Transplantation Reviews 31 (2017) 193–206

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Transplantation Reviews

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Neurological disorders in liver transplant candidates: Pathophysiology ☆ and clinical assessment

Paolo Feltracco a,⁎, Annachiara Cagnin b, Cristiana Carollo a, Stefania Barbieri a, Carlo Ori a a Department of Medicine UO Anesthesia and Intensive Care, Padova University Hospital, Padova, Italy b Department of Neurosciences (DNS), University of Padova, Padova, Italy abstract

Compromised liver function, as a consequence of acute liver insufficiency or severe chronic liver disease may be associated with various neurological syndromes, which involve both central and peripheral . Acute and severe hyperammoniemia inducing cellular metabolic alterations, prolonged state of “neuroinflamma- tion”, activation of brain microglia, accumulation of manganese and , and systemic inflammation are the main causative factors of in . The most widely recognized neurological complications of serious hepatocellular failure include hepatic , diffuse , Wilson disease, hepatic , acquired hepatocerebral degeneration, -related and osmotic demyelination syndrome. Neurological disorders affecting liver transplant candidates while in the waiting list may not only sig- nificantly influence preoperative morbidity and even mortality, but also represent important predictive factors for post-transplant neurological manifestations. Careful pre-transplant neurological evaluation is essential to de- fine severity and distribution of the neurological impairment, to identify the abnormalities still responsive to cur- rent treatment, and to potentially predict the inherent post-operative prognosis. The preferred specificindicesof neurological pre-transplant assessment may vary among centers, however, even with the aid of the current bio- chemical, neurophysiological, neuropsychological and neuroimaging diagnostic tools, the correct diagnosis and differential diagnosis of various syndromes may be difficult. In this article the relevant pathophysiological and clinical aspects of the most frequent brain and peripheral nervous system diseases affecting liver transplant can- didates with acute or advanced chronic liver failure are briefly reported. The practical diagnostic findings useful for the preoperative assessment and treatment, as well as the expected neurological evolution after liver trans- plantation are also evaluated. © 2017 Elsevier Inc. All rights reserved.

1. Introduction Liver transplant candidates may experience a great variety of neurological disorders while on the waiting list, which may significantly Compromised liver function as a consequence of either acute hepatic influence preoperative morbidity and even mortality. It has been recog- failure or severe chronic liver disease and liver cirrhosis leads to insuffi- nized that many neurological disorders associated with acute or chronic cient detoxification of some substances and catabolic products, which liver failure tend to improve or disappear after successful orthotopic accumulate in the blood and are responsible for a broad range of neuro- liver transplantation (OLT); however, some minor “residual” clinical logical and neuropsychiatric manifestations [1]. A strict relationship be- signs may persist postoperatively in a variable percentage of liver tween brain functioning and integrity of the liver is well known, and a transplanted patients. Furthermore, pre-transplant subclinical neuro- pathological liver may be responsible for various neurological syn- logical symptoms may become apparent in the event of graft dysfunc- dromes, which affect both the central nervous system (CNS) and the pe- tion or severe postoperative metabolic disturbances [4,5]. ripheral nervous system [2,3]. Liver transplant recipients are affected by the highest rate of CNS complications among solid organ transplants (incidence between 10% and 85%), with focal and diffuse neurological deficits sometimes representing a major obstacle to the improvement of short- and long- term outcomes [6]. Relevant adverse post-OLT neurological events ☆ Author contributions Carollo C and Barbieri S made literature search; Feltracco P and occur due to brain edema, increase of , metabolic Cagnin AC acquired and analyzed the data, and drafted the article; all authors contributed encephalopathy, cerebrovascular complications, osmotic demyelination to the manuscript preparation, data interpretation, revision for important intellectual con- syndrome, and opportunistic infections. Moreover, some pre-operative tent, editing, and approved the final version. neurological alterations such as dysarthria or akinetic mutism, confu- ⁎ Corresponding author at: Department of Medicine UO Anaesthesia and Intensive Care, Padua University Hospital, Via 8 febbraio 1848, 35128, Padua, Italy. Tel.: +39 498212222. sion and , may worsen due to the neurotoxic effects of calcine- E-mail address: [email protected] (P. Feltracco). urin inhibitors drugs required to prevent graft rejection [4,7].Full http://dx.doi.org/10.1016/j.trre.2017.02.006 0955-470X/© 2017 Elsevier Inc. All rights reserved. 194 P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 comprehension of the pathophysiology and proper management of the degeneration) or to diseases with concomitant hepatic and neurological neurological manifestations of end stage liver failure has not yet been involvement (i.e. Wilson disease). The neurological syndromes may re- completely attained. In fact, multiple factors have been associated quire a specific management, such in the case of , or in with brain damage, such as a prolonged state of brain “neuroinflamma- the context of chronic liver cirrhosis or portosystemic shunting. The rel- tion”, activation of brain microglia and inflammatory cells, accumula- evant pathophysiological and clinical aspects, the practical diagnostic tion of manganese and ammonia, altered permeability of the blood– findings useful for the preoperative clinical assessment and treatment, brain barrier, altered neurotransmission, and inflammation of the as well as the expected neurological evolution after liver transplanta- peripheral nervous system [8]. Other negative direct or indirect neuro- tion, are briefly described. logic effects are caused by chronic malnutrition, gastrointestinal hemor- rhages, cerebral hypoperfusion and renal dysfunction [9–12]. The most 2. Neurological aspects of widely recognized neurological complication of serious hepatocellular failure is the complex syndrome of hepatic encephalopathy (HE), but HE is a complex syndrome characterized by neuropsychiatric, many other brain alterations associated with liver cirrhosis may occur, neuropsychological and neurological disturbances caused by different as listed in Table 1 [13]. underlying liver diseases or peri-hepatic vascular shunting, and influ- Careful pre-transplant evaluation of the CNS and peripheral nervous enced by a variety of precipitating factors. The development of HE system disorders is essential for identifying the abnormalities still re- may manifest with a wide range of neurologic manifestations, which sponsive to current medical treatment, and potentially predicting the are characterized by potential reversibility once the abnormality of inherent post-operative prognosis. An accurate assessment of baseline liver function is corrected. Sudden onset of confusion evolving rapidly neurological features increases the understanding of how brain disor- into coma is a frequent presentation of acute HE episodes, often under ders can interfere with post-hospitalization quality of life in case of po- the trigger of some precipitating factors; in other circumstances, the tential incomplete recovery after OLT. Patients with end-stage liver may fluctuate slowly, with long periods without disease are usually evaluated with indices that predict advanced dis- HE events [14]. Based on the clinical practice guidelines of the ease, such as the Child–Turcotte–Pugh score, or those that predict prog- American Association for the study of liver diseases (AASLD) and the nosis, such as the Model for End-stage Liver Disease score (MELD, European Association for the study of the liver (EASL) [15], HE should MELD-Na). Preoperative neurological assessment is based on the specif- be classified according to four factors: ic evaluation of both CNS and peripheral nervous system functions. Ex- (1) the underlying disease; with type A HE resulting from acute liver amination of motor (pyramidal and extrapyramidal) and sensory failure, type B resulting predominantly from portosystemic by- system integrity, cranial nerves evaluation, as well as analysis of super- pass or shunting, and type C resulting from cirrhosis; ficial and deep-tendon reflexes and cerebellar signs should always be (2) the severity of manifestations; a summarized grading of severity performed as first step neurological assessment before searching for of clinical manifestations of HE, according to both the West more specific neurological features. Evaluation of the mental status, Haven criteria (Old Classification) and International Society for cognitive functions, speech characteristics, etc., is also extremely useful Hepatic and Nitrogen (ISHEN) in obtaining a detailed baseline neurological status and monitoring pos- classification, is reported in Table 2 [15], sible disease progression. Clinical and biochemical diagnostic tools, neu- (3) the time course; subdivided into episodic (spontaneous or pre- rophysiological assessments (electroencephalography (EEG) and visual, cipitated), recurrent (episodes occurring with a time interval of auditory, and somatosensory-evoked potentials (EPs) and neuroimag- 6 months or less), persistent (N2 weeks of mental status ing, have been adopted to correctly diagnose different stages of neuro- changes), logical impairment. However, the choice of the preferred clinical or (4) the existence of precipitating factors; subdivided into spontane- instrumental parameters for neurological pre-transplant assessment ous non precipitated or precipitated (with specification of the may vary among centers, and the differential diagnosis of various syn- precipitating factors). dromes may be difficult and critical, even with the use of “modern” technologies. This article mainly focuses on the most frequent CNS The so-called overt form of HE (OHE), defined when neurological and and peripheral nervous system diseases affecting liver transplant candi- psychiatric abnormalities are detected at the bedside, was divided into dates with acute severe or advanced liver dysfunction. Patients with four stages of severity based on the New Haven scale. However, given severe liver dysfunction can have a great range of neurologic manifesta- the largely subjective criteria for classifying a cirrhotic patient as stage tions due to direct effects of hepatic disease on the central and 1 HE, it was decided to abolish this stage of HE. Every cirrhotic patient peripheral nervous system (i.e. HE or acquired hepato-cerebral with disorientation to time has to be considered with definite OHE [16]. Minimal HE (MHE), once called covert HE, and defined when mini- mal or no symptoms are detected [17,18], occurs in nearly 70% of cir- Table 1 rhotic patients; it has grown in importance over the recent years as it fi Neurological manifestations associated with liver cirrhosis, from [13] with modi cations. may precede the development of OHE. MHE is defined as the presence Hepatic encephalopathy and minimal hepatic encephalopathy of test-dependent or clinical signs of brain dysfunction in patients

Cirrhosis-related parkinsonism with chronic liver disease who are not disoriented or display asterixis. Raised intracranial pressure, cerebral edema According to the ISHEN classification, covert HE (CHE) is essentially CNS infectious complications the amalgamation of stage 1 HE and MHE. Acquired hepatocerebral degeneration Cirrhotic or hepatic myelopathy 3. Neurological manifestations of acute liver failure (type HE) Cirrhosis related intracranial bleeding Neurologic complications related to specific aetiologies of liver disease Neurologic symptoms of Wilson disease Acute liver failure (ALF) is characterized by a rapid hepatocellular Hepatitis C infection related CNS complications necrosis that leads to the severe deterioration of liver function, Osmotic demyelination syndrome alterations of coagulation and encephalopathy, which occurs within Marchiafava-Bignami disease Wernicke encephalopathy days or weeks of the primary insult (less than 26 weeks) without Neurological disorders associated with malnutrition evidence of pre-existing cirrhosis [19]. The most common aetiologies are Alcoholic cerebellar degeneration, amblyopia, polyneuropathy, drug-induced liver injury (acetaminophen overdose being observed in Wernicke–Korsakoff Disease b45%), food intoxication, viral hepatitis, autoimmune liver disease and is- Alcohol related and cognitive decline chemic hepatitis. Neurologic manifestations are those of encephalopathy P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 195

Table 2 Clinical grading of severity of HE and operative criteria; from [15] with modifications.

WCH including MHE ISHEN Description Suggested operative criteria

Unimpaired No encephalopathy, no history of HE Tested and proved to be normal Minimal Covert Psychometric or neuropsychological alterations of tests exploring Abnormal results of psychometric or neuropsychological psychomotor speed/executive functions without clinical evidence testing without clinical manifestations or mental change Grade I Mild confusion, impaired attention, hypersomnia, insomnia or Despite oriented in time and space the patient appears inversion of sleep patterns, depression or irritability, euphoria to have some cognitive/behavioral decay with respect to or anxiety, intermittent disorientation his/her standard on clinical examination, or to the caregivers Grade II Overt Apathy, drowsiness, lethargy, evident disorientation (usually Disoriented for time (wrong day of the month, day of the for time), obvious personality changes, inappropriate behavior, week, month, season or year) ± the other mentioned symptoms obvious asterixis, important deficits in the ability to perform mental tasks Grade III Marked confusion, persistent disorientation and , Disoriented for space (wrong country state or region, somnolence to semi-stupor but responsive to intense verbal city or place) ± the other mentioned symptoms stimuli, unable to perform mental tasks, incoherent speech, gross disorientation for time and space, asterixis usually absent Grade IV Coma Patient without response to noxious stimuli

and brain edema. Encephalopathy is due to a rapid increase of blood and a comprehensive intensive care as HE progresses. Spontaneous liver ammonia level, which, in contrast to what happens in chronic liver fail- regeneration may occur approximately in 45% of patients with ALF, with ure, determines an intense osmotic gradient for water, not responsive the highest recovery and survival rate (55–65%) reported following to the cerebral compensatory osmotic mechanisms. Acute and severe acetaminophen overdose or hepatitis A infection [19].Thegeneralprin- hyperammonemia induces cellular metabolic alterations resulting in in- ciples of ICU management of ALF patients are listed in Table 3. tracellular accumulation of hypertonic osmotic molecules (ions and Prioritization in organ allocation systems and a timely performed amino acids), followed by an entry of water to re-establish the osmotic liver transplantation are fundamental in these patients since ALF is asso- equilibrium. Accumulation of water in the brain causes astrocytic swell- ciated with high morbidity and mortality. The King's College Hospital ing and degeneration (cytotoxic edema); this phenomenon leads ini- criteria have been extensively used for patient selection, and were the tially to an increase in brain volume and then to an increase in first to differentiate between paracetamol-induced and other aetiol- intracranial pressure (ICP), with an exponential relationship at ad- ogies of ALF [24,25].Patientsfulfilling the criteria are very likely to die vanced stages. Impaired cerebral vascular autoregulation with increase if they do not receive transplants [25]. However, the King's College in cerebral blood flow is another mechanism involved in the develop- criteria are acknowledged to have high degree of specificity but a low ment of brain edema. This is due to a physical breakdown of the level of sensitivity. In order to improve OLT candidate selection various blood–brain-barrier (BBB), which allows plasma macromolecules and prognostic models have been proposed, such as SOFA score, APACHE II, other compounds to enter into the extracellular space with an addition- MELD, and others based on composite scores of different clinical al increase in osmotic pressure within the brain (vasogenic edema). The markers on patient admission; however, all these models lack of signif- degree of water accumulation in the brain in acute and chronic liver failure icant predictive value, specificity and validation in this setting [25].Out- is different: higher quantities of water accumulate in ALF patients, which comes following OLT in ALF patients have improved in the recent years, are responsible for progressive elevation of ICP; patients with type B and with a better prognosis for ALF associated with paracetamol toxicity, type C HE less frequently develop intracranial hypertension [1]. and one­year survival ranging between 74% and 84%. Although these re- Early neurologic symptoms of ALF resembles a low grade HE, with sults are worse than those of patients grafted for other indications, they attention deficits, somnolence, temporal and spatial disorientation, ap- athy or excitement, slow responses and reasoning; as cerebral edema Table 3 worsens stupor, or severe acute delirium may Basic principles of intensive care management of ALF patients. rapidly evolve in a comatose state. Other associated symptoms may be Treatment of toxic injury, Antidotes; N–Acetylcysteine, activated or focal convulsive or non-convulsive seizures (generalized acetaminophen, mushroom poisoning charcoal penicillin seizures are uncommon), alteration of conjugate ocular gaze move- Sedation and mechanical ventilation Normoventilation or short term ments, and Babinski signs with increased muscle tone. Drowsiness (grade III HE, Glasgow Coma Score hyperventilation if ↑ ICP and asterixis are frequently seen, however, they appear poorly correlat- Scale ≤8) ed with progression to more severe encephalopathy and intracranial Optimal volume resuscitation and Mixture of colloid and cristalloids, hypertension [20]. Hyperreflexia and ankle clonus (involuntary and maintenance of osmotic gradient hypertonic saline or mannitol rhythmic contractions of muscles when stretched) have been correlated across BBB – Circulatory support and maintenance Inotropes, vasactive agents, steroids with an increased risk of progression from grade 3 4 coma and subse- of cerebral perfusion pressure quent development of severe brain edema [21]. When cerebral hyper- Treatment of brain edema Sedatives, 30° head up, mannitol, tension is severe, decerebrate or decorticate posturing is detectable, as dexamethasone, mild hypothermia, well as altered asymmetric pupillary responses suggestive of imminent hyperventilation, ultrafiltration, indometacin (barbitures) dangerous elevation of ICP. Diffuse bilateral brain edema eventually Treatment of subclinical seizures Phenitoin, levetiracetam leads to cerebral herniation and brain death [22,23]. Repeated EEG mon- Renal support Renal replacement therapies, itoring should be considered in ALF patients for detecting non- continuous hemofiltration convulsive seizures. Brain CT or MRI may detect indirect initial signs of Glycemic control Glucose administration, careful cellular edema, such as effacement of the cortical sulci, suprasellar and glycemic monitoring Antimicrobial treatment Broad spectrum antibiotics, antifungals perimesencephalic cisterns; the neuroimaging features of advanced Extracorporeal liver assistance Molecular Adsorbent Recirculating and irreversible forms may include complete disappearance of gray- and purification System (MARS) white matter differentiation, transtentorial or cerebellar herniation or Single Pass Albumin Dialysis (SPAD). intracranial bleed. ALF is a critical condition requiring ICU admission Prometeus System Plasmapheresis when the patient becomes agitated or has decreased levels of vigilance, 196 P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 compare very favorably or are even better than those seen in candidates Another mechanism involved in the etiology of HE includes some al- with end stage liver disease intensively treated or ventilated at the time terations in the permeability of the blood–brain barrier to water and of organ allocation (one­year survival of 64% and 54% respectively) other small molecules; these changes, secondary to the release of [26,27]. TNFa and interleukins from microglial cells and astrocytes, not only in- Brain edema and intracranial hypertension resolve within 48 h fol- crease the neuropsychological impairment due to hyperammonemia, lowing liver transplantation when the graft function is good; however, but also promote the misdistribution of neurotransmitters [33–35].In various neurological symptoms such as , seizures and speech dis- patients with HE, low grade brain edema, resulting as an osmotic re- orders can persist in the early postoperative course. Living­donor grafts sponse of the astrocytes to increased intracellular glutamine, and for ALF are frequently used in Asia (reported rates between 6% and brain white matter alterations on magnetic resonance-diffusion tensor 15%); in Europe and USA living donation approximates only 1% of trans- imaging (MR-DTI) were demonstrated by Gomez-Anson et al. [35]. plants for ALF. The emergency settings do not allow, in fact, sufficient The authors suggested that white matter alterations could be due to time to assess potential donor's spontaneous willingness to donate or the prolonged effects of neurotoxins and longstanding edema, which to rule out important ethical and medical issues. are factors that are capable of inducing demyelination and irreversible alterations. Persistent structural injuries to the white matter might not 4. Neurological manifestations of type B and type C HE be reversed with OLT [36]. Important factors that can precipitate HE in- clude gastrointestinal bleeding, hypokalemia, infections, dehydration, The pathogenesis of OHE associated with portal-systemic shunting constipation, hypotension, oral protein load, deteriorating liver func- (type B) and cirrhosis (type C) remains still not completely clear; sub- tion, anesthesia and surgery. However, sometimes no apparent precipi- stances such as ammonia that accumulate in the brain due to portal- tating factors are detectable. Many liver transplant candidates may systemic shunting, cerebral neuroinflammation and systemic inflam- experience one or more episodes of OHE at some time during their ill- mation, oxidative stress, and genetic difference in the conversion rate ness, with the possible occurrence of a wide range of mental and of glutamine to ammonia have been suggested to play major roles in motor dysfunctions. Acute episodes of HE are characterized by the sud- the development of OHE [28]. Ammonia stimulates the glutamine syn- den (or over hours to days) development of an acute confusional state, thetase enzyme in the brain, which converts glutamate and ammonia with impaired mental state, fetor hepaticus secondary to the exhalation into glutamine. Increased diffusion of ammonia and other gut-derived of mercaptans, and neuromuscular disorders. Frank confusion, stupor toxins into the brain leads to glutamine accumulation, which induces ox- and even deep coma may arise in case of delayed reversal or worsening idative stress, energy failure, and morphologic changes in astrocytes (as- of HE [16]. Neuropsychological deficits may initiate with apathy and trocyte swelling). Ammonia alters the transfer of amino acids and lethargy and may involve multiple cognitive abilities, such as memory, electrolytes across the astrocytes and neurons. Chronic hyperammonemia language, visuospatial skills, attentional processes and executive func- per se induces neuroinflammation and a great variety of neurotransmitter tions. Aggression and hyperactivity progressing to are other and neurochemical modifications, such as alterations in the function of possible behavioral disturbances. Neuromuscular abnormalities are the glutamate-NOcGMP pathway in the cerebellum [29].Systemic“pe- common, usually in the form of increased muscle tone, hyperreflexia, ripheral” inflammation, which mainly derives from bacterial infections, and asterixis. Signs of pyramidal tract dysfunction tend to disappear as spontaneous peritonitis with damage to the intestinal barrier and bacteri- HE progresses, and they are eventually replaced by hypotonia if coma al translocation, may also maintain and potentiate the neuroinflamma- develops. Extrapyramidal symptoms, including tremor, rigidity, brady- tion. Hyperammonemia and systemic inflammation play synergistic kinesia, and shuffling gait, have also been described. Asterixis, although roles and cause well-known triggers for the development of OHE not exclusive to HE, is a characteristic feature of this disease. It is caused [30,31]. The contribution of neuroinflammation to the pathogenesis of by dysfunction of diencephalic motor centers that regulate the tone of HE in patients with chronic liver diseases was studied using PET and li- agonist and antagonist muscles [37]. Testing for eliciting asterixis in- gands which bind to the translocator protein (18 kDa) (TSPO), a surrogate cludes dorsiflexion of the patient's hands with the arms extended and marker of microglial activation. In the study by Cagnin et al. [32]. in- the fingers separated; under these conditions, involuntary flapping creased binding of [11C](R)PK11195 to TSPO in the brains of cirrhotic pa- tremor and rapid, involuntary, flexion-extension movements of the tients suggested that the presence of neuroinflammation in patients with wrist may arise. This tremor can also manifest in the tongue and lower HE was correlated with altered microglial function and hence with the extremities, with difficulties in maintaining posture or position grade of cognitive impairment (Fig. 1b). [28,35]. Asterixis tends to reverse as HE progresses to coma; at this

Fig. 1. Brain MRI and PK11195-PET study of hepatic encephalopathy. T1 coronal brain MRI of a patient with hepatic encephalopathy showing hyperintense lesions in the bilateral (a), and the corresponding slice image obtained with 11C–PK11195-PET (b) showing diffuse microglial activation in the basal ganglia, midbrain and cerebral white matter. P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 197 stage, other signs of predominant pyramidal involvement may become Table 4 prevalent [16]. Focal neurological deficits, most often or Differential diagnoses of encephalopathy, from Refs. [48,50] with modifications. hemiplegia, and visual disturbances, although rare, have also been re- CNS infectious diseases: , , and intracranial abscess ported in patients with OHE. Serious damage to various cortical struc- Intracranial lesions: intracranial bleeding, cerebral edema, , tumor tures, also in the past medical history, and chronic injury to the retinal Metabolic encephalopathy: hypoglycemia, vitamin B1 deficiency, electrolyte glia have been suggested to be causative factors [38–40].Clinical abnormalities, hypothyroidism, anoxia, , and uremia manifestations of severe chronic HE may also occur in association with Toxic encephalopathies including delirium tremens , dysarthria, gait abnormalities, and tremor, which are typical Hyperammonemia from other causes: inherited urea cycle disorders fi Toxic encephalopathy: acute alcohol intoxication, alcohol withdrawal, ndings with other coexisting diseases, such as myelopathy, acquired Wernicke encephalopathy hepatocerebral degeneration, and cirrhosis-related parkinsonism. Bra- Encephalopathy from drugs: sedative-hypnotics, antidepressants, dykinesia and other mild parkinsonian signs are common permanent antipsychotic agents, and salicylates neurological disorders between recurrent episodes of OHE. MHE refers Post- encephalopathy to motor and cognitive deficits that are not noticeable on clinical exam- ination but are detected using specific neuropsychological or electro- physiological tests [41]. “Minimal” abnormalities of the neurocognitive available, while hospitalization being instead required, sometimes in and motor functions primarily affect information processing, coordina- an intensive care setting, for grade 3–4 HE individuals. Serious advanced tion, the ability to perform complex tasks, such as driving, and the skills HE may also require tracheal intubation to provide respiratory to maintain spatial orientation, all with a subtle but negative impact on assistance and to protect the patient from ab ingestis pneumonia, and a patient's quality of life [14]. Early identification and treatment of MHE supportive cardio-circulatory measures to revert hemodynamic insta- are important, not only to prevent deterioration of daily living but also bility. Correction of malnutrition e.g. avoidance of meals too rich in pro- to decrease the risk of the development of OHE, which is associated teins, but at the same time avoidance of excessive protein restriction with increased mortality in patients with cirrhosis and, hence, reduced (ammonia-lowering strategies with recommended daily protein intake survival for candidates on the waiting list for liver transplant [42].Dif- of 1.2–1.5 g/kg in a daily energetic regimen of 35–40 kcal/kg), avoid- ferent psychometric tests, such as the Psychometric HE Score (PHES), ance of sedatives, alcohol consumption, long fasting periods, prevention the Number Connection Test A and B, the Line Tracing Test, the Serial of renal hypoperfusion, hypovolemia, hypoglycemia, constipation, pre- Dotting Test, the Digital Symbol Test, etc., can be applied to identify im- vention of precipitating factors such as gastrointestinal bleeding, infec- pairments in memory, attention, visuospatial abilities, and fine motor tion, hyponatremia, thiamine deficiency, as well as reducing colonic skills. They are particularly useful in detecting the subclinical symptoms ammonia-producing gram-positive and gram-negative aerobic and an- of MHE and the severity of low-grade HE [43–45]. A detailed description aerobic bacteria, are the fundamental strategies of initial supportive of these tests is beyond the scope of this article. The diagnosis of HE re- care [51–53]. Although no consensus has emerged concerning the ben- lies essentially on the clinical assessment, along with specificEEG efits of branched chain aminoacid (BCAA) administration, avoiding a changes and neuroimaging findings, while the serum ammonia level is prevalent accumulation of aromatic amino acids and restoring the ap- not correlated with the presence or severity of HE. EEG may be useful propriate balance of BCCA levels might benefit HE patients [54].Colonic to diagnose and grade HE objectively. The classic EEG changes are and bowel cleansing with various laxatives, non-absorbable disaccha- high-amplitude low-frequency waves and triphasic waves. The degree rides, enemas administration, irrigation of the gut with mannitol via a of alterations is related to disease severity, i.e., more severe OHE is relat- p.o. tube, etc., may decrease colonic bacterial growth and potentiate ed to slower EEG activity [43–45]. However, some findings are not spe- the elimination of nitrogenous compounds. Lactulose is the mainstay cific to HE, and triphasic waves are found in many other metabolic of treatment to lower blood ammonia concentration, even though encephalopathies [46]. In patients with cirrhosis and altered mental sta- current standards of evidence-based medicine about its efficacy have tus, EEG is also important in excluding non-convulsive seizure activity. not met yet. Lactulose is catabolized by the bacterial flora to lactic acid Recently, Schiff and coworkers [47] applied a low-cost, user-friendly and acetic acid, which reduce colonic pH and favor the transformation

EEG system (the Emotiv EPOC 16 electrode cap), which also allows for of NH3 in the non-absorbable NH4+. Other effects include a EEG acquisition in settings with limited neurophysiological experience. hyperosmolar load that improves gastrointestinal transit, an increase This EEG recording tool is less expensive, wireless, non-invasive, porta- in stool volume which leads to increased fecal nitrogen excretion, and ble, and reusable, and it produces automated indices estimated to be an increased incorporation of ammonia by bacteria. Probiotics are capa- highly comparable to those from standard EEG. Brain CT imaging has ble to reduce plasma ammonia concentrations, but permanent clinically low sensitivity for detecting early signs or MHE. In contrast, acute epi- relevant benefit and positive outcomes have not been demonstrated sodes of OHE may display extensive cortical edema involving the deep [55]. Antibiotic treatment with oral neomycin, metronidazole, vanco- gray matter. An MRI scan can offer more specific information. In fact, mycin and rifaximin, has demonstrated to improve clinical and mental MRI with diffusion-weighted imaging (DWI) or fluid-attenuated inver- state and reduce the number of hospitalizations [56]. Other therapies sion recovery (FLAIR) images may show alterations of the cingulate such as dopaminergic agonists, benzodiazepine receptor antagonist gyrus and insular cortex, with sparing of the perirolandic and occipital flumazenil, L-ornithine-L-aspartate to lower serum ammonia levels, cortex. This pattern has been considered a characteristic feature of HE and levocarnitine have also been adopted, but with paucity of data on [48]. Cerebral edema, T1-weighted MRI hyperintensity of the globus the real benefit. Patients with nonresponsive HE should also be consid- pallidus and substantia nigra, white matter high signal intensities in- ered for interventional radiological occlusion of large spontaneous volving the hemispheric corticospinal tract, and diffuse cortical atrophy portal-systemic splanchnic shunts. The development of OHE should be have been commonly described in HE [49] (Fig. 1a). The clinical features considered a “high priority” criterion for OLT because a successful trans- of HE may be somewhat similar in several other clinical syndromes, plant procedure can improve the clinical course; however, prioritization which may enter the differential diagnosis. The most common diseases of the candidate based exclusively on severe HE is not common among in patients with liver disease leading to variable degrees of encephalop- various transplantation centers. Episodes of HE in liver transplant candi- athy and requiring diagnostic exclusion are reported in Table 4 [48,50]. dates usually recover without major neurological deficits, but severe or A detailed description of type B, and type C HE management is be- even non-severe forms of HE may have a considerably negative impact yond the scope of this article; briefly, the basic principles of treatment on post-transplant outcomes. A history of HE while on the waiting list of these syndromes firstly include the assessment of severity of the dis- may be a predictor of post-OLT neurologic disturbances, and some de- ease, with grade 1–2 HE patients being manageable as outpatients if suf- gree of persistent cognitive and/or motor deficit (permanent CNS dam- ficient adherence to treatment is demonstrated and caregivers are age) following the relapse of HE or MHE has been demonstrated [57]. 198 P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206

Worse long-term psychometric testing results and global cognitive and kinetic tremor may also be present in a mixed variety in severe function in patients who had HE prior to transplantation have been forms of WD [66]. Dysarthria with other features, such as ataxia, also demonstrated by Sotil et al. [58]. , and , as well as speech impairment, is found in al- Campagna et al. [59] reported that patients with a history of OHE most all cases of neurological WD. Ataxic dysarthria, hypophonic or showed greater improvements in cognitive alterations after OLT than slurred dysarthria with variations in word spacing and volume is very patients without a history; however, preoperative OHE was associated common in patients with tremor [67]. Dystonia is also frequent, and it with both poorer global cognitive performance and worse EEG at the often worsened with disease progression. Mild initial focal or segmental 1-year follow-up evaluation. Other studies have demonstrated that per- dystonia, , cervical dystonia (torticollis), and writer's manent deficits of memory, learning abilities, as well as minor motor may evolve into multifocal, bilateral and generalized dystonia, deficits may be irreversible and may persist even after the liver trans- with serious debilitating contractures in the most severe forms. A com- plant procedure [4,60]. However, in spite of potential and unpredictable mon dystonic facial expression is known as risus sardonicus. Parkinso- residual transient or permanent neurological deficits, and notwith- nian features mainly include bradykinesia, imbalance, and cogwheel standing the MELD-based organ allocation system does not assign prior- rigidity. Rigidity and tremor are typically asymmetric and are usually ac- ity for severe HE, patients with severe HE can have a rapid reversal of companied by other neurologic deficits, such as hypophonic speech and symptoms and good outcome with timely performed liver transplanta- micrographia [65]. is more often observed in younger tion [15]. patients. The movements are involuntary with unpredictable contrac- tions, and they are variable in speed and direction; they usually affect 5. Neurological manifestations of Wilson disease the distal limbs, but the face and trunk are also often involved. Slow writhing movements with a sinuous quality can be associated. Violent, Wilson disease (WD, hepatolenticular degeneration), an autosomal uncontrolled flailing movements of the extremities, with proximal mus- recessive disease caused by mutations in the ATP7B gene, is associated cle involvement (ballism), may be observed in advanced WD. Cerebellar with an impairment of cellular copper transport and consequent toxic involvement is associated with overshoot of the eyes and accumulation of copper in the liver, brain and cornea. In the liver, both limbs or ataxic dysarthria, limb incoordination, impaired acceleration macrosteatotic and microsteatotic changes may occur, followed by and braking, and impaired tandem gait. Frank limb ataxia is uncommon lobular necrosis, periportal inflammation, swelling, and diffuse necrosis [66]. Other manifestations include breakdown in the rhythm of repeti- [61]. When the disease progresses, an initial picture resembling tive, alternating single movements (dysrhythmia), breakdown of nor- autoimmune chronic hepatitis may lead to a mixed macronodular– mal coordination of joint rotations, hyperreflexia and myoclonus. Liver micronodular histological pattern, eventually resulting in manifest cir- transplant candidates affected by WD, while on the waiting list, may rhosis. In the setting of chronic “stable” liver disease, some patients manifest great variability in different neurological disturbances, often may develop acute liver failure and rapid functional impairment. in combination with the underlying hepatic manifestations. Among Brain lesions in WD are mainly localized in the lenticular nuclei, them, central pontine myelinolysis is often seen, and it may occur in where they present a brown color on gross pathology due to copper de- the absence of the commonly recognized etiological factors [68]. The di- position [62]. Other lesions, such as gliosis, cystic changes, and necrosis, agnosis of WD is based essentially on a high degree of suspicion in the may be discovered in the cerebellum, cerebral cortex, and presence of abnormal liver function and movement disorders with brainstem. Characteristic ophthalmologic manifestations, known as atypical presentations. Kayser–Fleischer ring should be sought by an ac- Kayser–Fleischer ring, are present in almost all patients with predomi- curate ophthalmological inspection with a slit lamp, and liver biopsy nant neurological WD and in approximately 50% of cases of hepatic should be performed in a timely manner to evaluate liver copper con- WD. Kayser–Fleischer ring, typically brown to brownish-green in color tent and structural degeneration. An increased urinary copper concen- and more visible in the superior and inferior regions of the cornea, is tration is highly suggestive of WD, as well as low serum levels of also due to copper deposits in the limbic region (Descemet membrane) ceruloplasmin, which is a copper-carrying protein normally bound to of the cornea. Apart from presenting with the clinical findings of 90% of circulating copper. Brain MRI images show areas of high T2 signal variable liver dysfunction, a large percentage of patients with WD are in the lentiform and caudate nuclei, thalamus, and white matter. The initially diagnosed because of the occurrence of neurological distur- classical signs of “face of the giant panda” in the midbrain, along with bances (neurologic WD) or psychiatric manifestations. Hepatic, neuro- tectal plate hyperintensity, central pontine myelinolysis-like abnormal- logical and psychiatric presentations of WD occur in roughly equal ities, and concurrent signal changes in basal ganglia, are common find- proportions [63]. ings [69,70]. Medical treatment of WD is very effective and includes Relevant psychiatric symptoms of WD include personality changes, pharmacologic agents capable of removing or detoxifying the tissue reckless, incongruous behavior, reactive depression or anxiety, irritabil- copper that has accumulated, reducing the amount of toxic free copper, ity, impulsivity and disinhibition, emotionality, apathy, mania, and cat- and preventing re-accumulation. Pharmacological treatment essentially atonia. Psychotic features are quite rare [64]. Subcortical dementia is includes: a) chelators (D-penicillamine [DPA], not indicated in case of associated with slowness of thinking, decreased attention, memory kidney disease or in patients who are allergic to penicillin) or trientine, loss, poor planning and decision making and executive dysfunction a second-line agent in case of intolerance to D-penicillamine; and b) may also be present. zinc salts, which mainly reduce copper absorption by increasing the en- Usually, neurologic manifestations of WD occur between early child- dogenous chelator metallothionein in enteric cells [71]. Ammonium hood and the fifth or sixth decade of life, and with a peak incidence be- tetrathiomolybdate, an agent which complexes copper in the intestinal fore the age of 20 [65]. Either when very subtle or when rapidly lumen and prevents its absorption, and in addition complexes copper progressive, neurological disorders may manifest in patients who are with albumin in the blood once it has been absorbed, has also been test- asymptomatic from their liver disease [64]. Typical features of neurolog- ed in patients with neurologic WD. However, its effects seem to be tran- ical WD include dysarthria, dystonia, tremor and parkinsonian signs. In sient and reverse with suspension of the drug [72]. Even though the earlier stages, poor coordination, tremor and loss of fine motor con- prospective, randomized studies directly comparing the safety and effi- trol are predominant, followed later by gait disturbance, rigidity, and cacy of these drugs in the treatment of WD are lacking, however, they pseudobulbar syndrome. Tremor can resemble ; the are included in the AASLD and EASL guidelines, which recommend arms, head and legs are frequently involved, with absence of voice trem- zinc salts as a first line of treatment in patients with neurological symp- or. In advanced WD, tremor may manifest with multiple position- and toms and in those who are presymptomatic, and chelators (DPA or task-dependent characteristics. The wing beating tremor (amplitude in- trientine) in non-neurological WD [73,74]. Zinc acetate therapy has creasing with duration of posture holding), rest tremor, postural tremor, been proved successful as preventative therapy and maintenance P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 199 therapy for neurological WD [65]. However, various authors only con- characteristics of fulminant liver failure; OLT may, in fact, potentially sider zinc as an adjunctive therapy for the initial treatment of symptom- correct the underlying hepatic metabolic defects. OLT may be also the atic patients especially those with a high copper load [75,76]. Zinc is only option for patients with ALF and chronic liver disease or those slow acting, it takes months to reverse copper toxicity, and careful mon- with cirrhosis and portal hypertension who are unresponsive to or itoring and follow-up for potential deterioration is recommended in the poorly compliant with chelating medications. Finally, a timely and symptomatic patients who better benefited from chelating agents [72]. justified OLT should be performed before neurological deficits become Improvement of symptoms in patients with neurologic WD is slow and irreversible. In fact, patients with severe long-term neurological impair- may be observed after 2–3 years. It has been shown that the neurologic ment are unlikely to recover after OLT. In the various evolving stages of status of WD patients may worsen with the initiation of D-penicillamine. WD, frequent and accurate neurological evaluations by an experienced The occurrence of new neurologic symptoms or any neurologic deteriora- neurologist, and preferentially by using standardized tools such as the tion after beginning of treatment, are likely due to the mobilization of he- Unified Wilson's Disease Rating Scale [86] are important. An accurate patic copper stores which may result in an increased brain copper assessment is essential not only to characterize the severity of disease exposure [77]. Hemodialysis, hemofiltration and plasma exchange with completely but also to emphasize the potential importance of fresh frozen plasma replacement, have also been used as temporizing performing OLT before neurological impairment becomes irreversible measures to remove copper. or even to contraindicate transplant in cases of definitive and perma- A low copper diet and avoidance of copper-rich foods are also rec- nent brain injury. ommended to prevent accumulation or re-accumulation of copper. In untreated WD and in patients scarcely adherent to treatment, 6. Acquired hepatocerebral degeneration (non-Wilsonian copper accumulation in the liver eventually leads to the development hepatolenticular degeneration) of cirrhosis, whereas the neurological disturbances progressively wors- en until serious dystonic, akinetic, and mutism complications occur. Chronic acquired hepatocerebral degeneration (AHCD) is a rare It has been recognized that, although OLT represents the definitive clinico-pathological syndrome in the context of chronic hepatic failure, treatment for WD after drug treatment failure, prioritization on the which occurs independently from the underlying liver disease and is transplant waiting list usually occurs when liver dysfunction signifi- not related to acute encephalopathy. It is characterized by extrapyrami- cantly worsens, an acute and severe impairment develops, or advanced dal, neuropsychiatric, and cerebellar disorders and almost always per- liver failure (unresponsive to treatment) is already present at the time manent damage to brain tissue. This heterogeneous neurological of diagnosis. Deterioration of neurological symptoms, even when signif- disorder has also been defined as non-Wilsonian hepatolenticular de- icant, is usually not considered for prioritization. The indication for OLT generation (NWHD) [87]. Patients affected by AHCD should not be ex- in patients with rather low-grade liver disease but disabling neurologic cluded from being listed for liver transplantation because OLT may be features is still debated [78]. However, successful reversal of behavioral the only effective therapy in some cases. The neuropsychiatric and cog- disorders, psychosocial functions, brain MRI findings, and improve- nitive manifestations of AHCD mainly affect the attention and executive ments of global neurological impairment with no recurrence of the dis- domains, whereas chronic injury to the cerebellum may manifest with ease have been reported following OLT in many case reports, small case ataxia and dysarthria, and basal ganglia involvement may induce abnormal series, and large multicentre studies [79–81]. In the recent literature and movements, such as dystonia, , and . The devel- in clinical practice, although many patients with intractable neurologic opment of a progressive hypokinetic-rigid syndrome in end stage liver fail- manifestations of WD have benefited from liver transplantation ure has been referred to as “cirrhosis-related parkinsonism”, which [82,83], evidence for both a positive final outcome after OLT and defin- appears to be unrelated to the etiology of liver disease. The incidence of itive reversal of neurological disturbances has not yet been demonstrat- cirrhosis-related parkinsonism has been reported at 1 to 21% [88]. ed. In fact, less favorable outcome when compared to transplantations Alterations in the basal ganglia, dysfunction of the circuits and dis- performed for other etiologies, have been reported in patients with pro- ruptions in the networks connecting the prefrontal and frontal–parietal gressive neurological deterioration not responsive to correct medical regions with the basal ganglia are considered the main pathogenetic treatment [84]. On behalf of the Italian AISF 2000 OLT Study Group, a mechanisms of parkinsonian motor features [89]. Histopathological scoring system was introduced by Medici et al. [81] to assess objectively brain damage has been attributed to a possible role of manganese toxic- the neurological symptoms of WD, not only retrospectively but also pro- ity. In the presence of significant porto-systemic shunts, an excessive spectively. According to this system, the impairment of neurological amount of manganese, usually removed via the hepatobiliary route, ac- signs (rigidity, bradykinesia, ataxia, tremor, dystonia, dyskinesia) and cumulates in the basal ganglia of patients with liver cirrhosis [90].The neurological function (walking, talking, eating and daily living activi- neurotoxic effects of increased brain manganese result in neuronal ties) is evaluated by the following score: 3 = no impairment; 2 = loss in the basal ganglia and cerebellum [91]. Other neuropathological mild impairment; 1 = moderate impairment; and 0 = severe impair- findings include patchy cortical necrosis, proliferation of Alzheimer ment. A higher score is suggestive of better preoperative neurological type II glial cells, and diffuse reactive fibrillary gliosis [92]. The potential- conditions and a reasonably better post-transplant outcome, while a ly broad range of clinical presentations of cirrhotic parkinsonism may lower score is indicative of poor neurological status and a more difficult suggest a multifactorial pathophysiology. However, a constant finding postoperative recovery. is the presence of portal hypertension and of different degrees of In accordance with both Wang et al. [80]. and Medici et al. [81]., liver portosystemic shunts, which are not always observed with Doppler ul- transplant may be the only life-saving treatment option for rapidly trasonography [93]. Many studies have documented a significant nega- evolving hepatic and neurological WD; however, patients with ad- tive influence of manganese on the (DA) neurotransmitter vanced neuropsychiatric and neurological symptoms showed a signifi- system, abnormality, which involves DA metabolism, receptor integrity, cantly lower survival rate than other WD patients. Furthermore, in the displacement from its storage site, transport and release from dopami- study by Medici, the presence of neuropsychiatric symptoms was a neg- nergic nerve endings [12,94]. An excessive amount of aromatic amino ative prognostic factor even when OLT led to complete resolution of the acids, which may shift to the brain across the blood–brain barrier, has neurological symptoms. A France experience on long-term results of been once advocated among the other causes by Fischer et al. [95], OLT for WD [85] reported a 5-year and 10-year patient survival rate of along with the presence of false dopaminergic neurotransmitters capa- 87%. In their study “pure neurological” patients have a significantly ble of inducing structural brain damages such as octopamine. Diagnosis worse prognosis after LT when compared to hepatic WD patients. Con- of AHCD is based on the assessment of cranial nerves, pyramidal and sidering the current data, emergency liver transplantation must be con- extra-pyramidal systems, cerebellar and sensory function, speech, cog- sidered when the initial manifestations of WD present with the nitive abilities and mental status. The onset of parkinsonian signs may 200 P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 be insidious, although the clinical picture can evolve rapidly into pro- pallidal MRI hyperintensities, have been reported following a successful gressive hypokinesia, hyperammonemia, tremor and rigidity, gait dis- OLT in N50% of patients with cirrhosis-related parkinsonism [110–112]. turbances and postural instability. Cognitive dysfunction and/or However, no improvement after OLT, and only transient improvement alteration of consciousness are often significant. Although parkinsonism followed by a gradual recurrence, has also been reported [110,113].A may coexist with HE in some cirrhotic patients, it should not be con- comprehensive neurological examination prior to transplant is manda- fused with a manifestation of HE because AHCD-related parkinsonism tory in order to assess the potential reversibility of the syndrome, and to presents long-term, persistent extrapyramidal signs and relatively less find out whether manganese deposition in the basal ganglia and nigral cognitive dysfunction [96]. The characteristics and severity of atypical substance had already resulted in extensive cell lesions and irreversible parkinsonism in potential candidates for liver transplantation can be cerebral damage. assessed using the Unified Parkinson's Disease Rating Scale (UPDRS); the International Cooperative Ataxia Rating Scale (ICARS) can be used to evaluate ataxia and cerebellar dysfunction [97,98]. 7. Hepatic myelopathy (cirrhotic or Porto-systemic myelopathy) Several features may differentiate cirrhosis-related parkinsonism from idiopathic Parkinson disease; the former syndrome presents a rel- Hepatic myelopathy (HM) is a rare and severe neurological compli- ative absence of resting tremor (kinetic hand tremor is more common cation of liver cirrhosis, characterized by chronic and progressive evolu- than resting tremor), early gait and balance dysfunction, mild cognitive tion and permanent loss of myelin in the dorsal or lateral corticospinal impairment at the time of presentation, symmetric signs more often tracts of the . It affects approximately 2.5% of patients with than asymmetric, variable/transient signs and no levodopa responsive- chronic liver dysfunction [114]. The clinical features of HM have ness [12,90]. These differences suggest that the cirrhotic-parkinsonism been reported in association with HE, post-shunt surgery or post- is different from idiopathic Parkinson disease, and various studies TIPSS (transjugular intrahepatic portal systemic shunting) proce- have reported clinical improvement in extrapyramidal symptoms after dures [115]. Increasing occurrence of HM has been documented OLT [99,100]. However, due to substantial, irreversible neuronal cell with the diffusion of TIPSS as the standard procedure for refractory loss in chronic advanced liver disease, parkinsonism in cirrhosis does variceal bleeding [116]. not always reverse with OLT [101]. The routine diagnostic work-up in- Enhanced portosystemic shunting, leading to nitrogenous products cludes brain MRI and single photon emission tomography (SPECT) of bypassing the liver, overproduction of fatty acids, indoles and mercap- the dopaminergic system (DaT-scan). In AHCD, T1-weighted MRI is tans, vitamin B deficiency, increased ammonia levels, hypoproteinemia characterized by signal hyperintensity in the internal pallidum, puta- and malnutrition are among the most commonly recognized causes of men, caudate nucleus, capsula interna, mesencephalon, and cerebellum. HM. Toxic metabolites and neurotoxins cause white matter demyelin- These abnormalities are associated with manganese deposition in the ation in the brain and the spinal cord, with a selective predisposition basal ganglia nuclei, but they may also be present in cirrhotic patients for the motor system. Neuropathological studies have demonstrated without extrapyramidal signs [102–104].Burkhardandcoworkers symmetrical demyelination, predominantly of the lateral corticospinal demonstrated that MRI hyperintensities may also involve the substantia pyramidal tracts. Demyelination is a hallmark of the early stages of nigra in patients with AHCD-associated parkinsonism symptoms [90]. HM, but with disease progression, a variable degree of irreversible axo- Neuroimaging is very helpful in differentiating AHCD from genetic nal loss occurs that does not extend beyond the cervical cord level hepatolenticular degeneration (Wilson disease), as previously reported. [115–117]. The typical features of HM include an insidious onset and SPECT studies of the striatal dopamine D2 receptors and measurement the progressive development of lower limb spastic or quad- of dopamine transporter function have also been applied to diagnose riplegia in the presence of symptoms of chronic liver disease, associated the severity of cirrhosis-related parkinsonism [105,106]. The beneficial with extensive portosystemic collateral circulation. Difficulty in walking effects of L-DOPA in the treatment of cirrhosis-related parkinsonism due to stiffness and weakness of the lower limbs, limping gait, and drag- have not been fully demonstrated, although in some reports, improve- ging of the feet, along with loss of proprioception and vibratory senses ments of hypokinesia and rigidity were noted following L-DOPA treat- in the territory of the posterior column, may be observed. Asymmetrical ment [103]. It has been suggested that dopaminergic treatment can symptoms may characterize the initial phases, but both legs are severely only succeed if striatal dopamine D2 receptors are available, both at affected in the overt disease stage. Patients develop progressive pure the presynaptic and post-synaptic sites, and that the loss of DA trans- motor spastic paraparesis without or with minimal involvement of the porter sites could contribute to the lack of response to L-DOPA [88]. upper extremities and without sensory, bladder or bowel disturbances. Treatment with bromocriptine (DA receptor agonist) has been associat- Neurologic examination usually reveals normal sensory findings, hyper- ed with significant improvements in motor coordination, gait ataxia and active muscle stretch reflex of the lower extremities, muscle rigidity tremor. Ammonia-lowering agents such as lactulose and antibiotics, and with normal muscle power, no evident muscle atrophy, and extensor ethylenediaminetetraacetic acid (EDTA), a chelator of manganese, have plantar responses. Although the symptoms of spinal cord injury do not also been administered, but with inconclusive results [95]. The adminis- parallel the mutable symptoms of HE, some similarities between HM tration of trientene, another drug with the capacity to chelate manga- and HE can be found, such as the coexistence of severe porto-systemic nese, was found to decrease circulating manganese, attenuate MRI shunting, common cerebral and spinal MRI abnormalities, and variable signal hyperintensities, and improve parkinsonism [107]. motor deficits at the lower extremities [118]. Sensorial involvement or Marked improvement of neurological signs and radiological abnor- sphincteric impairment is uncommon, as well as muscular atrophy. malities with persistent reversibility, was observed in two patients The disease mostly affects men, and in the severe forms it rapidly pro- after the administration of branched-chain amino acids (prolonged i.v. gresses until confining them to a wheelchair. Because axonal loss occurs infusion of 350–500 ml/day of BAA, followed by 100–150 g/day oral in the advanced stage of HM, an early diagnosis, at the time of initial de- BAA) [108], suggesting also a significant role of aromatic amino acids myelination of the spinal cord, is mandatory to include the candidate on in the AHCD pathogenesis. the liver transplant list. Diagnosis of HM remains difficult and may be The beneficial effect of liver transplantation, both in improving neu- based on the exclusion of other causes of spastic paraparesis. Problems rological disorders and in attenuating or even eliminating abnormal in diagnosis are associated with often coexisting HE, which may also MRI signals [100], has been reported in various case reports and in present with movement disorders. MRI spinal cord abnormalities and small case series. The association of parkinsonism, dementia and T1- motor-evoked potential (MEP) alterations may be suggestive of ad- MRI signal hyperintensity was considered by Fabiani et al. a determi- vanced HM. An early assessment of the central motor conduction time nant factor for indicating a liver transplant [109]. An improvement of with MEP studies (more sensitive), while on the transplant waiting bradykinesia, gait difficulties, rigidity, tremor and normalization of list may be helpful for an early diagnosis. P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 201

Abnormal MRI signal alterations of the brain corticospinal tract with rupture of myelin sheaths, may affect all of the fiber tracts, with sub- FLAIR images have also been reported in HM, emphasizing the possible stantial axonal damage. Moreover, concomitant significant deficits in involvement of lesions beyond the spinal cord [118,119]. organic osmolytes, which are a common condition of alcoholic and mal- Various disorders must be considered in the differential diagnosis, nourished patients, place oligodendrocytes at a high risk for cell shrink- including neurodegenerative amyotrophiclateral sclerosis, multiple age, permanent inflammatory infiltrates, and axonal demyelination sclerosis, hereditary spastic paraplegia, paraneoplastic syndromes, [129]. Although demyelination prevalently occurs in the central pontine demyelination syndromes, such as neuromyelitis optica, toxic myelopa- structures (Fig. 2), it also affects some extrapontine regions, including thy, radiation myelopathy, and spinal cord damage caused by compres- the midbrain, thalamus, basal ganglia nuclei, and cerebellum, in at sion or vascular disease [110]. Treatment strategies commonly adopted least 10% of patients (Fig. 3). ODS, rather than central pontine to reverse HE, such as reducing ammonia production and nitrogen ab- myelinolysis, more appropriately refers to demyelination in extrapontine sorption, and administration of benzodiazepine receptor antagonists, regions after the correction of hyponatremia [127,130]. Clinical manifes- have demonstrated little benefit in patients with HM [118].Othermea- tations of central pontine myelinolysis include an enormous variety of sures have included limitation of the intake of protein in the diet, large symptoms, such as head and neck weakness, lethargy, confusion, seizures, doses of B group vitamins, neurotrophic drugs, oral neomycin, lactulose, dysarthria, dysphagia, vertical ophthalmoparesis, initial flaccid quadriparesis, xifaxan, gabapentin, and pentoxifylline, control of enteric bacteria rapidly evolving paraparesis or quadriparesis (usually symmetrical), growth, and colonic exclusion [120–122]. delirium and coma. Neurological disorders may vary from minimal All these procedures have failed to produce significant improvement symptoms to a full “locked in” syndrome, with of the lower as spastic paraparesis seems to be refractory to medical treatment, and cranial nerves and limb muscles, vertical eye movement reduction, worsen even when encephalopathy is effectively averted. Occlusion of and intact alertness and breathing ability [131]. Due to the sometimes large splenorenal shunt using endovascular interventional procedures non-specific or minor signs, extrapontine myelinolysis may be under- has also been reported as an effective alternative therapeutic option, recognized. The most common manifestations of extrapontine however, an impaired gait and a progressive worsened mobility were myelinolysis may include tremor, abnormal movement disorders with observed in the long term course [123]. OLT should be considered the choreoathetosis, catatonia–dystonia, ataxia, myoclonic jerks, perma- first therapeutic option and the only approach to prevent disease pro- nent parkinsonism and mutism [131]. Central pontine myelinolysis, gression; therefore, an early diagnosis of HM and exclusion of other sim- which develops during postoperative recovery from liver transplanta- ilar syndromes are fundamental for transplant list prioritization, tion surgery, may initially manifest with confusion and/or weakness because OLT may improve and reverse the neurological motor deficit or other symptoms similar to peripheral neuropathy, muscle disease and prognosis only when performed on a timely basis [118,124]. The or critical illness neuromyopathy [132]. Neurological examination early stage of the disease, in fact, only involves demyelination of the spi- should detect the severity of the ODS and the involvement of the pons nal cord, while at the advanced stage, the benefit from OLT is minimal or or adjacent brainstem areas or more distal supratentorial structures. absent due to the occurrence of permanent axonal loss. Clinical and neu- , spastic quadriplegia, and involvement of upper roimaging improvements are the successful consequences of an expe- motor neurons or the corticospinal tracts are characteristic findings, dited OLT. However, despite the awareness of positive neurological with variable limb weakness, increased limb tone, hyperactive reflexes, outcomes achieved by early OLT, liver transplant candidates with evi- and the Babinski sign. Sensory function abnormalities are quite rare. dent HM and low MELD are not automatically prioritized on the waiting Abnormalities of brainstem-evoked potentials may be present, and list. The first report on prioritization for transplantation with consider- diffuse bihemispheric slowing may be observed on EEG. However, the ation of HM as an MELD exception was published by Caldwell et al. in classical symmetric demyelination in the pons is only detected with 2010 [118]. The authors were able to accomplish expedited OLT with a brain MRI, which can also demonstrate extrapontine myelinolysis good neurological outcome after the granting of MELD exception points (Figs. 2 and 3). On MRI, hyperintense lesions caused by relatively in- for HM and upgrading MELD every three months. Waiting for a high creased water content, without contrast enhancement, are visible on MELD may lead to possible worsening of HM, thus diminishing the like- T2 images, while on T1 sequences they are detected as hypointense le- lihood of both clinical and electrophysiological recovery following the sions. Osmotic myelinolysis is often characterized by concomitant in- transplant procedure. volvement of the basal ganglia and pons, the latter with a typical trident-shaped hyperintense signal in the central part with sparing of 8. Osmotic demyelination syndrome the ventrolateral pons and descending corticospinal tracts on T2- weighted or FLAIRM images [13]. However, a consistent drawback of Patients with chronic liver failure are at increased risk of chronic se- brain MRI is that myelinolysis may become clearly positive only 25– vere hyponatremia because of pseudo-hyponatremia, hypovolemia, 30 days after disease onset (initially negative). DWI imaging has the “beer” potomania syndrome in alcohol-addicted patients, malnutrition, ability to detect lesions not yet detectable on T2, thus allowing for an prolonged diuretic use, and cerebral salt wasting syndrome [125].Cere- earlier diagnosis [133]. Prevention of either the occurrence of severe bral edema and neurologic symptoms can arise due to water movement hyponatremia or the overly rapid rate of correction of the serum sodium into the brain caused by hypotonic hyponatremia, but usually cerebral is fundamental for preventing ODS. Patients with signs and symptoms adaptation with lowering of the cerebral volume reduces the likelihood consistent with ODS typically require ICU admission, with supportive of these complications. Central pontine and extrapontine myelinolysis, therapies aiming at potentially re-lowering their serum sodium and also called osmotic demyelination syndrome (ODS), is more common preventing any deleterious neurological and systemic manifestations in patients with alcohol-related chronic liver disease, and most of the of the disease. The approach to re-lowering serum sodium is the same cases are associated with overly rapid correction of chronic in patients who have exceeded correction limits but who have not yet hyponatremia. Rapid and large increases in serum sodium levels make developed manifestations of ODS. The optimal strategy to reverse the pontine and extrapontine structures extremely vulnerable to injury hypernatremia is still unclear, and the efficacy and safety unknown. Ad- induced by increased osmolarity. A similar mechanism, i.e. overtreat- ministration of hypotonic fluids, prevention of development of a water ment of chronic hyponatremia in the presence of decreased organic diuresis (i.e., urine osmolality less than 200 mosmol/kg), maintenance osmolytes, is also involved in the development of central pontine of stimuli to increase antidiuretic hormone release, general supportive myelinolysis after liver transplantation [126]. The osmotic effects in measures, and extracorporeal treatments are among the conventionally the setting of rapid correction of sodium levels particularly harm the ol- recognized measures for the hypernatremia-induced ODS. Quick re- igodendrocytes, which constitute the myelin sheaths [127,128]. Sym- lowering of sodium (within four hours of symptoms) has been associat- metrical myelin damage characterized by splitting, vacuolization, and ed with better outcomes in animal models; in humans no conclusive 202 P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206

Fig. 2. Brain MRI of pontine myelinolysis. MRI FLAIR axial images of the pons (a) and the corresponding magnification (b). The images show the symmetric signal alteration in the basis pontis, with a “trident” shape, typical of central pontine myelinolysis. evidence of benefit is reported when treatment has begun more than neuropathy in liver transplant candidates have not yet been defined, 24 h after the onset of ODS symptoms [134,135]. The rate of re-lowering and although nerve conduction abnormalities may be present in a sub- should not exceed 1 mEq/L per hour. Careful monitoring of the serum stantial percentage of patients, a causal relationship between liver dis- sodium concentration (initially, every two to three hours) is essential ease and neuropathy has been questioned [139,140]. Kharbanda et al. to avoid serum sodium rising again too quickly when urine output sig- [141] reported manifestations of peripheral neuropathy in a significant nificantly increases following dextrose load. Administration of intrave- number of patients with liver cirrhosis; clinical signs of peripheral neu- nous immunoglobulins over the course of a few days, thyrotropin ropathy were found in 21% of patients, and nerve conduction studies releasing hormone, methylprednisolone, and immunoglobulins associ- were abnormal in 73% of their patient population. Neuropathy was ated with plasmapheresis, have also demonstrated to be effective in present regardless of the etiology of cirrhosis. Both axonal sensory and this syndrome. The mechanism of clinical improvement has been attrib- motor polyneuropathy and autonomic neuropathy have been described uted to the reduction in inflammatory mediators with potential preser- in alcohol-related and non-alcohol-related cirrhosis, with the severity of vation of the blood–brain barrier [132,136]. Patients with severe ODS neuromuscular dysfunction not strictly associated with the severity of frequently develop aspiration pneumonia and long-lasting respiratory primary liver disease [142,143]. However, patients with child's class B failure; tracheostomy and mechanical ventilation are often required. and class C are usually affected by more severe neuropathy scores Recovery from ODS is extremely variable, incomplete, and long lasting; than those with child's class A [141]. Subclinical onset of peripheral neu- full recovery from severe forms is rare, and requires an extensive and ropathy, slow progression, and evident diagnosis only on electrophysi- prolonged neurorehabilitation. The commonest neurological sequelae ological studies may have been observed in many patients. Liver in survivors are cognitive deficits and extrapyramidal or cortico- transplant candidates may present with mild clinical signs, such as bulbar disorders. Many severe complications, such as ventilator depen- motor weakness, paresthesias, absent ankle jerks, and distal sensory dency, decubitus ulcers, muscle wasting, infectious disease and sepsis, loss. Abnormal muscle strength, muscle tone, muscle stretch reflexes, may affect the prognosis and increase the risk of death [137]. light touch, and pinprick and vibratory sensations are common. Anom- alous electrophysiological testing, such as abnormal sensory and motor 9. Peripheral neuropathy in liver diseases conduction velocities, reductions in amplitudes and prolonged median F-wave latency, etc., can be observed at the ulnar, median, sural and pe- Chronic excessive alcohol assumption, hepatitis C, and other chronic roneal nerves. Sensory-motor polyneuropathy and decreased muscle liver diseases have been recognized as important causes of neuropathies strength are among the various causes leading to an increased risk of and myopathies. Worsening of liver function is usually followed by falling and gait unsteadiness in patients with cirrhosis [35,144]. Axonal worsening of peripheral neuropathy, independent of the etiology of degeneration in neurons of both sensory and motor systems is the typ- the liver disease [138]. The incidence and severity of peripheral ical feature of alcohol-related peripheral neuropathy. Chronic alcohol P. Feltracco et al. / Transplantation Reviews 31 (2017) 193–206 203

Fig. 3. Brain MRI of extrapontine myelinolysis. Brain MRI: coronal (a,b) and axial (c,d) T2-weighted images showing symmetric hyperintense lesions at the level of the cerebral peduncle and centrum midollare (open arrowheads) and at the level of the pallidum (gray arrow heads) and putamen (short arrows) consistent with extrapontine myelinolysis. abuse, vitamin deficiencies, malnutrition, and “neurotoxins” are known diabetic neuropathy, lumbosacral plexopathy, amyotrophic lateral scle- to contribute to alcoholic polyneuropathy [145]. Patients with alcohol- rosis, peripheral and central nervous system diseases caused by vitamin related polyneuropathy experience pain and motor weakness in the deficits, and Guillain-Barre syndrome. Treatment options for peripheral feet, toes, and distal lower extremities and subsequently in other parts neuropathy will depend on the type of symptoms that the individual is of the body; multiple peripheral nerves are damaged. Axonal degenera- experiencing. Avoidance of alcohol intake is the most important step in tion often begins before clinical manifestations, which usually present treating alcohol induced peripheral neuropathy. Correction of malnutri- with a gradual onset over months or even years [146]. Sensory symp- tion, and in particular supplementation of B group vitamins and vitamin toms, such as paresthesias, dysesthesias, and weakness, generally ap- E are essential for the recovery of the glial and neuronal cells. Analgesics, pear prior to motor symptoms, and over time, the symptoms progress antidepressants and antiepileptic drugs seem to help with dealing with toward more proximal parts of the limbs. Symptoms develop symmet- the discomfort and pain associated with peripheral neuropathy. The ef- rically; the legs are usually affected first, followed by the arms and the ficacy of OLT on reversing peripheral and autonomic neuropathies asso- hands (stocking-and-glove pattern of sensory disturbances) [147]. Mus- ciated with severe chronic liver disease has not been studied cle , along with a burning sensation in the feet and calves, are extensively. Despite the paucity of literature clear benefits and signifi- very common. Painful sensations in the arms and legs may become con- cant improvement of muscle strength and other clinical signs have stant (“pins and needles,”), sharp, or lancinating in some individuals. been reported following OLT in various case reports and small case se- Motor deficits, such as weakness, muscle , muscle atrophy, gait ries. Abnormalities associated with the distal sensorimotor neuropathy ataxia, erectile dysfunction, etc., may follow the sensory deficits, but and slowing of sensory nerve conduction velocities in the un- they are sometimes evident at initial presentation. At neurological ex- myelinated small axons resolved almost completely following success- amination, the typical findings of alcohol-related polyneuropathy may ful transplant procedures [148–150]. Gane et al. [150] stated that pe- be detected in the presence of classical systemic manifestations of ripheral neuropathy in a patient with alcoholic cirrhosis is reversible chronic liver insufficiency; they include reduced sensation to vibration and should not constitute a contraindication to OLT, even when the neu- in a “stocking-to-glove” distribution, muscle wasting in the lower ex- ropathy is disabling. tremities, decrease in motor power, reduced deep tendon reflexes, ab- normalities of the gastrocnemius-soleus reflexes, reduced ankle/toe 10. Conclusion dorsiflexion, thermic and proprioceptive disorders, and a variable de- gree of gait ataxia. 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