is generally lower than 2.5 cm. However, in severe cases, the oscillations may exceed 2.5 cm. It is related to immunosuppressive drugs and can be treated both by modifying the immunosuppressive regime or by betablockers [5,7,15,23,25,26]. 3.1.2. Headache Headache is usually frontal, pulsing or continuous and it seldom has the features of migraine. During the first few weeks after transplantation, it can be due to fever, systemic hypertension or immunosuppressive treatment (vasomotor effect of calcineurin inhibitors). The possibility of brain haemorrhage, ischaemic stroke, meningitis or meningoencephalitis also needs to be considered. 3.1.3. Sleep disorders Sleep disorders usually occur in the first period after OLTx. They are characterized by difficulties in falling asleep and by vivid nightmares [25]. Their prevalence is about 27.4%, but only 2.7% are considered to be severe [25]. 3.1.4. Peripheral neuropathy Peripheral nervous system disorders may cause paraesthesia, dysaesthesia, burning sensation in hands or feet, lack of strength and hyporeflexia. Peripheral neuropathy is frequently due to pressure or traction of nervous plexuses and, therefore, is more frequent in transplanted patients with a prolonged operative course. Peripheral nerve damage has been reported only anecdotally in other types of transplant, whereas in OLTx series its prevalence is relevant, possibly because the operative and peri-operative phases of liver transplantation are the most demanding. The femoral nerve can be damaged by the occurrence of lymphocele due to lymphatic
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vessels damage which, in turn, can be caused by the large tube used for veno-venous bypass [27]. Infectious radiculopathy due to Herpes zoster, favoured by immunosuppression, can result in thoracic or cervical radiculitis. Immunomediated polyneuropathy or polyneuropathy related to drug side effects may also occur. Polyneuropathy can cause difficulties in weaning from artificial breathing [4,5,26,28]. 3.2. Restless leg syndrome Restless legs syndrome is reported in 4.3% of the patients after OLTx [5]. It is an overwhelming urge to move the legs, usually caused by an uncomfortable or unpleasant sensation within the legs themselves. The sensation has the following features: it occurs during periods of inactivity, becomes more obvious in the evening and at night, is relieved by movement of the limb, often causes difficulties in falling or remaining asleep, and may cause involuntary jerking of the limbs during sleep and sometimes also during wakefulness. 3.3. Major complications 3.3.1. Seizures Seizures are the second most common neurological complication reported after OLTx [7,10,29,30]. Seizures can be partial or generalized, most frequently of the tonic-clonic type. They can occur with or without MRI-detectable structural brain lesions and with or without EEG alterations within the inter-critical period. Immediately after OLTx, their prevalence may reach 10–40% [2,19,29,31,32], later their prevalence decreases to about 10% [30]. Seizures are likely to be due to immunosuppressors neurotoxicity, rapid electrolytes or osmolar changes, ischaemic brain lesions and demyelinization of any origin. Seizures can be isolated or be a sign of encephalopathy [5,7,23,25,26]. Usually, epilepsy after OLTx is self-limiting, but some patients may also develop severe treatment-resistant epilepsy [15,17]. The incidence of seizures after OLTx has declined in recent years, possibly because of the remarkable improvement in the management of the multiple metabolic and toxic abnormalities that may predispose to seizures. In addition, most transplant centres now avoid intravenous cyclosporine loading and both the use of tacrolimus and the monitoring of its plasma levels may have contributed to the decreasing rate of seizures [11]. 3.3.2. Cerebellar syndrome The disorder is heralded by headache, nausea, dizziness, emesis, encephalopathy, nystagmus and ataxia. Later, rigor nucalis may occur. Neuroimaging studies show cerebral ventricular widening and cerebral oedema. Histology shows unspecific oedema and loss of Purkinje cells. Pathophysiological mechanisms are not completely understood, but calcineurin inhibitors seem to be implicated. In particular, cerebellar syndrome seems associated with cyclosporine treatment [26].
3.3.3. Posterior leukoencephalopathy Posterior leukoencephalopathy is a severe but, as a rule, reversible syndrome, presenting with nausea, emesis, headache, fever and loss of vision. Visual hallucinations, cortical blindness, occipital headache, seizures and consciousness disorders can also occur. Cerebral MRI shows occipital and parietal extra-pontine demyelinization (due to reactive astrocytosis and a neuronal loss), which is likely to be due to calcineurin inhibitors. Such relationship is inferred from the observation that demyelinization occurs in patients treated with cyclosporine and tacrolimus, but not in those treated with other immunosuppressants. The pathophysiology of posterior leukoencephalopathy is related to brain perfusion alterations, due to vasoconstriction [14,33], rather than to a direct toxic effect of calcineurin immunosuppressants [5,17,23,26,34–36]. Likewise, the spontaneous resolution of the syndrome is probably related to a spontaneous reduction of the haemodynamic alterations. 3.3.4. Central pontine melinolysis syndrome Fluctuating levels of consciousness, convulsions, hypoventilation or hypotension may herald the onset of this syndrome. Eventually, pseudobulbar palsy and quariparesis may develop. Swallowing dysfunction (often with episodes of aspiration) and inability to speak may be the dominant clinical features. In severe cases, the patient may develop a ‘locked-in syndrome’: they are awake but unable to move or communicate. Although these symptoms are potentially reversible, central pontine myelinolysis is one of the most severe neurological complications of OLTx. It has been detected in about 10–30% of patients who died after liver transplantation at the beginning of the liver transplant era [31,37,38]. Now its frequency after transplant is about 2–3.5% [7,10]. It is characterized by symmetrical loss of myelin in the base of the pons, with relatively well-preserved axons and neuronal cell bodies [10,39]. Myelinolytic foci can be also found out of the area of the pons [40]. The most common, albeit not unique, cause of central pontine myelinolysis is a rapid correction of prolonged hyponatremia [9,40]. Prolonged chronic liver failure can limit the production of idiogenic osmoles needed to protect the brain during rapid osmolar shifts [15,38,41]. 3.3.5. Focal neurological deficits Focal neurological deficits usually cause muscular weakness with preserved sensitivity. Palpebral ptosis and dysarthria are the most frequent forms of focal deficit, which results from damage of the cortex or the underlying white matter within motor pathways, generally due to ischaemia and/or immunosuppressors neurotoxicity [6,22,26]. 3.3.6. Vegetative state In this syndrome, patients appear alert, but they make no attempt to communicate and eye contact is also absent. They do not have emotional reactions, even though painful stimuli may evoke facial grimacing and posturing of the
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extremities. Frontal release signs can occur. The pathophysiology of this condition is largely unknown, but it may be due to damage or dysfunction of the dopaminergic mesencephalic-frontal pathways. Reversibility with interruption of calcineurin immunosuppressors has been reported, suggesting a relationship with drug neurotoxicity [6,23,26]. 3.3.7. Metabolic and toxic encephalopathies Metabolic encephalopathy is multifactorial in nature and can be related to drugs (immunosuppresants in particular), electrolyte and osmotic disorders, systemic inflammation, infections, disturbance of energy metabolism and pH. Prolonged liver failure and persistent hepatic encephalopathy might represent risk factors. Metabolic encephalopaties may affect up to 11.8% patients after OLTx [5,15,21,23]; obviously, encephalitis has to be ruled out. Clinical signs are sleep disorders, apathy, disorientation in space and time, delirium, acute psychotic episodes with agitation, crying, repetition of illogical sentences, rambling speech, confusion, dysperceptive disorders (illusions or hallucinations both acoustic and visual, the latter characterized by bright flashing colours), autonomic dysfunction [8,42,43]. The syndrome can evolve to stupor and coma and seizures can occur. Acute psychotic reactions were reported in 43% of patients treated with high doses of cyclosporine after transplantation [8,43]. Symptoms reversed after reduction or discontinuation of cyclosporine.
4. Pathophysiology Metabolic and electrolyte disturbances, cardiovascular events, infections, acute draft rejection and immunosuppressant therapy are at the basis of OLTx-related brain dysfunction [8,17,22,44,45]. 4.1. Metabolic complications Primary non-functioning of the graft, rejection and multiorgan failure are the most common disorders at the basis of metabolic dysfunction. Disorders of electrolytic balance, like hypo- or hypernatremia and hypomagnesaemia, as well as hypo- and hyperglycaemia are also causes of central nervous system dysfunction [8,23].
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4.2.1. Cerebral ischaemia Brain hypoperfusion with ischaemia and hypoxia can be due to cerebral oedema and increased intracranial pressure in patients with severely compromised cerebral blood flow selfregulation [15,23]. In addition, cerebral ischaemia can be due to peri-operative detachment of arterial emboli from carotid or intracranial arteries, from endocarditis in post-OLTx or from mycotic arteritis (angioinvasive Aspergillosis) [2,15] or from paradoxical emboli of thrombotic material, originating from the deep leg or pelvic veins [29,49]. 4.2.2. Cerebral haemorrhage Subarachnoid, intracerebral or subdural haemorrhage can occur after liver transplantation. Cirrhotic patients who undergo OLTx are susceptible to these adverse events because of severe coagulopathy, thrombocaytopenia, blood loss and hypotension during transplantation followed by increased intracranial pressure after OLTx [1]. 4.2.3. Anterior spinal artery syndrome The classic anterior artery syndrome results in motor palsy, faecal and urinary incontinence, dissociated sensory loss of pain and temperature, with vibration and proprioceptive sparing below the lesion level [50,51]. This syndrome is due to the accidental damage of the great radicular artery of Adamkiewicz during liver explantation. Such lesion prevents blood supply to the anterior and lateral columns of the lower spinal cord, damaging them. 4.3. CNS infections Central nervous system infections are documented in 5–10% patients after OLTx. They are mainly due to opportunistic agents that, due to immunosuppression, can become fatal [6,23,52,55,57]. The diagnosis is often difficult because symptoms can be blunted by immunosuppressive therapy. The clinical syndromes include: • meningitis, meningo-encephalitis or encephalitis due to viruses (Herpes simplex virus or cytomegalovirus), bacteria or fungi and • focal deficits due to brain abscess, frequently caused by Aspergilla.
4.2. Cardiovascular events
4.4. CNS neoplasms
Profound cerebral and systemic haemodynamic alterations occur during the liver transplant procedure. The reperfusion of the transplanted liver is usually associated with a decrease in systemic arterial pressure and an increase in pulmonary pressure. Occasionally, reduced cardiac index, arrhythmias and right ventricular insufficiency may occur. Sudden changes of cerebral perfusion, favoured by disruption of cerebral blood flow autoregulation, can damage the brain during the transplantation procedure [24,46–48].
Organ transplant recipients have a three- to four-fold increase in the incidence of malignant diseases compared with the general population. The highest risk is for lymphoproliferative diseases. Due to immunosuppression, EBV infection can induce abnormal B-lymphocyte proliferation, which, eventually, can result in lymphoma. Lymphoma occurs in 3% of patients after OLTx, about 27% of the lymphomas concern CNS and meningi [15,23,53,56,58–60] in transplanted patients.
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4.5. Immunosuppressant neurotoxicity Neurotoxicity associated with cyclosporine or tacrolimus is a less common adverse effect than nephrotoxicity or hypertension; however, it can result in serious disease [17]. Immunosuppressant-related neurotoxicity can occur immediately after the transplant, due to the high doses of drugs needed to induce immunosuppression, or later, possibly due to a cumulative effect of the drugs. At any rate, the neurological toxicity of immunosuppressants is hardly correlated with their plasma levels. Sometimes, the relationship can be only indirectly inferred from the resolution of the clinical symptoms on treatment discontinuation [4,14,23]. Of all the immunosuppressant drugs used after liver transplantation, only mycophenolate mofetil does not have neurotoxic side effects, the major adverse effects of this drug being gastrointestinal and haematological [61–64]. In contrast, the other immunosuppressant drugs, i.e. corticosteroids, OKT3 and calcineurin inhibitors, do have remarkable neurotoxic potential. • Corticosteroids are associated with neuropsychiatric side effects in 3–4% of patients, the most common ones being: ◦ Mood changes and behavioural disorders including confusion, maniacal states, psychotic reactions [14,23,64] neuro-myopathy with muscular weakness affecting proximal and lower extremities [23,60]; ◦ Epidural lipomathosis causing radiculopathy due to spinal compression [65]. • OKT-3. The most common side effect of this murine monoclonal antibody directed against a T-cell surface molecular is a flu-like illness with headache and fever. The rare neurological side effects are: ◦ acute aseptic meningitis with headache, nucal rigidity and fever; cerebral fluid examination reveals a lymphocyte pleiocytosis; ◦ encephalopathy-like syndrome with impairment of consciousness, myoclonic activity and seizures. Cerebral oedema might be the underlying cause of this syndrome [23,26,66,67]. • Calcineurine inhibitors. The exact neurotoxic effect of these drugs is still unknown and the implicated target cells have not yet been clearly identified. ◦ Neurotoxicity may depend on the same mechanisms causing calcineurin inhibitors immunosuppressive action [34,68,69]. Both tacrolimus and cyclosporine bind to immunophillins which are low-molecularweight intracellular proteins facilitating protein folding, protein intracellular transport and the stability of multiprotein complexes. The high affinity binding of calcineurin inhibitors with immunophillins blocks calcineurin activity, which, in turn, inhibits calciumcalmodulin-dependent phosphatase activity and, by interacting with nuclear factors, inhibits interleukin2 gene transcription and, consequently, blunts the immune response. [26,57,58]. In addition, at least
as far as tacrolimus is concerned, the production of other cytokines (IL3, IL4, IFN-␥, GM-CSF, il TNF␣) [70,71], proto-oncogenes (ras, myc e ral) and the expression of the receptors for IL2 and IL7 are also reduced [72–74]. Calcineurin inhibitors might also block other important, albeit not yet elucidated, functions of calcineurin and immunophillins in the brain, causing neurotoxicity. Such hypothesis can be advanced because immunophillins reach very high levels in central nervous system cells (10 times higher than in white blood cells) [14,34,68,75]. An exception is provided by rapamicine, which, albeit structurally related to tacrolimus, binds to another site of immunophillins thus causing inhibition of mTOR instead of calcineurin. In turn, mTOR inhibition results in the arrest of cell cycle in G1 phase that does not cause neurotoxic effects [76–80]. ◦ Another neurotoxic mechanism is brain vessel vasoconstriction due to cyclosporine- and tacrolimus-induced reduction of brain NO. Severe vasoconstriction results from disturbance in endothelial control of vascular tone, leading to ischaemia [81,82]. Such a reduction is due the inhibition of calcineurin-mediated dephosforilation of calcium-dependent NO syntase [83]. Dephosphorilation is needed to revert Ca-dependent neuronal and endothelial NO syntase inhibition caused by phosphorilation. [84]. In addition, calcineurin inhibitors lower intracellular calcium, therefore reducing Cadependent NO synthase activity [85]. It is not yet clear if tacrolimus also enhances brain endotelin production, as it occurs in the kidney [84,86–89]. At any rate, the final effect of these events is vasoconstriction and microvascular damage of the nervous system and blood brain barrier. The sensitivity of various brain regions to vasoconstriction seems to be heterogeneous with a higher sensitivity of cerebral peduncle (causing visual disorders), motor cortex and Broca’s area [14,18,35,90,91]. ◦ Blood-brain barrier (BBB) alterations are reported to be caused by cyclosporine and tacrolimus: cellular apoptosis, vasoconstriction due to NO reduction, reduced expression of glycoprotein P, i.e. a ATPase transporter implicated in the export of toxic substances from the brain [69,81,92,93]. ◦ Selective toxic effect on oligodendrocytes. After having been cultured with cyclosporine, oligodendrocytes develop intracytoplasmic inclusions that have been identified as lysosomes containing neutral lipids [82,94]. Demyelization can eventually occur and it has a time course and a severity correlated with the length of cyclosporine exposure. Oligodendrocytes have a higher calcineurin content than astrocytes and, possibly for this reason, have a higher susceptibility to calcineurin-inhibitor-induced apoptosis than astrocytes [82]. At any rate, the time course and the reversibility of calcineurin-inhibitor-induced demyeli-
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nation suggest damage due to vasoconstriction (and, possibly, reperfusion with oxidative stress) rather than direct myelinolysis [14,18,34,54,95]. ◦ Interference with both excitatory and inhibitory amino-acid activity. The reduction of calcineurin phosphorilation has both presynaptic and postsynaptic effect on GABAergic neurotransmission and on neurotransmitter release induced by NMDA and depolarization [17,95–99]. In turn, the inhibition of NMDA-induced neurotransmitter release and long-term potentiation are involved in memory function [14,17,18,100]. In addition, tacrolimus-related inhibition of hippocampal neurons could be implicated in the pathophysiology of memory alterations and confusion [68,95]. Finally, the inhibition of GABAErgic tone may facilitate seizures [101], whereas alterations in serotoninergic neurotransmission may be implicated in the occurrence of tremor [102] and explain some forms of transplant delirium [14]. Conditions increasing the neurotoxic effects of immunosuppressant agents are pre-existing central nervous system damage and pre-existing BBB alterations causing toxic intracerebral drug levels [18,103], chronic hepatic encephalopathy, electrolyte disorders (hyper- and hyponatremia, hypomagnesaemia), dysmetabolic alterations (e.g., hyperglycaemia) and hypocholesterolemia, because it increases brain uptake of immunosuppressant drugs and drug interactions [7,18,26,88,103,104].
5. Conclusions The prevalence and the relevance of neurological complications after OLTx justify an accurate evaluation of the patients entering an OLTx programme, aiming at defining their base line conditions, so that even minor complications can be detected, properly characterized and appropriately managed. Such work-up requires highly integrated teems with interdisciplinary expertise.
Practice points • The baseline neurological and cognitive findings of patients entering an OLTx programme should be accurately checked, due to the high prevalence of neuropsychiatric complications after OLTx. • Behavioural and mood alterations in transplanted patients need immediate and accurate diagnosis by a highly integrated teem with interdisciplinary expertise.
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Research agenda • To compare sirolimus versus other calcineurin inhibitors in terms of long-term neurological sequelae of OLTx. • To improve the knowledge of the risk factors of neuropsychiatric complications of OLTx. and their management. • To improve the management of the neuropsychiatric complications of OLTx.
Conflict of interest statement None declared.
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Liver, Pancreas and Biliary Tract
Neurological complications after orthotopic liver transplantation P. Amodio a,∗ , A. Biancardi a , S. Montagnese a , P. Angeli a , P. Iannizzi a , U. Cillo b , D. D’Amico b , A. Gatta a a
Clinical Medicine 5 and Veneto Regional Reference Centre for Hepatic Diseases, University of Padova, Padova, Italy b Clinical Surgery I, Transplant Centre, University of Padova, Padova, Italy Received 13 November 2006; accepted 8 May 2007 Available online 3 July 2007
Abstract Background. The number of orthotopic liver transplantation performed each year is increasing due to increased safety and logistic facilities. Therefore, the importance of reducing adverse events is progressively growing. Aim. To review present knowledge on the neurological complications of orthotopic liver transplantation. Methods. The epidemiology, the clinical features and the pathophysiology of the neurological complications of orthotopic liver transplants, resulting from a systematic review of the literature in the last 25 years, are summarized. Results and conclusions. The review highlights that a relevant variety of neurological adverse events can occur in patients undergoing orthotopic liver transplantation. The knowledge of neurological complications of orthotopic liver transplantation is important for transplantation teams to reduce their prevalence and improve their management. In addition, the likelihood of neurological adverse effects provides evidence for the need of a careful cognitive and neurological work up of patients in the orthotopic liver transplantation waiting list, in order to recognize and interpret neurological dysfunction occurring after orthotopic liver transplantation. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Encephalopathy; Immunosuppressants; Liver cirrhosis; Liver transplantation; Neurological complication; Neurotoxicity; OLTx
1. Introduction Orthotopic liver transplantation (OLTx) is the only radical treatment for end-stage liver disease. Due to increased safety and logistic facilities, the number of transplanted patients is continuously increasing. In Italy, 744 OLTx were performed between 1992 and 1994 and this number increased to 2161 between 2000 and 2002, with a 1-year survival rate of about 84.1% (Italian National Transplant Center: http://www.ministerosalute.it/trapianti). The increased frequency of this procedure justifies a great effort to reduce post-transplant complications, since these may impinge on both survival and quality of life. Of all the complications of OLTx, the neurological ones are particularly relevant, since
∗ Corresponding author at: Clinical Medicine 5, Via Giustiniani 2, 35128 Padova, Italy. Tel.: +39 049 8218677; fax: +39 049 8754179. E-mail address: [email protected] (P. Amodio).
they affect up to a third of transplanted patients, causing significant mortality and morbidity [1]. Nonetheless, they are often neglected in routine clinical practice. Herein, we provide a short, schematic characterization of the neurological complications of OLTx in order to increase the insight of the clinical hepatologist in this field. 2. Epidemiology Studies pertaining the neurological complications of OLTx in human adults were searched within two on-line databases (Medline, Embase) in the period 1988–2005, using the key words ‘liver transplantation and neuropsychiatric effects’, ‘calcineurin inhibitors and side effects’, ‘calcineurin inhibitors and pharmacokinetic and pharmacodynamic mechanism’. Further information was obtained by references of the published papers dealing with transplant complications. Only articles in English or Italian were considered.
1590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2007.05.004
P. Amodio et al. / Digestive and Liver Disease 39 (2007) 740–747 Table 1 Prevalence of neurological complications after OLTx Patients examined (n) Adams et al. [2] Burkhalter et al. [3] Guarino [4] Casanova [5] Bronster et al. [6] Lewis and Howdle [7] Wijdicks et al. [8] Fryer et al. [9] Yu et al. [10] Saner et al. [11] Total
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Table 2 Neurological complications of OLTx Prevalence
Minor complications
Major complications
52 100 114 126 464 627 430 44 142 168
33 (CI95% : 20–47) 34 (CI95% : 25–44) 42 (CI95% : 34–51) 39 (CI95% : 30–47) 20 (CI95% : 16–24) 27 (CI95% : 24–31) 11 (CI95% : 8–14) 25 (CI95% : 13–40) 41 (CI95% : 33–49) 27 (CI95% : 21–34)
Tremors Headache Sleep disorders Mood alterations Sensory peripheral neuropathy
Seizures Cerebellar syndromes Posterior leukoencephalopathy Central pontine myelinolysis Vegetative state
1957
25 (CI95% : 23–27)
Six hundred and forty papers were retrieved; 57 of these were strictly pertinent to the topic and freely available from our library. These were finally considered for this review. The overall prevalence of neurological symptoms or disorders after OLTx ranges from 11 to 42% and their aggregate prevalence is 25% (CI95% : 23–27) (Table 1). Interestingly, such prevalence far exceeds that of other transplanted organs, such as kidney (0.5%) and heart (3.6%) [12–14]. The reasons why liver transplant is associated with such a high risk of neurological complications is reasonably ascribable to (i) the complexity of the surgical procedure, (ii) the unfavourable clinical conditions of the patients awaiting transplantation (malnutrition, coagulopathy, low platelet count) and (iii) hepatic encephalopathy [6,15]. This can be inferred from the observation that a transplantation time longer than 10 h is a risk factor for the occurrence of neurological complications (OR = 2.6; p = 0.04), as well as a high Child-Pugh score before OLTx (Child B versus Child A: OR = 2.4, p = ns; Child C versus Child A: OR = 8.7, p = 0.006) [4] and clinical history of overt hepatic encephalopathy (OR = 2.4, p = 0.05) [4,16]. The neurological complications of OLTx can greatly reduce patients’ compliance to immunosuppressive therapy and, therefore, increase the risk of rejection [17,18]. Patients with neuropsychiatric complications of OLTx show a high mortality rate, especially when the complications occur in the first period after transplantation [4,15]. In addition, patients with neurological complications have longer hospitalization [3,10,19], higher need of re-transplation [3,7], more infections [5,7], lower self-sufficiency and social reintegration [20] than patients without neurological complications.
3. Clinical features The neurological complications usually occur in the first period (1–3 months) after OLTx [2,15,17,21–23] and are associated with significant mortality and morbidity [1]. Neurological complications after OLTx can be classified into minor and major complications (Table 2), on the basis of clinical findings and severity [24]. Minor complications usu-
Flaccid paralysis Consciousness alterations Toxic-metabolic encephalopathy with or without psychorganic syndromes
ally disappear spontaneously and, therefore, treatment, if any, is merely symptomatic. Their prognosis is good. In contrast, major complications usually have ominous consequences. 3.1. Minor complications 3.1.1. Tremor Tremor frequently appears after OLTx and its features resemble those of tremor due to sleep deprivation, stress or exciting substances. It is more intentional than postural and causes rhythmic oscillations of a frequency of about 10 Hz and an amplitude which is generally lower than 2.5 cm. However, in severe cases, the oscillations may exceed 2.5 cm. It is related to immunosuppressive drugs and can be treated both by modifying the immunosuppressive regime or by betablockers [5,7,15,23,25,26]. 3.1.2. Headache Headache is usually frontal, pulsing or continuous and it seldom has the features of migraine. During the first few weeks after transplantation, it can be due to fever, systemic hypertension or immunosuppressive treatment (vasomotor effect of calcineurin inhibitors). The possibility of brain haemorrhage, ischaemic stroke, meningitis or meningoencephalitis also needs to be considered. 3.1.3. Sleep disorders Sleep disorders usually occur in the first period after OLTx. They are characterized by difficulties in falling asleep and by vivid nightmares [25]. Their prevalence is about 27.4%, but only 2.7% are considered to be severe [25]. 3.1.4. Peripheral neuropathy Peripheral nervous system disorders may cause paraesthesia, dysaesthesia, burning sensation in hands or feet, lack of strength and hyporeflexia. Peripheral neuropathy is frequently due to pressure or traction of nervous plexuses and, therefore, is more frequent in transplanted patients with a prolonged operative course. Peripheral nerve damage has been reported only anecdotally in other types of transplant, whereas in OLTx series its prevalence is relevant, possibly because the operative and peri-operative phases of liver transplantation are the most demanding. The femoral nerve can be damaged by the occurrence of lymphocele due to lymphatic
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vessels damage which, in turn, can be caused by the large tube used for veno-venous bypass [27]. Infectious radiculopathy due to Herpes zoster, favoured by immunosuppression, can result in thoracic or cervical radiculitis. Immunomediated polyneuropathy or polyneuropathy related to drug side effects may also occur. Polyneuropathy can cause difficulties in weaning from artificial breathing [4,5,26,28]. 3.2. Restless leg syndrome Restless legs syndrome is reported in 4.3% of the patients after OLTx [5]. It is an overwhelming urge to move the legs, usually caused by an uncomfortable or unpleasant sensation within the legs themselves. The sensation has the following features: it occurs during periods of inactivity, becomes more obvious in the evening and at night, is relieved by movement of the limb, often causes difficulties in falling or remaining asleep, and may cause involuntary jerking of the limbs during sleep and sometimes also during wakefulness. 3.3. Major complications 3.3.1. Seizures Seizures are the second most common neurological complication reported after OLTx [7,10,29,30]. Seizures can be partial or generalized, most frequently of the tonic-clonic type. They can occur with or without MRI-detectable structural brain lesions and with or without EEG alterations within the inter-critical period. Immediately after OLTx, their prevalence may reach 10–40% [2,19,29,31,32], later their prevalence decreases to about 10% [30]. Seizures are likely to be due to immunosuppressors neurotoxicity, rapid electrolytes or osmolar changes, ischaemic brain lesions and demyelinization of any origin. Seizures can be isolated or be a sign of encephalopathy [5,7,23,25,26]. Usually, epilepsy after OLTx is self-limiting, but some patients may also develop severe treatment-resistant epilepsy [15,17]. The incidence of seizures after OLTx has declined in recent years, possibly because of the remarkable improvement in the management of the multiple metabolic and toxic abnormalities that may predispose to seizures. In addition, most transplant centres now avoid intravenous cyclosporine loading and both the use of tacrolimus and the monitoring of its plasma levels may have contributed to the decreasing rate of seizures [11]. 3.3.2. Cerebellar syndrome The disorder is heralded by headache, nausea, dizziness, emesis, encephalopathy, nystagmus and ataxia. Later, rigor nucalis may occur. Neuroimaging studies show cerebral ventricular widening and cerebral oedema. Histology shows unspecific oedema and loss of Purkinje cells. Pathophysiological mechanisms are not completely understood, but calcineurin inhibitors seem to be implicated. In particular, cerebellar syndrome seems associated with cyclosporine treatment [26].
3.3.3. Posterior leukoencephalopathy Posterior leukoencephalopathy is a severe but, as a rule, reversible syndrome, presenting with nausea, emesis, headache, fever and loss of vision. Visual hallucinations, cortical blindness, occipital headache, seizures and consciousness disorders can also occur. Cerebral MRI shows occipital and parietal extra-pontine demyelinization (due to reactive astrocytosis and a neuronal loss), which is likely to be due to calcineurin inhibitors. Such relationship is inferred from the observation that demyelinization occurs in patients treated with cyclosporine and tacrolimus, but not in those treated with other immunosuppressants. The pathophysiology of posterior leukoencephalopathy is related to brain perfusion alterations, due to vasoconstriction [14,33], rather than to a direct toxic effect of calcineurin immunosuppressants [5,17,23,26,34–36]. Likewise, the spontaneous resolution of the syndrome is probably related to a spontaneous reduction of the haemodynamic alterations. 3.3.4. Central pontine melinolysis syndrome Fluctuating levels of consciousness, convulsions, hypoventilation or hypotension may herald the onset of this syndrome. Eventually, pseudobulbar palsy and quariparesis may develop. Swallowing dysfunction (often with episodes of aspiration) and inability to speak may be the dominant clinical features. In severe cases, the patient may develop a ‘locked-in syndrome’: they are awake but unable to move or communicate. Although these symptoms are potentially reversible, central pontine myelinolysis is one of the most severe neurological complications of OLTx. It has been detected in about 10–30% of patients who died after liver transplantation at the beginning of the liver transplant era [31,37,38]. Now its frequency after transplant is about 2–3.5% [7,10]. It is characterized by symmetrical loss of myelin in the base of the pons, with relatively well-preserved axons and neuronal cell bodies [10,39]. Myelinolytic foci can be also found out of the area of the pons [40]. The most common, albeit not unique, cause of central pontine myelinolysis is a rapid correction of prolonged hyponatremia [9,40]. Prolonged chronic liver failure can limit the production of idiogenic osmoles needed to protect the brain during rapid osmolar shifts [15,38,41]. 3.3.5. Focal neurological deficits Focal neurological deficits usually cause muscular weakness with preserved sensitivity. Palpebral ptosis and dysarthria are the most frequent forms of focal deficit, which results from damage of the cortex or the underlying white matter within motor pathways, generally due to ischaemia and/or immunosuppressors neurotoxicity [6,22,26]. 3.3.6. Vegetative state In this syndrome, patients appear alert, but they make no attempt to communicate and eye contact is also absent. They do not have emotional reactions, even though painful stimuli may evoke facial grimacing and posturing of the
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extremities. Frontal release signs can occur. The pathophysiology of this condition is largely unknown, but it may be due to damage or dysfunction of the dopaminergic mesencephalic-frontal pathways. Reversibility with interruption of calcineurin immunosuppressors has been reported, suggesting a relationship with drug neurotoxicity [6,23,26]. 3.3.7. Metabolic and toxic encephalopathies Metabolic encephalopathy is multifactorial in nature and can be related to drugs (immunosuppresants in particular), electrolyte and osmotic disorders, systemic inflammation, infections, disturbance of energy metabolism and pH. Prolonged liver failure and persistent hepatic encephalopathy might represent risk factors. Metabolic encephalopaties may affect up to 11.8% patients after OLTx [5,15,21,23]; obviously, encephalitis has to be ruled out. Clinical signs are sleep disorders, apathy, disorientation in space and time, delirium, acute psychotic episodes with agitation, crying, repetition of illogical sentences, rambling speech, confusion, dysperceptive disorders (illusions or hallucinations both acoustic and visual, the latter characterized by bright flashing colours), autonomic dysfunction [8,42,43]. The syndrome can evolve to stupor and coma and seizures can occur. Acute psychotic reactions were reported in 43% of patients treated with high doses of cyclosporine after transplantation [8,43]. Symptoms reversed after reduction or discontinuation of cyclosporine.
4. Pathophysiology Metabolic and electrolyte disturbances, cardiovascular events, infections, acute draft rejection and immunosuppressant therapy are at the basis of OLTx-related brain dysfunction [8,17,22,44,45]. 4.1. Metabolic complications Primary non-functioning of the graft, rejection and multiorgan failure are the most common disorders at the basis of metabolic dysfunction. Disorders of electrolytic balance, like hypo- or hypernatremia and hypomagnesaemia, as well as hypo- and hyperglycaemia are also causes of central nervous system dysfunction [8,23].
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4.2.1. Cerebral ischaemia Brain hypoperfusion with ischaemia and hypoxia can be due to cerebral oedema and increased intracranial pressure in patients with severely compromised cerebral blood flow selfregulation [15,23]. In addition, cerebral ischaemia can be due to peri-operative detachment of arterial emboli from carotid or intracranial arteries, from endocarditis in post-OLTx or from mycotic arteritis (angioinvasive Aspergillosis) [2,15] or from paradoxical emboli of thrombotic material, originating from the deep leg or pelvic veins [29,49]. 4.2.2. Cerebral haemorrhage Subarachnoid, intracerebral or subdural haemorrhage can occur after liver transplantation. Cirrhotic patients who undergo OLTx are susceptible to these adverse events because of severe coagulopathy, thrombocaytopenia, blood loss and hypotension during transplantation followed by increased intracranial pressure after OLTx [1]. 4.2.3. Anterior spinal artery syndrome The classic anterior artery syndrome results in motor palsy, faecal and urinary incontinence, dissociated sensory loss of pain and temperature, with vibration and proprioceptive sparing below the lesion level [50,51]. This syndrome is due to the accidental damage of the great radicular artery of Adamkiewicz during liver explantation. Such lesion prevents blood supply to the anterior and lateral columns of the lower spinal cord, damaging them. 4.3. CNS infections Central nervous system infections are documented in 5–10% patients after OLTx. They are mainly due to opportunistic agents that, due to immunosuppression, can become fatal [6,23,52,55,57]. The diagnosis is often difficult because symptoms can be blunted by immunosuppressive therapy. The clinical syndromes include: • meningitis, meningo-encephalitis or encephalitis due to viruses (Herpes simplex virus or cytomegalovirus), bacteria or fungi and • focal deficits due to brain abscess, frequently caused by Aspergilla.
4.2. Cardiovascular events
4.4. CNS neoplasms
Profound cerebral and systemic haemodynamic alterations occur during the liver transplant procedure. The reperfusion of the transplanted liver is usually associated with a decrease in systemic arterial pressure and an increase in pulmonary pressure. Occasionally, reduced cardiac index, arrhythmias and right ventricular insufficiency may occur. Sudden changes of cerebral perfusion, favoured by disruption of cerebral blood flow autoregulation, can damage the brain during the transplantation procedure [24,46–48].
Organ transplant recipients have a three- to four-fold increase in the incidence of malignant diseases compared with the general population. The highest risk is for lymphoproliferative diseases. Due to immunosuppression, EBV infection can induce abnormal B-lymphocyte proliferation, which, eventually, can result in lymphoma. Lymphoma occurs in 3% of patients after OLTx, about 27% of the lymphomas concern CNS and meningi [15,23,53,56,58–60] in transplanted patients.
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4.5. Immunosuppressant neurotoxicity Neurotoxicity associated with cyclosporine or tacrolimus is a less common adverse effect than nephrotoxicity or hypertension; however, it can result in serious disease [17]. Immunosuppressant-related neurotoxicity can occur immediately after the transplant, due to the high doses of drugs needed to induce immunosuppression, or later, possibly due to a cumulative effect of the drugs. At any rate, the neurological toxicity of immunosuppressants is hardly correlated with their plasma levels. Sometimes, the relationship can be only indirectly inferred from the resolution of the clinical symptoms on treatment discontinuation [4,14,23]. Of all the immunosuppressant drugs used after liver transplantation, only mycophenolate mofetil does not have neurotoxic side effects, the major adverse effects of this drug being gastrointestinal and haematological [61–64]. In contrast, the other immunosuppressant drugs, i.e. corticosteroids, OKT3 and calcineurin inhibitors, do have remarkable neurotoxic potential. • Corticosteroids are associated with neuropsychiatric side effects in 3–4% of patients, the most common ones being: ◦ Mood changes and behavioural disorders including confusion, maniacal states, psychotic reactions [14,23,64] neuro-myopathy with muscular weakness affecting proximal and lower extremities [23,60]; ◦ Epidural lipomathosis causing radiculopathy due to spinal compression [65]. • OKT-3. The most common side effect of this murine monoclonal antibody directed against a T-cell surface molecular is a flu-like illness with headache and fever. The rare neurological side effects are: ◦ acute aseptic meningitis with headache, nucal rigidity and fever; cerebral fluid examination reveals a lymphocyte pleiocytosis; ◦ encephalopathy-like syndrome with impairment of consciousness, myoclonic activity and seizures. Cerebral oedema might be the underlying cause of this syndrome [23,26,66,67]. • Calcineurine inhibitors. The exact neurotoxic effect of these drugs is still unknown and the implicated target cells have not yet been clearly identified. ◦ Neurotoxicity may depend on the same mechanisms causing calcineurin inhibitors immunosuppressive action [34,68,69]. Both tacrolimus and cyclosporine bind to immunophillins which are low-molecularweight intracellular proteins facilitating protein folding, protein intracellular transport and the stability of multiprotein complexes. The high affinity binding of calcineurin inhibitors with immunophillins blocks calcineurin activity, which, in turn, inhibits calciumcalmodulin-dependent phosphatase activity and, by interacting with nuclear factors, inhibits interleukin2 gene transcription and, consequently, blunts the immune response. [26,57,58]. In addition, at least
as far as tacrolimus is concerned, the production of other cytokines (IL3, IL4, IFN-␥, GM-CSF, il TNF␣) [70,71], proto-oncogenes (ras, myc e ral) and the expression of the receptors for IL2 and IL7 are also reduced [72–74]. Calcineurin inhibitors might also block other important, albeit not yet elucidated, functions of calcineurin and immunophillins in the brain, causing neurotoxicity. Such hypothesis can be advanced because immunophillins reach very high levels in central nervous system cells (10 times higher than in white blood cells) [14,34,68,75]. An exception is provided by rapamicine, which, albeit structurally related to tacrolimus, binds to another site of immunophillins thus causing inhibition of mTOR instead of calcineurin. In turn, mTOR inhibition results in the arrest of cell cycle in G1 phase that does not cause neurotoxic effects [76–80]. ◦ Another neurotoxic mechanism is brain vessel vasoconstriction due to cyclosporine- and tacrolimus-induced reduction of brain NO. Severe vasoconstriction results from disturbance in endothelial control of vascular tone, leading to ischaemia [81,82]. Such a reduction is due the inhibition of calcineurin-mediated dephosforilation of calcium-dependent NO syntase [83]. Dephosphorilation is needed to revert Ca-dependent neuronal and endothelial NO syntase inhibition caused by phosphorilation. [84]. In addition, calcineurin inhibitors lower intracellular calcium, therefore reducing Cadependent NO synthase activity [85]. It is not yet clear if tacrolimus also enhances brain endotelin production, as it occurs in the kidney [84,86–89]. At any rate, the final effect of these events is vasoconstriction and microvascular damage of the nervous system and blood brain barrier. The sensitivity of various brain regions to vasoconstriction seems to be heterogeneous with a higher sensitivity of cerebral peduncle (causing visual disorders), motor cortex and Broca’s area [14,18,35,90,91]. ◦ Blood-brain barrier (BBB) alterations are reported to be caused by cyclosporine and tacrolimus: cellular apoptosis, vasoconstriction due to NO reduction, reduced expression of glycoprotein P, i.e. a ATPase transporter implicated in the export of toxic substances from the brain [69,81,92,93]. ◦ Selective toxic effect on oligodendrocytes. After having been cultured with cyclosporine, oligodendrocytes develop intracytoplasmic inclusions that have been identified as lysosomes containing neutral lipids [82,94]. Demyelization can eventually occur and it has a time course and a severity correlated with the length of cyclosporine exposure. Oligodendrocytes have a higher calcineurin content than astrocytes and, possibly for this reason, have a higher susceptibility to calcineurin-inhibitor-induced apoptosis than astrocytes [82]. At any rate, the time course and the reversibility of calcineurin-inhibitor-induced demyeli-
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nation suggest damage due to vasoconstriction (and, possibly, reperfusion with oxidative stress) rather than direct myelinolysis [14,18,34,54,95]. ◦ Interference with both excitatory and inhibitory amino-acid activity. The reduction of calcineurin phosphorilation has both presynaptic and postsynaptic effect on GABAergic neurotransmission and on neurotransmitter release induced by NMDA and depolarization [17,95–99]. In turn, the inhibition of NMDA-induced neurotransmitter release and long-term potentiation are involved in memory function [14,17,18,100]. In addition, tacrolimus-related inhibition of hippocampal neurons could be implicated in the pathophysiology of memory alterations and confusion [68,95]. Finally, the inhibition of GABAErgic tone may facilitate seizures [101], whereas alterations in serotoninergic neurotransmission may be implicated in the occurrence of tremor [102] and explain some forms of transplant delirium [14]. Conditions increasing the neurotoxic effects of immunosuppressant agents are pre-existing central nervous system damage and pre-existing BBB alterations causing toxic intracerebral drug levels [18,103], chronic hepatic encephalopathy, electrolyte disorders (hyper- and hyponatremia, hypomagnesaemia), dysmetabolic alterations (e.g., hyperglycaemia) and hypocholesterolemia, because it increases brain uptake of immunosuppressant drugs and drug interactions [7,18,26,88,103,104].
5. Conclusions The prevalence and the relevance of neurological complications after OLTx justify an accurate evaluation of the patients entering an OLTx programme, aiming at defining their base line conditions, so that even minor complications can be detected, properly characterized and appropriately managed. Such work-up requires highly integrated teems with interdisciplinary expertise.
Practice points • The baseline neurological and cognitive findings of patients entering an OLTx programme should be accurately checked, due to the high prevalence of neuropsychiatric complications after OLTx. • Behavioural and mood alterations in transplanted patients need immediate and accurate diagnosis by a highly integrated teem with interdisciplinary expertise.
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Research agenda • To compare sirolimus versus other calcineurin inhibitors in terms of long-term neurological sequelae of OLTx. • To improve the knowledge of the risk factors of neuropsychiatric complications of OLTx. and their management. • To improve the management of the neuropsychiatric complications of OLTx.
Conflict of interest statement None declared.
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