Page 1 of 110

The Nervous Liver: Neurological complications associatedwith Cirrhosis & Liver Transplantation

Poster No.: C-1397

Congress: ECR 2014

Type: Educational Exhibit

Authors: A. Arora, A. Mukund, S. Rajesh, Y. Patidar, S. K. Sarin; New Delhi/IN

Keywords: Transplantation, Metabolic disorders, Education and training,Education, MR-Diffusion/Perfusion, MR, CT, CNS

DOI: 10.1594/ecr2014/C-1397

Any information contained in this pdf file is automatically generated from digital materialsubmitted to EPOS by third parties in the form of scientific presentations. Referencesto any names, marks, products, or services of third parties or hypertext links to third-party sites or information are provided solely as a convenience to you and do not inany way constitute or imply ECR's endorsement, sponsorship or recommendation of thethird party, information, product or service. ECR is not responsible for the content ofthese pages and does not make any representations regarding the content or accuracyof material in this file.As per copyright regulations, any unauthorised use of the material or parts thereof aswell as commercial reproduction or multiple distribution by any traditional or electronicallybased reproduction/publication method ist strictly prohibited.You agree to defend, indemnify, and hold ECR harmless from and against any and allclaims, damages, costs, and expenses, including attorneys' fees, arising from or relatedto your use of these pages.Please note: Links to movies, ppt slideshows and any other multimedia files are notavailable in the pdf version of presentations.www.myESR.org

Page 2 of 110

Learning objectives

That there is a relationship between the brain and the liver has been known for manyyears, and patients with chronic liver disease frequently experience a wide spectrum ofneurological problems that can adversely affect patient's neurocognitive functioning [1-3].

These neurological problems range from neurological complications such as hepaticmyelopathy, acquired hepatocerebral degeneration, cognitive and mental status changessuch as hepatic encephalopathy to metabolic, infective and hemorrhagic complicationsof liver cirrhosis; and, can severely restrict the patient's functioning and also result insignificant morbidity and mortality [3-6].

Fig. 1: The Nervous Liver!References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 3 of 110

The present exhibit aims:

1. To appraise the wide array of neurological syndromes and disorderes that canbe associated with liver cirrhosis, highlighting their most pertinent neuroimagingmanifestations and providing an up-to-date information on these relatively understudiedentities.

2. To study and illustrate perioperative neurological complications which may originatebefore, during or after orthotopic liver transplantation.

Background

LIVER-BRAIN AXIS

Normal brain functioning depends on several aspects of normal liver functioning. Forexample, the liver supplies certain nutrients to the brain that the brain itself cannotproduce. The liver also cleanses the blood of substances that could damage brain cells(i.e., neurotoxins, for e.g. ammonia, manganese, and other chemicals).

In chronic liver disease and cirrhosis, the liver loses its capacity to remove toxicsubstances from the blood due to loss of functional liver cells (i.e., hepatocytes).Moreover, some of the blood that normally flows through the portal vein into the liver forcleansing is diverted directly into the general circulation without first passing through theliver, a phenomenon known as portal-systemic shunting. As a result, the shunted blood isnot detoxified and blood levels of toxic substances rise. Persistently elevated neurotoxinlevels can damage brain cells and cause a wide spectrum of neurocognitive decline.

NEUROLOGY OF LIVER CIRRHOSIS

A neurological syndrome associated with a liver disease may affect the CNS, theperipheral nervous system, or both; and, could represent a direct complication of thedisease, or part of spectrum of pathologies that affect the brain and liver concurrently[1-6].

Boradly, neurological disorders in cirrhosis can be attributed to:

Page 4 of 110

(A) Direct effects of cirrhosis on the nervous system:

• Neuroimaging alterations with/without clinical symptoms• Hepatic encephalopathy• Cirrhotic or hepatic myelopathy• Acquired hepatocerebral degeneration• Cirrhosis-related Parkinsonism• Cirrhosis related intracerebral hemorrhage• Infective comlpications of cirrhosis• Raised intracranial pressure (acute-on-chronic liver failure)

(B) Neurological complications related to chronic alcohol use:

• Osmotic demyelination syndromes• Wernicke encephalopathy• Marchiafava-Bignami disease• Alcohol withdrawal syndrome• Cerebral atrophy and cognitive dysfunction• Alcoholic cerebellar degeneration

(C) Induced by a factor that also contributes to the (hepatic) disease:

• Wilson disease• Hepatitis C virus infection

(D) De#cits unrelated to liver disease, such as:

• Residual de#cits of prior strokes

LIVER TRANSPLANTATION-RELATED COMPLICATIONS

Among solid organ transplant recipients, recipients of liver transplantation have thehighest incidence of neurological complications. Neurological complications followingliver transplantation have an overall incidence of 13 - 47%.

These complications can be broadly classified into:

(1) Immunosuppressive neurotoxicity

(2) Opportunistic infections

Page 5 of 110

(3) Osmotic demyelination

(4) Cerebrovascular complications

(5) Post transplant encephalopathy

(6) Hepatic encephalopathy

(7) Seizures

(8) Post transplant lymphoproliferative disorder

Findings and procedure details

NEUROLOGY OF LIVER CIRRHOSIS

NEUROIMAGING CHANGES IN CHRONIC LIVER DISEASE

• Cirrhotic patients frequently display changes on neuroimaging studies;although, these patients may or may not develop neurological symptoms[1-7].

• The most striking neuroimaging manifestation includes high symmetrical andbilateral signal intensities of various extents involving the basal ganglia andthe hypothalamus on T1WI [1, 7, 8].

• Hyperintense signals in the basal ganglia, namely the globus pallidus, canbe seen in as many as 70-100% of patients with liver cirrhosis (Fig 2) [1, 7].

Page 6 of 110

Fig. 2: Symmetrical T1-hyperintensity involving the bilateral globus pallidus (arrows) inan asymptomatic 54-year old male with hepatitis-B related liver cirrhosis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Other sites of involvement include the pituitary gland, contiguous internalcapsule of the hypothalamus, putamen, caudate, substantia nigra, andmesencephalic tegmentum (Fig 3) [8].

Page 7 of 110

Fig. 3: Axial T1-weighted MR images showing hyperintense signal of the caudatenucleus (black arrows) in addition to the involvement of the globos pallidi (whitearrows).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• The exact causes and mechanisms of the increased signal intensity remainindefinite, however several hypotheses have been proposed. Deposition ofparamagnetic substances, particularly manganese (Mn), is speculated to beresponsible for the signal alteration [1, 7, 8].

• Manganese (Mn) deposition has been attributed to liver dysfunction(hepatocellular failure) and/or portosystemic shunting [7-9]. In addition,pallidal deposition of manganese also reflects the presence of an adaptiveprocess designed to improve the efficacy of ammonia detoxification byastrocytes [10, 11].

• Although the mechanisms of manganese neurotoxicity are poorlyunderstood, there is evidence to suggest that manganese deposition in thepallidum may lead to dopaminergic dysfunction [12, 13].

• The pituitary gland is another commonly affected site shown on the MRimages; and when involved appears homogeneously bright on spin echoT1-weighted images. The hyperintense signal of the pituitary gland makesit impossible to distinguish between the normal isointense anterior pituitarysignal and the posterior pituitary hyperintensity [8].

• Abnormalities on T2-WI within the globi pallidi have been reported toaccompany the T1-WI findings, but these findings may be masked by T1shortening (Fig 4) [7].

Page 8 of 110

Fig. 4: (A) Axial T2-WI and (B) FLAIR sequence delineating subtle symmetricalhyperintensity involving the bilateral lentiform nuclei in a young 26-year old lady withliver cirrhosis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Asymptomatic symmetric high-signal intensity in the hemispheric whitematter on fast-FLAIR MR images is present in cirrhosis. Normalization ofthis finding after successful liver transplantation and its correlation with MTRvalues suggest that this signal abnormality reflects mild edema (Fig 5) [8].

Page 9 of 110

Fig. 5: A 40-year old male with alcoholic liver cirrhosis and grade-I hepaticencephalopathy. Fast-FLAIR MR images reveal diffuse high-signal intensity in thehemispheric white matter on either sides.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• DWI (and ADC maps) has also identified abnormalities within theperiventricular white, thalami, and basal ganglia in studies of patients withcirrhosis with hepatic encephalopathy [9, 10].

• Although no significant relationship has been demonstrated betweenthe presence of these signal intensity changes and the patients'neuropsychiatric status, nevertheless, their presence has been shown torelate to both the severity of the liver disease and the presence and degreeof portal-systemic shunting of blood [10].

• Another common neuroimaging manifestation in cirrhotic patients is thepresence of cerebral atrophy. Zeneroli et al reported brain atrophy in 87.5%of alcoholic and in 50% of nonalcoholic liver cirrhosis patients (Fig 6) [14].

Page 10 of 110

Fig. 6: Cerebral atrophy accompanying typical intracranial signal intensity changesin a 36-year old patient with long standing cryptogenic cirrhosis. Axial T1-WI showssymmetrical T1-prolongation of the basal ganglia (asterisk) representing manganesedeposition. Attendant widening of the sylvian fissures (thick arrows) and ventricularenlargement (thin arrows) suggest cerebral parenchymal atrophy.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Computerized (CT or MR) morphometric studies of liver-disease brains haverevealed ventricular enlargement, cisternal and sulcal prominence, selectiveloss of subcortical white matter, and prominent subarachnoid CSF spaces.

• Brain atrophy in alcoholic patients can be attributed at least in part to thetoxic effect of alcohol, whereas, brain atrophy in nonalcoholic liver cirrhosisseems to indicate that the chronic exposure to toxins leads to neuronalalterations and cortical loss (Fig 7) [14-16].

Page 11 of 110

Fig. 7: Ventricular enlargement (white arrow) and subarachnoid CSF-space (sylvianfissure) widening represent cerebral involutional changes in a 30-year old male withalcohol induced liver cirrhosis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Amodio et al has shown that brain atrophy in liver cirrhosis is associatedwith a poor psychometric performance and both brain atrophy and EEGalterations independently predict cognitive dysfunction in cirrhotic patients[16].

• Classical, MR spectroscopy (MRS) findings include elevated glutamine/glutamate peak coupled with decreased myo-inositol and choline signals onproton MRS [17].

HEPATIC ENCEPHALOPATHY

• Hepatic encephalopathy (HE) is the most frequent cause of altered mentalstatus and coma in cirrhotic patients.

• Patients suspected of acute HE are typically subjected to CT or MR imagingto exclude emergent phenomena such as intracranial hemorrhage orinfarction [18].

• Classically, the most accepted MR imaging finding in patients with chronichepatic failure has been hyperintensity on T1-WI in the globi pallidi related

Page 12 of 110

to manganese, but this only variably correlates with the plasma ammonialevels and acute HE symptoms.

• Acute HE has an acute phase followed by a chronic one. Pathologically,during the acute phase, there is acute brain edema, and in the chronicphase, there is a thin cortex and cortical laminar necrosis [18].

• The proposed cytotoxic edema mechanism in HE is hyperammonia inducingintracerebral accumulation of glutamine, resulting in astrocyte swelling andbrain edema [18].

• On MR imaging, presence of extensive cortical edema including the deepgray matter, with symmetric involvement of the cingulate gyrus and insularcortex on DWI or FLAIR imaging, associated with sparing of the perirolandicand occipital cortex, appears to be a unique imaging feature of acute HE(Fig 8) [19, 20].

Fig. 8: Typical imaging manifestations of HE. Fast FLAIR images exhibit symmetricalcortical edema involving the insular cortex (arrow) and cingulate gyrus (arrowhead).Note that the occipital cortex (asterisk) is characteristically spared.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 13 of 110

• Thus, the cingulate gyrus and insular cortex appear to be particularlyvulnerable to hyperammonemic-hyperglutaminergic encephalopathy, whilethe perirolandic and occipital cortex seem relatively resistant. These MRmanifestations therefore should alert the radiologist to the possibility of acutehyperammonemic encephalopathy in appropriate clinical settings (Fig 9) [19,20].

Fig. 9: Acute HE. DWI displaying extensive symmetrical gyral edema whichcharacteristically involves the insular cortex (arrow) and cingulate gyrus (arrowhead);and, typically spares the perirolandic and occipital cortex (dotted arrow).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 14 of 110

• Diffuse cortical involvement although can be reversible; often has a higherpotential for neurologic sequelae [21]. Concomitant subcortical white matter,basal ganglia, thalami, and brain stem involvement suggests more severeinjury [19].

• The MRI extent of cortical involvement on FLAIR and DWI has been shownto strongly correlate with the maximal plasma ammonia level, and plasmaammonia level correlates well with the clinical outcome. However MRIseverity correlates only moderately with the clinical outcome [21, 22].

• On proton MR spectroscopy: an elevated glutamine/glutamate peak coupledwith decreased myo-inositol and choline signals, representing disturbancesin cell-volume homeostasis secondary to brain hyperammonemia, constitutethe characteristic imaging manifestations of HE.

• Follow-up MR imaging may show diffuse cortical atrophy with T1 highsignals, involving both basal ganglia and temporal lobe cortex, representingcortical laminar necrosis (chronic stage of HE) (Fig 10) [19].

Fig. 10: Chronic HE. Axial T1-WI showing cortical atrophy with gyriform T1-hyperintensity representing cortical laminar necrosis in a follow-up case of livercirrhosis with recurrent episodes of grade-3 HE in the past.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• As opposed to cortical laminar necrosis of chronic HE, cortical laminarnecrosis of hypoxic brain damage preferentially involves the watershed

Page 15 of 110

zones or the parieto-occipital regions (as opposed to the temporal lobecortices) [19].

• It is important to note that although pallidal (T1-WI) hyperintensities arefound in approximately 90% of patients with cirrhosis, these signal-intensityalterations are not closely linked to the presence of HE.

• Patients with cirrhosis and no clinical, neuropsychological, orneurophysiologic signs of HE can also show severe signal-intensityalterations, whereas others with manifest HE may present only slight signal-intensity alterations.

ACQUIRED HEPATOCEREBRAL DEGENERATION

• Acquired (non-Wilsonian) hepatocerebral degeneration (AHD) is a rarechronic progressive debilitating neurologic syndrome that occurs in patientswith chronic liver disease associated with multiple metabolic insults [23, 24].

• The pathophysiology and the locations of the cerebral injuriesare incompletely understood and are not necessarily related tohyperammonaemia. However, cerebral deposition of manganese may havea pathogenetic role [25, 26].

• AHD occurs in approximately 1% of patients with liver cirrhosis and seemsrelated to portosystemic shunts [23].

• Clinically, it is characterized by a combination of parkinsonism andcerebellar signs, with neuropsychiatric changes and movement disordersusually being prominent clinical manifestations [23-26].

• The syndrome is poorly responsive to medical (antiparkinsonism drugs)therapy, thus being considered largely irreversible [25].

• MR imaging reveals pallidal and extrapallidal lesions in most patients,probably reflecting intracerebral deposits of manganese [23, 24].

• In addition to T1-weighted hyperintensities in the globus pallidus, up to 75%patients also exhibit extrapallidal involvement in the form of T2-weightedhyperintensities involving the brachium pontis (middle cerebellar peduncles)and subcortical white matter (Fig 11) [23, 24].

Page 16 of 110

Fig. 11: A 50-year old liver cirrhosis patient developed cognitive deficits, ataxia,dysarthria, movement disorders, and features of parkinsonism. MR images revealsymmetrical T1-hyperintensity of the basal ganglia (A) with attendant T2-hyperintensechanges involving the bilateral middle cerebellar peduncles (B). Imaging findings in thelight of the clinical details are in keeping with acquired hepatocerebral degeneration.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• The increased signal intensity in the middle cerebellar peduncles or dentatenuclei bilaterally on T2-weighted images is often indistinguishable fromWilson disease [23-27].

• Since the clinical symptoms, neuropathological features and MR imagingappearances of AHD are almost similar to those seen in Wilson disease, soit is also named pseudo-Wilson disease [27].

• The discrimination depends on the following aspects: (1) Age: Wilsondisease is a genetic disease that rarely starts after the third decade,whereas AHD occurs in those with severe liver disease of many causesat different ages. (2) Copper metabolism: copper metabolism in Wilson'sdisease is out of balance so that overload copper deposits in the liver, brain,kidney, cornea, etc, while the copper metabolizes normally in patients withAHD. (3) Wilson disease is characterized by Kayser-Fleischer ring of thecornea which is typically absent in AHD [27].

CIRRHOSIS-RELATED PARKINSONISM

Page 17 of 110

• Rapidly progressing parkinsonian symptoms, which are unresponsive totreatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism[28].

• Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%)in a recent study by Tryc et al. In 2 patients, cirrhosis-related Parkinsonismwas associated with hepatic myelopathy [28].

• The presence of significant porto-systemic shunts is considered aprecondition for the development of Parkinsonism in patients with cirrhosis.Moreover, the observation of an increased manganese deposition in thebasal ganglia of patients with liver cirrhosis and its relationship to the degreeof porto-systemic shunting has pointed to a possible role of manganeseneurotoxicity [28-32].

• The aforementioned hypothesis is supported by the observation thatcirrhosis-related Parkinsonism and dystonia could be effectively treatedwith chelating agents, and by reports which have shown an improvement ofextrapyramidal symptoms after successful liver transplantation in parallel tothe disappearance of cerebral MRI signal alterations ascribed to manganesedeposition [28-32].

• MR T1-weighted images show characteristic hyperintensity of the basalganglia including the globus pallidus, putamen, and caudate, subthalamic,and dentate nuclei with sparing of the thalamus and ventral pons (Fig12). When the disease is extensive, white matter and anterior pituitaryinvolvement can be present [32].

Page 18 of 110

Fig. 12: Symmetrical T1-hyperintensity can be seen involving the basal ganglia (A, B),cerebral peduncles (C), and the dorsal aspect of pons (D) in a patient of liver cirrhosispresenting with features of parkinsonism.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• On T2-weighted images the changes may be appreciated, however, to amuch lesser extent. More often than not they are reported as normal on T2-WI [32].

• It has been shown that normalization of manganese blood levels improvesthe findings on brain MRI [33].

CIRRHOTIC or HEPATIC MYELOPATHY

Page 19 of 110

• Hepatic or cirrhotic myelopathy is a rare complication of chronic liver diseasethat is associated with extensive portosystemic shunts [34, 35].

• The main clinical feature of hepatic myelopathy is progressive spasticparaparesis in the absence of sensory or sphincter impairment. Typically,a patient with underlying chronic liver disease, develops progressive puremotor spastic paraparesis with minimal or no sensory deficit and withoutbowel and bladder involvement [34].

• The exact pathogenesis of HM is still unclear. However, it has beenhypothesized that the hepatocerebral dysfunction secondary to recurrentepisodes of hepatic encephalopathy, and prolonged exposure to bypassednitrogenous waste (ammonia, fatty acids, indoles, and mercaptans) causemyelin damage resulting in the pathological white matter demyelination inthe brain and the spinal cord (Fig 13) [35].

Page 20 of 110

Fig. 13: A 50-year old male patient with hepatic myelopathy. MR spine failed todepict any overt intramedullary signal alteration; however, screening of brain revealedsymmetrical hyperintensity along the bilateral corticospinal tracts.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Neuropathological studies show demyelination in the corticospinal tracts withvarying degrees of axonal loss. The selective predisposition for the motorsystem has been demonstrated by involvement of the lateral corticospinaltracts in autopsy studies [35].

• Motor-evoked potential studies may be suitable for the early diagnosis ofhepatic myelopathy, even in patients with preclinical stages of the disease[34-37].

• Early and accurate diagnosis of hepatic myelopathy is important becausepatients with early stages of the disease can fully recover following livertransplantation [34-36].

• Hepatic myelopathy remains a default diagnosis assigned only after theexclusion of other causes of spastic paraparesis and partial transversemyelopathy. Accordingly, a detailed and accurate history along withappropriate imaging and laboratory findings remain crucial for establishingthe diagnosis [37].

• Imaging features include increased signal intensity in lateral pyramidal tractsin the cervical cord and caudally, on T2-weighted MRI. However, many atimes MR may not reveal any abnormality yet the motor-evoked potentialstudies may indicate corticospinal electrophysiologic abnormalities [34-38].

• Motor-evoked potential studies thus play a pivotal role for diagnosing andmonitoring disease progression and response to treatment [38].

• In contrast to hepatic encephalopathy, hepatic myelopathy does notrespond to blood ammonia lowering therapies but must be considered as anindication for urgent liver transplantation [6].

CIRRHOSIS-RELATED INTRACEREBRAL HEMORRHAGE

• Spontaneous intracerebral hemorrhage (ICH) accounts for 10-15% of allcases of stroke and systemic hypertension, elderly age group and alcoholconsumption constitute the most important risk factors [39, 40, 44].

Page 21 of 110

• The risk for development of ICH in patients with liver cirrhosis is debatable;nonetheless, various studies have proposed that liver cirrhosis is a riskfactor for ICH [39-44].

• Chronic liver disease is a risk factor for ICH primarily due to impairedcoagulation. Coagulopathy in patients with liver disease results fromimpairments in the clotting and fibrinolytic systems, as well as from reducednumber and function of platelets (Fig 14, 15) [41].

Fig. 14: Unenhanced CT in a liver disease patient with deranged coagulation profileshows a large intraparenchymal hematoma (thick white arrow) in right frontal lobe withcontiguous extension into the ipsialteral ventricle (dotted arrow). In addition, there issynchronous contralateral intracerebral bleed seen in the left frontal region (thick blackarrow). Furthermore, there is evidence of extra-axial bleed that can be seen along theinterhemispheric fissure (thin black arrow).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 22 of 110

Fig. 15: Infratentorial bleed in a delirious patient with decompensated liver cirrhosis.Axial CT sections reveal a large hematoma involving the cerebellar vermis (arrow)causing compression and effacement of the fourth ventricle with upstream obstructiveventriculomegaly (arrowhead). The cerebral sulci are effaced and the cortico-medullaryjunction indistinct (asterisk) suggesting raised intracranial pressure.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Huang et al recently reported an overall incidence of 0.8% in a retrospectivestudy of 4515 patients with liver cirrhosis. The incidence in the alcohol-related group was 1.9% whereas the virus-related group had an incidenceof 0.3%. A combined group (patients with both virus- and alcohol-relatedcirrhosis) had an incidence of 3% [39].

• The relation between high alcohol intake and ICH may involve severalmechanisms among which alcohol-induced hypertension and coagulationdisorders are speculated to be the most likely etiological factors [41].

INFECTIVE COMPLICATIONS OF CIRRHOSIS

• Cirrhosis has been characterized as the commonest acquiredimmunodeficiency syndrome worldwide (exceeding even AIDS) andinfectious complications in cirrhotic patients can cause severe morbidity andmortality [45, 46].

Page 23 of 110

• Bacterial infections have been acknowledged as an important factor indisease mortality and are estimated to cause up to 25% of deaths in cirrhoticpatients [45, 46].

• The specific risk factors for infection in cirrhotic patients are low serumalbumin, gastrointestinal bleeding, repeated intensive care unit admissionsfor any cause, and therapeutic endoscopy [45].

• Certain infectious agents that are more virulent and more common inpatients with liver disease include Vibrio, Campylobacter, Yersinia,Plesiomonas, Enterococcus, Aeromonas, Capnocytophaga, and Listeriaspecies, as well as organisms from other species [45].

• Changes in gut motility, mucosal defense and microflora allow fortranslocation of enteric bacteria into the blood stream (bacteremia).Additionally, the cirrhotic liver is ineffective at clearing bacteria andassociated endotoxins from the blood thus allowing for seeding of the sterileperitoneal fluid [47].

• Compared to the general population, the mortality of infections is more than20 times increased in cirrhosis. The incidence of bacteremia, peritonitis,urinary tract infection, pneumonia, meningitis, and tuberculosis is increasedmore than tenfold, and the mortality of each episode 3-10 times higher [48].

• Liver cirrhosis patients are at increased risk of bacterial meningitis and oftenhave a poor prognosis (Fig 16) [49, 50].

• Molle et al in a nation-wide cohort of 22,743 patients (with liver cirrhosisin Denmark) reported an incidence rate of bacterial meningitis of 54.4 per100,000. The highest incidence rate was found in patients with alcoholiccirrhosis, 65.3 per 100,000 person-years. The 30-day case fatality ratewas 53.1% (95% CI 38.3-67.5), and high age and alcoholic cirrhosis wereassociated with the highest case fatality rates [50].

Page 24 of 110

Fig. 16: Pyogenic meningitis and ventriculitis in a 42-year old patient with NASHrelated liver cirrhosis. Post gadolinium T1-WI reveals inflammation, thickening andabnormal enhancement of the right lateral ventricle ependyma (A, B) and choroidplexus (C) in keeping with ventriculitis and choroid plexitis. In addition, abnormalleptomeningeal enhancement can be seen along the right mesial temporal lobe (D) inkeeping with leptomeningitis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• The main bacterial pathogens include Streptococcus pneumoniae,Escherichia coli, Listeria, and unspecified bacteria [49-51].

• Often, nuchal rigidity may be a delayed or even absent clinical sign. Also,the initial presentation of brain abscess may not be fever or leukocytosis, butfocal neurologic deficits [49-51].

Page 25 of 110

• Mortality may reach 80% in patients with Child-Pugh stage C cirrhosis [49,50].

Fig. 17: Miliary tuberculosis in a middle aged liver cirrhosis patient with history oflongstanding alcohol abuse. Contrast enhanced T1-WI shows multiple pinhead sizedenhancing granulomas randomly scattered in the bilateral cerebral hemispheres.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Lastly, intracranial tuberculosis should also be kept in mind when confrontedwith brain space-occupying lesions in the immunocompromised ormalnutritional hosts such as liver cirrhosis (Fig 17) [52].

DIFFUSE CEREBRAL EDEMA IN ACUTE or ACUTE-ON-CHRONIC LIVER FAILURE

Page 26 of 110

• Cerebral edema is very common in patients with fulminant or acute liverfailure. In severe cases, this can lead to potentially fatal herniation [53].

• Whilst the primary cause of death in patients with acute liver failure (ALF) ismulti-organ failure; cerebral edema and ensuing brain herniation constitute amajor cause of mortality [54].

• Brain swelling in acute liver failure is produced by a combination ofcytotoxic (cellular) and vasogenic edema [53-55]. Although cytotoxic edemaappears predominant event leading to cerebral edema, vasogenic edemapresumably represents secondary event causing intracranial hypertension[56].

• Cytotoxic brain edema is presumably secondary to astrocytic accumulationof glutamine, whilst vasogenic edema represents an increase in cerebralblood volume and cerebral blood flow, in part due to inflammation toglutamine and to toxic products of the diseased liver [54-56].

• Astrocyte swelling has been demonstrated to be the commonest histologicalfeature in patients with ALF [56].

• Ranjan et al have demonstrated significantly lower apparent diffusioncoefficient in cortical and deep white and gray matter regions of interest(on MRI performed in patients with ALF) compared to controls (p < 0.001),suggesting cytotoxic cell swelling as the primary cause of cerebral edema[57].

• The most accurate method of diagnosing cerebral edema is intracranialpressure monitoring [54].

• CT & MR imaging is valuable not only to visualize signs of cerebral edemawhich include sulcal and cisternal effacement, loss of distinction betweenthe grey and white matter and indistinct boundaries of the lenticular nucleus,but, also for excluding hemorrhagic complications as most of these patientsare coagulopathic (Fig 18, 19) [53].

Page 27 of 110

Fig. 18: Diffuse cerebral edema in a patient with acute on chronic (Hepatitis-B and Crelated)liver failure. Noncontrast CT shows effaced sulci with loss of cortico-medullarydifferentiation and indistinct margins of the lenticular nuclei suggesting diffuse cerebraledema and raised intracranial tension.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 28 of 110

Fig. 19: Fulminant hepatic failure. T2W MR imaging reveals effaced cerebralsulci with slit-like ventricles (A, B) and diffuse gyral swelling (C, D) in keeping withdiffuse ceerbral edema. The cisternal spaces are also effaced suggesting impendingherniation (C, D).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Although CT and MR imaging have been traditionally considered unreliablefor the diagnosis of intracranial hypertension (owing to their poor correlationwith intracranial pressure); nonetheless, if interpreted carefully they canprovide pivotal information [53, 58, 59].

• Also, cross sectional imaging is effective at establishing the diagnosisof cerebral herniation, which will guide important decisions regardingtherapeutic options and prognosis (Fig 20).

Page 29 of 110

Fig. 20: (A, B) Sagittal and axial T2-WI show bilateral medial part of the temporallobes protruding over the tentorial edge in keeping with uncal herniation (black arrows).In addition, there is downward cerebellar herniation (tonsillar herniation or coning) seenin this patient of fulminant hepatic failure. The patient was subsequently declared braindead and succumbed to the disease.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Therapeutic measures proposed to control intracranial hypertension in liverfailure patients mainly include administration of mannitol, hypertonic saline,indomethacin, thiopental, and hyperventilation [53-56].

ALCOHOL-RELATED NEUROLOGICAL DISORDRES

• The pathogenesis of alcohol#related neurological damage has beenconsidered to be multifactorial and attributed to genetic predisposition,nutritional factors, and the neurotoxic effects of ethanol or its metabolites[60, 61].

• Alcohol related neurological disorders that may complicate alcohol relatedliver disease may range from Wernicke's encephalopathy, hepatocerebraldegeneration, head trauma, central pontine myelinolysis, Marchiafava-Bignami syndrome to ethanol neurotoxicity [61, 62].

OSMOTIC DEMYELINATION SYNDROMES

Page 30 of 110

• Adams and colleagues in 1959 described central pontine myelinolysis(CPM) as a disease affecting alcoholics and the malnourished [63].

• The concept was extended from 1962 with the recognition that lesionscan occur outside the pons, so-called extrapontine myelinolysis (EPM). In1976 a link between these disorders and the rapid correction of sodiumin hyponatraemic patients was suggested, and by 1982 substantiallyestablished [64].

• The association with alcoholism was the first to be noted and continuesto be particularly frequent (in up to 40% of cases). It has been suggestedthat alcohol itself interferes with sodium/water regulation by suppression ofantidiuretic hormone, and inadequate nutrition of alcoholics is an obviousaccompaniment [64-66].

• CPM is also a recognized complication of liver transplantation. In a 10 yearretrospective series of 627 transplants it occurred in 2% of cases (andcontributed to the overall neurological complication rate of 26%) [64, 65].

• Clinically, whenever a patient who is gravely ill with alcoholism andmalnutrition or a systemic medical disease develops confusion, quadriplegia,pseudobulbar palsy, and pseudo coma ('locked-in syndrome') over a periodof several days, a diagnosis of osmotic demyelination (CPM) should beconsidered [64].

• Radiological confirmation is necessary to exclude other diagnosisand to determine the exact extension of the demyelination. Since CTcan underestimate the real extension MRI plays a pivotal role in thedetermination of the presence, number and extension of the lesions [65].

• In acute CPM, MRI shows signal alteration in the central pons with sparingof the tegmentum, ventrolateral pons and corticospinal tracts (Fig 21, 22).

Page 31 of 110

Fig. 21: Central pontine myelinolysis. Sagittal T2-WI shows relatively bulky appearingpons with attendant signal intensity changes (black arrow) in a 48-year old patient withalcoholic liver cirrhosis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 32 of 110

Fig. 22: (A, B) Axial Fast FLAIR and T2-WI of the aforementioned patient showshyperintensity involving the central pons with characteristic sparing of the periphery.Careful evaluation suggests that there is predominant involvement of the transversepontine fibres - finding which is quite characteristic of CPM.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• In EPM, symmetric signal alterations can be seen in the basal ganglia,thalami, lateral geniculate body, cerebellum, and cerebral cortex (Fig 23)[66].

Page 33 of 110

Fig. 23: Extra-pontine myelinolysis. Axial FLAIR images showing extra-pontine areasof signal alteration (demyelination) involving the left thalamus (white arrow) and theright cerebellar hemisphere (black arrow) in a malnourished chronic alcoholic malepatient with decompensated liver cirrhosis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• About 25-50% of patients with CPM also have EPM; this usually affectsthe cerebellum but may also affect parts of the cerebrum. In up to 25% ofpatients the demyelination is exclusively extrapontine [67].

WERNICKE ENCEPHALOPATHY

• Wernicke encephalopathy (WE) is a neurologic emergency caused by athiamine deficiency. It is commonly seen in the alcoholic population but canalso be seen with malignancy, total parenteral nutrition, abdominal surgery,hyperemesis gravidarum, hemodialysis, or any situation that predisposes anindividual to a chronically malnourished state [66].

• If untreated, irreversible brain damage may ensue and could even lead tocoma, death, or Korsakoff syndrome, a permanent brain injury that resultsin antegrade amnesia and confabulation. The classic triad of WE includesataxia, global confusion, and opthalmoplegia.

• CT has been shown to have a low sensitivity for the detection of WE, andwhen findings are present, they are often nonspecific areas of low density[66].

Page 34 of 110

Fig. 24: Wernicke encephalopathy. Axial T2-WI showing confluent areas of increasedintensity surrounding the aqueduct and the third ventricle in a debilitated andmalnourished patient of alcohol induced liver cirrhosis complaining of ataxia andopthalmoplegia.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 35 of 110

Fig. 25: Coronal T2-WI showing bilateral areas of increased intensity surrounding theaqueduct and the third ventricle contiguously extending into the mamillary bodies.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

Page 36 of 110

Fig. 26: Fast FLAIR images of the same patient showing symmetrical signalalterations at characteristic sites including periventricular region of the third ventricle,periaqueductal area, thalamus, and mamillary bodies.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• On MRI, typical manifestations include symmetrical areas of increased T2-and FLAIR signal intensity surrounding the aqueduct and the third ventricle,at the floor of fourth ventricle, in the medial thalami, and in the capita ofcaudate nuclei (Fig 24-26) [66].

• MR spectroscopy (MRS) may depict lactate peak and low levels of N-acetylaspartate (N-NAA)/creatine (Cr) in the affected areas but does nothave a clinical prognostic impact [66].

MARCHIAFAVA-BIGNAMI DISEASE (MBD)

• MBD is a rare disorder that results in progressive demyelination andnecrosis of the corpus collosum. MBD is generally associated with chronicalcohol abuse but is occasionally seen in nonalcoholic patients. MBD is mostprevalent in men between 40 and 60 years of age [66].

• The main pathologic change associated with MBD is degeneration of thecorpus callosum, which may vary from demyelination to frank necrosis.

Page 37 of 110

• The disease may present in two major clinical forms: acute and chronic.In the acute form, which often results in death, patients present withsevere impairment of consciousness, seizures, and muscle rigidity. Thechronic form of the disease may last for several months or years and ischaracterized by variable degrees of mental confusion, dementia, andimpairment of gait.

• CT shows diffuse periventricular low density and focal areas of low densityin the genu and splenium of the corpus callosum. On MRI, there is highT2-and FLAIR signal intensity changes involving the body of the corpuscallosum, genu, splenium, and adjacent white matter. These appearhypointense on T1-WI and during the acute phase, may show peripheralcontrast enhancement [66].

Page 38 of 110

Fig. 27: Sagittal T2-WI in a chronic alcoholic male showing relatively atrophic posteriorbody of the corpus callosum (white arrow) with focal area of signal alteration within thesplenium (black arrow). In addition, note is made of disproportionate cerebellar atrophy(arrowhead) - likely representing alcoholic cerebellar degeneration.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• As the disease progresses, signal alterations become less evident, butresidual atrophy of the corpus callosum is usually observed (Fig 27). MBDmay be found in association with other alcohol-related diseases, includingWE, Korsakoff syndrome, and central pontine myelinolysis [66].

ALCOHOL WITHDRAWAL SYNDROME (AWS)

• Alcohol withdrawal syndrome (AWS) is a constellation of symptomsobserved in a person who stops drinking alcohol after a period of continuousand heavy alcohol consumption [66].

• In AWS, disturbances in cognition, perception hallucinations, visualimpairment, nausea, and tinnitus are thought to relate to cortical dysfunction.Tremor, sweating, depression, and anxiety are related to effects on thelimbic system. Changes in consciousness and gait disorders are associatedwith brainstem involvement.

Page 39 of 110

Fig. 28: Axial FAST FLAIR image in a liver cirrhosis patient with auditory hallucinationsfollowing alcohol withdrawal showing subtle symmetrical bi-temporal hyperintensity(arrows).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• In alcoholics with withdrawal seizures, MRI depicts cytotoxic edema intemporal regions during the acute and subacute phases and significantvolume loss (Fig 28). It could therefore be deduced that epileptic seizuresaffect alcoholic subjects similarly to temporal epilepsy, in which reversibleedema with some volume loss and consequent hippocampus atrophy isobserved [66].

• Reversible vasogenic edema in the cerebellum; thalami; and cortical,subcortical, and deep parietal white matter has also been described

Page 40 of 110

in the clinical setting of posterior reversible encephalopathy syndromecomplicating alcohol withdrawal [66].

ALCOHOLIC COGNITIVE DECLINE AND CEREBRAL ATROPHY

• Approximately 50 - 70 % of alcohol abusers have cognitive deficits onneuropsychological testing. Imaging tests, neuropathological observations,and animal studies suggest that ethanol neurotoxicity may contribute to thiscognitive dysfunction [68-70].

• Nevertheless, there is no unequivocal evidence for a brain lesion in humansthat is caused solely by chronic ethanol ingestion and that is unrelated tocoexisting nutritional deficiency, liver disease, or trauma.

• CT and MRI show enlargement of the cerebral ventricles and sulci in themajority of alcohol abusers. There is evidence for regional vulnerabilityin the brains of alcohol abusers with frontal lobe changes being the mostpronounced (Fig 29).

• Neuronal density in the superior frontal cortex was reduced by 22 percentin alcohol abusers compared with nonalcoholic controls in one report.Selective loss of neurons in frontal brain regions is mirrored by regionalhypometabolism on PET studies, and might correlate with deficits in workingmemory observed in alcohol abusers [68-69].

Page 41 of 110

Fig. 29: Axial FLAIR and T2WI showing selective bi-frontal cerebral atrophy in a 36-year old chronic alcoholic male patient with underlying liver cirrhosis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Quantitative morphometry suggests that alcohol abusers, includingthose with liver disease and Wernicke encephalopathy (WE), lose adisproportionate amount of subcortical white matter compared with corticalgray matter [68, 69].

• The loss of cerebral white matter is evident across a wide range of ages,and is of sufficient magnitude to account for the associated ventricularenlargement. Diffusion-tensor imaging detects microstructural abnormalitiesin the white matter tracts of alcohol abusers even in the absence ofmacroscopic lesions.

• MRI imaging of alcohol abusers shows an increase in white matter volumefollowing three months of abstinence, suggesting that a component of thewhite matter injury is reversible.

ALCOHOLIC CEREBELLAR DEGENERATION

• Besides the frequently reported effects of ethanol on supratentorial brain,cerebellar involvement is also commonly observed in chronic alcoholics [71,72].

• Alcoholic cerebellar degeneration typically occurs after 10 or more years ofalcohol abuse. These chronic ethanol abusers develop a chronic cerebellarsyndrome related to the degeneration of Purkinje cells in the cerebellarcortex.

• Midline cerebellar structures, especially the anterior and superior vermis arepredominantly affected [71, 72].

• Symptoms, primarily related to gait disturbance, usually develop graduallyover weeks to months, but it may also evolve over years or commenceabruptly.

Page 42 of 110

Fig. 30: Alcoholic cerebellar degeneration. DIffuse cerebellar atrophy is seen in theform of cerebellar foliar prominence, ventricular enlargement and prominence of theinfratentorial subarachnoid CSF spaces in a 44-year old male cirrhotic with history ofchronic alcohol abuse.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• CT or MRI scans typically show cerebellar cortical atrophy, however, one-half of alcoholic patients with this finding may not be ataxic on examination.In addition, a structural imaging study is also required to exclude masslesions or other diagnoses (Fig 30) [71, 72].

• The absence of cranial nerve abnormalities differentiates alcoholiccerebellar degeneration from vascular disorders of the posterior circulation,mass lesions, and demyelinative disease. The age of onset and clinicalcourse sets this disorder apart from some of the spinocerebellar ataxias.Multiple systems atrophy, including olivopontocerebellar degeneration, may

Page 43 of 110

be difficult to distinguish on clinical grounds alone and require corroboratoryimaging studies.

WILSON DISEASE-RELATED NEUROIMAGING MANIFESTATIONS

• Wilson disease is an uncommon, autosomal recessive, inborn defect incopper metabolism characterized by abnormal accumulation of copper invarious tissues, particularly in the liver and the brain [73].

• In Wilson disease, ceruloplasmin, the serum transport protein for copper, isdeficient. Copper accumulates in the tissues of patients primarily in the liverand later in the brain.

• Despite the ubiquitous presence of toxic copper within the brain, pathologicfindings are limited primarily to the basal ganglia, thalamus, and brainstem. The initial neurological presentations frequently include dysarthriaand tremors, with later manifestations of neuropsychiatric problems, andParkinsonian tremors, ataxia, dystonia, and chorea.

• The most frequently identified abnormality on MR imaging was bilateralsymmetric high signal intensity in the putamen on T2-weighted images,followed by the caudate nucleus, globus pallidus, thalamus, midbrain (Fig31) [73, 74].

Page 44 of 110

Fig. 31: Axial T2-WI in a patient with Wilson disease depicting symmetrical increasedsignal intensity of the bilateral lentiform nuclei (ahite arrow), thalami (black arrow) andcaudate nuclei (arrowhead).References: Image reproduced from: Arora A et al. Intracranial MR manifestationsof Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518

• Diffusion-weighted images can show areas of restricted diffusion early in thedisease process due to cytotoxic edema or inflammation due to excessivecopper deposition (Fig 32). However, this restricted diffusion is not seen inchronic cases [73].

Page 45 of 110

Fig. 32: DWI in a patient with Wilson disease depicting diffusion restriction involvingthe lentiform and caudate nuclei (hepatolenticular degeneration) during the acutephase of the disease.References: Image reproduced from: Arora A et al. Intracranial MR manifestationsof Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518

• Hypointensity on T2-weighted images can be seen sometimes, secondary tocopper deposition or iron deposition (Fig 33) [73].

Page 46 of 110

Fig. 33: Axial T2WI (A) and T2*GRE (B) showing hypointense signal and bloomingreflecting heavy metal deposition in the lentiform nuclei in a patient of Wilson disease.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• High-signal-intensity lesions in the basal ganglia on T1-weighted imagesreflects hepatic involvement of Wilson disease-namely, chronic liver diseaseor liver cirrhosis; and, is often the most common initial abnormality detected(Fig 34).

Fig. 34: Symmetrical increased T1-signal intensity involving the lentiform nuclei in apatient of Wilson disease.References: Image reproduced from: Arora A et al. Intracranial MR manifestationsof Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518

• Diffuse brain atrophy suggests a generalized susceptibility and longstandingeffect of the central nervous system to copper intoxication.

• 'Face of the Giant Panda' is an uncommon intracranial manifestation ofWilson's disease which was first described by Hitoshi et al in 1991. Thisappearance is caused by a combination of signal intensity changes atthe level of midbrain on T2-WI. These include: high signal intensity in thetegmentum, normal signals in the red nuclei and lateral portion of the parsreticulata of the substantia nigra, and hypointensity of the superior colliculus(Fig 35) [73, 74].

Page 47 of 110

Fig. 35: (A, B) Giant panda sign in a young patient of Wilson disease. (C) The signis due to a combination of high signal intensity in the tegmentum (black arrow) withsparing of the red nuclei (dotted arrow), pars reticulate (white arrow) and the superiorcolliculi (arrowhead).References: Image reproduced from: Arora A et al. Intracranial MR manifestationsof Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518

Page 48 of 110

Fig. 36: Giant panda cub. Axial T2WI in a patient of Wilson disease depicting signalalteration in the dorsal pons simulating the face of a giant panda - popularly referred toas 'giant panda cub' sign.References: Image reproduced from: Arora A et al. Intracranial MR manifestationsof Wilson disease. Poster no. C-1518 on EPOS (ECR 2011). DOI: 10.1594/ecr2011/C-1518

• The exact pathogenesis of this SIGN is not known, but it is postulated thatthe paramagnetic effects of the deposition of heavy metals, such as ironand copper, may be responsible. It is believed that iron is assumed to playa more important role than copper in reducing the signal intensity of thesuperior colliculi on the T2-weighted scan. At times, signal alteration mayalso be encountered within the dorsal pons which has been popularly calledas 'Giant Panda Cubs' (Fig 36) [74].

HCV-RELATED CNS COMPLICATIONS

• Chronic infection with hepatitis C virus (HCV), a hepatotropic andlymphotropic agent, is a growing global health issue affecting an estimated170 million people [75].

• Neurological complications occur in a large number of patients and thespeculative pathogenetic mechanisms responsible for nervous systemdysfunction are mainly related to the upregulation of the host immuneresponse with production of autoantibodies, immune complexes, andcryoglobulins [75].

• HCV-related CNS complications encompass a wide spectrum of disordersranging from cerebrovascular events to autoimmune syndromes [75-79].

• ACUTE CEREBROVASCULAR EVENTS: including ischemic stroke,transient ischemic attacks, lacunar syndromes (Fig 37), or rarely

Page 49 of 110

hemorrhages (secondary to occlusive vasculopathy and vasculitis), havebeen reported, being the initial manifestation of HCV infection in some cases[75, 76].

Fig. 37: Transient ischemic attacks in a 39-year old patient with chronic (hepatitis-C related) liver disease. DWI reveals multiple acute lacunar infarcts involving the leftpareito-temporal and right cerebellar hemisphere - possibly secondary to occlusivevasculopathy or vasculitis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• ACUTE OR SUBACUTE ENCEPHALOPATHIC SYNDROMES: clinicallycharacterized by cognitive impairment, confusion, altered consciousness,

Page 50 of 110

dysarthria, dysphagia, and incontinence, have been associated with diffuseinvolvement of the white matter in HCV chronically infected patients. Anischemic pathogenesis of these rapidly evolving syndromes is supported byMRI findings showing small lesions in subcortical regions and periventricularwhite matter (Fig 38). Moreover, severe and diffuse infra- and supratentorialwhite matter alterations, highly suggestive of vasculitis, are observed insubjects with coincidental systemic vasculitis [75].

Fig. 38: A young 36-year old patient of hepatitis-C related liver cirrhosis andprogressive neurocognitive decline. Axial FAST FLAIR imaging reveals bilateralmultifocal patchy and confluent areas of subcortical white matter hyperintensities.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• COGNITIVE DECLINE: slowly evolving cognitive decline, clinicallycharacterized by impairment of attention, executive, visual constructive,and spatial functions, has been correlated to an increased occurrence ofperiventricular white matter high intensity signals on T2-weighted MRI (Fig39). White matter hyperinyensities likely reflect the occurrence of smallvessel disease, which leads to chronic hypoperfusion of the white matterand local alteration of the blood-brain barrier [75].

Page 51 of 110

Fig. 39: A 45-year old male with (hepatitis-C) liver cirrhosis and rapidly progressivedementia and neurocognitive decline. FAST FLAIR images reveal patchy and confluentareas of signal alteration involving the periventricular as well as hemispheric whitematter.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM): Sacconi andSim et al. have described ADEM, an autoimmune postinfectious CNSdisease, developing after HCV infection and responsive to steroid therapy,further supporting the role of cellular immune mediated mechanisms in CNScomplications of HCV infection [77, 78].

• MYELITIS: is an infrequent neurological complication in patients chronicallyinfected with HCV. HCV-related myelitis occurs acutely or subacutely, theneurological presentation ranging from transverse myelitis to acute partialtransverse myelopathy, or spastic paraplegia; many patients present arecurrent course and have a multisegmental spinal involvement at MRI,usually at cervical and thoracic levels [75, 79].

LIVER TRANSPLANTATION-RELATED COMPLICATIONS

Neurologic complications are more common after liver transplantation than othersolid-organ transplants primarily due to the poorer clinical condition of liver diseasepatients due to malnutrition, coagulopathy, electrolyte imbalance, and pre-transplantencephalopathy. In addition, the highly complex and lengthy surgical procedure with

Page 52 of 110

major hemodynamic changes and blood/fluid shifts also predisposes these patients todevelop diverse neurological problems [80, 81].

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME

• Posterior reversible encephalopathy syndrome (PRES) is an increasinglyrecognized neurological complication after transplantation with an overallincidence of approximately 1% following liver transplantation [82, 83].

• The syndrome is likely initiated by a leakage of fluid into the interstitium ofthe brain tissue that is detected as vasogenic edema.

• The exact pathophysiology is poorly understood but the widespreadvasoconstriction induced by calcineurin inhibitors (cyclosporine/ tacrolimus)may lead microvascular damage with disruption of the blood-brain barrier,increasing the risk of neurologic dysfunction posttransplant [82, 83].

• Other vascular phenomena, such as hypertension with the failure of vascularautoregulation and hyperperfusion, have also been implicated as the causeof edema development in PRES.

• Patients with a pre-liver transplant history of alcoholic liver disease are morelikely to develop PRES. Chronic alcohol presumably creates alterations incerebral blood flow and induce morphologic and biomechanical changesin cerebral vessels resulting in more friability and less elasticity of bloodvessels which may influence cerebral blood flow distribution possiblycontributing to the development of PRES [82, 83].

• Characteristic clinical findings include altered mental status, seizures, visualabnormalities, and/or focal neurological deficits.

• PRES is diagnosed radiologically, often by a distinguishing imaging patterninvolving the cortical or subcortical areas of the parietal or occipital lobes(hence the name 'posterior').

• CT or MR imaging typically show reversible vasogenic edema of the whitematter commonly in areas of parenchyma supplied by posterior circulation;however, involvement of other areas such as frontal lobes, basal gangliaand brain stem are also reported (Fig 40) [82, 83].

Page 53 of 110

Fig. 40: PRES in a post liver-transplant patient. Axial FAST FLAIR sequenceexhibiting cortico-subcortical areas of T2-hyperintensity in the parieto-occipital region.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Additionally concomitant hemorrhage can occur in up to 15% of patients withPRES (Fig 41).

Page 54 of 110

Fig. 41: Axial T2*GRE image of the hitherto discussed patient with PRES showingpunctate areas of blooming in keeping with petechial hemorrhages in the left occipitallobe.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• If timely diagnosed, the patients experience a good recovery withoutsequelae. Nevertheless, when unrecognized, PRES can progress toischemia or massive infarction with significant morbidity and mortality [82,83].

IMMUNOSUPPRESSANT-RELATED LEUKOENCEPHALOPATHY

Page 55 of 110

• A wide variety of neurologic side effects has been described with the use ofimmunosuppressant drugs - most of them being minor (for e.g. headache,tremor, paresthesia). However, immunosuppression-associated majorneurotoxicity such as leukoencephalopathy may develop in some posttransplant recipients [84-86].

• Leukoencephalopathy syndrome is a neurologic complication causedprimarily by the neurotoxic effects of immunosuppressive agents on cerebralwhite matter [84].

• Tacrolimus and cyclosporine are lipophilic immunosuppressant agents thatcross the blood-brain barrier and are speculated to have a direct neurotoxiceffect especially on the lipid-rich white matter [85].

• The reported incidence of leukoencephalopathy syndrome in liver transplantrecepients is 0.4% to 6% [84].

• Time to onset of leukoencephalopathy syndrome in liver transplantationtends to be shorter than in other organ transplantations, and in most cases,it occurs within first three months of the transplantation [84].

• Clinically, it is characterized by a reversible syndrome of headaches, suddenonset of seizures, visual abnormalities, and hemiparesis [84-87].

• The diagnosis of leukoencephalopathy requires either CT or MR imaging -MR imaging indubitably has a higher sensitivity for delineating the pathology.T2-WI MRI characteristically shows high-signal intensity involving theoccipital, parietal, and temporal white matter in a scattered fashion (Fig 42)[84].

Page 56 of 110

Fig. 42: Immunosupressive leukoencephalopathy. A 56-year old post liver transplantpatient on tacrolimus complaining of unrelenting headaches and visual disturbances.MR images show multifocal areas of white matter signal alteration involving the parieto-occipital lobes and right fronto-parietal region appearing bright on T2WI (A) and darkon T1WI (B).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Clinico-radiological differentiation from progressive multifocalleukoencephalopathy (PML) can be challenging [84, 85]. A biopsy procedureis usually not considered to be necessary to differentiate between the twoespecially when after cessation or dose reduction of tacrolimus the clinicalcondition improves.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Progressive multifocal leukoencephalopathy (PML), a progressivedemyelinating disease of the brain caused by JC virus (JCV), can beseen following liver transplantation and other conditions associated withimmunosuppression [88].

• Clinical course of PML is characterized by a rapid progressive neurologicaldecline (hemiparesis, visual field deficits, and cognitive impairment)coinciding with the presence of white matter lesions on cross sectionalneuroimaging [89].

Page 57 of 110

• In late stages of disease, patients can develop cortical blindness,quadriparesis, severe dementia and even coma. Death usually occurs within6 months of diagnosis [90].

• MRI is undoubtedly more sensitive than CT in depicting the white matterchanges [89].

• On MRI, PML lesions typically appear as hyperintense signal on T2-weighted and FLAIR images (corresponding hypointense signal on T1-WI)involving the subcortical white matter, devoid of contrast enhancement ormass effect [88]. The lesions are multifocal albeit most commonly involvethe parieto-occipital white matter (Fig 43).

Fig. 43: Suspected PML in a 44 year old post liver transplant patient withneurocognitive decline. Axial FLAIR images showing patchy and conflueent scatteredhyperintensities in bilateral parieto-temporal and frontal white matter.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• The gold standard for the diagnosis of PML is a brain biopsy, although thecombination of a recent onset of neurological disease with white matterlesions on MRI and a positive PCR for the JC virus in the CSF can confirmthe diagnosis in the absence of a brain biopsy [89].

• PML is distinguished from immunosuppressant neurotoxicity by its rapidradiological and clinical progression [91].

Page 58 of 110

• There is no direct antiviral therapy available against the JC polyomavirus.Restoration of the immune response achieved by tapering or terminatingthe immunosuppressive regimen is the mainstay of treatment. However, theprognosis remains extremely poor regardless of treatment [89].

CEREBROVASCULAR COMPLICATIONS

• Cerebrovascular complications, including ischemic strokes and intracranialhemorrhage, have been reported to be prevalent in 2-4% of liver transplantrecipients [92].

• An increased risk of intracranial hemorrhage has been demonstrated inpatients with thrombocytopenia, old age, and overwhelming infections. Thatrisk is further compounded by coagulopathy associated with hepatic failure(Fig 44) [92].

Fig. 44: Multifocal areas of bilateral intracerebral hemorrhage in a 56-year old postliver-transplant patient.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Other less common causes of intracranial bleeding in post transplantrecipients include Aspergillus angiopathy and mycotic aneurysms.

Page 59 of 110

• In addition, hypercholesterolaemia, diabetes, and hypertension secondary tolong term use of immunosuppressive therapy may also compound the risk ofcerebral bleeds.

• Ischemic strokes are overall less common than intracranial hemorrhages,and are often associated with similar risk factors as in general population,including hypertension. Hepatic encephalopathy is also associated withdysregulation of cerebral blood flow autoregulation (Fig 45) [92].

Fig. 45: Right middle cerebral artery (MCA) infarct. Axial T2WI (A) and DWI (B)showing acute infarct with diffusion restriction involving the right temporal lobe in theMCA territory.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Perioperative events, such as cerebral hypoperfusion and massivetransfusion, may also favor cerebrovascular injury.

• Post anoxic cerebral ischemia is most commonly encountered followingcardiac arrest or cardiopulmonary resuscitation in which there has beencessation of cerebral blood flow (Fig 46).

Page 60 of 110

Fig. 46: Anoxic-hypoxic ischemic encephalopathy following liver transplant (day-3).DWI showing diffusion restriction and extensive gyral swelling involving the bilateralcerebral hemispheres in a contiguous fashion.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Diffuse cortical (laminar) necrosis in the setting of acute anoxic insult (globalhypoperfusion) has a universally poor prognosis with most patients eitherprogressing to brain death or remaining in a persistent vegetative state [92].

POST-TRANSPLANT ENCEPHALOPATHY

• Common causes of post-transplant encephalopathy in liver allograftrecipients include hepatic dysfunction, medication toxicity, infectious causes(CNS infections or septic encephalopathy), complex metabolic disturbances(uremia, CPM), cerebrovascular events or seizures.

• Higher risk of encephalopathy has been reported in patients with history ofsevere hepatic encephalopathy, alcohol-induced hepatic disease, metabolicliver disease, greater severity of pre-transplant liver injury [92].

Page 61 of 110

Fig. 47: Severe hyperammonemic encephalopathy in a 35 year old post livertransplant patient (post operative day 6). Axial FLAIR images showing extensivecortical swelling and T2 prolongation especially along the insular cortices and cingulategyrus.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Delayed allograft function can precipitate hepatic encephalopathy withclinical manifestations of ranging from subtle cognitive slowing and memorydifficulties, to somnolence, stupor and coma (Fig 47).

• In addition, during early post-transplant period, a delayed arousal canbe related to persisting hepatic dysfunction, immunosuppressant relatedneurotoxicity or intracerebral hemorrhage [92].

OPPORTUNISTIC INFECTIONS

• Chronic immunosuppression increases the risk of opportunistic infection inliver transplant recipients with an overall reported incidence of 5% [92].

• The highest risk of developing a post transplant CNS infection is seenbetween 1 - 6 months after transplantation.

• Fungal and viral infections are the most common in post transplantrecipients, while bacterial and protozoic infections are less common.

Page 62 of 110

• Exposure to infectious agents may stem from donor-related infections,recipient-related infections, nosocomial infections and community infections.

• Fungal CNS infections are usually associated with systemic fungalinfections, and may also extend locally following fungal sinusitis (Fig 48)[92].

Fig. 48: Post-transplant invasive fungal sinusitis, orbital cellulitis & meningitis in a 26year old female. Axial CT section showing destruction of the lamina papyracea (whitearrow) with extension of the fungal elements into the right orbit with attendant orbitalcellulitis (asterisk).References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Candida is the most common fungal infection after liver transplantation, butCNS infections caused by Candida species are rare.

• Most common fungal CNS infections are caused by Cryptococcusneoformans and Aspergillus species [92].

• Increased risk of CNS aspergillosis has been reported after liverretransplantation. Vasoinvasive CNS fungal infections (e.g., Aspergillusspecies) are often associated with hemorrhagic strokes.

Page 63 of 110

Fig. 49: Invasive mucormycosis. Post liver-transplant patient with invasive fungalsinusitis (asterisk) invading the left orbit (star) and ipsilateral cavernous sinus (whitearrow) with contiguous extension into the left peri-mesencephalic cistern (arrowhead).References: Dr Rajiv Gupta, Radiology, Medanta, The Medicity, Gurgaon, India

• Opportunistic bacterial CNS infections are relatively less common after livertransplantation but the risk may be increased with environmental exposure.

• Toxoplasmosis is the most common protozoal infection in transplantrecipients.

• Neuroimaging, spinal tap after excluding increased intracranial pressure,and a search for signs of systemic infection are the core of diagnosis. Brainbiopsy may be warranted in selected cases [92, 93].

OSMOTIC DEMYELINATION

• Up to 1-2% of liver transplant recipients may develop osmotic demyelination(pontine or extrapontine) [66, 92].

• Relatively high prevalence of central pontine (CPM) or extrapontinemyelinolysis (EPM) in the early period after liver transplantation isprobably attributable to large fluid shifts, similarly as in rapid correction ofhyponatremia [92].

Page 64 of 110

Fig. 50: Central pontine myelinolysis in a post liver transplant patient. Axial FLAIRimage showing predominant involvement of the transverse pontine fibres (white arrow)with characteristic sparing of the descending corticospinal tracts (asterisk). Notethe peripheral pontine fibers (black arrow) are also spared - hence the term 'central'pontine myelinolysis.References: RADIODIAGNOSIS, INSTITUTE OF LIVER & BILIARY SCIENCES,INSTITUTE OF LIVER & BILIARY SCIENCES - New Delhi/IN

• Due to massive fluid shifts in early posttransplant period, the risk of CPM/EPM is also higher in first 48 h after transplantation (Fig 49).

• In addition, higher risk of has been reported in patients with preoperativehyponatremia and worse liver dysfunction [92, 93].

POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDER

• Lymphoma is the commonest cerebral brain tumor seen in transplantrecipients; and, the CNS may be the primary site of involvement orassociated with systemic posttransplantation lymphoproliferative disorder(PTLD) [94].

• Majority of the PTLD cases are associated with Epstein-Barr virus (EBV)infection and occur a few years following solid organ transplantation.

Page 65 of 110

• Intracranial involvement is more often parenchymal than leptomeningeal[94].

• On imaging, the lesions tend to be multiple (often periventricular) and oftenshow avid enhancement.

• Differentiation from toxoplasmosis may be challenging. However, anincreased uptake on single-photon emission CT (SPECT) may be useful todifferentiate the two entities [94].

Images for this section:

Fig. 2: Symmetrical T1-hyperintensity involving the bilateral globus pallidus (arrows) inan asymptomatic 54-year old male with hepatitis-B related liver cirrhosis.

Page 66 of 110

Fig. 3: Axial T1-weighted MR images showing hyperintense signal of the caudate nucleus(black arrows) in addition to the involvement of the globos pallidi (white arrows).

Fig. 4: (A) Axial T2-WI and (B) FLAIR sequence delineating subtle symmetricalhyperintensity involving the bilateral lentiform nuclei in a young 26-year old lady with livercirrhosis.

Page 67 of 110

Fig. 5: A 40-year old male with alcoholic liver cirrhosis and grade-I hepaticencephalopathy. Fast-FLAIR MR images reveal diffuse high-signal intensity in thehemispheric white matter on either sides.

Fig. 6: Cerebral atrophy accompanying typical intracranial signal intensity changesin a 36-year old patient with long standing cryptogenic cirrhosis. Axial T1-WI showssymmetrical T1-prolongation of the basal ganglia (asterisk) representing manganesedeposition. Attendant widening of the sylvian fissures (thick arrows) and ventricularenlargement (thin arrows) suggest cerebral parenchymal atrophy.

Page 68 of 110

Fig. 7: Ventricular enlargement (white arrow) and subarachnoid CSF-space (sylvianfissure) widening represent cerebral involutional changes in a 30-year old male withalcohol induced liver cirrhosis.

Page 69 of 110

Fig. 8: Typical imaging manifestations of HE. Fast FLAIR images exhibit symmetricalcortical edema involving the insular cortex (arrow) and cingulate gyrus (arrowhead). Notethat the occipital cortex (asterisk) is characteristically spared.

Fig. 9: Acute HE. DWI displaying extensive symmetrical gyral edema whichcharacteristically involves the insular cortex (arrow) and cingulate gyrus (arrowhead);and, typically spares the perirolandic and occipital cortex (dotted arrow).

Page 70 of 110

Fig. 10: Chronic HE. Axial T1-WI showing cortical atrophy with gyriform T1-hyperintensityrepresenting cortical laminar necrosis in a follow-up case of liver cirrhosis with recurrentepisodes of grade-3 HE in the past.

Fig. 11: A 50-year old liver cirrhosis patient developed cognitive deficits, ataxia,dysarthria, movement disorders, and features of parkinsonism. MR images revealsymmetrical T1-hyperintensity of the basal ganglia (A) with attendant T2-hyperintensechanges involving the bilateral middle cerebellar peduncles (B). Imaging findings in thelight of the clinical details are in keeping with acquired hepatocerebral degeneration.

Page 71 of 110

Fig. 12: Symmetrical T1-hyperintensity can be seen involving the basal ganglia (A, B),cerebral peduncles (C), and the dorsal aspect of pons (D) in a patient of liver cirrhosispresenting with features of parkinsonism.

Page 72 of 110

Fig. 13: A 50-year old male patient with hepatic myelopathy. MR spine failed to depict anyovert intramedullary signal alteration; however, screening of brain revealed symmetricalhyperintensity along the bilateral corticospinal tracts.

Page 73 of 110

Fig. 14: Unenhanced CT in a liver disease patient with deranged coagulation profileshows a large intraparenchymal hematoma (thick white arrow) in right frontal lobe withcontiguous extension into the ipsialteral ventricle (dotted arrow). In addition, there issynchronous contralateral intracerebral bleed seen in the left frontal region (thick blackarrow). Furthermore, there is evidence of extra-axial bleed that can be seen along theinterhemispheric fissure (thin black arrow).

Page 74 of 110

Fig. 15: Infratentorial bleed in a delirious patient with decompensated liver cirrhosis.Axial CT sections reveal a large hematoma involving the cerebellar vermis (arrow)causing compression and effacement of the fourth ventricle with upstream obstructiveventriculomegaly (arrowhead). The cerebral sulci are effaced and the cortico-medullaryjunction indistinct (asterisk) suggesting raised intracranial pressure.

Fig. 16: Pyogenic meningitis and ventriculitis in a 42-year old patient with NASH relatedliver cirrhosis. Post gadolinium T1-WI reveals inflammation, thickening and abnormalenhancement of the right lateral ventricle ependyma (A, B) and choroid plexus (C)in keeping with ventriculitis and choroid plexitis. In addition, abnormal leptomeningealenhancement can be seen along the right mesial temporal lobe (D) in keeping withleptomeningitis.

Page 75 of 110

Fig. 17: Miliary tuberculosis in a middle aged liver cirrhosis patient with history oflongstanding alcohol abuse. Contrast enhanced T1-WI shows multiple pinhead sizedenhancing granulomas randomly scattered in the bilateral cerebral hemispheres.

Page 76 of 110

Fig. 18: Diffuse cerebral edema in a patient with acute on chronic (Hepatitis-B and Crelated)liver failure. Noncontrast CT shows effaced sulci with loss of cortico-medullarydifferentiation and indistinct margins of the lenticular nuclei suggesting diffuse cerebraledema and raised intracranial tension.

Page 77 of 110

Fig. 19: Fulminant hepatic failure. T2W MR imaging reveals effaced cerebral sulci withslit-like ventricles (A, B) and diffuse gyral swelling (C, D) in keeping with diffuse ceerbraledema. The cisternal spaces are also effaced suggesting impending herniation (C, D).

Page 78 of 110

Fig. 20: (A, B) Sagittal and axial T2-WI show bilateral medial part of the temporal lobesprotruding over the tentorial edge in keeping with uncal herniation (black arrows). Inaddition, there is downward cerebellar herniation (tonsillar herniation or coning) seenin this patient of fulminant hepatic failure. The patient was subsequently declared braindead and succumbed to the disease.

Page 79 of 110

Fig. 21: Central pontine myelinolysis. Sagittal T2-WI shows relatively bulky appearingpons with attendant signal intensity changes (black arrow) in a 48-year old patient withalcoholic liver cirrhosis.

Page 80 of 110

Fig. 22: (A, B) Axial Fast FLAIR and T2-WI of the aforementioned patient showshyperintensity involving the central pons with characteristic sparing of the periphery.Careful evaluation suggests that there is predominant involvement of the transversepontine fibres - finding which is quite characteristic of CPM.

Fig. 23: Extra-pontine myelinolysis. Axial FLAIR images showing extra-pontine areas ofsignal alteration (demyelination) involving the left thalamus (white arrow) and the rightcerebellar hemisphere (black arrow) in a malnourished chronic alcoholic male patientwith decompensated liver cirrhosis.

Page 81 of 110

Fig. 24: Wernicke encephalopathy. Axial T2-WI showing confluent areas of increasedintensity surrounding the aqueduct and the third ventricle in a debilitated andmalnourished patient of alcohol induced liver cirrhosis complaining of ataxia andopthalmoplegia.

Page 82 of 110

Fig. 25: Coronal T2-WI showing bilateral areas of increased intensity surrounding theaqueduct and the third ventricle contiguously extending into the mamillary bodies.

Page 83 of 110

Fig. 26: Fast FLAIR images of the same patient showing symmetrical signal alterationsat characteristic sites including periventricular region of the third ventricle, periaqueductalarea, thalamus, and mamillary bodies.

Page 84 of 110

Fig. 27: Sagittal T2-WI in a chronic alcoholic male showing relatively atrophic posteriorbody of the corpus callosum (white arrow) with focal area of signal alteration within thesplenium (black arrow). In addition, note is made of disproportionate cerebellar atrophy(arrowhead) - likely representing alcoholic cerebellar degeneration.

Page 85 of 110

Fig. 28: Axial FAST FLAIR image in a liver cirrhosis patient with auditory hallucinationsfollowing alcohol withdrawal showing subtle symmetrical bi-temporal hyperintensity(arrows).

Page 86 of 110

Fig. 29: Axial FLAIR and T2WI showing selective bi-frontal cerebral atrophy in a 36-yearold chronic alcoholic male patient with underlying liver cirrhosis.

Page 87 of 110

Fig. 30: Alcoholic cerebellar degeneration. DIffuse cerebellar atrophy is seen in theform of cerebellar foliar prominence, ventricular enlargement and prominence of theinfratentorial subarachnoid CSF spaces in a 44-year old male cirrhotic with history ofchronic alcohol abuse.

Page 88 of 110

Fig. 31: Axial T2-WI in a patient with Wilson disease depicting symmetrical increasedsignal intensity of the bilateral lentiform nuclei (ahite arrow), thalami (black arrow) andcaudate nuclei (arrowhead).

Page 89 of 110

Fig. 32: DWI in a patient with Wilson disease depicting diffusion restriction involving thelentiform and caudate nuclei (hepatolenticular degeneration) during the acute phase ofthe disease.

Fig. 33: Axial T2WI (A) and T2*GRE (B) showing hypointense signal and bloomingreflecting heavy metal deposition in the lentiform nuclei in a patient of Wilson disease.

Page 90 of 110

Fig. 34: Symmetrical increased T1-signal intensity involving the lentiform nuclei in apatient of Wilson disease.

Page 91 of 110

Fig. 35: (A, B) Giant panda sign in a young patient of Wilson disease. (C) The sign isdue to a combination of high signal intensity in the tegmentum (black arrow) with sparingof the red nuclei (dotted arrow), pars reticulate (white arrow) and the superior colliculi(arrowhead).

Page 92 of 110

Fig. 36: Giant panda cub. Axial T2WI in a patient of Wilson disease depicting signalalteration in the dorsal pons simulating the face of a giant panda - popularly referred toas 'giant panda cub' sign.

Page 93 of 110

Fig. 37: Transient ischemic attacks in a 39-year old patient with chronic (hepatitis-C related) liver disease. DWI reveals multiple acute lacunar infarcts involving the leftpareito-temporal and right cerebellar hemisphere - possibly secondary to occlusivevasculopathy or vasculitis.

Page 94 of 110

Fig. 38: A young 36-year old patient of hepatitis-C related liver cirrhosis and progressiveneurocognitive decline. Axial FAST FLAIR imaging reveals bilateral multifocal patchy andconfluent areas of subcortical white matter hyperintensities.

Fig. 39: A 45-year old male with (hepatitis-C) liver cirrhosis and rapidly progressivedementia and neurocognitive decline. FAST FLAIR images reveal patchy and confluentareas of signal alteration involving the periventricular as well as hemispheric white matter.

Page 95 of 110

Fig. 40: PRES in a post liver-transplant patient. Axial FAST FLAIR sequence exhibitingcortico-subcortical areas of T2-hyperintensity in the parieto-occipital region.

Page 96 of 110

Fig. 41: Axial T2*GRE image of the hitherto discussed patient with PRES showingpunctate areas of blooming in keeping with petechial hemorrhages in the left occipitallobe.

Page 97 of 110

Fig. 42: Immunosupressive leukoencephalopathy. A 56-year old post liver transplantpatient on tacrolimus complaining of unrelenting headaches and visual disturbances.MR images show multifocal areas of white matter signal alteration involving the parieto-occipital lobes and right fronto-parietal region appearing bright on T2WI (A) and dark onT1WI (B).

Fig. 43: Suspected PML in a 44 year old post liver transplant patient with neurocognitivedecline. Axial FLAIR images showing patchy and conflueent scattered hyperintensitiesin bilateral parieto-temporal and frontal white matter.

Page 98 of 110

Fig. 44: Multifocal areas of bilateral intracerebral hemorrhage in a 56-year old post liver-transplant patient.

Fig. 45: Right middle cerebral artery (MCA) infarct. Axial T2WI (A) and DWI (B) showingacute infarct with diffusion restriction involving the right temporal lobe in the MCA territory.

Page 99 of 110

Fig. 46: Anoxic-hypoxic ischemic encephalopathy following liver transplant (day-3). DWIshowing diffusion restriction and extensive gyral swelling involving the bilateral cerebralhemispheres in a contiguous fashion.

Fig. 47: Severe hyperammonemic encephalopathy in a 35 year old post liver transplantpatient (post operative day 6). Axial FLAIR images showing extensive cortical swellingand T2 prolongation especially along the insular cortices and cingulate gyrus.

Page 100 of 110

Fig. 48: Post-transplant invasive fungal sinusitis, orbital cellulitis & meningitis in a 26 yearold female. Axial CT section showing destruction of the lamina papyracea (white arrow)with extension of the fungal elements into the right orbit with attendant orbital cellulitis(asterisk).

Page 101 of 110

Fig. 49: Invasive mucormycosis. Post liver-transplant patient with invasive fungal sinusitis(asterisk) invading the left orbit (star) and ipsilateral cavernous sinus (white arrow) withcontiguous extension into the left peri-mesencephalic cistern (arrowhead).

Fig. 50: Central pontine myelinolysis in a post liver transplant patient. Axial FLAIRimage showing predominant involvement of the transverse pontine fibres (white arrow)with characteristic sparing of the descending corticospinal tracts (asterisk). Note theperipheral pontine fibers (black arrow) are also spared - hence the term 'central' pontinemyelinolysis.

Page 102 of 110

Conclusion

Only with better understanding of the prevalence, clinical features and imagingmanifestations of different neurological complications associated with liver cirrhosisand liver transplanatation, can we hope to aptly & promptly diagnose them and offerappropriate therapeutic options.

Personal information

Ankur Arora, MD, DNB, FRCR, EDiR

Assistant Professor

Department of Radiology/ Interventional Radiology

Institute of Liver & Biliary Sciences

New Delhi, India

Email: aroradrankur@yahoo.com

Page 103 of 110

Fig. 51: Thank you!References: Ankur Arora

References

1. Lewis M, Howdle PD. The neurology of liver failure. QJM. 2003Sep;96(9):623-33.

2. Ardizzone G, Arrigo A, Schellino MM, Stratta C, Valzan S, Skurzak S,Andruetto P, Panio A, Ballaris MA, Lavezzo B, Salizzoni M, Cerutti E.

Page 104 of 110

Neurological complications of liver cirrhosis and orthotopic liver transplant.Transplant Proc. 2006 Apr;38(3):789-92.

3. Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairmentin cirrhosis: Implications for the assessment of hepatic encephalopathy.Hepatology. 2009 Dec;50(6):2014-21. doi: 10.1002/hep.23216.

4. Jones EA, Weissenborn K. Neurology and the liver. J Neurol NeurosurgPsychiatry. 1997 Sep;63(3):279-93.

5. Butterworth RF. The liver-brain axis in liver failure: neuroinflammation andencephalopathy. Nat Rev Gastroenterol Hepatol. 2013 Sep;10(9):522-8. doi:10.1038/nrgastro.2013.99.

6. Weissenborn K, Bokemeyer M, Krause J, Ennen J, Ahl B. Neurologicaland neuropsychiatric syndromes associated with liver disease. AIDS. 2005Oct;19 Suppl 3:S93-8.

7. Das K, Singh P, Chawla Y, Duseja A, Dhiman RK, Suri S. Magneticresonance imaging of brain in patients with cirrhotic and non-cirrhoticportal hypertension. Dig Dis Sci. 2008 Oct;53(10):2793-8. doi: 10.1007/s10620-008-0383-y.

8. Genovese E, Maghnie M, Maggiore G, Tinelli C, Lizzoli F, De Giacomo C,Pozza S, Campani R. MR imaging of CNS involvement in children affectedby chronic liver disease. AJNR Am J Neuroradiol. 2000 May;21(5):845-51.

9. Vymazal J, Babis M, Brooks RA, Filip K, Dezortova M, Hrncarkova H, HajekM. T1and T2 alterations in the brains of patients with hepatic cirrhosis. AJNRAm J Neuroradiol. 1996 Feb;17(2):333-6.

10. Morgan MY. Cerebral magnetic resonance imaging in patients with chronicliver disease. Metab Brain Dis. 1998 Dec;13(4):273-90.

11. Morgan MY. Noninvasive neuroinvestigation in liver disease. Semin LiverDis. 1996 Aug;16(3):293-314.

12. Layrargues GP, Rose C, Spahr L, Zayed J, Normandin L, Butterworth RF.Role of manganese in the pathogenesis of portal-systemic encephalopathy.Metab Brain Dis. 1998 Dec;13(4):311-7.

13. Skehan S, Norris S, Hegarty J, Owens A, MacErlaine D. Brain MRI changesin chronic liver disease. Eur Radiol. 1997;7(6):905-9.

14. Zeneroli ML, Cioni G, Vezzelli C, Grandi S, Crisi G, Luzietti R, Ventura E.Prevalence of brain atrophy in liver cirrhosis patients with chronic persistentencephalopathy. Evaluation by computed tomography. J Hepatol. 1987Jun;4(3):283-92.

15. Kulisevsky J, Pujol J, Junqué C, Deus J, Balanzó J, Capdevila A. MRIpallidal hyperintensity and brain atrophy in cirrhotic patients: two differentMRI patterns of clinical deterioration? Neurology. 1993 Dec;43(12):2570-3.

16. Amodio P, Pellegrini A, Amistà P, Luise S, Del Piccolo F, Mapelli D,Montagnese S, Musto C, Valenti P, Gatta A. Neuropsychological-neurophysiological alterations and brain atrophy in cirrhotic patients. MetabBrain Dis. 2003 Mar;18(1):63-78.

17. Rovira A, Alonso J, Córdoba J. MR imaging findings in hepaticencephalopathy. AJNR Am J Neuroradiol. 2008 Oct;29(9):1612-21. doi:10.3174/ajnr.A1139.

Page 105 of 110

18. Toru S, Matumura K, Kawaguchi R, Kobayashi T, Irie T. Widespreadcortical lesions on diffusion-weighted imaging in acute portal systemic shuntencephalopathy caused by primary biliary cirrhosis. AJNR Am J Neuroradiol.2011 Mar;32(3):E55-6. doi: 10.3174/ajnr.A2466.

19. Choi JM, Kim YH, Roh SY. Acute hepatic encephalopathy presentingas cortical laminar necrosis: case report. Korean J Radiol. 2013 Mar-Apr;14(2):324-8. doi: 10.3348/kjr.2013.14.2.324.

20. Takanashi J, Barkovich AJ, Cheng SF, Kostiner D, Baker JC, Packman S.Brain MR imaging in acute hyperammonemic encephalopathy arising fromlate-onset ornithine transcarbamylase deficiency. AJNR Am J Neuroradiol.2003 Mar;24(3):390-3.

21. McKinney AM, Lohman BD, Sarikaya B, Uhlmann E, Spanbauer J,Singewald T, Brace JR. Acute hepatic encephalopathy: diffusion-weightedand fluid-attenuated inversion recovery findings, and correlation withplasma ammonia level and clinical outcome. AJNR Am J Neuroradiol. 2010Sep;31(8):1471-9. doi: 10.3174/ajnr.A2112.

22. Arnold SM, Els T, Spreer J, Schumacher M. Acute hepatic encephalopathywith diffuse cortical lesions. Neuroradiology. 2001 Jul;43(7):551-4.

23. Fernández-Rodriguez R, Contreras A, De Villoria JG, Grandas F. Acquiredhepatocerebral degeneration: clinical characteristics and MRI findings. Eur JNeurol. 2010 Dec;17(12):1463-70. doi: 10.1111/j.1468-1331.2010.03076.x.

24. Lee J, Lacomis D, Comu S, Jacobsohn J, Kanal E. Acquired hepatocerebraldegeneration: MR and pathologic findings. AJNR Am J Neuroradiol. 1998Mar;19(3):485-7.

25. Stracciari A, Guarino M, Pazzaglia P, Marchesini G, Pisi P. Acquiredhepatocerebral degeneration: full recovery after liver transplantation. JNeurol Neurosurg Psychiatry. 2001 Jan;70(1):136-7.

26. Wijdicks EF, Wiesner RH. Acquired (non-Wilsonian) hepatocerebraldegeneration:complex management decisions. Liver Transpl. 2003Sep;9(9):993-4.

27. Chen WX, Wang P, Yan SX, Li YM, Yu CH, Jiang LL. Acquiredhepatocerebral degeneration: a case report. World J Gastroenterol. 2005Feb 7;11(5):764-6.

28. Tryc AB, Goldbecker A, Berding G, et al. Cirrhosis-related Parkinsonism:prevalence, mechanisms and response to treatments. J Hepatol. 2013Apr;58(4):698-705. doi: 10.1016/j.jhep.2012.11.043.

29. da Rocha AJ, Braga FT, da Silva CJ, Maia AC Jr, Mourão GS, GagliardiRJ. Reversal of parkinsonism and portosystemic encephalopathyfollowing embolization of a congenital intrahepatic venous shunt: brain MRimaging and 1H spectroscopic findings. AJNR Am J Neuroradiol. 2004Aug;25(7):1247-50.

30. Shulman LM, Minagar A, Weiner WJ. Reversal of parkinsonism followingliver transplantation. Neurology. 2003 Feb 11;60(3):519.

31. Rose C, Butterworth RF, Zayed J, et al. Manganese deposition in basalganglia structures results from both portal-systemic shunting and liverdysfunction. Gastroenterology. 1999 Sep;117(3):640-4.

Page 106 of 110

32. Tuschl K, Clayton PT, Gospe SM Jr, et al. Dystonia/Parkinsonism,Hypermanganesemia, Polycythemia, and Chronic Liver Disease. 2012 Aug30 [Updated 2012 Nov 8]. In: Pagon RA, Adam MP, Bird TD, et al., editors.Gene Reviews™ [Internet]. Seattle (WA): University of Washington, Seattle;1993-2013.Available from: http://www.ncbi.nlm.nih.gov/books/NBK100241/

33. Quadri M, Federico A, Zhao T, et al. Mutations in SLC30A10 causeparkinsonism and dystonia with hypermanganesemia, polycythemia, andchronic liver disease. Am J Hum Genet. 2012 Mar 9;90(3):467-77. doi:10.1016/j.ajhg.2012.01.017.

34. Koo JE, Lim YS, Myung SJ, Suh KS, Kim KM, Lee HC, Chung YH, LeeYS, Suh DJ. Hepatic myelopathy as a presenting neurological complicationin patients with cirrhosis and spontaneous splenorenal shunt. Korean JHepatol. 2008 Mar;14(1):89-96. doi: 10.3350/kjhep.2008.14.1.89.

35. Premkumar M, Bagchi A, Kapoor N, et al. Hepatic Myelopathy in aPatient with Decompensated Alcoholic Cirrhosis and Portal Colopathy.Case Reports in Hepatology (2012), Article ID 735906, 4 pages, 2012.doi:10.1155/2012/735906.

36. Sobukawa E, Sakimura K, Hoshino S, Hoshino M, Miyoshi K. Hepaticmyelopathy: an unusual neurological complication of advanced hepaticdisease. Intern Med. 1994 Nov;33(11):718-22.

37. Ben Amor S, Saied MZ, Harzallah MS, Benammou S. Hepatic myelopathywith spastic paraparesis: report of two cases and review of the literature. EurSpine J. 2013 Jun 1. [Epub ahead of print] PubMed PMID: 23728397.

38. Kori P, Sahu R, Jaiswal A, Shukla R. Hepatic myelopathy: an unusualneurological complication of chronic liver disease presenting asquadriparesis. BMJ Case Rep. 2013 Jun 7;2013. pii: bcr2013009078. doi:10.1136/bcr-2013-009078.

39. Huang HH, Lin HH, Shih YL, Chen PJ, Chang WK, Chu HC, ChaoYC, Hsieh TY. Spontaneous intracranial hemorrhage in cirrhoticpatients. Clin Neurol Neurosurg. 2008 Mar;110(3):253-8. doi: 10.1016/j.clineuro.2007.11.010.

40. Grønbaek H, Johnsen SP, Jepsen P, Gislum M, Vilstrup H, Tage-Jensen U,Sørensen HT. Liver cirrhosis, other liver diseases, and risk of hospitalizationfor intracerebral haemorrhage: a Danish population-based case-controlstudy. BMC Gastroenterol. 2008 May 24;8:16. doi: 10.1186/1471-230X-8-16.

41. Lai CH, Cheng PY, Chen YY. Liver cirrhosis and risk of intracerebralhemorrhage: a 9-year follow-up study. Stroke. 2011 Sep;42(9):2615-7. doi:10.1161/STROKEAHA.111.617076.

42. Boudouresques G, Hauw JJ, Meininger V, Escourolle R, Pertuiset B, BugeA, Lhermitte F, Castaigne P. Hepatic cirrhosis and intracranial hemorrhage:significance of the association in 53 pathological cases. Ann Neurol. 1980Aug;8(2):204-5.

43. Niizuma H, Suzuki J, Yonemitsu T, Otsuki T. Spontaneous intracerebralhemorrhage and liver dysfunction. Stroke. 1988 Jul;19(7):852-6.

Page 107 of 110

44. McCormick WF, Rosenfield DB. Massive brain hemorrhage: a reviewof 144 cases and an examination of their causes. Stroke. 1973 Nov-Dec;4(6):946-54.

45. Brann OS. Infectious complications of cirrhosis. Curr Gastroenterol Rep.2001 Aug;3(4):285-92.

46. Christou L, Pappas G, Falagas ME. Bacterial infection-related morbidity andmortality in cirrhosis. Am J Gastroenterol. 2007 Jul;102(7):1510-7.

47. Ghassemi S, Garcia-Tsao G. Prevention and treatment of infections inpatients with cirrhosis. Best Pract Res Clin Gastroenterol. 2007;21(1):77-93.

48. Vilstrup H. Cirrhosis and bacterial infections. Rom J Gastroenterol. 2003Dec;12(4):297-302.

49. Pauwels A, Pinès E, Abboura M, Chiche I, Lévy VG. Bacterial meningitis incirrhosis: review of 16 cases. J Hepatol. 1997 Nov;27(5):830-4.

50. Mølle I, Thulstrup AM, Svendsen N, Schønheyder HC, Sørensen HT. Riskand case fatality rate of meningitis in patients with liver cirrhosis. Scand JInfect Dis. 2000;32(4):407-10.

51. Chung CL, Lieu AS, Chen IY, Kwan AL, Howng SL. Brain abscess inadult cirrhotic patients: two case reports. Kaohsiung J Med Sci. 2007Jan;23(1):34-9.

52. Guzel A, Tatli M, Aluclu U, Yalcin K. Intracranial multiple tuberculomas: 2unusual cases. Surg Neurol. 2005;64 Suppl 2:S109-12.

53. Rabinstein AA. Treatment of brain edema in acute liver failure. Curr TreatOptions Neurol. 2010 Mar;12(2):129-41. doi: 10.1007/s11940-010-0062-0.

54. Detry O, De Roover A, Honore P, Meurisse M. Brain edema and intracranialhypertension in fulminant hepatic failure: pathophysiology and management.World J Gastroenterol. 2006 Dec 14;12(46):7405-12.

55. Vaquero J, Butterworth RF. Mechanisms of brain edema in acute liverfailure and impact of novel therapeutic interventions. Neurol Res. 2007Oct;29(7):683-90. doi: 10.1179/016164107X240099.

56. Thumburu KK, Taneja S, Vasishta RK, Dhiman RK. Neuropathology ofacute liver failure. Neurochem Int. 2012 Jun;60(7):672-5. doi: 10.1016/j.neuint.2011.10.013.

57. Ranjan P, Mishra AM, Kale R, Saraswat VA, Gupta RK. Cytotoxic edemais responsible for raised intracranial pressure in fulminant hepatic failure: invivo demonstration using diffusion-weighted MRI in human subjects. MetabBrain Dis. 2005 Sep;20(3):181-92.

58. Muñoz SJ, Robinson M, Northrup B, Bell R, Moritz M, Jarrell B, Martin P,Maddrey WC. Elevated intracranial pressure and computed tomographyof the brain in fulminant hepatocellular failure. Hepatology. 1991Feb;13(2):209-12.

59. Mukherjee KK, Chhabra R, Khosla VK. Raised intracranial pressure inhepatic encephalopathy. Indian J Gastroenterol. 2003 Dec;22 Suppl2:S62-5.

60. Charness ME. Brain lesions in alcoholics. Alcohol Clin Exp Res. 1993Feb;17(1):2-11.

Page 108 of 110

61. Nicolás JM, Fernández-Solà J, Robert J, Antúnez E, Cofán M, CardenalC, Sacanella E, Estruch R, Urbano-Márquez A. High ethanol intake andmalnutrition in alcoholic cerebellar shrinkage. QJM. 2000 Jul;93(7):449-56.

62. Nicolás JM, Estruch R, Salamero M, Orteu N, Fernandez-Solà J, SacanellaE, Urbano-Márquez A. Brain impairment in well-nourished chronic alcoholicsis related to ethanol intake. Ann Neurol. 1997 May;41(5):590-8.

63. Adams RD, Victor M, Mancall EL. Central pontine myelinolysis: a hithertoundescribed disease occurring in alcoholic and malnourished patients. AMAArch Neurol Psychiatry. 1959 Feb;81(2):154-72.

64. Martin RJ. Central pontine and extrapontine myelinolysis: the osmoticdemyelination syndromes. J Neurol Neurosurg Psychiatry. 2004 Sep;75Suppl 3:iii22-8.

65. de Morais BS, Carneiro FS, Araújo Rde M, Araújo GF, de Oliveira RB.Central pontine myelinolysis after liver transplantation: is sodium the onlyvillain? Case report. Rev Bras Anestesiol. 2009 May-Jun;59(3):344-9.

66. Zuccoli G, Siddiqui N, Cravo I, Bailey A, Gallucci M, Harper CG.Neuroimaging findings in alcohol-related encephalopathies. AJR Am JRoentgenol. 2010 Dec;195(6):1378-84. doi: 10.2214/AJR.09.4130.

67. Love S. Demyelinating diseases. J Clin Pathol. 2006 Nov;59(11):1151-9.68. Mechtcheriakov S, Brenneis C, Egger K, Koppelstaetter F, Schocke M,

Marksteiner J. A widespread distinct pattern of cerebral atrophy in patientswith alcohol addiction revealed by voxel-based morphometry. J NeurolNeurosurg Psychiatry. 2007 Jun;78(6):610-4.

69. Ratti MT, Soragna D, Sibilla L, Giardini A, Albergati A, Savoldi F, BoP. Cognitive impairment and cerebral atrophy in "heavy drinkers". ProgNeuropsychopharmacol Biol Psychiatry. 1999 Feb;23(2):243-58.

70. Chick JD, Smith MA, Engleman HM, Kean DM, Mander AJ, Douglas RH,Best JJ. Magnetic resonance imaging of the brain in alcoholics: cerebralatrophy, lifetime alcohol consumption, and cognitive deficits. Alcohol ClinExp Res. 1989 Aug;13(4):512-8.

71. de la Monte SM, Kril JJ. Human alcohol-related neuropathology. ActaNeuropathol. 2013 Dec 27. [Epub ahead of print] PubMed PMID: 24370929.

72. Jaatinen P, Rintala J. Mechanisms of ethanol-induced degeneration in thedeveloping, mature, and aging cerebellum. Cerebellum. 2008;7(3):332-47.doi: 10.1007/s12311-008-0034-z.

73. Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW, Seo JK, YeonKM. MR imaging of the brain in Wilson disease of childhood: findings beforeand after treatment with clinical correlation. AJNR Am J Neuroradiol. 2006Jun-Jul;27(6):1373-8.

74. Shivakumar R, Thomas SV. Teaching NeuroImages: face of the giantpanda and her cub: MRI correlates of Wilson disease. Neurology. 2009 Mar17;72(11):e50.

75. Monaco S, Ferrari S, Gajofatto A, Zanusso G, Mariotto S. HCV-relatednervous system disorders. Clin Dev Immunol. 2012;2012:236148. doi:10.1155/2012/236148.

Page 109 of 110

76. Carvalho-Filho RJ, Narciso-Schiavon JL, Tolentino LH, Schiavon LL,Ferraz ML, Silva AE. Central nervous system vasculitis and polyneuropathyas first manifestations of hepatitis C. World J Gastroenterol. 2012 Jan14;18(2):188-91. doi: 10.3748/wjg.v18.i2.188.

77. Sacconi S, Salviati L, Merelli E. Acute disseminated encephalomyelitisassociated with hepatitis C virus infection. Arch Neurol. 2001Oct;58(10):1679-81.

78. Sim JE, Lee JB, Cho YN, Suh SH, Kim JK, Lee KY. A case of acutedisseminated encephalomyelitis associated with hepatitis C virus infection.Yonsei Med J. 2012 Jul 1;53(4):856-8. doi: 10.3349/ymj.2012.53.4.856.

79. Stübgen JP. Immune-mediated myelitis associated with hepatitis virusinfections. J Neuroimmunol. 2011 Oct 28;239(1-2):21-7. doi: 10.1016/j.jneuroim.2011.09.001

80. Vizzini G, Asaro M, Miraglia R, et al. Changing picture of central nervoussystem complications in liver transplant recipients. Liver Transpl. 2011Nov;17(11):1279-85. doi: 10.1002/lt.22383.

81. Saner FH, Gensicke J, Olde Damink SW, et al. Neurologic complicationsin adult living donor liver transplant patients: an underestimated factor? JNeurol. 2010 Feb;257(2):253-8. doi: 10.1007/s00415-009-5303-3.

82. Cruz RJ Jr, DiMartini A, Akhavanheidari M, et al. Posterior reversibleencephalopathy syndrome in liver transplant patients: clinicalpresentation, risk factors and initial management. Am J Transplant. 2012Aug;12(8):2228-36. doi: 10.1111/j.1600-6143.2012.04048.x.

83. Santos MM, Tannuri AC, Gibelli NE, et al. Posterior reversibleencephalopathy syndrome after liver transplantation in children: a rarecomplication related to calcineurin inhibitor effects. Pediatr Transplant. 2011Mar;15(2):157-60. doi: 10.1111/j.1399-3046.2010.01430.x.

84. Umeda Y, Matsuda H, Sadamori H, Shinoura S, Yoshida R, Sato D, UtsumiM, Yagi T, Fujiwara T. Leukoencephalopathy syndrome after living-donorliver transplantation. Exp Clin Transplant. 2011 Apr;9(2):139-44.

85. Schuuring J, Wesseling P, Verrips A. Severe tacrolimusleukoencephalopathy after liver transplantation. AJNR Am J Neuroradiol.2003 Nov-Dec;24(10):2085-8.

86. Frühauf NR, Koeppen Dagger S, Saner FH, Egelhof Dagger T, StavrouG, Nadalin S, Broelsch CE. Late onset of tacrolimus-related posteriorleukoencephalopathy after living donor liver transplantation. Liver Transpl.2003 Sep;9(9):983-5.

87. Singh N, Bonham A, Fukui M. Immunosuppressive-associatedleukoencephalopathy in organ transplant recipients. Transplantation. 2000Feb 27;69(4):467-72.

88. Lima MA, Hanto DW, Curry MP, Wong MT, Dang X, Koralnik IJ. Atypicalradiological presentation of progressive multifocal leukoencephalopathyfollowing liver transplantation. J Neurovirol. 2005 Feb;11(1):46-50.

89. Verhelst X, Vanhooren G, Vanopdenbosch L, Casselman J, Laleman W,Pirenne J, Nevens F, Orlent H. Progressive multifocal leukoencephalopathy

Page 110 of 110

in liver transplant recipients: a case report and review of the literature.Transpl Int. 2011 Apr;24(4):e30-4. doi: 10.1111/j.1432-2277.2010.01190.x.

90. Mohanty SR, Testa G, Labrecque DR, Mitros FA. Progressive multifocalleukoencephalopathy with peripheral demyelinating neuropathy in a livertransplant patient. Gastroenterol Hepatol (N Y). 2007 Jan;3(1):70-3.

91. Bronster DJ, Lidov MW, Wolfe D, Schwartz ME, Miller CM. Progressivemultifocal leukoencephalopathy after orthotopic liver transplantation. LiverTranspl Surg. 1995 Nov;1(6):371-2.

92. Zivkovi# SA. Neurologic complications after liver transplantation. World JHepatol. 2013 Aug 27;5(8):409-16. doi: 10.4254/wjh.v5.i8.409.

93. Guarino M, Benito-Leon J, Decruyenaere J, et al. Neurological problemsin liver transplantation. In: Gilhus NE, Barnes MP, Brainin M, editor(s).European handbook of neurological management. 2nd ed. Vol. 1. Oxford(UK): Wiley-Blackwell; 2011. p. 491-9.

94. Dhar R, Human T. Central nervous system complications aftertransplantation. Neurol Clin. 2011 Nov;29(4):943-72. doi: 10.1016/j.ncl.2011.07.002.